HB of Psychopharmacology

Handbook
of
Psychopharmacology
Volume 11
Stimulants
Handbook of
Psychopharmacology
SECTION I: BASIC NEUROPHARMACOLOGY
Volume 1
Volume 2
Volume 3
Volume 4
Volume 5
Volume 6
Biochemical Principles and Techniques in Neuropharmacology

Principles of Receptor Research
Biochemistry of Biogenic Amines
Amino Acid Neurotransmitters
Synaptic Modulators
Biogenic Amine Receptors
SECTION II: BEHAVIORAL PHARMACOLOGY IN ANIMALS

Volume 7
Volume 8
Volume 9
Principles of Behavioral Pharmacology

Drugs, Neurotransmitters, and Behavior
Chemical Pathways in the Brain
SECTION III: HUMAN PSYCHOPHARMACOLOGY

Volume 10
Volume 11
Volume 12
Volume 13
Volume 14
Neuroleptics and Schizophrenia

Stimulants
Drugs of Abuse
Biology of Mood and Antianxiety Drugs
Affective Disorders: Drug Actions in Animals and Man
Volume 11
Stimulants
Edited by
Leslie L. Iversen
Department of Pharmacology
University of Cambridge
Susan D. Iversen
Department of Psychology
University of Cam bridge
and
Solomon H. Snyder
Departments of Pharmacology and Psychiatry
The Johns Hopkins University
School of Medicine
PLENUM PRESS NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data

Main entry under title:
Handbook of psychophannacology.
Includes bibliographies and indexes.
CONTENTS: v.I. Biochemical principles and techniques in neuropharmacology.
-v. 2: Principles of receptor research. - v. 3. Biochemistry of biogenic amines. v. 4. Amino acid neurotransmitters. - v. 5. Synaptic modulators. - v. 6. Biogenic
amine receptors. - v. 7. Principles of behavioral pharmacology. - v. 8. Drugs,
Neurotransmitters, and Behavior. - v. 10 Neuroleptics and Schizophrenia. -. 11.
Stimulants. 1. Psychopharmacology. I. Iversen, Leslie Lars. ll. Iversen Susan D.,
m: Snyder, Solomon H., 1938[DNLM: 1. Psychopharma1940
cology. QV77 H236]
RC483.H36
615'.78
75-6851
ISBN 978-1-4757-0512-6
ISBN 978-1-4757-0510-2 (eBook)
DOI 10.1007/978-1-4757-0510-2
1978 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1978

A Division of Plenum Publishing Corporation
227 West 17th Street, New York, N.Y. 10011
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted,
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording or otherwise, without written permission from the Publisher
CONTRIBUTORS
Neuropsychopharmacology Research Unit, Department if
Psychiatry, New York University Medical Center, New York, New York
J. H. BIEL (Deceased), Aldrich Chemical Company, Inc., Milwaukee, Wisconsin
B. A. Bopp, Abbott Laboratories, North Chicago, Illinois
NEAL CASTAGNOLI, JR., Department if Pharmaceutical Chemistry, School if
Pharmacy, University if California, San Francisco, California
ELLEN R. GRITZ, Veterans Administratzon Hospital Brentwood, and Department
if Psychiatry, University of California, Los Angeles, California
LEO E. HOLLISTER, Veterans Administration Hospital, and Stanford University
School of Medicine, Palo Alto, California
MURRAY E. JARVIK, Veterans Administration Hospital Brentwood, and Departments of Psychiatry and Pharmacology, University of California, Los Angeles,
California
KENNETH E. MOORE, Department if Pharmacology, Michigan State University,
East Lansing, Michigan
DANIEL J. SAFER, Baltimore County Department if Health, Rosedale, Maryland
RICHARD EVANS SCHULTES, Botanical Museum, Harvard University, Cambridge, Massachusetts
ALEXANDER T. SHULGIN, Lafayette, California.
ABRAHAM SUDILOVSKY, Neuropsychopharmacology Research Unit, Department
if Psychiatry, New York University Medical Center, New York, New York
BURTON ANGRIST,
PREFACE
Underlying the design of the Handbook of Psychopharmacology is a prejudice

that the study of drug influences on the mind has advanced to a stage where
basic research and clinical application truly mesh. These later volumes of the
Handbook are structured according to this conception. In certain volumes,
groups of drugs are treated as classes with chapters ranging from basic
chemistry to clinical application. Other volumes are assembled around topic
areas such as anxiety or affective disorders. Thus, besides chapters on
individual drug classes, we have included essays addressing broad areas such
as "The Limbic-Hypothalamic-Pituitary-Adrenal System and Human Behavior" and "Peptides and the Central Nervous System."
Surveying these diverse contributions, one comes away with a sentiment
that, far from being an "applied" science borrowing from fundamental brain
chemistry and physiology, psychopharmacology has instead provided basic
researchers with the tools and conceptual approaches which now are
advancing neurobiology to a central role in modern biology. Especially
gratifying is the sense that, while contributing to an understanding of how
the brain functions, psychopharmacology is a discipline whose fruits offer
genuine help to the mentally ill with promises of escalating benefits in the
future.
L.L.1.
S.D. I.
S.H.S.
VII
CONTENTS
CHAPTER 1
Amphetamines: Structure-Activity Relationships
J. H. BIEL and B. A. Bopp
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2: Effects of Biogenic Amines ...........................
2.1. Norepinephrine................................
2.2. Dopamine.....................................
2.3. Serotonin......................................
3. Central Stimulatory Effects ...........................
3.1. Phenethylamine Derivatives. . . . .. . . .. . . . . . . . . . . ..
3.2. Structurally Modified Phenethylamine Derivatives .,
3.3. Pemoline .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Anorexic Effects ....................................
5. Inhibition of Monoamine Oxidase .....................
6. Psychotomimetic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Summary...........................................
8. References .........................................
1
2
2
5
8
12
12
16
17
18
26
30
34
35
CHAPTER 2
Amphetamines: Biochemical and Behavioral Actions in Animals
KENNETH E. MOORE
1. Introduction " . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Chemistry..........................................
3. General Pharmacological Actions ......................

4. Behavioral Effects in Animals Pretreated with Drugs That
Modify Catecholaminergic Neurotransmission Processes
ix
41
41
42
43
CONTENTS
5.
6.
7.
8.
9.
10.
4.1. Drugs Which Enhance Catecholaminergic

Transmission ..................................
4.2. Drugs Which Disrupt Catecholaminergic
Transmission ..................................
Behavioral Effects in Animals Pretreated with Drugs That
Modify Noncatecholaminergic Transmission Processes. . . .
5.1. 5-Hydroxytryptaminergic Transmission ...........
5.2. Acetylcholinergic Transmission. . .. . .. . . .. . . ... . . .
Interactions of Psychomotor Stimulants with Neurotransmitters in Brain .....................................
6.1. Catecholamines ................................
6.2. 5-Hydroxytryptamine ...........................
6.3. Acetylcholine ..................................
Comparisons of Biochemical and Behavioral Effects of
d- and l-Amphetamine ...............................
Effects of Chronic Administration of Psychomotor
Stimulants .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary and Speculations ...........................
References .........................................
45
46
58
58
59
60
60
74
75
76
81
83
85
CHAPTER 3
Central Nervous System Stimulants: Historical Aspects and Clinical
Effects
BURTON ANGRIST and ABRAHAM SUDlLOVSKY
1.
2.
3.
4.
5.
6.
7.
8.
Introduction-Early Use of Plant Preparations.. . . . .. . . .

Cocaine............................................
Amphetamine and Methamphetamine .................
Phenmetrazine......................................
Methylphenidate ....................................
Diethylpropion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ephedrine..........................................
Clinical Aspects of CNS Stimulant Use.. . . .. . . .. . . . . . . .
8.1. General Considerations .........................
8.2. Low-Dose Nonmedical Stimulant Use .............
8.3. High-Dose Nonmedical Stimulant Use ............
8.4. Withdrawal Effects .............................
9. Medical Uses of Stimulants ...........................
9.1. Narcolepsy ....................................
9.2. Hyperkinetic Behavior Disorders in Children ......
9.3. Obesity........................................
9.4. Parkinson's Disease.. . . . .. . . . . . .. . ... . . .. . . . . . . .
99
107
111
123
125
126
128
129
129
133
134
146
148
148
148
149
150
xi
CONTENTS
9.5. Depression ....................................

10. Problems Raised by Stimulants ............ '" . . . . . . . . .
10.1. Problems with Respect to Society and Legislative
Control .......................................
10.2. Problems in Research. . . . . . . . . . . . . .. . . . . . . . . . . . .
11. References .........................................
150
151
151
152
153
CHAPTER 4
Drug Treatment in Child Psychiatry
DANIEL
J.
SAFER
1. Introduction........................................
2. Childhood Psychosis. . .. . . . . .. . . .. . . . . . . . . . ... . .. . . . .
2.1. Characteristics, Occurrence, and Outcome. . . . . . . .. .
2.2. Nondrug Treatment ............................
2.3. Drug Treatment ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. General Considerations Using Major Tranquilizers
for Psychotic Children ...........................
3. Behavior Disorders of the Mentally Retarded ...........
3.1. Characteristics, Occurrence, and Outcome. . . . . . . . . .
3.2. Nondrug Treatment ............................
3.3. Drug Treatment ...... . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. Clinical Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Hyperactivity .......................................
4.1. Characteristics, Occurrence, and Outcome .........
4.2. Nondrug Treatments ...........................
4.3. Drug Treatments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Enuresis............................................
5.1. Occurrence and Outcome.............. .........
5.2. Nondrug Treatments ...........................
5.3. Drug Therapies. . . . . . . . . . . . . . . . . .. . .. . . . . .. . . . .
5.4. Clinical Considerations Using Tricyclics for Enuresis
5.5. Possible Mechanism of Action of Tricyclics in
Enuresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Tics and Gilles de la Tourette's Syndrome.. . .. . . . . . . . . .
6.1. Characteristics, Occurrence, and Outcome. . . . . . . . .
6.2. Nondrug Treatments...........................
6.3. Drug Treatment...............................
7. Anorexia Nervosa ...................................
7.2. Nondrug Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3. Drug Treatment ...............................
8. Nightmares and Related Sleep Disorders. . .. . . ... . . . . . .
167
168
168
168
169
172
173
173
173
174
175
176
176
177
177
182
182
182
183
184
185
185
185
186
186
187
187
188
188
189
xii
CONTENTS
9.
10.
11.
12.
13.
8.1. Characteristics, Occurrence, and Outcome . . . . . . . . .

8.2. Nondrug Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3. Drug Treatment ...............................
8.4. Clinical Considerations For Drug Treatment. . . . . . .
School Phobia. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . .
9.2. Nondrug Treatment..... . ..... ......... ..... ...
9.3. Drug Treatment ...............................
9.4. Combining Nondrug and Drug Treatment.... . ...
Stuttering ..........................................
10.1. Occurrence and Outcome .......................
10.2. Nondrug Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3. Drug Treatment ...............................
10.4. Dose Side Effects and Duration of Haloperidol
Treatment ....................................
10.5. Treatment Considerations . . . . . . . . . . . . . . . . . . . . . . .
Learning Disorders ..................................
11.1. Characteristics, Occurrence, and Outcome . . . . . . . . .
11.2. Nondrug Treatments. . . . . . . . . . . . . . . . . . . . . . . . . . .
11.3. Chemical Treatment of the Learning-Impaired ....
11.4. Drug Treatments ..............................
11.5. Theoretical Issues .... . . . . . . . . . . . . . . . . . . . . . . . . . .
Seizure Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.1. Effect of Psychotropic Drugs on the Seizure
Threshold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2. Psychological Effects of Anticonvulsants on Epileptic
Children ......................................
References .........................................
5
Plants and Plant Constituents as Mind-Altering Agents
Throughout History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
189
190
190
190
191
191
191
192
193
194
194
195
195
195
196
196
196
197
197
197
200
200
200
201
203
CHAPTER
219
RICHARD EVANS SCHULTES
CHAPTER
Psychotomimetic Drugs: Structure-Activity Relationships

ALEXANDER T. SHULGIN
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Definition of Psychotomimetic. . . . . . . . . . . . . . . . . . . .
1.2. Qualitative Differences. . . . . . . . . . . . . . . . . . . . . . . . . .
243
243
247
CONTENTS
1.3. Quantitative Differences . . . . . . . . . . . . . . . . . . . . . . . . .

1.4. Sources of Information .........................
1.5. Classes to Be Considered. . . .. . . . . . . . .. . . . . . . . . . .
2. The Phenethylamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Variations of Ring Substitution. . . . .. . . . . .. . . . . . . .
2.2. Nitrogen-Substituted Phenethylamines ............
3. The Phenylisopropylamines . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Methoxylated Phenylisopropylamines .............
3.2. Methylenedioxyphenylisopropylamines ............
3.3. Alkoxyphenylisopropylamines .......... " .... , . . .
3.4. Alkylphenylisopropylamines .....................
3.5. Halo- or Sulfur-Substituted Phenylisopropylamines.
4. References .........................................
CHAPTER
xiii
250
252
257
259
259
273
276
278
288
298
302
313
321
Drug Metabolism: Review of Principles and the Fate of One-Ring

Psychotomimetics
NEAL CASTAGNOLI, JR.
1. Principles of Drug Metabolism. . . . . .. . .. . .. . . . .. . . . . . .

1.1. Aromatic Hydroxylation. . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Aliphatic Epoxidations ..........................
1.3. Allylic and Related Oxidations ...................
1.4. Oxidations of Carbon Attached to Heteroatoms ....
1.5. Oxidations and Reductions of Nitrogen-Containing
Moieties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Metabolism of One-Ring Psychotomimetics .............
2.1. Amphetamine (Benzeneethaneamine, a-Methyl) ....
2.2. Metabolism of Mescaline (Benzeneethaneamine,
3,4,5-Trimethoxy) ..............................
2.3. The Metabolism of Ring-Substituted
1-Phenyl-2-aminopropane Psychotomimetics .......
3. Conclusion .........................................
4. References .........................................
CHAPTER
337
339
341
342
343
346
351
352
359
364
369
370
Psychotomimetic Drugs in Man

LEO E. HOLLISTER
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Chemical Basis for Classification.. . . . . . . . . . . . . . . . . . . . . .
389
390
CONTENTS
XIV
3. Clinical Effects of Psychotomimetic Drugs ..............

3.1. LSD Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. LSD Homologs ................................
3.3. Mescaline......................................
3.4. Psilocybin .....................................
3.5. Piperidyl Benzilate Esters. . . . . . . . . . . . . . . . . . . . . . . .
3.6. Phencyclidine ..................................
3.7. Miscellaneous Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Psychological Effects in Experimental Studies ...........
4.1. Intellectual Functions ...........................
4.2. Perceptual Functions. . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Psychomotor Functions. . . . . . . . . . . . . . . . . . . . . . . . . .
404 Projective Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Other Psychological Effects. . . . . . . . . . . . . . . . . . . . . .
5. Electroencephalographic and Neurophysiological Studies.
6. Physiological Effects .................................
7. Kinetics of LSD in Man ..............................
8. Adverse Reactions-Psychiatric. . . . . . . . . . . . . . . . . . . . . . . .
9. Adverse Effects-Physical ............................
9.1. Chromosomes, Dysmorphogenesis, and
Carcinogenesis .................................
9.2. Miscellaneous Other Types. . . . . . . . . . . . . . . . . . . . . .
10. Therapeutic Uses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1. Psychoneuroses ................................
10.2. Schizophrenic Reactions. . . . . . . . . . . . . . . . . . . . . . . . .
10.3. Depressions ...................................
lOA. Alcoholism....................................
11. Psychotomimetics and Model Psychoses ................
12. Conditions for Endogenous Psychotogens ..............
13. Concept of Endogenous Psychotogens. . . . . . . . . . . . . . . . . .
14. Model Psychosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15. Patterns of Social Use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16. References .........................................
390
391
392
392
393
394
395
396
397
397
398
398
399
399
400
401
402
402
405
405
406
407
407
408
409
410
411
412
413
416
417
417
CHAPTER 9
Nicotine and Smoking
ELLEN R. GRITZ and MURRAY E. JARVIK
1. The Initiation of the Smoking Habit . . . . . . . . . . . . . . . . . . .
2. Why Do People Keep Smoking? . . . . . . . . . . . . . . . . . . . . . . .
2.1. Do People Smoke for Nicotine? ..................
426
431
431
CONTENTS
2.2. Effects of Nicotine on Physiological and

Psychological Functions .........................
2.3. Is Nicotine Addicting? ..........................
3. Cessation of Cigarette Smoking: Why Do People Stop
Smoking and How Do They Do It? . . . . . . . . . . . . . . . . . . . .
4. References .........................................
Index..................................................
xv
435
443
444
459
465
AAIPHETA1\IIINES: STRUCTUREACTIVITY RELATIONSHIPS
J.
H. Bielt and B. A. Bopp
1. INTRODUCTION
Amphetamine is a unique drug with respect to the simplicity of its structure
and the multiplicity of its biological effects. Pharmacologically, amphetamine
possesses central stimulant, anorexic, vasoconstrictor, and hyperthermic
properties. Biochemically, amphetamine releases catecholamines from the
neurons and inhibits the uptake of norepinephrine and dopamine but does
not affect brain serotonin levels. It also is a moderately active inhibitor of
monoamine oxidase. Clinically, amphetamine has been used as a stimulant,
antidepressant, and appetite suppressant, but with repeated administration
tolerance frequently develops to many of its effects. On chronic administration of increasingly higher doses, amphetamine may precipitate paranoid
psychosis.
Chemically, the important structural features of amphetamine include
(1) the unsubstituted phenyl ring, (2) the two-carbon side chain between the
phenyl ring and the nitrogen, (3) the a-methyl group, and (4) the primary
amino group (Fig. 1). All these factors appear to be critical for amphetamine's characteristic spectrum of pharmacological and biochemical activities.
Amphetamine has become a favorite target for extensive molecular modifications since most structural changes will accentuate some of its effects,
attenuate others, or even introduce new activities not found in the parent
molecule.
J. H. Biel
Aldrich Chemical Company, Inc., Milwaukee, Wisconsin. Dr. Biel died in May,
1977. B. A. Bopp Abbott Laboratories, North Chicago, Illinois.
a
V
FIG.
J. H.
BIEL AND B. A. BOPP
CH2""Hi-CHa
NH2
1. Amphetamine.
2. EFFECTS ON BIOGENIC AMINES

2.1. Norepinephrine
The mechanism of action of amphetamine, like that of other indirectly
acting sympathomimetic amines, involves the inhibition of norepinephrine
uptake and the release of the neurotransmitter. The structure-activity
relationships of various sympathomimetic and related amines, including the
phenethylamines and phenylisopropylamines, have been extensively investigated using the uptake of et]norepinephrine by the isolated rat heart
(Burgen and Iversen, 1965) and the in vivo release of [3fi]norepinephrine
from the mouse heart (Daly et at., 1966). The ,a-phenethylamine skeleton is a
critical feature of the molecule since either increasing or decreasing the
number of carbons between the phenyl ring and the nitrogen reduced or
abolished the activity. Both the y-phenylpropylamines (e.g., I-phenyl-3aminobutane, y-phenylpropylamine, y-phenyl-N-N-dimethylpropylamine)
and the benzylamines (e.g., a-methylbenzylamine, N,N-diethylbenzylamine,
benzylamine) were found to be inactive as releasers of norepinephrine (Daly
et al., 1966).
Since amphetamine is considerably more potent than phenethylamine
(Table 1), the a-methyl group must at least be partially responsible for the
high affinity for the norepinephrine neuronal membrane systems. The
importance of the configuration of the a-methyl group can be seen in the
marked difference in the activity of d- and l-amphetamine. Further methylation in the a-position to form phentermine or mephentermine greatly
reduced the effects on norepinephrine uptake and release, while shifting the
methyl group to the ,a-position abolished the ability of the compound to
release norepinephrine. N-methylation progressively decreased the characteristic actions of the phenethylamines on the norepinephrine neuronal
membrane systems. d-Methamphetamine was considerably less potent than damphetamine as an inhibitor of norepinephrine uptake. In the phenethylamine series, the secondary amine was less active than the primary amine as a
norepinephrine releaser, while the tertiary amine was inactive.
Hydroxylation had variable effects depending on the placement of the
group. Generally, side chain hydroxylation diminished the activity on norepinephrine uptake and release while hydroxylation of the phenyl ring enhanced it. The effects of ,a-hydroxylation are illustrated in Table 2. Phen-
a Burgen and Iversen (1965).

Daly et al. (1966) (10 mg/kg, s.c.).
N,N - Dimethylphenethylamine
N - Methylphenethylamine
Phenethylamine
dl- Am phetamine
d-Amphetamine
I-Amphetamine
Phentermine
d- Metham phetamine
Mephentermine
Compound
CHa
CHa
CHa
(CHah
CHa
(CHah
CHa
13
CHa
CHa
CHa
CHa
(CHah
QlN
13
of Norepinephrine
100
240
610
30
165
110
6.7 x 10-7
1.0 x 10-6
x
x
x
x
10-6
10- 7
10- 7
10-6
1.1
4.6
1.8
3.7
IDso (M)
Relative
affinity
58
86
95
62
100
104
80
102
65
Release of NE from
mouse heart, b
% control NE
fry Phenethylamines
Uptake of NE by rat heart"
Effects of Methylatian on the Inhibitian of Norepinephrine Uptake and the Release
TABLE
<.>0
I
::j
:::
::j
C"'l
i
t>l
:,.
'"
;;j
~
....,
'"
S2
t>l
::...
Burgen and Iversen (1965).

Daly et at. (1966) (10 mg/kg, s.c.).
dl-Amphetamine
dl-Phenylpropanolamine
d-Methamphetamine
Ephedrine
Pseudoephedrine
~-Phenethanolamine
Phenethylamine
Compound
CH3
CH3
CH 3
CH 3
CH 3
oil
OH
OH
OH
CH3
CH3
CH3
v1
100
23
240
55
165
50
x
x
x
x
x
x
10-8
10-6
10-7
10-8
10-7
10-8
IDw (M)
1.1
4.8
4.6
2.0
6.7
2.2
Relative
affinity
65
91
58 (d); 86 (l)
68
62
91
84
Release of NE from
mouse heart, b
% control NE
rf Norepinephrine by Phenethylamines
Uptake of NE by rat heart a
TABLE 2
Effects of Side Chain Hydroxylation on the Inhibition of Norepinephrine Uptake and the Release
b:l
0
;...
:l..
t--
t>1
b:l
?::
>10
AMPHETAMINES; STRUCTURE-ACTIVITY RELATIONSHIPS
ethylamine, amphetamine, and methamphetamine were all considerably more

active than the corresponding hydroxylated derivatives, /3-phenethanolamine, phenylpropanolamine, and ephedrine. In contrast, ring hydroxylation
imparted a greater affinity to the compounds (Table 3). Tyramine, m-tyramine, and especially dopamine were considerably more potent than phenethylamine. Likewise, p- and m-hydroxyamphetamine and a-methyldopamine were more active than amphetamine. Metaraminol with hydroxy
groups in both the ring and /3-position had the highest affinity for the
norepinephrine neuronal uptake system among all the derivatives tested.
In contrast to the effects of ring hydroxylation, methoxylation of the
phenyl ring markedly decreased both norepinephrine release and the
inhibition of the reuptake of norepinephrine (Table 4). As was evident in the
phenethylamine series, increasing the number of methoxy substituents
progressively decreased the activity of the compounds. Mescaline, 3,4,5trimethoxyphenethylamine, was the least active, having an affinity for the
uptake site of 14,000 times less than that of phenethylamine.
Iversen (1963, 1965) has identified two uptake systems by which
norepinephrine can be accumulated in the rat heart. The first system, uptake
1, operates at a lower norepinephrine concentration than the second (uptake
2). As previously described, affinity for the first system was decreased by /3hydroxylation, N-methylation, or ring methoxylation but was increased by
hydroxylation in the phenyl ring and a-methylation. The structural specificity required for high affinity in uptake 2 was generally opposite to that in
uptake 1. a-Methylation and ring hydroxylation decreased affinity while Nsubstitution, /3-hydroxylation, and especially ring methoxylation increased it.
Thus, amphetamine was considerably less active as an inhibitor of the second
uptake system (IDso = 1.1 X 10-4 M) than the first (ID5o = 4.6 X 10-7 M)
(Burgen and Iversen, 1965).
2.2. Dopamine
In contrast to the marked difference in the affinity of d- and 1amphetamine for norepinephrine neuronal uptake systems, such stereospecificity at the a-carbon does not appear to exist in dopaminergic neurons.
Snyder and his colleagues (1970b; Taylor and Snyder, 1970; Coyle and
Snyder, 1969) have compared the effects of the two amphetamine isomers
on norepinephrine and dopamine uptake by synaptosomes from the rat
hypothalamus and corpus striatum, respectively. The dextro isomer was ten
times more potent than the levo isomer in inhibiting norepinephrine uptake
but the two isomers were equipotent in inhibiting dopamine uptake. The
marked difference in the potency (tenfold) of the two isomers in increasing
locomotor activity contrasted with a relatively small (twofold) difference in
potency in eliciting stereotyped behavior. This observation led to the
suggestion that norepinephrine might be primarily involved with central
" Burgen and Iversen (1965).

"Dalyetal. (1966) (10 mg/kg, s.c. or *5 mg/kg, s.c.).
dl-Amphetamine
4-H ydroxy-dl-amphetamine
3-Hydroxy-dl-amphetamine
a-Methyldopamine
I-Metaraminol
Phenethylamine
Tyramine
m-Tyramine
Dopamine
Compound
pt1a
TABLE
4-0H
3-0H
3,4-diOH
4-0H
3-0H
3,4-rliOH
3-0H
x
CH 3
CH 3
CH3
CHs
CHs
OH
610
1440
100
245
215
650
4.6 x 10-7
1.8 x 10-7
x
x
x
x
x
x
10-7
10-8
10-6
10-7
10-7
10-7
240
610
1D5O (M)
1.8
7.6
1.1
4.5
5.1
1.7
Relative
affinity
Uptake of NE by rat hearta
38
34
39*
22*
65
48*
46
50*
58 (d);86 (I)
Release of NE from
mouse heart,
% control NE
Effects of Ring Hydroxylation on the Inhibition of Norepinephrine Uptake and the Release oj Norepinephrine by Plumethylamines
b:!
;...
!J:I
::....
!l:
b:!
til
t-<
':--
O'l
Burgen and Iversen (1965).

b DaIy et al. (1966) (10 mg/kg s.c.).
Mescaline
Phenylpropanolamine
Methoxamine
Methamphetamine
Methoxyphenamine
dl-Amphetamine
3,4-di-OCH3
2-0CH 3
2,5-di-OCH 3
4-0CH3
3,4-di-OCH 3
3,4,5-tri-OCH3
CH 3
CH 3
CH3
CH 3
CH 3
CH 3
OH
OH
CH3
CH3
1.1
1.0
2.0
1.5
2.0
1.0
6.7
1.1
4.6
10- 8
10-5
10-4
10-2
10-8
10-3
X 10-7
X 10-5
x 10-7
x
x
x
x
x
x
IDso (M)
0.55
0.007
55
0.11
165
10
240
II
100
Relative
affinity
Uptake of NE by rat heart"
65
102
96
99
68
101
62
66
58 (d); 86 (I)
109
Release of NE from
mouse heart, b
% control NE
~:
-.J
~
en
~:::J
::::
:::J
:!..
~
?3
....,
;;;
en
TABLE
~
~
en
4
Effects of Ring Methoxylation on the Inhibition of Norepinephrine Uptake and the Release of Norepinephrine by Phenethylamines
Phenethylamine
Compound
::...
J.
H. BIEL AND B. A. BOPP
stimulatory effects while dopamine was implicated in causing stereotyped

behavior patterns.
2.3. Serotonin
In contrast to its effects on dopaminergic and noradrenergic neurons,
amphetamine has little, if any, influence on serotonergic neurons. However,
certain amphetamine derivatives, especially those with electron-withdrawing
substituents on the phenyl ring, do have marked effects on serotonin
neurons. Pletscher et al. (1964) initially reported that p-chloro-N-methylamphetamine decreased the brain serotonin and 5-hydroxyindoleacetic acid
levels but did not diminish either dopamine or norepinephrine concentrations.
The mechanism of action by which the p-chlorinated amphetamine
derivatives decrease 5-hydroxyindole levels has not been completely elucidated as yet. It is known that these analogues inhibit the uptake of serotonin
(Carlsson, 1970; Wong et al., 1973), release serotonin (Bartholini and
Pletscher, 1964; Pletscher et al., 1965; Wong et al., 1973; Gallager and
Sanders-Bush, 1973), inhibit monoamine oxidase (Pletscher et al., 1965;
Fuller, 1966; Fuller and Hines, 1970), and may inhibit brain tryptophan
hydroxylase and thus serotonin biosynthesis (Sanders-Bush and Sulser, 1970;
Sanders-Bush et al., 1972a,b). Some or all of these actions may be responsible
for the characteristic effects of the chlorinated amphetamines. Inhibition of
serotonin synthesis or release of serotonin might account for the reduction in
brain serotonin levels while MAO inhibition might also contribute to the
decreased levels of the acidic metabolite. Moreover, recently Sanders-Bush et
al. (1972b; 1975) and others (Fuller and Molloy, 1974) have demonstrated
that the serotonin and 5-hydroxyindoleacetic acid levels as well as the
turnover of serotonin were still diminished for several weeks after the
administration of p-chloroamphetamine. These long-lasting effects might
imply either a prolonged retention of the compounds in the serotonergic
neurons or, more likely, destruction of the neurons similar to that caused by
5,6-dihydroxytryptamine or 6-hydroxydopamine (Harvey et al., 1975).
Certain structure-activity correlations have been made with respect to
serotonin depletion. Neither amphetamine nor methamphetamine was active
but both their 4-chlorinated derivatives were quite potent. The effect of pchloro-N-methylphenethylamine was approximately equivalent to that of pchloromethamphetamine (Pletscher et al., 1964), butp-chloro-a-methylbenzylamine had no effect on serotonin levels (Fuller and Molloy, 1974) (Table 5).
Thus, it appears that at least a two-carbon chain between the nitrogen and
phenyl ring may be necessary for activity, but the presence of an a-methyl
group may not be a structural requirement. However, the addition of a
second methyl group to form chlorphentermine practically abolished the
serotonin-depleting properties (M~ller-Nielsen and Dubnick, 1970). In con-
AMPHETAMINES: STRUCTURE -ACTIVITY RELATIONSHIPS

TABLE
Effects
of Alterations in the Side Chain on the Serotonin-Depleting Activity of Chlorinated
OR
Amphetamine Derivatives
CH 2CH(CH a)NH 2
CH 2CH(CH s)NH 2
CH 2CH(CH a)NHCH a
CH 2CH(CH a)NHCH a
CH 2CH 2 NHCH a
CH(CHa)NH2
CH 2C(CH ahNH 2
4-CI
4-CI
4-CI
4-CI
4-CI
Serotonin,
% of control
5-HIAA,
% of control
95 a
34 b
105 a
103 a
55 b
91 a
32 a
39 a
40 a
50 a
104 b
91 c
Pletscher et at. (1964); serotonin and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain 16 hr after
intraperitoneal administration of dose equivalent to 25 mg/kg (0.11 mmole/kg) of p-chloro-N-methylamphetamine.
bFuller et at. (1973), Fuller and Molloy (1974); serotonin and 5-HIAA in rat brain 6 hr after
intraperitoneal administration of 0.1 mmoVkg .
Mf,;!ller-Nielsen and Dubnick (1970); serotonin in rat brain 4 hr after intraperitoneal administration of
32 mg/kg.
trast to the relative actiVities of the optical isomers of amphetamine as

releasers of norepinephrine, the characteristic effects of p-chloroamphetamine and p-chloromethamphetamine on serotonin appear largely to reside in
the l-isomers rather than the d-isomers (MfPller-Nielsen and Dubnick, 1970).
The position of the chloro substituent also markedly affects the activity
of the compounps (Table 6). The effect of the meta derivative was
approximately equivalent to that of the para derivative but only after
inhibition of para-hydroxylation, while the ortho-substituted compound
actually slightly raised rather than lowered the serotonin levels (Fuller and
Molloy, 1974). The effects of dichloro substitution also varied with the
position. 2,4-Dichloroamphetamine was considerably less active as a serotonin
depletor than the 4-chloro derivative, but their effects on 5-hydroxyindoleacetic acid were similar due to the potent MAO inhibitor activity of the
dichlorinated compound (Fuller and Molloy, 1974). However, the activity of
3,4-dichloroamphetamine was generally comparable to that ofp-chloroamphetamine (Pletscher et al., 1964). These observations are consistent with the
finding that ortho substitution is detrimental to the serotonin-depleting
activity of chlorinated amphetamines.
The effects of substitution with other groups in the para position have
also been investigated (Fuller et al., 1973). p- Trifluoromethylamphetamine
caused a small decrease in the serotonin concentration but a somewhat
greater reduction in 5-hydroxyindoleacetic acid (Table 7). The p-phenoxy
J. H.
10
BIEL AND B. A. BOPP
TABLE
Effects of the Position of the Chlorine on the

Serotonin-Depleting Activity of Chlorinated
~CHa
~
NH2
X
Serotonin,
% of control
4-CI
3-CI*
2-CI*
2,4-di-CI
3,4-di-CI
36 a
34 a
124 a
68 a
43 b
Fuller and Molloy (1974); serotonin in rat brain 6

hr after intraperitoneal administration of 0.1
mmollkg; *, in desmethylimipramine treated rats to
prevent para hydroxylation.
Pletscher et al. (1964); serotonin in rat brain 16 hr
after intraperitoneal administration of dose equivalent to 25 mg/kg of 4-chloro-N-methylamphetamine.
a
TABLE
Effects
of Ring Substitution on Serotonin-Depleting Activity of

Chlorinated Amphetamine Derivatives
~CHa
NH2
X
Serotonin,
5-HlAA,
% of control a
% of control a
4-CI
34
55
4-CFa
80
55
4-0-{))
80
113
4-CHa
94
94
4-0CH 3
96
87
Fuller et al. (1973); serotonin and 5-hydroxyindoleacetic acid (5HIAA) in rat brain 6 hr after intraperitoneal administration of 0.1
mmollkg.
AMPHETAMINES.' STRUCTURE -ACTIVITY RELATIONSHIPS
II
substituted compound had only a slight effect on both the 5-hydroxyindole

levels, while the p-methoxy and p-methyl derivatives were inactive.
Substitution on the side chain did not enhance activity and frequently
had an adverse effect (Table 8). The depletion of serotonin produced by the
{3-hydroxy derivative was considerably less than that caused by comparable
brain levels of p-chloroamphetamine (Fuller et at., 1973). The {3-difluoro
analog decreased serotonin but was less potent and much shorter acting than
p-chloroamphetamine (Fuller and Molloy, 1974).
Most substitution on the amino group also appeared to have a detrimental effect (Table 8). The exception was, of course, p-chloromethamphetamine, which was as potent a serotonin depletor as p-chloroamphetamine.
The N -cyclopropyl derivative did not decrease serotonin but was a potent,
irreversible MAO inhibitor and therefore decreased 5-hydroxyindoleacetic
acid (Fuller and Molloy, 1974). The effects of two possible metabolites of pchloroamphetamine, the oxime and the hydroxylamine, have also been
investigated (Fuller et at., 1974a). The former had only a slight effect, while
the latter caused a reduction in serotonin similar to that produced by pchloroamphetamine but appeared to be reduced in vivo to the amine. The
introduction of large groups on the amino group appeared to change the
characteristics of the serotonin depletion. Pletscher et at. (1965, 1970) found
that bis(3,4-dichlorophenethyl)-amine decreased dopamine as well as serotonin and increased homovanillic acid and 5-hydroxyindoleacetic acid. Deriv-
TABLE
Effects of Substitutirm on the Side Chain or Amino Group

on the Serotonin-Depleting Activity of Chlorinated
d'r
CH
CI
Serotonin,
f3
OH
diF
% of control"
NH2
NH2
NH2
36
80
28
NH<]
127
NHOH
=NOH
33
80
Fuller and Molloy (1974) and Fuller et at. (1973. 1974a);

serotonin in rat brain 6 hr after intraperitoneal administration of 0.1 or 0.4 (*) mmoVkg.
J.
12
FIG. 2. Lilly-l10140.
atives with other large complex substituents on the nitrogen as well as para
nitro-substituted compounds had similar effects. Like reserpine, these derivatives may interfere with the intracellular accumulation of amines in storage
granules.
Lilly-ll0140 [3-(P-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine] (Fig. 2), which represents a more radical departure from the
structure of amphetamine, was found to be a very selective inhibitor of
serotonin uptake in brain both in vitro and in vivo. Its selectivity for
serotonergic neurons has been demonstrated by its ability to prevent the
depletion of serotonin induced by p-chloroamphetamine without affecting
the depletion of norepinephrine induced by 6-hydroxydopamine (Fuller et
ai., 1974b). Lilly-l10140 decreased the 5-hydroxyindoleacetic acid levels
without affecting the serotonin concentration but did reduce the turnover of
the indoleamine (Fuller et ai., 1974c). These effects presumably result from
the enhanced activity at serotonergic neurons due to the inhibition of
reuptake of neurotransmitter. The selectivity of Lilly-llOl40 for serotonin
neurons makes it a unique agent among the many compounds that inhibit
the uptake of biogenic amines and offers an opportunity for possibly
separating the functions of the catecholamines and the indoleamines. This
compound is now being investigated clinically as an antidepressant.
3. CENTRAL STIMULATORY EFFECTS

3.1. Phenethylamine Derivatives
Perhaps the most outstanding pharmacologic characteristic of amphetamine is its central stimulatory activity. A prerequisite for the eNS activity Of
amphetamine and its congeners appears to be moderate to high affinity for
the norepinephrine neuronal uptake. The converse, however, is not true,
since some of the compounds with the highest affinity for the norepinephrine uptake systems do not have stimulatory effects (e.g., metaraminol).
These compounds may be too polar to pass through the blood-brain barrier,
AMPHETAMINES: STRUCTURE-ACTIVITY RELATIONSHIPS
13
may be metabolized too rapidly, or may be sufficiently similar in structure to

norepinephrine so that they serve either as substitute transmitters or
stimulants of the negative feedback mechanisms of norepinephrine synthesis,
thereby interfering with adrenergic neurotransmission, which may be necessary for eliciting the stimulant effects (Biel, 1970).
Although the central stimulatory properties of amphetamine and its
derivatives have been extensively investigated, the multiplicity of experimental procedures and techniques used to evaluate the stimulant effects makes
comparison of the results obtained in different studies difficult. Van der
TABLE
Effects of Alterations in the Side Chain on Stimulant Activity of

Phenylisopropylamine Derivatives in Mice
Stimulant
activity
CH2 NH 2
Inactive
CH3
CHNH 2
Inactive
CH 2CH 2 NH 2
<3
CH3
CH2 CHNH 2
100
CH3
CH2-(;-NH2
49
CH3
CH2 CH,CH 2 NH 2
Inactive
CH 3
CH2 CH2CH-NH 2
Inactive
CH3
CH2----c-NH 2
Inactive
CH,CH3
Van der Schoot et ai. (1961); effect on spontaneous locomotor
activity of mice relative to the effect of amphetamine (100). All
compounds administered intraperitoneally.
J. H.
14
TABLE
BIEL AND B. A. BOPP
10
Effects of Substitutiun on the Amino Group on Stimulant Activity of

Phenylisopropylamine Derivatives in Mice
Rl
Stimulant
activity
100
168
60
51
15
H
H
H
H
H
H
H
CHa
CHzCH a
CH1CHzCHa
(CHzhCH a
(CHz)5 CHa
CHz-Q
(CHzk-\Q>
CHa
CHa
Inactive
19
Van der Schoot et at (1961); effect on spontaneous locomotor activity of

mice relative to the effect of amphetamine (100). AU compounds administered intraperitoneaUy.
Schoot et al. (1961) have examined the stimulant effects of a large number of
phenylisopropylamines on the spontaneous motor activity of mice. A twocatbon chain between the phenyl ring and the nitrogen was necessary for
activity, since neither compounds with one carbon nor three or more carbons
possessed central stimulant effects (Table 9). The a-methyl group was also a
significant feature of the amphetamine molecule with respect to central
stimulation. J3-Phenethylamine had only minimal activity compared to amphetamine, while phentermine was only half as active. Thus, binding of the
amino group to a secondary carbon atom appears to be necessary for
maximal activity.
Some substitution on the amino group was allowable (Table 10).
Methamphetamine was the only derivative tested that was more potent than
amphetamine (Van der Schoot et al., 1961). Larger substituents appeared to
decrease activity as observed in the progressive reduction in stimulant effects
as the alkyl chain length was increased. Even larger alkyl or aralkyl
substituents led to compounds that were inactive or at best had minimal
activity. N-Dimethylation also caused a marked reduction in the psychostimulant properties.
Substitution on the side chain also had detrimental effects (Van der
Schoot et al., 1961). The J3-hydroxy derivatives had only minimal activity,
15
while the l3-keto derivatives retained stimulant properties but their potency
was considerably reduced (Table 11). Ring hydroxylation essentially abolished the activity (Van der Schoot et at., 1961). Other ring substituents, such
as methyl and methoxy groups, also markedly diminished or abolished the
stimulant properties (Table 12).
In summary, both the l3-phenethylamine skeleton and the a-methyl
group appeared to be critical features of the molecule for potent stimulant
activity. N-Methylation was allowable and even slightly enhanced the potency.
However, most other structural modifications, including the introduction of
larger alkyl or aralkyl substituents on the amino group, N-dialkylation, side
chain oxidation, and ring substitution, resulted in a decrease or even a loss of
the characteristic stimulant effects of amphetamine.
The configuration of the a-methyl group is also an important determinant of the stimulant activity. The dextro isomers of both amphetamine and
methamphetamine are considerably more potent as stimulants than the levo
isomers. Depending on the parameter measured, the potency difference may
range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b;
Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The
anorexic activity of the dextro isomers also exceeds that of the levo isomers
(Lawlor et at., 1969). However, the two isomers are approximately equipotent
in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).
TABLE II
Effects of Substitution on the Side Chain on Stimulant
Activity of Phenylisopropylamine Derivatives in Mice
H
=0
=0
OH
OH
CH 3
H
CH 3
H
CH 3
<Q)
Stimulant
activitya
100
168
51
68
4
8
18
Van der Schoot et aI. (1961); effect on spontaneous locomotor activity of mice relative to the effect of amphetamine (100). All compounds administered intraperitoneally.
J.
16
TABLE 12
Effects of Ring Substitution on .Stimulant Activity
of Phenylisopropylamine Derivatives in Mice
Stimulant
activity
x
3-0H
4-0H
3-CH a
4-CH a
3-0CH a
4-0CH a
2-0CH a
3,4-di-CH a
3,4-di-OCH a
Inactive
Inactive
14
9
10
5
<3
<3
Inactive
der Schoot et at. (1961); effect on spontaneous

locomotor activity of mice relative to the effect of
amphetamine (100). All compounds administered
intraperitoneally.
a Van
3.2. Structurally Modified Phenethylamine Derivatives

The incorporation of the aminoalkyl side chain into a ring structure
represents another important structural modification that has been made in
the amphetamine molecule. Two well-known stimulants, methylphenidate
and pipradrol (Fig. 3), both contain a piperidine ring and can be considered
as cyclized amphetamine derivatives. Some structural features that are
associated with the stimulant activity of these piperidine derivatives have
been reviewed by Krueger and McGrath (1964).
Methyl-a-phenyl-3-piperidine acetate was considerably less potent than
methylphenidate (methyl-a-phenyl-2-piperdine acetate) (Scholz and Panizzon, 1954), suggesting that once again increasing the number of carbons
between the phenyl ring and nitrogen to three reduced the stimulant activity.
Variations have also been made in the ester group of methylphenidate
o
II
dD
FIG.
3. Methylphenidate and pipradrol.
17
(Portoghese and Malspeis, 1961). None of the derivatives was as potent as the
methyl ester, and increasing the size of the group appeared to progressively
decrease the activity. However, the free acid has also been found to be
inactive (Sheppard et al., 1960).
Since methylphenidate contains two centers of asymmetry, two diastereoisomers exist. The threo form of methylphenidate was found to possess all
the central stimulant properties while the erythro form was inactive (Krueger
and McGrath, 1964; Shafi'ee et al., 1967; Shafi'ee and Hite, 1969). Resolution of the active racemate into its optically active forms indicated a fivefold
difference in activity (Krueger and McGrath, 1964).
As with methylphenidate, alterations in the structure of pipradrol that
increased the number of carbons between the phenyl ring and nitrogen
markedly reduced or abolished the stimulant activity (Krueger and McGrath,
1964). Neither a,a-diphenyl-4-piperidinemethanol (Fabing, 1955) nor a,adiphenyl-2-piperidine ethanol (Tilford and Van Campen, 1954) was active as
a stimulant. Several compounds in which the phenyl rings of pipradrol were
substituted or replaced with a heterocyclic ring have been synthesized and
evaluated for CNS activity (McCarty et al., 1957). Generally, stimulant effects
were retained in derivatives containing a phenyl ring substituted with an
alkyl, alkoxy, hydroxy, fluoro, chloro, or dimethylamino group in the para
position. Para substitution in both rings or ortho or meta substitution in
either ring caused a reduction in potency. Stimulant activity was also reduced
when a phenyl ring was replaced with a 2-piperidyl, 2-furyl, 2-tetrahydrofuryl, benzyl, or 2-thienyl group. Also, the piperidine group of pipradrol
may be replaced by other heterocyclic rings (e.g., 2-pyrrolidyl, 3-morpholinyl,
3-tetrohydroisoquinolinyl, and 3-thiomorpholinyl) without a loss of stimulant
activity (Winthrop and Humber, 1961; Belleau, 1960).
The two enantiomers of pipradrol have been prepared, and the
levorotary isomer was found to be a potent CNS stimulant while the dextrorotary isomer was inactive (Portoghese et al., 1968). However, the configuration
of the active form was not superimposable on the more active (dextro)
isomer of amphetamine, suggesting a different mechanism of action for the
two stimulants.
3.3. Pemoline
Pemoline (Fig. 4) differs from the structurally modified amphetamines
in having a carbonyl function at the a-position of the side chain, which in
turn is incorporated into a heterocyclic ring system (oxazolidinone). Pemoline
possesses mild central stimulant properties but has minimal sympathomimetic properties. It has recently been approved for use in the treatment of
hyperkinesis or minimal brain dysfunction in children.
One of the greatest limitations to the therapeutic use of amphetamine
and related stimulants has been the development of tolerance and drug
J.
18
FIG. 4. Pemoline.
dependence. Self-administration techniques have been widely used to study

the abuse liability of various classes of eNS active compounds. A number of
phenethylamine derivatives, including amphetamine (Deneau et ai., 1964,
1969; Schuster et ai., 1969; Yanagita et ai., 1969; Balster and Schuster, 1973;
Hoffmeister and Goldberg, 1973; Wilson and Schuster, 1973; Yokel and
Pickens, 1973), methamphetamine (Deneau et ai., 1969; Yanagita et ai., 1970;
Schuster et ai., 1969; Dren et ai., 1971, 1972; Balster and Schuster, 1973;
Yokel and Pickens, 1973), methylphenidate (Wilson et ai., 1969, 1971;
Schuster et ai., 1969; Dren et ai., 1971, 1972), phenmetrazine (Wilson et al.,
1969, 1971; Wilson and Schuster, 1973; Schuster et ai., 1969; Yanagita, et ai.,
1970), and pipradrol (Wilson et ai., 1969, 1971; Schuster et ai., 1969;
Yanagita et ai., 1970) have been found, like cocaine, to be reinforcers of selfadministration in rhesus monkeys.
In contrast, the psychostimulant, pemoline did not have the capacity to
reinforce self-administration behavior in rhesus monkeys (Dren et ai., 1971,
1972; Wilson et ai., 1969; Schuster et ai., 1969). Dren et ai.(1971, 1972)
trained rhesus monkeys with chronic in-dwelling jugular catheters to selfadminister cocaine. When pemoline was substituted for cocaine, the animals
did not continue to self-administer the drug. However, when either methamphetamine or methylphenidate was substituted for cocaine, self-administration behavior was maintained. Also, drug-naive monkeys failed to initiate
self-administration behavior when given access to pemoline but did start to
self-administer cocaine or methylphenidate.
4. ANOREXIC EFFECTS
Another prominent pharmacologic action of amphetamine is anorexia.
For therapeutic use as an appetite suppressant, stimulant activity represents
an important and frequently a limiting side effect. Therefore, much effort
has been directed toward achieving a separation of the two activities. It will
be recalled that the addition of a second a-methyl group, the introduction of
an oxygen function at the ,8-position, and substitution of the terminal amino
group with bulky groups attenuated the central stimulant effects. Derivatives
containing these structural modifications, e.g., phentermine, diethylproprion,
19
and benzphetamine, still retain anorexic properties and have been used
clinically as appetite suppressants. Other anorexic agents have resulted from
the incorporation of the amphetamine side chain into ring structures, such as
the morpholine derivatives phenmetrazine and phendimetrazine or the
oxazoline derivative aminoxaphen (aminorex). However, the most important
structural modification for achieving good separation of the stimulant and
anorexic properties of amphetamine has been the introduction of a trifluoromethyl group into the phenyl ring.
Cox and Maickel (1972) have compared the anorexic and stimulant
potencies of selected phenethylamine derivatives in rats. Anorexic effects
were assessed by the depression of hunger-induced food intake while the
behavioral effects were measured using the response rate in a continuous
avoidance situation. Only five compounds tested-fenfluramine, p-chloroamphetamine, aminoxaphen, p-chloromethamphetamine, and methamphetamine-had more potent appetite suppressant effects than amphetamine
(Table 13). However, the separation between the anorexic ED50 and stimulant ED50 is even more important than anorexic potency per se. Obviously,
best in this respect were the three compounds, fenfluramine, p-methylamphetamine, and p-chlorobenzphetamine, that possessed depressant rather
than stimulant properties. Also, three other derivatives, chlorphentermine,
benzphetamine, and p-hydroxyamphetamine, failed to cause stimulation at
TABLE 13
Comparison of the Anorexic and Behavioral Effects of Selcrted Phenylisopropylamine Derivatives in
Rats
Compound
Fenfluramine
p-Chloroamphetamine
Aminoxaphen
p-Chlorometham phetamine
Methamphetamine
Amphetamine
Phentermine
Chlorphentermine
Diethylpropion
Benzphetamine
p-Methylamphetamine
p-Chlorobenzphetamine
Phenmetrazine
Phendimetrazine
p- H ydroxyamphetamine
a
b
Anorexia
D 50 , a,b
/Lmol/kg
8.7
8.8
9.9
11.4
12.1
14.1
31.5
31.5
40.0
52.3
59.1
71.6
73.4
178.5
249.7
Behavior D 50 ILmollkga,C
Stimulant
Depressant
17.3
4.7
9.3
20.5
2.0
5.9
47.7
>87.0
13.7
>133.9
16.1
91.3
24.3
52.9
>397.4
Cox and Maickel (1972).

Dose required to cause 50% decrease in hunger-induced food intake by rats.
Dose required to cause 50% increase or decrease in response rate of rats in a continuous avoidance
situation.
J.
20
the highest doses tested. The only other compounds with anorexic EDso's at
levels below the stimulant EDso were p-chloromethamphetamine and phentermine. Several derivatives that have frequently been used as anorexic
agents, such as aminorex, diethylproprion, phenmetrazine, and phendimetrazine, failed to show significant anorexia at doses below the stimulant level
in this test procedure. Thus, although the stimulant potency of these
derivatives may have been reduced, it appears that the anorexic activity may
also have been diminished by these structral modifications. The most
selective anorexic agents appear to have resulted from (1) ring substitution
with electron-withdrawing groups such as chloro or especially the trifluoromethyl group present in fenfluramine, (2) substitution on the terminal amino
group with large bulky groups such as in benzphetamine and p-chlorobenzphetamine, and (3) dimethylation in the a-position as in phentermine
and chlorphentermine.
Holm et at. (1960) have compared the anorexic and stimulant properties
of a series of nuclear-substituted phenyl-tertiary-butylamines (Table 14). The
desired combination of a marked reduction in food consumption and a lack
of stimulant activity was achieved in compounds with chloro or bromo
substituents in the aromatic ring, whereas methyl, methoxy, or hydroxy
substitution gave compounds without anorexic activity. Only chloro substitution in the para or meta positions produced the desired effects; the orthosubstituted derivative lacked potent appetite suppressant properties. Likewise, the meta- and para-, but not the ortho-, substituted trifluoromethyl
TABLE
Anorexic and Stimulant Effects
14
of Selected Phentermine Derivatives

{3
()Jl"
Anorexia in rats
X
4-Cl
3-Cl
2-Cl
4-Br
4-CH 3
4- 0CH 3
4-0H
% in Diet
Weight change (g)
Stimulant activity
in mice,
DMIb 100 (mg/kg)
CH 3
(CH 3h
(CH 3)2
(CH 3h
(CH 3h
(CH 3h
(CH 3h
(CH 3h
(CH 3h
0.025
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
-38
-38
-29
-33
+27
-34
+23
+ 7
+22
3
10
>50
20
>50
>50
>60
>30
>50
. Holm et al. (1960).

DMI 100 defined as dose necessary to cause 100% increase in spontaneous motor activity of mice.
Effects
of N-Substitution
TABLE
on the Anorexic Activity
15
of Phenylisopropylamine Derivatives in Rats
~CH'
f- R1
R2
Rl
R2
Dose,
mg/kg
% Inhibition
of food intake a
26
CH2-Q
CHa
50
47
CH'-o
50
38
CHa
50
42
50
19
CHa
50
50
50
20
CHa
50
50
CHa
50
50
CHa
100
15
50
CHa
100
12
50
48
CHa
50
61
100
17
CHa
100
55
50
CHa
100
Cl
CH2-\O>-C1
CH2-oSr
CH2-oF
CH2-o-CHa
CH2-o-0CHa
CH'-Q
CFa
---CJ
-CJ
CH 2
CH2
50
16
CH2D
S
CHa
10
33
CH2D
100
16
CHa
100
34
S
a
Boisser et al. (1966).
J.
22
phentermine derivatives retained appetite suppressant activity but were not

superior to the p-chloro derivative (Beregi et al., 1970).
. Boissier et al. (1966, 1970) have compared the anorexic activities of
various N-substituted phenylisopropylamines (Table 15). The introduction of
benzyl, substituted benzyl, and furfuryl groups gave compounds that possessed appetite suppressant effects but were somewhat less potent than
amphetamine. In this series, the tertiary amines were generally as active or
more active than the secondary amines.
Fenfluramine and other trifluoromethyl-substituted derivatives are outstanding among the phenethylamine anorexic agents in possessing potent
appetite suppressant effects but minimal central stimulant and vasopressor
effects. A detailed investigation of the structure-activity relationships of the
trifluoromethylphenylisopropylamines has been conducted by Beregi et al.
(1970).
The effects of ring substitution are summarized in Table 16. Compared
to amphetamine, the fluoro- and trifluoromethyl-substituted derivatives
generally retained potent anorexic activity in both rats and dogs but were
significantly less toxic in mice. Substitution in the para or meta positions was
more favorable than in the ortho position. However, the most notable
TABLE
16
Effects oj Fluoro and Trifluoromethyl Substitution on the Anorexic Activity of Phenylisopropylamines
JOt
CHa
NH
I
R
Anorexia a
X
Rat
Doge
4-F
3-F
2-F
4-CFa
3-CFa
2-CFa
H
H
H
H
H
H
H
4.4
3.5
7.5
15
3
2
>40
0.9
2
1.5
4-CFa
CH 2CH 2 OCO-
3-CFa
CH 2CH 2OCO-
2-CFa
CH 2CH 2OCO-
20
5.4
>20
a Beregi et at. (1970).

Oral dose (mg/kg) that inhibited food intake of rats by 50% for 2 hr.
e Minimal oral dose that delayed food ingestion by dogs for 2 hr.
Acute toxicity, mg/kg, i.p.
8
2
>20
Toxicity,
mouse a /1
13
46
63
100
153
51
171
10
7.5
>20
108
300
23

TABLE
17
Effects of Alterations of the Side Chain on the Anorexic Activity

Trifluoromethyl-Substituted Phenylisopropylamine Derivatives
yR
of
CFa
R
CH 2 CH 2 NH 2
Anorexia,,b
rat
Toxicity."'c
mouse
>20
131.5
CHa
CH 2 CHNH 2
51
>20
152
>20
130
CHa
CH 2 CH 2 CHNH2
CH 2 CH a
CH 2 CHNH2
CHa
CH2 CNH2
10
127,5
CHa
Beregi et al. (1970).
Oral dose (mg/kg) that inhibited food intake of rats by 50% for 2 hr.
C Acute toxicity, mg/kg, i.p.
a
feature of the trifluoromethyl derivatives was the lack of central stimulant

properties (Beregi et at., 1970).
Most modifications of the basic phenylisopropylamine skeleton resulted
in a marked decrease in the anorexic activity (Table 17). In the trifluoromethyl series, the separation of the phenyl ring and the nitrogen by no more
than two carbons and the presence of an a-methyl group appeared to be
essential for maximal anorexic activity. However, one allowable change was
the introduction of a second methyl group in the a-position.
The effects of a variety of substituents on the amino group have also
been determined (Beregi et at., 1970). Many monoalkylated derivatives
retained high potency as anorexic agents and, most significantly, exerted a
considerably smaller vasopressor effect in rats (Table 18). For example, the
rise in blood pressure with the methyl and ethyl derivatives was only onequarter that produced by the unsubstituted analogue. Other compounds that
possessed good anorexic activity with minimal vasopressor effects included
J.
24
18
orten,
TABLE
Effects
of N-Monoalkylation on the Anorexic and Vasopressor Activity of Trifluoromethyl-Substituted

Phenylisopropylamine Derivatives
N-R
CF 3
R
H
CH 3
CH 2 CH 3 (Fenfluramine)
CH 2 CH 2 CH 3
CH(CH 3h
(CH 2 laCH 3
CH 2 CH.Ci
CH.CH=CH.
CH.C==CH
CH.CH=CHCH 3
CH.CH=C(CH 3 ).
Anorexia, a.b
rat
2
6.8
5.2
10.4
8.7
10
10
8.4
7.6
>20
>20
Vasopressor, a.c
rat
+100
+24
+27
+21
0
0
+15
+17
+11
Toxicity, a.d
mouse
51
130
71
87
142
94.6
123.4
109
283
78
79
a Beregi et al. (1970).

Oral dose (mglkg) that inhibited food intake of rats by 50% for 2 hr.
c Increase in blood pressure (mm Hg) following intravenous dose of 5 mg/kg.
d Acute toxicity, mg/kg, i.p.
the propenyl and propargyl derivatives. However, somewhat larger substituents on the amino group resulted in a loss of the appetite-suppressant
effects. N-Dialkylation generally led to a marked decrease in activity (Table
19).
Various other derivatives, including amides, carbinols, ethers, and esters,
were also synthesized and tested (Beregi et at., 1970). Only one of the amides,
the propinyl derivative, possessed significant anorexic activity and had quite
low toxicity (Table 20). In the series of carbinols, ethers, and esters, a twocarbon chain between the nitrogen and hydroxy group was found to be
essential for good activity (Table 21). The ethers were generally more toxic
and less active than the hydroxyethyl derivative while esterification of the
hydroxylalkyl group was more beneficial. The anorexic activity of the alkyl
esters was only slightly reduced and their toxicity was unchanged. In
contrast, the toxicity of many aryl and aralkyl esters was substantially
decreased while the activity was maintained, thus resulting in high therapeutic ratios. However, large differences frequently existed in the oral and
intraperitoneal toxicity of these derivatives. No consistent effects were
observed with substitutions in the phenyl ring of these esters. The final
group of compounds tested by Beregi et at. (1970) was the amino acid
25
derivatives. Generally the presence of one carbon between the nitrogen and
carboxy group was required for potent anorexic activity (Table 22).
The potencies of the optical isomers of certain trifluoromethyl derivatives have been compared by Beregi et ai. (1970) (Table 23). The dextro
isomer of fenfluramine was more active than the racemic mixture, which in
tum was more active than the levo isomer. This relationship was valid for
most of the derivatives tested but certain exceptions occurred. For example,
the racemic mixture of S-992 was more potent as an appetite suppressant in
rats than either isomer while in dogs the order of potency followed the
general trend (d > di > i).
Several conclusions can be drawn about the structure-activity relationships of the trifluoromethyl-substituted phenethylamines from this detailed
TABLE 19
Effects of N-Dialkylation on the Anorexic and Vasopressor Activity of Trifluoromethyl-Substituted
Phenylisopropylamines
QirCH'
CF 3
Anorexia, a,b
rat
2
6.8
20
20
NH2
NHCH3
N(CH3)2
N(CH 2CH 3 )2
CH 3
/
N
>20
"
Vasopressor, a,c
rat
Toxicity,",d
mouse
+100
+ 24
+ 48
51
130
144
132
+ 15
149
263
15
"
CH 2 C==CH
CH 3
"CH2 C==e-D
N(CHs)s
>20
+ 20
600
>20
+1l5
35

b Oral dose (mg/kg) that inhibited food intake of rats by 50% for 2 hr.
C Increase in blood pressure (mm Hg) following intravenous dose of 5 mg/kg.
d Acute toxicity, mg/kg, i.p.
26
J.
TABLE 20
Effects of Acylation on the Anorexic Activity of Trifluoromethyl-Substituted
Phenylisopropylamine Derivatives
yrrcCH.
NCOR
CFa
Anorexia, a,b
rat
>20
4.3
>20
CHa
CH2CH a
CH 2Cl
(Q)
NH2
CH 2CH 2 - N
Toxicity,a,c
mouse
750
2000
>2000
30
900
>20
1500
>20
300
a Beregi et al. (1970).

Oral dose (mglkg) that inhibited food intake of rats by 50% for 2 hr .
Acute toxicity, mg/kg, i.p.
study. Most notably, trifluoromethyl substitution resulted in a loss of stimulant properties. Substitution in the meta position was most beneficial in
retaining anorexic activity while ortho-substituted derivatives had only minimal activity. As was true in the unsubstituted phenylisopropylamine series,
the distance between the amino group and the phenyl ring was restricted to a
two-carbon chain and the binding of the amino group to a secondary carbon
atom was necessary for maximal activity. Small substituents in the amino
group were allowable and the formation of secondary amines led to a
marked reduction in the vasopressor effects. In contrast to the amphetamine
series, the introduction of large substituents and disubstitution on the amino
group tended to decrease or abolish the anorexic activity. Hydroxyethyl
substitution on the amino function was beneficial, and some of the aryl and
aralkyl esters combined potent anorexic activity and low toxicity. However,
there are indications that the N-hydroxyethyl group is cleaved metabolically,
thereby yielding the primary amine.
5. INHIBITION OF MONOAMINE OXIDASE

The presence of an a-methyl group protects amphetamine from rapid
degradation by monoamine oxidase (MAO) but amphetamine still retains at
least moderate MAO inhibitory properties. However, this MAO inhibitory
27
TABLE 21
Anorexic Activity of Hydroxyalkyl Derivatives of Trifluoromethyl-Substituted Phenylisopropylamines
QlfCH,
N-H
CF 3
Anorexia, a,b
rat
Toxicity, a,c
mouse
CH,CH,OCH,CH,
>20
10
IS4
300*
207
liS
CH,CH,O-Q
>20
100
CH,CH,OH
5.2
CH,CH,CH,OH
CH,CH,OCOCH,
10
125
CH,CH,OCOCH,CH,
10
17S
CH,CH,OCO-Q
5.4
lOS
2300*
CH,CH,OCO-Q-F
7.5
1000*
CH,CH,OCO-O-CI
15
1000*
CH,CH,OCO-Q-CH,
10
1000*
CH,CH,OCO-(O)-NH,
15
400*
CH,CH,OCO-Q-NO,
20
1000*
750*
10
150
1000*
CH,CIl,OCO
-Q
CF,
CH,CH,OCOCH,-Q
Oral dose (mg/kg) that inhibited food intake of rats by
C Acute toxicity, mg/kg, i.p. or p.o. (*).
50% for 2 hr.
J. H. BIEL AND B. A. BOPP
28
TABLE
22
Anorexic Activity of Amino Acid Derivatives of TrifluoTomethyl-Substituted

Phenylisopropylamines
q)CH'
N-H
CFa
R
CH.COOH
CH.CH.COOH
CH.CONH.
CH.CONHCH a
CH.CON(CHa).
CH.CONHNH.
Anorexia, a.b
rat
Toxicity, a,c
mouse
125
500*
300
350*
250
150
250
35
7.5
3.0
7.5
4

Oral dose (mg/kg) that inhibited food intake of rats by 50% for 2 hr .
Acute toxicity, mg/kg, i.p. or p.o. (*).
effect can be markedly enhanced by certain structural modifications. Three

potent, irreversible MAO inhibitors, tranylcypromine, pheniprazine, and
deprenyl (Fig. 5), have been derived from relatively simple changes in the
amphetamil).e molecule.
Incorporation of the a-methyl group into a cyclopropane ring led to
tranylcypromine (Burger and Yost, 1948; Zirkle and Kaiser, 1964). When
this group is "tied back" in such a fashion, it exposes the amino group,
thereby facilitating receptor interaction and binding. Furthermore, the less
stable cyclopropane ring could conceivably contribute to the increased
binding with the receptor protein through a ring-opening reaction. Tranylcypromine is about 5000 times more potent as a MAO inhibitor than
amphetamine, and judging by its duration of action it is probably an
irreversible enzyme inhibitor. Recently it has been recognized that MAO
exists as at least two isoenzymes with different substrate specificities and
different affinities for inhibitors (Neff and Yang, 1974). While amphetamine
has been found to be about 50 times more effective as an in vitro inhibitor of
rat brain mitochondrial MAO when serotonin is the substrate than phenethylamine, tranylcypromine was about 15 times more potent in blocking
phenethylamine oxidation than serotonin oxidation (Fuller, 1972). Tranylcypromine shares some of the other pharmacological properties of amphetamine. It also possesses eNS stimulant effects and has the ability to inhibit the
uptake of norepinephrine and to release norepinephrine, but is considerably
less potent than amphetamine in all these activities.
29
orr
TABLE
23
Anorexic Activity of Isomers of Trifluoromethyl-Substituted Phenylisofrropylamine Derivatives
H
N-H
CF 3
Anorexia o
R
Isomer
CH1CHa
dl
d
(Fenfluramine)
I
CHzCHzOCo--Q
(S-992)
dl
d
Rat b
Doge
5.2
2.8
10.0
6.5
4.0
21.2
5.4
12.5
>30
7.5
3.0
15.0
Toxicity,o.d
mouse
71
60
105.2
2300
300
850

Oral dose (mglkg) that inhibited food intake of rats by 50% for 2 hr .
Minimal oral dose which delayed food ingestion by dogs for 2 hr.
d Acute toxicity, mg/kg, i. p.
A marked increase in the MAO inhibitory activity can also be achieved

by substitution of the amino group of amphetamine with a hydrazine moiety,
thus producing pheniprazine (Biel et al., 1964). A similar change in the
structure of phenethylamine leads to the formation of phenelzine. The
highly reactive hydrazine group causes a pronounced, irreversible inhibition
of the enzyme that lasts for several days. Pheniprazine demonstrates relatively little substrate specificity, being only slightly more potent in inhibiting
serotonin oxidation than phenethylamine oxidation (Fuller, 1972). Like
tranylcypromine, pheniprazine also retains moderate eNS stimulant activity,
but it lacks any significant anorexic properties.
The introduction of a propargyl group on the terminal amino group of
methamphetamine produced deprenyl, another potent, irreversible MAO
inhibitor (Knoll and Magyar, 1972). Deprenyl is considerably more active in
blocking the oxidation of benzylamine than serotonin. A marked stereospecificity was evident in the in vitro and in vivo MAO inhibitory effects of
deprenyl with the levo isomer being considerably more potent in both brain
FIG. 5. Tranylcypromine, pheniprazine, and deprenyl.
30
J.
and liver. However, the d-isomer proved to be considerably more effective in

blocking the uptake of norepinephrine in rat brain slices and had much
greater eNS stimulant activity than the l-isomer. Deprenyl, especially the lisomer, is unique among MAO inhibitors in that it blocked the tyramineinduced pressor effects on blood vessels and the contractile responses of the
cat nictitating membrane. One of the greatest drawbacks to the therapeutic
use of MAO inhibitors as antidepressants has been the occurrence of
hypertensive crises precipitated by the ingestion of tyramine-rich foods, such
as cheese. The lack of tyramine potentiation and possible antagonism of the
effects of tyramine should minimize the risk of the so-called cheese reaction
following the administration of deprenyl.
6. PSYCHOTOMIMETIC EFFECTS
Amphetamine administered chronically in increasing doses may produce
severe symptoms of paranoid psychosis within as short a time interval as five
days (Ellinwood, 1967, 1968; Griffith et al., 1968). This inherent psychotogenic propensity of amphetamine was enhanced by polyalkoxylation of the
phenyl ring. Several methoxyphenethylamine and methoxyphenylisopropylamine derivatives have been synthesized and tested as psychotomimetic
agents in man (Shulgin et al., 1969). The potency of each compound was
compared to that of mescaline (3,4,5-trimethoxyphenethylamine), a wellknown hallucinogen that occurs naturally in several cacti, including Lophophora williamsii. The addition of the a-methyl group appeared to enhance
the activity as the methoxy analogs of amphetamine were generally considerably more potent than the corresponding phenethylamines (Table 24).
Replacement of the a-methyl group with an ethyl decreased the psychotomimetic effects.
A total of three methoxy groups appeared to provide optimal activity in
the phenylisopropylamine series (Shulgin et al., 1969). The mono-, di-,
and tetra-substituted derivatives were less potent than certain trimethoxyamphetamines (Table 25). However, the positions of the methoxy groups had a
marked effect on activity (Table 26). For example, 3,4,5-trimethoxyamphetamine was approximately twice as potent as mescaline, while 2,4,5-trimethoxyamphetamine was 17 times as potent as mescaline. In general, para
and ortho substitution enchanced activity, while meta substitution decreased
it. Replacement of the para methoxy group with an ethoxy group had little
effect on the potency, but ethoxy substitution in the ortho position tended to
reduce activity (Table 27). However, the introduction of a methyl group in
the para position led to a marked rise in the potency. DOM (2,5-dimethoxy4-methylamphetamine), also known as STP, is one of the most potent of the
psychotomimetic phenylisopropylamines, presumably due to reduced metabolic degradation in the para position (Snyder et al., 1970a).
31
24
TABLE
Effects of a-Methylation on the Psychotomimetic

Potency of Methoxyphenethylamine Derivatives in Man
ex
Relative
potency
H
CHa
H
CHa
H
CHa
H
CHa
4-0CHa
4-0CHa
3,4-di-OCH a
3,4-di-OCH a
3,4,5-tri-OCH a
3,4,5-tri-OCH a
2,4,5-tri-OCH a
2,4,5-tri-OCH a
<1
5
<0.2
<1
1.0
2.2
1
17
a Shulgin et al. (1969); potency relative to that of mescaline (1.0).
The incorporation of two adjacent methoxy groups into a methylenedioxy ring generally caused no loss of activity and frequently led to a distinct
increase (Shulgin et al., 1969). For example, the relative potency of 2methoxy-4,5-methylenedioxyamphetamine (12) was generally comparable to
that of its analog, 2,4,5-trimethoxyamphetamine (17), while 2-methoxy-3,4methylenedioxyamphetamine (10) was considerably more potent than its
corresponding trimethoxy analog 2) (Table 28).
TABLE
Psychotomimetic Potency
25
aur
of Mono-,
Di-, and Tetramethoxyamphetamine

Derivatives in Man
2
.V6
CHa
NH2
Ring substituents
2
Relative
potency
H
OCHa
OCHa
H
OCHa
H
H
H
OCHa
OCHa
OCHa
H
OCHa
OCHa
OCHa
H
OCHa
H
H
OCHa
H
H
H
H
H
5
8
5
<1
6
a Shulgin
e/ al. (1969); potency relative to that of mescaline (1.0).
J. H. BIEL AND B. A. BOPP
32
TABLE
26
Psychotumimetic Potency of Trimethoxyamphetamine Derivatives in Man

2
-V.
a u rCHa
NH2
5
Ring substituents
Relative
potencya
OCHa
OCHa
OCHa
OCHa
H
OCHa
H
OCHa
H
OCHa
OCHa
OCHa
OCHa
H
OCHa
H
OCHa
OCHa
OCHa
H
H
OCHa
OCHa
H
H
OCHa
OCHa
H
H
H
17
13
10
4
2.2
<2
Shulgin et al. (1969); potency relative to that of mescaline (1.0).
The psychotomimetic activity of the phenethylamine derivatives has

been correlated with the ability of the structures to form a ring system that
would closely resemble the C ring of LSD (Snyder et al., 1970a). An ortho
methoxy group that could assume a relatively rigid spatial conformation
would be necessary for the formation of such a ring system. The presence of
a second methoxy group in the meta position and therefore adjacent to the
ortho methoxy group would sterically hinder the ability of the latter to fulfill
this requirement. Thus, compounds with methoxy groups at both C2 and C3
or Cs and C5 would be relatively weak psychotomimetics, while compounds
TABLE
Effects
27
of Ethoxy and Methyl Substitution of Trimethoxyamphetamine

Derivatives in Man
a u r ' CHa
-V.
NH2
Ring substituents
OCHa
OCzHs
OCHa
OCHa
OCHa
H
H
H
H
H
4
OCHa
OCHa
OC,H s
OCHa
CHa
5
OCHa
OCHa
OCHa
OC,H s
OCHa
Relative
potencya
H
H
H
H
H
17
<7
15
<7
80
a Shulgin et al. (1969); potency relative to that of mescaline (1.0).
33

TABLE 28
Psychotomimetic Potency oj Methylenedioxy-Substituted Amphetamine
Derivatives in Man
-V
a a r rCHa
NH z
Ring substituents
2
H
O-CHz- 0
H
H
O-CHz- 0
OCHa
H
O-CHz- 0
OCHa
H
O-CH z- 0
OCHa
H
O-CHz-O
OClIa
O-CHz- 0
OCHa
OCHa
O-CH 2-O
OCHa
OClIa
H
O-CH 2-O
oelIa
Relative
potency
H
H
H
H
H
H
H
H
3
12
10
3
2.7
12
5
<1
Shulgin et at. (1969); potency relative to that of mescaline (1.0).
with unhindered ortho-substituents should be among the most potent

derivatives. In the methylenedioxy series, incorporation of the methoxy
groups at the 3 and 4 positions into a ring lessens the steric hindrance of the
methoxy group at C2 and thus might enhance the potency of such compounds.
Thus, the addition of methoxy groups changes the activity spectrum of
the amphetamine derivatives rather drastically. As well as enchancing the
psychotogenic propensity of the compounds, progressive methoxylation of
the phenyl ring practically abolishes the ability of the compounds to inhibit
the neuronal uptake of norepinephrine (uptake 1) and to release norepinephrine from its binding sites (Burgen and Iversen, 1965; Daly et at., 1966).
Therefore, unlike amphetamine, these drugs presumably do not exert their
characteristic effects through norepinephrine as an intermediate neurotransmitter, but perhaps rather through a direct interaction with the receptor.
Although methoxy substitution in the phenyl ring abolished the affinity of
the compounds for uptake 1, it appeared to increase the ability of the
phenethylamines to inhibit the accumulation of norepinephrine by the socalled second uptake system (Burgen and Iversen, 1965). Norepinephrine
and normetanephrine are also taken up extraneuronally in sympathetically
innervated tissues by a process thought to be similar to uptake 2. The
potency of the trimethoxyamphetamine derivatives as inhibitors of normetanephrine uptake by this system was found to correlate with their hallucinogenic potency (Hendley and Snyder, 1971). For example, 2,4,5,-trimethoxy-
34
J.
amphetamine, 2,4,6-trimethoxyamphetamine, and DOM were highly active

as uptake inhibitors and were among the most potent psychotogenic
compounds in man. Conversely, 3,4,5-, 2,3,5-, and 2,3,4-trimethoxyamphetamines were all quite weak both as psychotomimetics and inhibitors of
normetanephrine uptake. This finding led to the suggestion that the site of
action of these drugs may be related to the site of normetanephrine uptake,
which may possible involve the postsynaptic norepinehprine receptor.
7. SUMMARY
Amphetamine remains the medicinal chemist's "Cinderella" molecule.
No other compound has displayed such a plethora of pharmacological,
biochemical, and physiological effects, which have endowed this drug with a
variety of therapeutic applications and made it a highly effective tool for the
pharmacologist and biochemist in the study of the role of neurotransmitter
amines in the control of the emotional state and the chemical etiology of
certain mental disorders. Nor have many other molecules served as so
versatile a starting base for the synthetic elaboration of a host of novel
therapeutic agents.
Pharmacologically, amphetamine per se is a potent central stimulant,
vasoconstrictor, anorexigenic agent, uptake inhibitor, and releaser of dopamine and norepinephrine at the neuronal level. Therapeutically, these
pharmacological and biochemical properties of amphetamine translate into
drugs for the treatment of mild depressions, fatigue states, hyperkinesis,
nasal congestion, and obesity.
From the standpoint of human toxicity, the chronic abuse of amphetamine has lead to severe drug addiction, paranoid psychosis, and ultimately
death, when high intravenous doses of the drug are self-administered. Its
biochemical properties of releasing dopamine and inhibiting the cellular
uptake of dopamine coupled with its ability to produce stereotypical behavior
in animals have given rise to the plausible hypothesis that the neutransmitter
dopamine may be implicated in the chemical genesis of psychoses. Further
credence in support of this hypothesis is lent by the major antipsychotic
drugs, all of which are potent antagonists of dopamine and the fact that
increasing doses of amphetamine can precipitate a model psychotic state in
humans within a period of five days.
Even more fascinating has been the impressive array of drugs that have
resulted from the diverse molecular modification of the amphetamine
molecule: nonaddicting antiobesity drugs, antihyperkinetic agents, potential
antidepressants (selective inhibitors of serotonin uptake) devoid of the
anticholinergic properties of the tricyclics, irreversible MAO inhibitors in the
treatment of hypertension and mental depression, long-acting nasal decongestants, and powerful psychotomimetic agents. More recently, cyclization of
35
FIG. 6. Wy-16225.
the amphetamine side chain has yielded a potent, nonaddicting analgetic

agent (Figure 6).
Thus amphetamine remains a valuable laboratory tool for the biochemist and pharmacologist, a seemingly inexhaustible starting base for the
synthetic medicinal chemist in the design and development of novel medicinals, and the wellspring of a continuous flow of novel therapeutic agents for
the practicing physician.
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AMPHETAMINES: STRUCTURE-ACTIVITY RELA110NSHIPS
39
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2
AAIPHETAMINES: BIOCHEAIICAL
AND BEHAVIORAL ACTIONS IN
ANIMALS
Kenneth E. Moore
1. INTRODUCTION
Amphetamine and a number of pharmacologically related drugs act in the
brain to increase alertness, suppress appetite, and reduce sleep and fatigue.
In animals these drugs generally facilitate ongoing spontaneous and operant
behaviors. High doses of these drugs cause stereotyped behaviors that are
characteristic for each species, and in humans they can cause toxic psychoses.
Acting in the periphery the drugs also have sympathomimetic properties.
The purpose of this chapter is to review the results of experiments that
have attempted to correlate the behavioral effects of these drugs with their
biochemical actions in the brain. In effect, an effort will be made to answer
the question, "What are the mechanisms of the central actions of amphetamine and other psychomotor stimulants?" Answers to this question will be
sought by reviewing the results of experiments designed to examine the in
vivo and in vitro interactions of these drugs with putative neurotransmitter
substances.
2. CHEMISTRY
Amphetamine and its pharmacological congeners are derivatives of f3phenethylamines. The chemical structures of some of the compounds
discussed in this chapter are depicted in Fig. 1; the phenethylamine
structure is indicated in bold type. Only those compounds that have
Kenneth E. Moore
Department of Pharmacology, Michigan State University, East
Lansing, Michigan.
41
42
KENNETH E. MOORE
OtHiCHrNt\
Phenethylomine
O~~
Methylphenidate
Phenmetrazine
OCHr~Hz
O~-~H-NH2
CHz
Amphetamine
OCH2~~H
CH
O~~:~H
0- CHt-CH
Tranylcypromine
3
Methamphetamine
O~g:~~~
o~-Q
H
Pipradrol
OCHrCH-NH-NH2
CH 3
Pheniprazine
aJCOOH
N
C HS
Amfonelic acid
O~-C~N
Ephedrine
FIG. 1. Derivatives of phcncthylamine.
pharmacological properties similar to amphetamine (psychomotor stimulation and anorexia at low doses and stereotyped behaviors at higher doses)
will be considered in detail, but there are many other pharmacologically
active phenylethylamine derivatives. Any substitution on the phenyl ring
radically alters the central pharmacological actions of these compounds. For
example, substitutions of hydroxyl groups make the compounds devoid of
central excitatory actions following systemic administration (e.g., p-hydroxyamphetamine). Substitutions of electronegative groups such as Cl or CF3
produce compounds that interact with 5-hydroxytryptaminergic neuronal
systems (e.g., p-chloroamphetamine) or have anorexigenic but little CNS
stimulant properties (e.g., fenfluramine), and substitutions of methoxy
groups make compounds that have psychotomimetic properties (e.g., 2,5dimethoxy-4-methylamphetamine, DOM). The addition of a methyl group
on the ex carbon of phenylethylamine is essential for the central actions of
amphetamine, as it protects the compound from destruction by monoamine
oxidase (MAO) and even imparts mild MAO inhibitory properties to the
molecule. Because it is so rapidly destroyed by MAO, phenylethylamine has
little CNS stimulant properties, but if MAO is inhibited the pharmacological
properties of this compound resemble those of amphetamine (Mantegazza
and Riva, 1963; Stein, 1964). Some alterations of the ethylamine side chain
can produce compounds that are extremely potent inhibitors of MAO (e.g.,
tranylcypromine and pheniprazine). For discussions of the structure-activity
relationship of amphetamine and its derivatives see Biel (1970) and Van
Rossum (1970).
3. GENERAL PHARMACOLOGICAL ACTIONS

Amphetamine was first synthesized in the 1920s and the peripheral
sympathomimetic and central stimulant properties of this drug were de-
AMPHETAMINES:
BIOCHl~'MICAL
AND BFHAVIORAL ACTIONS IN ANIMALS
43
scribed in the 1930s (for historical details see Leake, 1958). Acting in the
brain amphetamine elevates mood, increases alertness, reduces fatigue,
stimulates respiration, and depresses appetite. These central pharmacological
properties form the basis for the clinical use of the drug in the treatment of
simple depression, narcolepsy, fatigue, obesity, and overdosage of CNS
depressants. Tolerance appears to develop to some (e.g., anorexia) but not to
other actions (e.g., antinarcoleptic) of the drug. Repeated high doses of the
drug cause the development of toxic psychoses that are similar to those seen
in acute paranoid schizophrenia (Angrist et at., 1974, and others).
In animals, amphetamine generally facilitates ongoing spontaneous and
operant behaviors; it stimulates locomotor activity, continuous avoidance
responding, intracranial self-stimulation, etc. Low doses of the drug also
reduce food intake and cause hyperthermia. Higher doses of amphetamine
cause stereotyped behaviors that appear to be purposeless and that are
generally characterized by continuous repetition of motor acts that are
characteristic for each species (Wallach, 1974; Randrup and Munkvad, 1972).
In rodents stereotypies are generally seen as the replacement of normal
exploratory and grooming activities with continuous head swaying or bobbing, sniffing, licking, and gnawing. Stereotyped behaviors in monkeys and
man are more varied but generally take the form of repetitive movements of
lips, tongue, hands, and arms.
The mechanisms of action of amphetamine and its congeners, which will
be referred to collectively as psychomotor stimulants, have been inferred
from a variety of behavioral experiments in which these compounds have
been administered to animals pretreated with drugs that alter central
neurotransmission processes. As a result of these studies it has been
proposed that psychomotor stimulants (a) directly stimulate catecholaminergic receptors (Smith, 1963) or 5-hydroxytryptaminergic receptors (Gelder
and Vane, 1962; Innes, 1963); (b) inhibit MAO (Mann and Quastel, 1940;
Burn, 1957); (c) release catecholamines (Stein, 1964; Carlsson, 1970; Moore
et at., 1970); and/or (d) block the reuptake of neurogenically released
catecholamines (Glowinski and Axelrod, 1965; Taylor and Snyder, 1971).
These possible mechanisms of action will be critically evaluated in the
following sections.
4. BEHAVIORAL EFFECTS IN ANIMALS PRETREATED

WITH DRUGS THAT MODIFY CATECHOLAMINERGIC
NEUROTRANSMISSION PROCESSES
Three catecholamines have been identified in mammalian brain: norepinephrine (NE), dopamine (D), and epinephrine; only the former two amines
will be considered. It has been postulated that these catecholamines serve as
neurotransmitters of activating systems in the brain (Schild kraut et al., 1967;
44
KENNETH E. MOORE
Stein, 1968; Crow, 1972, 1973) and that increased activity of these systems is
associated with arousal, increased alertness, or excitement. Psychomotor
stimulants have been proposed to act by facilitating catecholaminergic
transmission processes. Schematic diagrams of central dopaminergic and
noradrenergic synapses that may be part of such an arousal system are
depicted in Fig. 2.
Tyrosine is actively transported into the neuron (a), where it is converted
to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (b), which is
located exclusively in catecholaminergic neurons. DOPA in tum is decarboxylated to D; this reaction is catalyzed by an ubiquitous enzyme, aromatic-Lamino acid decarboxylase (c). In dopaminergic neurones D can be stored in
vesicles (e), metabolized by intraneuronal MAO (f), or be released (g) in
response to neuronal activity or drugs. In noradrenergic neurons D is
transported into storage vesicles where it is converted to NE by dopamine-,Bhydroxylase (D,BH) (d), and like D, the NE may be stored, metabolized, or
released from the nerve terminal.
With the arrival of the nerve action potential, either NE or D is released
and diffuses across the synaptic cleft to activate specific receptors on the
postsynaptic neurons (h). Following this interaction, which completes the
transmission process, the transmitter must be removed from the receptor
area. This is accomplished by diffusion and the subsequent metabolism of
the released amine by extraneuronal MAO or catechol-o-methyltransferase
(COMT) (i), but more importantly by the active transport of the amine back
into the presynaptic nerve terminal (j). Once inside the neuron the amine
may be stored, metabolized, or again released.
The sites at which amphetamine has been proposed to act are depicted
in Fig. 2. This drug may mimic the actions of NE or D at postsynaptic
receptor sites [1], or it may increase the concentrations of these amines at the
same receptors by inhibiting MAO [2], by causing the release [3], and/or by
blocking the reuptake of the released amine [4]. The following sections deal
TYROSINE
DEAM-MET
TYROSINE~DOAl\"::" 0
d.
f~-'
COMT/
~M
FIG. 2. Schematic diagram of a dopaminergic and noradrenergic synapse depicting possible

sites (indicated by numbers 1 to 4) at which amphetamine has been postulated to act. See
text for details and the identification of (a)-(j). Abbreviations: NE, norepinephrine; D,
dopamine; MAO, monoamine oxidase; COMT, catechol-o-methyltransferase; NM, normetanephrine; 3MT, 3-methoxytyramine; DOPAC, dihydroxyphenylacetic acid; DEAM-MET,
deaminated metabolites.
AMPHETAMINES: BIOCHEMICAL AND BEHAVIORAL ACTIONS IN ANIMALS
45
with how the actions of amphetamine and other psychomotor stimulants can
be altered by drugs that modify the dopaminergic or noradrenergic transmission processes.
4.1. Drugs Which Enhance Catecholaminergic Transmission

4.1.1. Drugs Which Inhibit MAO
MAO inhibitors block the oxidative deamination of a variety of amines,
including the catecholamines, and thereby increase the concentrations of
these amines in the brain. This does not necessarily mean that the concentration of the amines at the postsynaptic receptors is increased, since much of
the MAO is located intraneuronally and the amines may accumulate only
inside the neuron. Nevertheless, the amine may leak out and thereby activate
the postsynaptic receptors. If this occurs MAO inhibitors might be expected
to have psychomotor stimulant properties. Some MAO inhibitors (e.g.,
tranylcypromine, pheniprazine) have amphetamine-like stimulant actions,
whereas other MAO inhibitors do not (iproniazid, pargyline) (Stein, 1964;
Poschel and Ninteman, 1964). Since these drugs have similar MAO-inhibiting capabilities, it might be assumed that the central stimulant actions are not
directly related to their ability to inhibit MAO. Some MAO inhibitors have
other actions that might be responsible for the central pharmacological
properties; they block the amine uptake process (Hendley and Snyder, 1968)
and release catecholamines in vivo (Carlsson, 1970; Besson et at., 1971b).
MAO inhibitors do enhance the central stimulant properties of some
psychomotor stimulants. For example, the central effects of phenylethylamine Jre greatly enhanced by MAO inhibitors, but this is to be expected
because the drug itself is enzymatically destroyed by this enzyme (Mantegazza
and Riva, 1963; Stein, 1964). MAO inhibitors, however, do enhance the
actions of some psychomotor stimulants (e.g., amphetamine) that are not
substrates for MAO (Stein, 1964; Van Rossum and Hurkmans, 1964). This
suggests that these stimulants increase the synaptic concentration of amines
that are substrates for MAO, either by causing release or by blocking the
presynaptic neuronal uptake process. In addition, some MAO inhibitors may
increase the brain concentration of the psychomotor stimulants by inhibiting
their metabolism in the liver (Lew et at., 1971).
Some psychomotor stimulants have MAO-inhibiting properties and it
has been suggested that this property may be responsible for part of their
central stimulant effects (Burn, 1957). It is not, however, an important
mechanism for the pharmacological properties of amphetamine because (1)
this drug has very weak MAO-inhibiting properties, (2) many potent MAO
inhibitors do not have amphetamine-like properties, and (3) amphetamine
produces marked central stimulant effects in animals that already have MAO
totally inhibited. Furthermore, after the administration of reasonable phar-
46
KENNETH E. MOORE
macologically active doses, the concentration of amphetamine in the brain is

not sufficient to inhibit the enzyme direcdy, although there are some reports
that high doses of amphetamines increase brain contents of 5-hydroxytryptamine (5-HT) and also reduce the formation of deaminated metabolites of
catecholamines (McLean and McCartney, 1961; Glowinski and Axelrod,
1965). Rudedge (1970) suggested that since amphetamine blocks neuronal
uptake of amines that are substrates for MAO, the apparent inhibition of this
enzyme may be due to the inability of amine substrates to reach the site of
the intraneuronal enzyme.
4.1.2. Drugs Which Block Catecholamine Uptake

A number of drugs classified as tricyclic antidepressants have the ability
to block the transport of amines into noradrenergic and to a lesser extent
into dopaminergic nerve terminals (see review by Koe, 1975). Some of these
antidepressants (desipramine, imipramine, amitryptyline, and protryptyline)
enhance the effects of amphetamine and methamphetamine on (1) locomotor activity in rats (Sulser et al., 1966) but not in mice (Lew et al., 1971), (2)
the amplitude of evoked cortical responses in the rabbit (Plotnikoff and
Everett, 1965), and (3) the rate of electrical self-stimulation in rats (Stein,
1964). It has been suggested that this potentiation is related to the amine
uptake-blocking properties of these drugs, but the central stimulant effects of
amphetamine are also increased by iprindole, an antidepressant that is
devoid of uptake-blocking properties (Freeman and Sulser, 1973). The
results of experiments in a number of different laboratories indicate that, at
least in the rat, the enhancement of the amphetamine central stimulant
effects by antidepressant drugs is due, in part, to an increased brain
concentration of amphetamine. This, in turn, is the result of a reduced rate
of metabolism of the drug. Specifically, these drugs appear to block the
enzymatic p-hydroxylation of amphetamine in the liver (Consolo et al., 1967;
Lewander, 1969; Freeman and Sulser, 1973). p-Hydroxylation is only a
minor pathway in the metabolism of amphetamine in other species (Smith
and Dring, 1970; Williams et al., 1973) and it is not known if the
antidepressants block other routes of metabolism (N-dealkylation, deamination, aliphatic hydroxylation). At present, therefore, it is difficult to evaluate
the relative contributions of blocking amphetamine metabolism and blocking
catecholamine uptake in the enhancement of the central effects of amphetamine by tricyclic antidepressant drugs.
4.2. Drugs Which Disrupt Catecholaminergic Transmission

4.2.1. Drugs Which Block Catecholaminergic Receptors
Both the phenothiazine and butyrophenone classes of neuroleptics block
amphetamine-induced locomotor and stereotyped behaviors in animals and
47
toxic psychoses in man. Indeed, the ability of these compounds to antagonize

some of the effects of amphetamine has been utilized as a screening test for
neuroleptics Oanssen et at., 1965). The neuroleptics appear to be specific
antagonists because, in contrast to other CNS depressants such as barbiturates and benzodiazepines, the antiamphetamine effects are obtained with
doses that do not produce severe central depression. Some neuroleptics (e.g.,
chlorpromazine and ace promazine) have both noradrenergic- and dopaminergic-receptor-blocking properties and so it is difficult to determine if the
antiamphetamine effect of these drugs results from the blockade of either
one or the other receptor. Other neuroleptics, however, appear to have only
dopaminergic receptor-blocking properties (e.g., spiramide, pimozide, and
haloperidol) and these drugs block the locomotor stimulant and stereotyped
actions of amphetamine (Van Rossum, 1967; Janssen et at., 1965; Wallach,
1974; Roberts et at., 1975). Therefore, dopaminergic transmission processes
appear to be important for both of these central actions of amphetamine-like
drugs.
A number of investigators have attempted to reduce the central stimulant actions of amphetamine-like drugs with phentolamine and propranolol,
which block peripheral a- or ,8-adrenergic receptors, respectively. It is
generally agreed that adrenergic blocking drugs alter neither the stereotyped
behaviors in animals (Randrup et at., 1963; Janssen et at., 1965; Wallach,
1974) nor the euphoria in man 06nsson, 1972), but there are some reports
that they reduce some of the other central actions of amphetamine. For
example, Cahn and Herold (1970) reported that propranolol and phentolamine reduced d-amphetamine-induced exploratory behavior in rats, but only
at doses that severely depressed activity in control animals. Thus, the
blockade of the central stimulant effects of amphetamine by a- and ,8adrenergic receptor antagonists appears to be related to central CNS
depressant effects of the drugs rather than to specific antagonism of the
receptors. Since evidence cited above and elsewhere (see Sections 4.2.3 and
4.2.4) strongly suggests that dopaminergic rather than noradrenergic neuronal systems are important for the locomotor stimulation and stereotyped
behaviors caused by psychomotor stimulants, it is not surprising that classical
NE receptor antagonists have little inhibitory action on these behaviors.
Nevertheless, noradrenergic systems do appear to be involved with some of
the central pharmacological actions of amphetamine-like drugs. Wise et at.
(1973) reported that intraventricularly administered phentolamine, but not
propranolol, blocked the facilitatory effect of amphetamine on electrical selfstimulation of the medial forebrain bundle. Furthermore, d-amphetamine
facilitated electrical self-stimulation if electrodes were implanted into brain
regions containing only noradrenergic neurons; this facilitation was reduced
by chlorpromazine, which has both noradrenergic- and dopaminergicreceptor-blocking properties, but not by pimozide, which produces only
dopaminergic receptor blockade (Ritter and Stein, 1973). Phillips et at.
(1975), however, have found that pimozide does disrupt self-stimulation of
48
KENNETH E. MOORE
electrodes III NE neuronal sites. The latter authors discuss some of the
difficulties in interpreting results of self-stimulation experiments employing
psychomotor stimulants and noradrenergic and dopaminergic antagonists.
Self-administration of drugs is a behavioral event in which the drug
serves as a reward or a reinforcer for the behavior leading to its administration. d-Amphetamine and methamphetamine are effective positive reinforcers in rats and monkeys; these animals will press a lever to receive injections
of these drugs (Pickens and Harris, 1968; Deneau et al., 1969; Davis and
Smith, 1972). Animals that are accustomed to self-administering amphetamine will respond by increasing their rate of i~ections if the unit dose of the
drug is reduced (Thompson and Pickens, 1970) or if the reinforcing effects
of the drugs are blocked. Yokel and Wise (1975) reported that low doses of
pimozide increased the rate of self-administration of d-amphetamine whereas
phentolamine and propranolol caused just the opposite effect. The authors
proposed that blockade of D receptors disrupts the positive reinforcing
action of amphetamine, whereas blockade of NE receptors disrupts behavioral
support mechanisms for self-administration. Using a different experimental
procedure Davis and Smith (1975a) demonstrated that very high doses of
haloperidol blocked the reinforcing action of d-amphetamine and also
blocked the establishment of a conditioned reinforcer based on amphetamine
as a primary reinforcer.
Pijnenburg et al. (l975a,b) reported that injections of D directly into the
nucleus accumbens of rats pretreated with a MAO inhibitor increased
locomotor activity and, as would be expected, this dopaminergic effect was
blocked by systemic administration of haloperidol but not by phentolamine.
Injections of haloperidol into the nucleus accumbens, but not into the
striatum, also blocked the locomotor stimulant actions of amphetamine. The
blocking effect bf haloperidol was not mimicked by injections of phentolamine or propranolol. These results suggest that locomotor stimulant effects
of amphetamine result from dopaminergic agonistic actions in the nucleus
accumbens; a similar conclusion has been reached by Kelly et al. (1975) using
a different experimental approach (see Section 4.2.4).
4.2.2. Drugs Which Deplete Catecholamines

Reserpine depletes the brain and peripheral tissues of catecholamines
and 5-HT by disrupting the ability of neuronal storage vesicles to accumulate
and retain these amines. Concomitant with the amine depletion this drug
causes profound behavioral depression (reduced locomotor, conditioned
avoidance, and operant behaviors, etc.; for review see Sulser and Bass, 1968).
The behavioral depressant actions of reserpine are believed to be causally
related to the depletion of catecholamines because both are reversed by the
administration of L-dopa but not 5-hydroxytryptophan (5-HTP) (Carlsson et
al., 1957).
49
The sympathomimetic actions of amphetamine on the nictitating membrane and the cardiovascular system are markedly reduced in animals in
which peripheral sympathetic nerves have been depleted of NE by reserpine
pretreatment, suggesting that this sympathomimetic amine acts indirectly by
releasing NE (Burn and Rand, 1958; Trendelenburg, 1963). Although acute
or chronic reserpine pretreatment may reduce or shorten the duration of the
facilitating effect of amphetamine on some behavioral tests (e.g., selfstimulation behavior; Stein, 1964), it generally does not inhibit and may even
enhance the stimulation of locomotor, Sidman avoidance, self-stimulation,
and stereotyped behaviors (Van Rossum et at., 1962; Smith, 1963; Rech,
1964; Stolk and Rech, 1968; Rech and Stolk, 1970; Fibiger et at., 1972;
Cooper et at., 1974). The lack of a blocking action of reserpine prompted
early investigators to postulate that amphetamine had direct agonistic actions
on catecholaminergic or serotonergic receptors in the brain (Smith, 1963,
1965; Gelder and Vane, 1962; Innes, 1963). It was subsequently noted that
reserpine pretreatment also failed to block the locomotor stimulant and
stereotyped actions of methamphetamine and phenmetrazine, but did prevent the stimulation produced by ephedrine, pipradrol, methylphenidate,
and amfonelic acid (Aceto et at., 1967; Scheel-Kruger, 1971; for general
confirmation but with some discrepancies see Rech and Stolk, 1970; Sayers
and Handley, 1973; Wallach, 1974). The latter drugs were believed to act
indirectly by releasing catecholamines from a reserpine-sensitive or storage
pool in brain neurons. On the other hand, amphetamine, methamphetamine, and phenmetrazine were believed to act indirectly by releasing
catecholamines from a reserpine-insensitive pool (Sulser et at., 1968). The
characteristics of this second pool were defined by studies with a-methyltyrosine (aMT) (Weissman et at., 1966).
4.2.3. Drugs Which Inhibit Catecholamine Synthesis

In 1965 Spector et at. reported that aMT inhibited tyrosine hydroxylase,
the rate-limiting enzyme for the synthesis of catecholamines, and thereby
reduced the brain contents of NE and D. Unlike reserpine, aMT did not
alter the brain contents of 5-HT, and unlike a-methyldopa and a-methyl-mtyrosine it was not metabolized to amines that might functionally substitute
for the depleted catecholamines (false transmitters). aMT depressed responding in a variety of behavioral tests and when used with appropriate
precautions to avoid nonspecific behavioral depressant and toxic effects
(Rech et at., 1966; Moore et at., 1967) aMT caused behavioral depression
that appeared to be causally related to the deficiency of brain catecholamines
(see reviews by Moore et at., 1970; Moore and Dominic, 1971).
It was also reported that acute administration of aMT, in doses that
produced no behavioral depression and little depletion of catecholamines,
50
KENNETH E. MOORE
blocked the locomotor activity, anorexia, avoidance responding, and stereotypies in rats and mice produced by amphetamine, methamphetamine, and
phenmetrazine (Weissman et at., 1966). These actions of aMT appeared to
be due to inhibition of tyrosine hydroxylase because other inhibitors of this
enzyme also antagonized the actions of amphetamine. Drugs that tend to
enhance or prolong catecholaminergic transmission (monoamine oxidase
inhibitors, imipramine, and dopa) partially antagonized the antiamphetamine
properties of aMT (see also Stolk and Rech, 1970). The antiamphetamine
properties of aMT have also been noted in cats (Hanson, 1966; Wallach and
Gershon, 1972), monkeys (Houser, 1973), and humans (Jonsson et at., 1969).
Subsequent workers confirmed the observations that aMT also inhibited the
central stimulant effects of ephedrine, methamphetamine and phenmetrazine (Dominic and Moore, 1969a,b; Rech and Stolk, 1970; Scheel-Kruger,
1971; Thornburg and Moore, 1973b; Sayers and Handley, 1973; Wallach et
at., 1973) reinforcing the suggestion that these drugs act by selectively
releasing newly synthesized NE and/or D. aMT was unable to block the
stimulant actions of several other psychomotor stimulants such as methylphenidate, pipradrol, and amfonelic acid (Aceto et at., 1967; Dominic and
Moore, 1969b; Rech and Stolk, 1970; Scheel-Kruger, 1971; Thornburg and
Moore, 1973b; Franklin and Herberg, 1974). These latter drugs appear to
act indirectly by releasing catecholamines from a reserpine-sensitive store. A
summary of actions of psychomotor stimulants in animals pretreated with
neuroleptics, reserpine, and aMT is presented in Table 1.
It is generally believed that the antiamphetamine property of aMT is
related to the ability of this drug to block catecholamine synthesis, as first
suggested by Weissman et at. (1966). This mechanism, however, has not been
TABLE
The Actions
rf Psychomotor Stimulants in Animals Pretreated with Drugs That Disrupt

Catecholaminergic Transmission a
Pretreatment
Drug
Amphetamine
Methamphetamine
Phenmetrazine
Ephedrine
Pipradrol
Methylphenidate
Amfonelic acid
Neuroleptics
Reserpine
a-Methyltyrosine
!
!
!
!
!
!
o or i
o or i
!
!
!
!
!
!
!
or
0
0
0
a In nonpretreated animals all the psychomotor stimulants produce similar behavioral effects. 1 or t
indicates that the drug pretreatment reduced or increased the actions of the psychomotor stimulant; 0
indicates that the action of the psychomotor stimulants is not altered. The data were reported in Aceto et
al. (1967), Dominic and Moore (1969b), Moore et al. (1970), Rech and Stolk (1970), Sayers and Handley
(1973), Scheel-Kruger (1971), and Thornburg and Moore (1973b).
51
accepted universally, probably because aMT can prevent the central actions
of amphetamine without altering the brain contents of catecholamines. It had
been suggested that aMT might have catecholamine-receptor-blocking properties, but direct experimentation revealed that the drug does not block
peripheral a- or J3-adrenergic receptors (Moore and Dominic, 1971) and
there are no reports that it blocks D receptors. For example, it does not block
the central effects of apomorphine (Weissman et at., 1966; Von Voigtlander
and Moore, 1973b). Enna et at., (1973) reported that aMT blocks amphetamine-induced release of catecholamines from brain slices, but it has not been
possible to duplicate this observation in vivo (Chiueh and Moore, 1974c).
Small amounts of aMT metabolites (p-hydroxyamphetamine and p-hydroxynorephedrine) have been identified in brain shortly after the systemic
administration of aMT (Doteuchi et at., 1974), but the possible role that these
metabolites play in the pharmacological properties of aMT has not been
evaluated. The generally accepted viewpoint is that the aMT-induced
blockade of the central effects of amphetamine is related to the disruption of
catecholamine synthesis. This, in turn, suggests that amphetamine acts by
preferentially releasing newly synthesized catecholamines. There is some
precedent for this in peripheral sympathetic neurons; during times of
increased neuronal activity or in response to drugs such as amphetamine,
newly synthesized rather than stored NE is preferentially released from
nerve terminals (Kopin et at., 1968). Similar evidence has now been obtained
in the CNS with regard to amphetamine-induced release of D (see Section
6.1.5.; Besson et at., 1969b; Glowinski, 1973; and Chiueh and Moore, 1975a).
Since a-MT blocks the synthesis of both NE and D, it is not possible to
relate the antiamphetamine properties of this drug to a disruption of
synthesis of either one or the other of these two catecholamines in the brain.
If the antiamphetamine effects of aMT result from inhibition of NE
synthesis, then inhibition of DJ3H should duplicate the actions of aMT. On
the other hand, if DJ3H inhibitors do not block the stimulant actions of
amphetamine, then the aMT effect may result from inhibition of D
synthesis. Results of most experiments support the latter contention.
Disulfiram and its metabolic product, diethyldithiocarbamate, two of the
earliest reported in vivo inhibitors of DJ3H, reduced the concentration of D
but not of NE and blocked the conversion of radioactive D to NE in the brain
(Goldstein et at., 1964; Musacchio et at., 1966). The results of early
behavioral studies revealed that these compounds blocked the locomotor
stimulation (Maj et at., 1968) but not the stereotypies (Randrup and ScheelKruger, 1966) produced by amphetamine. Despite the fact that these two
compounds influence a number of biological systems (e.g., they chelate trace
metals and disrupt energy metabolism; Van der Schoot and Creveling, 1965)
it was proposed that the decrease in amphetamine-stimulated motor activity
was related to an inhibition of NE synthesis. Nevertheless, the behavioral
depressant and NE-depleting actions of these two compounds do not appear
52
KENNETH E. MOORE
to be causally related. When disulfiram was injected intraperitoneally (Lp.) it

caused a marked increase in the plasma concentration of corticosterone and
glucose (Thornburg and Moore, 1971), indicating that the injection of this
insoluble drug was stressful to the animals. When this effect was prevented
by administering the compound orally the drug no longer reduced motor
activity even though it still produced the characteristic reduction of NE and
the increase of D concentrations in the brain (Moore, 1969). These results
suggested that the behavioral depression resulted from stressful peritoneal
irritation.
Subsequently, more potent DJ3H inhibitors were developed: FLA 63
[bis(4-methyl-l-homopiperazinyl-thiocarbonyl disulfide] (Corrodi et ai.,
197fu) and U-14,624 [1-phenyl-3(2-thiazolyl)-2-thiourea] (Johnson et ai.,
1969). When injected i.p. both of these compounds reduced the brain
content of NE without altering or slightly increasing the content of D, and
both reduced spontaneous locomotor activity (Svensson and Waldeck, 1969;
Von Voigtlander and Moore, 1970). When these insoluble compounds were
administered Lp. as a suspension they caused peritoneal irritation and
increased the plasma concentration of corticosterone and glucose (Corrodi et
ai., 197fu; Thornburg and Moore, 1971). This was avoided by administering
FLA-63 intravenously (Corrodi ef ai., 1970b) or by administering FLA-63 and
U-14,624 orally or mixed with the diet (Von Voigtlander and Moore, 1970;
Thornburg and Moore, 1973b). When administered in these manners the
characteristic neurochemical effects of DJ3H inhibitors were obtained, but
there was no reduction in spontaneous motor activity and there was no
blockade of the locomotor stimulation produced by amphetamine (see Fig. 3
and Corrodi et ai., 197<YJ; Von Voigtlander and Moore, 1970; Moore and
Thornburg, 1973; Thornburg and Moore, 1973b). In agreement with these
results it is reported that aMT but not U-14,624 blocked the locomotor
stimulation (Hollister et ai., 1974) and facilitation of self-stimulation (Cooper
et ai., 1974) by d-amphetamine in reserpine-pretreated rats. Unexpectedly,
aMT but not U-14,624 is reported to block the locomotor stimulant actions
of methylphenidate in reserpine-pretreated rats (Breese et ai., 1975). This is
in contrast to reports of the effects of this drug in normal animals (ScheelKriiger, 1971; Thornburg and Moore, 1973b; Franklin and Herberg, 1974).
Perhaps methylphenidate can mobilize newly synthesized D after the catecholamine stores are depleted with reserpine.
Svensson (1970) reported that FLA-63 administered Lp. reduced spontaneous and amphetamine-stimulated motor activity in mice, and this reduction could be prevented by pretreatment with dihydroxyphenylserine
(DOPS), which is decarboxylated directly to NE in the brain. Experiments
with dihydroxyphenylserine are difficult to interpret because, although this
amino acid is converted to NE, the synthesized amine is not restricted to
noradrenergic neurons. Rather, because of the ubiquitous nature of aromatic-L-amino acid decarboxylase, this conversion can take place in blood
..,..
300
~
f
c
<3
200
300
53
:~
..
~
100
Day
QMT
Mphet.
200
00000
4 5 6 7 8 9
0 + + 0 0 0
0 0 + 0 0 +
100
00
DO
Day
4 5 6 7 8 9
U-I4,624 0 + + 0 0 0
Amphet. 0 0 + 0 0 +
FIG. 3. Effects of diets containing d-amphetamine (0.02%) and (a) aMT (0.4%) or (b) U14,624 (0.4%) on locomotor activity of mice. Groups of four mice were accommodated to
activity cages for four days before they were presented diets in the sequence described at the
bottom of the figure. Diets were presented during the dark period (1700-0800 hr) and
motor activity recorded between 2200 and 0800 hr. Bars represent the means of duplicate
experiments and represent the percentage of mean control activity on days 3 and 4. From
Thornburg and Moore (1973b).
vessels, or in 5-HT and D neurons in the brain. In the latter instances, the
NE may act as a false transmitter. In these experiments, the effects of
amphetamine on the level of locomotor activity of mice pretreated with FLA63 were less than those seen in nonpretreated controls. The activity of
animals receiving FLA-63 alone, however, was also much lower than the
saline controls so that when the activities of saline-pretreated and FLA-63pretreated mice were subtracted from the respective values following the
administration of amphetamine, there was no difference in the response to
amphetamine. The results suggest therefore that in contrast to the author's
conclusion NE systems do not play a mctior role in the stimulation of
locomotor activity produced by amphetamine.
As noted previously (Section 4.2.1), a-noradrenergic blocking drugs
abolished amphetamine-facilitated electrical self-stimulation (Ritter and Stein,
1973; Wise et al., 1973), suggesting an interaction of amphetamine with NE
neurons. The same conclusion was reached by these investigators as a result
of experiments employing D~H inhibitors (Wise and Stein, 1970). They
reported that disulfiram and diethyldithiocarbamate block self-stimulation
and abolish the rate-enhancing effect of amphetamine, and both effects are
restored by intraventricular injections of l-NE, but not of d-NE or D. These
D~H inhibitors can cause CNS depression independent of blocking NE
synthesis (Moore, 1969), and Roll (1970) has suggested that this might be the
case with the self-stimulation experiments. By arousing the animals from the
disulfiram-induced central depression, she was able to restore self-stimulation. Lippa et al. (1973) were unable to depress self-stimulation with FLA-63,
and Cooper et al. (1974) reported that aMT but not V-14,624 blocked the
54
KENNETH E. MOORE
facilitatory effect of amphetamines on lateral hypothalamic self-stimulation in

rats pretreated with reserpine or 6-hydroxydopamine (6-0HD) (see also
Section 4.2.4). Nevertheless, the fact that amphetamine can facilitate selfstimulation of brain regions containing only NE neurons and that this effect
is not blocked by D antagonists (Ritter and Stein, 1973) is convincing
evidence that amphetamine exerts some central stimulant effects by interacting with noradrenergic neurons. It should be noted, however, that amphetamine also facilitates self-stimulation of brain regions containing D neurons
(Crow, 1972; Phillips and Fibiger, 1973) although potential problems with
these experiments have been discussed by Stein et ai. (1974).
aMT blocks the normal pattern of the self-administration of amphetamine or methamphetamine, suggesting a catecholaminergic mechanism in
the primary reinforcing action of these drugs (Pickens and Harris, 1968;
Davis and Smith, 1972). Large doses of D,8H inhibitors (diethyldithiocarbamate and V-14,624) also disrupted the reacquisition of self-administration of
amphetamine and prevented the development of a secondary conditioned
reinforcer based on the primary reinforcement of amphetamine (Davis et ai.,
1975). The authors suggested that noradrenergic mechanisms are involved
with mediating the reinforcement by amphetamine. The conclusions of these
experiments, however, should be tempered by the fact that the very high
doses of D,8H inhibitors used blocked not only the self-administration of damphetamine but also of morphine. This suggests that the blockade may not
be due exclusively to the inhibition of NE synthesis.
In summary, the results of behavioral studies with drugs that disrupt
catecholamine synthesis suggest that the central stimulant effects of amphetamine are generally more dependent upon ongoing synthesis of D than of
NE. Similar conclusions about the relative importance of noradrenergic and
dopaminergic neuronal systems in the central actions of amphetamine have
been made on the basis of experiments in which these systems were
selectively destroyed by 6-0HD.
4.2.4. Drugs Which Destroy Catecholaminergic Neurons

6-Hydroxydopamine (6-0HD) has become an extremely useful tool for
determining the functional significance of catecholaminergic neuronal systems in the brain since it is specifically taken up by and ultimately destroys
catecholaminergic nerves (see reviews by Jonsson et ai., 1975; Kostrzewa and
Jacobowitz, 1974). 6-0HD does not penetrate the blood brain barrier so that
when it is used to destroy catecholaminergic nerves in the CNS it must be
administered by intracisternal or intraventricular injections, or by injection
directly into circumscribed brain regions. The drug destroys both D and NE
neurons, with the latter neurons generally being more sensitive.
Results of early studies on the behavioral effects of 6-0HD administration were disappointing in that the behavioral depressant and catecholaminedepleting effects were not temporally related; with time the animals re-
55
covered from the behavioral depression but the catecholamine content

remained reduced. It became evident, however, that reversible behavioral
depression resulted from incomplete destruction of catecholaminergic
nerves; the increased turnover of amines in the remaining nerves in
co~unction with the development of supersensitive postsynaptic catechol aminergic receptors permitted a restoration of normal transmission (Zigmond
and Stricker, 1975). By giving multiple injections of 6-0HD or by pretreating
animals with MAO inhibitors so as to prevent the enzymatic destruction of 6OHD, it is possible to reduce the brain concentrations of catecholamines by
more than 90%. Methods were also developed to preferentially deplete the
brain of either NE or D. NE was selectively depleted by administering
multiple intracisternal or intraventricular injections of small amounts of 6OHD, and D was selectively depleted by pretreating animals with desipramine, which blocks the uptake of 6-0HD into NE but not into D neurons,
prior to the administration of 6-0HD (Breese and Traylor, 1971).
Results of early studies indicated that 6-0HD pretreatment did not
reduce amphetamine-stimulated locomotor activity or stereotypies, and in
some instances the central stimulant actions of amphetamine were increased
(Evetts et ai., 1970). These negative results probably reflected the destruction
of noradrenergic but not dopaminergic neurons because in subsequent
studies in which brain contents of D or both NE and D were reduced the
central actions of amphetamine were blocked. For example, the locomotor
stimulation and stereotypies caused by amphetamine were reduced in
animals that received an MAO inhibitor prior to an intraventricular injection
of 6-0HD (Fibiger et al., 1973), and Creese and Iversen (1973) reported a
similar blockade of amphetamine actions in rats which were treated shortly
after birth with 6-0HD. Hollister et al. (1974) noted that treatments with 6OHD that produced only moderate reductions of brain NE and D did not
alter amphetamine-stimulated motor activity, but treatments with 6-0HD
and a MAO inhibitor, which drastically reduced the brain concentration of
both NE and D, blocked the locomotor stimulant action of amphetamine.
Furthermore, these investigators noted that selective depletion of D markedly
reduced the central actions of amphetamine. Cooper et al., (1974) demonstrated that the ability of amphetamine to facilitate electrical self-stimulation
in the lateral hypothalamus was not altered in animals with selective
destruction of NE neurons, whereas it was drastically reduced in animals with
selective loss of D neurons. The reduction of amphetamine-induced effects is
not related to a general depression of activity because the locomotor
stimulant actions of L-dopa and apomorphine are enhanced in 6-0HDtreated animals. This is a general finding in animals with selective chronic
loss of D neurons. That is, the central actions of indirect-acting psychomotor
stimulants such as amphetamine are reduced, whereas the actions of drugs
that can directly stimulate postsynaptic D receptors, such as apomorphine,
are enhanced. The latter effect is presumably due to the development of
supersensitive postsynaptic dopaminergic receptors and is most readily
56
KENNETH E. MOORE
quantified in rats or mice in which the ascending nigrostriatal pathway is

destroyed unilaterally. In such lesioned animals amphetamine and other
indirect-acting dopaminergic agonists cause circling toward the side of the
lesion, presumably because D can be released only from neurons on the
intact side. On the other hand, apomorphine and other direct-acting agonists
cause the animals to reverse their direction of circling so that they rotate
away from the lesioned side (Ungerstedt, 1971; Von Voigtlander and Moore,
1973b). The slow onset of the development of the latter effect suggests the
development of supersensitive D receptors, which cause a relatively greater
stimulation by direct-acting D agonists on the denervated side (Ungerstedt,
1971; Thornburg and Moore, 1975).
Peterson and Sparber (1974) reported that pretreatment with 6-0HD,
which reduced brain contents of NE but not of D, reduced the ability of ibut not of d-amphetamine to suppress responding by rats on a fIXed-ratio
schedule. They concluded that operant behavioral actions of i-amphetamine
but not of d-amphetamine may be dependent upon noradrenergic neuronal
systems. Additional comments on studies with d- and i-amphetamine are
made in Section 7.
6-0HD has been employed to selectively lesion catecholaminergic neurons in circumscribed regions of the brain. For example, Creese and Iversen
(1975) reported that injections of 6-0HD into the ventral portion of the
midbrain, which selectively destroyed the cell bodies of ascending D neurons,
blocked the central stimulant effects of amphetamine, whereas selective
destruction of ascending NE neurons did not. Thus, consistent with the
results of studies with inhibitors of catecholamine synthesis, the effects of
amphetamine on locomotor activity, self-stimulation rates, and stereotypies
appear to be causally related to the disruption of dopaminergic rather than
of noradrenergic transmission processes. Furthermore, the different behavioral effects of amphetamine appear to result from actions on D transmission
ip different brain regions. Stereotypies appear to be dependent upon the
actions of amphetamine at the terminals of the nigrostriatal dopaminergic
neurons ..Price and Fibiger (1974) demonstrated that bilateral injections of 6OHD into the substantia nigra, which drastically lowered the concentration
of D in the striatum, abolished the amphetamine-induced but enhanced the
apomorphine-induced stereotypies. On the other hand, the locomotor stimulant actions of amphetamine appear to be related to an action of the drug at
the terminals of mesolimbic dopaminergic neurons. Bilateral microinjections
of 6-0HD into the striatum deplete the D concentration in this region and
selectively block the stereotypies induced by high doses of amphetamine,
whereas similar i~ections of 6-0HD into the nucleus accumbens deplete D in
terminals of mesolimbic D neurons and block only the locomotor stimulation
produced by low doses of amphetamine (Kelly et ai., 1975; see Fig. 4).
Associated with the selective diminution of amphetamine actions was the
enhancement of the effects of apomorphine. That is, 6-0HD lesions in the
40
80
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160
200
240
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FIG. 4. Effects of d-ampnetamine on locomotor activity (left) (1.5 mg/kg 14 days post-op) and stereotypy (right) (5.0 mg/kg) in rats with selective
6-hydroxydopamine-induced lesions in the nucleus accumbens or striatum. From Kelley et at. (1975).
Z
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58
KENNETH E. MOORE
striatum enhanced the stereotypies and lesions in the nucleus accumbens

enhanced the locomotor-stimulating effect of apomorphine.
5. BEHAVIORAL EFFECTS IN ANIMALS PRETREATED

WITH DRUGS THAT MODIFY
NONCATECHOLAMINERGIC TRANSMISSION
PROCESSES
The results of experiments described in the foregoing sections suggest
that amphetamine and related psychomotor stimulants act by facilitating the
release of catecholamines, primarily D, from neurons that may function as
part of a general arousal system in the brain. There is also evidence to
suggest that 5-hydroxytryptaminergic and acetylcholinergic neuronal systems
exert an inhibitory action over this arousal system (Brodie et at., 1959;
Carlton, 1968; Stein, 1968; Wise et at., 1973). If correct, one might expect
that elimination or blockade of acetylcholinergic or 5-hydroxytryptaminergic
systems should enhance the actions of psychomotor stimulants, whereas
enhancement of acetylcholinergic or 5-hydroxytryptaminergic systems should
reduce the actions of these same drugs. The results of some behavioral
studies are consistent with this proposal.
5.1. 5-Hydroxytryptaminergic Transmission

Almost all 5-HT neuronal input into the forebrain oTIgInates from
neurons having cell bodies in the midbrain raphe nuclei (Fuxe and Jonsson,
1974). The functional activity of this system can be disrupted by lesioning the
raphe nuclei or the ascending 5-HT axons in the medial forebrain bundle, by
intracerebral injection of 5,6- or 5,7-dihydroxytryptamine, or by administering p-chlorophenylalanine (PCPA), which inhibits the synthesis of 5-HT (Koe
and Weissman, 1966). Animals in which these procedures have been
employed exhibit an enhanced response to amphetamine.
The locomotor stimulant actions of amphetamine were significantly
increased in animals with lesions of the midbrain raphe (Neill et at., 1972),
and lesions in the medial forebrain bundle that reduced telencephalic 5-HT
increased the response to the rate-increasing effects of amphetamine on lever
pressing under a variable-interval-60-sec schedule of reinforcement (Green
and Harvey, 1974). Pharmacological disruption of 5-HT neuronal systems
also enhanced the central stimulant actions of amphetamine. Administration
of pCPA increased the locomotor stimulation produced by amphetamine and
methylphenidate, but did not alter the stereotypic effects of amphetamine
(Breese et at., 1974, 1975). The pCPA-induced increase in the actions of
59
amphetamine and methylphenidate could be reversed by administering 5hydroxytryptophan (Mabry and Campbell, 1973; Breese et at., 1975). The
reduction of brain concentrations of 5-HT by intracisternal injections of 5,6or 5,7-dihydroxytryptamine also enhanced the locomotor stimulation induced by amphetamine and methylphenidate (Breese et at., 1974, 1975).
There are problems in relating the results of behavioral studies in animals
that have been pretreated with pCPA and the dihydroxytryptamines exclusively, to a decrease in brain concentrations of 5-HT (e.g., Sanders-Bush et
at., 1974). Nevertheless, when the results of all the experiments described
above are considered, it is apparent that when 5-HT transmission is
disrupted, regardless of the method employed, the locomotor stimulant
effects of amphetamine are enhanced. It appears therefore that amphetamine exerts a primary effect on dopaminergic neuronal systems, but these
systems in turn are under inhibitory control of serotonergic neurons.
Reduction of transmission in the 5-HT system thereby permits amphetamine
to exert a greater effect on behavior.
5.2. Acetylcholinergic Transmission

The results of pharmacological studies suggest an antagonistic interaction between acetylcholinergic and dopaminergic neuronal systems in the
brain. Acetylcholine receptor antagonists enhance and cholinergic receptor
agonists depress the central stimulant actions of amphetamine-like drugs. In
rodents, atropine, scopolamine, and other antimuscarinic drugs act synergistically with amphetamine on stereotyped behaviors (Arnfred and Randrup,
1968; Naylor and Costall, 1971; Klawans et at., 1972) and conditioned
avoidance responding (Carlton, 1961; Carlton and Didamo, 1961). Atropine
also enhances amphetamine self-administration in rats (Davis and Smith,
1975b). On the other hand, cholinergic agonists such as oxytremorine,
physostigmine, or arecoline reduce stereotyped behaviors induced by amphetamine (Arnfred and Randrup, 1968; Costall et at., 1972; Klawans et at.,
1972) or methylphenidate Qanowsky et at., 1972); they also inhibit amphetamine-stimulated locomotor activity (Mennear, 1965).
A hypothetical scheme of interactions between cholinergic and dopaminergic neurons in the striatum is depicted in Fig. 5. Evidence suggests that D
has inhibitory actions on cholinergic neurons in the striatum (Bloom et at.,
1965; Trabucchi et at., 1975). Blockade of D receptors by neuroleptics
disinhibits the cholinergic nerves, causing an increase in their activity as
evidenced by the in vivo release of ACh (Stadler et at., 1973). The cataleptic
effects of neuroleptics in animals and the extrapyramidal effects in man are
believed to be due, in part, to increased cholinergic transmission. Cholinergic
blocking drugs neutralize some of the effects of dopaminergic blockade in
the basal ganglia (e.g., extrapyramidal effects of neuroleptics). Conversely,
dopaminergic agonists appear to decrease the activity of cholinergic neurons
60
KENNETH E. MOORE
SUBSTANTIA
NIGRA
STRIATUM
D~ACh
?
+f""L_
TO MOTOR
~ SYSTEMS
ACh
FIG. 5. Schematic diagram of possible dopaminergic-cholinergic interactions in the striatum.
(Trabucchi et al., 1975). Cholinergic blocking drugs therefore should enhance the functional actions of D agonists, such as amphetamine, by
inhibiting further the cholinergic transmission process. Cholinergic agonists,
on the other hand, should antagonize the inhibitory actions of D agonists on
cholinergic neurons. The results of behavioral experiments described above
and of biochemical experiments discussed in Section 6.3 are consistent with
the scheme depicted in Fig. 5. Other schemes of cholinergic-dopaminergic
neuronal interactions have also been proposed (Corrodi et al., 1972).
6. INTERACTIONS OF PSYCHOMOTOR STIMULANTS

WITH NEUROTRANSMITTERS IN BRAIN
6.1. Catecholamines
6.1.1. Steady State Concentrations
Single i~ections of large doses or repeated injections of smaller doses of
d- or l-amphetamine reduce the concentration of NE, but not of D or 5-HT,
in the brains of mice (Moore, 1963), rats (McLean and McCartney, 1961;
Moore and Lariviere, 1963), and cats (Vogt, 1954). These results have been
confirmed subsequently by many other investigators.
In rats the depletion of NE after a single large dose of d- but not lamphetamine persists for several days and appears to be related to the
replacement of NE stores by p-hydroxynorephedrine, a metabolite of d but
not of l-amphetamine (Brodie et al., 1970; Costa and Groppetti, 1970). The
accumulation of p-hydroxynorephedrine does not appear to play a major
role in the acute neuropharmacological actions of d-amphetamine because
the properties of the drug in species that do not form this metabolite are the
same as they are in the rat. Furthermore, the actions of amphetamine are not
altered when the formation of the metabolite is blocked (Groppetti and
Costa, 1969; Lewander, 1974). It has been suggested, however, that the
accumulation of p-hydroxynorephedrine plays a role in the development of
61
tolerance to some of the effects of d-amphetamine (Brodie et at., 1970; see

Section 8).
In animals pretreated with a MAO inhibitor, amphetamine did not alter
the concentrations of the amines but caused a dose-related increase in the rat
brain concentrations of normetanephrine (NM) and 3-methoxytyramine
(3MT), the o-methylated metabolites of NE and D, respectively (Carlsson et
at., 1966; Carlsson, 1970). In other experiments animals were pretreated
with reserpine to deplete catecholamines from storage granules. The extragranular stores were then repleted by administering an MAO inhibitor and
L-dopa. In these animals amphetamine reduced the brain contents of NE
and D and increased the contents of NM and 3MT, suggesting that
amphetamine released catecholamines from an extragranular source within
the neurons so that they could then be metabolized by extraneuronal
COMT. Scheel-Kruger (1971,1972) measured the concentrations ofNM and
3MT in brains of animals pretreated with an MAO inhibitor to characterize
the in vivo catecholamine-releasing abilities of a variety of psychomotor
stimulants. High doses of amphetamine, methamphetamine, phenmetrazine,
methylphenidate, amfonelic acid, and pipradrol increased the brain contents
of 3MT and NM without altering the contents of NE or D. Scheel-Kruger
concluded that the effects of the psychomotor stimulants were due to a
releasing action rather than to blockade of reuptake because benztropine and
tricyclic antidepressants, drugs with potent D and NE uptake-blocking
properties, respectively (Coyle and Snyder, 1969b; Koe, 1975), did not
increase NM or 3MT concentrations in the brain.
Large doses of amphetamine increase the brain concentrations of
homovanillic acid (HVA) in rats, mice, and cats (Lewander, 1974; Jori and
Bernardi, 1969, 1972). Lower doses of amphetamine reduce the brain
concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) without altering
the concentrations of HV A, prompting the suggestion that d-amphetamine
blocks the uptake or synthesis of D (Bunney et at., 1973; Gessa and
Tagliamonte, 1975).
Intraventricularly or intracisternally injected Clff]NE or [3H]D accumulates within catecholaminergic nerve terminals in the brain. Disposition and
metabolism of the accumulated amines can be altered by the administration
of various drugs. Large doses of amphetamine accelerate the rate of
disappearance of [~]NE; this effect is associated with an increase in the
concentration of [3H]NM and a decrease of [~]deaminated metabolites
(Glowinski and Axelrod, 1965; Strada et at., 1970). Lewander (1970)
reported that the administration of amphetamine or phenmetrazine to
animals pretreated with [3H]dopa caused an increased accumulation of
[~]3MT, but not [3H]NM, suggesting that both drugs released only D.
In summary, steady state concentrations of catecholamines and their
metabolites in the brain are altered by amphetamine and related psychomotor stimulants. Since these steady state concentrations are influenced by
62
KENNETH E. MOORE
synthetic, storage, release, metabolic, and reuptake processes, the effects of

these drugs must be considered on each of these factors separately.
6.1.2. Synthesis
The synthesis of catecholamines is believed to operate under control of a
feedback mechanism in which increased concentrations of the end-products
D and NE inhibit tyrosine hydroxylase, the initial and rate-limiting step in the
synthesis of catecholamines. For example, increased intraneuronal concentrations of D or NE after MAO inhibitor pretreatment reduces tyrosine
hydroxylase activity. When amphetamine is added to synaptosomes or slices
of brain regions containing catecholaminergic nerve terminals the catechol amines are released (Ferris et ai., 1972; Azzaro and Rutledge, 1973; Heikkila
et ai., 1975a,b) and tyrosine hydroxylase activity increases (Harris et ai., 1975;
Kuczenski, 1975). The latter effect presumably results because amphetamine
releases catecholamines and prevents their reuptake so that the concentration
of the amines at specific intraneuronal sites is reduced and the inhibitory
action on tyrosine hydroxylase is thereby removed. i-Amphetamine and
methylphenidate also increase tyrosine hydroxylase activity in striatal synaptosomes, although neither drug is as potent as d-amphetamine (Kuczenski
and Segal, 1975). These in vitro effects of amphetamine on catecholamine
synthesis are not in accord with the results of in vivo experiments.
When experiments are carried out completely in vivo, d-amphetamine
has been reported to increase the synthesis of D in substantia nigra but
decrease the synthesis in the striatum Uavoy et ai., 1970), to increase the
synthesis of D but not NE in whole brain (Costa et ai., 1972), and to inhibit
synthesis of both NE and D (Lewander, 1970). Differences in methodology
and doses of amphetamine may be responsible. More consistent, but
somewhat surprising in view of the in vitro studies, are the results of
experiments in which the animals are pretreated with amphetamine, and
brain tyrosine hydroxylase is subsequently measured in vitro.
Besson et al. (1969a,b) noted that when slices of brain tissue containing
D or NE nerve terminals prepared from animals pretreated with amphetamine were incubated with [3Ji]tyrosine, the amount of [3Ji]catecholamine
appearing in the media was increased. This suggested a catecholaminereleasing action of amphetamine. The amount of [3Ji]NE remaining in brain
stem slices was unaltered by d-amphetamine, whereas the amount of [3Ji]D
in striatal slices was reduced. It was proposed that the reduced tissue content
of [3H]D reflected an inability of synthesis to keep pace with release. The
same investigators subsequently demonstrated, however, that the administration of amphetamine reduced tyrosine hydroxylase activity in the striatum
(Besson et ai., 1971a). Fibiger and McGeer (1971) and Koda and Gibb (1973)
reported that chronic administration of large doses of methamphetamine
reduced tyrosine hydroxylase activity in D nerve terminals in the striatum,
but not in NE nerve terminals in the hypothalamus, and Kuczenski and Segal
63
(1975) reported that acute administration of d- and I-amphetamine, but not

methylphenidate, reduced tyrosine hydroxylase activity in striatal synaptosomes.
The inhibitory action of amphetamine on striatal tyrosine hydroxylase is
difficult to reconcile with the D-releasing action of this drug, which might be
expected to reduce the end product inhibition of tyrosine hydroxylase. The
addition of amphetamine in vitro has no inhibitory action on partially
purified tyrosine hydroxylase (Kuczenski, 1975; Carenzi et al., 1975) and
when administered to rats, amphetamine did not alter striatal tyrosine
hydroxylase when measured under cell-free conditions in the presence of an
excess of pteridine cofactor (Besson et al., 1973). Harris et al. (1975), in
attempting to elucidate the mechanism by which systemically administered
amphetamine inhibits tyrosine hydroxylase in striatal homogenates, found
that the effect was not due to the inhibition of tyrosine transport into nerve
or to an action of amphetamine metabolites (see also Kuczenski, 1975).
Furthermore, the inhibition of tyrosine hydroxylase was not related to
amphetamine-induced hyperthermia. They postulated that amphetamineinduced reduction of D neuronal activity (Bunney et al., 1973) might result
in the accumulation of D within the neuron, causing end product inhibition
of tyrosine hydroxylase. Chlorpromazine blocked the amphetamine-induced
decrease of nigrostriatal nerve activity and also blocked the inhibitory effects
of amphetamine on tyrosine hydroxylase activity. The latter effect may result
from the ability of the neuroleptic to block postsynaptic receptors and
thereby disrupt neuronal feedback inhibition of nigrostriatal activity, and/or
it might block the ability of D in the synaptic cleft to activate presynaptic
receptors (Kehr et al., 1972).
d-Amphetamine is also reported to inhibit Df3H activity measured in
vitro (Goldstein and Contrera, 1961) and in vivo (Stolk, 1975). At present
there appears to be no single mechanism by which all the actions of
amphetamine on catecholamine synthetic processes can be explained.
The true rate of synthesis of catecholamines may greatly exceed the
estimation of synthesis obtained from turnover studies (Sedvall et at., 1968)
because newly synthesized amines may be preferentially released and metabolized (Kopin et at., 1968; Besson et at., 1971b). The rate of turnover
generally applies to the total neuronal pool of catecholamine, whereas
synthesis may be occurring in only a single compartment in the nerve.
Nevertheless, as is the case with synthesis, the results of studies on the effects
of psychomotor stimulants on catecholamine turnover are somewhat confusing.
6.1.3. Rates of Turnover

Turnover rates of neurotransmitters provide a better index of the
functional state of neurons containing these transmitters than do steady state
concentrations, which in many instances represent a nonfunctional storage
64
KENNETH E. MOORE
pool (Kopin et al., 1969). There are shortcomings with all of the currently
employed methods for estimating catecholamine turnover rates in vivo
(Weiner, 1974), but these methods can provide an estimate of comparative
rates of turnover when two or more experimental situations are being
compared.
In early studies the disappearance rates of [3JI]NE or [3JI]D, which were
either injected intraventricularly or intracisternally or synthesized endogenously from systemically administered [3JI]tyrosine or [3JI]dopa, were either
increased, decreased, or not changed by administration of large doses of
amphetamines or phenmetrazine (Glowinski, 1970a; Lewander, 1970). The
rate of incorporation of [lX::]tyrosine into [lX::]NE was decreased by amphetamine and phenmetrazine (Lewander, 1970). In these studies the brains were
analyzed from 1 to 6 hr after fairly large doses of psychomotor stimulants
were administered. In more recent studies low doses of d-amphetamine
sulfate (0.3 mg/kg, i.v.), increased the turnover of D in the striatum, but not
of NE in the telencephalon (as determined by rates of conversion of
[3JI]tyrosine to [3JI]catecholamines), whereas larger i.v. doses of I-amphetamine and phenmetrazine failed to alter the turnover of either NE or D
(Costa et al., 1971, 1972). These authors suggested that phenmetrazine
stimulated motor activity by a mechanism that did not involve brain
catecholamines, but the results of numerous other studies implicate these
amines in actions of this drug. In more recent studies (Gerhards et al., 1974;
Carenzi et al., 1975) rats were injected with low doses of d-amphetamine
sulfate (0.5-1.2 mglkg, i.p.) 10 min prior to i.v. administration of [3JI]Ltyrosine and killed 10 min later. Turnover rates of NE and D were calculated
from the specific activities of tyrosine and D in striatum and nucleus
accumbens and the specific activities of tyrosine and NE in the hypothalamus. Amphetamine caused a dose-related increase of D turnover in both the
striatum and nucleus accumbens, but did not alter the turnover of NE.
Several groups of investigators have employed non-steady-state methods
for calculating catecholamine turnover rates. In an early study, the aMTinduced decline of brain concentrations of NE and D was accelerated by
large doses (15 mg/kg) but not by lower doses (1.5 mglkg) of d-amphetamine
(Corrodi et al., 1967). Subsequent investigators reported that d-amphetamine
reduced the rate of decline of D but increased the rate of decline of NE
when the stimulant was administered prior to aMT (Gerhards et at., 1974;
Papeschi, 1975). When the order of drug administration was reversed it was
noted that d-amphetamine increased the rate of decline of rat brain D but
the drug had no effect on the rate of decline of NE (Papeschi, 1975).
The discrepancy between the effects of d-amphetamine on turnover
rates of catecholamines obtained by steady state and non-steady-state methods remains to be resolved, but the results of the most recent experiments
with both methods (Carenzi et al., 1975; Papeschi, 1975) suggest that a dose
of amphetamine that stimulates motor activity increases the rate. of turnover
of brain D preferentially.
65
6.1.4. Release and Blockade of Uptake in Vitro

In order to determine the actions of drugs on transmitter dynamics, in
vitro experiments have the advantage over those carried out in vivo in that
they provide a closed system for biochemical analysis and permit large
numbers of experiments to be performed with relative ease. They also
permit a more accurate evaluation of the mechanisms by which drugs can
interact with transmission processes. Early studies on the effects of drugs on
the dynamics of putative neurotransmitters using brain slices have been
reviewed by Katz and Chase (1970). Numerous other in vitro studies on the
release and uptake of putative neurotransmitters have also been carried out
with synaptosomes. This section reviews in vitro experiments on the release
and/or reuptake of catecholamines by amphetamine and other psychomotor
stimulants.
Both d- and l-amphetamine block the uptake of [3Jf]catecholamines into
brain synaptosomes, but there has been some controversy regarding the
relative potencies of these isomers on specific uptake of NE or D (see
discussion in Section 7). Other psychomotor stimulants such as ephedrine,
deoxypipradrol, methylphenidate, and a number of amphetamine analogs
are aU reported to block uptake of [3Jf]D and [3Jf]NE into brain synaptosomes (Ferris et at., 1972; Horn and Snyder, 1972; Hendley et at., 1972); the
structural requirements for the uptake-blocking actions of these compounds
are discussed in these papers.
Most in vitro "release" studies have been carried out using brain slices,
although Ferris et al. (1972) measured the release of [3Jf]NE and [3Jf]D from
synaptosomes. After loading brain tissue preparations with [3Jf]NE or [3Jf]D,
d-amphetamine caused a similar release of [3Jf]NE into the incubation
medium from chopped slices, homogenates, and synaptosomes (Ziance et al.,
1972). These workers found that higher concentrations of d-amphetamine
were required to release [3Jf]D from brain slices than were required to
release [3Jf]NE. d-Amphetamine blocked the uptake of [3Jf]NE into
chopped brain slices and the concentrations required to block uptake were
slightly less than those needed to cause release (Azzaro et al., 1974) although
Heikkila et at., (l975b) found d-amphetamine was equipotent in blocking
uptake and the release of [3Jf]D from striatal slices. In these in vitro
experiments the amphetamine-induced increases in the medium concentrations of [3Jf]NE were considered to result from an active releasing action
rather than from the blockade of reuptake of spontaneously released amine
because (1) drugs such as cocaine and desipramine are as effective as
amphetamine in blocking [3Jf]NE uptake, but they cause little release of
[3Jf]NE (Azzaro et al., 1974; Heikkila et at., 1975b) and (2) the release of
[3Jf]NE from brain slices was increased by amphetamine even when neuronal uptake of NE was completely blocked by prior treatment with
desipramine or cocaine (Azzaro et al., 1974). Thus, although inhibition of
reuptake does not appear to be the primary mechanism by which the efflux
66
KENNETH E. MOORE
of [3JI]NE from brain slices is increased, inhibition of neuronal uptake of NE

by amphetamine may play a role in the increased synaptic concentration of
NE following release of this amine from the nerve terminal. After loading
brain slices with [3JI]NE or [3JI]D, Farnebo (1971) was able to release these
amines by electrical field stimulation. The addition of amphetamine to the
medium enhanced the catecholamine release induced by electrical field
stimulation, probably by blocking the reuptake of the amines released by
electrical stimulation. Heikkila et ai. (1975a) have suggested that the apparent
block of uptake by amphetamine in vitro is really due to the releasing action
of this drug. Raiteri et ai. (1975) employed a rapid superfusion technique in
an effort to minimize the influence of reuptake on amphetamine-induced
efflux of [3JI]catecholamines. After preloading synaptosomes from various
brain regions with [3JI]NE or [3JI]D, amphetamine was found to be less
effective in increasing the efflux of [3JI]catecholamines from NE-containing
regions of the brain (hypothalamus, cerebellum, pons-medulla) than from Dcontaining brain regions (striatum).
In the presence of blockers of NE uptake (desipramine and cocaine) the
dose-response curve for amphetamine-induced release of [3JI]NE from
cerebral cortex slices is shifted to the right (Azzaro et ai., 1974) and in the
presence of blockers of D uptake (cocaine and benztropine) the release of
[3JI]D from striatal slices was reduced (Heikkila et ai., 1975b). These results
prompted the investigators to propose that uptake blockers inhibit the
penetration of amphetamine into the neuron. Ross and Renyi (1966) failed
to find a diminution of [3JI]amphetamine uptake into slices of mouse brain
pretreated with cocaine or desipramine, but Azzaro et at. (1974) reported
that these drugs did inhibit the uptake of amphetamine into synaptosomes
prepared from the cerebral cortex.
These studies, in which the efflux of exogenously administered [3H]NE
is measured, suggest that amphetamine may enter the neuron and displace
stored [3JI]NE. The importance of release of exogenously administered
amines by amphetamine must be tempered by the fact that both in vivo and
in vitro behavioral and biochemical studies suggest that in the brain amphetamine preferentially releases catecholamines from a newly synthesized pool.
There are, however, relatively few in vitro studies in which catecholamines
have been labeled by the administration of radioactive tyrosine. Besson et at.
(l969b) and Glowinski (l97Ob) incubated slices of striatum with [3JI]tyrosine,
and then superfused the slices and analyzed the perfusates for [3JI]D. The
addition of low concentrations of d-amphetamine to the perfusing solution
increased the efflux of newly synthesized [3JI]D.
Neurogenic release of catecholamines is believed to occur by exocytosis,
a process in which storage vesicles fuse with the neuronal membranes prior
to extruding their contents from the nerve ending. Calcium ions appear to
be intimately involved in this process. Amphetamine may not release
catecholamines through an exocytotic mechanism because this release is not
blocked by reserpine pretreatment, which disrupts granular stores of NE
67
(Kalisker et at., 1975). Furthermore, amphetamine-induced release of

[~]NE is only partially dependent upon calcium ion, and reserpine pretreatment removes the calcium ion requirement (Ziance et at., 1972; Kalisker et
at., 1975). Thus, amphetamine appears to be equally capable of releasing
[~]NE from reserpine-sensitive (storage vesicles) and reserpine-insensitive
(extragranular sites) in the nerve terminal. Results of these studies again
should be tempered by the fact that the tissues were loaded with exogenously
administered and not endogenously synthesized catecholamines. That is, the
effects of calcium on amphetamine-induced release of newly synthesized
catecholamines have not been examined.
Without minimizing the important information derived from in vitro
studies, it is necessary to demonstrate that the effects observed in vitro are
not artifacts of the system. For example, the permeability characteristics and
structural integrity of neurons may be altered and the influence of neuronal
control of activity are removed in vitro. Accordingly, it is necessary to check
in vivo where possible the results of in vitro experiments. In the next section
the effects of amphetamine and other psychomotor stimulants on the in vivo
release of catecholamines are discussed.
6.1.5. Release in Vivo

Because of anatomical complexities and the inaccessibility of many
neuronal systems in the mammalian brain, special techniques have had to be
developed in order to demonstrate the release of putative transmitter
substances in vivo (see review by Myers, 1972). Three of these procedures-surface-cup superfusion, push-pull cannulation, and cerebral ventricular
perfusion-have been used to detect the release of putative transmitter
substances in response to the administration of psychomotor stimulants.
Acetylcholine (Ach) and other transmitter substances have been collected
in small cups placed on the surface of the cerebral or cerebellar cortex. This
technique is suitable for collecting neurotransmitters released from nerve
terminals near the exposed surfaces of the brain, but Besson et at. (1 971h)
have modified this procedure in order to perfuse deep structures. They have
been able to monitor the efflux of D by removing parts of the brain overlying
the caudate nucleus and then placing a collecting cup on the newly exposed
surface. The push-pull cannula permits the collection of substances from
circumscribed brain regions and it can be implanted deep into brain
structures (Myers, 1972). This technique has the advantage that small
circumscribed regions in the brain of conscious animals performing behavioral tasks can be perfused (e.g., Stein and Wise, 1969). One of the
disadvantages of this technique is that the tissues being perfused are
damaged by the placement of the cannula (Chase and Kopin, 1968). Some
investigators have overcome this objection by placing the cannula tip into the
cerebral ventricles and sampling CSF (Tilson and Sparber, 1972). The
cerebral ventricular perfusing technique has been used to study the efflux of
68
KENNETH E. MOORE
a variety of neurotransmitter substances such as ACh, 5-HT, D, NE, and

HVA. The advantage with this technique is that there is little damage to the
perfused region. The major disadvantage is that only brain structures
adjacent to the cerebral ventricular system can be examined because of the
slow diffusion of amines and their metabolites into and out of brain tissue.
All three techniques have been modified so that they can be employed
chronically in conscious animals (Myers, 1972), but each technique has
advantages and disadvantages.
One of the major difficulties in using the in vivo procedures is that very
small amounts of transmitter are released in response to drugs and electrical
stimuli. In early studies bioassay procedures were used to detect release of
endogenous neurotransmitters. Recent studies have employed sensitive radioenzymatic methods to detect these same transmitters. Most of the studies,
however, have employed the use of radioactive tracer techniques. Brain
stores of catecholamines have been labeled by administering the amine
directly into the brain, and following a period of washout the effects of drugs
on the effiux of these amines and their metabolites have been recorded.
a. Release oj Exogenously Administered Radioactive Catecholamines. A
number of investigators have demonstrated the abilities of amphetamine and
other psychomotor stimulants to increase the effiux from the brain of
radioactive catecholamines and their metabolites. In early experiments the
brain was labeled with intraventricular injections of [3fi]NE; in subsequent
studies [3fi]D was employed. In experiments reported by Stein and Wise
(1969), [3fi]NE was injected into the lateral ventricle of the rat and the
hypothalamus and amygdala were subsequently perfused by means of
implanted push-pull cannulae. Systemic administration of d-amphetamine
increased the effiux of radioactivity, consisting primarily of [3fi]NM, from
the amygdala but not from the hypothalamus.
In order to avoid objections to the use of the push-pull cannula (Vogt,
1969), Carr and Moore (1969, 1970a) employed a cerebroventricular perfusing technique in cats to detect the in vivo release of catecholamines. In these
experiments tissues lining the cerebroventricular system were labeled with an
intraventricular microinjection of [3fi]NE. After a period of washout, serial
samples of perfusate were collected and analyzed for [3fi]NE and its
metabolites. d-Amphetamine, added to the perfusing CSF or administered
systemically, caused an immediate increase in the effiux of [3fi]NE and a
delayed increase in the effiux of [3fi]NM. Following intraventricular injections of [3fi]D, d-amphetamine increased the effiux of both [3fi]NE and
[3fi]D. The same procedure was subsequently employed to demonstrate an
increased effiux of [3fi]NE and [3fi]NM following the addition of ephedrine,
p-chloroamphetamine, methylphenidate, and pipradrol to the perfusing CSF
(Carr and Moore, 197Ob; Moore et al., 1970).
Because amphetamine caused a greater release of [3fi]catecholamines
into the lateral than into the third ventricle it was suggested that most of the
[3H]catecholamines appearing in the brain perfusate originated from the
69
caudate nucleus (Carr and Moore, 1970a). Subsequent investigations confirmed this suggestion. A series of experiments were carried out in which
[3Jf]D was injected into the lateral ventricle of cats. After a period of
washout, amphetamine or tyramine was added to the perfusing CSF and the
perfusate was analyzed for [3Jf]D. In control cats both drugs increased the
efflux of [3Jf]D. When the experiments were repeated in cats with chronic
lesions of the nigrostriatal dopaminergic neurons, the spontaneous and druginduced efflux of [3Jf]D was markedly reduced, indicating that the [3Jf]D
released by these drugs originated primarily from D nerve terminals in the
caudate nucleus (Fig. 6). When similar lesions in the ascending nigrostriatal
pathway were made during the perfusion there was an immediate drop in
the efflux of [3Jf]D, indicating part of the [3H]D appearing in the perfusate
was the result of ongoing neuronal activity in the dopaminergic nigrostriatal
pathway. This acute lesion reduced the ability of amphetamine but not of
tyramine to increase the efflux of [3Jf]D (Fig. 7). It was concluded that the
12
12
10
10
.....~
......
i
......
UJ
Z
1 u-
..1..
-Lf.-L
f-L
0
0
II)
J:
0
4
mfDrrrn: m:fI1ru
CJ
AMPHETAMINE
TYRAMINE
6. Efflux of [3H]dopamine evoked by an intraventricular pulse of d-amphetamine (1.6 x

10-4 M) or tyramine (3.2 x 10-4 M) in cats in which unilateral electrolytic lesions in the
nigrostriatal pathway had been made 2-8 weeks prior to the experiment. The lateral
ventricle contralateral to (top) and ipsilateral to (bottom) the lesions were perfused. The
height of each bar represents the mean concentration of [3H]dopamine in consecutive 2-min
samples of perfusate. Modified from Von Voigtlander and Moore (l973a).
FIG.
70
KENNETH E. MOORE
12
12
E
......
uc
LU
~
~
<
a..
c
I
12
12
TYRAMINE
'"
Cl
TYRAMINE
FIG. 7. Efflux of [3H]dopamine evoked by ventricular infusions of d-amphetamine or
tyramine contralateral to (top) and ipsilateral to (bottom) an acute unilateral lesion of the
nigrostriatal pathway. See legend to Fig. 6 for additional details; modified from Von
Voigtlander and Moore (l973a).
efflux of [3J.I]D evoked from central dopaminergic neurons by tyramine is

not dependent upon ongoing nerve activity; this drug may release [3H]D by
entering the nerve and then displacing stored D; Lee et al. (1967) suggest this
occurs in peripheral NE neurons. On the other hand, the efflux of [3J.I]D
evoked by amphetamine is at least partially dependent upon ongoing
impulse activity of neurons in the nigrostriatal pathway. It was suggested that
amphetamine either facilitated neurogenic release of D or blocked the
reuptake of neurogenically released D. The facilitation of neurogenic release
of D is the most appealing mechanism because (1) results of in vitro
experiments with catecholamine uptake-blocking drugs suggest that these
compounds are not very effective in releasing catecholamines from slices
(Azzaro et al., 1974; Heikkila et al., 1975b), and (2) benztropine, a potent
inhibitor of D uptake in vitro, is not as effective as d-amphetamine in
releasing D in vivo (Cheramy et at., 1973; Goodale and Moore, 1975).
Nevertheless, both mechanisms are probably involved in the "releasing"
action of amphetamine.
Tilson and Sparber (1972) have overcome the objections to tissue
damage induced by the push-pull cannula, by implanting the cannula into
71
the rat brain so that the tip is in the lateral cerebral ventricle. In this way they
have been able to detect the release of catecholamines while animals are
performing behavioral tasks. After injecting [3H]NE into the lateral cerebral
ventricle, rats were placed in a Skinner box and allowed to work on a fIxedratio schedule of reinforcement while their brains were being perfused.
Systemic administration of amphetamine caused a concomitant dose-dependent disruption of operant behavior and an increase in the efflux of [3H]NE.
b. Release of Endogenously Synthesized Catecholamines. Radioactive
catecholamines administered into the cerebral ventricles are not taken up by
and subsequently released from catecholaminergic nerve terminals exclusively. In order to pinpoint the site at which psychomotor stimulants act, it is
necessary to demonstrate the release of endogenous catecholamines. Until
recently, analytical techniques were not suffIciently sensitive to detect the
small amounts of these amines in perfusates collected from the brain (V ogt,
1969). McKenzie and Szerb (1968) employed the fluorometric ethylenediamine condensation method to analyze for D in perfusates collected from a
push-pull cannula implanted into the caudate nucleus of the cat brain. They
were unable to detect spontaneous efflux of this amine, but the addition of a
very high concentration of amphetamine (0.5 mg/ml) to the perfusing
solution did increase the amount of D appearing in the perfusate. More
recently, Lloyd and Bartholini (1975), employing a sensitive radioenzymatic
method to analyze for D, noted that a large dose of d-amphetamine (10 mg/
kg, i.v.) increased the concentration of this amine in perfusates collected
from a push-pull cannula in the caudate nucleus of the cat.
Monitoring the release of radioactive catecholamines synthesized from
tyrosine is an alternative to measuring the release of endogenous catechol amines. Radioactive catecholamines synthesized from radioactive tyrosine
must originate exclusively from catecholaminergic neurons because tyrosine
hydroxylase is located only in these neurons. Several technical diffIculties had
to be overcome before this procedure became suitable for measuring the
effects of psychomotor stimulants on in vivo release of catecholamines.
Riddell and Szerb (1971) attempted to detect endogenously synthesized
D in perfusates collected from push-pull cannulae implanted into the
caudate nucleus or the lateral ventricle of cats. With the addition of
e't;]tyrosine to the perfusing solution, the number of counts in the e't;]D
fraction of the perfusate was barely above background, although the addition
of amphetamine (0.5 mg/ml) to the perfusing solution did induce a temporary increase in the efflux of [~]D. The spontaneous efflux of [l't;]D was
increased if [l't;]dopa was added to the perfusing solution, but because of
the widespread distribution of aromatic L-amino acid decarboxylase this D
could not have originated exclusively from D nerve terminals. Chiueh and
Moore (1973) injected [l't;]tyrosine into a lateral ventricle before the
ventricular system was perfused. The addition of a pulse of d-amphetamine
to the perfusing CSF increased efflux of e't;]catechols. Because the number
72
KENNETH E. MOORE
of counts in the perfusate samples was so small it was not possible to analyze
each sample for p4C]catecholamines, but when samples were combined 40%
of the counts in the [~]catechol fraction were found to consist of P4C]D.
With the availability of [~]tyrosine of high specific activity it became
possible to detect [~]catecholamines synthesized during perfusion of the
brain with [~]tyrosine. Besson et al. (197Ib) were the first to overcome some
of the technical difficulties employing this radioactive precursor. By carefully
purifying [~]tyrosine just before use, in order to remove impurities of
[~]dopa, and by combining alumina adsorption and ion-exchange chromatographic techniques in order to detect small amounts of [~]catecholamines
in the presence of very large amounts of [~]tyrosine, they were able to
continuously monitor the efflux of [3fI]D from the superfused caudate
nucleus of the cat. Amphetamine, added to the perfusing solution or
administered systemically increased the efflux of endogenously synthesized
[~]D. Employing similar procedures this same group of researchers has
demonstrated that local infusions of amphetamine increased the efflux of
endogenously synthesized [~]D from the superfused monkey caudate
nucleus (Gauchy et al., 1974) and increased the efflux of [~]NE and [~]D
from a push-pull cannula implanted into the posterior hypothalamus of cats
(Philippu et al., 1974).
Chiueh and Moore (1974a,b) injected [~]tyrosine into the lateral
ventricle of the cat brain prior to the start of perfusion. The addition of a
pulse of amphetamine to the perfusing CSF increased the efflux of endogenously synthesized [~]D. In subsequent experiments the cerebral ventricles
were perfused with CSF containing [~]tyrosine for 2 hr prior to the start of
a continuous intraventricular infusion of amphetamine (Chiueh and Moore,
1975a). Amphetamine caused an immediate increase in the efflux of [3J-I]D,
which declined with time despite the continued presence of the drug in the
CSF. The addition of aMT to the CSF concurrently with amphetamine did
not alter the initial increased efflux of [~]D, but accelerated the decline in
the efflux of this amine. These results suggested that amphetamine initially
released D from a storage pool, but that continued release was dependent
upon ongoing amine synthesis.
The addition of amphetamine to [~]tyrosine-containing CSF at the
start of perfusion immediately increased the efflux of [~]D (Chiueh and
Moore, 1975a; see Fig. SB). This effect was completely blocked if aMT was
added to the CSF. Pretreatment of cats with reserpine depleted the caudate
nucleus of endogenous and [~]D, but did not alter the ability of amphetamine to increase the efflux of the newly synthesized amine. These results
indicated therefore that amphetamine can release both stored and newly
synthesized [~]D, but that the maintenance of amphetamine-induced release of D is dependent primarily upon a. newly synthesized pool of the
amine. These results are consistent with behavioral studies that indicate that
pretreatment with aMT, but not with reserpine, blocks the central stimulant
actions of amphetamine. A similar approach was employed to examine the

40
20
73
32
ic(
II.
8I
:I:
1'1
PERFUSION TIME (min)
FIG. 8. Effects of (A) methylphenidate and (B) d-amphetamine on the effiux of endogenously synthesized [3Hldopamine from the brain of control and reserpine-pretreated cats.
CSF containing [3Hltyrosine (0) or [3Hltyrosine and drug (e) was infused into the lateral
cerebral ventricles of nonpretreated cats for 60 min, and 10 min samples of perfusate were
analyzed for [3Hldopamine. CSF containing eHltyrosine and drug was also infused into the
lateral cerebral ventricles of cats pretreated with reserpine (0.5 mg/kg, Lv.) 2 hr prior to the
start of perfusion (b). Modified from Chiueh and Moore (1975a,b).
ability of methylphenidate to increase the efflux of [3JI]D (Chiueh and

Moore, 1975b; Fig. SA). Like amphetamine, the addition of methylphenidate
to [3JI]tyrosine-containing CSF at the start of perfusion of the cerebroventricles of control cats caused an immediate increase in the efflux of [3JI]D.
Unlike the effects of amphetamine, however, the ability of methylphenidate
to increase the efflux of endogenously synthesized [3Jf]D was blocked in
reserpine-pretreated cats. These experiments provide direct biochemical
evidence in support of the hypothesis that the central stimulant actions of
amphetamine and methylphenidate result from their abilities to preferentially release D from newly synthesized and stored pools, respectively (see
discussion of behavioral studies, Sections 4.2.2 and 4.2.3).
6.1.6. Adenylate Cyclase

A dopamine-sensitive adenylate cyclase identified in homogenates of rat
striatum is believed to be involved with activation of postsynaptic dopami-
74
KENNETH E. MOORE
nergic receptors (Kebabian and Greengard, 1971). The activity of this

enzyme system is increased by D and direct-acting D agonists, but not by
indirect D agonists such as amphetamine (Iversen et ai., 1975). Furthermore,
the D-stimulated increase in adenylate cyclase is blocked by neuroleptics
(Clement-Cormier et ai., 1974; Miller and Hiley, 1975).
Early investigators failed to detect an increase in 3',5'-cyclic AMP
concentrations in gross brain regions of animals treated with d-amphetamine
(Schmidt et ai., 1972). Subsequent studies, however, revealed that systemic
administration of both direct- and indirect-acting dopaminergic agonists
(apomorphine and d-amphetamine) increase the cyclic AMP concentrations
of brain regions containing terminals of dopaminergic neurons (striatum and
nucleus accumbens) (Carenzi et ai., 1975). These results suggest that amphetamine increases the cyclic AMP concentration by releasing D onto the
postsynaptic receptor. The functional importance of the amphetaminestimulated increase in cyclic AMP in the postsynaptic neuron remains to be
elucidated.
6.2. 5-Hydroxytryptamine
As suggested in Section 5.1, excitatory catecholaminergic neuronal
systems activated by d-amphetamine may be inhibited by 5-HT neurons. One
might expect, therefore, that the 5-HT systems would be activated by the
administration of amphetamine-like drugs. Reports on the effects of amphetamine on the biochemical measures of 5-HT neurons in the CNS are
inconsistent. Endogenous brain concentrations of 5-HT have been reported
to be increased or decreased by acute administration of amphetamine; some
of these differences may be related to the magnitude of the dose of the drug
or the time after administration that the brains were analyzed (Lewander,
1974). In general, the acute administration of amphetamine, in contrast to pchloroamphetamine, has little effect on 5-HT concentrations in the brain.
Scheel-Kruger and Hasselager (1974) reported that even very large doses of
a number of amphetamine-like indirect-acting D agonists (amphetamine,
phenmetrazine, pipradrol, methylphenidate, amfonelic acid) failed to increase the brain content of 5-HT but did increase the 5-hydroxyindole acetic
acid (5-HIAA) concentration. Lewander (1974) reported that amphetamine
increases the concentrations of tryptophan and 5-HIAA but not 5-HT, while
phenmetrazine had no effect on brain contents of either 5-HT or 5-HIAA.
Apomorphine, a direct-acting D agonist, also elevates the brain concentration
of 5-HIAA. Since amphetamine does not interfere with the rate of elimination of 5-HIAA from brain (Reid, 1970), these results suggest an increased
turnover of 5-HT. Hyperthermia increases brain concentrations of tryptophan, and increases the rate of synthesis and turnover of 5-HT (Tagliamonte
et ai., 1971; Weiss and Aghajanian, 1971). The increased 5-HIAA concentration caused by psychomotor stimulants may result therefore from the ability
AMPHETAMINES; BIOCHEMICAL AND BEHAVIORAL ACTIONS IN ANIMALS
75
of these drugs to increase body temperature (Reid, 1970). Scheel-Kriiger and

Hasselager (1974), however, did not find a simple correlation between the
increase in brain 5-HIAA and the hyperthermia produced by psychomotor
stimulants.
Although the results of in vivo biochemical and behavioral experiments
(see Section 5.1) suggest some interaction of psychomotor stimulants with 5HT neuronal systems, there is little evidence from in vitro experiments to
suggest that these drugs have important direct actions at 5-HT nerve
terminals. Amphetamine causes only weak inhibition of 5-HT uptake into
synaptosomes (Ross and Renyi, 1969; Wong et at., 1973) although at high
concentrations (10-5 M) it increases the release of 5-HT from chopped brain
slices (Azzaro and Rutledge, 1973) and superfused synaptosomes or slices
(Raiteri et at., 1975; Glowinski, 1970b). When tested in vivo, however,
amphetamine has only very weak 5-HT releasing properties (Glowinski,
1970a,b; Sparber and Tilson, 1972; Chiueh and Moore, 1976).
In general, therefore, doses or concentrations of psychomotor stimulants
that have definite behavioral effects do not appear to have pronounced
effects on the biochemical dynamics of 5-HT neurons in the brain, although
some halogenated analogs of amphetamine do have marked actions on 5-HT
neurons. Foote et at. (1969) reported that reasonably low doses of amphetamine (0.1-1 mglkg, i.v.) increased the firing rate of midbrain raphe neurons.
It is not known, however, if this effect is the result of a direct action of
amphetamine releasing catecholamines from neurons synapsing with the
raphe cells, or if the increased firing is a response to the central stimulant or
some other action of the drug.
6.3. Acetylcholine
Behavioral studies suggest an action of psychomotor stimulants on
cholinergic neurons in the striatum and possibly elsewhere within the brain.
Cholinergic agonists depress and cholinergic antagonists enhance some of
the central actions of the psychomotor stimulants (see Section 5.2). Dopaminergic neurons are believed to inhibit the activity of cholinergic nerves in the
striatum. By releasing D, amphetamine and similar drugs should reduce
cholinergic nerve activity. Large doses of amphetamine (5-10 mglkg) and of
direct-acting D agonists (apomorphine) increase the concentration of ACh in
the rat striatum (Consolo et at., 1974; Sethy and Van Woert, 1974; Ladinsky
et at., 1975). These authors suggest that this effect results from an inhibition
of ACh release. Lower doses of amphetamine were found to have no effect
on ACh or choline concentrations in the rat striatum or cerebral cortex
(Carenzi et at., 1975). However, consistent with the suggestion that dopamine
inhibits cholinergic activity, amphetamine reduced ACh turnover in the
striatum but not in the cerebral cortex (Trabucchi et at., 1975). On the other
hand, Pepeu and Bartholini (1968) reported that systemic administration but
76
KENNETH E. MOORE
not direct application of amphetamine increased the efflux of ACh from the
cat cerebral cortex, while Jones et ai. (1973) found no alteration in ACh
release during superfusion of the ventricular surface of the caudate nucleus
of cats treated with amphetamine.
7. COMPARISONS OF BIOCHEMICAL AND BEHAVIORAL

EFFECTS OF d- AND l-AMPHETAMINE
Coyle and Snyder (1969a) reported d-amphetamine to be 10 times more

potent than i-amphetamine in blocking catecholamine uptake into crude
synaptosomes of the cerebral cortex, a predominantly NE-containing brain
region, but the isomers of amphetamine were equipotent in inhibiting D
uptake into synaptosomes of the striatum, a D-containing region. Taylor and
Snyder (1971) subsequently reported a similar selectivity when the accumulation by brain regions of intraventricularly administered [3J-I]NE or [3J-I]D was
determined. Systemic administration of a rather large dose (10 mg/kg) of dbut not of i-amphetamine blocked the accumulation of [3J-I]catecholamines
into NE-containing regions (e.g., hypothalamus), whereas both d- and iamphetamine inhibited the accumulation of [3J-I]catecholamines in the striatum. It was suggested that the greater stereoselectivity of noradrenergic than
of dopamergic neurons in the brain afforded a way of evaluating if d- or iamphetamine exert behavioral actions by interacting with either NE or D
neuronal systems. That is, behaviors mediated by NE should be affected
more by d- than by i-amphetamine, while the isomers should have similar
effects on behaviors mediated by D. On the basis of lO: 1 and 2: 1 potency
ratios of d- and l-amphetamine on locomotor activity and stereotyped
gnawing in rats, Taylor and Snyder (1971) related these behaviors to
interactions with NE and D neuronal systems, respectively. The proposed
mechanism of amphetamine-induced stereotypy, but not of locomotor activity, is consistent with that reached by other experimenters employing
receptor-blocking drugs, inhibitors of catecholamine synthesis, or 6-0HD
(see Section 4.2).
Some investigators have postulated therapeutic approaches to clinical
problems on the basis of the relative effects of d- and i-amphetamine on NE
and D neurons. Arnold et ai. (1973) postulated that different subgroups of
hyperkinetic children might benefit from either d- or i-amphetamine because
of their different actions on catecholaminergic neurons. Other investigators
have postulated mechanisms for their studies on the basis of differential
effects of d- and i-amphetamine. Because there was little difference in the
abilities of d- and i-amphetamine to evoke toxic psychosis, Angrist et ai.
(1971) suggested that the effect was related to an action of the drugs at D
synapses. On the other hand, Stein et ai. (1974) evoked the difference in the
relative effects of d- and i-amphetamine in self-stimulation experiments to
AMPHETAMINES; BIOCHEMICAL AND BEHAVIORAL ACTIONS IN ANIMALS
77
support their contention that the facilitory effects of these drugs result from
interactions with NE neurons. Consistent with this idea are reports that damphetamine is more effective than i-amphetamine at increasing selfstimulation from electrodes aimed at NE neurons in the medial forebrain
bundle or the dorsal ascending NE bundle, while the two isomers are
equipotent in animals with electrodes aimed at D neurons in substantia nigra
or nucleus accumbens (Phillips and Fibiger, 1973; Phillips et ai., 1975).
There are problems in ascribing the psychopharmacological effects of dand i-amphetamine to specific effects on NE or D neurons based on their
relative abilities to selectively inhibit catecholamine uptake. First, the relative
effective doses of these two isomers to produce behavioral effects generally
fall somewhere between the 2: 1 and 10: 1 ratios reported by Taylor and
Snyder (1971). A summary ofreported values listed in Table 2 indicates that,
TABLE 2
A Comparison of Some Behaviural ActitmS of d- and I-Amphetamine
Effect
Species
Approximate
potencya
Source
Locomotor activity
Cat
4*
4*
4
4-8
6*
10*
4*
10
5
10
Fairchild and Alles (1967)

Thornburg and Moore (1972)
Maj et at. (1972)
Stromberg and Svensson (1975)
Rech and Stolk (1970)
Taylor and Snyder (1971)
Maj et al. (1972)
Scheel-Kriiger (1972)
Segal (1975)
North et al. (1974)
Mouse
4-8
Maj et al. (1972)
Rat
2*
4
4-6
4
2-3
2-4
2.5-3*
6*
4
Mouse
Rat
Stereotyped behaviors
(a variety of rating
techniques)
Cat
Self-administration
Operant behavior
enhancement of FI
suppression of FR
Rat
Dog
Monkey
Rat
Rat
4*
4*
Taylor and Snyder (1971)

Maj et al. (1972)
Scheel-Kriiger (1972)
Ellinwood and Balster (1974)
Wallach and Gershon (1972)
North et al. (1974)
Yokel and Pickens (1973)
Risner (1975)
Balster and Schuster (1973)
Tilson and Sparber (1973)
Peterson and Sparber (1974)
In studies indicated by an asterisk (*), potencies were calculated from parallel dose-response curves by
dividing ED50 I-amphetamine by ED50 d-amphetamine. In the remaining studies where complete doseresponse curves were not generated, or they were not parallel, potency ratios were estimated.
78
KENNETH E. MOORE
in general, potency ratios of doses of i-amphetamine: d-amphetamine that

stimulate locomotor activity are less than the value reported by Taylor and
Snyder (1971). On the other hand, the ratios of doses that cause stereotypies
are greater than the value reported by these investigators.
A second problem associated with the proposal is that the relative
abilities of d- and i-amphetamine to block the uptake of catecholamines into
specific NE or D neurons reported by Coyle and Snyder (1969a) have not
been confirmed by other investigators. In fact, just the opposite results have
been reported. Both isomers of amphetamine were found to be equipotent
in inhibiting NE uptake into synaptosomes or slices of NE containing brain
regions, but d-amphetamine was 3-5 times more potent in inhibiting D
uptake into tissue preparations from D-containing regions (Ferris et ai., 1972;
Thornburg and Moore, 1973a; Harris and Baldessarini, 1973; Heikkila et ai.,
1975b). Differences in procedures may account for some of the discrepancies
in these results (some studies were performed in reserpine-pretreated rats),
but an electrophysiological study described below is consistent with the more
recently reported biochemical experiments.
The activities of D and NE neurons are reduced or increased when
postsynaptic D or NE receptors are activated or blocked (Corrodi et ai., 1967;
Bunney et at., 1973). Amphetamine, by releasing D or NE to activate
postsynaptic receptors, appears to depress firing of D or NE neurons by a
neuronal feedback mechanism. Bunney et al. (1975; Fig. 9) recorded unit
activity of NE neurons in locus coeruleus and of D neurons in substantia
nigra during systemic administration of d- or i-amphetamine. Both isomers
were equally effective in depressing the activity of NE neurons. d-Amphetamine was a potent inhibitor of D neuronal activity while i-amphetamine was
either without effect or only ! to ~ as potent as d-amphetamine. These
results, as well as those of other behavioral tests (Peterson and Sparber,
1974), suggest that low doses of i-amphetamine have a preferential action on
NE neurons.
Finally, the catecholamine-uptake-inhibiting abilities of psychomotor
stimulants may have little to do with the behavioral effects of these drugs.
Benztropine is a potent inhibitor of D uptake (Coyle and Snyder, 1969b) and
tricyclic antidepressants are potent inhibitors of NE uptake (Koe, 1975), but
unlike amphetamine they do not produce characteristic locomotor stimulation or stereotypies. The catecholamine-releasing actions of amphetamines
may be more important to their psychopharmacological actions than are the
uptake-blocking actions (Scheel-Kruger, 1972).
Ferris et ai. (1972) reported that d-amphetamine was three times more
potent than i-amphetamine in releasing [3fI]catecholamines from synaptosomes prepared from the striatum, whereas the two isomers caused only
minimal release from synaptosomes prepared from NE-containing brain
areas (hypothalamus, cerebral cortex). Enna and Shore (1974) loaded slices
of brain and heart with [3fI]metaraminol, as a marker for NE, and found
that d-amphetamine released three to four times more [3fI]metaraminol
100
\zI&J
20
40
60
.1
.5
I"
-.
c-:::'"~"""""&l-+ ....:r
1_
'-AMP, N-8
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MP, N= 12
I
"
I,
I
N- 9
.5
fi
d-AMP,N7
jY\
I-AMP,tY
l~
I-AMP,
~ L-f'\
~/(
t
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\I~!
d-AMP, N -II
.1
50
CUMULATIVE DOSE (mg/kg)
10
.L'
'''''I I-A
5I
,"'--1
,;1"'1
,;r. .
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-L .. :-+-"='1
--------
LOCUS COERULEUS (NE)
PARALYZED
ANESTHETIZED
FIG. 9. Effects of d- and l-amphetamine on the firing rate of neurons in locus coeruleus and substantia nigra zona compacta in anesthetized (chloral
hydrate) or paralyzed (gallamine) rats. The results demonstrate the marked difference between the inhibitory action of d- and l-amphetamine on D
neurons and the lack of difference of these two isomers on NE neurons. Each value represents the mean 1 S.E. of inhibition of cumulative doses of
amphetamine administered intravenously in increasing incremental doses 1-2 min apart. Asterisks represent significant differences in the inhibition
induced by equal doses of d- and l-amphetamine. From Bunney et al, (1975).
a..
I&J
a: 80
20
40
J:
~
CD
60
80
100
SUBSTANTIA NIGRA (DA)
::..
-l
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::..
S2
::j
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::..
t-<
::s
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80
KENNETH E. MOORE
from cerebral cortex than l-amphetamine, whereas both isomers were equally
effective in releasing [3fi]metaraminol from heart. Heikkila et al. (l975b)
found that both isomers of amphetamine were equally potent in releasing
catecholamines from slices of cerebral cortex, whereas d-amphetamine was
approximately three times more potent than l-amphetamine in releasing
these amines from the striatum.
It is difficult to separate drug-induced "release" from blockade of uptake
employing these in vitro procedures. That is, by measuring tissue/medium
ratios of [3fi]catecholamines or the loss from tissues and the increase in the
media of [3fi]catecholamines, it is difficult to determine if the drug causes
actual release or merely blocks the reuptake of spontaneously released
amines. There is some suggestion that in vitro release is not due primarily to
blockade of uptake. Azzaro et al. (l974) reported that when compared with
amphetamine, cocaine and desipramine are more effective in blocking
uptake than in causing release of [3fi]NE. Heikkila et al. (1975b) found that
concentrations of cocaine that block uptake do not cause a marked release of
[3fi]D from striatal slices, while an effective uptake-blocking concentration of
amphetamine causes a marked release of the amine. These results suggest,
therefore, that in vitro release caused by amphetamine is a real phenomenon
that cannot be ascribed exclusively to blockade of uptake.
Results of in vitro release experiments may not truly represent what is
happening in vivo since there is some indication that amphetamine may
facilitate the ongoing neurogenic release of catecholamines, an event that
does not occur in in vitro preparations (Von Voigdander and Moore, 1973a).
Thus, there may be complex interactions between psychoactive drugs and
neurogenic-releasing mechanisms associated with the arrival of the action
potential at the nerve terminal. There is, however, considerable evidence
from in vivo experiments that amphetamines do release catecholamines (see
Section 6.1). By employing a cerebroventricular perfusing technique in cats it
was demonstrated that following an intraventricular injection of [3fi]NE, a
single fixed concentration of d-amphetamine but not l-amphetamine increased the efflux of [3H]NE and [3fi]NM (Carr and Moore, 1970a). Using a
similar preparation it was subsequently reported that d-amphetamine was 310 times more potent than l-amphetamine in increasing the efflux of [3fi]D
(Von Voigtlander and Moore, 1973a; Chiueh and Moore, 1974a).
By using the accumulation in the brain of o-methyl metabolites of D and
NE as an index of release of these amines, Scheel-Kruger (1972) noted that
d- and l-amphetamine increased the brain concentrations of both amines.
Dose-response curves were not generated, but 10 mg/kg of d- and lamphetamine produced equivalent increases in the content of NM, but the
increase in the concentration of 3MT after d-amphetamine was 1.7 times
higher than that after l-amphetamine. The increase in the o-methylated
metabolites of NE and D after amphetamines probably reflects active release
rather than blockade of reuptake since a number of uptake-blocking drugs
81
(desipramine, imipramine, benztropine) do not increase the brain content of

these catecholamine metabolites.
The results of most experiments on the behavioral effects of amphetamine suggest an action on D neurons (see Section 4.2). This may be due to
the fact that these neurons are more sensitive to the uptake-blocking or
releasing actions of amphetamine than are the NE neurons. Taylor and
Snyder (1971) observed that blockade of catecholamine accumulation into
NE neurons occurred only with a high dose of amphetamine (10 mglkg) ,
whereas the blockade into the striatum was observed at half this dose. From a
standpoint of behavioral studies these doses are extremely high (except for
studies on stereotyped behavior), but the results of the study suggest that D
neurons are more sensitive to the action of amphetamine. A greater
sensitivity of D neurons was also observed in some in vitro studies on the
amphetamine-induced blockade of uptake or release of brain catecholamines
(Coyle and Snyder, 1969a; Harris and Baldessarini, 1973; Thornburg and
Moore, 1973a), but not in other studies (Ferris et al., 1972; Ziance et al.,
1972; Heikkila et al., 1975b).
In summary, the use of stereoisomers of amphetamine to unravel the
biochemical substrates for the behavioral effects of these drugs has provoked
some controversy, but importantly, it has stimulated research into the
behavioral and biochemical actions of these compounds. Depending on the
biochemical study one wishes to quote, the neuropharmacological actions of
d- and l-amphetamine can be related to interactions with either NE or D
neuronal systems. A concluding statement from a recent paper by Bunney et
al. (1975) seems most appropriate:
... what appeared at first as a simple clear-cut pharmacological tool for
determining the specific catecholamine system responsible for mediating
certain behaviors has become exceedingly complex. Consequently, all interpretations and conclusions concerning the etiology of various behaviors
derived from the use of this tool must be made with great care and must be
based on all available evidence, not just that derived solely from the
amphetamine stereoisomer test.
8. EFFECTS OF CHRONIC ADMINISTRATION OF

PSYCHOMOTOR STIMULANTS
In the rat, tolerance develops to the anorexigenic, hyperthermic, and
cardiovascular actions of d-amphetamine; the latter two effects are probably
due to interactions of amphetamine with peripheral NE neurons. Tolerance
also develops to the actions of d- and l-amphetamine on some operant
behavioral tests (Tilson and Sparber, 1973). Tolerance does not develop to
the locomotor stimulating or stereotypic effects of d-amphetamine (Kosman
82
KENNETH E. MOORE
and Unna, 1968; Lewander, 1971a). Tolerance is not due to a reduced brain
concentration of amphetamine or to an increased rate of metabolism of this
drug (Lewander, 1974).
It has been suggested that tolerance develops to some of the actions of damphetamine because p-hydroxynorephedrine is synthesized and stored in
NE neurons and serves as a less potent transmitter than NE. That is, after
chronic administration of d-amphetamine both NE and p-hydroxynorephedrine (a false transmitter) are released from NE nerve terminals (Groppetti
and Costa, 1969; Brodie et ai., 1970). The replacement of NE by phydroxynorephedrine cannot account exclusively for the depletion of brain
NE following chronic administration of d-amphetamine because this effect
occurs in guinea pigs and rabbits (Lewander, 1971b; 1974). Chronic amphetamine also reduces the brain content of D and HVA in the guinea pig
(Lewander, 1974), and Jori and Bernardi (1972) report that tolerance
develops to the ability of d-amphetamine to increase HVA concentrations in
the rat brain.
Injections of p-hydroxyamphetamine that result in the accumulation of
p-hydroxynorephedrine in both central and peripheral NE neurons reduced
the cardiovascular and hyperthermic actions of amphetamine, but not the
anorexigenic, locomotor stimulant, or sterotypic actions of the drug. The lack
of effect of p-hydroxyamphetamine on the latter two actions of d-amphetamine is consistent with the lack of tolerance development to these actions of
the drug. As noted in Section 4.2.3 the effects of d-amphetamine on
locomotor and stereotyped activities are probably due to interactions with
central D neurons that, because they lack D,BH, cannot synthesize phydroxynorephedrine. Lewander (1971a) demonstrated that p-hydroxynorephedrine did not appear to be involved in the development of tolerance to
the anorexigenic effects of d-amphetamine and concluded that this metabolite may play a role in the development of tolerance to those actions of
amphetamine that are dependent upon peripheral NE nerves, but not to the
effects dependent on interactions with central NE neurons (anorexigenic
effects?). Although p-hydroxynorephedrine may play some role in tolerance
development to d-amphetamine in the rat it obviously would not be
important in tolerance development in other species that do not synthesize
this metabolic product of amphetamine (guinea pig, rabbit). Even in the rat,
it cannot explain tolerance to other psychomotor stimulants. For example,
tolerance develops to the anorexigenic effects of i-amphetamine, which is not
metabolized to p-hydroxynorephedrine. Furthermore, cross tolerance develops between the anorexigenic actions of d- and i-amphetamine and phenmetrazine, indicating perhaps a common mechanism of action. This would
suggest therefore that p-hydroxynorephedrine does not play an important
role in the development of tolerance to the anorexigenic action of damphetamine.
As described in Section 6.2, acute administration of d-amphetamine
increases the brain concentrations of tryptophan and 5-HIAA, and this effect
83
may be related to the hyperthermic actions of the drug (Reid, 1970). The
increase in the concentration of 5-HIAA seen after acute administration is
not observed following chronic administration of d-amphetamine, at a time
when tolerance has developed to the hyperthermic actions of the drug
(Lewander, 1974). Furthermore, tolerance develops to the ability of damphetamine to increase brain concentrations of tryptophan, although the
temporal developments of tolerance to the hyperthermia and to the elevation
of tryptophan induced by d-amphetamine do not parallel one another.
Lewander (1974) did not find any change in the 5-HT or 5-HIAA brain
concentrations after acute or chronic administration of phenmetrazine.
9. SUMMARY AND SPECULATIONS

Phenethylamine derivatives that have psychomotor stimulant properties appear to exert their characteristic central actions by facilitating the
release of catecholamines from nerve terminals in the brain. The results of
behavioral studies, except for those on self-stimulation, suggest that the
stimulant actions of these drugs result primarily from facilitation of dopaminergic transmission processes. Evidence that supports this contention includes the following: (1) a- or ,B-Adrenergic-receptor-blocking drugs do not
alter the central stimulant effects whereas neuroleptics with relatively specific
dopaminergic receptor blocking properties abolish the central stimulant
actions of amphetamine-like drugs. (2) Inhibition of the synthesis of dopamine, but not of norepinephrine, blocks the central actions of amphetaminelike drugs. (3) Selective 6-hydroxydopamine-induced lesions of dopaminergic
neuronal systems, but not of noradrenergic neuronal systems, block amphetamine-induced stimulation.
The phenylethylamine-type psychomotor stimulants can be divided into
two groups on the basis of the abilities of reserpine and aMT to inhibit their
central actions. Amphetamine, the prototype of the drugs that are blocked by
aMT, appears to facilitate the release of D from a newly synthesized pool,
whereas methylphenidate, the prototype of the drugs that are blocked by
reserpine, appears to release D from a storage pool. These mechanisms
appear to be the preferential but not the absolute mechanism by which these
drugs act, because after aMT it is still possible to demonstrate some stimulant
effects of amphetamine (Moore and Rech, 1967; Rech and Stolk, 1970) and
after reserpine it is possible to demonstrate some stimulant actions of
methylphenidate (Breese et at., 1975).
It is generally believed that neurotransmitters are released from nerve
terminals by exocytosis or reverse pinocytosis, a process in which the storage
vesicle is actively involved. Once the contents of the storage vesicle are
released in response to the nerve action potential or drugs, the vesicle may be
refilled by amines entering the neuron via the uptake process or by synthesis.
84
KENNETH E. MOORE
This restoration process may occur over a shorter duration of time than it
takes for those storage vesicles that are not immediately adjacent to the
neuronal membrane to move into position to release their contents. This
idea, suggested by Franklin and Herberg (1974), is supported by the results
of studies by Stinus et al. (1972) who found that if aMT-pretreated rats are
allowed to rest for half an hour after they have stopped self-stimulating, their
response rates will recover briefly after the electrical current is restored. This
suggests that when synthesis is blocked, catecholamines may be supplied at a
slow rate by the mobilization of vesicles containing catecholamine stores.
Thus, in order to maintain transmission during times of increased activity the
nerve has to rely on synthesis or reuptake of amines into those vesicles that
are already located at the neuronal membrane.
Many drugs that appear to facilitate the release of catecholamines, such
as amphetamine, also block the neuronal uptake process so that the only way
by which the storage vesicles can be refilled is through synthesis of new amines.
Therefore, amphetamine appears to act by preferentially releasing D from a
newly synthesized pool, whereas in effect it is releasing D from the only
source available. If the mobilization of the storage vesicle is so slow that it
does not playa significant role in maintaining transmission in the presence of
amphetamine, it is not surprising that elimination of the storage pool by
reserpine does not alter the central stimulant effect of this drug. A different
situation must apply at the terminals of noradrenergic neurones in the
sympathetic nervous system because reserpine pretreatment does block the
peripheral actions of amphetamine. The ability of reserpine to block the
peripheral but not the central actions of amphetamine may be related to the
fact that different neurotransmitters are involved: D in the brain and NE in
the periphery. Reserpine is reported to block the synthesis of NE by
interfering with the transport of D into the storage vesicle and the site of
Df3H (Rutledge and Weiner, 1967; Roth and Stone, 1968). Thus in the
periphery reserpine may block the action of amphetamine by depleting the
storage vesicles and by blocking NE synthesis.
If the mobilization of the storage vesicle to the neuronal membrane
adjacent to the synaptic cleft is a slow process, necessitating that the supply of
transmitter comes from synthesis, it is difficult to devise a scheme by which
CONTROL
d-AMPHETAMINE
METHYLPHENIDATE
10. Schematic diagram of possible mechanisms by which d-amphetamine and methylphenidate facilitate the release of D from newly synthesized (reserpine-insensitive) and
storage (reserpine-sensitive) pools, respectively.
FIG.
85
reserpine blocks the central stimulant actions of methylphenidate. That is,

how does methylphenidate selectively release D from a reserpine-sensitive or
storage pool? The drug may increase the rate at which the storage vesicles
approach the neuronal membrane, but there is no evidence in support of
such a suggestion. Figure lOis a schematic diagram depicting the manner in
which amphetamine and methylphenidate may interact with central D
neurons.
In summary, amphetamine and other psychomotor stimulants appear to
produce most of their central stimulant actions indirectly, by facilitating the
release of D from ascending mesolimbic and nigrostriatal neuronal systems.
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CENTRAL NERVOUS SYSTEM

STIMULANTS: HISTORICAL ASPECTS
AND CLINICAL EFFECTS
Burton Angrist and Abraham Sudilovsky
1. INTRODUCTION-EARLY USE OF PLANT

PREPARATIONS
The effects of central stimulants were identified early in the history of
mankind; plants containing these substances are among the most ancient of
known drugs. The use of rna huang (Ephedra vulgaris) in China, khat (Catha
edulis) in Africa, and coca (Erythroxylon coca) in South America are examples
of this early recognition. Thus, the Chinese herb rna huang, of acknowledged central stimulating activity, had been in use as a circulatory stimulant,
diaphoretic, antipyretic, and antitussive agent (Chen and Schmidt, 1925) for
some 5100 years before its main active ingredient, the sympathomimetic
ephedrine, was introduced into clinical practice in the West for the treatment
of asthma and similar conditions.
Likewise, the use of khat as a "food stimulant" originated many centuries
ago in the eastern region of Africa that corresponds to present-day Ethiopia.
The earliest reference to such use appears in a chronicle on Amda Seyon,
who reigned in Abyssinia from 1314 to 1334 (Alles et al., 1961), a time in
which khat chewing was already a socially accepted habit. This then spread to
Northern and Southern Africa as well as to the Middle East and became also
prevalent among the inhabitants of Somaliland, Kenya, and Yemen, where
Burton Angrist and Abraham Sudilovsky Neuropsychopharmacology Research Unit, Department of Psychiatry, New York University Medical Center, New York, New York.
99
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BURTON ANGRIST AND ABRAHAM SUDILOVSKY
the plant is currently commonly found in home gardens of the lowland

areas. The khat plant grows as an evergreen shrub or a tree, the fresh leaves
of which are either chewed along with green stem tips and then swallowed or
are dried up and prepared in powder form to be taken as an infusion (khat
tea) or as a paste with honey. For commercial purposes it is extensively
cultivated mainly in the highlands, and because the product partially loses its
activity if stored, the fresh leaves and twigs, packed in bundles, are
transported soon after being picked to the consumption centers of Harar,
Hodeida, and Aden, in which special marts exist (Hesse, 1946; Alles et ai.,
1961). In Somaliland markets, freshness of the khat leaves and twigs is
temporarily preserved by wrapping them with banana leaves, which also are
used as an advertising sign.
The chewing of khat is a gregarious activity and its effects consist of a
state of mild mental stimulation characterized by feelings of contentment,
loquacity, mild psychomotor excitation, increased muscular capacity, suppression of both fatigue and need to sleep, and loss of appetite. As with coca in
certain regions of the New World, these attributes are intensely valued by the
khat eater and explain the popularity of the habit among native tribal
warriors. As is usually the case with euphoriant drugs, the popular lore has
ascribed to khat aphrodisiac properties. Distinct subjective stimulation, comparable to that induced by 10 mg of racemic amphetamine sulfate, was
experienced by Alles (Alles et ai., 1961) for about 6 hr after eating leaves and
stem tips in the amount of 300 g. More specifically, he reported increased
tendency to move about, feeling of increased alertness with "better than usual
vision and interest in reading," anorexia, and some gastrointestinal discomfort after ingestion of various aqueous extracts of dried leaves. The latter
manifestation might be analogous to symptoms of gastritis not infrequently
observed as untoward effects in habitual khat eaters, which are apparently
due to the large amount of tannin and other substances harmful to digestive
processes contained in the leaves.
In 1930, following the advent of ephedrine into Western medicine,
Wolfes isolated d-norpseudoephedrine (which is known to be present in ma
huang) as an extractable base material in khat. This is currently considered
similar to cathine, one of three alkaloidal fractions previously obtained by
Stockman (1912), the other two being called cathinine and cathidine. The
proportion of these components (in crystalline form) in the khat leaves has
been estimated to be 0.27, 0.15, and 0.32%, respectively (Stockman, 1912).
Besides d-norpseudoephedrine (cathine), the presence of another closely
related amphetamine-like substance, which disappears when the plant is
dried and presumably is a precursor in the biosynthesis of the alkaloid, has
been determined (WHO, 1964).
Although all of the above stimulant effects have since long been
attributed to cathine, a nonalkaloidal component (probably an essential oil)
has been suggested to playa role in the production of the stimulant effects,
since the fresh leaf is considerably more active than the total alkaloids that it
CENTRAL NERVOUS SYSTEM STIMULANTS
101
contains (Paris and Moyse-Mignon, 1957). Alles et at. (1961), on the other
hand, reported that cathine alone is responsible for the psychomotor effects
of khat. There is no development of tolerance or of physical dependence
with chewing of khat and the toxicity of its amphetamine-like alkaloids is said
to be reduced to some extent by the tannins present in the leaves (Paris and
Moyse-Mignon, 1958). However, as with amphetamine, when overindulgence
of khat occurs, the sense of elation and euphoria may give way to an episode
of mania, auditory hallucinations, other schizophrenic-like symptoms, or to a
confused delusional syndrome (Laurent, 1962; Carothers, 1945). Heisch
(1945) reported a case of poisoning that developed a stupor-like state with
motor incoordination, spasmodic and jerky movements of the limbs, resistance of the extremities to passive flexion or extension, and marked hyperesthesia manifested by occurrence of muscular twitching as a result of sudden
noises or touching of any part of the body.
The WHO Expert Committee on Addiction Producing Drugs recognized that the habitual chewing of khat led in some areas, through loss of
man-hours and diversion of income, to malnutrition and aggravation of
disease, and recommended that because of the similarity of its medical effects
and those of amphetamine both these stimulants should be considered in the
same light (WHO, 1964).
Of all plants with stimulant properties used in ancient times it is perhaps
coca that was regarded with greatest reverence as charmingly described in
the Book of Plants by Abraham Cowley in 1662 (Mortimer, 1901):
Endow'd with leaves of wond'rous Nourishment,
Whose Juice Succ'd in, and to the Stomach tak'n
Long Hunger and long Labour can sustain;
From which our faint and weary Bodies find
More Succor, more they cheer the drooping Mind,
Than can your Bacchus and your Ceres join'd.
Chewing of coca leaves was widespread through western and northwestern regions of South America prior to the advent of the Incas (Radin, 1942).
It appears that the first people to use coca were the Arhuaca Indians
(Buhler, 1948), who introduced the plant from the equatorial jungles to the
mountainous areas and from whom it would have been adopted by the
Aymara and Quechua tribes, the original nucleus of the Inca Empire. Coca
became then intimately associated with religion and customs and was
interwoven in the highly organized sociopolitical structure of the Incas, who
at the time of their highest development occupied what is now Colombia,
Ecuador, Peru, Bolivia, and the northern regions of Chile and Argentina.
The plant was, in fact, regarded as a symbol of divinity, an object of
adoration, and deemed a gift bestowed by Inti (the Sun God) upon his royal
son, the mythical first Inca, Manco Capac.
The first written record of the use of coca to reach Europe was dated
1499 and occurred in the correspondence of Father Tomas Ortiz to his
superiors relative to his traveling along the northern coast of the continent
102
(Gutierrez-Noriega, 1944). Subsequent references to the religious implications, superstitious beliefs, customary applications, and effects of coca among
the Indians, as well as descriptions of the plant and its cultivation, can be
found in the chronicles of early travelers to the new world, in the official
reports of governmental representatives of the king of Spain, and in the
writings of missionary priests (Mortimer, 1901; Guerra, 1974). While these
accounts are contradictory in regard to the extent of the consumption of coca
during the times of the Inca Empire (Gutierrez-Noriega, 1944) it is generally
accepted that this was strictly confined to the royal family and, as a special
designation of the sovereign's favor, to members of the nobility (Curacas, i.e.,
high-ranking imperial officers and chieftains of subjugated tribes). The
commoners (Purics) very seldom had access to the prized leaf. This situation,
however, rapidly changed with the arrival of the Spanish conquerors and the
collapse of the empire at the beginning of the 16th century, when the
Indians, compelled to work intensively in mines situated at considerable
altitude in the mountains, resorted to the use of coca to endure their
hardships. Consequently several ordinances were issued during the colonial
period that regulated its value as currency (a modality that has persisted until
this day) and promoted its cultivation and consumption.
The first European publication of a technical nature on coca appeared
in 1565 in Seville as part of the writings of Nicolas B. Monardes, one of the
founders of pharmacognoscy. This work, based both on second-hand
information (the author never went to America) and on his own observation
of samples of the plant kept in a botanical garden that he cultivated while
practicing as a physician, served as reference for many years to come since it
was translated into Latin in 1582 and into English in 1577, as well as
reprinted and enlarged several times (Guerra, 1974). It provided a correct
description of the plant, its cultivation, uses, and consumption by the natives,
all of which are essentially valid nowadays. For example: "using of it all the
tyme that they have neede, whiche is when they travaill by the waie, and
especially if it be by waies where is no meate, or lacke of water. For the use of
these little Bawles dooe take the hunger and thurste from them, and they say
that they dooe receive substaunce, as though that they did eate" (Monardes,
1577).
References to other pharmacologically relevant uses of coca appear
scattered in the writings of chroniclers who through the years of the Spanish
colonization, or after that, had direct contact with the Indians of the Andean
regions of South America. Father Valera said: "Cuca preserves the body
from many infirmities, and our doctors use it pounded for applications to
sores and broken bones, to remove cold from the body or to prevent it from
entering, as well as to cure sores that are full of maggots" (Garcilaso de la
Vega, 1871). Antonio de Ulloa, in his historical account published in 1798
wrote: "This herby is so nutritious and invigorating that the Indians labor
whole days without anything else, and on the want of it they find a decay in
their strength. They also add theat it preserves the teeth sound and fortifies
103
the stomach" (Pinkerton, 1813). About the same time, Unanue (1794), a
noted Peruvian physician and statesman, impressed by the hunger- and
fatigue-suppressing properties attributed to coca during the siege of the city
of La Paz in 1771 and on infantry soldiers deprived of provisions while
advancing in forced marches, suggested its regular use by the army.
Further indications for the use of coca continued to be recorded by later
travelers. Tschudi, an enthusiastic supporter of the use of coca, told about
the benefit in sustaining respiration that he himself experienced when
ascending to high altitudes during his traveling in South America in 1838.
Markham (1862) confirmed this and added a rather modem pragmatic
commentary to it: "it enabled me to ascent precipitous mountain-sides with a
feeling of lightness and elasticity and without loosing breath. This later
quality ought to recommend its use to members of the Alpine Club, and to
walking tourists in general." He noted also that "Applied externally, Coca
moderates the rheumatic pains caused by colds, and cures headaches. When
used to excess, it is like everything else, prejudicial to the health, yet of all the
narcotics used by man Coca is the least injurious and the most soothing and
invigorating." In addition, in his 1880 account of cinchona (the "fever tree"
of the aborigines, from which quinine had been isolated in 1820), Markham
recorded the use of coca for the relief of malaria, in which it was considered
superior to cinchona bark by the Indians. Bearing also on the fatigueinhibiting action of coca, Stevenson (1825) described its use by relays,
couriers, or runners (Chasquis) in conveying messages between distant points
of the empire, which they used to do at a rate of about 150 miles a day
(Mortimer, 1901).
Testimonies such as those above on the "marvelous" attributes of coca,
kept cropping up in the lay South American and European literature of the
17th, 18th, and 19th centuries. For a long initial period, although unchallenged, they were either ignored or received with disdain, disbelief, or
suspicion by the conservative medical groups. By the middle of the 19th
century, however, the habitual use of coca had already been associated in the
writings of some (von Poeppig, 1836; Weddell, 1853; von Tschudi, 1846)
with adverse effects such as gastrointestinal disturbances, apathy, mental and
moral depravity, emaciation, and terminal cachexia. However, claims for
both adverse and beneficial effects were subsequently quoted by later writers
in accordance with their own biases. For example, at the beginning of the
20th century, von Tschudi is quoted by Mortimer (1901, p. 172) as follows:
I am clearly of the opinion that moderate use of Coca is not merely
innocuous, but that it may even be very conducive to health. In support of
this conclusion, I may refer to numerous examples of longevity among
Indians, who, almost from the age of boyhood, have been in the habit of
masticating Coca three times a day, and who in the course of their lives have
consumed no less than two thousand seven hundred pounds if at the age of
one hundred and thirty, and they commenced masticating at ten years-one
ounce a day, yet nevertheless enjoy perfect health.
104
Some decades later, however, the same reporter is quoted by Hesse (1946,
pp. 60-61) with quite different implications:
All those who chew coca have a highly unpleasant perspiration, an evilsmelling breath. Their lips are pale, their teeth green and blunt, and a
disgusting blackish foam drips from the corners of their mouths. They can
be recognized by their unsteady gait, their loosely hanging grayish-yellow
skin, their hollow, lusterless eyes, surrounded by deep purplish circles, their
quivering lips, their incoherent speech and their dull, apathetic attitude.
They are mistrustful, undecided, false and treacherous. They are old men
even before reaching their full physical maturity, and when they are
actually advanced in years, insanity is the inevitable consequence of their
incontrollable passion.
By 1806, Unanue came close to the discovery of the active principle in

the coca leaf (Moll, 1944); however, no other significant chemical investigations were undertaken until about 1850, when Weddell and others suggested
that the effects of coca might be due to theine, an alkaloid that was then a
subject of much discussion and that soon after was shown not to be present
in coca. In 1860, as part of his doctoral thesis, Niemann (1860), a young
pharmacist student of the great chemist Wohler, reported the isolation from
specimens of Peruvian coca leaves of an alkaloid that he called cocaine. Five
years earlier, however, Gaedcke (1855) had obtained from coca leaves
brought from Brazil a sublimate of small needle-shaped crystals that he
named erythroxyline and that has been considered either identical to cocaine
or a mixture of coca alkaloids. An alkaloid of coca (coincidentally named
erythroxyline) had been prepared also by S. R. Percy and reported to the
New York Academy of Medicine in 1857 (Mortimer, 1901). The work of
Niemann, however, came about at a moment in which medical interest in
coca was, perhaps for the first time, at a high point because of the publication
of a prize-winning essay on coca by Mantegazza (1859). This dealt with
results of experiments conducted both upon the author himself and other
subjects while a resident of Peru and following his return to Italy.
Mantegazza, using the leaves both by chewing and in infusion, observed
a sensation of comfort in the stomach with facilitation of digestion, increased
frequency of pulse and respiration, increased body temperature, and a
general exaltation characterized by gradual increase of muscular strength
with feeling of agility and impulse to exertion, easiness in the flow of ideas,
and a peculiar feeling of isolation from the environment with clear consciousness. Occasionally, also dryness of the mouth and throat as well as increased
urination occurred. Upon intake of a dose similar to that used daily by the
"Serranos" (direct descendants of the Quechua Indians, living in the mountains), he noted intensification of these effects with intense mental exhilaration and hallucinations: "Borne on the wings of two Coca leaves, I flew about
in the spaces of 77,438 worlds, one more splendid than another. .. It seemed
to me that I was separated from the whole world, and I beheld the strangest
105
images most beautiful in color and in form than can be imagined."

Mantegazza qualified coca as "one of the most powerful nervines and
analeptics" and proposed its use in a variety of conditions and clinical entities
of that time (gastrointestinal disorders, anemia, debility following fever,
hypochondriasis, hysteria, mental diseases usually treated with opium, "spinal
irritation," "nervous erethism," and idiopathic convulsions).
Both the work of Mantegazza and of Niemann marked the beginning of
a period of intense but disappointing research, which extended to 1884,
when Koller (1884) demonstrated the local anesthetic properties of cocaine.
Use was made during that period of various preparations of coca leaves
obtained either through chemical processes that paralleled those of the native
users or through the investigator's own chemical and pharmaceutical knowledge. For the most part, however, the experiments yielded negative, contradictory, or nonsignificant results, leading to the belief that coca, other than as
a mild stimulant comparable to tea or coffee, was therapeutically uninteresting. Dowdeswell, for instance, summed up his studies of the effects of various
preparations of coca (1876) as follows:
It has not affected the pupil nor the state of the skin; it has caused neither
drowsiness nor sleeplessness; assuredly it has occasioned none of those

subjective effects so fervidly described and ascribed to it by others ... This
examination was commenced in the expectation that the drug would prove
important and interesting physiologically, and perhaps valuable as a therapeutical agent. This expectation has been disappointed.
Meanwhile, however, a number of commercial preparations of coca

leaves to be used as tea or in the form of fluid extracts, tinctures, and wines
were introduced in Europe and America by A. Mariani, E. Merck, ParkeDavis, and E. R. Squibb among others. These came into widespread general
use as part of a "new remedy" craze, which particularly affected America in
the 1870s. Among these uses were the observations of W. H. Bentley
(1880a,b) on the efficacy of a coca extract for the treatment of opium,
morphine, and alcohol "habits." These were initiated in 1874 and continued
during 1878 and 1879. Other physicians reported similar efficacy for coca in
these conditions and disregarded its potential for creating a new "habit"
(which had been mentioned by Bentley). These publications provided Freud
(1884) with the idea that cocaine could be used for the same purpose.
Also during this time, early observations on effects of coca leaf extract
foreshadowed later documentation of the local anesthetic effects of cocaine
itself. A preparation for topical application was provided by Mariani in 1865
to the French physician C. Fauvel for trial in the treatment of laryngeal pain.
This use was subsequently adopted in both England and the United States
(Mortimer, 1901). Anesthetic properties of both the chewed leaf and the
alkaloid had previously been noted (Demarle, 1862; Schroff, 1862).
The widespread empirical use of coca in the absence of definitive
106
evidence for its efficacy met with criticism, after amounting to ridicule, by
scientifically oriented professional circles. Thus, in July 1884 (barely two
months before Koller's communication on the anesthetic effect of cocaine in
the eyes), E. R. Squibb stated: "But if Mr. Dowdeswell's results be accepted as
being conclusive, the annual consumption of 40,000,000 pounds of coca, at a
cost of $10,000,000, promotes this substance to take rank among the large
economic blunders of the age." After reviewing the available scientific
evidence and noting that the sale of coca extract was profitable, he declared
that "the writer has finally decided to give up making a fluid extract of coca,
and has left it off his list, adopting a fluid extract of tea instead, as a superior
substitute for those who may choose to use it, and regrets that this course was
not taken a year ago" (Squibb et at., 1885).
With the advent of more modem preparations of cocaine itself, which
was offered in the form of inhalants, ointments, tablets, hypodermic injections, in an oleate vehicle, or as solutions of various concentrations of
different salts, the medicinal use of the coca leaf as such decreased
dramatically. It was dropped as an offical drug from the pharmacopoea of
the United States in 1910.
Rather than through contact with vegetable drugs as such, subsequent
medical experience with central stimulants has been mostly through contact
with the more potent purified derivatives of anciently known plants (cocaine,
ephedrine) or with equally potent synthetic drugs such as amphetamine,
methylphenidate, an phenmetrazine. The purity of these compounds has led
to a more precise exploitation of their individual pharmacological effects for
medical purposes. Their potency, on the other hand, has at times led to early
detection of their undesirable effects and sometimes grotesque toxicity.
In retrospect, the introduction of a new central stimulant has initiated a
rather characteristic historical pattern of events:
1. The medical profession has explored its therapeutic potential in
many conditions with hopeful enthusiasm.

2. Abusers have been quick to demonstrate the effects of the drug's
most reckless use.
3. The drug is viewed with some alarm.
4. A sense of perspective emerges wherein possible benefits and dangers are balanced with sophisticated understanding of both.
5. Very specific medical indications for which the drugs are to be used
are defined.
This pattern of events was seen at its most extreme after the introduction of cocaine. It was repeated again almost verbatim after the discovery of
amphetamine. A similar pattern of initial enthusiasm and subsequent alarm
or disappointment can be noted in reviewing the literature and history of
more recently developed stimulants such as phenmetrazine and methylphenidate.
107
2. COCAINE
Cocaine, the alkaloid isolated from coca leaves by Niemann, is a
levorotatory crystalline base, the methyl ester of benzoyl-ecgonine. It is also
present in the bark, seeds, and roots of the plant and occurs to the extent of
0.10-0.80% of the total plant weight associated with other alkaloidal components such as cinnamylcocaine, cinnamylecgonine, hygrine, a-truxilline, ~
truxilline, isatropilcocaine, tropacocaine, and benzoyl-ecgonine. In the leaves
the total alkaloid content varies from 0.50 to 1.50%, but higher percentages
(1.0-2.5%) can be obtained from particular species. Because the alkaloid
content of the leaves diminishes with storage (and is practically lost in about
six months) it is first extracted as a crude material that can eventually be used
for the production of cocaine by methylation and benzoylation of the
ecgonine content. The estimation of this in the coca leaves has therefore a
commercial value.
Cocaine is obtained as odorless and colorless white crystals (white
powder), scarcely soluble in water, which are bitter in taste and produce a
sensation of tingling and numbness on the tongue. This mild anesthetic
effect was first noted by Niemann and, as mentioned above, by Schroff in
1862. Moreno y Maiz (1868), who experimented with cocaine acetate on
frogs, was the first to raise the possibility of its use as a local anesthetic. Many
years later, Von Anrep (1880), on the basis of his observation in various
animal species that cocaine affects the sensory nerve endings, hinted the
future importance of such action if applied for anesthetic purposes. These
suggestions, however, as well as the empirical topical utilization of the drug to
control laryngeal pain by practitioners of that time, did not attain any
significant consequence.
Early in 1884, Freud became interested in the study of cocaine because
of a recently published report by Aschenbrandt (1883) on its stimulant
effects on Bavarian soldiers during military maneuvers. After trying the drug
on himself and (inspired by the American publications on its use for the
treatment of narcotic addiction) on his friend von Fleischl, who was a highly
regarded physiologist addicted to morphine because of severe pain at the site
of a thumb amputation, Freud initiated a series of six reports published
between 1884 and 1887 with a comprehensive, though overenthusiastic
review of coca and cocaine (Freud, 1884). In it parallels are drawn between
the effects of both agents and cocaine is recognized as "the agent of the coca
effect." Negative results previously reported are attributed mainly to the
quality of the preparations then available.
Freud's focus on the therapeutic potential of cocaine caused wide
repercussions in medical circles. While bringing him credit in relation to the
subsequent work by Koller, it also promoted a bitter controversy with Lewin
and Erlenmeyer (1885), who contended that the use of cocaine for the
treatment of opiate addiction would create a "twofold craving" (Lewin, 1924).
108
Detailed accounts of this episode can be found in a recent compilation of

Freud's writings on cocaine and other related material (Byck, 1974). Interestingly, as a result of the recently renewed interest in cocaine, Freud has been
named from different perspectives as "one of the founders of psychopharmacology" (Byck, 1974), "the first psychopharmacologist maTUJui" (Caldwell,
1970), "the first of the consumer advocates" (Ray, 1972), and "the first
scientist to be blamed for a major drug disaster" (Gay et al., 1975).
Central to Freud's interests were the therapeutic possibilities of the drug
in those psychiatric functional disorders characterized by depressed mood
and tiredness that were then categorized as "neurasthenia." Freud described
in detail the effects of small doses of cocaine on his own depressive feelings
as consisting of "exhilaration and lasting euphoria, which does not differ in
any way from the normal euphoria of a healthy person." The uplifting
qualities of cocaine had already been stressed in American publications; an
editorial of the Detroit Therapeutic Gazette (1880) concluded, quoting from the
Louisville Medical News, "'One feels like trying coca with or without the opium
habit. A harmless remedy for the blues is imperial.' And so say we." In
addition, Freud enumerated as other potential indications of the drug its use
for digestive disorders, cachexia, asthma, and as an aphrodisiac and local
anesthetic.
Just a few months after Freud's initial publication on coca, his friend and
colleague Koller recognized the practical applicability of its chief alkaloid by
instilling a cocaine solution in the eyes of animals and man. The report of his
experiments, in September 1884 at a meeting of the German Ophthalmological Society in Heidelberg, initiated an important series of events in the field
of surgery such as the discovery of the neuroregional method of anesthesia
by Halsted and his associates (Hall, 1884), its introduction into general
practice after 1900 by both Crile and Cushing, and the use of cocaine by the
spinal route, first attempted by Corning in 1885. Similarly, the search for
and the development of new local anesthetics was greatly stimulated. Because
of the presence of the benzoyl moiety in cocaine, benzoic acid, and benzoyltropine, all of which possess distinct local anesthetic properties, and the lack
of these in tropine itself, the chemist W. Filehne deduced that such
properties were related to this moiety. On this basis, Einhorn initiated in
1892 a series of investigations that led, in 1905, to the synthesis of procaine,
another benzoyl compound.
Following the rapid confirmation of Koller's discovery by numerous
physicians on both sides of the Atlantic the demand for coca leaves suddenly
increased and the price of cocaine, formerly $2.50 per gram went up to
about $7.50 by mid-November (Bull, 1884). Consequently, factories in Peru
implemented the manufacturing of crude cocaine for export (in 1890, 1730
kg of the alkaloid were exported to America and Europe, a figure that
increased to 10,600 kg by 1901; Chopra and Chopra, 1931) and efforts were
made to stimulate large-scale plantations in South America and other
appropriate parts of the world. Experimental cultivations were taken up in
109
India (where it proved a commercial failure), Java, Ceylon, Malaysia, and

Formosa. More recently the cultivation of coca has been reported in the West
Indies, particularly in Jamaica, and in Zanzibar, Australia, and Cameroon.
These developments, the increasing popularization of the drug, which
during the 1890s was included (unlabeled) in all sorts of nerve tonics, "patent
medicines," and home remedies, and its widespread use by the medical
profession for the treatment of conditions warranting the introduction of
inhalant and injectable preparations laid the ground for the occurrence and
spread of cocaine abuse. Already in 1885, "a very complete cocaine case,
containing every essential for the topical application of cocaine, including a
hypodermic syringe, camel's hair pencil, a minim pipette, a vial to contain a
solution of cocaine muriate, five capsules, each containing directions for
making a two-per-cent and four-per-cent solution of muriate of cocaine" was
being advertised by Parke, Davis & Co. (Byck, 1974). Soon the use of
dependence and toxic manifestations began to appear in the European
literature. In January of 1886, Obersteiner confirmed the earlier fears of
Erlenmeyer (1885) regarding cocaine addiction, reporting several patients
with chronic intoxication who developed psychotic episodes with hallucinations of tiny animals crawling over the skin. This type of haptic hallucination
(formication) was first observed after cocaine by Freud's friend von Fleischl,
who was the first to suffer a full-fledged cocaine psychosis "with white snakes
creeping over his skin" (jones, 1953). Nonetheless the widespread use of
cocaine inhalers and powder in "catharr cures" provided the users with an
easy method of taking the drug in the form of snuff or rubbed on the gums.
In this regard Towns (1912) wrote: "Most of the cases of the cocaine habit
have been admittedly created by the so-called catharr cures ... In the end,
the snuffer of catharr powder comes to demand undiluted cocaine."
Initially, the dangers arising from misuse were underrated by Freud in
Europe on the basis of character predisposition (Freud, 1887). Similarly, in
America a former U.S. Surgeon General, Hammond (1886), conducted selfexperiments in which hypodermic injections of 1 g of cocaine hydrochloride
were taken and concluded that the cocaine habit was unlike the opium habit
and similar to that of tea or coffee. However, an opposite view was expressed
by Mattison, who in the discussion following Hammond's presentation stated:
"the effects of cocaine (are) even more unfavorable than those of morphine
and (I) would not advise any physician to repeat Hammond's experiment."
By the end of 1886, cocaine had become a dread word in the German
medical literature (Bernfeld, 1953), and its potential for inducing dependence and psychosis was well understood in medical circles by 1890. Nonetheless controversy persisted and no legal controls were felt necessary for
another 15 years. In fact, throughout the last 20 years of the 19th century,
the shelves of drug and grocery stores across the nation displayed preparations such as "Vin Mariani a la Coca du Perou" and "Dr. Pemberton's French
Wine of Coca-Ideal Nerve and Tonic Stimulant." In 1886 a syrup made with
extracts of coca leaf (containing cocaine) and kola nut (containing caffeine)
110
was introduced and developed by 1888, under the trade name Coca-Cola
as one of the most popular soft drinks of all time. This was originally sold as
a "sovereign remedy" for a long list of ailments, including melancholy.
While such products, and cocaine itself, were being used and acclaimed
as medical wonder drugs by thousands, including Edison, Pope Leo XIII,
Gounod, Massenet, Robert Louis Stevenson, Queen Victoria, Sarah Bernhardt, the fictitious prototype of detectives Sherlock Holmes, and other
celebrities (Mariani, 1896; Musto, 1968; Horowitz, 1974), dependence problems were increasingly frequently reported. These included the medical
pioneers-Halsted and his associates Hall and Hartley (Bett, 1952). A survey
conducted in 1902 revealed that not more than 8% of the total amount of
cocaine sold in major American cities went into the practice of medicine,
dentistry, or veterinary (National Clearinghouse for Drug Abuse Information, Report Series 11:1, 1972).
In 1906, with the passing of the Pure Food and Drug Act in the u.S.
making accurate labeling of proprietary medications mandatory the commercialization of coca came under strict control. By this time, the producers of
Coca-Cola had switched from using the ordinary coca leaves to "decocainized" coca extracts, large quantities of which are still used for flavoring
purposes (Taylor, 1966). However, self-medication and prescription of
cocaine still continued unrestricted. Meanwhile, use of the drug had become
known in such distant places as China and India and acquired considerable
proportions in European countries. In France and England cocaine snuff
was used to further sociability and in Germany "it was in vogue among thirdrate artists, disreputable characters and hangers-on, reinforced by young
people who were curious to try a new experience of which they heard
glowing accounts, or who were pressed by their companions to join in"
(Lewis, 1968). French physicians called attention to the cocaine clubs thriving
in the Montmartre district of Paris during the first decade of 1900.
Widespread use was certainly established before World War I, and throughout it cocaine was openly traded in the streets of the great cities of Europe. It
was only after the upsurge of its consumption following the end of the war
that legislation was adopted in Europe to regulate the production and sale of
the alkaloid.
In America, restriction of coca products commenced in 1914 with the
Harrison Tax Act. While exempting "decocainized" coca leaves to prior
proprietary interests, this act mislabeled cocaine-containing preparations as
"narcotics" and penalized its illicit possession, sale, and giving away. Consequently, cocaine nostrum ceased to be commonly used and a black market
appeared, with the use of the drug being driven underground and becoming
almost exclusive to bohemian circles in major metropolitan centers and to the
ghetto. The smuggling of cocaine into the U.S. was curtailed during the
1930s, 1940s, 1950s, and most of the 1960s with its abuse commanding a
very small following. Beginning in 1932 the use of cocaine was mainly
replaced by the newly introduced synthetic agents of the amphetamine
III
group, which, in addition to being cheaper, had the advantage of a more

prolonged duration of the stimulating effect and were at first readily
accessible and thereafter not as severely penalized. Nonetheless, in the late
1960s when implementation of law enforcement procedures against the
illegal traffic of these compounds became effective, a rise in the smuggling
and use of cocaine started to take place on the basis of the high profit
involved in its illegal traffic, and it reached alarming proportions in subsequent years. In fact, the popularity of the drug in the past few years has been
statistically illustrated by a sevenfold increase in cocaine seizures between
1969 and 1974, as well as by a survey taken for the Commission on
Marijuana and Drug Abuse showing that in 1972, 10.4% of all college
students had used cocaine at least once (Crittenden and Ruby, 1974).
3. AMPHETAMINE AND METHAMPHETAMINE

Amphetamine was first synthesized in 1887 by Edeleano. Its pharmacology was first studied by Barger and Dale in 1910, but because these studies
were done on anesthesized animals its central stimulant effects were not
noted (Bonhoff and Lewrenz, 1954). It was independently resynthesized in
1927 by Gordon Alles as part of work oriented toward developing synthetic
sympathomimetics that might substitute for Ephedrine in the treatment of
asthma (Leake, 1958). Its stimulant effects were probably first noted in 1930
by Piness, Miller, and Alles. These are not specifically indicated in their
report, although dryness of the mouth and pressor effects are documented.
Nonetheless they must have been apparent, for this first human study used
doses of 50 mg, administered both orally and subcutaneously! In the same
year amphetamine began to be used in nasal inhalers in Germany and very
soon its central stimulant effects became apparent: "patients treated in the
afternoon were noted to be refreshed, have a sense of well being and
competence and, for the most part, could not sleep that night" (Bonhoff and
Lewrenz, 1954). Thereafter amphetamine began to be used nonmedically,
particularly by university students in the U.S. (Editorial, J.A.M.A., 1937;
Bonhoff and Lewrenz, 1954).
Several disparate accounts of the origins of methamphetamine appear in
the literature. Brill and Hirose (1969) cite Tatetsu as indicating that "Nagai
extracted methamphetamine from a crude drug" as early as 1888. Connell
(1962, 1966) states that it was first synthesized by Ogata in Japan in 1919 and
credits its introduction into Western medicine to Emde, who prepared the
drug in Basle in 1929. Bonhoff and Lewrenz (1954) state that Dobke, Keil,
and Temler synthesized methamphetamine in 1934, and attribute the first
studies of pharmacology to Hauschild. These studies (Hauschild, 1938)
identified the central stimulant effects of methamphetamine in animals. In
addition, Hauschild injected himself with 5 mg of methamphetamine,
112
identified its subjective effects and their similarity to benzedrine, and named
the drug Per-Vitin.
Myron Prinzmetal, who worked with Alles, was the first to exploit the
stimulant effects of amphetamine for medical purposes. In 1935 he and
Bloomberg reported its effectiveness in the treatment of narcolepsy. By 1936
an oral preparation of amphetamine (Benzedrine tablets, 10 mg) had been
produced and was available without prescription (Meyerson, 1936).
In the period between 1936 and the onset of World War II, the medical
profession exploited the possible therapeutic potential of amphetamine
energetically and with enthusiasm. Less than four years after the first
reported medical use of amphetamine in the treatment of narcolepsy
Reifenstein and Davidoff (1939) reviewed the current status of "Benzedrine
sulfate therapy." Their article contains 115 references published between
1935 and 1938. Therapeutic trials in the following conditions are described:
narcolepsy, postencephalitic Parkinsonism, Myasthenia Gravis, alcoholic stupor, alcohol hangover, barbiturate and morphine overdose, organic psychoses, dementia praecox, manic-depressive psychosis--depressed type,
psychoneuroses, orthostatic hypotension, hypotension produced by spinal
anesthesia, spasm of the gastrointestinal tract, nasal congestion, weight
reduction, seasickness, carotid sinus syncope, enuresis, migraine, asthma,
vomiting of pregnancy, and for induction of pupillary dilatation. By 1946
amphetamine had been tried in 39 separate diseases (Bett, 1946).
In view of this widespread medical use, it is surprising that the medical
profession was so slow to appreciate the toxic somatic and psychotogenic
effects, as well as the dependence-inducing qualities of the drug. This delay is
perhaps accounted for by the fact that these effects are quite inconsistent in
their occurrence. Regarding physical toxicity, for example, it is now known
that individuals vary greatly in their sensitivity to amphetamine actions. This
extreme variation in sensitivity must undoubtedly have been apparent and
perplexing to early workers. Idiosyncratic reactions were alluded to by Davies
(1937) and were certainly already noted by 1939 when Reifenstein and
Davidoff described: (1) an elevation of blood pressure from 110/60 to 200/
100 after 10 mg of amphetamine administered intravenously; (2) unconsciousness and clonic convulsions 9 hr after 30 mg of the drug; and (3) coma
of 36-hr duration, convulsions, circulatory collapse, signs of cerebral irritation, and depression with eventual recovery following injection of 140 mg of
Benzedrine. Yet the same authors indicated: "We have given a patient 200
mg orally without untoward effects," "Patients with orthostatic hypotension
have received 150 mg of the drug daily for 6 months," and "we have injected
intravenously 40 mg as a single dose and a total of 105 and 130 mg over a
period of an hour in two patients without alarming reaction." They therefore
concluded that "although many untoward, paradoxical, and unpredictable
effects of benzedrine sulfate occur, the exceedingly alarming reactions just
mentioned must be considered to represent idiosyncrasy to the drug or the
113
result of gross overdosage because of the large number of patients in whom

no such serious effect has appeared."
Similarly, prior to World War II only one report suggesting psychotogenic potential, which included two cases of amphetamine psychosis, had
appeared in the English literature (Young and Scoville, 1938). This report
conservatively avoided the assumption that amphetamine was the cause of de
novo psychosis but stressed the possibility of an unmasking effect on latent
psychotic traits in patients with narcolepsy being treated with the drug. By
1942 only eight additional cases had been reported by four other investigators and these reports were all in the German literature (Kalant, 1973). In
retrospect, it is possible either that other cases occurred and were misdiagnosed as acute schizophrenic episodes, or that the taking of the large doses
usually associated with amphetamine pyschosis had not yet become common.
The potential of amphetamine for causing dependence was also detected by some of the early investigators. Guttmann and Sargeant (1937)
concluded their paper as follows:
The possibility of addiction needs to be guarded against and the case of a
person who has been purchasing Benzedrine at chemists' shops without
medical supervision has already come to our notice, although none of our
patients have so far shown a tendency to addiction ... At present, however,
Benzedrine may be purchased at any chemist's shop without prescription
and this seems inadvisable with a drug all of the properties of which have
yet to be fully investigated ... It is to be hoped that this drug will not be
discredited by misuse.
Waud, in 1938, wrote, "The question of addiction to benzedrine is not settled

but I believe the possibility is not to be treated lightly, for most drugs that
produce a pleasant effect on the brain (either stimulating or quieting in
.nature) have their addicts."
Reifenstein and Davidoff (1939), who were impressed with the therapeutic possibilities of amphetamine, also expressed the following reservations
in a paper published the same day that benzedrine was made obtainable in
the U.S. only on prescription Uanuary 1, 1939) but that was read the
preceding year: "We are convinced that in certain persons at least, benzedrine sulfate is habit-forming. We have noticed this tendency in individuals
addicted to alcohol, morphine and other drugs, in neurotic persons who
crave medication, and in people who work under excessive strain such as
actors, students, nurses and physicians." In addition, they listed "persons who
request the drug" among the "circumstances in which benzedrine sulfate
should be administered with considerable caution because of possible harmful effects" and stated in their summary: "Emphasis is placed on the
unconfirmed and controversial nature of much of the reported data, on the
occurrence of untoward effects and habituation, on the danger of indiscriminate use and on the necessity of administering the drug with caution."
However, these warnings were (often strenuously) debated. As early as
114
1936, Meyerson described the subjective effects of amphetamine and indicated that "none [of his normal subjects] experienced any craving for the
drug afterwards." Two years later, Lesses and Meyerson (1938) stated
(inaccurately),
As to addiction, the drugs to which human beings become addicted are
the narcotics ... There is no evidence in the entire literature of medicine
that stimulants become habit-forming. Akohol,morphine,cocaine-to select
a few-are narcotics ... One of us (Meyerson) has had clinical experience
with benzedrine sulfate for more than 2 years in a very large number of
cases and has not seen a single case of addiction in the sense that a person
otherwise well now finds it necessary to take the drug habitually and in
ascending doses to produce a desired effect.
A subsequent report (Bloomberg, 1940) describing the absence of

abnormal clinical findings and laboratory results, and the lack of craving in
three patients with narcolepsy who had received 70 to 120 mg of Benzedrine
daily for from 20 to 32 months, must have suggested to the medical
profession that the drug was, globally, rather innocuous.
Thus, the possible potential of amphetamine for inducing dependency
had been suggested, but remained debated by the time of America's entrance
into World War II. In retrospect, several reasons for this can be adduced.
First, the prototypic model of an addictive state in most physicians' minds at
the time was opiate addiction. The fact that clear-cut physiologic signs did
not appear with arithmetic inevitability after amphetamine withdrawal was
inconsistent with this model. The importance of "craving" in the absence of
classic withdrawal signs was minimized, particularly as craving itself was
noted by some and denied by others. Second, the drug was still somewhat
new, and it is possible that no cases of severe dependence had yet developed,
or that if some cases had developed they went, because of their scarcity,
unrecognized by the medical community.
Nonmedical use of amphetamine, however, had already occurred. The
drug had been available to the public, without prescription, since 1932 (in
inhalers containing large amounts of the drug as free base) and, as noted, an
oral form was available over the counter in 1936. A 1937 editorial in the
J.A.M.A. documents, the first described nonmedical use:
Tablets of the sulfate were used in the department of psychology at the
University of Minnesota for the purpose of determining its effects in mental
efficiency tests. It was noted that the drug prevented sleepiness and
"pepped up" the person who was fatigued. Apparently, this information
was disseminated to the student body by word of mouth and the drug has
been and still is being obtained by the students from drug stores for the
purpose of avoiding sleep and fatigue when preparing for examinations.
In the same year, a report in Time magazine (1937) indicated that this use of
benzedrine had spread to other campuses. Such practice was widely and
sensationally reported in the lay press and aroused widespread curiousity
and interest in a drug that was readily available. Benzedrine tablets became
115
known as "brain," "confidence," and "Superman" pills (Bett, 1946; Snyder,

1974; Grinspoon and Hedblom, 1975).
In 1938, Waud reported the effects of toxic doses of amphetamine
administered by inhalation and Young and Scoville reported the first cases of
amphetamine psychosis. Whether due to these reports, buttressed by the
caution recommended by the physicians cited above, or to widespread
notoriety in the lay press, amphetamine was made available only on
prescription after January 1, 1939.
Amphetamine was first used for military purposes during the Spanish
Civil War (Mira, 1942). During World War II many of the belligerent powers
exploited its effects. Pervitin was "widely issued" to the German troops and
Benzedrine was also used (Zondek, 1958). In Japan the drug was used
"almost compulsorily" both in the air force and among civilians engaged in
wartime industry to increase productivity (Hemmi, 1969). The RAF and U.S.
Army Air Corps in England often used the drug on extended European
bombing missions. Bett (1946) indicates that approximately two million
Benzedrine tablets were dispensed to the British combatant forces and
approximately the same number to the U.S. Armed Froces. Grinspoon and
Hedblom (1975) estimated that if 10% of American soldiers had used
amphetamine during the war, "over 1.5 million men must have returned to
this country with some first-hand knowledge of their effects."
The now classic paper by Monroe and Drell (1947) indicates the
Benzedrine inhalers were used by approximately 25% of an inmate population of a military stockade. (A group that might be expected to have a
considerably higher incidence of drug abuse than the army at large.) These
inhalers contained a paper folded into eight sections or "strips" impregnated
with 250 mg of amphetamine base. The papers were marked "Warning: For
Inhalation Only! Unfit for Internal Use. Dangerous if Swallowed." Each
section of paper contained a convenient dose of approximately 31 mg.
Monroe and Drell indicate that the usual dose take was one-half to two strips
(15-60 mg) every two to four hours. In addition, they documented and
described four cases of psychotic reaction as a result of this practice.
The period between World War II and 1958 was one in which
amphetamine use apparently increased in the general population. That
benzedrine inhalers were used by civilians as well as in the military is
indicated by the article "On a Bender with Benzedrine," which appeared in
Everybody's Digest in September, 1946. The introduction to Monroe and
Drell's paper cites this article and further indicates the widespread public
interest in amphetamine at the time: "The song 'Who put the benzedrine in
Mrs. Murphy's ovaltine?' has been popular recently. A newspaper advertisement featuring a charm bracelet with a pill box attached states the following,
'For benzedrine if you're having fun and going on forever; aspirin if it's all a
headache.' " The medical profession's increased interest in the drug continued; as mentioned, a review in 1946 by Bett cited 158 references documenting therapeutic applications of amphetamine in 39 separate conditions. This
116
interest was paralled by occasional but increasing reports in the world

medical literature of cases of amphetamine psychosis and dependency
without psychosis. These have been tabulated in detail by Kalant (1973) and
are summarized in Table 1.
The rarity of cases of amphetamine dependence and psychosis reported
in the Western literature, however, stands in contrast to development in
Japan that took place between the end of World War II and 1955. During
this time, an epidemic of intravenous methamphetamine use of unprecedented proportions occurred. The onset and course of this epidemic has
been described by Masaki (1956) and by Brill and Hirose (1969) and
attributed to the "dumping" on the open market of war stocks of stimulant
agents. The drug (amphetamine) known as Zedrine or the more commonly
used methamphetamine that was known as Philopon, Wake-amine or
Hospitan was made available without prescription in ampule form and
widely advertised to a demoralized population as providing "elimination of
drowsiness and replenishing of the spirit"(Masaki, 1956; Hemmi, 1969;
Snyder, 1974). Each ampule contained 3 mg. The drug was usually taken
intravenously in daily doses estimated as between 3-15 and 600-1200 mg.
The average daily dose was estimated as 90 mg (Brill and Hirose, 1969). Use
of the drug started shortly after the close of hostilities and originally was
noted in "the major commercial and industrial centers of Japan: Tokyo,
Osaka, Kobe, Yokohama. From there the drug spread to smaller towns and
thence to rural areas. Shortly no prefecture of all Japan was free of
amphetamine addicts, addicts being defined in Japanese law and practice as
persons who, of their own free will, are unable to give up the use of drugs"
(Brill and Hirose, 1969).
By 1949 methamphetamine had been listed as a dangerous drug and its
use was restricted by law. At approximately this time the first examples of
"home brew" variety began to appear. These ampules varied in contents of
TABLE
Cases of Amphetamine Psychosis and Dependence Reported between

1945 and 1958 a
Country
United States
France
Germany
Italy
United Kingdom
Puerto Rico
Australia
Canada
a
Derived from Kalan! (1973).
Psychosis
Dependence
17
10
5
7
4
9
3
6
3
1
0
0
117
amphetamine from none to 3.3 mg/ml. Bacteria were found in 45% of one
series (Brill and Hirose, 1969). The peak of the epidemic appears to have
been in 1954, when the number of users of Wake-amine among a population
estimated at about 83 million (McConnell, 1963) was variously estimated at
between 500,000 and 1,000,000, with half the users considered to be
addicted (Masaki, 1956). Over 55,000 were arrested for violating the
awakening-drug control law. In one slum area 10.2% of the bathers in public
baths showed injection marks on their arms, and in another 35% of a more
carefully studied group was considered addicted (Brill and HIrose, 1969). In
June 1954, the awakening-drug control law drafted in 1951 was revised. The
already severe penal clause was made even more so (Masaki, 1956), following
which the epidemic dropped off sharply. By 1957 relatively few cases of
amphetamine abuse were noted (Brill and Hirose, 1969; Hemmi, 1969).
Between 1947 and 1960, Tatetsu examined 492 cases of methamphetamine intoxication in hospitals, houses of correction, and parks frequented by
vagrants and saw 131 cases in one hospital alone (Tatetsu, 1964). The
differences in symptomatology and in the course of illness between these
cases and those reported in the Western literature remain perplexing
discrepancies in the world literature on amphetamine psychosis. Western
literature has tended to emphasize the schizophreniform aspects of amphetamine intoxication-the "paranoid psychosis with ideas of reference, delusions
of persecution, auditory and visual hallucinations in a setting of clear
consciousness" so meticulously documented by Connell (1958). In addition,
most western observers (Beamish and Kiloh, 1960; Bell, 1965) concur with
Connell's observation that the psychosis clears promptly when the drug has
been withdrawn. By contrast Tatetsu (1964) described a wider range of
psychiatric symptomatology. 92% of his cases showed a "psychotic state,"
which he characterized as follows: "schizophrenic-19%, manic-depressive23%, mixed schizophrenic or manic-depressive-19%, apathetic exhausted31 %"; the remaining 8% were considered to show a psychopathic-like state,
which he further subdivided according to personality characteristics. More
important, the same author (Tatetsu, 1964) stated that only half (50.8%) of
his cases could be discharged in less than 6 months, that 14.4% "have stayed
in hospitals for more than 5 years after withdrawal of injections," and
(Tatetsu, 1972) that in some cases "mental disorders continue for 8 to 22
years after the withdrawal of methamphetamine, and relapse is often
observed."
The differences in psychiatric syndromes can perhaps be accounted for.
First, it should be noted that a wide dispersion of psychiatric syndromes has,
in fact, been reported in the West. These include delirium (Brown, 1949;
Connell, 1958; Beamish and Kiloh, 1960; Griffith, 1966; Angrist and
Gershon, 1969a,b, 1972), mania (O'Flannagan and Taylor, 1950), anxiety
states (McConnell, 1963; Angrist and Gershon, 1972), emotional lability
syndromes (An grist and Gershon, 1969a,b), and exhaustion syndromes
(Angrist and Gershon, 1969a,b; Smith, 1969). Second, it is well known that
l18
diagnostic criteria in psychiatry vary very widely from country to country.

This is known to be the case even in England and the U.S., which share a
common language. Thus, it is possible that subtle differences in the usage of
diagnoses in Japan and the West might account for the differences in
syndromes reported, and that these differences could, in fact, be largely ones
of semantics.
The discrepant durations of illness reported by Tatetsu and most
Western authors is less easy to resolve. While this certainly cannot be
achieved in the context of a review such as this, it should be noted that the
following issues have been raised:
(1) Since these cases were not seen prior to hospitalization, the possibility
exists that amphetamine brought about a worsening of a preexisting schizophrenic state from which the patient was unable to recover. Tatetsu has
counterpointed that the age distribution curve of methamphetamine psychotics differed from that of patients diagnosed as suffering from schizophrenia
(Brill and Hirose, 1969), and that methamphetamine psychotics have a lower
incidence of schizophrenia in their siblings and parents than is found in the
siblings and parents of schizophrenic patients (Tatetsu, 1972). (Interestingly,
however, the incidence of schizophrenia in the relatives of methamphetamine psychotics was higher than was found in the general population.) In
addition, Tatetsu had indicated (Cole and Tatetsu, 1972) that many of his
confined methamphetamine psychotics were prisoners, whose prior mental
condition would not have caused them to be put into a public mental hospital
had they been outside prison. Our experience and that of Janowsky and
Davis is inconsistent with preexisting psychosis as a sole explanation for a
continuation of symptoms. Amphetamine indeed is known to cause florid
exacerbation of schizophrenic psychopathology (Delay et ai., 1947; J anowsky
and Davis, 1974). Such acute worsening of symptomatology, however, does
not result in prolonged psychotic reactions Uanowsky, 1975). Furthermore,
in a study in which a comparison was made between presumed schizophrenics and nonschizophrenics who entered the hospital after taking amphetamine (Angrist et ai., 1969), the difference in duration of symptoms between
the two groups, while attaining significance in some cases, was not as striking
as might have been expected, both groups showing rapid clearing when
amphetamine was discontinued. Similarly, administration of L-dopa to
known schizophrenics has also exacerbated these patients' symptoms, but this
has not been observed to last longer than 96 hr after L-dopa was discontinued (Angrist et ai., 1973).
(2) Other Japanese investigators (Sano and Nagasaka, 1956; Utena,
1966; Sakurai, cited in McConnell, 1963) have reported a lower incidence of
chronic disability among amphetamine psychotics than that noted by Tatetsu.
These discrepancies raise the possibility that his observations might have
been made at a chronic treatment center among a population skewed for
chronicity and severity.
(3) Amphetamine psychotics who have recovered and no longer elabo-
119
rate new delusional material may still continue to believe in the reality of
delusions experienced during past episodes of their psychosis (Kramer et ai.,
1967, 1972).
(4) Perhaps most important, McConnell (1963) has pointed out that no
laboratory tests for amphetamine in body fluids were available to the
Japanese investigators. Thus their patients' continued symptomatology might
simply represent continued drug intake. This consideration should probably
not be taken lightly since amphetamine abusers are notoriously competent at
obtaining the drug even under strict supervision. Indeed, one study has
shown an incidence of up to 15% of psychiatric inpatients' urines positive for
amphetamine. Most of these had been hospitalized for over a week (Robinson and Wolkind, 1970).
By 1958 the effects of amphetamine had been extensively publicized
and it was widely used both medically and nonmedically. The degree of
controversy about its detrimental effects can be appreciated, as Kalant has
pointed out, by contrasting two major monographs published in that year,
those of C. Leake and P. H. Connell. Connell's monograph remains the
authoritative documentation of amphetamine psychosis. Subsequent experience with amphetamines and other CNS stimulants has justified its tone of
caution concern. That the drug was frequently abused in England is
suggested by the fact that Connell was able to document 42 cases of
amphetamine psychosis in less than 31 years. The very first of Connell's
conclusions was: "Psychosis associated with amphetamine usage is much more
frequent in this country than would be expected from reports in the
literature." In the same year, in the U.S., production of the drug was on the
order of 75,000 pounds. Production figures estimated for this and subsequent years are given in Table 2.
These figures, however, probably constitute minimum estimates because,
as noted by Grinspoon and Hedblom (1975), many firms refused to reveal
production or sale statistics. Overproduction of amphetamine tablets coupled
TABLE
Estimated Productian in the United States between 1958 and 1970
Year
1958
1962
1966
1968
1970
a Grinspooln
Pounds
75,000a,.
100,000c
> 100,000d
Doses
Doses per
capita
3,500,000a,.
20a,.
8,000,000e
8,000,00ot
10,000,000a
35 e
and Headblom (1975).

b Kalant (1973).
Committee on Alcoholism and Addiction,lAMA (1966).
d Griffith (1966).
e Sadusk (1966).
f Time magazine, October 31, 1969 (quoted in Bartholomew, 1970).
C
120
with widespread demand led to the development of an extensive black

market in the U.S. In 1966, amphetamine tablets cost only $0.50 per
thousand to produce and were wholesaled for $1.00 to $2.00 per thousand.
The same tablets often sold on the black market for $1.00 per dozen
(Salsbury and Wayland, 1966; Sadusk, 1966). Sadusk (1966) has estimated
that 50% of the quantity commercially produced was diverted into illicit
channels, and that 90% of this illegal traffic emanated from truck stops,
gasoline stations, and restaurants. Griffith's (1966) description of the organization of illegal amphetamine traffic in Oklahoma City, published the same
year, however, makes it clear that truckers were not the only population
involved in the illicit use of amphetamine.
Large-scale dealers were arrested as early as 1959 (Salsbury and
Wayland, 1966). Illegal diversion of amphetamine appears to have been
simple. The drug companies were lax in investigating the legitimacy of those
to whom large quantities of the drug were supplied, as Grinspoon and
Hedblom (1975) document, citing a case in which large amounts were sold to
a distributing company whose license had already been revoked because of
illegal amphetamine sales. One individual is known to have obtained 13.5
million amphetamine tablets from four separate firms between 1961 and
1963 (Sadusk, 1966). In 1964, a CBS news producer set up a bogus "importexport" firm and using this firm's letterhead was able to obtain more than a
million doses of amphetamine and barbiturates from nine drug companies
and suppliers (Grinspoon and Hedblom, 1975). When the laws were changed
and became more stringent in their regulation of sales within the U.S., a new
ploy developed. Large quantities of amphetamine were then ordered and
sent to post office boxes, for nonexistent "drug stores" in Mexico, which
were, in fact, way stations for smugglers reentering the U.S. (Grinspoon and
Hedblom, 1975). Indeed, in 1971 Griffith et ai. commented that (in sharp
contrast to illegal narcotic sales) "diversion of amphetamine from legitimate
distribution is so efficient that illegal tablets are available in almost every
American city and cost little more than if the item were to be bought through
a pharmacy."
During the late 1960s particularly, this increased use was paralleled by
increased attention both to the extent of use of amphetamines and examination of its effects upon users. Numerous polls and surveys were conducted to
assess the extent of drug use of various types in colleges and secondary
schools. Many of these have been critically reviewed by Dorothy Berg (1970).
A series of eight college surveys done between 1967 and 1969 indicated that
amphetamines had been used once or more by 6.8-24.7% of students
depending on the college polled. The mean percentage that was calculated
from these studies was 12.7%. This figure is close to that found in Gallup
polls of 57 colleges, 13.5% (Gallup Organization, 1969).
The clinical effects of amphetamine (as opposed to incidence of use)
were also further delineated. Ellinwood (1967), using retrospective accounts
from 25 abusers, reconstructed the symptomatology of the amphetamine
121
psychosis and emphasized such clinical aspects as polymorphous hypersexuality, olfactory hallucinations, "ideas of a presence" deja vu, extreme
curiosity, and visual-constructive preoccupations. In a subsequent paper
(Ellinwood, 1968), he elaborated the theoretical implications of these observations and pointed out the similarity of amphetamine psychosis to that
associated with temporal lobe epilepsy.
Kramer et al. (1967) described the characteristic cyclic pattern of abuse
and intense effects noted in high-dose intravenous "speed freaks" in California. In the same year (1967), a nonmedical article by McNeil described the
same pattern of abuse in New York City. In the following year (1968),
Rockwell and Ostwald, using thin-layer chromatography, demonstrated
amphetamine in the urine of 15% of a sample of acute psychiatric admissions
at San Francisco General Hospital. Hekimian and Gershon (1968), doing
random interviews of only a fraction of patients admitted to Bellevue
Psychiatric Hospital in New York because of drug problems, were able to
identify 22 amphetamine-related admissions in the course of only seven
months. In the following year, Angrist and Gershon (1969a), reported
demographic social and psychiatric data from 60 amphetamine-related
admissions to Bellevue Psychiatric Hospital identified and interviewed over
22 months (indicating a minimal rate of 2.7 amphetamine-related admissions
to this hospital monthly). The bizarre characteristics of the "speed freak"
community that developed in Haight-Ashbury was described in 1969 with at
times chilling vividness by Roger Smith (1969a). The capacity of amphetamines to cause schizophreniform psychosis de novo in nonpsychotics (and not
merely release latent psychotic traits) had been first indicated by Connell's
monograph (1958). This capacity was definitively confirmed by Griffith et
al.'s reports (1968, 1970) of the first experimental indication of amphetamine
psychosis in nonschizophrenic amphetamine-abuser volunteers. Griffith's
findings and his observations on the symptomatology induced by experimental amphetamine intoxication were both replicated and extended in 1970 by
Angrist and Gershon, in a paper supporting the appropriateness of amphetamine psychosis as a model for the study of schizophrenia.
It is clear from the medical literature from other countries that
amphetamine use was becoming widespread during the late 1960s outside of
the U.S. as well. In England, Beamish and Kiloh (1960) reported six
additional cases of amphetamine psychosis. Kiloh and Brandon (1962)
examined all prescriptions written for the population of a city in Britain and
found that 3.4% of all prescriptions were for amphetamine preparations.
These amounted to approximately 200,000 5-mg tablets dispensed to approximately 2600 patients, indicating an average consumption per patient of
77 tablets per month. The authors stressed, however, that some patients
obtained larger quantities and that local physicians estimated that approximately 20% of those for whom amphetamine was prescribed showed some
dependence on the drug. McConnell (1963) indicated that "thirty-one of
1,460 referrals, that is 2.1%" of patients seen at a psychiatric hospital in
122
Dublin, "had symptoms caused by amphetamine as a prominent aspect of

their illness." In 1964, the widespread use of Drynimal (an amphetaminebarbiturate mixture) by London adolescents was reported in the press
(Sharply, 1964; Pharoh, 1964). Connell (1966) has subsequently described
the spectrum of clinical problems posed by these youths and made suggestions for their treatment. In 1965, Scott and Wilcox reported finding
amphetamine (by paper chromatography) in the urine of 14-16% of
adolescents admitted to two London remand centers. A subsequent series
(Cockett and Marks, 1969) from a similar population showed only 6.9% of
the specimens positive for amphetamine. This latter study used gas chromatography, a much more specific method of amphetamine detection. Studies
of the incidence of amphetamine use in patients admitted to psychiatric
wards were also undertaken with results ranging from 3.5% "positive"
Qohnson and Milner, 1966) to as high as 15% in a later study, which
used gas chromatography for amphetamine identification (Robinson and
Wolkind, 1970).
In Australia, a group of 14 severe amphetamine abusers were observed
in the 1960s by Bell and Trethowan. These observations were the basis of an
important clinical paper on the psychopathology, personality and background, and longitudinal course of the condition (Bell and Trethowan,
1961a). In a separate communication Bell and Trethowan (1961b) assessed
the impact of large-dose amphetamine abuse on their users' already disturbed sexual adjustment and in some cases documented spectacular and
bizarre effects. In 1968 Briskoe and Hinterberger conducted an extensive
study in which urine was screened for amphetamine using paper chromatography. They examined 1577 specimens from prisons, child welfare institutions, psychiatric admission centers, a college, a school, general medical
facilities, and two private practices. The total pooled group showed 6.6%
urines positive for amphetamine with a range of 1.85% (private practice) to
21.2% (female prisoners). Subsequent papers by Bell (1967) and Bartholomew (1970) suggest that some nonmedical use of stimulants persists in that
country.
Use of central stimulants in Scandinavia apparently began and was most
extensive in Sweden. After 1965, cases were seen increasingly in Denmark
and, to a lesser extent, in Norway and Finland (Teigen, 1970). The
experience with central stimulants in Sweden has been reviewed by Inghe
(1969) and Rylander (1969). Introduced into Sweden in 1938, amphetamine
was made available only on a doctor's prescription in 1939. By 1942 to 1943
the drug was used by an estimated 200,000 people (3% of the Swedish
population), but generally on occasional basis. At this time the number of
"serious" abusers (those who took up to 50 to lOO tablets daily) was estimated
at less than 200 (Inghe, 1969). After World War II amphetamine began to be
abused on a collective basis by gang and bohemian groups. The first western
intravenous amphetamine use is stated to have begun in Sweden in the early
1950s (Inghe, 1969). By the mid-1950s Inghe states that central stimulant
abuse had "become endemic among social and criminal groups. Instances of
123
breaking into chemists' shops, forging of prescriptions, etc., became common,

the number of narcotic gangs increased and the seizing of smuggled tablets
started." In 1955, phenmetrazine was introduced into Scandinavia and
rapidly replaced amphetamine as the "stimulant of choice" in that country.
Its use increased there in 1958 (Bejerot, 1968), and it was classified as a
narcotic in 1959. In the same year intravenous use began (Rylander, 1969)
and increased dramatically between 1964 and 1969. The clinical effects of
high-dose intravenous phenmetrazine use, including the euphoric "rush," the
development of psychoses, stereotyped behavior, and medical complications
from unsterile injection techniques are essentially identical to those reported
for high-dose amphetamine users (Bejerot, 1968, 1969; Inghe, 1969; Rylander, 1969).
Like Scandinavia, Czechoslovakia also experienced a marked increase in
the use of central stimulants between 1960 and 1965 in which phenmetrazine
and dexphenmetrazine were the preparations of choice (Vondracek et al.,
1968). Developments since 1968 are not known.
Thus, either gradually or suddenly epidemics of stimulant use have
occurred in Japan, Scandinavia, the United States, England, and Czechoslovakia, and judging from the lack of recent reports, have tended spontaneously to decline. In countries such as Japan and Sweden, legislative
measures apparently helped to control these outbreaks. In the United States,
a decline in stimulant use probably preceded the increase of legislative
control, and this drug's use is now very much diminished as compared with
the late 1960s. This is particularly striking since opiate use has not declined
dramatically within the same time. Why this pattern of increased use and
spontaneous decline occurs is a fascinating issue about stimulant drugs. It
does not appear to be completely explained by legal countermeasures.
Thompson and Pickens' (1970) studies with monkeys enabled to self-inject
stimulants and opiates may be relevant to this problem. In these studies, the
animals showed dramatic but transitory bursts of drug-acquiring behavior
when stimulants were withdrawn. Such pattern was in contrast with the more
sustained attempts at drug acquisition shown by the opiate-conditioned
animals. Gunne has also observed anecdotally that with long-term use
euphoric effects might decline, and dysphoric or psychotic effects become
more prominent (Gunne, personal communication). This, if documented,
could provide clues to a neuropharmacologic basis for such spontaneous
cessation of usage. Nonetheless, epidemics of use of many types of drugs are
known to have appeared and abated without any apparent pharmacologic
reason.
4. PHENMETRAZINE
Phenmetrazine was discovered and developed at Boehringer Laboratories by Thoma and Wick (1954), who delineated its sympathomimetic
124
properties. Spiegelberg (1954), describing the early studies done at Boeringer, gives (without using the word specifically) a recognizable description of
stimulant-induced stereotyped behavior in dogs: "the dogs were quite lively
and reacted by pacing back and forth and turning their heads to and fro."
The first clinical studies of A66 (as the drug was then known) compared its
somatic and cardiovascular effects to those of adrenaIin and metamphetamine (Spitsbarth et al., 1953). Spiegelberg (1954) then administered the drug to
both healthy volunteers and to psychiatric patients and thought the drug to
be helpful particularly in depressions of short duration, endogenous depression, aesthenic states, some psychopathic states, organic dementias, and
convalescence from insulin shock. He considered the drug's energizing
effects to be its main characteristic and indicated that no physical toxicity was
observed in the normal therapeutic dosages. The drug was then marketed as
an anorectic in 1954.
It was introduced in Scandinavia in 1955 where, as noted above, its
properties were rapidly identified by amphetamine users (Inghe, 1969).
Originally considered innocuous, it was classified as narcotic in 1959. In the
same year, according to Rylander (1969) a method of extracting phenmetrazine from crushed tablets for intravenous use was devised. Solutions at first
were made from 20 to 30 tablets per injection and these were shown to yield
intravenous doses of 200 to 300 mg. Subsequently users have reported
injecting solutions from 100 tablets, which have been shown by analysis to
yield over 1 g phenmetrazine. This practice at first spread slowly and then
increased dramatically after 1964. Beginning in 1965, Bejerot (1968, 1969)
begun collecting data on the incidence of needle marks of those arrested by
the police and documented a dramatic increase in this practice among
criminals until 1967. In 1968, the incidence was sustained but the increase
ceased. Thereafter judging from the lack of reports in the literature and
anecdotal conversations with Swedish colleagues, intravenous phenmetrazine
use began to decline and recently has done so dramatically. The drug
apparently was preferred to amphetamine. Bejerot (1968) indicated that
users believed "it (to be) more euphoric and have less side effects." Inghe
indicated that "phenmetrazine is still most in demand but amphetamine,
methamphetamine, dexamphetamine, methylphenidate and other drugs
(diethylpropion) are used as well" (Inghe, 1969).
The first reports of phenmetrazine abuse originated from England,
where the drug was introduced in 1956 (Bethell, 1957) and was originally
available without prescription. Three individual cases of abuse documenting
the development of dependence and psychosis were reported in one journal
volume in 1957 (Bethell, 1957; Clein, 1957; Glatt, 1957). In the same year,
Preludin was made available only on prescription (Evans, 1959). By 1959,
two large series of phenmetrazine psychoses were reported (Evans, 1959;
Bartholomew and Marley, 1959). Evans, whose report was published just one
year after Connell's monograph, also emphasized the importance of awareness of a drug's use and its clinical characteristics for identification: "I
125
supposed the condition to be rare but within six months I saw no fewer than
sixteen patients who had taken Preludin and became ill." He reported 12
cases of psychosis, five of which differed from typical cases of amphetamine
psychosis in requiring a longer period of time (5-12 weeks) for clearing. Two
of these were noted to display "definite schizophrenic thought disorder with
vagueness, overinclusiveness and bizarre associations." Bartholomew and
Marley'S report contains detailed psychiatric and neurologic data and emphasizes the diagnostic importance of signs such as mydriasis, impaired pupillary
light reflex, tremors of the upper limb, and facial twitching, which were
noted in 11, 8, 7, and 7 of their 12 cases, respectively. With these exceptions,
the cases reported by Evans, and Bartholomew and Marley and those
described by Scandinavian investigators such as Inghe, Rylander, and Bejerot
seem difficult to distinguish from reported cases of amphetamine psychosis.
Similarly, the acute effects of phenmetrazine, when administered to
addicts under controlled experimental conditions, were qualitatively similar
to amphetamine and methamphetamine insofar as cardiovascular effects,
subjective effects, and increased urinary excretion of epinephrine were
concerned (Martin et at., 1971). This study contradicts the frequent anecdotal
reports by addicts that they prefer to, in fact, can reliably distinguish one
stimulant from another. The clinical similarities between amphetamine,
phenmetrazine, and other stimulants such as cocaine and methylphenidate
are of theoretical interest, for although the same drugs show rather similar
behavioral effects, many differences in their mechanism of action have been
delineated by studies of their behavioral and biochemical pharmacology
(Graubner and Beinert, 1968; Lewander, 1969, 1972, 1974; Scheel-Kruger,
1971, 1972; Wallach, 1974; Angrist and Gershon, 1974).
5. METHYLPHENIDATE
Methylphenidate was developed in Ciba Laboratories. Its toxicology,
stimulant effects, and behavioral pharmacology were reported in 1954 by
Meier et at. As occurred in the first studies of phenmetrazine, the authors
described the induction of stereotyped behavior in dogs without specifically
designating it as such: "They pace excitedly, making repetitive ticlike head
movements ... In the next half hour the restlessness increases and the animal
circles in one spot." In summarizing their results, Meier et at. emphasized
that the drug produced central stimulation and a coordinated increase in
motility and suggested that it be categorized between amphetamine and
caffeine. Subsequent clinical trials (Drassado and Schmidt, 1954) documented
stimulant effects and the drug was then marketed primarily for its effects on
mood and not, as had been the case with other stimulants, as an anoretic
agent. Initial clinical trials were again reported in numerous conditions.
These included psychiatric disorders of various types, debilitation and
126
BURTON ANGRlST AND ABRAHAM SUDILOVSKY
depression associated with terminal malignancies, convalescence from medical illness, antagonism of the effects of sedative drugs, geriatric depressive
disorders, and stimulation of respiration in anesthesia (Nathensohn, 1956;
Landeman et ai., 1958; Hartert and Browne-Mayers, 1958; Jacobson, 1958;
Gale, 1959; Siegler, 1962; Guile, 1963; Ayd, 1964). In general, the tone of
these reports was enthusiastic. They tended to stress clinical efficacy, absence
of "rebound letdown" and lack of toxicity. In addition, the drug was
considered to be milder, to show less "harsh" sympathomimetic effects, to
induce less euphoria than amphetamine, and therefore to have less addictive
potential. A report of a patient who, in spite of her physician's "restrictions,"
took 1200 mg daily without any detrimental effects implied that the
therapeutic index of the drug was remarkable (Pollack, 1964).
In 1960, Rioux reported a case of severe and unequivocal methylphenidate dependence with periodic intoxication and some psychotic features.
Between 1960 and 1961, 11 cases of abuse or addiction were reported in the
Scandinavian literature (Noreik, 1960; Borg, 1961; Peters, 1961; Jorgensen
and Kodahl, 1961). In 1963, McCormick and McNeil reviewed the literature
and added a 13th case in which parenteral self-administration of 100 to 200
mg per day induced a state of florid psychosis with paranoid delusions,
agitation, and visual hallucinations. Since that time cautionary editorials and
letters warning of potential addictiveness have appeared in medical journals
(Perman, 1970; Willey, 1971), and the psychotogenic potential of methylphenidate has been confirmed by observations of accidental overdoses in
children (Lucas and Weiss, 1971) and by two further cases of psychosis
characterized by delusions of persecution and of infestation and parasitosis
(Spensley and Rockwell, 1972).
Thus, though only 16 cases of abuse and psychosis have been reported
in detail over 20 years of clinical use of methylphenidate, it is stated to have
been abused considerably (Inghe, 1969; Willey, 1971). Martin et ai. (1971)
have done controlled studies that suggest that it is "liked" as much as
amphetamine or methamphetamine by addicts to whom it has been administered under double-blind conditions. Its capacity to provoke dramatic
worsening in cases of preexisting schizophrenia was first suggested by Guile's
(1963) observations. This has been defmitively documented by Janowsky et
ai. (1973) and Janowsky and Davis (1974), who have exploited this effect in
investigations of the etiologic role of dopaminergic hyperactivity in schizophrenia. The case reports of McCormick and McNeil (1963), and Spensley
and Rockwell (1972) also suggest quite strongly that the drug can be
psychotogenic de novo.
6. DIETHYLPROPION
Diethylpropion was introduced in 1958 as an anorectic agent and
marketed by Merrell-National Laboratories. Originally it was claimed by the
127
manufacturers to be "virtually free of central nervous system stimulation"

(Kalant, 1973). Early uncontrolled clinical studies concurred in this conclusion (Revitz, 1959) as did subsequent controlled trials (Seaton et al. 1961;
Jones, 1962) in which it was specifically noted that "there was no evidence of
undue central nervous stimulation or insomnia" (Seaton et al., 1961) and
that "the absence of side effects and stimulating action (was) confirmed"
Oones, 1962).
However, Clein and Benady (1962) had reported the case of a young
female diethylpropion abuser who took 9 to 90 tablets daily and had had
four psychiatric hospitalizations over 16 months for brief episodes with
paranoid ideation and auditory hallucinations. In the same year, 1962
Kuenssberg added two additional cases of psychosis-one of a woman who
on therapeutic doses (75 mg daily) presented a personality change of "being
unable to concentrate, finding fault and unpleasant intent and hidden
meanings with most of her social and work contacts, being hyperexcitable
and ready to weep," all of which disappeared upon withdrawal of the drug.
The second case of psychosis was that of an examphetamine abuser. In the
following year, Caplan (1963) reported a case of severe dependence on the
drug resulting in "financial and social distress" in a woman with severe
preexisting personality problems and a history of phenmetrazine and dexamyI abuse, who consumed 7500 mg diethylpropion daily.
In 1969, Jonsson reported a blind comparison of diethylpropion 50 mg,
dextroamphetamine 10 mg, phenmetrazine 50 mg, and caffeine 250 mg in
college-student volunteers. It was found that diethylpropion more closely
resembled dextroamphetamine and phenmetrazine than caffeine, and that
50 mg caused as much euphoria as 10 mg dextroamphetamine, but less than
that caused by 50 mg phenmetrazine. The authors concluded that "diethylpropion is no doubt a stimulant" and cited further cases of abuse from the
Scandinavian literature.
By 1971, 54 cases of diethylpropion abuse had been reported by the
manufacturer (The Medical Letter, 1971). Kalant (1973), after reviewing the
literature on diethylpropion abuse, concluded that
diethylpropion, or any drug with central stimulating properties, has the
same potential for abuse as the amphetamines. That the individuals who do
abuse these drugs are emotionally disturbed or addiction prone, or possess
psychopathic or inadequate personalities, cannot be used as an argument to
exonerate the drugs since it takes both the drug and a susceptible individual
to produce addiction or milder degrees of dependency.
While we concur that diethylpropion certainly can and has been abused,
some observations do suggest that this may be somewhat less likely than
occurs with other stimulant drugs. Rylander (1969) reported a gang of seven
diethylpropion abusers and noted that "diethylpropion causes anxiety very
soon. After two of three days the abuser must stop because of this. The boys
took sleeping drafts or smoked Hashish which had a good calming effect."
More recently, Johanson and Schuster (1975) have reported studies in which
l28
a technique was developed whereby monkeys are enabled both to selfadminister stimulant drugs intravenously, and to "choose" one of two
different stimulants. In these, cocaine was "preferred" to diethylpropion.
7. EPHEDRINE
Ephedrine, one of the oldest known stimulants, and a potent bronchodilator has long been used in treatment of asthma (Chen and Schmidt, 1925).
As noted above, it was the search for a synthetic substitute for this drug that
led to Alles' synthesis of amphetamine. In 1927 Emde "illucidated the
chemical structure of Ephedrine and demonstrated that (it) could be simply
and inexpensively synthesized" (Grinspoon and Hedblom, 1975). Only two
cases of clear-cut ephedrine abuse have been reported in the English
literature (Herridge and a'Brook, 1968), both in asthmatic patients who
increased their dosage to amounts far in excess of those prescribed (over
1700 mg and 2250 mg daily, respectively). Both patients developed psychoses
reminiscent of those seen after other CNS stimulants. The first "was
convinced that his wife was being persistently unfaithful to him with an exlodger; he claimed that he had seen this man climbing over the wall on
several occasions and repeatedly heard him talking to his wife. He also
described seeing flashing lights in the garden at night and armed with an
iron bar had been searching for this phantom intruder." The second had "a
10 year history of recurring episodes of atypical psychosis characterized by
depression with paranoid features and vivid auditory hallucinations." After
recurrence of "auditory hallucinations of a persecutory nature in clear
consciousness" it was found that "many of her attacks of psychiatric illness
appear to have coincided with exacerbations of her chest condition and to
have been associated with marked tension and tremulousness and increased
difficulty in sleeping."
In 1971, another case of psychosis associated with a bronchodilator
containing ephedrine was reported-this associated with much lower doses
estimated at 125 mg per day (Kane and Florenzano, 1971). In the same year,
Martin et al. (1971) reported a controlled study (noted above) in which the
following drugs administered subcutaneously to addicts under double-blind
conditions were compared: (a) d-amphetamine (7.5, 15, and 30 mg per 70
kg), (b) methamphetamine (15 and 30 mg per 70 kg), (c) ephedrine (75 and
150 mg per 70 kg), (d) phenmetrazine (35 and 70 mg per 70 kg), and (e)
methlyphenidate (15 and 30 mg per 70 kg). In these studies, ephedrine was
found capable of producing the subjective and physiologic effects of the
other stimulants studied. In spite of widespread medical use, ephedrine has
in fact been abused only very seldom. Whether this represents an oversight
on the part of abusers or an intrinsic difference in some qualitative aspects of
the drug's effects is unclear at this point. It also is noteworthy that ephedrine
129
is considered a mixed noradrenergic agonist and not generally thought of as

having effects on dopamine systems. Recent studies in our laboratories
(An grist and Rotrosen, unpublished), however, indicate that ephedrine is
capable of inducing dose-related stereotyped behavior in rats and that this
behavior can be blocked by pretreatment with haloperidol but not by a or {3
adrenergic blockers. These results suggest that ephedrine affects central
dopamine systems in a way similar to other eNS stimulants.
8. CLINICAL ASPECTS OF CNS STIMULANT USE

8.1. General Considerations
While we have, because of clinical considerations, divided this section
into discussions of high- and low-dose stimulant use, it should be noted at the
onset that these terms are relative. Individuals' sensitivity to amphetamine
effects is extremely variable. This variability was noted as early as 1939 in the
review by Reifenstein and Davidoff cited above. In studies done by our
group (Angrist and Gershon, 1970) in which amphetamine psychoses were
induced experimentally in abuser-volunteers we were also struck by this
extremely variable vulnerability to the psychotogenic effects of amphetamine.
One subject consistently developed olfactory hallucinations and ideas of
reference at approximately 100 mg cumulative oral dose (racemic amphetamine), while another was behaviorally abnormal but not formally psychotic
even after ingesting 955 mgt Bell (1973) has recently confirmed this finding
iIi studies in which psychoses were introduced with intravenous amphetamine, observing psychotic reactions to doses varying from 55 to 640 mg.
Further support for the concept that individuals may form a continuum
in their sensitivity to psychotogenic (and perhaps other) effects of stimulants
is derived from studies with methylphenidate and L-dopa. These studies
suggest that some if not all schizophrenics represent the most sensitive pole
of this continuum. Janowsky et al. (1973) reported that schizophrenics given
0.5 mg/kg of methylphenidate intravenously very frequently showed dramatic and florid worsening of psychotic symptomatology although this dose
is euphoriant but not psychotogenic in nonschizophrenics. Janowsky and
Davis (1974, 1976) have also noted the same effect after administering
sterioisomers of amphetamine to schizophrenic subjects. Similarly, 10 schizophrenics receiving L-dopa showed florid worsening of psychopathology at a
mean daily dose of just over 5 g (Angrist et al., 1973), while nonschizophrenics who received the drug under the same conditions on the same ward
tolerated a mean daily dose of 8.8 g before showing a variety of behavioral
effects, of which a de novo schizophreniform psychosis was one (Sathananthan et al., 1973). Thus schizophrenics appear to represent one extreme end
130
of a continuum of sensitivity to stimulants in which others, such as the subject

who took 955 mg amphetamine without psychosis, represent the other.
A possible biologic basis for this variability in responsiveness is suggested
by Everett's (1973) report that different genetic strains of mice vary widely in
the brain levels of biogenic amines via which amphetamine effects are
thought to be mediated. More recently Garattini et al., (1976) has reported
differential sensitivity and response to amphetamine in genetic strains of
mice with high vs low rates of dopamine turnover. A possible test of this
concept in humans is in progress at NIMH, comparing responsiveness to
amphetamine in nonpsychotic relatives of schizophrenics with that of "normals" unrelated to schizophrenics (E. Gershon, personal communication).
This study tests the possibility that stimulant responsiveness might constitute
a genetic "marker" for schizophrenia.
Apart from variations in individual sensitivity to stimulant effects is the
concept of a spectrum of dose-related effects in anyone individual. A fair
amount of clinical evidence suggests that relatively low doses rather consistently produce euphoria, which within limits increases with dose and then is
replaced by dysphoric anxiety. Further dose increase frequently results in
psychosis, while at even higher doses delirium (an uncommon response
except in very high dose users) may occur. Post (1975a) has specifically
postulated this concept of a continuum of dose-related effects after cocaine
use, while Angrist and Gershon (1972) have reported a somewhat similar
spectrum of effects after amphetamine. Delirium is not a characteristic
response to stimulants but has been reported occasionally (Connell, 1958;
Angrist and Gershon, 1972).
Two concomitants of chronic use might further affect the response of a
given individual to a given stimulant dose: supersensitivityand tolerance.
8.1.1. Supersensitivity
It is known that chronic treatment with neuroleptics or catecholaminedepleting agents induce increased sensitivity to dopaminergic agonists (Dominic and Moore, 1969; von Voigtlander et al., 1975). The extensive pharmacologic evidence suggesting the importance of such dopaminergic supersensitivity in the pathophysiology of tardive dyskinesia has been reviewed by
Klawans (1973).
Paradoxically, chronic treatment with stimulants might also induce
heightened sensitivity to these drugs themselves. Thus:
1. The behavioral response to amphetamines under conditions of

chronic intoxication becomes increasingly disorganized, fragmented,
and bizarre over time (Ellinwood et al. (1972, 1973; Sudilovsky et al. ,
1974).
2. Recent studies by Post et al. (1975, 1977) have documented behavioral and electrophysiological evidence of progressively heightened
131
sensitivity to cocaine over time, the development of a "kindling"-like

phenomenon, and the progressive emergence of catalepsy, dyskinesias, and bizarre hallucinatory-like glancing about.
3. Klawans and Margolin (1975) have shown that chronic amphetamine
pretreatment results in increases sensitivity to the stereotyped behavior induced by both amphetamine itself and apomorphine.
These observations have provocative implications for the development of
chronic hypersensitivity states and ultimately of psychoses or movement
disorders. Recently reported observations by Seiden (1975) indicating longlasting localized dopamine depletion after chronic stimulant intoxication may
help to resolve the apparent paradox implicit in these observations in which
chronic exposure to both dopamine blockers and agonists induces a supersensitive state.
In this framework, Gunne's impression (cited above) that chronic users
either experience less euphoria or become more sensitive to the dysphoric
and/or psychotogenic effects of stimulants could reflect either (1) sensitization, resulting in a shift on the individual's dose-response continuum, so that
previous euphoriant doses become dysphoric or psychotogenic, or (2)
tolerance to euphoric effects with a likely resultant increase in absolute dose
taken.
8.1.2. Tolerance
Tolerance to stimulants is an extraordinarily complex issue. These drugs
have multiple effects in man and animals, including changes in feeling, tone,
social behavior, and locomotor activity, induction of stereotyped behavior,
anorexia, and insomnia, and effects on cardiovascular measures and body
temperature. Tolerance of these effects is not "across the board" and
"parallel," but differential. In humans, tolerances is well documented with
regard to anorexia and is assumed to occur with respect to cardiovascular
effects (because of the massive doses taken by abusers with only rare deaths).
Tolerance to stimulant effects apparently does not develop, as patients with
narcolepsy can be maintained on fIxed doses over years and abusers are only
very rarely able to sleep even briefly. Tolerance does not develop to the
dysphoric and psychosis-inducing effects and, as mentioned, it is possible that
chronic users might become more sensitive to these.
Similarly, in animals "tolerance develops to certain effects (of amphetamine): anorexia, hyperthermia, increased urinary excretion of noradrenalin
and adrenalin, and to the lethal effects of the drug, while not to other(s):
stereotyped behavior, increased motor acticity" (Lewander, 1972).
As noted by Lewander,
the absence of tolerance to some effects of amphetamine seems to rule out
such explanations as an increasing metabolic degradation of amphetamine
and, in fact, there was no difference in the Tlf2 of amphetamine in brain or
in the urinary pattern of metabolites of amphetamine in brain or in the
132

urinary pattern of metabolites of amphetamine between tolerant and
nontolerant rats
(Lewander, 1972). Similarly, studies by Anggard et ai. (1973) on chronic

high-dose amphetamine abusers gave "quantitative information of the metabolism of amphetamine that is similar to that observed with small single
amphetamine doses in drug naive volunteers."
Other possible mechanisms of this differential tolerance have been
intensively studied in several animal species by Lewander (1974). His findings
are complex: in rats tolerant to amphetamine-induced hyperthermia, brain
norepinephrine decreased with tolerance development but rose quickly to
normal even though residual tolerance persisted. This dissociation was even
more striking with respect to brain tryptophan levels. Acute and chronic
amphetamine caused depletion of brain norepinephrine in the rat, guinea
pig, and rabbits. Brain dopamine was increased in rats, decreased in guinea
pigs, and unchanged in rabbits by an acute dose of amphetamine. Chronic
treatment, on the other hand, caused dopamine depletion in rats and guinea
pigs but not in rabbits. Effects on brain HVA (an index of dopamine release)
showed similar complexities of species specificity. It increased after acute
administration of amphetamine to rats, mice, and cats but did not change in
rabbits and was decreased in the guinea pig. Tolerance to this effect
developed in rats but not mice (Jori and Bernardi, 1972). In humans, a
report of one subject given probenecid and amphetamine in large doses
showed greater accumulation of HV A in CSF than was seen with probenecid
alone (An grist et ai., 1974).
In rats (Lewander, 1974), brain tryptophan increased after acute amphetamine administration and partial tolerance to this effect was noted in
chronically treated animals. Serotonin was unchanged acutely and was
somewhat lower after chronic treatment. 5-HIAA was affected by acute
amphetamine in a biphasic fashion, decreasing after one hour and increasing
after four. This effect disappeared after chronic treatment when it stayed
consistently depleted. This loss of biphasic change in brain 5-HIAA correlated with the development of tolerance to the anorectic and hyperthermic
effects of amphetamine.
Finally, phenmetrazine, the clinical effects of which resemble amphetamine so closely, had effects on brain catecholamines markedly different from
amphetamine: acute treatment produced no change while chronic treatment
caused a small increase in brain NE and DA. Nonetheless, normetanepherine
and methoxytyrame, methoxylated metabolites of NE and DA respectively,
were increased by acute phenmetrazine administration in animals pretreated
with monoamine oxidase inhibitors, suggesting that like amphetamine,
phenmetrazine may act through release of brain catecholamines. However,
in spite of these differences in effects on brain catecholamines between
phenmetrazine and amphetamine, chronic phenmetrazine treatment was
demonstrated to cause cross tolerance to the anorectic effects of d-amphetamine (Lewander, 1974).
133
In the context of all of this the "speed freak" emerges as a complex

subject to study. He is more likely than most to be related to a schizophrenic
(Tatetsu, 1972) or to be one (Ellinwood, 1972). He generally has experienced
profound social, occupational, and sexual maladjustment prior to using
speed (Bell, 1967; Angrist and Gershon, 1969a,b). Finally, his response to
amphetamine may be distorted by development of tolerance to some of its
effects and supersensitivity to others.
8.2. Low-Dose Nonmedical Stimulant Use

The characteristic effects of a minimal effective dose of stimulants
consists of feelings of "relaxed" alertness, energetic vitality, and confident
assertiveness. Appetite and fatigue disappear, the person is not inclined to
eat and cannot sleep. As these effects diminish, a period of mild dysphoria
often supervenes during which many individuals experience some tension,
jitteriness, irritability, and at times some feelings of helplessness and demoralization. These effects would be noted by most people at doses of 2.5 to 15 mg
amphetamine.
With somewhat larger doses (usually in the range of 20 to 50 mg of
amphetamine) all effects are intensified but the initial sense of "relaxed"
alertness is replaced by a "driven" feeling. Thoughts rapidly replace one
another leading to impulsive "forgetfulness" and the capacity to concentrate
begins to break down. Mild emotional liability or a sense of earnestness and
decreased frivolity are often felt (a prelude to the sense of portentiousness
and heightened significance in high-dose user). These feelings, combined
with increased talkativeness, may lead to intrusiveness, introduction of
somewhat inappropriately "serious" and introspective topics of conversation,
and (a definite risk of stimulant use in this dose range) becoming a "bore," or
nuisance to others.
Stimulants are used nonmedically in this dose range to counteract
feelings of fatigue and are usually taken under conditions of increased effort
where such feelings would be inevitable under normal circumstances but
sleep must be deferred (students studying all night for exams, long-distance
truck drivers, etc.). The euphoria and sense of increased energy experienced
is also helpful in disregarding unusual physical rigors (such as experienced
by coca users in the Andes or in war-time situations in the military).
The use of stimulants by athletes to enhance performance is a matter of
controversy. That these drugs can have such effect is documented in the now
classic studies of Smith and Beecher (1959), who tested highly trained college
swimmers, runners, and weight throwers, both when rested and fatigued,
after administering d-amphetamine (14 mg per 70 kg), secobarbital (100 mg
per 70 kg), or placebo under double-blind conditions. Their results indicated
that "in all 3 classes of athletes the majority of these subjects performed
better under the influence of amphetamine than placebo." The degree of
134
improvement, although small (0.59 to 4%), was statistically significant for all
three classes of athletes. The implications of these findings have been noted
by Weiss (1969): "a 1% change is of great significance in competitive
athletics--l % of a four minute mile is 2.4 seconds, the difference between
fame and oblivion."
Reduction of fatigue could explain some of the enhancement induced
by stimulants and indeed, bike racers, whose sport is particularly grueling,
have somewhat of a reputation for stimulant use (Beckett, 1969). However,
Smith and Beecher's data suggest enhancement via effects other than
diminished fatigue. Surprisingly "the weight throwers obtained the greatest
amount of improvement from amphetamine (from 3% to 4%)," followed by
runners (1.5%) and swimmers (0.59-1.16%). In discussing these results Weiss
noted, "It is difficult to see how events such as shot-putting could be affected
by fatigue, lack of interest or boredom. With such an acute expenditure of
effort, improvement after amphetamine is a very convincing argument for
true enhancement." Furthermore, he noted that in the studies by Smith and
Beecher "the effects of amphetamine were more apparent in rested than in
fatigued subjects."
The use of stimulants in sport is often decried with pious outrage.
Nonetheless, the temptations to resort to them are great and this practice, if
undesirable, is certainly understandable. The most serious consequence of
this practice appears to be the possibility of detrimental effects to the athletes
themselves. Objections on grounds of sportsmanship, however, do appear
valid since these drugs offer selective advantages to users over nonusers in
competition.
This discussion of low-dose nonmedical stimulant use might appear
frivolous to some because it lacks the tone of alarm often used in discussing
such matters. Frivolity is not intended, since we do feel that undesirable
effects occur with this type of use. Chief among these is the development of a
type of dependence, more subtle than a desperate craving, in which
achievements accomplished when the drug is taken are ascribed to the drug
and not to the abilities of the taker, with a resultant lowering of self-image
and self-esteem, and the generally false impression that the drug is necessary
to function effectively.
Notwithstanding, most who use stimulants in this way do not escalate the
dose or become severely dependent. Indeed many exploit these drugs'
effects to achieve socially desirable ends and increase their level of accomplishment. To respond to this type of use with horror is, we feel, somewhat
hypocritical.
8.3. High-Dose Nonmedical Stimulant Use

"Drug dependence of the amphetamine type," as characterized by the
World Health Organization Expert Committee (1964), is a "state arising from
CENTRAL NERVOUS SYSTEM STIMUlANTS
135
repeated administration of amphetamine or an agent with amphetamine-like

effects on a periodic or continuous basis." Its characteristics include:
1. A desire or need to continue taking the drug.
2. Consumption of increasing amounts to obtain greater excitatory and
euphoric effects or to combat fatigue, accompanied in some measure
by the development of tolerance.
3. A psychic dependence on the effects of the drug related to a
subjective and individual appreciation of the drug's effects.
4. General absence of physical dependence so that there is no characteristic abstinence syndrome when the drug is discontinued.
It differs from low-dose use in that dependence is more severe and in that
the dose is escalated. The resulting high doses are incompatible with normal
functioning and carry with them the liabilities of toxicity, severely disturbed
behavior, dysphoria, and psychosis.
High-dose users usually have disturbed backgrounds preceding use of
the drug. Connell (1958) noted the "high incidence of abnormal personality
and instability as well as of alcoholism and other drug addictions" in
amphetamine users, although he emphasized that amphetamine psychosis
could occur in "apparently normal and well-adjusted individuals." Ellinwood
(1972) indicated that 70% of individuals who develop amphetamine pyschosis have predrug history of antisocial personality or of schizophrenia.
Angrist and Gershon (1969a,b) have noted the severity of social and
personality pathology (prior arrest records, poor occupational histories,
extensive drug taking, sexual problems) before involvement with "speed."
Bell and Trethowan (1961b) have specifically mentioned severe sexual
problems prior to (and aggravated by) amphetamine use. This is not
presented to exonerate these drugs, which indeed can be seductive.
Usually normal social functioning and high-dose stimulant use are
incompatible, but although extraordinarily rare, cases of "controlled high-dose
use" do exist. One such case that we have encountered was that of a skilled
crane operator who after taking large doses of amphetamine became
alarmed at their effect on his judgment while working and asked to be
replaced on the job. Thereafter he continued to work in a sober condition,
but every month or two for several years would take an "amphetamine
holiday" during which he would purchase "diet pills" in large amounts
(containing up to 1000 mg of the stimulant) and would swallow them "on the
spot" because of his fear of the legal repercussions of being apprehended
with them. He would then return to his apartment and spend the next three
or four days playing music or reading. He became known to us only because
the dysphoria at the end of one such "holiday" led him to buy some
barbiturates in order to sleep. After swallowing them, as was his custom, "on
the spot" he lost consciousness and was brought to the hospital.
Some of the clinical aspects and features frequently associated with highdose stimulant use are as follows.
l36
8.3.1. The "Rush"

Kalant (1973) has noted that frequent references are made to "high dose
intravenous use as opposed to low dose oral use," and indicated that this
"sharp contrast" is "unwarranted and misleading." We concur with this
assessment that dose, not route, is the most important factor in determining
the immediate danger to the individual at a given time. However, as Kalant
also noted "the use of the intravenous route of administration introduces
specific additional complications ... these include the rapidity and intensity of
the onset of drug effect and hence the rate and strength of development of
psychological dependence, and also the occurrence of physical complications
related to the practice of injection." Indeed, the "rush" or "flash" (as the
initial effect of intravenous use is called) is a highly prized and psychologically potent effect, which often profoundly alters much of the user's
subsequent relationship to the drug. It has been described by Rylander
(1969) as follows: "One of the addicts. . . said that at first he feels numbed
and if he is standing he goes down on his knees. The heart starts beating at a
terrible speed and his respiration is very rapid. Then he feels as if he is
ascending into the cosmos, every fiber of his body trembling with happiness."
This experience, frequently explicitly described as a "full-body orgasm"
(Smith and Fischer, 1970), usually becomes autonomously desired. This, in
turn, leads to overall increased dosage; Jonsson et ai. (1969) ha d cumented that the intensity of the rush is dose related, hence the tendency for
users to inject larger doses. Moreover, the desire to reexperience the rush
occurs well before the overall effects have cleared and leads to additional
injections and larger cumulative doses at a time when an oral user might
judge that he has "had enough." This type of stimulant use leads to cycles of
unproductive frenzied activity, stereotypy, or psychosis alternating with
exhaustion, extended sleep, and subsequent dysphoric lethargy. Thus the
desire for the rush itself becomes a determinant of cyclic use, increased
cumulative dose, severity of effects, and particularly a more severe degree of
dependence often amounting to continuous preoccupation with the drug
and its effects.
Several investigators have specifically focused on these aspects of stimulant use. Jonsson et ai. (1969) studied the neurochemical determinants of the
amphetamine rush by assessing the effectiveness of various pharmacological
antagonists in blocking the effects of a large intravenous "challenge dose" in
abusers. a-Methyl-tyrosine, 6 g over 26 hr, was found to be an effective
antagonist, implicating the role of catecholamines in this response. In a
second publication (Jonsson et ai., 1971a) it was demonstrated that this
blockade does not diminish amphetamine blood levels, which were unchanged by a-methyl-tyrosine pretreatment, and that tolerance to the
blockade develops rapidly. Subsequent studies (jonsson, 1972; Gunne et ai.,
1972) documented that pimozide and chlorpromazine blocked euphoria, but
that phenoxybenzamine and propranolol did not, implicating dopaminergic
137
neurons in this response. It has also been shown (Pickens and Harris, 1968)
that rats enabled to self-administer stimulants intravenously will develop, like
human abusers, a cyclic pattern leading usually to weight loss, body multilation, and sometimes death (Pickens et al., 1972). The same cyclic pattern and
autotitration has been documented in monkeys (Schuster et al., 1969).
8.3.2. Psychosis
The most dramatic effect of stimulant abuse usually seen with high-dose
use, though not specifically associated with the intravenous route, is the
development of psychosis. This is most frequently characterized by intense
emotional lability, hallucinatory phenomena, and paranoid ideation in a
setting of clear consciousness. Affect may be blunted or pathologically
intense, although disorder is seen in some but not all cases.
Cases of amphetamine psychosis were originally observed in patients
with narcolepsy, the first condition for which the central stimulant effects of
the drug were exploited. These were reported in 1938 by Young and
Scoville. Thereafter, sporadic reports of single cases or small series of
amphetamine psychosis appeared in the medical literature (tabulated in
detail by Kalant, 1973). Seven patients in a series of eight who entered a
psychiatric hospital after ingesting the contents of benzedrine inhalers
(Herman and Nagler, 1954) showed paranoid-hallucinatory syndromes
"with a minimal disturbance in the intellectural and cognitive functions." The
backgrounds of these patients indicated severe sociopathy, but were not
indicative of schizophrenia. This suggested that amphetamine could induce a
schizophrenic-like symptomatology in nonschizophrenic patients.
Connell's monograph (1958), a detailed study of 42 patients with
amphetamine psychosis, also indicated that this was the case. In addition, the
size of his series made it clear that amphetamine psychosis was not nearly so
rare an entity as had been previously thought. Connell described the clinical
picture as "primarily a paranoid psychosis with ideas of reference, delusions
of persecution, auditory and visual hallucinations in a setting of clear
consciousness," and concluded that symptomatology induced by amphetamine could be "indistinguishable from acute or chronic paranoid schizophrenia." This conclusion was the subject of some debate. In 1959 Slater,
reviewing Connell's monograph, wrote:
... an experienced clinician would probably suspect a toxic psychosis if he
bore the possibility in mind. Features in which it tends to differ from a
schizophrenic state are the past history of psychopathic traits, the rapidity of
onset, the dreamlike quality of these experiences, the tendency toward
visual hallucination, and the brisk emotional reaction, usually in the
direction of anxiety. Only the most hyperacute of paranoid schizophrenic
states will mimic this syndrome and all its pecularities.
A second author, Bell (1965), while underlining the similarity of amphetamine pyschosis or paranoid schizophrenia, indicated that in the former the
138
prominence of visual hallucinations, when present, and the lack of thought

disorder were distinctive features.
Studies at our center tended to bear out Connell's contention that the
symptomatology of amphetamine psychosis might replicate that of schizophrenia quite closely. This is exemplified by the following case history of a
young man who presented with an acute schizophreniform episode that
cleared in less than a week without residual pathology of thinking and affect,
and who was thereafter diagnosed in independent interviews by two research
psychiatrists as a sociopath with no clinical features suggestive of schizophrenic illness. Both amphetamine and methamphetamine were present in
urine collected after his transfer to the research ward (Angrist and Gershon,
1969b).
This 18 year old male had been in a reformatory because of refractory
truancy in the past and arrested for possession of marijuana and petty
larceny. At the time of his hospitalization a trial was still pending for
violation of the Sullivan Law (possession of a loaded pistol). He had sniffed
glue and Carbona from ages 12 to 13, drunk heavily from ages 13 to IS,
and had used amphetamine orally (5 or 10 capsules per day) and intravenously from age 16 onwards. He had used Heroin for 3 or 4 months
between the ages of 17 and 18. He left high school in the eleventh grade
and therafter worked in a Pizza stand, bicycle stores, and as a messenger but
no job had lasted for more than 5 to 6 months.
In the 2 weeks prior to admission he stayed in his brother's and sisterin-law's apartment and had taken 3 to 7 injections per day of a powder of
unknown purity that he was told was methamphetamine. During this time
he heard his brother tell his sister-in-law that he had killed his mother and
planned to kill him (the patient) as well. He panicked and, in an attempt to
escape, ran into the street without shoes or shirt and jumped on the rear
fender of a passing mail truck. This led to his being taken to Bellevue
Psychiatric Hospital by the police. In the hospital he was frightened,
apprehensive and felt that the staff and other patients were implying that
"he knew something" that he refused to tell. When he was seen by the
research staff, two days after admission (a Monday), his affect was blunt,
constricted and, at times, incongruent. After being transferred to the
research ward he became frightened and tearful fearing that this was a
place where patients were sent to be punished and perhaps even killed. He
showed a formal thought disorder, some examples of which are as follows:
on the day of his transfer, speaking of his brother's drug use he said "My
brother has been playing with the fires of hell." On the same day when
asked what "a stitch in time saves nine" meant, he said "hurry up with that
date and don't be late" (laughs) "make that first stitch right and the rest will
follow." On the next day persecutory ideation had diminished and was
replaced by diffuse referentiality-Le., other patients on the ward were
looking at him peculiarly. Affect was still somewhat blunt, constricted and
incongruent to expressed ideation. On the following day (his third on the
research ward and fifth in the hospital) he responded to proverb about glass
houses, thus "If you throw stones you risk your life. Living in a glass house
would shatter your whole being." He was apprehensive about a female
patient on the ward that he referred to, idiosyncratically, as "the girl I call
Bonnie" (after the movie Bonnie and Clyde). These mental status features
then cleared rapidly.
139
In 1968 Griffith et al. demonstrated that amphetamine psychosis could

be induced under controlled experimental conditions in volunteer subjects.
These subjects received 5-10 mg d-amphetamine hourly by mouth for as
long as was tolerated. All subjects developed paranoid delusions, often with
cold detached affect, but did not hallucinate or show formal thought
disorder. Since a diagnosis of schizophrenia excluded subjects from this
experiment, these results definitively answered the question of whether
amphetamine could induce de novo psychosis in nonschizophrenia individuals
or whether it merely released "latent" schizophrenic symptoms. Experimental
induction of amphetamine psychoses in non psychotic amphetamine abuservolunteers has subsequently been undertaken at our Center. In these studies
we followed Griffith's fundamental methodology but administered somewhat
larger doses (up to 50 mg racemic amphetamine per hour). During these
experiments, olfactory, auditory, and visual hallucinations were noted in some
subjects, suggesting that the lack of hallucinatory experience in Griffith's
cases might have been a function of the relatively lower dosage used (Angrist
and Gershon, 1970). These findings were consistent with those previously
observed in naturally occurring amphetamine psychosis (Angrist et al., 1969),
which suggested that hallucinatory experience is a phenomenon that occurs
with relatively high doses of amphetamine and is a labile symptom that clears
well before paranoid ideation.
The occurrence of thought disorder in amphetamine psychosis has been
debated (Bell, 1965, 1973; Evans, 1959; Angrist et al., 1969, 1974; Angrist
and Gershon, 1969b, 1970). In our studies we have observed disorders of
thinking of several types. One type, consisting of irrelevance, tangentiality,
diffuseness of thought, inability to focus on a point, and loss of goal
direction, was documented in two abuser-volunteers to whom amphetamine
was administered. Both were long-term heavy users of the drug and in both
it occurred in conjunction with distinctly flattened affect. One subject, for
example, became progressively illogical as amphetamine was administered
and stated that the investigator could not affect the way he (the subject) felt
"because you aren't high." A second subject, when asked how he felt (after
430 mg I-amphetamine), answered, "agitated and annoyed." Asked why, he
responded, "it's a ridiculous thing, like the marijuana laws, or birth control.
That's totally ridiculous! Just like a thunderstorm in the forest. It affects
young trees. There is a balance of nature. You mess with the balance of
nature, you lose buffalo, you lose birds. Things become extinct. For man,
you lose philosophies."
Other subjects, however, have shown more dramatic disorganization of
thought. One nonschizophrenic subject after receiving 595 mg of the racemic
amphetamine showed verbal and written productions that were disorganized,
rambling, and very bizarre. He felt that he had become "a prophet" who was
being addressed directly by God. He stated:
My consciousness in the form of what you know as human. My feeling
which I received from him. I bring the answer to the unknown and yet.
140
They who do not hear or show laugh or murder my love. In my human

form he might let me act human for the rest must still wonder at my actions
which make them doubt my having been used to enlighten. Every thought
that stops me from accepting all knowledge more than man has ever known.
It is just part of the supreme game to make you wait until it is time for you
to receive everlasting good. It is not mine to give. I am his, I bring his will,
call it prophet.
An example of his written production is illustrated in Fig. 1.

Nonetheless, other subjects experienced acute psychotic episodes in
which content of thought was grossly psychotic yet form remained quite
intact: One, for example, after 465 mg racemic amphetamine over 23 hr
experienced an acute and florid paranoid hallucinatory psychosis. He first
saw "colored halos" around lights, then "heard" a gang coming in the ward to
kill him. His paranoid feelings included the experimenter, who he assumed
had "set up the trap." At times he was quite hostile. Explanations that his
experiences were drug induced were rejected with sardonic mock agreement,
e.g., "Oh sure! Ha! Is that the way it's going to be?" At other times he would
become tearful and beg the experimenter to explain "what was really going
on." He had visual hallucinations of gangsters, doors opening and closing in
the shadows, and visual illusions, i.e., paper on a bulletin board "turned into"
a gangster in a white raincoat. He jumped at the slightest sound, assuming it
was the gang coming to "get" him and was so frightened that he refused to
investigate the ward to "prove" that no one was really there. When the gang
was not "heard" or "seen" he constantly "sensed their presence." He was
certain that the endpoint of the experiment was for him to be killed. He
experienced intermittent auditory hallucinations-accusations that he was a
FIG. 1. Written production of a nonschizophrenic subject who felt that he had become a
"prophet" after ingesting 595 mg of racemic amphetamine.
141
thief, e.g., "hide your money, the thief is here!" On the basis of these studies,
we concluded that Connell's statement that amphetamine psychosis "may be
indistinguishable from acute or chronic paranoid schizophrenia" had been
confirmed.
In the course of our studies various management regimens were utilized
after symptomatology was established and documented. Barbiturates and
other sedative hypnotics were often requested by abusers at the termination
of the experiment. These were given but proved quite unsatisfactory.
Titration proved difficult: a less than hypnotic dose induced a drunken state
in which the emotional lability associated with the "let-down" was compounded and management became quite difficult. Since that time Bell (1973)
has indicated that barbiturates, in fact, potentiate the cardiovascular effects of
stimulants, another reason for avoiding their use. We then assessed the effect
of various phenothiazines and haloperidol subsequent to large-dose amphetamine administration and found them helpful in management. Characteristically subjects responded almost immediately in a way similar to the response
seen over longer periods of time in schizophrenics. Agitation would diminish
and, if delusional ideation persisted, subjects noted that "it doesn't frighten
me now." Griffith (1970) has also noted similar patterns of response to low
doses of chlorpromazine in patients with amphetamine psychosis.
Chlorpromazine has been specifically recommended for the treatment
of amphetamine poisoning (Hopkin and Jones, 1956) and has been dramatically efficacious in this condition (Gullat, 1957; Espelin and Done, 1968).
Haloperidol has also been shown to have dramatic efficacy in reversing
amphetamine-induced psychiatric symptomatology as well as its cardiovascular effects (Angrist et ai., 1974). Since chlorpromazine is known to have
antiadrenergic and antidopaminergic effects it might well be, theoretically, a
drug of choice in cases in which both physical toxicity, on the basis of
peripheral effects, over psychosis are of concern. On the other hand,
chlorpromazine has been shown to increase the half-life of amphetamine in
brain and its blood levels while haloperidol did not (Lemberger et al., 1970).
In the absence of controlled comparative studies we hesitate to recommend
the use of one of these drugs over the other.
8.3.3. Stereotypy
Amphetamine abusers may persist in a repetitious thought or act for
hours. This peculiar phenomenon was specifically referred to by Scher
(1966) under the argot "being hung-up." The user "may sit in a tub and
bathe all day long, clean up the home or a particular item, hold a note or
phrase of music, or engage in non-ejaculatory intercourse for extended
periods." Other forms documented include repetitive car polishing for hours
at a time, elaborate sorting of soft small objects, endless dismantling of radios
or clocks, or doodling for hours. McNeil (1967) has described an amphetamine abuser's apartment as "a distinctive dwelling; clutter competes with
142
examples of obsessed meticulousness. A carpet could be picked free of dust

by hand while dishes fester in a sink."
Rylander (1969) introduced the term "punding" to describe this form of
behavior in Swedish phenmetrazine users, which he defined (Rylander,
1971) as "an organized goal directed but nevertheless meaningless activity"
and as "an automatic behavior with something of the compulsive factor,
which is typical for obsessive-compulsive states". Although compulsiveness is
not usually extreme and punding can be broken, particularly by external
stimuli such as an approaching policeman, one such extreme case was
described (Rylander, 1969) occurring in the midst of a burglary in which a
user desperately wished to stop for fear of being caught, but was unable to.
Almost all addicts questioned by Rylander (1971) indicated this repetitious
behavior to be rather enjoyable, exclusive of social interaction but dependent
on the sociocultural pattern, characteristic of the individual and accompanied
by a marked change of the time motion.
Repetitive stereotyped patterns of behavior are also obtained in many
animal species with amphetamine and other stimulants and this has been
extensively documented (Randrup and Munkvad, 1967, 1970; Ellinwood et
al., 1973, Sudilovsky et at., 1974). These behaviors appear to be an
intensified expression of the animal's characteristic exploratory mode and
tend to become more variable and complex as one ascends the philogenetic
ladder, so that in rodents sniffing and sitting behaviors are seen, cats show
head and eye turning or sniffing, and in primates, hand-eye stereotypies are
first seen to emerge (Ellinwood and Sudilovsky, 1973). An extensive and
systemic series of studies utilizing such techniques as selective enzyme
inhibition, agonist-antagonists relationships, and local microinjections carried
out in the laboratories of A. Randrup (reviewed by Randrup and Munkvad,
1970) have documented the importance of central dopaminergic facilitation
(particularly in the striatum) in mediating this stereotyped behavior. These
studies led to the development of the invaluable concept that drug-induced
stereotyped behavior in animals might serve as a model for stimulant
psychoses in humans and for naturally occurring schizophrenic states
(Angrist et at., 1971; Sudilovsky, 1975a).
8.3.4. Violence
Kramer (1969) has noted that the hyperactivity, SUSploousness, and
lability of mood associated with amphetamine use may "lead to precipitous
and unwarranted assaultive behavior" and has noted that "most high dose
amphetamine users describe involvement either as aggressor or victim, in
episodes in which murder or mayhem was avoided by the slimmest of
margins." Carey and Mandel (1969) have also noted frequent instances of
violence, "which could be considered unprovoked under conventional circumstances," but estimate that the occurrence of this behavior "more than
once during every two or three runs would be unusual." In their experience
143
these "acts are usually not premeditated but triggered by perceived insults or
inconveniences." Ellinwood (1971) has collected data on murders committed
while under the effects of amphetamine documenting their capricious
impulsive quality.
In our study, based on hospital admissions, assaultive ness was infrequently noted (2 out of 60 cases), but was frightening because of the
unprovoked, arbitrary, and grossly psychotic qualities of the acts themselves.
One patient, for example, saw his roommate sleeping and felt that he
"looked dead." He thereupon took a door knob and beat his head with it
until restrained by a second roommate. Such unprovoked pharmacologically
induced violence, however, is only one aspect of the violence in the addicts'
subculture. A more calculated type of violent behavior often stems from the
weird rules, mores, and practices of the community itself. These are vividly
described in the writings of R. Smith (1969a,b) on the "speed-freaks" world.
In this underworld, "rip offs" (armed robberies, usually of drugs) are
commonplace, and "dime-dropping" (a phone call to the police) is punishable
by severe beatings or even death.
8.3 .5. Sexuality

Exact documentation of the effects of stimulants on sexuality is made
difficult by the high incidence of sexual maladjustment in amphetamine
users' premorbid personalities. In a most detailed study of these effects, Bell
and Trethowan (1961b) noted that 13 of their 14 patients had some
abnormality in their premorbid sexual adjustment. After taking amphetamine, five showed marked intensification of sexual feelings and three others
reported a consistent but less intense int:rease in sexuality. Of the remaining
six patients two reported diminution of sexuality while four noted little
effect. The authors noted that those patients with the most overtly perverse
sexual adjustments prior to amphetamine use were those who tended to
show higher intensification of sexual behavior after using amphetamine. In
this group, heightened sexual fantasy, compulsive masturbation, promiscuity,
prostitution, exhibitionism, sadism, pedophilia, and penile mutilation were
noted after amphetamine was taken. In other patients impotence and
increased sexual inhibition were manifestations of diminished sexuality.
In Connell's (1958) series, decrease of sexual feelings occurred in 5 of 42
patients while a striking increase in sexual pressure, often with markedly
compulsive and perverse expression, was noted in 7. In our series of 60
patients, 8 of 43 males reported a consistent increase in libido after
amphetamine use; 4 reported concomitant delayed ejaculation. This led to
episodes of "marathon" intercourse (up to 18 hours with only one or two
orgasms), which were reported to be intensely pleasurable. Females experienced heightened sexuality somewhat more frequently. This occurred in the
majority of the 17 females seen. Promiscuity, compulsive masturbation or
seeking out of intercourse, prostitution, and intensification of sadomasochis-
144
tic fantasies were reported as consistent sequelae of amphetamine use in

these patients. One claimed to have become orgastic only after using
amphetamine.
Similarly, in studies in which L-dopa was administered to both schizophrenic (Angrist et al., 1973) and nonschizophrenic (Sathananthan et al.,
1973) psychiatric inpatients, sexual effects were quite striking in the frequency of their occurrence and quality. In one patient a usual masturbation
rate of 5 times/week increased to 5 times/day. In subsequent reports of the
effects of dopamine receptor stimulants, which are not at all characteristically
euphoriant, sexual effects were also noted (Angrist et al., 1975).
8.3.6. Physical Toxicity

The general condition of stimulant abusers is one of striking dilapidation. They are usually grossly malnourished and at the end of a "run" are
often markedly dehydrated. Anggard et al. (1970) have observed dehydration amounting to 6.7% of total body weight in about half of their
amphetamine-dependent subjects. This dehydration probably leads to decreased renal excretion of amphetamine, prolonging the psychosis. On the
other hand, because of decreased food intake these individuals are often
acidotic, which in all likelihood, exerts some protective effects, since amphetamine excretion is greater under these conditions (Beckett and Rowland,
1964, 1965). Numerous pathophysiologic changes have been noted in highdose stimulant abusers in various organ systems. Among these are the
following.
(a) Kramer (1969) has noted that these individuals have a tendency for
poor wound healing and ulceration of the skin, possibly on the basis of poor
nutrition. Self-inflicted excoriations are also seen at times, representing
"picking" phenomena or frank delusions of parasitosis closely resembling the
Parasitenwahn of cocaine psychosis (Kalus, 1950; Knapp, 1952; McCormick,
1962; Meyler, 1960; Ellinwood, 1967). Other dermatologic phenomena have
also been described by Goldsmith (1939) and by Kauver et al. (1943), who
documented pruritic lichenified eruption that waxed and waned with amphetamine intake.
(b) The effects of amphetamine on the cardiovascular system were the
first of its actions documented (Barger and Dale, 1910; Piness et al., 1930;
Alles, 1933). Consistent increases in blood pressure and/or pulse (often with
an inverse relationship) and frequent sinus arrythmia were noted in the
course of experimental administration of large doses of amphetamine
(Angrist and Gershon, 1970). Anderson and Scott (1936) have reported chest
pains, multiple extrasystolies, and heart block after use of moderate doses.
Waud (1938 documented paroxysmal tachycardias and orthostatic hypotension following inhalation of large doses of amphetamine. Pulmonary hypertension has also been specifically reported (Malmquist et al., 1970), presumably due to the sympathomimetic effects of these amines on the pulmonary
145
vascular tree. Several effects on cerebral blood vessels have been reported.
These include, in man, necrotizing angeitis (Citron et al., 1970; Margolis and
Newton, 1971) and intracraneal "beading" (Gericke, 1945; Goodman and
Becker, 1970; Weiss et at., 1970,. In monkeys similar "beading" of cerebral
vessels with segments of slow flow or block and extravasation of radiologic
contrast medium, petechial hemorrhages, and cerebral edema have been
noted (Rumbaugh et al., 1971), and similar changes have been observed in
rabbits intoxicated with methamphetamine (Kasirsky et al., 1972). The
mechanism of these changes was not documented but a combination of acute
hypertension and local vasoconstriction is suspected, particularly in view of
negative findings in monkeys chronically (3-6 months) intoxicated with
progressive doses (from 0.5 to 52 mg/kg per day) in order for cardiovascular
tolerance to develop. None of the above effects were replicated in these
animals in spite of the terminal high doses (Schuster and Fischman, 1975).
Histopathologic changes in brain substance such as neuronal chromatolysis,
gliosis, and petechial hemorrhages reported in cats and monkeys (Ellinwood
and Escalante, 1970; Escalante and Ellinwood, 1972) could also be due to
hypertensive or vascular changes.
(c) In blood, several conditions have occasionally been associated with
stimulant use. A polycythemia was reported by Myerson et al. (1937). The
coexistence of amphetamine abuse and acute leukemia was noted by Berry
(1966) and a case of fatal pancytopenia has been reported (Mitchell and
Denton, 1950).
(d) The vasoconstrictive effect on the nasal mucosa leading to necrosis
and perforation of the nasal septum after chronic intranasal cocaine is well
documented. Amphetamine is also frequently taken intranasally but we are
not aware of reports of similar sequelae to its use.
(e) Dyskinetic movements of various types have been observed with
stimulant abuse. Connell (1958) did not note these specifically but did refer
to sore tongue in three of his cases. Bartholomew and Marley (1959) noted
facial twitching in seven of twelve cases of phenmetrazine abuse. Ashkroft et
al. (1965) pointed out bruxism (teeth grinding) and continuous chewing
movements with rubbing of the tongue along the inside of the lower lip,
which may lead to buccolingual ulcers, as useful signs to recognize amphetamine addicts. Grimacing and lipsmacking were reported by Mattson and
Calverley (1968) with therapeutic doses in two children who also reported
chorea-athetoid movements of the hands, arms, and legs as well as twisting of
the head after therapeutic doses of stimulants. We have observed a choreoathetoid syndrome (unpublished) after amphetamine and choreoathetosis of
the head, trunk, and upper (more than lower) limbs after administration of
the dopamine receptor stimulant ET-495 (Angrist et al., 1975). The similarity
of some of these movements to those seen after L-dopa treatment of
Parkinsonism and to tardive dyskinesias is striking (Sudilovsky, 1975b).
Rubovitz and Klawans (1972) and Klawans (1973) have summarized the
extensive pharmacological evidence suggesting common pathophysiologic
146
disturbances in acute amphetamine effects, L-dopa treatment, and neuroleptic-induced tardive dyskinesias.
Deaths directly attributable to amphetamine are rare, particularly in
view of the massive doses often taken by abusers. Grinspoon and Hedblom
(1975) have collected those in the literature, but in most instances concomitant alcoholism or use of other drugs complicates the issue. The most clearcut cases of deaths directly related to overdose are those reported by Gericke
(1945), Zalis and Parmley (1963), and Smith (1969), all of which indicate
autopsy findings. Smith also reports methamphetamine levels in blood,
urine, liver, and brain. Zalis and Parmley's report emphasizes pathologic
findings and reviews those reported in prior cases. Both Zalis and Parmley's
and Smith's notes on the clinical course of their patients' illness indicate
terminal dysautonomia with hyperpyrexia and hypotension. We have encountered another case of death (unpublished) in a user who, confronted in
a raid, "swallowed the evidence" and died 14.5 hr therafter. Witnesses
estimated that he had taken 10-15 g. He became delirious and also
developed terminal hyperpyrexia and hypotension. Unfortunately, autopsy
and toxicologic studies were not adequate to contribute further to understanding the mechanisms of death.
8.4. Withdrawal Effects

Monroe and Drell (1947) were to our knowledge the first to document
the occurrence of complaints after discontinuance of amphetamine and to
qualify them as withdrawal symptoms. Among these, feelings of fatigue and
sleepiness were most frequently indicated by their subjects. Feelings of
depression were also recorded. Connell (1958) specifically noted the occurrence of depression and hypersomnia when amphetamine was discontinued.
He considered these symptoms "mainly of little moment" but did emphasize
that the depression could be accompanied by suicidal ideas or attempts.
Schildkraut et al. (1971) stressed this "withdrawal depression" and proposed
it as a potential model for naturally occurring depressive illness. These same
authors reported that the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl glycol (MHPG) was elevated in the urine while amphetamine was
being taken and its level dropped when amphetamine was discontinued.
They interpreted this finding as supporting the proposed role of norepinephrine in naturally occurring depressive illness. More recently, Seltzer and
Tonge (1976) observed behavioral depression in rats after chronic methamphetamine treatment and reported its reversal by imipramine. This led them
to suggest that the behavioral depression induced in the rats "may provide a
model for the depressive state which may be useful in the evaluation of
potential antidepressant drugs."
In our experience, depression has been observed to occur after largedose amphetamine administration, but its clinical symptomatology differs
147
somewhat from the classical "endogenous" depressive syndrome. Qualitative

differences are the presence of hyperphagia and hypersomnia rather than
anorexia and insomnia. Quantitatively, psychomotor retardation is generally
less severe after amphetamine than in psychotic depression. We also question
whether urinary MHPG excretion can be used as an index of central
neurochemical events when amphetamine is taken. Several lines of evidence
suggest that urinary MHPG may be an index of peripheral rather than
central effects of amphetamine. Jonsson et al. (1971b) have found that
urinary norepinephrine was increased 2.2-fold and urinary epinephrine
(completely peripheral in origin) was increased 5.S-fold after amphetamine
was administered. Both can be precursors of urinary MHPG (Axelrod et al.,
1959). Furthermore, in studies at our center (An grist et al., 1972) in which
amphetamine was administered in large doses and both urine and cerebrospinal fluid were assessed for amine metabolites, the MHPG excretion pattern
in urine described by Schild kraut et al. did not correlate with changes in
cerebrospinal fluid. Taken together these studies suggest that the urinary
pattern of MHPG excretion described by Schild kraut represents peripheral
rather than central adrenergic effects.
Despite these reservations, however, the use of amphetamine withdrawal
in animals as a model state for screening potential antidepressants (Seltzer
and Tonge, 1976) remains a real possibility awaiting corroboration by
assessment of the effects of antidepressants of known efficacy other than
imipramine.
Other possible "withdrawal" effects described after stimulant are as
follows:
(1) Hypersomnia and lethargy: Long periods of sleep are not surprising
after several days of frenzied activity as a result of stimulant abuse. However,
even after adequate sleep, a period of anergic lethargy often occurs, usually
lasting several days or more. Depletion of amines is a possible explanation for
this phenomena, particularly in view of Lewander's work, cited above.
(2) Effects upon sleep: In 1963, Oswald and Thacore reported suppression of rapid eye movement (REM) sleep during amphetamine use and a
marked rebound of REM sleep after the drug was discontinued. These
findings were interpreted as indicating a physiological abnormality related to
withdrawal and hence documentation of a true abstinence phenomenon.
Since the same phenomenon is known to occur after use of many drugs of
different categories (alcohol, sedative-hypnotics, some opiates, and antidepressants) we question whether this phenomena is of either sufficient
specificity or clinical import to warrant its being considered evidence of an
abstinence syndrome.
(3) Hyperphagia: Characteristically upon awakening the high-dose amphetamine user is voraciously hungry. This does not appear to be simply the
result of reduced food intake concomitant to the use of amphetamine since
in non-drug-assisted starvation appetite becomes diminished rather than
increased (Kramer, 1969). Kramer cites an unpublished study by Seevers,
148
Gentz, and Deneau in which chronic intoxication with extremely high doses
of amphetamine (32 mg/kg per day) induced polyphagia with continued
weight loss. Post (1975b) has reported the same phenomenon occurring at
identical dosages.
9. MEDICAL USES OF STIMULANTS

Stimulants are generally considered to be indicated in the treatment of
narcolepsy, hyperkinetic behavior disorders in children, and in the shortterm treatment of obesity. In addition they are known to be of therapeutic
benefit in some specific forms of Parkinsonism. Their use in the treatment of
depression is somewhat more controversial, but recent literature suggests
some specific indications for their use in this disorder as well.
9 .1. Narcolepsy
Narcolepsy is characterized by pathologically sudden and irresistible
sleep attacks, loss of muscle tone often in response to emotional stimuli
(cataplexy), hypnogogic hallucinations, and sleep paralysis (Yoss and Daly,
1960). Its exact incidence in unknown. While generally considered rare,
some investigators have found the incidence (100 new cases per year)
considerably higher than was generally thought to be the case (Yoss and
Daly, 1960). The use of amphetamine in narcolepsy by Prinzmetal and
Bloomberg in 1935 represents the first specific exploitation of the drug's
CNS-stimulating properties. Its long-term use in this condition without
evidence of toxicity was noted by Bloomberg as early as 1940. Patients
suffering from narcolepsy frequently require larger doses of amphetamine
than normals to obtain therapeutic effects. Apparently, tolerance to these
effects does not develop since such patients can be maintained over long
periods at a fixed dose (Leake, 1958).
9.2. Hyperkinetic Behavior Disorders in Children

The role of stimulants in the therapy of these disorders has been
reviewed from a historical point of view by Cole (1969), who pointed out that
modern clinical psychopharmacology could be considered to have originated
with Bradley's report in 1937 on the effectiveness of benzedrine in the
treatment of hyperkinetic children, rather than Delay and Deniker's use of
chlorpromazine in 1952. The initial observations by Bradley (1937) and
Bradley and Bowen (1941) were confirmed subsequently in a number of
carefully controlled studies (Cytryn et al., 1960; Connors and Eisenberg,
149
1963; Eisenberg et ai., 1963; Eisenberg, 1964; Connors et ai., 1967).

Consequently certain CNS stimulants are widely used to treat this common
and, in all likelihood, heterogeneous syndrome, a practice that has stirred
considerable social controversy. Grinspoon and Hedblom (1975) cite as an
example an article in the Washington Post stating, inaccurately, that 5-10% of
the 62,000 elementary school children in Omaha, Nebraska, were being
treated with "behavior modifying drugs." Indeed, there is a possibility that
these drugs are being used in this condition somewhat indiscriminately,
particularly since some, but not all, hyperactive children respond well to
stimulant therapy. However, those that do respond generally do so dramatically and immediately. Therefore, because this disorder is one that causes
serious behavioral and adaptational problems, and interferes significantly
with a child's subsequent schooling and socialization, we feel that a therapeutic trial of stimulants of brief duration is generally indicated in hyperactive
children, as the potential benefits so far outweigh the long-term detrimental
effects of withholding an effective treatment. A recent noncomparative study
has reported quantitatively similar improvement in the treatment of hyperactive children with imipramine (Waizer et ai., 1974). However, seizures have
been reported as a result of imipramine administration (Brown et ai., 1973),
and a subsequent comparative study suggests that improvement on imipramine is apt to be less sustained over time than occurs with methylphenidate
(Quinn and Rapaport, 1975). Regarding adverse effects, this latter report
noted that both imipramine and methylphenidate reduced weight gain but
that neither drug had a significant effect on growth in height. It should be
specifically noted that a controlled follow-up study of adolescents treated
with methylphenidate as children did not indicate that methylphenidate
contributed to later drug abuse (Beck et al., 1975).
9.3. Obesity
The use of amphetamines in the treatment of obesity has been reviewed
by Penick (1969). As he noted, "in reviewing the literature on the use of
amphetamine compounds in obesity, it becomes obvious that there is an
enormous quantity of such literature and the quality of much of it is very
poor." Evaluation of efficacy of anorectic drugs in obesity is complicated by
many factors such as subject's expectations, the use of adjunctive diet, the
time at which the drug is given, and the trial period. These last two factors
deserve special comment. Penick has noted that "titrated d-amphetamine
does not appear in the blood until at least 54 to 60 minutes .... " Some
studies report giving anorexics only 30 min before mealtime. This regimen
in itself would be expected to negate any therapeutic efficacy. Length of trial
is also of great importance, since it is well-documented that tolerance
develops to the anorexigenic effects of central stimulants. As Penick has
noted, "the length of the trial in most published studies is approximately 4
150
weeks, and in most controlled studies, there is a marked difference between

the drug and placebo when the study is four weeks old. This effect becomes
less pronounced as the trial is continued, and in studies lasting 6 months, the
drug effect is usually not significant." Thus, rational use of stimulants in the
treatment of obesity dictates these not be given for longer than a 4-6 week
period. If their use if to be continued they should be administered on an
intermittent basis with interim drugfree periods in order that loss of
tolerance may occur.
It should be noted that obesity is a chronic condition requiring longterm treatment and that any efficacy of amphetamines or other stimulants
occurs on a short-term basis, perhaps providing the patient with encouragement and incentive to continue dieting but in no way substituting for this.
Most obese individuals who had sustained success at weight reduction are
emphatic in asserting that a global extensive and long-term change in eating
habits and pattern constitutes the only effective form of treatment.
9.4. Parkinson's Disease

Recently Parkes et at. (1975) have reviewed the role of amphetamines in
the treatment of Parkinson's disease. As they indicate,
Benzedrine (d,l-amphetamine) was first used for its alerting effects in
patients with postencephalitic Parkinsonism, many of whom were somnolent. This treatment caused a subjective improvement in energy and mood,
but little objective change in the signs of Parkinsonism. . . although some
patients showed a slight lessening of rigidity comparable with that produced
separately by anticholinergic drugs. The combination of these with Benzedrine resulted in considerable subjective improvement in most patients.
In patients receiving amphetamine similar results were described by Davis

and Stewart's early trials. Little improvement in the motor features of
Parkinsonism were noted, but oculogyric crises were observed by Parkes et at.
(1975) to be specifically abolished or reduced in all those with that particular
symptom. in this recent trial, although d-amphetamine induced a significant
but slight (20%) reduction in total disability, improvement was greater in "the
most disabled patients, including those also on L-dopa."
9.5. Depression
As Klein and Davis (1969) have pointed out,
the use of stimulants such as dextroamphetamine in retarded depression is
unrewarding. Patients treated with large doses of dextroamphetamine often
become nervous and irritable but retain their retarded depression. Some
therapists start patients on dextroamphetamine and imipramine simultaneously, in the hope that there will be an immediate lift from the dextroam-
151
phetamine that will help the patient bear the two-week or more delay
period before the imipramine clinical effect takes place
but indicate that in their experience this practice is of limited usefulness.

Klein and Davis, however, delineate very specific uses for stimulants as
adjuncts in the treatment of depression. These specific uses depend on the
recognition of a distinction between depression and demoralization. As Klein
and Davis point out, demoralization does not affect a person's capacity for
erTIoyment in the same fundamental way as depression but represents a
change in the self-image in which self-doubting trends are incorporated and
the individual feels capable of coping with the demands of his existence:
"The demoralized person can enjoy himself in a setting in which no demands
are made upon him. His appetites are not inhibited and his sleep pattern is
normal." However, since demoralization is often a sequela of the depressive's
illness, Klein and Davis have indicated that "an occasional patient will
respond moderately well to imipramine in terms of mood elevation, but still
maintains many self-doubting demoralized trends. The addition of small
doses of dextroamphetamine, 5 to 10 mg daily, is often of marked help."
More recently two other quite specific indications for the use of
stimulants in the treatment of depression have been described. Fawcett and
Siomopoulos (1971) have indicated that an elevation of mood in response to
an acute dose of amphetamine might be predictive of a positive therapeutic
response to imipramine. Since the clinical effects of imipramine in depression
are often not apparent for two weeks or more, such a predictive index would
be of considerable clinical value in choosing the patients in whom to use this
drug. This finding requires further confirmation. Yet another use of
methylphenidate specifically in the treatment of depression has recently been
defined by Perel et at. (1969) and Wharton et ai. (1971). These investigators
have found that methylphenidate has a competitive inhibitory effect on the
metabolism of imipramine with the resulting effect of a rise in imipramine
blood levels (Perel et ai., 1969). They have treated patients unresponsive to
imipramine with small doses of methylphenidate and found not only increase
in blood levels of the drug, but at times rather dramatic clinical response
where none had been evidenced previously (Wharton et ai., 1971). This
finding obviously represents significant advance in the clinical management
of depressive states, particularly those that have proven refractory to
antidepressants.
10. PROBLEMS RAISED BY STIMULANTS

10.1. Problems with Respect to Society and Legislative Control
It is quite apparent that stimulant dependence and abuse can be socially
harmful; violence and homicide have occurred in cases of stimulant psy-
152
choses. Even in the absence of psychosis it is clearly undesirable for

widespread use and dependence to prevail in a country's population. The
degree of lagislative control required to prevent it without hampering
medical practice or research is a delicate issue perhaps best approached by a
process akin to titration in which the current situation is assessed and
responded to with sensitivity but not hysteria. The effect of complete lack of
control was seen in Japan. Undercontrol was the case for years in the U.S.
and led for a time to progressively increased use. In Sweden stringent
controls were utilized with some success in decreasing use. In the U.S.,
however, stimulant use has sharply decreased without need to resort to the
same measures. It therefore seems at this time that the existing laws in the
U.S. suffice, although subsequent changes in patterns of use might necessitate further readjustments.
Some specific and clear-cut recommendations do emerge from past
experience: (1) New stimulants to be developed in the future should
probably be viewed with suspicion as to their abuse potential from the onset
rather than be made available on an unregulated basis initially; (2) parenteral
forms of stimulants should be made available only for research purposes,
their use in clinical medicine being, in general, not justified.
10.2. Problems in Research

The CNS stimulants have played an invaluable role in the development
of the "dopamine hypothesis of schizophrenia." The clinical similarity
between this ahd the stimulant psychoses first explicitly noted by Connell
(1958) and subsequently confirmed by Griffith et al. (1968), Angrist and
Gershon (1970), and Angrist et at. (1971) suggested their validity as a model
of naturally occurring schizophrenia. The stereotyped behavior induced in
abusers and animals was the subject of an extensive and systematic series of
studies in the laboratories of Dr. Axel Randrup. These (reviewed by
Randrup and Munkvad, 1970) led to the all important development of an
animal model for stimulant psychosis and documentation of the importance
of central dopaminergic hyperactivity in the mediation of this behavior. A
series of studies (reviewed by Angrist, 1975) suggested a similar importance
for dopaminergic mechanisms in de novo stimulant psychosis in humans and
in the stimulant-induced worsening of schizophrenic psychopathology. Simultaneously, studies of the biochemical pharmacology of neuroleptics
(reviewed by Snyder, 1973, and Matthysse, 1974) indicating the critical
importance of dopamine receptor blockade in their antipsychotic effects gave
impetus to the "dopamine hypothesis of schizophrenia."
This hypothesis must undoubtedly have seemed glib and simplistic to
some, particularly when initially formulated. It appeared to imply, derivatively, that dopamine blockade would constitute an "answer" to all the
problems of schizophrenia. This has not proven to be the case. Rather than
153
providing simplistic "short-cut" solutions, the dopamine hypothesis has

underscored the need and provided impetus for laborious systematic dissections of the mechanisms of working of central dopamine systems and their
modulation by other central systems. The eNS stimulants have been and will
certainly continue to be potent research tools in studies searching for an
understanding of pathogenic mechanisms of psychotic states.
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DRUG TREATMENT IN CHILD

PSYCHIATRY
Daniel J. Safer
l. INTRODUCTION
There are now over 20 review articles in pediatric psychopharmacology and
they appear to be increasing in the 1970s (Sprague and Werry, 1971; Di
Mascio et at., 1970; Renshaw, 1975; Freeman, 1970; Blackwell and Currah,
1973; Conners, 1972; Campbell, 1975b,c; Eisenberg and Conners, 1971;
Greenberg and Lourie, 1972; Eveloff, 1970; Kornetsky, 1975). They function to simplify the process of keeping up with the ever-expanding number
of papers in the field and to organize the numerous findings of separate
studies.
Some reviewers (Freeman, 1966, 1970; Sprague and Werry, 1971) in
their philosophical comments tend to lament the state of the field, stressing
that a large number of drug studies in child psychopharmacology are
uncontrolled. Others (e.g., Renshaw, 1975; Blackwell and Currah, 1973;
Conners, 1972; Campbell, 1975) show respect for initial uncontrolled studies
and imply satisfaction with the growth of the field over the last 15 years.
These two positions are not mutually exclusive. Nonetheless, my sentiments
are with the latter group of reviewers.
This general review will differ from many others in that it will be
organized around major clinical categories in pediatric psychiatry. Furthermore, drug treatment will be viewed within the framework of the natural
course of a clinical disorder and in relation to nondrug treatments. The
clinical categories include hyperactivity, learning disorder, childhood psyDaniel J. Safer
Baltimore County Department of Health, Rosedale, Maryland.
167
168
DANIEL]. SAFER
chosis, enuresis, tics, school phobia, stuttering, anorexia nervosa, mental

retardation, sleep disorders, and seizures. In these conditions, drug treatments have been tried extensively. Left out of this review are categories of
children (e.g., those suffering from asthma, psychoneurosis, child abuse) who
only rarely have been treated with psychotropic drugs.
When available, double-blind studies have been the exclusive references
to document points on drug treatment. This was possible (with rare
exceptions) in the sections of childhood psychosis, mental retardation,
enuresis, and hyperactivity. In discussions covering school phobia, tics, and
learning disability, the studies cited were for the most part controlled.
However, in some areas--anorexia nervosa, seizures, stuttering, and sleep
disorders--a large number of uncontrolled studies were discussed because of
the limited number of controlled reports in the literature.
2. CHILDHOOD PSYCHOSIS
2.1. Characteristics, Occurrence, and Outcome
Childhood psychosis is a vaguely defined diagnostic category characterized basically by a gross and sustained impairment in the child's ability to
relate to people (Creak et al., 1961). The malady is usually apparent between
the ages of one and three, with a male-female ratio of approximately 3 : 1.
In the general population, the frequency of childhood psychosis is 1-6 per
10,000 (Werry, 1972b). However, some clinicians identify bizarre children
who are preoccupied with fantasies as psychotic. As a result, estimates of the
percentage of childhood psychoses in the caseloads of some mental health
centers range as high as 22% (Sabot et al., 1969).
Psychotic children tend to have low IQs, speech retardation, neurological abnormalities, and a high rate of epilepsy (Rutter, 1965). The disorder is
extremely serious and only one fourth-<>n the average-<>f these children go
on to make an adequate adult adjustment (Werry, 1972b; Eisenberg, 1967).
2.2. Nondrug Treatment

The results of psychotherapy have been systematically studied for
schizophrenia in adults (May, 1968), but not for childhood psychoses (Werry,
1972b). However, available evidence suggests that the long-term effect of
psychotherapy on psychotic children is minimal (Goldfarb, 1970). Behavior
therapy has resulted in some measurable changes in psychotic behavior, but
the durability of these changes has not been studied (Werry and Wollersheim, 1967).
The long-term outcome of shock treatment for psychotic children is said
DRUG TREATMENT IN CHILD PSYCHIATRY
169
to be fair in that one fourth to one third improve and go on to an adequate

adult adjustment (Bender, 1953). However, this is similar to the general rate
of improvement expected for these children.
2.3. Drug Treatment

2.3.1. Minor Tranquilizers
Rawitt (1959), in a double-blind (DB) study using high doses of
meprobamate for six weeks reported that the drug was not very useful for
psychotic children. Kraft et al. (1959) in a controlled study found meprobamate to be of no benefit. Diazepam also has not received good reports (Lucas
and Pasley, 1969). Fish (1960) reported that diphenhydramine (Benadryl)
helped only 6 out of 18 schizophrenic children, a generally unimpressive
result. Chlordiazopoxide (Librium) can worsen a preexisting psychotic condition in children (Le Vann, 1962; Pilkington, 1961) and should therefore not
generally be used for this population. Hydroxyzine (Atarax) was reported to
be useful for psychotic children but this was only based on laboratory
observations before the drug was administered and after two weeks on the
drug (Freedman et al., 1960).
2.3.2. Stimulants, LSD, and Tricyclic Antidepressants

Stimulants disorganize the thinking of psychotic children (Campbell et
al., 1972a; Fish, 1971). LSD can exacerbate psychotic symptoms in children,
although it can also increase alertness, lessen motor inhibition (Campbell,
1973), and increase insight and language use (Bender, 1970; Morgar and
Aldrich, 1969) in some autistic youngsters. Tricyclic antidepressants, such as
imipramine, can disorganize the thinking of seriously disturbed and anxious
children and thus produce or aggravate childhood psychosis (Campbell et al.,
1971a; Pilkington, 1962).
2.3.3. Major Tranquilizers

Major tranquilizers can significantly decrease many overt behavioral
symptoms (e.g., hyperactivity, aggressiveness, and impulsiveness) of young
psychotic patients. As a group, they also tend (for psychotic youngsters) to
decrease anxiety, improve sleep patterns, increase socialization, improve
communication, and increase appetite (Waizer et al., 1972; Saletu et al.,
1974).
2.3.3.1. Phenothiazines
1. Chlorpromazine. Chlorpromazine, although one of the most commonly used drugs in psychiatric psychopharmacology (Simeon et al., 1974a)
and a standard to evaulate major tranquilizers in adults, is not considered by
most investigators to be the best drug to treat childhood psychosis. In
170
DANIEL J. SAFER
psychotic children under age 6, it is not very effective (Campbell et at., 1970,
1972b). In adolescent schizophrenics, it is one useful phenothiazine drug
(Campbell, 1973; Fish, 1960). Fish (1973) among others (Campbell et at.,
1972c) stresses its induction of underactivity (lethargy and apathy) and
therefore leans away from its use. In childhood psychosis, clinicians use
chlorpromazine in an average dose of 200 mg/day (Simeon et at., 1974a).
2. Thioridazine. Thioridazine (Mellaril) in single-blind comparisonstudies by Engelhardt et at. (1972) was found to be quite effective in the
treatment of childhood psychosis. It has been given in doses averaging 167
mg/day (Simeon et at., 1974a).
Of all the major tranquilizers, it causes the most weight and appetite
gain (Engelhardt et at., 1972; McAndrew et at., 1972). When the drug is
discontinued, a weight loss follows (Engelhardt, 1973). Very high doses of
thioridazine (over 800 mg/day) over a prolonged period can lead to
pigmentary retinal changes (Davidorf, 1973; Irwin, 1974).
3. Trifluperazine. In their studies, Fish et at. (1966) found trifluperazine (Stelazine) to be an effective phenothiazine for psychotic children (more
effective than chlorpromazine). However, Engelhardt et at. (1972) in a singleblind study found its effects to be not comparable to other major tranquilizers. Engelhardt et at. (1972) also noted that its induction of extrapyramidal
signs (EPS) was frequent.
4. Fluphenazine. Engelhardt et at. (1972) found in a single-blind,
comparative study that fluphenazine is an extremely valuable drug in the
treatment of childhood psychosis. However, their dose of fluphenazine was
unusually high-IO-25 mg/day. Saletu et at. (1975a) using an average dose of
5 mg/day of fluphenazine also reported that the drug significantly reduces
aggression and hyperactivity in psychotic children. The induction of EPS by
fluphenazine is one of the highest among the major tranquilizers, although
this can easily be counteracted with anticholinergic drugs (Saletu et at.,
1975a). When a persistently high dose (e.g., 25 mg/day) of this drug is
abruptly withdrawn, irregular, involuntary muscular movements frequently
follow and last for weeks (Polizos et at., 1973).
2.3.3.2. Butyrophenones
1. Haloperidol. Engelhardt et at. (1973) found in a DB comparative
study that haloperidol was as effective for childhood psychosis as was
fluphenazine. They consider haloperidol to be one of the most effective
major tranquilizers on the market. Their dose range of the drug, 8-10 mg/
day, is high. Major side effects of haloperidol at that dose are sedation and
EPS.
2. Trifluperidol. Trifluperidol was reported by Campbell et at. (1972b)
in a DB crossover study to be impressively useful for psychotic children.
They did note the frequent occurrence of irritability as a side effect of the
drug. Fish (1973) also noted that trifluperidol causes a large number of other
side effects.
171
2.3.3.3. Thioxanthenes. The literature reports on thiothixene (Navane)

for psychotic children are thus far uniformly positive. Waizer et al. (1972)
found that this drug in doses of 10-24 mg/day produced (in a single-blind
study) significant benefits for sleep, concentration, affect, coordination,
motor activity, and stereotyped behavior. Saletu et al. (1974) likewise reported (in a DB study) that thiothixene in doses averaging 14 mg/day
measurably benefited psychotic boys in their motor behavior, speech, social
relationships, anger, mood, attention, appetite, and emotional responsiveness. In still another study, Campbell et al. (1970) found that thiothixene in
doses ranging from 1 to 16 mg/day produced significantly better results than
placebo. Campbell et al. (1970) concluded that thiothixene was the preferred
psychotropic drug for psychotic children. One reason for this conclusion was
that they felt that notable side effects for thiothixene occurred only when
four to six times the average dose needed for a therapeutic effect was
administered.
In two studies, mild EPS occurred for 4 out of 18 children (Waizer et al.,
1972) and 3 out of 9 children (Campbell et al., 1970) when on thiothixene.
Saletu et al. (1974) concurrently administered an anticholinergic drug, so that
no EPS developed. Other side effects of thiothixene are weight gain and
drowsiness (Simeon et al., 1974b).
2.3.3.4. Other Psychotropic Drugs
1. Thyroid preparations. Campbell et al. (1973) gave the thyroid
preparation liothyronine (Cytomel) to 20 pyschotic and severely disturbed
children. The investigators reported that the drug in doses averaging 46 mg/
day significantly improved attention span, communication, motor activity,
and behavior. They concluded that this drug had both stimulating and
antipsychotic effects. However, to attain the desired effect, the drug produced signs of overactive thyroid function (i.e., tachycardia, elevated blood
pressure, decreased cholesterol, diarrhea).
In a nonblind study with triiodothyronine (T3) in doses of 12.5-75 ILg/
day, Campbell et at. (1972a) reported similar therapeutic results. Likewise,
thyroid-releasing hormone (TRH) in doses of 40 ILg intravenously was
regarded as beneficial in respect to affect, speech, and activity for seven
autistic children (Campbell, 1975a).
2. Lithium. Campbell et al. (1972c) found that lithium was not very
useful in that only one out of ten psychotic children improved on the drug.
Gram and Rafaelsen (1972) (in a DB crossover study) gave lithium to 18
young psychotic children for a six-month period. Their results showed that
lithium at a serum level of 0.6-1 mEqlliter was on average mildly better than
placebo. However, 13 out of the 18 children showed inconsistent or poor
results on the drug.
3. L-Dopa. Campbell (1973) gave L-dopa in doses of 900-2250 mg/day
and reported that psychotic children had gains in social interaction, verbal
production, and play, and a decrease in psychotic speech. Ritvo et al. (1971),
172
DANIEL J. SAFER
however, found no substantive changes in the clinical picture as a result of

the drug.
4. Niacinamide. Greenbaum (1970) reported no beneficial results with
megavitamin treatment of psychotic children. He administered doses of 1-3
g/day of niacinamide to S7 schizophrenic children for a period of six months
in a DB study and the results were clearly negative.
S. Methysergide. Fish et at. (1969) reported that 6 out of the 11
psychotic children became worse (i.e., more disorganized) on methysergide
(Sansert), whereas 2 out of the II-who were mute-became more alert and
vigorous on low doses of the drug.
2.4. General Considerations Using Major Tranquilizers for

Psychotic Children
In view of numerous DB, controlled studies consistently reporting
beneficial effects of major tranquilizers in psychotic children, it is now
evident that this drug treatment is frequently useful in the management of
these children. Whereas major tranquilizers do not remove psychotic symptoms and probably do not change the long-range outlook, they characteristically do decrease disturbing psychotic behavior and often lessen emotional
deviance.
Of the drugs evaluated in controlled studies in psychotic children, three
major tranquilizers consistently come out well: thiothixene, haloperidol, and
fluphenazine. Others (e.g., trifluperazine and thioridazine) may be comparable and need to be further evaluated in relation to the top three. Still others,
notably chlorpromazine and prochlorperazine, have been judged comparatively less generally effective, particularly for preschool psychotic youngsters
(Engelhardt et at., 1972; Fish et at., 1966; Campbell et at., 1972b).* If the
comparative data hold up, the dictum from adult psychiatry that "all the
major tranquilizers, except for promazine, are equally effective in the
treatment of schizophrenia ... " (Irwin, 1974) may not apply to the childhood
psychoses.
Side effects of the major tranquilizers are dose related in general and
can present a problem in the drug management of psychotic children. This is
particularly true because psychotic children appear to respond best to a
neuroleptic in an adult dose (Engelhardt et at., 1972). Of note in this respect
is that drug-induced EPS in children may differ from those reported in
adults. EPS that have been reported for psychotic children on major
tranquilizers include tremor, restlessness, drooling, catatonic state, cogwheel
rigidity, increased salivation, rocking, and involuntary movements (Campbell
* It
should be noted, however, that chlorpromazine is considered still quite effective in

decreasing hyperactivity and aggressiveness in older psychotic children (Grant, 1962;
Freedman et ai., 1955).
173
et al., 1970, 1971b; Waizer et al., 1972). Also, motor signs following the
withdrawal of a major tranquilizer differ in children from the tardive
dyskinesias that have been reported for adults. In children, gross body
movements have been more prominent than tongue, motor, and jaw
movements (Polizos et al., 1973; McAndrew et al., 1972), and ataxias have
developed (Engelhardt et al., 1975).
3. BEHAVIOR DISORDERS OF THE MENTALLY

RETARDED
The prevalence of mental retardation in children is generally considered
to be 3% (Rutter, 1971). Mental retardates with IQs over 50 usually live at
home and attend special educational classes in schools. As a group, they go
on to an adequate community adjustment during and after adolescence
(Tarjan et al., 1973). Children with IQs under 50 are generally cared for at
home until their middle to late teens. After that, most are sent to institutions
(Tizard, 1970). In the United States, approximately 200,000 mental retardates live in institutions (Lipman, 1970).
Mentally retarded children are prone to behavioral and emotional
deviance. Approximately 5% of mentally retarded children seen in an outpatient setting are psychotic (Menolascino, 1969) and at least 8% of institutionalized mentally retarded children are diagnosed as such (Iivanainen,
1974). Furthermore, some 30-45% of retarded children are hyperactive
(Moore et al., 1968; Jenkins and Stable, 1971) and 21-42% are aggressive
(Moore et al., 1968; Nihira, 1973; Menolascino, 1965). Generally, mental
retardates have a three- to fourfold greater rate of emotional and behavior
difficulties than do their mentally more competent age-mates (Rutter, 1971).
To cope with the deviance of the institutionally mentally retarded,
psychiatrists and other physicians commonly use psychotropic medication. In
1970 in the United States, 51 % of all institutionalized mentally retarded were
on psychotropic drugs (Lipman, 1970). In England, approximately 30%
receive such drugs (Griffiths, 1970; Kirman, 1975).

Behavioral therapy is increasingly being used to manage the misconduct
of impulsive retardates in institutions. It can be effective for specified goals
(Gardner, 1971).
DANIEL J. SAFER
174
3.3. Drug Treatment

3.3.1. Minor Tranquilizers
Craft (1958), Rudy et al. (1958), Heaton-Ward and Jancar (1958), and
La Veck and Buckley (1961) found that meprobamate was not useful for
adjustment problems of the mentally retarded. La Veck and Buckley (1961)
and Griffiths (1970) similarly found chlordiazopoxide not useful. In fact, it

occasionally worsened behavior (La Veck and Buckley, 1961). Craft (1957a)
also reported negative results from hydroxyzine.

Of the institutionalized children on psychotropic drugs during the late
1960s, 58% received either chlorpromazine or thioridazine (at doses averaging 400-600 mg/day). Most children were treated with these drugs for 6-12
months. However, 25% received such medication for four or more years
(Lipman, 1970).
3.3.2.1. Chlorpromazine. Essentially all investigators have reported that
chlorpromazine (in doses of 100-600 mg/day) decreases hyperactivity and
aggressiveness in mentally retarded children with behavior problems (Rudy
et al., 1958; Adamson et al., 1958; Craft, 1957; Hunter and Stephenson,
1963; Bair and Herold, 1955). In one comparative DB study, the drug was
found to be generally less effective than haloperidol in the treatment of
behavior disorders of the retarded (Le Vann, 1971).
3.3.2.2. Thioridazine. Alexandris and Lundell (1968) and Le Vann
(1970) found thioridazine to be significantly more effective than placebo in
reducing aggression and hyperactivity in inpatient behavior-problem children with mental retardation. Veer and Kreger (1969), using only an average
of 55 mg/day of thioridazine, reported that the drug was dearly less effective
than haloperidol (in average doses of 2.3 mg/day) in the treatment of
retarded patients with deviant conduct. However, the doses of thioridazine
prescribed by Veer and Kreger were so low as to make these comparative
results suspect. Le Vann (1970) found a thioxanthene drug, chloprothixine,
to be mildly more effective than thioridazine (in doses up to 450 mg/day).
3.3.2.3. TriJluperazine. Sharpe (1962) and Hunter and Stephenson
(1963) reported that trifluperazine is useful in the treatment of behaviorally
deviant retardates.
3.3.2.4. Haloperidol. Haloperidol-in doses of 1-8 mg/day-has been
reported to be quite useful to decrease behavioral problems in mental
retardates (Barker and Fraser, 1968; Burk and Menolascino, 1968; Veer and
Kreger, 1969; Le Vann, 1971). Le Vann (1971), in a DB eight-week study,
reported that haloperidol reduced impulsiveness, hostility, and aggressiveness significantly more than did chlorpromazine. Veer and Kreger (1969)
found haloperidol more useful than thioridazine. Doses of haloperidol
175
generally used in the studies have averaged 2 mg/day (Vcer and Kreger,
1969; Le Vann, 1971).
3.3.2.5. Reserpine. Although the results of controlled studies are somewhat mixed (Freeman, 1970), the weight of evidence is that reserpine lessens
aggressive behavior in intellectually subnormal children (Rudy et al., 1958;
Freeman, 1970; Adamson et al., 1958; Timberlake et al., 1957). However, it
is less useful than chlorpromazine in managing behavior difficulties in
retardates (Rudy et al., 1958; Adamson et al., 1958; Sprogis et al., 1957) and
entails more risk (Craft, 1959).
3.3.2.6. Other Major Tranquilizers. Data on other major tranquilizers for
the mentally subnormal are fragmentary or negative (Freeman, 1970;
Griffiths, 1970).
3.3.3. Stimulants
Stimulants are major drugs in the treatment of behavior problems of
outpatient children (Krager and Safer, 1974), but they are not often used for
the retarded (Lipman, 1970). Alexandris and Lundell (1968) found dextroamphetamine-when administered to hyperactive retardates--to be more
useful than placebo, a finding matched by Blacklidge and Ekblad (1971)
using methylphenidate, and Spencer (1970) using pemoline. It is of note,
though, that Alexandris and Lundell (1968) found thioridazine to be more
generally useful than dextroamphetamine for restless retardates. This finding has not been replicated; nonetheless, for nonretardates, stimulants are
preferred over the phenothiazines for the treatment of hyperactivity and its
commonly associated features (Weiss et al., 1968; Sprague et al., 1970).
3.4. Clinical Considerations

Available evidence clearly suggests that certain popular major tranquilizers (chlorpromazine, thioridazine, trifluperazine, and haloperidol) decrease
aggression and hyperactivity in behavior problem, mentally retarded children
and adolescents who reside in institutions. These drugs affect aggressive,
subnormally intelligent outpatients similarly, but there are far less drug
outcome data on retardates living at home.
The effect of major tranquilizers to decrease hyperactivity and aggression is not specific for mental retardates. Seriously disturbed, misbehaving,
non retarded youngsters react similarly to these drugs in inpatient (Cunningham et al., 1968; Barker and Fraser, 1968; ltil et al., 1967; Lucas and
Pasley, 1969) and outpatient settings (Barker and Fraser, 1968; Kenny et at.,
1968; Serrano and Forbis, 1973; Wong and Cock, 1971). Also, nonretarded,
misbehaving children characterized primarily by their hyperactivity react
likewise to such drugs (Weiss et at., 1968; Werry and Aman, 1975).
Institutions for the retarded are often crowded, and psychotropic drugs
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DANIEL J. SAFER
are probably the least expensive method for increasing social control over
disruptive behavior (Kirman, 1975). In the treatment of schizophrenia, major
tranquilizers are more justifiable because (in adolescents and adults) they also
shorten hospital stays and decrease the likelihood of relapse after discharge.
As yet, there is no evidence to suggest that major tranquilizers serve such
ends for the mentally retarded.
A second concern about the frequent use of drugs in inpatient settings is
the issue of side effects from long-term use. At this point, data on this matter
are spotty (Di Mascio et ai., 1970). However, prolonged EPS from major
tranquilizers have become an increasing concern (McAndrew et ai., 1972;
Engelhardt et ai., 1975).
4. HYPERACTIVITY
Hyperactivity (HA) is the most common child psychiatric disorder in the
United States. HA children are those who persistently find it very difficult to
stay seated and maintain attention in quiet and learning type situations. The
signs of the disorder commonly become evident from age 2 to 6 and fade to
a great extent during adolescence. They are usually most apparent in the
classroom. The pattern occurs in about 5% of elementary school children
and is present more so in boys (in a 3 : 1 ratio over girls). In most instances, it
is associated with short attention span, misconduct, learning disability, and
immaturity (Safer and Allen, 1976).
Thus far the outcome of the disorder has only been well studied until
the middle and late teens (Weiss et ai., 1971a; Mendelson et ai., 1971).
Commonly, the presence of hyperactivity results in moderate adjustment
problems during the elementary and junior high school years. In the middle
and late teens, the restlessness of HA children gradually fades (Weiss et ai.,
1971a). Nevertheless, throughout their childhood and adolescence, HA
children are at greater risk to fail in school, to be suspended, to be taken to
juvenile court, and to have personality problems (Safer and Allen, 1976). Of
note is the fact that young adult adjustment of hyperactivity is more
influenced by such generally important prognostic variables as IQ, family
support, and emotional stability than by the mere presence of the hyperactive
behavior pattern (Weiss et ai., 1971a).
Short-term outcome of the disorder is most simply and accurately
assessed by changes in the classroom ratings of these children (Conners,
1973). Long-term outcome can be evaluated by the use of such measures as
IQ, promotion in school, juvenile court involvement, school suspensions,
vocational adjustment, academic achievement, school grades, and psychiatric
hospitalization.
177
4.2. Nondrug Treatments

The major nondrug treatment for hyperactivity is behavior modification. It is applied primarily in the classroom to reinforce good academic
behaviors such as being on task, successfully completing the work, and not
disrupting others. Compliance with these expectations is scored preferably at
frequent intervals. Scores or tokens received for success are later cashed in
for home (parent-given) and/or school (individual or classroom) rewards
(O'Leary and O'Leary, 1976; Christensen, 1975).
If the rewards are attractive and goal attainment always within reach,
behavioral therapy generally serves to improve the academic achievement
and behavior of HA children. The academic benefits from these programs
may remain for periods up to a year beyond the termination of the program
(Hewett et al., 1969), whereas the classroom conduct usually lasts as long as
the behavioral program is operational and successful, fading rapidly after its
termination.
Behavior modification programs may yield behavioral benefits for many
HA children close to those obtained through the use of stimulants (O'Leary
et al., 1976). However, other evidence suggests that their effect is relatively
less (Gittelman-Klein et al., 1975). In terms of academic achievement, the
weight of evidence points to the superiority of behavior modification
programs over the use of stimulant drugs (Safer and Allen, 1976).
Psychotherapy does not appear to appreciably influence the hyperactive
clinical pattern (Eisenberg et al., 1961).
Diets for HA children that are devoid of food additives have received
enthusiastic anecdotal reports (Feingold, 1974). However, the only controlled
study on the subject reported no notable degree of parent- and teacher-rated
improvement on (as compared to off) the diet (Conners et al., 1975).
4.3. Drug Treatments

4.3.1. Stimulants
4.3.1.1. Use and Effectiveness. In 1973, over 300,000 elementary school
children in the United States were receiving stimulants for hyperactivity. In
effect, about one third of all HA children of primary school age were on
these medications (Krager and Safer, 1974). Furthermore, it appears that
stimulants are the most frequently prescribed drugs for childhood psychopathology in the United States.
From numerous DB studies, there is little doubt that stimulants effectively reduce classroom HA behavior (Safer and Allen, 1976). They produce
dramatic benefits for 50% of HA children, fair results for 30%, and no (or
worse) results for 20%. Placebo results are usually minor and temporary
(Conners, 1969; Gross and Wilson, 1974).
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DANIEL J. SAFER
The primary indication for stimulant drug treatment is hyperactivity.

Generally, although the data are somewhat mixed, the more hyperactive and
neurologically deviant the child, the better will be his clinical response to
stimulants (Safer and Allen, 1976). HA children not only evidence improved
classroom behavior on stimulants, they also show---{)n drugs-improved
attention and performance skills. Because of these beneficial effects, HA
children often score somewhat higher on short-term achievement and IQ
tests when on stimulants. However, taking a stimulant does not improve
retention of new information (Aman and Sprague, 1973; Conners, 1974).
Furthermore, taking stimulants does not result in significant long-term gains
in achievement (Rie, 1975; Conrad et al., 1971; Gittelman-Klein and Klein,
1973; Weiss et al., 1975).
4.3.1.2. Types of Stimulants. Of the stimulants available on the United
States market, only three are in common use for HA children. These are
methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and pemoline
(Cylert). All are comparable in their effects on hyperactivity (Conners et at.,
1972; Winsberg et al., 1974). At present, methylphenidate has the lion's share
of the United States market (Krager and Safer, 1974). Caffeine was also
reported to be useful for HA behavior (Schnackenberg, 1973) but on further
study it has been shown to be of no value (Huestis et al., 1975).
4.3.1.3. The Drug Trial. Since stimulant medication is not always
beneficial, it must be started as a trial. Before the drug trial is initiated,
baseline teacher ratings are needed. The duration of this trial can be as short
as one to three weeks. Follow-up teacher ratings are needed again during the
drug trial, and if long-term drug treatment is adopted, they are needed once
every three to six months thereafter. Stimulants are best administered once
in the morning, or once in the morning and once at noon. If the initial dose
is not successful, higher doses (up to 60 mg of methylphenidate, 30 mg of
dextroamphetamine, and 112.5 mg of pemoline) can be tried. If one
stimulant is not clinically useful, and on reevaluation the child is still judged to
be hyperactive, a different stimulant should be tried, because in approximately 20% of the cases a different stimulant can be useful following a
failure of the first (Winsberg et al., 1974).
4.3.1.4. Drug Administration. Methylphenidate and dextroamphetamine
come in tablets that have therapeutic effects lasting 3-5 hr (depending upon
the dose). Pemoline exerts a therapeutic effect for approximately 6-10 hr.
Dextroamphetamine is usually begun at a dose of 5 mg twice daily or 10 mg
in the morning. Methylphenidate is generally initiated in a dose of 10 mg
twice daily or 20 mg in the morning. Pemoline is usually started at a dose of
37.5 mg in the morning. Dextroamphetamine also comes in long-acting
capsules, trade-named spansules. These have an effect for 6-8 hr. A
common starting dose for Dexedrine spansules is 10 mg in the morning.
Methylphenidate and dextroamphetamine are given mainly on school
days but can be given as needed on nonschool days for such activities as
church, visiting, and Sunday school. Pemoline can be discontinued over the
179
summer but should probably be continued regularly during weekends

during the school year. This is because its effects build up over time; in fact,
it may take up to one to three weeks of daily administration for pemoline to
achieve its maximum clinical effect (Conners et al., 1972).
4.3.1.5. Side Effects
1. Short Term. During the first week on stimulants and occasionally
during the second, about 15% of HA children evidence or complain of one
of the following: headaches, moodiness, stomach aches, and increased
talkativeness. Appetite suppression occurs for 25-50% of children on stimulants and usually lasts for a month or two; it is more of a problem when
dextroamphetamine is used but can occur with higher doses of methylphenidate or pemoline (Safer and Allen, 1975a; Page et al., 1974). Insomnia can
occur if a noon dose of a stimulant or a long-acting tablet or capsule is
administered. Insomnia persisting for a few months is particularly common
when an after-school dose of a stimulant is given. Other-usually rare-side
effects that have been reported with stimulants in HA children are hallucinations, dyskinesia, pupillary dilation, and pallor (Di Mascio et al., 1970).
2. Long Term. As yet, the matter of side effects from the long-term
use of stimulants in children has been insufficiently studied. The only "longterm" side effect that has been reported is the minor suppression of the
growth rate, that is most evident following regular use of destroamphetamine
(Safer and Allen, 1975a). However, after a stimulant drug is stopped, a
growth rebound (above the normal growth rate) occurs (Safer et al., 1975).
Thus prolonged growth changes to not appear to be a notable risk for HA
children who receive stimulants judiciously.
Stimulants, particularly when administered after noon, can slightly alter
REM and stage 4 sleep patterns in HA children (Safer and Allen, 1975a).
Methyl?henidate can cause a heart rate increase initially, averaging 10-15
beats per minute; a tolernace, however, develops to this effect so that the
drug's induction of tachycardia becomes no longer measurable after four
months of regular drug administration (Safer and Allen, 197 5a).
4.3.1.6. Problems with Continued Stimulant Drug Treatment. Sometimes
even though a stimulant is initially useful, later reports suggest that it is not.
In one fourth to one half the cases, a degree of tolerance develops to the
stimulant's therapeutic effects and a moderate dose increase is then necessary
to maintain the drug effect (Sleator et al., 1974). Another fairly common
problem in continued stimulant drug treatment is that the HA child stops
taking the pill (unbeknownst to others).
Each year the medication should be stopped for a few days or more to
ascertain if the HA child can adjust adequately in the classroom without it.
This process usually needs to be repeated annually until the child is in his
midteens. Commonly the HA child's restlessness in the classroom decreases
to a tolerable level at age 14 or 15 and the medication can then be stopped.
4.3 .1.7. Some Clinical Considerations with Stimulants. Hyperactive children do not become euphoric on stimulants, whereas approximately two
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DANIEL]. SAFER
thirds of adults do. Thus, the drug is not habit forming for HA children.
The only other response to stimulants that generally differentiates HA
children from adults is restlessness; stimulants usually decrease restlessness in
HA children in a classroom-type situation, whereas they may increase the
activity level of adults.
Reports on the effects of stimulants on HA mentally retarded children
are mixed. Some find that these drugs are useful for such children
(Blacklidge and Ekblad, 1971; Alexandris and Lundell, 1968; Spencer,
1970), but others do not (Christensen, 1975; Anton and Greer, 1969). As a
group, these studies suggest that the effects of stimulants are less consistently
positive for HA retarded children than they are for more typical HA children.
Preschool HA children are said to respond favorably to stimulants.
However, Schleifer et at. (1975) report that preschool HA children are less
benefited by stimulants than are older HA children; Conners (1975), on the
other hand, finds the responses of these two groups of HA children to be
similar. Adolescent hyperactives respond to stimulants generally as do grade
school HA children (Safer and Allen, 1975b). Psychotic HA children commonly become more disorganized on stimulants (Fish, 1971).
Lately, there has been an increasing interest in combining stimulant
drugs with behavior modification programs for the HA child (Christensen
and Sprague, 1973; Christensen, 1975; Gittelman-Klein et at., 1975). Generally, the combination makes sense because stimulants appear to be most
effective for HA behavior (Gittelman-Klein et at., 1975) and behavior
modification appears to be more useful for the learning disability (Ayllon et
at., 1975).
4.3.2. Phenothiazines
4.3.2.1. Use, Type, and Dose. About 5-10% of hyperactive elementary
school children on drugs for their behavior receive a phenothiazine tranquilizer (Krager and Safer, 1974). Of the phenothiazines, only two are commonly
used for HA children; these are thioridazine (Mellaril) and chlorpromazine
(Thorazine). These drugs are comparable; both reduce restlessness (Werryet
at., 1966; Sprague et at., 1970). Doses of thioridazine and chlorpromazine for
this condition range from 30 to 150 mg/day (Werry et at., 1966; Simeon et
at., 1974a) and generally are administered three times daily.
4.3.2.2. Side Effects. The two most common side effects of phenothiazines in HA children are drowsiness and an appetite increase leading to
weight gain. The drowsiness is most prominent during the initial weeks.
Photosensitivity can particularly be a problem with chlorpromazine (Weiss et
at., 1971b). Extrapyramidal side effects, particularly dystonias, can occur in
children on any of the phenothiazines. They are dose related and are
infrequent with chlorpromazine and uncommon following thioridazine. A
more comprehensive listing of the side effects of these drugs is found
elsewhere (Di Mascio et al., 1970).
181
Side effects from the long-term use of phenothiazines have been

reported for institutionalized (mostly retarded or psychotic) children who
usually receive high doses of these drugs (Paulson et al., 1975; McAndrewet
al., 1972). The only report of the long-term use of phenothiazines for
hyperactivity has been an outcome study of HA outpatients who received
chlorpromazine for five years. In that study, Weiss et al. (1975) found no
adverse effects from the long-term use of chlorpromazine.
4.3.2.3. Clinical Considerations. Psychotic hyperactives do better on
major tranquilizers than on stimulants. Mentally retarded hyperactives do as
well (or better) on phenothiazines as on stimulants (Alexandris and Lundell,
1968). Typical hyperactives do better on stimulants than on phenothiazines
(Saletu et al., 1975b; Millichap and Fowler, 1967). Consequently, nonretarded non psychotic hyperactives should be tried first on stimulants; if one
does not work, a different stimulant should be tried before switching to a
trial of a phenothiazine drug.
4.3.3. Antidepressants
Of the antidepressants, only imipramine (Tofranil, Imavate, or SK
Pramine) has been extensively researched in the treatment of hyperactivity.
Also, imipramine is the only one of the tricyclic antidepressants to be
recommended-thus far in the United States--for use in children under age
12 (for enuresis). The total daily dose of imipramine for hyperactivity has
been 50-180 mg/day and caution is urged for doses over 200 mg/day (Saraf
et al., 1974). A single evening dose, or a morning and evening dose schedule
is generally recommended. Unlike its action on depressive symptoms--when
the drug takes weeks to be effective-the response of HA behavior to
imipramine takes a day or two.
The major side effects of imipramine in HA children and adolescents
are dry mouth, suppression of appetite, weight loss, nausea, sweating, and
tremor (Saraf et al., 1974). Seizures, too, have been reported (Brown et al.,
1973). Of note is the fact that modest but significant cardiovascular changes
(e.g., increased heart rate and diastolic blood pressure) have also been
reported with imipramine in conduct-problem (enuretic) children following
bedtime doses of 50 mg (Werry et al., 1975) and in HA children following
average daily doses of 80 mg (Rapoport et al., 1974).
Although imipramine is clinically useful to decrease HA behavior and
improve attention, it is less effective for HA than are stimulants (Rapoport et
al., 1974; Quinn and Rapoport, 1975). Recent evidence suggests also that
tolerance often develops to the effect of imipramine on HA symptoms
(Waizer et al., 1974; Quinn and Rapoport, 1975).
Because of the synergistic effects of methylphenidate and imipramine
(Parel et al., 1969), these two drugs can be used simultaneously in treatment
(Gross, 1973). However, their side effects are in all likelihood additive as well,
so that caution must be used.
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DANIEL]. SAFER
4.3.4. Other Drugs

Double-blind studies with diphenhydramine (Benadryl), hydroxyzine
(Atarax), and diazepam (Valium) suggest that they are not very effective for
hyperactivity (Safer et al., 1972; Greenberg et al., 1972; Zrull et al., 1964).
Lithium likewise has not received favorable reports (Whitehead and Clark,
1970; Greenhill et al., 1973). Haloperidol (Haldol) is slowly coming into use
for HA children and in low doses may be of value (Werry and Aman, 1975).
Diphenylhydantoin (Dilantin) has not been shown to be useful for HA
symptoms (Conners et al., 1971; Lindsley and Henry, 1942). Phenobarbital
tends to aggravate hyperactivity (Eisenberg, 19600).
5. ENURESIS
5.1. Occurrence and Outcome
Enuresis, or urinary incontinence (over age 3), is a common problem in
childhood. Wetting the bed at night at least once a week occurs on average
for 12% at age 6-8, 10% at age 8-10, 5-6% at age 10-12, 3% at age 12-14
and 1-2% in young adulthood (De Jonge, 1973; Forrester et al., 1964;
Turner, 1973). Each year, 11-16% of nocturnal enuretics have a spontaneous remission (Forsythe and Redmond, 1974). Thus the natural course of
this disorder is extremely favorable.
Nocturnal enuresis is usually not a primary psychiatric problem, although it is often distressing to parents and embarrassing to children. It
tends to be associated with a family history of enuresis (Bakwin, 1973) and
with behavioral deviance (Rutter et al., 1973); usually it occurs in relation to
stages of deep sleep (Graham, 1973). Diurnal (daytime) enuresis, one or
more times per month, occurs for only 1-2% of children at age 6-8; after
that age, it is rarely a problem. It tends to be associated with emotional
problems (Rutter et al., 1973).

5.2.1. Psychotherapy
Psychotherapy has not been shown in controlled studies to have an
appreciable effect on enuresis. In two studies it has resulted in "cure" rates of
18-20%; these were not notably different from rates of spontaneous
remission or rates with placebo (DeLeon and Mandell, 1966; Werry and
Cohrssen, 1965).
183
5.2.2. Conditioning
The so-called bell and pad approach to treatment consists of a bellwhich rings when the child's first few drops of urine complete the circuitand a pad-which is placed under a sheet covering the mattress protector
and which is wired to a dry cell and the bell. When the urine "touches off'
the bell, the child hopefully awakens, turns off the alarm, and completes his
urination in the toilet. The bell and pad apparatus is used nightly for 6-11
weeks. Its use results in an average initial success rate (a dry bed for 14 or
more consecutive nights) of 60-90%. At follow-up 4-12 months later, only
15-35% of responders have relapsed (Turner, 1973). This approach is at
least as successful as the use of tricyclic antidepressants for nocturnal enuresis
and is far more durable. The disadvantages reported with the bell and pad
are minor. Some (particularly older) enure tic alarm systems were wired
poorly, used too strong a dry cell, or were not turned off when the circuit
was completed, resulting in small skin ulcers. With present equipment, wiring
and dry cell problems are now infrequent. Sometimes, though, the alarm
arouses other family members, and not the child.
5.3. Drug Therapies

5.3.1. Stimulants
In one controlled DB study, the clinical response to an amphetamine for
enuresis was found to be no better than to placebo (McConaghy, 1969). In a
controlled study with methylphenidate (Breger, 1962), the rate of improvement with the drug (43%) was similar to that obtained with placebo in a
previous study by the author (Breger, 1961). Likewise, phenometrazine
produced no significant benefit over placebo in the treatment of enuresis
(Harrington, 1960).
5.3 .2. A nticholinergics

In two recent controlled DB studies, propantheline (Wallace and Forsythe, 1969) and emepronium (Petersen et at., 1974) resulted in no significant decrease in enuresis. Three previous studies with anticholinergic drugs
have resulted in similar findings (Blackwell and Currah, 1973).
5.3.3. Tranquilizers and Sedatives

Meprobamate (600-1000 mg/day) did not significantly differ from
placebo in its effect on enuresis (Breger, 1961), nor did hydroxyzine (20-40
mg/day) (Breger, 1962) and oxazepam (30 mg/day) (Salmon, 1973).
Salmon (1973) reported in a DB crossover study that chlordiazopoxide
(30 mg/day) produced a highly significant benefit over that of placebo.
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DANIEL]. SAFER
5.3.4. Monamine Oxide Inhibitors

Uncontrolled studies have not supported that this drug group is useful
for enuresis (Blackwell and Currah, 1973).
5.3.5. Tricyclic Antidepressants

Tricyclic antidepressants have been used in the treatment of nocturnal
enuresis since 1960 (McLean, 1960). Clearly, the fact that over 85% of the
DB studies with this drug group result in a significant clinical benefit over the
effect of placebo (Blackwell and Currah, 1973) indicates that these drugs are
quite useful in the treatment of nocturnal enuresis and represent the best
psychopharmacologic treatment available for the disorder (with the possible
exception of chlordiazopoxide). Studies with imipramine, amitriptyline, nortiptyline, and desipramine all show such results and appear (in general)
equally efficacious (Blackwell and Currah, 1973).
5.4. Clinical Considerations Using Tricyclics for Enuresis

5.4.1. Dose
Most clinicians begin the enuretic child on 25 mg of one of the abovementioned tricyclic antidepressants at bedtime. If this is not effective, the
dose is raised-in a week or two-to 50 mg at night. Raising the dose above
this for enuresis has not been shown to be clearly useful (Poussaint et al.,
1966; Shaffer et al., 1968). However, some clinicians prescribe a nighttime
dose as high as 75 mg (Cohen, 1975).
5.4.2. Response
The drug effect occurs within the first few days of use (Blackwell and
Currah, 1973). Approximately 25-45% of the children have a total remission
on such treatment (Cohen, 1975; McKendry and Stewart, 1974). In Alderton's (1970) group data analysis, enuretic children decrease (on average)
from 60% wet nights on placebo to 31 % on a tricyclic drug. In the group
data presented by Petersen et al. (1974), the children lessen their wet nights
per week from 4.5 on placebo to 2.5 on a tricyclic drug.
5.4.3. Duration
of Response and Relapse Rate
The drug effect generally persists (in responders) as long as the drug is
taken. When the drug is stopped, approximately 70-90% of the responders
at least partially relapse and increase their rate of nocturnal enuresis
(Blackwell and Currah, 1973). At follow-up 3-16 months later, 5-40% of
enuretics who received a trial of tricyclics are regularly dry (Blackwell and
185
Currah, 1973). On average, this suggests that six months after termination of
treatment with tricyclics, 26% of previously enuretic children are dry. This
rate of dryness following tricyclic treatment appears on average to be mildly
better than the rate of spontaneous remission and only slightly better than
that following placebo.
5.4.4. Side Effects

Adverse effects due to tricyclics used in doses up to 75 mg at night have
been assumed to be minor and (for the most part) temporary. Of the
symptoms found to result from tricyclic drugs taken at night for enuresis,
dizziness and anorexia have been the most common (Blackwell and Currah,
1973). However, Werry et al. (1975) also reported physiological changes in
enuretic boys due to imipramine, 50 mg at night. In a 3-week DB study,
Werry et al. (1975) found significant drug-induced increases in diastolic
blood pressure and resting pulse (measured in the morning) and a significant-but minor-degree of drug-related weight loss. Imipramine in bedtime doses of 75 mg and over can cause sleep disturbances in some (Meadow,
1974). With amitryptyline, drowsiness is more common than following
Imipramme.
Another "side" effect of imipramine for enuresis is improved behavior
in those with both enuresis and misconduct (Werry et al., 1975). Because of
this "double-barreled" effect, the use of tricyclic drugs for this subgroup of
enuretic youngsters may be as generally efficacious as conditioning approaches.
5.5. Possible Mechanism of Action of Tricyclics in Enuresis

The present evidence suggests that none of the three major theories to
explain the decrease in enuresis due to tricyclic antidepressants--(l) the
antidepressant effect, (2) anticholinergic effect on the bladder, (3) the
alteration of sleep-satisfactorily explains the drug's effect. However, a
number of authors find the anticholinergic explanation most plausible
(Werry, 1972).
6. TICS AND GILLES DE LA TOURETTE'S SYNDROME

The peak age period for the onset of tics is 4-7 years. About 5% of
children aged 4-8 are reported to have this type of disorder (Macfarlane et
al., 1954). By age 9-12, only 1-2% of children are reported to have tics
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DANIEL J. SAFER
(Macfarlane et al., 1954; Shepherd et al., 1971), and over age 12 the number
decreases to below 1% (Macfarlane et al., 1954). The male-female ratio is
3: 1 (Corbett et al., 1969). Most tics are facial (e.g., blepharospasm), but a
small proportion of ticquers have shoulder, torso, and pelvic tics (Corbett et
al., 1969). Uncommonly, too, some severe ticquers have vocal (coughing,
barking, verbal) tics. Ticquers with multiple tics (including vocal ones) are
generally considered to have Gilles de la Tourette's syndrome.
In clinical follow-up studies of mixed age groups of ticquers, tics have
ceased (on average) in 25% of cases within 3 years, and in 50-70% within 89 years after psychiatric evaluation (Corbett et al., 1969). Thus the long-term
prognosis is generally favorable, particularly when the symptom begins in
early childhood and is uncomplicated (Corbett et al., 1969). Tourette's
syndrome is, however, far more likely to persist (Bruun et at., 1975).

Psychotherapy, hypnosis, ECT, isolation, and behavior therapy have all
been reported to decrease tics (Kelman, 1965). These treatment methods
have not, however, resulted in changes as dramatic as those produced by the
administration of haloperidol for multiple tics (Kelman, 1965; Bruun et al.,
1975).
6.3. Drug Treatment

6.3.1. Haloperidol (Haldol) and Its Competitors
Haloperidol is the drug treatment of choice for the symptom of multiple
tics. Clinical reports of this treatment since 1961 have been overwhelmingly
positive (Chapel et at., 1964; Shapiro et at., 1973); in fact, an estimated 75%
of ticquers with multiple tics are said to benefit from this medication (Bruun
et at., 1975). The drug has also been reported to stop the obsessivecompulsive pattern that some 13-33% of ticquers reportedly show (Tapia,
1969; Corbett et at., 1969).
The only other drugs that have received notable mention in the
treatment of tics have been the phenothiazine tranquilizers and diazepam
(Valium). Phenothiazine drugs are generally useful for multiple tics (Lucas,
1964; Kelman, 1965), but have not been nearly as beneficial as haloperidol.
Diazepam can cause partial remissions in some, but relapses while on the
drug are frequent (Frederiks, 1970; Connell et at., 1967). Amphetamines can
make the condition worse (Kelman, 1965; Snyder and Meyerhoff, 1973).
187
6.3.2. Dose, Duration, and Side Effects of Haloperidol

Daily doses of haloperidol that have been reported in the treatment of
tics in children and adolescents have been 1.5 mg (Connell et ai., 1967), 1-2.5
mg (Tapia, 1969), 2-5 mg (Chapel et ai., 1964), 6-180 mg (Shapiro et ai.,
1973), 1-55 mg (Bruun et ai., 1975), and 16 mg (Still and Hans, 1973). In
doses over 4 mg/day, EPS (e.g., dystonia) are common (Ban, 1973). Consequently, many investigators routinely use an anticholinergic drug concurrently with haloperidol. The side effects of haloperidol generally increase
with dose. Side effects include restlessness, drowsiness, akinesia, akathesia,
and dermatitis (Ban, 1973; Shapiro et ai., 1973).
Systematic follow-up reports of haloperidol treatment for multiple tics
are few (Bruun et ai., 1975; Shapiro et ai., 1973). However, such reports
indicate that haloperidol's effect (on tics) persists. In fact, Shapiro et ai. (1973)
note that for their patients the dose of haloperidol can often be reduced over
time.
7. ANOREXIA NERVOSA
Anorexia nervosa is a disease entity characterized mainly by a loss in
body weight (usually over 25 Ib) that is caused by the purposeful avoidance
of food intake. In postpubertal girls, it is usually accompanied by a cessation
of menstruation (which occasionally precedes the weight loss). Psychologically, patients with this disorder have a characteristic fear of becoming fat;
usually they also deny the serious implications the weight loss has for their
health and survival. The disorder occurs primarily during adolescence and
almost exclusively in girls (Russell, 1970; Theander, 1970). Approximately
50% of adolescents with anorexia nervosa have a notable degree of psychopathology, particularly obsessive-compulsive features (Kay and Leigh, 1954;
Theander, 1970).
The disorder is uncommon and the incidence of hospitalized cases has
been estimated to be 0.5 per 100,000 (Theander, 1970). In one follow-up
study, 18 months after hospitalization 43% of the cases were reported to
have achieved an adequate sexual and appetite pattern (Crisp, 1966). In
another outcome study of 3-5 years, 72% were said to be reasonably well
adjusted (Dally and Sargant, 1966). In still other outcome studies, an average
of 15 years after hospital discharge, approximately 35-80% were said to have
recovered (Russell, 1970). Long-term outcome studies also reveal that
approximately 10-15% die from this disorder (Theander, 1970; Kay and
Leigh, 1954; Russell, 1970).
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DANIEL]. SAFER
The outcome of anorexia nervosa, however, cannot only be seen in

terms of survival and the general level of adjustment. One-third to one-half
of those who regain their weight and are discharged from the hospital are
readmitted to a hospital because of subsequent weight loss (Dally and
Sargant, 1966; Morgan and Russell, 1975). Weight fluctuations and sexual
maladjustments commonly persist in those with this condition (Kay and
Leigh, 1954; Russell, 1970). Furthermore, 27-50% of formerly hospitalized
anorexia nervosa patients have prominent symptoms of psychopathology
when examined at follow-up (Kay and Leigh, 1954; Dally and Sargant, 1966;
Morgan and Russell, 1975).

Behavior therapy, psychotherapy, and electroconvulsive therapy have all
been used to treat anorexia nervosa. Tube feeding is occasionally used as a
last resort, and leukotomy (Crisp and Kalucy, 1973) as a treatment has been
described.
All treatments have weight gain as an initial major goal of treatment. To
achieve this, most therapists use a behavioral approach. That is, the anorexic
adolescent-in order to gain freedom of movement and access to visitors and
to avoid tube feeding-must gain weight daily. Usually, 3-5 lb/week is
considered successful in this regard (Blinder et al., 1970).
7.3. Drug Treatment

A number of drugs have been used in the treatment of anorexia
nervosa. These include anabolic agents such as nandrolone (Tee, 1971,
1974a); major tranquilizers such as chlorpromazine (Pinkerton, 1975; Benady,
1970; Dally and Sargant, 1966), trifluperazine (Tee, 1974a), thioridazine
(Benady, 1970; Werry and Bull, 1975), and fluphenazine (Maxmen et al.,
1974); antihistamines such as cyproheptadine (Benady, 1970); insulin (Dally
and Sargant, 1966); and antidepressants (Morgan and Russell, 1975). Of
these, only insulin and antidepressants have received negative reports.
The best drug treatment outcome study in the literature is the one by
Dally and Sargant (1966). In their comparative outcome study, they reported
that treatment with insulin alone was clearly inferior to chlorpromazineinsulin treatment and that chlorpromazine-insulin treatment was mildly
superior to nondrug treatment. Of note in their study was that the
chlorpromazine-insulin treatment resulted in an average weight gain of 4-5
Ib/week, and that the average hospital stay for their patients was 5 weeks.
Doses of chlorpromazine used in the treatment of this condition range from
300 to 1600 mg/day (Benady, 1970; Crisp, 1966; Dally and Sargant, 1966).
189
The best comparative data on the initial phase of treatment for anorexia
nervosa have been presented by Blinder et at. (1970). They reported that in
terms of weight gain/week in the hospital, relative treatment efficacy (from
least to most effective) is as follows: psychotherapy (1-2 lblweek), high-calorie
diet (2-4 lb/week), behavior therapy (2-5 lblweek), and chlorpromazine (4-5
lb/week).
Although chlorpromazine does not always cause weight gain in hospitalized patients with anorexia nervosa (Werry and Bull, 1975; Blinder et at.,
1970), it seems generally to assist in this regard (Crisp, 1966; Dally and
Sargant, 1966). Furthermore, there is a good deal of other data on
thioridazine and chlorpromazine showing that these drugs enhance weight
gain in young psychiatric patients (McAndrew et at., 1972).
The usefulness of medication after the patient has regained his customary or expected weight and has left the hospital is not discussed much at all
in the literature. Presumably it is of limited value.
8. NIGHTMARES AND RELATED SLEEP DISORDERS

Frightening dreams that result in an arousal from sleep are a common
experience in childhood (Foster and Anderson, 1936). Foster and Anderson
(1936) reported that 93% of children aged 1-4 had "bad" dreams, compared
to 71 % of ages 5-8 and 39% at ages 9-12. La Pouse and Monk (1958)
reported that 28% of children aged 6-12 were said by their parents to have
nightmares. Macfarlane et at. (1954) found that approximately 20% of
children at age 7 had disturbing dreams two or more times per month,
compared to 35% at age 10 and 10% at age 13. The decline of this
phenomenon with age is supported by Shepherd et at. (1971), who found
that only 30% of children who reported nightmares in 1961 reported this
symptom three years later. Boys and girls are equally affected. Severe anxiety
dreams usually occur during deep (stages 3 and 4) sleep (Fisher et at., 1973;
Broughton, 1968).
Separating bad dreams from nightmares and night terrors is an
arbitrary matter (Mack, 1970). Generally, nightmares are associated with an
overwhelming fear (usually of death) and result in panicky awakening (Mack,
1970). In night terrors, the child is both terrified and confused, and only
partially awakens from sleep (Anthony, 1959). Somnambulism or sleepwalking reportedly occurs in only 6% of children, diminishes markedly in
adolescence, is often familial, and is not often associated with psychopathology (Bakwin and Bakwin, 1972).
190
DANIEL]. SAFER

Psychotherapy is often recommended for recurrent nightmares and
night terrors (Sperling, 1971). Case reports attest to its effectiveness.
8.3. Drug Treatment

Only two drugs have achieved repeated mention in the drug treatment
of recurrent, anxiety-related sleep loss.
Imipramine is given at night in doses of 10-50 mg (Tec, 1974b; Pesikoff
and Davis, 1971). It is usually administered for 2-8 weeks and then stopped.
In most clinically reported cases, it has been said to be helpful for nightmares
(Pesikoff, 1973). When stopped, relapse commonly occurs within three days
(Pesikoff, 1973).
Diazepam likewise has received uniformly excellent clinical reports for
its ability to stop nightmares in children (Glick et al., 1971). In a study of
adults treated with diazepam, the drug reduced the occurrence of nightmares fourfold (Fisher et al., 1973) but the nightmares generally returned
after the cessation of medication.
Imipramine has only a minor effect on the deep sleep of children (Ritvo
et at., 1969), whereas diazepam prominently reduces stage 4 sleep (Fisher et
at., 1973). Thus the suppression of stage 4 sleep does not appear vital to
drug treatment of nightmares.
8.4. Clinical Considerations for Drug Treatment

The selection of a drug of choice to aid in the treatment of children with
recurrent nightmares or night terrors is premature because no comparative
or well-controlled drug studies exist at this time on the subject.
In planning a course of drug treatment for nightmares, one would
certainly first want to consider the child's psychopathological state. Obviously,
if the child were psychotic or borderline, a major tranquilizer-not imipramine or diazepam-would be the preferred drug.
Maintenance drug treatment is said to be quite useful for half of the
children with recurrent nightmares (Pesikoff, 1973). If diazepam is used for
this purpose in children, one should be cautious because the drug can
notably suppress stage 4 sleep, a sleep period necessary for the adequate
secretion of growth hormone.
191
9. SCHOOL PHOBIA
School phobia is better viewed as a behavioral symptom than as a specific
psychological malady. The term applies when a child refuses to attend school
because of anxiety and instead doggedly tries to remain home. The symptom
is characteristically accompanied by apprehension or panic (when the child is
pressured to attend) and somatic-usually abdominal-complaints. It occurs
generally when there is apoorly resolved dependency relationship between a
mother and her child and when environmental factors precipitate acute
anxiety for the child and/or threaten the security of the mother (Johnson,
1957). Some 30% of these children also have features of depression
(Gittelman-Klein and Klein, 1971).
School phobia occurs most commonly in young school children. Its
occurrence peaks in the first grade (Waldfogel et at., 1959) and again-to a
lesser extent-in the seventh and eighth grades. Boys and girls are equally
affected. The disorder occurs in school children at an estimated rate of 1.4%
(Shepherd et at., 1971) to 1.7% per year (Kennedy, 1965); it constitutes 2-8%
of the caseload of child guidance clinics (Kahn and Nursten, 1962).
Many parents and nearly all school and clinic professionals actively
attempt to dislodge the school-phobic child from his home. Consequendy,
the rate of a nonintervention recovery from this clinical entity is unknown.
However, available data clearly suggest that delays in instituting therapy
result in a poor school attendance outcome (Waldfogel et at., 1959; Eisenberg, 1958).
Following active psychological intervention, 58-81 % of these children
returned to school within one to three weeks (Waldfogel et at., 1959;
Kennedy, 1965). By three months, 77% returned to school (Waldfogel et at.,
1959). One to three years later, good school attendance was noted to be
present in 71, 89, and 95% of these children (Rodriguez et ai., 1959;
Waldfogel et at.. 1959; Glaser, 1959), and five to ten years later, 96% of
previously school-phobic children were found to have subsequendy attended
school (Coolidge et at., 1964). Outcome was prominendy influenced by two
factors: (1) the age of the child-with the younger child faring better
(Rodriguez et at., 1959); (2) the psychopathology of the child and his
family-with the less-impaired group faring better (Rodriguez et at., 1959;
Waldfogel et at., 1959).

Management efforts for the vast majority of school-phobic children are
handled by school personnel (Waldfogel et at., 1959). School staff blend
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DANIEL J. SAFER
coercion and emotional support and are usually successful (Waldfogel et ai.,
1959). Only when they fail or find the going rough (approximately one in
every five instances) do they refer the child and his parents to a guidance
clinic (Waldfogel et at., 1959).
Psychotherapists as a group also blend coercion and emotional support
(Kennedy, 1965; Hersov, 1960; Eisenberg, 1958) and in the process more or
less utilize a behavior therapy position for the management of this disorder.
Most work with (and through) the parents (Eisenberg, 1958; Kennedy,
1965). Recent modifications of this general approach have been the use of a
strict behavioral approach (Lazarus et ai., 1965) and family therapy.
The comparative results of differing psychological-behavioral therapies
on the outcome of school phobia have not been studied. However, it would
be a difficult task to clearly better the average return to school results that
have been alluded to (70% within three weeks, 77% by three months, 85% in
two years, and 96% in eight years).
9.3. Drug Treatment

9.3.1. Imipramine
The most impressive studies on the drug treatment of school-phobic
children have come from the research team at the Hillside-Long Island
Jewish Hospital in Glen Oaks, New York. Their first report was a clinical
outcome study (uncontrolled) on the value of imipramine for school-phobic
children. In that study, the investigators found that 24 out of 28 (86%)
school-phobic children on imipramine returned to school within six weeks
(Rabiner and Klein, 1969). The next endeavor of this team was a DB
matched-sample study comparing the effects of imipramine with placebo in
school phobics over a six-week period (Gittelman-Klein and Klein, 1971).
Both the imipramine and placebo groups also received customary psychological intervention.
The dose of imipramine was set at 75 mg/day for the first two weeks and
adjusted thereafter. At three weeks it averaged lO7 mg/day, and at six weeks
it averaged 152 mg/day. At the end of the first three weeks, the outcome of
the placebo group did not significantly differ from that of the imipramine
group. However, at the end of six weeks, only 9 out of 19 (47%) of the
pakebo group were back in school compared to 13 out of 16 (81 %) of the
group that received imipramine. In addition, ratings by the children, their
mothers, and examining psychiatrists paralleled this difference.
In a later paper, Gittelman-Klein (1975) discussed further the use of
imipramine in the treatment of school-phobic children. She recommended a
single bedtime dose of the drug (not above 200 mg) and that the drug be
continued for four weeks after a clinical remission. Furthermore, she stated
that if no response at all occurred following a trial of 100 mg/day of
193
imipramine, there was no need to raise the dose. She stressed that the major
benefit of this drug is that it decreases the panic school-phobic children so
commonly experience.
There are, however, a few reservations about the major imipramineschool-phobic study of the Kleins (Gittelman-Klein and Klein, 1971). For
one, the back-to-school outcome for the placebo-psychotherapy group (47%)
is lower than that of all other reported treatment efforts. Had the imipramine-psychotherapy result (81 %) been compared with other reported psychotherapy-nondrug, six-week outcomes (which average 70-75%), the comparative results would not have been statistically significant. Second, the
outcome of the two placebo dropouts and the five imipramine dropouts was
not reported in the write-up of the study.
As would be expected, imipramine (in the high doses used) resulted in
significantly more side effects than did placebo (Gittelman-Klein and Klein,
1971). However, the fact that imipramine treatment for school phobia
extends only 6-10 weeks considerably lessens concerns about prolonged
drug side effects.
9.3.2. MAO Inhibitors

Although MAO inhibitors have not been studied specifically for the
treatment of school phobia, 15 of the 32 depressed children who were
treated with phenelzine and chlordiazopoxide in the study by Frommer
(1967) were phobic (primarily school phobic). In Frommer's DB crossover
study, the "depressed" children received either phenobarbital (up to 90 mg/
day), or phenelzine (up to 45 mg/day) and chlordiazopoxide (up to 30 mg/
day). The drug trials each lasted only two weeks, and at outcome the
phenelzine-chlordiazopoxide group improved more than the other. The
result is unfortunately clouded by the short duration of the treatment and
the use of phenobarbital as a comparison drug. Phenobarbital was not a good
choice, as attested by the fact that 11 out of the 32 children became worse on
that drug.
Nonetheless, there is other evidence-from studies of phobic adults and
children-to indicate that MAO inhibitors can be useful to decrease phobic
anxiety (Stack, 1972). Kelly et al. (1970), Stack (1972), and Tyrer et al. (1973)
reported this with phenelzine; and Lipsedge et al. (1973) found it was true
for iproniazid.
9.4. Combining Nondrug and Drug Treatment

Imipramine can represent a justifiable addition to the treatment program for school phobia when the clinical outcome is otherwise in doubt.
Thus, it might be relatively more useful for older or for more intransigent
school phobics. Its use has also been justified because of its effects in
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DANIEL]. SAFER
decreasing phobic anxiety. Supporting the use of antidepressants in phobic

children are studies using imipramine (Klein, 1964) and MAO inhibitors in
phobic adults.
Whereas the addition of a drug can decrease phobic anxiety, it does not
appear (by itself) to decrease avoidance behavior. To achieve this, behavioral-psychological support and structure are usually needed. In school and
child guidance practice, such management efforts are generally quite effective for school-phobic children.
Two questions central to the treatment of school-phobic children merit
answers at this time:
1. Are the strict behavioral approaches more successful for school
phobia than behavioral-psychological ones? Studies of the treatment
of adult phobics suggest that they are (Tyrer et at., 1973).
2. Does a drug-induced reduction of panic and anxiety improve the
overall treatment outcome in school phobia? Not only does the study
by Gittelman-Klein and Klein (1971) suggest this, but one study with
phobic adults does as well (Lipsedge et at., 1973).
10. STUTTERING
10.1. Occurrence and Outcome
Approximately 4% of the general population have experienced stuttering as a problem (Van Riper, 1971; Beech and Fransella, 1968; Andrews and
Harris, 1964). The most common age of onset of this disorder is 2-4 years of
age with a peak onset at 3. Customarily, the disorder at this age lasts only a
few months, so that by age 6, most children who stuttered at age 2-3 no
longer stutter. The male-female ratio is approximately 4: 1 (Van Riper,
1971).
The rate of stuttering in the population declines very appreciably-with
or without treatment-from early childhood until ages 10-12 (Sheehan and
Martyn, 1970; Andrews and Harris, 1964). However, three fourths of those
who stutter at age 10 maintain this pattern into adulthood (Andrews and
Harris, 1964). In general, four fifths (of all college students) who reported
that they had stuttered indicated that the pattern ceased by young adulthood
(Sheehan and Martyn, 1970). A major influence on the remission rate is the
severity of the stuttering; seven eights of the mild stutterers, three fourths of
the moderate stutterers, and one half of the severe stutterers experience a
remission. Improvement is also better when there is less social pathology in
the family of the stutterer (Wyatt, 1969). In global terms, the prevalence of
stuttering is over 4% in childhood, 1-2% in school-aged children, and less
than 1% in adulthood (Van Riper, 1971; Lapouse and Monk, 1958; Andrew
and Harris, 1964).
195

There is a good deal of controversy concerning the success of traditional
speech correction in hastening remission in stuttering (Sheehan and Martyn,
1970; Wells and Malcolm, 1971). However, there is little doubt that in
selected cases, active speech correction can lessen the handicap (Van Riper,
1971). Various behavioral approaches have also been used to treat disorder
and they have produced at least temporary benefits (Beech and Fransella,
1968).
10.3. Drug Treatment

A number of psychotropic drugs have been used in the treatment of
stuttering and have been reported to be successful. These include thioridazine (Goldman, 1966), chlorpromazine (Hackett et al., 1958), and meprobamate (Kraft et al., 1959).
However, more drug treatment studies to affect stuttering have been
done using haloperidol and there is better evidence that haloperidol is of
clear benefit for some stutterers. The data supporting this conclusion come
primarily from drug studies of adult stutterers. Swift et al. (1975) in a DB
controlled study found that 6 out of 7 young adults improved on haloperidol, a significant result. Wells and Malcolm (1971) in another controlled
study with adolescent and adult stutterers found that lO out of 12 improved
on haloperidol, also a statistically significant finding. Furthermore, 9 out of
the lO who improved maintained some improvement in fluency for three
years after the drug trial (Cookson and Wells, 1973). Although the results of
Quinn and Peachey (1973) and Rosenberger et al. (1976) with haloperidol
for adult stutterers were less impressive, they too showed significant results
for the drug.
Studies of haloperidol for childhood and early adolescent stutterers have
been less well controlled. However, the results are nearly as positive as those
reported for adults. Milman (1974) reported that 5 out of 6 stuttering
children improved on haloperidol. Healy (1974) reported one dramatic
beneficial result with this drug, and Tapia (1969) reported that 6 (2
measurably) out of 12 childhood stutterers improved with haloperidol.
10.4. Dose Side Effects and Duration of Haloperidol Treatment

The doses of haloperidol used for the treatment of stuttering have been
1-2.5 mg/day (Tapia, 1969), 0.5 mg t.i.d. (Healy, 1974), 0.75-1.5 mg t.Ld.
(Wells and Malcolm, 1971), and 2.5 mg/day (Swift et al., 1975; Quinn and
Peachey, 1973). Wells (1974) feels that doses over 3.5 mg/day yield better
results in the treatment of stuttering than do lower doses.
196
DANIEL J. SAFER
The major side effect of haloperidol at the above listed doses has been
drowsiness (Cookson and Wells, 1973; Quinn and Peachey, 1973). Wells and
Malcolm (1971) also reported depression and Swift et al. (1975) reported
EPS. Because of the frequent drowsiness, the drug can be given mostly at
night (Healy, 1974).
The duration of haloperidol treatment for stuttering is mentioned by
Wells (1974); he treated children for two months with this drug. Cookson
and Wells (1973) noted that an abrupt withdrawal from haloperidol worsens
stuttering; consequently, they argue for consideration of maintenance treatment.
10.5. Treatment Considerations

For numerous reasons (e.g., the large degree of spontaneous improvement of stutterers during childhood, the increasing treatment effectiveness
reported with behavioral therapy), there appears little reason to start a
prolonged program of medication treatment for the vast majority of young
stutterers. However, childhood and adolescent stutterers who are severely
handicapped by their symptoms and who are at best marginally improved by
nondrug efforts may benefit from the addition of haloperidol to the
treatment regimen.
11. LEARNING DISORDERS

Learning disability is usually assumed when there is a major discrepancy
between the child's mental and/or chronological age and his age-expected
academic achievement. Most researchers feel that an achievement level more
than 15% or 2.8 years below that expected indicates a prominent learning
deficit (Rutter et al., 197Ob; Mykelbust and Boshes, 1969). The problem is
greater in poor urban areas than in middle class areas (Berger et al., 1975;
Eisenberg, 1966), for biological (Berger et al., 1975), cultural (Eisenberg,
1966), and possibly genetic (Jencks, 1972) reasons.
The problem of academic difficulty and lag is most pressing during the
school years, 6-16, because one of the child's major tasks then is to master an
academic curriculum. Thus mild mental retardation is identified at a 3%
level of prevalence in children (Rutter, 1971). In adults, however, a moderate
degree of literacy and abstract reasoning is all that is required for most tasks.
Consequently the percentage of adults judged functionally to be mildly
retarded is less than 1% (TaIjan et al., 1973). Similarly, severe reading
diability is most prevalent (at a rate of 5-10%) in the elementary school years
197
(Berger et al., 1975). In later life, most with this developmental disorder
become "adequate" readers (HeIjanic and Penick, 1972); the others often
take jobs when reading is not vital to their productivity.
1l.2. Nondrug Treatments

There is no doubt that an educationally supportive home can positively
influence the IQ and achievement of the children who reside within, both
learning able and learning disabled (Jencks, 1972; Kugel and Parsons, 1967).
Externally engineered enrichment programs are far less influential. School
enrichment programs have a positive effect (Silberberg et al., 1973) but the
benefits of school remediation generally fade over time (Balow, 1965).
Parent-focused enrichment programs also usually yield only modest benefits;
their durability is largely unknown (Horwitz and Paden, 1973).
1l.3. Chemical Treatment of the Learning-Impaired

For learning-disabled children, a persistent adult hope has been that a
"magic bullet" (Wolfsenberger and Menolascino, 1968) of chemicals will be
found to correct the defect. Because a few disorders that impair learning are
treatable with diet or drugs (e.g., phenylketonuria, galactosemia, cretinism)
and because some drugs are magic bullets (e.g., penicillin), the hope persists.
At this time unfortunately, data from child psychopharmacological
studies clearly suggest that, except for some identifiable metabolic deficiency
diseases, chemical therapy adds little to the treatment of learning disability.
Some of the evidence to support this statement will be reviewed. Additionally, the presentation will include evidence that some psychotropic drugs may
impair learning.
1l.4. Drug Treatments

11.4.1. Stimulants
The major psychostimulants that are prescribed for children are the
amphetamines (e.g., Dexedrine), methylphenidate (Ritalin), and pemoline
(Cylert). Their CNS effects on children appear similar enough to warrant
discussing them as a group.
D,L-Amphetamine (Benzedrine) was touted in the 1930s, when it came
into medical use, as a boon to learning. Early studies indicated that single,
moderate to high doses of this drug resulted in mild increases (4-8%) over
placebo in test scores of intelligence for adult psychiatric patients and
delinquent boys (Sargant and Blackburn, 1936; Molitch and Eccles, 1937).
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DANIEL]. SAFER
Since then, approximately half the studies of stimulants in children have

shown mild but significant drug-induced IQ increases-usually in the
performance areas (Conners, 1972). Likewise, children taking tests of
achievement have tended to do better when on the drug than on placebo
(Molitch and Sullivan, 1937; Conners et al., 1969), although some achievement results have also been negative (Finnerty et al., 1971).
On specific performance tests, hyperactive children have repeatedly
shown numerically better scores following moderate to high doses of
stimulants than following placebo. Specifically, stimulant-induced improvements have been shown on the following: tests of motor steadiness (Knights
and Hinton, 1969; Conners et al., 1972), the Porteus maze test (Conners et
al., 1969), the draw-a-person test (Millichap et al., 1968), and on vigilance
measures (Conners and Rothschild, 1968; Sroufe, 1975). In general, performance measures have shown more change following the administration of
stimulants than have language measures (Conners et al., 1972; Epstein et al.,
1968).
The'improvement in test scores following the administration of stimulants can be largely attributed to the improved attention that is commonly
produced by stimulants (Conners, 1972; Sroufe, 1975). Some performance
test improvements may also be due to the effect of stimulant drugs in
decreasing impulsiveness and improving visual-motor coordination skills
(Conners, 1972; Sroufe, 1975).
Although test taking is frequently more successful after stimulants are
administered, longer-duration studies of children on stimulants suggest that
intelligence and achievement are not significantly benefited by these drugs.
Gittelman-Klein and Klein (1973) reported some significant achievement
changes for children at four weeks on-drug compared to predrug baseline
scores, but no relative improvement during the next eight weeks on the
drug. Rie (1975) and Conrad et al. (1971) reported only minimal achievement improvements (over control groups) for HA children on stimulants for
periods of 4-6 months, and Weiss et al. (1975) found no relative differences
in IQ or achievement in HA children who received stimulants for five years
(compared to those who were on no medication or chlorpromazine for that
period). Aman and Sprague (1973) and Conners (1974) conclude that
although stimulants improve attention they do not improve the retention of
new information. Of note in this regard is that appreciable state-dependent
learning does not occur when stimulants are given in therapeutic doses to
hyperactive children (Aman and Sprague, 1974).

11.4.2.1. Chlorpromazine and Thioridazine. A major point of a number of
drug studies is that some phenothiazine drugs, particularly chlorpromazine
and thioridazine, can impair learning (Hartledge, 1965). This is dose related
and appears to be particularly true during the first few weeks after drug
199
administration, when hypnotic drug effects are most prominent (Werry et at.,
1966; Sprague et at., 1970; Helper et at., 1963). Specifically, learning
impairments caused by the major phenothiazines used in children include
prolonged reaction time, impaired accuracy on vigilance tests, and performance decrements in paired-associate learning and Porteus Maze scores
(Sprague et ai., 1970; Werry et at., 1966; Helper et ai., 1963). Presumably,
drug-induced learning impairments present during the first month of
phenothiazine treatment can be explained by one of Irwin's postulates: "The
more hypnotic a drug, the more impairing it tends to be to psychic and
motor function" (Irwin, 1974).
Long-term effects of phenothiazines on learning have been insufficiently
studied. McAndrew et at. (1972) presented evidence that the removal of
thioridazine resulted in improved academic achievement for three institutionalized children. However, in a larger, better-designed outcome study,
Weiss et at. (1975) found that five years of outpatient treatment with
chlorpromazine resulted in no differential achievement or IQ changes for
hyperactive children. Likewise, studies of hyperactive and of retarded
children given chlorpromazine or prochlorperazine for periods ranging from
2 to 12 months revealed no drug effects on IQ (Craft, 1957b; Werry et at.,
1966; Mitchell et at., 1959; Adamson et at., 1958; Ison, 1957). If the postulate
of Irwin relating hypnotic drug effects to impaired "learning" applies, then
presumably another one by Irwin (1974) would account for the lack of a
long-term phenothiazine effect on learning: "With chronic administration,
patients develop a tolerance to the hypnotic effects of all classes of drugs ..."
This explanation appears useful even though it is oversimplified.
Complicating the issue is the fact that there have been two reports indicating
that average doses of 75 mg/day of chlorpromazine for 2-6 months have
tended to improve IQ and achievement in hyperactive children (Freed and
Peifer, 1956; Bair and Herold, 1957). Nonetheless, studies in adults reinforce
the concepts that during the first month chlorpromazine can impair learning
skills (Pollack, 1970; Hartlage, 1965; Mirsky and Rosvold, 1960) and that no
long-term attention or perceptual changes result from the drug (Owen,
1971).
11.4.2.2. Reserpine. Four studies document that modest doses (.75-2 mg/
day) of reserpine do not significantly influence IQ or achievement in
retarded or disturbed children (Graham et at., 1958; Pallister and Stevens,
1957; Timberlake et at., 1957; Zimmerman and Burgemeister, 1958).
Patients in these studies received reserpine for periods from 1 to 12 months.
11.4.3. Other Drugs

Therapeutic doses (60-200 mg/day) of phenobarbital given over prolonged periods result in no IQ changes (Somerfeld-Ziskind and Ziskind,
1940; Barnes and Fetterman, 1938; Wapner et at., 1962).
A number of drugs have been tried to "normalize" the retarded mind.
200
DANIEL J. SAFER
Prominent among these are chorionic gonadotrophin, glutamic acid, and

nialamide. The reports in the literature on these and other drugs that have
been said to raise IQ in retardates are mixed or negative. Two reviews cover
this territory well (Freeman, 1966; Louttit, 1965). Since these reviews, DSMO
has received favorable comments relative to enhancing learning (Giller and
Bernadou, 1975; Gabourie et al., 1975).
11.5. Theoretical Issues

Although clinical studies have not demonstrated that therapeutic doses
of psychotropic drugs improve learning in children, some drug studies in
animals have shown such effects (McGaugh, 1969; Essman, 1971). Drugs
such as pentylenetetrazol (Metrazol), picrotoxin, and strychnine in low doses
have been shown to facilitate the acquisition of new information in rodents
(McGaugh, 1969; Essman, 1971).
Presumably with these animal studies in mind, Barnett and Lampert
(1957) gave pentylenetetrazol to mentally defective children. However, their
14-month drug trial yielded negative results. Likewise, other studies have
shown that changes in learning skills following dextroamphetamine are quite
different for monkeys, rats, and people Oarvik, 1969). In view of this and
other research cited, it appears that the field of drug facilitation of learning is
in its early stages of development.
12. SEIZURE DISORDERS

12.1. Effect of Psychotropic Drugs on the Seizure Threshold
Some psychotropic drugs lower, whereas others raise the seizure threshold. This is particularly an important consideration when prescribing drugs
to treat emotionally ill children who are seizure disordered or seizure prone.
Psychotropic drugs that can increase the risk of seizures are ( 1)
chlorpromazine-psychomotor and grand mal (Rudy et al., 1968; Itil and
Myers, 1973; Di Mascio et al., 1970); (2) imipramine-grand mal (Brown et
al., 1973; Petti and Campbell, 1975); (3) meprobamate, in high doses-grand
mal (Itil and Myers, 1973).
Drugs used in psychiatric treatment that can decrease the likelihood of
seizures include (1) diazepam-myoclonic and petit mal (Bamberger and
Matthes, 1966; Weinberg and Harwell, 1965); (2) thioridazine-grand mal
(Di Mascio et al., 1970; Pregelj and Barkauskas, 1967; Pauig et at., 1961),
although some report that the drug has no effect on the rate of grand mal
seizures (Paulson and Buffaloe, 1964); (3) chlordiazopoxide---temporallobe
201
and petit mal (Pilkington, 1961; Itil and Myers, 1973); (4) d-amphetaminepetit mal (Livingston et al., 1948).
Still other psychotropic drugs appear to have no effect on the frequency
of seizures in children and adolescents. These include thiothixene, haloperidol, and fluphenazine (Itil and Myers, 1973). Prochlorperazine has been
reported to decrease grand mal siezures (Carter, 1959) but one case report
suggests that it can cause status epilepticus (Tec, 1968).
12.2. Psychological Effects of Anticonvulsants on Epileptic

Children
Seizure-disordered children as a group have approximately a fivefold
greater risk of behavioral and emotional problems than do nonepileptic
children (Rutter et al., 1970). In fact, nearly 1of all epileptic children exhibit
hyperactivity (Ingram, 1956; Hutt and Hutt, 1964; Bradley, 1951) and/or
behavioral-emotional problems (Rutter et al., 1970). Epilepsy is also more
prevalent in children who are mentally retarded (Brett, 1973) or are
psychotic (Rutter, 1965).
Thus, the possibility that anticonvulsant medication will not only be
effective in reducing seizures but will also produce behavioral, cognitive, and
emotional benefits is an attractive one. On the other hand, because many
anticonvulsants have sedative-hypnotic effects, there is a legitimate concern
that these drugs will aggravate existing psychological difficulties.
In general, hard evidence supporting both the hopes and the fears that
anticonvulsants will have distinct psychological effects is limited. Controlled
DB studies on these issues are not the rule. Nonetheless, available data on the
psychological effects of six common anticonvulsant drugs will be presented.
12.2 .1. Phenobarbital

Phenobarbital is probably the safest and one of the most effective drugs
presently available to treat grand mal seizures in children (Wapner et at.,
1962; Nellhaus, 1974). The drug is also a frequently prescribed hypnotic.
During the first month it is administered, it produces mild sedating effects
(Gestaut et al., 1973). A recent case report suggested that high doses of
phenobarbital (up to 200 mg/day) caused a prominent impairment in
learning for one young preschool child; furthermore, the effect proved to be
reversible following removal of the drug (Cordes, 1973). On the other hand,
there is a good deal of evidence showing that the administration of
customary therapeutic doses of phenobarbital produces no change in the IQ
or the personality of epileptic children (Wapner et al., 1962; Barnes and
Fetterman, 1938; Somerfeld-Ziskind and Ziskind, 1940). In addition, other
clinical data suggest that there is no relationship between the use of
202
DANIEL J. SAFER
phenobarbital in epileptic children and inattentiveness (Holdsworth and

Whitmore, 1974).
An adverse effect of more concern following the use of phenobarbital is
irritability and hyperactivity (Sunderland et ai., 1974). This is particularly a
problem for the child who is already developmentally hyperactive (Eisenberg,
1966).
12.2.2. Diphenyhydantoin (DPH)

Although the evidence that DPH is an excellent anticonvulsant for
grand mal epilepsy is virtually unchallenged (Sunderland et ai., 1974), claims
that the drug produces benefits in the psychological sphere in children
appear doubtful. Matti et ai. (1969) reported that whereas DPH and
phenobarbital were equally efficacious to control epilepsy in retardates, the
children on DPH were more mentally alert. Viukari (1969) also reported this.
On the other hand, Millichap (1969) noted that DPH does not behaviorally
benefit hyperactive epileptics, Stores (1975) found that children on DPH
over a two-year span improved significantly iess in reading than did
comparable children on other anticonvulsants, and Troupin et ai. (1975)
found that DPH given over a four-week period to children and adults in
doses up to 800 mg/day resulted in no IQ or perceptual benefits.
12.2.3. Ethosuximide (Zarontin)

Ethosuximide is now the recommended drug for petit mal epilepsy
(Sunderland et ai., 1974). Its effect on learning is unclear. Guey et ai. (1967)
reported that the drug-together with phenobarbital-significantly lowered
IQ and visual memory scores of children who experienced petit mal seizures.
Gestaut et ai. (1973) reported likewise that the "verbal quotient" declined and
"psychological disturbances" developed on the drug. On the other hand,
Smith et ai. (1968) for nonepileptic children given small doses and Buchanan
(1972) for epileptic children given customary clinical doses found no druginduced intellectual or perceptual decrements.
12.2.4. Primadone (Mysoline)

Primadone is a useful anticonvulsant drug, which in one study produced
no salutory behavioral effects in retarded epileptics (Rettig, 1956).
12.2.5. Carbamazepine (Tegretol)

Carbamazepine is increasingly used for the treatment of psychomotor
epilepsy (Livingston et ai., 1974). Dalby (1971) reported that the drug
lessened depression in 11 out of 18 patients. Its beneficial effects on behavior
are supported by case reports from a number of sources (Bonduelle, 1972;
203
Arieff and Mier, 1966). However, in two DB studies of adolescent and adult
epileptics, there were no significant behavioral differences when comparing
the effects of carbamazepine and placebo (Rodin et al., 1974; Bird et al.,
1966).
12.2.6. Sulthiame (Ospolot)

Sulthiame is an anticonvulsant that has been used for 12 years, mainly in
western Europe. It is not available in the United States, possibly in large
measure because the drug is said to be only a weak anticonvulsant (Green et
al., 1974; Moffat et al., 1970). Nonetheless, several reports attest to the
benefit of sulthiame for behavior in epileptics (Grant, 1974). Al-Kaisi and
Mcguire (1974) reported that the drug significantly reduced aggressiveness
and hyperactivity, and Griffiths (1970), Moffat et al. (1970), and Kneebone
(1968) all found that the drug improved behavior. On the negative side, Hutt
et al. (1966) noted in one case report that sulthiame impairs performance on
objective tests and decreases alertness.
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PLANTS AND PLANT CONSTITUENTS

AS iVlIND-ALTERING AGENTS
THROUGHOUT HISTORY
Richard Evans Schultes
There appears to be no human society so simple in material culture as to lack

some sort of mood-altering drug as an escape from the workaday world.
-La Barre
1
From his earliest gropings as a distinct animal, man undoubtedly experimented with his vegetal surroundings. He put into his stomach anything
from the plant kingdom in his frantic search for nourishment. He early
discovered that some plants served to assuage hunger and sustain him;
others relieved symptoms of illness; still others were dangerous, making him
ill or killing him outright; but a few, he found, transported him from this
monotonous and not-too-pleasant mundane existence to realms of ethereal
wonder and inexplicable separation from everyday existence. He had discovered the narcotics, especially the hallucinogenic plants, capable of much more
than activity on the physical body but able, through their psychoactivity on
the central nervous system, to alter in ways most extraordinary the psyche
and its relationship to the natural affairs of man.
Richard Evans Schultes
Botanical Museum, Harvard University, Cambridge, Massachu-
setts.
219
220
Much of the experimentation that led man to his hallucinogens was very
early. One of man's earliest cultigens, Cannabis, dates from well nigh the
beginnings of agriculture in the Old World-lO,OOO years ago. Specimens of
coca leaves have been found in mummy bundles in some of the very early
graves of Peru, in sites too early even for maize. Peyote buttons have recently
been recovered from dry caves in New Mexico, which have been dated at
4000 years of age.
Material evidence of the use of plant products as hallucinogens is
certainly not lacking in archaeological sites. Yet from the importance of
hallucinogens in aboriginal mythology and religion we know that they have
played roles so ancient that they are basic concepts even in the origin myths
of peoples in primitive societies around the world. There has been the
suggestion that one of the oldest hallucinogens-Amanita muscaria-may go
back as a narcotic so far in man's prehistory that it engendered the notion of
divinity and the supernatural.
It requires only a glance at beliefs surrounding some of the hallucinogens to appreciate their basic nature and significance to aboriginal concepts
concerning the origin of man and his cultures: hence their great age.
The fact that hallucinogens in many aboriginal societies permeate all aspects of living is evidence of their antiquity fully as convincing as material
remaIns.
They reach into prenatal life and influence life after death; they operate
throughout earthly existence. They play roles not only in health and sickness
but in the relationships between individuals, villages, and tribes, in peace and
war, at home and in travel, in hunting and in agriculture-there is hardly
any aspect of living or dying where hallucinogenic plants do not playa major
role.
It is not at all difficult to understand why hallucinogens have penetrated
so deeply into all aspects of primitive societies. Man in primitive societies had
to explain why a few plants possessed unearthly powers that could transfer
him temporarily from everyday existence to realms of ethereal wonder. His
explanation maintained that these plants were the abode of a divinity or
spiritual force, and they became sacred. This concept, actually, is not wholly
confined to so-called primitive societies, since many of the religions of the
more advanced cultures are based on similar beliefs: witness the widespread
Christian thesis that a divinity could incarnate itself into the body of a man,
Jesus. But in societies based on the belief that all of nature is controlled by
the supernatural, that all of man's existence--even sickness and death-is
ruled by powers in outer realms, what is more logical than to assume that
these plants enable mortal man---4)r at least certain individuals in society-to
communicate through hallucinogens of various kinds with the ruling forces?
As La Barre (1970) maintains: "Sacred knowledge is commonly traceable,
even by natives themselves, to an origin in revelation given to the ancestors
or to some similarly charismatic individual, such as a shaman, visionary
221
prophet or other culture hero believed to have been able to 'tap' the unseen
world of the 'supernatural.' "
There are many characteristics of hallucinations that can and do deeply
influence primitive religion and ideas of the cosmos. Certain hallucinogenic
plants-peyote, for example-induce indescribably deep and rich colors that
are so unlike those normally experienced that only a supernatural origin
seems possible; others produce only reds, oranges, or yellows; still others
tend to be responsible for duller tones of blues, purples, or greys. The
intoxication caused by some of these plants, especially those containing
tryptamines, is characterized by macropsia and undoubtedly has played a
role in mythology in connection with giants; others, however, have an
opposite effect, micropsia, and have influenced belief-such as with the
oprita of the Kofans-in the "little people." Other hallucinogens enable man
to fly through the air by inducing the sense of levitation: shanshi of the
Ecuadorian highlands; vinho de jurema in Brazil, the fly agaric in Siberia,
the solanaceous species of medieval witches' brews of Europe.
Similarly, auditory hallucinations may enable medicine men and often
others to speak with the controlling spirit forces: sinicuichi, gi-i-wa and gi-isa-wa, and thle-pela-kano in Mexico fall into this category. The peyote
intoxication may, at certain phases, induce auditory aberrations and, like
other hallucinogens such as Cannabis, may evoke peculiar response to
chanting, singing, music, drumming, or natural sounds like that of rippling
waters-an effect clearly suggesting in aboriginal thinking supernatural
connections between the causative drug and man.
2
There are very definite classes of chemical constituents in plants that
induce hallucinations of given kinds: visual, auditory, tactile, gustatory, and
olfactory. They are, when known, of only a few types, which can be grouped
into two broad categories: the nonnitrogenous and the nitrogenous.
The nonnitrogenous hallucinogens are, primarily, the dibenzopyransthe cannabinolic constituents known only from the genus Cannabis-and the
phenylpropanes present in essential oils found in certain spice plants.
The nitrogenous hallucinogens-the active principles in by far the
greater number of mind-altering plants-are alkaloids or related bases. They
are conveniently arranged into nine groups: the isoxazoles (Amanita), tropanes (in many solanaceous narcotics: Datura, Atropa, Mandragora, Hyoscyamus, Latua, Methysticodendron) , quinolizidines (Cytisus, Sophora, Heimia),
phenylethylamines (known from a number of cactaceous species in Lophophora, Trichocereus, etc.), isoquinolines (Lophophora), tryptamines [Justicia(?),
certain mushrooms in Conocybe, Panaeolus, Psilocybe, Stropharia, and Anadenanthera, Mimosa, Banisteropsis, Virola, Psychotria], ,B-carbolines [Banisteriopsis,
222
Tetrapteris(?), Peganum1 ergolines (Ipomoea, Rivea, and the ascomycete

genus Claviceps), iboga indoles (Tabernanthe). New types may, of course, turn
up when phytochemical investigations on some of the still poorly understood
hallucinogenic plants elucidate their composition.
While it is known that some of the active principles may induce
characteristically visual or auditory hallucinations, there is no sound scientific
evidence to support suggestions that definite kinds of visual hallucinations
may tend to be produced by specific compounds. It has been, for example,
intimated that the importance of huge serpents and felines in certain South
American hallucinogenic ceremonies has "biochemical" explanations: that the
great frequency of jaguars and other felines and snakes in descriptions of
caapi intoxication might be due to an ability of the active chemical constituents to induce visions of definite kinds of subjects. There is, however, not a
shred of scientifically sound evidence that such a degree of specificity exists.
One is necessarily left with the near certainty that underlying the primacy of
the jaguar in so many cultures are ancient, deeply ingrained, and highly
positive experiences that are now part of the mind of aboriginal man. It isto put it in really an oversimplified statement-that man, living in the South
American jungle, has long since learned to respect and fear the stealth and
power of gigantic snakes and cats and that, under conditions obtaining when
his mind is altered by drugs, he sees and fears these overpowering animalsactually the only ones in his environment that he has experienced difficulty
in overcoming.
3
One of the most ancient of the hallucinogens-although only very
recently has it been deeply studied-is soma, the ancient god-narcotic of the
early Aryan invaders of northern India. Whereas all other hallucinogens
have been considered merely as sacred elements, soma was actually deified. It
has long since died out of use in India, but scholars know of it in great detail
through the hundreds of references to it in the rich Vedic literature.
Its sacred narcotic use among the Aryans goes back some 3500 years.
Long an enigma that baffled botanists who tried to identify it, soma has only
recently yielded to determination as Amanita muscaria, the widely recognized
hallucinogenic fly agaric mushroom, which is still in ritualistic use in remote
parts of northern Asia.
In modern times, this mushroom has been valued as a hallucinogen
among isolated Finno-U grian tribesmen in eastern and western Siberia.
Although first reported in the 18th century, the Siberian use of the fly
agaric obviously is of great age, and it may be that the knowledge of these
primitive peoples stems from the early days when the mushroom was
undoubtedly more widely employed as a sacred narcotic than even 3500
years ago, the period of the Aryan invasion of India. The Chuckchis, for
223
example, believe that the mushrooms possess powerful spirits that delight in
visiting places where the dead dwell; that, while it delights in playing practical
jokes on a person under its influence, it may also guide him to other realms
or guard him from harm in this world. The Koryaks maintain that the god
Vahiynin (Existence) left the mushroom on earth to instruct man in the
mysteries of nature. It is difficult to entertain any concept indicative of a
more basic significance of a plant to the life of a people.
The most spectacular of the African hallucinogens, iboga (Tabernanthe
iboga) , now of ever increasing social importance in the Congo and Gabon,
goes far back in prehistory to primitive Pygmy hunting societies. It is the
basis of the Bwiti cult, and sorcerers take it to consult with the ancestors.
Tabernanthe iboga is, strangely enough, the only member of the extremely alkaloid-rich family Apocynaceae known to be employed as a
hallucinogen. The part of the plant used is the yellowish root, which contains
about 6% alkaloids: twelve indole alkaloids have been found in the plant.
The most important is ibogaine-a cholinesterase inhibitor-which acts as a
strong central nervous stimulant in addition to its effects as a hallucinogen.
Cannabis may well rank as our oldest hallucinogen. It is most certainly
one of man's oldest cultivated plants, going back at least to the beginnings of
agriculture in the Old World-some 10,000 years ago. Whether it was first
valued for its mind-altering properties or for one of its several other
economic uses cannot now be ascertained. Its psychoactive properties,
however, are noted in the oldest recorded history in China and India, and
obviously knowledge of them must predate the earliest records. An archaeological find in a Bronze Age urn in Germany, containing fragments of
cannabis leaves and fruit, suggests that the plant material was valued for
narcotic or medicinal purposes, not for fiber. In the 7th millenium B.C., the
Chinese knew cannabis, but the Emperor Shen Nung in 2723 B.C. wrote
about its "medicinal" properties. Ayurvedic medicine in India, which is
rooted in great antiquity, employed cannabis early in the Christian era, even
though its use in India goes back much earlier. In the 5th century B.C.,
Herodotus recorded the Scythian narcotic use of cannabis in sweat baths.
Later, cannabis spread widely as a narcotic in many parts of Africa.
It is not only historical records and archaeological remains of cannabis
that attest to its great antiquity in man's economy. The wide distribution and
extreme polymorphism, especially of its principal species Cannabis sativa,
indicate long manipulation by man in his agricultural history. Even though
its value as a source of fiber, edible fruits, useful seed-oil, and medicine may
have undoubtedly contributed to this manipulation and consequent variation
as much as its employment as a narcotic, there is no room for doubt that
selection for strains high in the intoxicating principles, especially in C. sativa
and C. indica, has been carried on in some regions for milennia.
We know next to nothing about the use of hallucinogens in European
prehistory. There has probably never been a part of the world, however,
where the sinister use of hallucinogenic plants was more spectacular than
224
Europe of the Middle Ages, an area that with its Christian society was hostile
to the use of mind-altering drugs. The role that the several solanaceous
species-henbane (Hyoscyamus niger), belladonna or deadly nightshade
(Atropa belladonna)-played in the preparation of witches' brews and the
uncanny hold for so many centuries of the mandrake (Mandragora ofJicinarum) in black magic are examples of this importance. The folk names of
some of these plants attest their great age as narcotics: in German, H exenkraut early related them to witchcraft; the English name dwale for the deadly
nightshade stems from the ancient Scandinavian word for trance or stupor.
The technical generic epithet Atropa goes back to the Greek for "unalterable"
and the name of Atropos, one of the Fates, who cuts the thread of life; the
generic name Mandragora is believed to be derived from a Sanskrit word
signifying "sleep-drug."
Other members of this highly toxic family Solanaceae, however, are
deeply and often anciently involved in cultural patterns in many diverse parts
of the world. The genus Datura has enjoyed a major role in both New and
Old World cultures and continues to do so.
Many if not most tribes north of Mexico were familiar with the
psychoactive potency of several species of Datura, especially of D. stramonium
in the eastern half of North America and D. inoxia (equivalent to D.
meteloides) and D. wrightii in the Southwest and California. The Algonkians
of the area of Virginia made a highly intoxicating medicine, called wyosoccan
and believed to contain D. stramonium. Young boys, to undergo initiation
to manhood, were kept intoxicated for some twenty days in order to lose all
memory of their former life. In the Southwest, toloache or D. inoxia also
played important roles in initiation rites. The Yumas took it to acquire occult
powers; the Luisenos gave it to youths, who danced screaming until they fell
into a stupor in which they found their adult life. Among the Zuni, only rain
priests, who own the plant, may collect the roots, which are powdered and
put into the eyes that they may see at night, commune with the feathered
animals, and contact the dead that they may intercede for rain. The Zuni
have a myth ascribing direct divine origin to this Datura.
In Mexico, however, Datura attained an exalted place in the rich
pharmacopoea of psychoactive drugs. Utilization goes far back in Mexican
Indian life, and the hallucinogenic use of several species, especially D. inoxia,
was widely and firmly established by the time of the Spanish Conquest.
Datura is still highly esteemed in many Mexican tribes, such as the Tarahumares, who add it to tesgiiino, a fermented maize drink, and who use it
ceremonially for the diagnosis of disease. A Mexican species of very special
importance was D. ceratocaula, a fleshy plant with thick, forking stems that
grows in swamps or in standing water. Known as "sister of ololiuqui" (a
sacred convolvulaceous hallucinogen of Mexico), this unusual species played
a major role among the Aztecs, who invoked the spirits of the plant in the
treatment of certain diseases.
In South America, the native species of Datura (often considered to
225
represent a distinct genus, Brugmansia) are arborescent. All of the species are
indigenous to high cool areas of the Andes, except D. suaveolens from the
warmer lowland areas. They are handsome trees with large, showy flowers
and have long been a favorite in horticulture, but they appear to be
chromosomally aberrant cultigens no longer known in the wild state. Their
narcotic use in aboriginal groups in South America varies from tribe to tribe,
but in many areas their importance in ritual attests to great age as
hallucinogenic agents. Always extremely dangerous as intoxicants, they are
usually employed under the control of medicine men. The Jivaros, for
example, administer D. candida to refractory children in the belief that
ancestral spirits will correct their waywardness. In ancient Colombia, the
Chibchas gave women and slaves of dead warriors and chieftains potions of
D. aurea prior to their being buried alive to accompany their departed
masters. The beautiful red-flowered D. sanguinea, valued throughout the
Andes from Colombia south to Peru, was sacred to the Indians, who used the
seeds in rites in the Temple of the Sun at Sogamozo in northern Colombia.
In the mountain-girt Valle de Sibundoy in the highlands of southern
Colombia, Ingano and Kamsa Indians have such a tradition of using D.
candida and the closely related Methysticodendron amesianum that a number of
morphologically atrophied and chemically distinct "races"-possibly representing virally affected strains-are kept by vegetative reproduction for
employment for very specific hallucinogenic and medicinal purposes. This
peculiar botanical phenomenon may well indicate great age of this culture
trait in Sibundoy.
There is another solanaceous hallucinogen the use of which bespeaks
antiquity. Latua pubiflora- the arbol de los brujos or latue of central Chile-is
a very strict endemic. Its virulent poison can cause delirium, visual hallucinations, and often leads to permanent insanity. First reported in the middle of
the 19th century, it was obviously of long tradition among the Mapuche
Indians, whose medicine men employed it. The use of the drug has now
apparently died out. It contains potent tropane alkaloids typical of so many
members of the Solanaceae.
In ancient Mexic(}-and down to the present time--sacred, intoxicating
mushrooms were, together with the peyote cactus and ololiuqui, the most
important hallucinogenic agents.
Mushroom ikons-the so-called mushroom stones-have during the past
century been excavated from highland Maya cultures of Guatemala, and
archaeologists were at a loss to explain their significance. Now it is known
that they represent idols connected with worship that employed intoxicating
mushrooms as a sacrament. Some of these idols are dated from about 1000
B.C. and indicate that, at least 3000 years ago, there was a sophisticated ritual
using these toxic plants as holy hallucinogenic sacraments.
Recent investigations have indicated that the hallucinogenic use of
mushrooms-some 25 species in four genera (Conocybe, Panaeolus, Psilocybe, and Stropharia}-has survived in at least nine Indian groups in Oaxaca.
226
Detailed studies of the mushroom ritual have been made among the
Mazatecs.
Frescoes from central Mexico dated at 300 A.D. have designs of the
sacred mushrooms. There are numerous other indications of the great
antiquity of mushrooms as hallucinogenic agents in Mexico. The Aztecs
valued them greatly, and they are figured commonly on archaeological and
other precolonial art objects.
Paintings at Tepantitla show mushrooms in close association with
depictions of the Aztec god of rain. Furthermore, Xochipili-the so-called
Aztec God of Flowers-has on his pedestal stylized engravings of Psilocybe
aztecorum. The many references to hallucinogenic use of mushrooms by
chroniclers reporting just after the Conquest indicate the extraordinary
importance and antiquity of the use of these fungi. Several post-Conquest
reports tell of the deep importance to Mexican religious life of mushrooms
or teonanacatl ("flesh of the gods"), as they were then called in Nahuatl.
They were served at the coronation feast of Montezuma in 1502. Hernandez,
in his great study of Mexican materia medica, wrote that three kinds of
mushrooms were used hallucinogenically and that one-teyhuintli--caused
"not death but a madness that on occasion is lasting ... [and that] there are
others again which, without inducing laughter, bring before the eyes all sorts
of things, such as wars and the likeness of demons. Yet others ... not less
desired by princes for their festivals and banquets. . . ."
Due to intense Roman Catholic persecution of native religions, the
rituals that employ these mushrooms were driven into the hinterlands and
were not known until 1939. In 1916, an ethnobotanist, faced with the
complete lack of knowledge of mushrooms so employed, suggested that the
natives had misinformed the Spanish authorities and had pointed out
mushrooms in an attempt to protect their true hallucinogen, peyote. He
reasoned that dried peyote heads or "buttons" resembled dried mushrooms.
Consequently, he misidentified teonanacatl, insisting that it was in reality the
same as the peyote cactus. But research during the past forty years has
shown not only that mushrooms were used but that they represented
extremely important elements in the native cultures.
These mushrooms are biochemically significant because of the discovery
that their active principles are curious indoles: psilocine and the structurally
curious psilocybine. Psilocybine, a hydroxyindole alkylamine with a phosphorylated hydroxyl radical, represents a wholly new type of structure that
not even the synthetic chemist had ever prepared: 4-phosphoryloxy-N,N-dimethyltryptamine. It is known only from these mushrooms.
Missionaries of the 18th century reported that the Yurimagua Indians in
Amazonian Peru took an intoxicating beverage made from a "tree fungus."
Even though no field evidence has substantiated this use of a fungus in the
Amazon, it has been suggested that the known hallucinogenic mushroom
Psilocybe yungensis may have been the fungus to which reference was made.
227
The early Spanish chroniclers of Mexico likewise reported the use of

ololiuqui and tlitliltzin among the natives as sacred intoxicants. Ololiuqui was
described repeatedly as a vine and was at least twice illustrated as a morning
glory. Again, however, as in the case of the mushrooms, morning glory seeds
had never been seen employed in modern Mexico as intoxicants. Furthermore, no intoxicating principle was known in this family, the Convolvulaceae.
Consequently, it was long presumed that the natives, to confound the
Spanish ecclesiastical authorities, were pointing out morning glories to
protect the sacred hallucinogen toloache, D. inoxia, of the Solanaceae, which
has flowers superficially resembling those of the Convolvulaceae. This
misidentification persisted in the literature until recently, when two species of
morning glories employed to this day by Indians in Oaxaca were identified:
Rivea corymbosa, the ololiuqui of the ancients, and Ipomoea violacea, the
tlitliltzin. From the seeds of both species chemists eventually isolated a
number of ergoline alkaloids related to the synthetic lysergic acid diethylamide (LSD). The total alkaloid content of R. corymbosa seeds is 0.012%, of 1.
violacea 0.06%, the reason why natives use smaller quantities of the latter
than of the former.
The chroniclers gave very detailed descriptions of ololiuqui and its
effects. One wrote that "it is remarkable how much faith the natives have in
the seed ... which they consult as an oracle to learn many
things ... especially those beyond the power of the human mind to penetrate." Another reported how the "seeds are held in great veneration ....
The Indians place offerings to the seeds in secret places ... and put them
amongst the idols of their ancestors" and that they do "all in their power so
that the use of the plants does not come to the attention of the authorities."
Modern Indians in Oaxaca call the seeds of R. corymbosa "semilla de 1a
Virgen." They grind the seeds to a powder on a metate, soak the powder in
water, strain the liquor through a cloth. This liquid is then drunk. Unless the
seed is crushed and soaked, it is not active. Contemporary use of these
morning glory seeds concerns itself mainly with divination, prophecy, and
diagnosis of disease.
In the same region of Oaxaca, the leaves of a mint, Salvia divinorum,
known as hojas de la Pastora, are often employed as a hallucinogen. It has
been suggested that S. divinorum, now used apparently only in Oaxaca, may
have been the pipiltzintzintli of the ancient Aztecs. The plant is reproduced
vegetatively, as it seems not to produce seeds---due possibly to great age of
cultivation. Most Mazatec Indian families own a tiny plot of this mint hidden
away in remote areas away from roads and trails. The intoxicating effects of
these leaves are less marked than those induced by the mushrooms or
morning glories and are of shorter duration. Although the psychoactivity has
been experimentally established, no biodynamic constituent has as yet been
isolated from S. divinorum.
It is probable, but not yet certain, that the leaves of two species of
228
Coleus-C. blumei and C. pumilus-are similarly employed in Oaxaca. Both are

Old World plants introduced early into Mexico.
Undoubtedly the most important of the sacred Aztec hallucinogens and
one the significance of which in native religions has grown is peyote, a small
spineless cactus of central and northern Mexico and the Rio Grande area of
Texas. Two species are recognized: Lophophora williamsii, the most widely
distributed, and L. diffusa, restricted to Queretaro. There appear to be
chemical as well as morphological differences between the two species.
Known to the Aztecs as peyotl, this cactus was a holy mediator between
man and the divinities. Hernandez, the King of Spain's personal physician
who studied Aztec medicines, wrote in 1576 that "this root ... conceals itself
in the ground as though unwilling to harm those who may find and eat it."
The early Spanish literature was fanatically and vituperatively condemnatory
of peyote? and its use was equated with cannibalism. Attempts to extirpate
the religious use of peyote resulted in its retreat into remote areas where it
survived. The Tarahumares, Huichols, and other tribes of central Mexico
still venerate this holy sacramental plant, and the Huichols practice an annual
ceremonial pilgrimage to the areas where peyote grows to gather supplies.
The purpose of this pilgrimage is to find their "life." To them, peyote is
identical with the deer, their sacred animal, and with maize, their sacred food
plant: all three are fused into a single symbol complex. They "hunt" peyote,
and their first peyote-hunting ceremony was led by Tatewari (Our Grandfather)-equivalent to Fire and the original Shaman-and the leader of the
modern peyote quest becomes the embodiment of Tatewari.
The Tarahumares have perhaps the keenest appreciation of peyote.
They assert that the severed heads of the cactus sing happily in the bags once
they have been collected. The plant, they insist, prolongs life, protects
hunters from wild animals, guards mourners from ghosts, and they assert
that an individual who has not eaten peyote must never touch the plant, lest
he become demented.
The extraordinary and complex peyote intoxication, as well as its
reputation as a physical and psychic Indian medicine, led to its spread far to
the north of its range in Mexico. During the last century, Indians from the
United States encountered this native cactus-centered religion. Following
1880, it was accepted with great speed among many tribes in North America
as the central sacrament of a new peyote cult-a blend of the ancient pagan
and modern Christian elements-which was legally organized into the Native
American Church, now claiming 250,000 members in the United States and
Canada. These Indians, distant from the source of peyote, import legally the
dried tops of the plant-peyote buttons-the form in which the cactus is
usually ingested, even in Mexico.
The most outstanding characteristic of the peyote intoxication is the
extraordinary series of visual hallucinations in indescribably brilliant colors in
constant kaleidoscopic motion. This is often accompanied by auditory, tactile,
gustatory, and olfactory hallucinations. It is consequently not difficult to
229
understand why natives would accord such a biodynamically potent plant a

special place of honor and reverence in their thinking and living.
Lophophora williamsii contains some 33 alkaloids or related bases. Both
phenylethylamines and isoquinolines are present. Mescaline, 3,4,5-trimethoxyphenylethylamine, is solely responsible for the characteristic visual hallucinations.
The Tarahumares and other Mexican Indians consider as "false peyotes" other cactus plants. Some of these have been investigated chemically
and contain toxic principles. Among these false peyotes are species of
Ariocarpus, Pelecyphora, and Astrophytum. "All of these various species,"
reported the anthropologist Lumholtz, "are considered good, as coming
from Tata Dios, and well disposed toward the people. But there are some
kinds of hikuli [peyote] believed to come from the Devil. One of these, with
long white spines, is called ocoyome. It is very rarely used, and only for evil
purposes."
That peyote enjoys great antiquity as a sacred intoxicant is attested by
the recent discovery of dried peyote buttons in archaeological sites in Texas
of some 4000 years of age.
In prepeyote days in the American Southwest and Mexico, the toxic red
seeds of the leguminous Sophora secundiflora were ingested in a visionseeking ritual variously known as the Wichita Dance, Red Bean Dance, or
Mescal Bean Dance. The bean, which contains the alkaloid cytisine, is
dangerously toxic and can cause death through asphyxiation. When peyote, a
relatively safe drug, came north, the Indians turned to its use and gave up
ingestion of the mescal bean. It persists today, however, in the dress of the
peyote leader as a necklace-a vestige of a once sacred plant.
Mexican Indians possess certain plants that characteristically induce
auditory hallucinations. The most important of these is sinicuichi, Heimia
salicifolia, with five quinolizidine alkaloids, the most important of which is
cryogenine. Wilted leaves of sinicuichi are crushed in water, which is allowed
slightly to ferment. The drink brings on drowsiness, a feeling that the
surroundings are shrinking, auditory hallucinations, and a general isolation
from reality. Another plant causing alteration of hearing is the composite
Calea zacatechichi, which the Chontal Indians of Oaxaca, who call it thle-pelakano or "leaf of god," take in an infusion for divination through conversation
with supernatural powers. Similarly, the Mixtecs of Oaxaca employ two
species of puffball-Lycoperdon marginatum and L. mixtecorum-as auditory
hallucinogens. Nothing is known of the active principles capable of altering
auditory perception in the Calea or the Lycoperdon.
The value that Mexican Indians place on auditory hallucinogens is
evident in the use of the sacred mushrooms, morning glories, and peyote, all
of which, in addition to visual hallucinations, occasionally cause distortion of
the hearing-a reaction that is considered of great significance among the
indigenous users of these drugs.
In South America, perhaps the most renowned hallucinogen is the drink
230
variously called ayahuasca, caapi, natema, pinde, and yaje and prepared
basically from the bark of several species of the malpighiaceous Banisteriopsis:
especially B. caapi and B. ineb'Tians. Either a boiled decoction or a cold-water
infusion may be made. On occasion, other plant ingredients are added. This
narcotic is widely used in the western Amazon and upper Orinoco and along
the Pacific coast of Colombia and Ecuador.
The Kechwa term ayahuasca means "vine of the soul" and stems from
the frequent experience that the soul separates from the. body and wanders
free during the intoxication. Many Indians insist that they even come to
know death under the influence of the drug, and that those who take it
"die," only to be reborn in a state of greater wisdom.
The effects of ayahuasca or caapi can be violent and with unpleasant
after effects. Nausea and vomiting are almost always early characteristics of
the effects of the drink. These are followed by a pleasant euphoria, then by
visual hallucinations, initially of a bluish or purplish cast. Excessive doses
cause nightmarish and frightening visions-often of jaguars and snakes.
Banisteriopsis caapi and B. inebrians, when used alone in the preparation
of the intoxicant, possess hallucinogenic properties due to the presence in the
bark of three Ji-carboline alkaloids: harmine, harmaline, and tetrahydroharmine. Recent research, however, has indicated many plants occasionally
added to strengthen, lengthen, or alter the inebriating effects. Only a few
have been chemically studied, but the results have been astonishing. Two of
the additives-the leaves of the rubiaceous Psychotria viridis and the leaves of
another species of Banisteriopsis, B. rusbyana----contain N,N -dimethyltryptamine. The tryptamines are ineffective when eaten, unless taken in the
presence of a monoamine oxidase inhibitor. The Ji-carbolines act as this
inhibitor, allowing the tryptamines to exert their hallucinogenic effect.
Another occasional additive----D. suaveolens----contains highly hallucinogenic
tropane alkaloids.
In the northwest Amazon of Brazil, the malpighiaceous vine Tetrapteris
methystica is employed alone as the basis of a drink called caapi, which has
effects identical with the drink prepared from B. caapi. In view of the close
relationship of the two genera, it is probable that T. methystica contains the
same or similar Ji-carboline alkaloids, but chemical investigation has not yet
confirmed this suspicion.
Several other South American hallucinogenic preparations owe their
activity to tryptamines: vinho de jurema, ebena or nyakwana, yopo, and
huilca.
In Pernambuco, Brazil, the famous drihk ajuca or vinho de jurema is
made from the root of Mimosa hostilis, a small tree or large shrub of the
Leguminosae. The ancient jurema cult was practiced formerly by five or six
tribes: priests, young men, warriors, and old women took it with bowed
heads before battle, and the warriors about to fight would see glorious visions
of the spirit world, glimpses of the clashing rocks that destroy the souls of the
dead journeying to their destination, and the mystical thunder bird with
23l
lightning bolts flashing from a huge tuft on his head producing claps of
thunder.
Reported in the literature as early as 1788 and 1843, jurema was
definitely identified only in 1946. At that time, a new alkaloid named
nigerine was reported from the roots, but it was later shown to be identical
with N,N-dimethyltryptamine.
Historically, one of the most famous South American hallucinogens is
the snuff known in the Orinoco as yopo and prepared from beans of the
leguminous Anadenanthera peregrina, known also as Piptadenia peregrina.
Many early explorers of the region-including von Humboldt and Sprucewrote about this strikingly powerful drug. Undoubtedly the earliest reportthat of Pane-described the cohoba powder of the Taino Indians of
Hispaniola in 1496. This description was first published in 1511, when the drug
was detailed as being "so strong that those who take it lose consciousness ...
the arms and legs become loose and the head droops" and "almost immediately
they believe they see the room upside down and men walking with their
heads downwards." It is probable that the tree-together with the custom of
using the snuff prepared from its seeds-was taken to the Antilles by the
Indians who invaded the islands from South America. The hallucinogenic
use of Anadenanthera has, however, died out in the West Indies, and cohoba
was not actually identified as the same drug as yopo until 1926.
The flat black beans are gently toasted, pulverized, and mixed usually
with lime or alkaline ashes. Early explorers mistakenly felt that the biodynamic activity was due to the alkaline admixture. It is now known that the
seeds contain several potent tryptamines, including relatively high concentrations of N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine, as
well as bufotenine or 5-hydroxy-N,N-dimethyltryptamine.
The activity of yopo is rapid in onset but not of long duration, unless
continued snuffing is practiced. Initial twitching of muscles and nervousness
is quickly followed by a stage during which dancing, chanting, shouting, and
violent physical action-such as gesticulating and fighting the hekula or
enormous spirits-is characteristic. Eventually the Indian sinks down into a
lethargic condition, during which visual hallucinations occur, and later into
an almost comatose nightmarish sleep. Macropsia is very characteristic of the
intoxication.
In the southern parts of South America-in Peru, Bolivia, and Argentina-the natives made intoxicating snuffs in preconquest times, but their use
has long since died out. The term vilca in modern Peru refers often to A.
colubrina, as does the term sebil in Argentina. An early report, dating from
about 1571, stated that Inca sorcerers prophesied by contacting the devil
through chicha (maize beer) and an herb called vilca. And in Argentina, the
Comechingon Indians took something called sebil through the nose. However weak and circumstantial the evidence that vilca and sebil were prepared
from Anadenanthera, there is no biochemical reason why this species could
not have been the source of the snuff: the seeds contain tryptamines in
232
concentrations similar to those of the seeds of the morphologically related

and more northerly species A. peregrina.
Another major South American snuff is prepared from the blood-red
resin of the inner bark of several species of the myristicaceous Virola: V.
calophylla, V. calophylloidea, V. elongata, and especially V. theiodora. This snuff
is variously known as paricci, ebena, nyakwana, or yakee. The area of use of
Virola comprises the northwest Amazon of Brazil and Colombia and the
uppermost Orinoco of Venezuela, but its greatest use centers among the
Waikci Indians of Brazil and Venezuela. Methods of preparing the snuff
vary, but the end-product is a fine brownish powder, usually with the alkaline
admixture of ashes and sometimes also with the powdered dried leaves of the
acanthaceous Justicia pectoralis var. stenophylla.
Like yopo, ebena snuff causes initial excitement and nervousness,
numbness of the limbs, twitching of facial muscles, often nausea, increased
lacrimation and nasal discharge, macropsia, hallucinations, and finally a deep
sleep. Macropsia enters into Waikci beliefs about the hekula or spirits resident
in the drug.
That the effects of ebena snuff should be so similar to those of yopo is
due undoubtedly to similarity in chemical composition of the two drugs.
Although from a family unrelated to that of yopo, Virola snuffs are
tryptaminic. A snuff prepared from V. theiodora contained up to 8% 5methoxy-N,N-dimethyltryptamine. Tryptamine content of the snuff made
from this species reaches 11 %.
The Witotos, Boras, and Muinanes of Amazonian Colombia utilize the
resin of V. theiodora and other species orally as a hallucinogen. Pellets of the
boiled resin are rolled in a "salt" left upon evaporation of the fIltrate of the
bark ashes of Gustavia poeppigiana and ingested to bring on a rapid
intoxication, during which the shamans see and speak with the "litde people."
In this oral use of Virola, the monoamine oxidase inhibitor activating the
tryptamines is a minute concentration of a ~-carboline alkaloid present in the
resin.
In Peru, a tall columnar cactus known as San Pedro or aguacolla is the
basic ingredient of a vision-inducing drink that curanderos administer to their
patients or ingest themselves for diagnosis, divination, and confrontation
with hostile spirits. The moon-oriented San Pedro cult is dearly of great age.
The intoxicating drink prepared from this cactus, Trichocereus pachanoi, is
called cimora. It may often contain additives, such as Neoraimondia macrostibas, another cactus, and the campanulaceous Isotoma longiflora, the euphorbiaceous Pedilanthus tithymaloides, and a species of Datura. While some of
these additives may contain hallucinogenic principles, the active constituent
of the Trichocereus is mescaline.
There are a number of minor intoxicants employed in sundry parts of
the world. For the most part, their use is poorly understood, and in most
cases, litde if anything is known of ceremonies connected with their employ-
233
ment nor of their chemistry. Some may have narcotic effects, yet not be true
hallucinogens.
One of the most interesting of these anomalous intoxicants is the mint
Lagochilus inebrians of central Asia. For centuries, tribesmen living on the dry
steppes of Turkestan have made a tea of the toasted leaves, stems, fruiting
tops, and flowers. Sweetened with honey, it is drunk for inebriation. Recent
studies have indicated the presence of a polyhydric alcohol that presumably
is the psychoactive constituent.
Another enigmatic intoxicant is channa or kanna of the Hottentots of
southern Africa. Some 225 years ago, it was reported that these people
chewed a root, keeping the masticated material in the mouth for some time,
and that shortly after the chewing, "their animal spirits were awakened, their
eyes sparkled and their faces manifested laughter and gaiety," and that if
taken to excess the drug caused them to lose consciousness and fall into a
"terrible delirium." Since the use of this drug has apparently ceased, it has
been impossible to identify it with certainty. The name kanna is, however,
applied to several species of Mesembryanthemum: M. expansum and M.
tortuosum, members of the Aizoaceae or carpet weed family that contain
mesembrine, an alkaloid that produces torpor in man.
There are several unusual solanaceous species employed in South
America as narcotics-in addition to the well known members of Datura and
Methysticodendron. In the westernmost Amazon, a species of Brurifelsia is used
alone as a hallucinogen by the Kofan Indians of Colombia and Ecuador and
among the Jivaros of Ecuador, it is valued as an additive of the ayahuasca
drink. The identity of the intoxicating principle has not yet been established.
It has recently been learned that a species of Iochroma is employed on
occasion in the Andes of southern Colombia as an hallucinogen. The active
constituent, probably alkaloidal, has not yet been determined. The .genus
Petunia, native of the Andes, has recently been reported as an intoxicant of
highland peoples of Ecuador. Nothing is known of psychoactive principles in
Petunia. It has similarly been reported that Ecuadorian Indians eat the
highly toxic fruits of shanshi, Coriaria thymifolia of the Coriariaceae, for the
sensation of flying. Although this plant has long been recognized as a potent
cattle poison, the hallucinogenically active principle is not known. Several
species of the ericaceous genus Pemettya are suspected as being used
hallucinogenically in the Andes: taglli in Ecuador (P. parvifolia) and hierba
loca or huedhued in Chile (P. furiens). The toxic constituents andromedotoxine, a resinoid, and arbutine, a glyoside or hydroquinone, are common in
this family and may be responsible for the activity of these species. In the
southern Andes in Peru, Lobelia tupa of the Campanulaceae, locally called
tupa or tabaco del diablo, is smoked for its intoxicating properties. It contains
lobeline and related bases. In the same general area, the poorly understood
Deifontania spinosa, belonging to the anomalous family Desfontaniaceae, is
reputedly employed as a narcotic, but again phytochemical studies are
234
lacking. Gomortega keule, the only species in the family Gomortegaceae, may
once have been employed as a narcotic in Chile, where it is called keule or
hualhual. The fruits are said to be intoxicating, especially when fresh, due
possibly to an essential oil. In the central Amazon of Brazil, the fruit of a
large jungle tree, the moraceous Maquira sclerophylla, is reputedly used to
prepare a snuff formerly employed by the Indians of the Pariana region.
Nothing is known of its chemical constituents. There is suspicion that the
beans of both Erythrina and Rhynchosia of the Leguminosae may once have
been valued as narcotics in Mexico, but further studies are needed for
verification. In northern Canada, the rootstock of flag root, the aroid Acorus
calamus, which is known to induce visual hallucinations, may be employed for
this purpose by local Indians. It contains asarones. The Old World Cytisus
canariensis is reputedly employed as a minor hallucinogen by Yaqui medicine
men in northwestern Mexico. Its active principle apparently is cytisine.
Several hallucinogens have been reported from southeast Asia but are
not very well understood. Natives in Papua are said to eat leaves of ereiba, a
species of the aroid Homalomema, together with the bark and leaves of
agara, the himantandraceous Galbulimima belgraveana, as a narcotic preparation. It brings on a violent and crazed condition, leading to a deep sleep with
dreams of men or animals that they are destined to kill. No hallucinogenic
principle is known from Homalomema, but several isoquinoline alkaloids
have been isolated from the Galbulimima. In New Guinea, Kaempferia
galanga, known as galanga or maraba, is used as a hallucinogen. A member
of the ginger family, Zingiberaceae, galanga is rich in essential oils. The
rhizome is the part employed. The Bushmen of Botswana consider kwashi,
the amaryllidaceous Pancratium trianthum, to be psychoactive. The bulb of
this perennial is sliced and rubbed on incisions made in the skin of the head
to induce visual hallucinations. The genus contains alkaloids, some of which
are strong cardiac poisons.
4
It is clear that much still needs to be accomplished before we know most
of the psychoactive plants used in primitive societies around the world. New
ones are constantly turning up, and many are but imperfectly known.
Furthermore, the study of plant additives is new and has already presented
several fascinating problems. However, only an interdisciplinary study can
lead to progress in this investigation-an investigation that boasts both
academic and very practical aspects. The future-if we can keep ahead of the
rapid disappearance of truly aboriginal life and customs-promises many
amazing discoveries in the field of hallucinogens and plant narcotics.
235
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WASSEN, S. HENRY, 1964, Some general viewpoints in the study of native drugs, especially
from the West Indies and South America, Ethnos 1-2:97-120.
WASSEN, S. HENRY, 1969, Om bruket av hallucinogena snuser av sydamerikanskt ursprung,
Sydsvenska Med.-Hist. Salsk. Arsschr., 70-98.
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241
WASSON, R. GORDON, 1963, Notes on the present status of Ololiuhqui and other hallucinogens of Mexico, Bot. Mus. Leafl., Harvard Univ. 20:161-193.
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PSYCHOTOMIMETIC DRUGS:
STRUCTURE -ACTIVITY
RELATIONSHIPS
Alexander T. Shulgin
l. INTRODUCTION
1.1. Definition of Psychotomimetic

1.1.1. Lewin's Classifications
The field of psychophannacology has its sources in a number of different
medical disciplines involved with the function of the brain. In the area of
pharmacology, a major contribution has been made by the study of those
drugs that are collectively known as psychotropic agents. The tenn "psychotropic" is used to describe a drug that turns or changes the mind, following
quite literally from the Greek stem t/Jvx.fI meaning soul, mind, or understanding, and Tp7TELV, to turn. A sizable proportion of our present phannacopoea
contains medicines designed to playa role in the changing or modification of
a person's mood or mental state. A classification of these materials into
families defined by the nature of the mental state change evoked is a useful
way of defining the subdivision known as "psychotomimetic drugs." An
historically interesting procedure was established by Lewin (1924), who
characterized these drugs in five subdivisions according to the nature of their
action.
a. Excitantia. This group is composed of drugs that, when used in
modest amounts, produce a central stimulation, an increase in alertness, and
Alexander T. Shulgin
1483 Shulgin Road, Lafayette, California 94549.

243
244
a relief from fatigue. Many of these drugs have come from plant sources and
have been intimately spun into our social behavior patterns. Coffee, tea, and
tobacco are so generally accepted that they are in fact no longer considered
drugs. Similarly, other societies have also brought botanical agents, such as
kola, betel nut, and khat, into their daily behavior patterns. The most
important of the component alkaloids of many of these plants are caffeine
and ephedrine, and both have found extensive medical application. An
extremely effective local anesthetic, cocaine, has been broadly used for its
central stimulation effects.
In current medical practice most of the drugs employed for achieving
this form of psychotropic action are synthetic in origin, and are based largely
upon the chemical structure of amphetamine. The many variations and
evolutions of this paradigm drug have been discussed elsewhere in this
volume, as have their various clinical uses.
b. Inebriantia. The ubiquitous social maneuver of "getting drunk" is a
form of psychopharmacological toxicity that is widely recognized and generally acceptable. The best known drug in this classification is, of course,
ethanol. This material has been incorporated, in one form or another, into
virtually every culture in the history of man. The syndrome of intoxication,
the generalized loss of inhibition and intellectual control, is easily recognized
and quite consistent in appearance. Drinking has become a social ritual and
many people have lost sight of the fact that alcohol is an effective, although
low potency, psychotropic drug. Virtually all of the drugs that have found
use as central anesthetics or as hypnotics can provoke, in the early stages of
intoxication, a disinhibition similar to that of alcohol, and many have been
used to provide this form of "social" intoxication. Ether (by itself, or mixed
with alcohol), nitrous oxide, chloroform, trilene (trichloroethylene), and the
hydrocarbons such as benzene and hexane are among the many volatile
chemicals that have been employed as intoxicants. Many of the clinically
effective sedatives have been used, with appropriate attention to dosage, in
this manner.
c. Hypnotica. As suggested above, there is a very close connection
between excitement and hypnosis. Most of the drugs that, at clinically
effective levels, effect hypnosis (a sleeping state from which there can be
arousal but little recall) have proven to be disinhibitors and intoxicants at
subclinical levels. The barbiturates, the quinazolones (such as methaqualone
and mecloqualone), the carbamate paralytic tranquillizers (such as meprobamate), and the benzodiazipines (as chlordiazepoxide and diazepam) can all
show stimulation and an alcohollike intoxication. These responses are usually
merely minor side-effects, but can become major symptoms during the early
stages of intoxication (or during chronic light medication) when there is
social reinforcement to forestall or divert overt hypnosis.
A major pharmacological class of drugs, the anticholinergics, should be
classified in this area. Although commonly thought of as psychotomimetic,
PSYCHOTOMIMETIC DRUGS: STRUCTURE-ACTIVITY RELATIONSHIPS
245
these compounds have been employed clinically as anesthetics. There is no

question but that there are vivid psychotropic aspects of the intoxication
produced by plants such as belladonna and jimson weed, or of chemicals
such as ditran and phencyclidine, but the amnesiac properties of these drugs
sets them apart from the larger family of psychotomimetics. Their use leads
to a loss of contact with reality and a sensory isolation, but the substantially
complete lack of recall of the events that occur during intoxication places
these substances closer to the anesthetic class. However, there is at no point a
clinical loss of consciousness, although they have been used medically in close
association with anesthetics.
d. Euphorica. Lewin chose this name for a group embracing the
compounds he felt to be mental sedatives rather than soporific physical
sedatives. His major entry, opium and the alkaloids found in opium, still
represents the chemical point of departure for most of the drugs that are
today classified in this division. The sensory analgesics in this area are
characterized not by an amplification of sensory awareness, nor by a
confusion of it, but by a replacement of it with a euphoric insulation wherein
problems and worries are of less importance. The best known drug in this
classification, one that has played a major role in the structuring of both
legislation and medical practice, is morphine. Morphine, in addition to being
a central analgesic, was broadly championed in the late nineteenth century as
a safe alternative for alcohol in medical alcoholism cases. When its capability
to produce a physical dependence itself was appreciated, its diacetate, heroin,
was employed as a nonaddictive cure for morphine addiction. It was used in
this role for more than a decade, until its own dependence liability was
understood.
A second role that has been played by morphine in this euphorica
classification has been to serve as the structural prototype for an incredible
cascade of analgesic drugs, a large number of which have maintained the
psychotropic pharmacology of heroin.
e. Phantastica. Phantastica or hallucinatoria was the name given by Lewin
to encompass many drugs that he held as "thaumaturgic agents-which
evoke sense-illusions in a great variety of forms." At the time of his writing,
only a few plant sources had been recognized, and their actions could be
accounted for by a handful of chemicals. Peyote, the Banisteriopsis snuffs,
marijuana, and the Amanita mushrooms were known, but only a few of these
had been analyzed with sufficient interest or care to provide drugs that
satisfactorily reproduced the actions of the natural intoxicant. Today, many
additional plant sources have been studied, and the art of the chemist and
the pharmacologist has swelled the list of examples to well in excess of 100. A
comparison of the structures, and an attempt to correlate their potency and
qualitative actions with these structures for the most broadly represented
groups of these, the phenethylamines and alpha-methylphenethylamines, will
be the purpose of this chapter.
246
1.1.2. Synonyms for the Term Psychotomimetic

The contrived word "psychotomimetic" finds its origin in the combination of "psychoto-" from psychosis, and "-mimetic" from the Greek
JL'JLT/TtKOS meaning "in imitation of." There has been an inordinate amount
of confusion and conflict in the search for agreement upon a name for this
class of compounds. The difficulties stem from an inadequacy of describers
for the nature of the induced intoxication. Lewin's term phantastica stemmed
from his holding that the effects of these drugs were "mysterious and
incomprehensible." An incapability of adequately naming them is evident
from phrases such as "the chief character of the visions (this, in reference to
mescaline) is their indescribableness" (Ellis, 1898), and "we enter [upon
taking these compounds] a world beyond language, so it is hardly surprising
that they may be difficult to name" (Kliiver, 1928).
A number of the names essayed to define this field of central intoxicants
within the medical community have grown directly out of the symptomatology of intoxication. An occasionally encountered symptom of drug effect is a
distortion of some sensory modality with the perception of a synthetic feature
that upon objective analysis appears to be undocumentable. This event,
commonly called a hallucination, has provided the term "hallucinogen," or
literally, a material that gives rise to a hallucination. Hellpach (1941)
proposed the term "eidetika" to put emphasis upon the particular nature of
the hallucination evoked. With special emphasis upon the disruption of the
central nervous system, Delay (1959) suggested the name "psychodysleptic"
to place these drugs in direct comparison with those which depressed the
mood (psycholeptics) and those which stimulated the mood (psychoanaleptics). The parallels of the drug-induced intoxication and mental illness have
given rise to the term "psychotica" (Haase, 1966) and the above-mentioned,
broadly used term "psychotomimetic" (Lehmann, 1958, 1959). These latter
terms are aimed toward the research branch of the medical community, since
they support the concept of the pharmacological generation of a "model
psychosis." All of these terms are faulted in that the properties that have
inspired them are not invariably seen or agreed upon, and at best they
represent only one aspect of a very complex intoxication.
In the literary community, an entirely different family of names has
been employed, with origins from Homer to Huxley. One of the most widely
accepted has been the one suggested by Osmond in 1956, "psychedelic."
Choosing the prefix "psyche-," to represent the mind or soul (he eschewed
the proper spelling "psycho-" due to its resemblance to the word psychosis
and the connotation of mental illness), a number of syntheses were proposed.
psychephoric
psychehormic
psycheplastic
psychezymic
(mind-moving)
(mind-rousing)
(mind-molding)
(mind-fermenting)
psycherhexic
psychelytic
psychedelic
247
(mind-bursting-forth)
(mind-releasing)
(mind-manifesting)
These terms all give particular emphasis to the reports and beliefs that these
drugs can enrich the mind and can be explored as a positive tool in mental
research, rather than giving continuous reinforcement to the negative
features of intoxication (disruption, psychosis, and 8vs or "bad" in dysleptic).
The last of these terms, psychedelic, caught the fancy of the popular press,
and with the unfortunate lay promotion of these drugs during the late 1960s
became the ubiquitous adjective for many aspects of the drug culture. Its use
as a describing term for these drugs now carries with it the subtle implication
of approval of uncontrolled drug use for entertainment purposes, if not the
active promotion of drug-intoxication philosophy. For this reason the word is
seldom encountered in the scientific literature.
Many other names have been created to represent this class of drugs;
each of them reflects some classical point of reference or some particular
aspect of the induced intoxication. Some additional examples that have
appeared on occasion in the literature are:
delirients
delusionogens
dysleptics
misperceptinogens
mysticomimetics
phanerothymes
phantasticants
pharmakons
psychosomimetics
psychotaraxics
psychoticants
psychotogens
psychogens
schizo gens
and agents that are eidetic, hypnogogic, hypnopompic, psychoactive, psychotoxic, and consciousness-expanding.
This thesaurus is continuously expanding, as new emphases are desired
or new predilections are apparent. For this chapter, we shall limit our
vocabulary to the single, and admittedly inadequate word, psychotomimetic.
1.2. Qualitative Differences

1.2.1. Nature
if the Psychotomimetic Syndrome
If there is confusion in choosing a term to describe the class of drugs

that we shall call the psychotomimetics, then there is chaos in agreeing upon
a description of their effects. To a large measure, their peripheral effects are
minor and not deserving of attention. It is the area of the state of awareness
modification, the changes in interpretation of one's environment, and the
property of a catalytic unfettering of imagination that have commanded the
psychiatrist's attention and the public's fancy.
248
Hofmann (1959) has described this as follows:

The psychotomimetics produce profound and acute changes in the sphere
of experience, in the perception of reality, changes even in space and time
and the consciousness of self. Phenomena of depersonalization may also
occur. Retaining full consciousness, the subject experiences a kind of dream
world, which in many respects seems to be more real than the customary
normal world. Objects and colours, which generally become more brilliant,
lose their symbolic character, they stand detached and assume an increased
significance, having, as it were, their own more intense existence.
At the intellectual level, the experience has been analyzed as containing

contributions from a number of components (Pahnke and Richards, 1966): a
psychotic aspect, a truly dysphoric element that gives weight to the term
psychotomimetic; a psychodynamic contribution, usually shown as the availability to the subject of subconscious and preconscious material; a cognitive
component, characterized by astonishingly lucid thought; an esthetic value,
which is realized by an increased perceptual ability in all sense modalities;
and a transcendental or mystical quality. This aspect of the intoxication
syndrome has been described as an experience wherein "one replaces a real
world with an alternate real world which is equally real and yet different"
(Shulgin, 1970a). The many facets of the psychotomimetic intoxication have
assumed as many names, and each needs extensive definition and illustration
before being safely employed. One can find reference to subjective phenomena such as positive (and negative) hallucinations, including pseudohallucinations; visualizations, including illusions, dread-states, eidetic images (with or
without reality character, memory images (including projected images,
afterimages, and pseudomemory images), reperceptions; deja vu phenomena; depersonalization (or derealization) phenomena; Sinnengedachtnis; and
so on. The fine structure of these psychological nuances is discussed in detail
in this volume by Hollister in Chapter 8.
1.2.2. Variability
of Drug Effects
The complex generalized symptomatology ascribed to the use of psychotomimetic drugs is an amalgamation of thousands of studies involving dozens
of different drugs. When one drug at a time is considered, an emphasis on
one or another aspect of this syndrome is generally encountered. This would
be of a peculiarity felt to be characteristic of the specific drug in question. But
this very fractionation of symptoms of intoxication can give rise to a new type
of difficulty in making drug-to-drug comparisons. An observer may be
attentive to some expected facet of intoxication, and thus measure the
effectiveness of a drug by whether this particular clue is or is not elicited.
Take, as an oversimplified illustration, a case where the evocation of
color distortion might be used as a yardstick for the determination of the
nature of a psychotomimetic drug. With a drug such as mescaline, an
experimental subject will regularly volunteer comments concerning the
249
exaggeration of the colors and the shapes of objects. With another drug such
as psilocybin there are often spontaneous descriptions of the details of some
highly entertaining scene, with no mention of color at all. Here, if one's
criterion of a drug's effectiveness happened to be the distortion of the
appreciation of color one would believe the first drug to be effective and the
second one not. Yet if a specific question were put to the second person
concerning the coloration of his "scene," he might say that indeed the colors
were gaudy and distorted, but that was not what was entertaining.
It is most important that there be maintained a close communication
between the experimental subject and the observer. Such rapport will allow
an intellectual probing that can alert the observer to the nature and the
depth of intoxication. There is also the need to minimize the varieties of
expression that the experiment may take; in practice this is most easily
realized by restricting the dosage of drug to be administered to those which
may be expected to produce a modest or threshold stage of intoxication. If
the subject is also the observer, then this communication problem must be
met by exposure to a reproducable environment, equipped with familiar
clues, which will potentially provoke recognized sensory distortions, and with
some form of record-keeping that will permit facile recall of the details of the
experience and yet not distort the experience itself.
1.2.3. Variability of an Individual's Response

An additional complication that must be considered in the description of
the effects of a psychotomimetic drug is the unpredictable variability that
may exist from person to person. This variability can exist both in the
qualitative as well as the quantitative response to a drug, and the two are
intimately interwoven. Some agreement must be made as to the nature of the
drug response that shall be considered adequate before any value can be
placed upon its potency.
False positives are not uncommon, wherein a subject, due to a combination of expectations, anxiety, and some form of self-hypnosis, can believe that
he is experiencing a real effect following exposure to what eventually proves
to be an ineffective level, or a placebo. In an effort to minimize these errors,
the technique of employing an "active placebo" is occasionally reported. All
of the psychotomimetic drugs, in addition to eliciting central effects, have
minor, secondary indicators of activity as side-effects. There may be indications of mydriasis, light-headedness from blood-pressure changes, parasthesia, nausea, perhaps just a generalized feeling of discomforture. With a
person who is familiar with these prodromal signs, there may be the
subconscious synthesis of indicators of central disruption leading to a false
positive response. This complication might be controlled by employing as a
control an agent that mimics these aspects of toxicity but that is not
psychotomimetic. False negative responses are rare.
The most desirable way of circumventing the problems inherent in
250
individual variability between experimental subjects is to evaluate the effects

of several drugs within a single subject. This allows, as far as possible, a
consistent background of past experience and of sensory sensitivity, permitting the design of a true control component in clinical experimentation.
1.3. Quantitative Differences

1.3.1. Threshold Activity Levels
With the acceptance of two drugs being qualitatively similar in their
action, the remaining problem in a structure-activity relationship is to
compare their relative potencies. As has been mentioned above, and in detail
in the chapter by Hollister, at drug dosage levels that produce a complete
intoxication the nature of this intoxication can be most variable. The dosage
requirements to produce such a degree of disruption will strongly reflect the
specific parameter that is used to measure this disruption. A frequently used
stratagem to minimize this variability is to exploit the observation that at
threshold levels of intoxication there is seen quite a consistent constellation of
clues. These are sufficiently easily recognized to distinguish active drug from
placebo, but not sufficiently elaborate to define the drug state itself, the state
that would be characteristic of the specific drug being evaluated. This
technique is excellently illustrated by the studies of Abramson and Rolo
(1967) in the quantitative comparisons of psilocybin, LSD, methysergide, and
several homologous lysergic acid amides. An excellent consistency was shown
among his experimental subjects in detecting threshold action at drug dosage
levels that were not sufficiently high to permit the identity of the drug to be
deduced. Additional advantages to this approach to quantitative analysis are
that the clinical environment is obviously more easily managed, and that
there is a minimum of psychological turmoil on the part of the experimental
subjects.
1.3.2. Tolerance
The property of tolerance induction is a well-recognized pharmacological fact. This introduces yet another degree of uncertainty in the quantitative
ranking of psychotomimetic drugs. To the extent that an experimental
protocol calls for multiple drug exposures within the same individual, there is
the possibility of the response to a later drug exposure being affected by an
earlier drug experience. Fortunately there is little difficulty encountered
from this source. Studies that have explored the development of tolerance,
either from one drug to its own effects, or from one drug to a chemically
related drug through chronic low-level exposure, have shown that there is
frequently the quick development of an appreciable tolerance, but that this
tolerance is as quickly lost. The usual prudence of adequate spacing of
experimental challenges seems to be quite enough to minimize errors from
this source.
PSYCHOTOMIMETIC DRUGS: STRUCTURE-ACTIVI1Y RELATIONSHIPS
251
1.3.3. Subject's Experience

A major paradox confronts the experimenter in the decision whether to
use subjects who are experienced and are familiar with the effects of the
psychotomimetic drugs, or whether to use subjects who are pharmacologically naive. A principal advantage with the experienced subject is the
familiarity with the extraordinary symptoms that can develop along with the
drug's induction of intoxication. Recognition of unnatural sensory input
permits a relatively unemotional record to be made of the events taking
place. The conviction that the experiment is transient and reversible minimizes the anxiety component of the syndrome. Mention has been made
earlier concerning the appearance of false positive reactions from the
misinterpretation of the physical distress clues that can precede a psychotomimetic experience, but to a drug-sophisticated subject these clues themselves,
with an active compound, can alert him to the possibility of active threshold
levels.
On the other hand, such a population can also contain people who, for
one motive or another, may tend to exaggerate or even falsify their reports
of a drug's effects. The use of prisoners as subjects is clearly compromised by
some tacit understanding that pleasing the observer might produce fringe
rewards. The use of subjects who are enthusiasts of one or another feature of
psychotomimetic drug intoxication may lead to distorted reports motivated
by the desire to have further opportunity to participate in such experiments.
These criticisms are difficult to answer.
The use of naive subjects presents different problems. There can be
complicated ethical questions that are not encountered with drug experiments that lead to more prosaic central nervous system changes. The small
but real possibility exists of effecting long-term changes, or changes that are
slow to reverse themselves. The risks of precipitating some long-lived
psychotic state can be largely circumvented by the appropriate screening of
the experimental volunteer. However, there are numerous examples on
record in which the intensity of the psychotomimetic experience and the
insight and self-evaluation that it can inspire have led to changes in personal
priorities and even in social behavior patterns. These risks from both longterm effects and from possible immediate adverse reactions have been
summarized by Cohen (1960). In general, most research clinicians in these
areas have preferred to avoid the responsibilities inherent in these latter
examples and have restricted themselves to subjects with some past drug
experience.
1.3.4. Dosage Dimensions

A number of different conventions can be found in the scientific
literature for the designation of the dosages employed in clinical studies.
Most frequently one finds the weight of the dosage administered, although
252
the physical form (free base, salt of some acid) is usually omitted. In an
attempt to parallel the conventions in pharmacological research, this is often
presented as the dosage of drug per weight unit of the subject (i.e., 5 mg/kg),
but if the weight of the subject is not reported, the total dose can only be
approximated. The usefulness or appropriateness of this per weight presentation is questioned by many researchers, especially with drugs that are
effective on neural systems. The neural complexity of a person appears to be
quite independent of his body weight. A further unnecessary refinement that
has recently become quite popular is the expression of a drug's weight in
terms of moles. This form precludes the ambiguities of salt-form mentioned
above, but of course it cannot be applied to botanical extracts, to mixtures, or
to other preparations of unknown molecular weight.
For reasons of consistency all dosage values presented in this chapter are
converted (if necessary) to weight of drug administered, as specified, to an
experimental subject of about 75 kg.
1.4. Sources of Information

1.4.1. Biochemical and Animal Screening
One of the greatest disappointments to the scientists involved in research
in the area of the psychotomimetic drugs, has been the failure to find a
satisfactory screening process or assay procedure that will duplicate the
human psychopharmacological intoxication syndrome in animal models.
Some of the better studied psychotomimetics are effective agonists or
antagonists in biological in vitro systems, and these have been explored as
potential screening tools. The close biochemical relationship between LSD
and serotonin has been exploited to offer proposed mechanisms of action of
the former drug, but efforts to extrapolate these relationships to structural
analogs of LSD have led to disappointing correlations with human effectiveness. A constant stumbling block, as an example, is 2-bromo-LSD (BOL),
which is as active an antiserotonin agent as LSD, but which is substantially
without psychotomimetic activity in man. Within small chemical families,
there has been promising correlation between in vitro titration and in vivo
effectiveness; the anticholinergic activity of a family of glycolate esters
(Abood, 1968), the sympathetic stimulation such as mydriasis and hyperthermia in a family of amide variations of lysergic acid (Cerletti, 1959); serotonin
agonist potency in a homologous series related to DOM (Shulgin and Dyer,
1975). Most assays are faulted by showing valid correlations over only a small
and closely related group of compounds, although a recent study by Aldous
et al. (1974) suggests that rabbit hyperthermia might serve to bridge the gap
between LSD, DOM, and mescaline (which covers three orders of magnitude
difference in human dose requirements).
The literature with in vivo animal assessment of psychotomimetic
253
potency is not much more satisfactory although it is much more extensive.

With most areas of CNS activity, such as stimulation, sedation, and analgesia,
effects can be readily produced and recognized in experimental animals.
This allows quantitative ranking of a synthetic series. Such a structureactivity relationship determination, coupled with conventional toxicity measurement, would allow the determination of a therapeutic index of a drug,
and an educated guess of the potential physical hazard of its effects in man.
With the psychotomimetic drugs, the effects in man are largely interpretative
and subjective in nature, and depend upon intelligent communication for
recognition. As these facilities are not present in subhuman species, it is not
surprising that no satisfactory model has been discovered.
A number of promising assays have been explored based on body
response or on behavioral changes induced in the intact animal. The
hyperthermia observations have already been mentioned. Horita and Dille
(1954) observed that rabbits were very responsive to small quantities of LSD
(0.5 ILg/kg), showing a rise in body temperature apparently of central origins.
A reasonably good parallel in rabbits between this hyperthermia response
and the known "excitatory syndrome" of LSD was extended throughout the
family of lysergic acid amides and paralleled quite closely the reported
human psychopharmacological potency (Hofmann, 1960). This work was
extended by Jacob and his co-workers Qacob et al., 1962; Jacob and Lafille,
1963), and Brimblecombe and co-workers (Brimblecombe et al., 1964;
Brimblecombe, 1967) found that the parallel could be extended to the
tryptamines. Aldous et al. (1974) have shown its applicability to the phenethylamine-like psychotomimetics discussed in this chapter, and it is felt that this
is probably the best animal test at present for estimating psychotomimetic
potency.
Several behavioral approaches have been studied. The use of unrestrained or untrained animals was the basis of Hall's open-field test (Hall,
1934) in which animal activity patterns (rearing, preening, defecation,
ranging) were found to be influenced to a degree proportionate to a drug's
potency in man. Lipman et al. (1963) have applied this test to a series of
piperidinoglycolates, and Brimblecombe (1963, 1967) to a number of tryptamines. Behavioral tests in other animals [in mice, a head-twitch assay
(Corne and Pickering, 1967) and interference with nest-building (Schneider
and Chenoweth, 1970); in cats (Brimblecombe et al., 1964), and a sham-rage
response syndrome (Benington et al., 1958); in monkeys (Hunt and Brimbleco'mbe, 19(7)] are usually restricted to small groups of closely related
compounds. A behavioral response assay (the Bovet-Gatti drug profile) has
been restructured to allow for the evaluation of psychotomimetic drugs
(Smythies et al., 1969). A recent review (Brawley and Duffield, 1972) has
analyzed the extensive literature concerning these correlates. A failing with
most of these assays is the need to employ large doses of the drug. In most
cases these are approaching the lethal dose, and are certainly well above the
dose/weight equivalent employed in man. Several specific assays have been
254
critically analyzed (Silva and Calil, 1975) and it has been shown that not all
families of drugs are validly detected and certain CNS agents that are not
psychotomimetic respond as if they were; in general it is concluded that they
are of limited value.
1.4.2: Physical Properties

In attempts to circumvent some of these biological model limitations and
to explore possible molecular correlates of action, a number of research
groups have evaluated the physical-chemical properties of the psychotomimetic drugs. A number of attempts have involved the actual calculation of
molecular parameters. Interatomic separations within a molecule would
influence intermolecular hydrogen bonding to other molecules or to potential sites of action (Smythies et at., 1970; Kelley and Adamson, 1973).
Intramolecular conformations are possible that might allow one active
psychotomimetic to resemble another (Snyder and Richelson, 1968). A
number of groups have made energy calculations at various orbital sites
within groups of known psychotomimetics (Snyder and Merrill, 1965; Kang
and Green, 1970) but in the one case where such studies were directed to a
very narrow chemical class (LSD homologs), Kumbar and Siva Sankar (1973)
found a poor correlation with human potency.
A number of molecular properties have been studied that are amenable
to experimental measurement. Studies of crystal lattice geometry of active
compounds by Baker and co-workers (1973) and Chothia and Pauling (1969)
have provided three-dimensional portraits of molecular conformation, but
extrapolation to an in vivo solution environment leaves such results difficult
to interpret. Three physical-chemical approaches have overcome this theoretical difficulty by employing solutions in their analyses. Sung and Parker
(1972) have estimated that the 1T-bonding potential of a number of known
active psychotomimetics through a spectroscopic measurement of the
strengths of the charge-transfer complexes formed with p-dinitrobenzene.
An extensive partition coefficient study (Barfknecht et ai., 1975) has shown a
fair correlation between the values of l-octanol: water partition (either
measured or calculated) and human activity. They suggest that a partition of
about 1400: 1 (at pH 7.4) is optimal for members of the phenylisopropylamine family of psychotomimetics, with loss of potency with change in either
direction. The native fluorescence of dilute solutions of several known
psychotomimetics has been determined and correlated with human activity
(Antun et ai., 1971).
1.4.3. Clinical Data

The most reliable source of information concerning the qualitative and
the quantitative nature of the psychotomimetic drugs must come from
experimentation with normal human subjects. But these studies, by their very
255
nature, are both ethically and legally difficult to perform. In the area of
medical ethics it must be borne in mind that the study of such drugs employs
the use of normal, healthy, and sane subjects, and involves the disruption of
sensory and intellectual integrity in a way that could be considered to be to
the subject's disadvantage. Many research groups feel that the rewards to be
derived from such studies do not warrant the risks that are inherently
present, and choose not to participate in this area of inquiry. Most medical
institutions believe that no academic study is justified that does not produce
information that can bear directly upon a problem of medical practice.
Obviously, the classical approach employing animal experimentation cannot
be followed fruitfully. And since there is a small but admittedly real risk that
some of the psychological changes may not be rapidly reversible, or may be
recurrent, experiments must be conducted with the subject's advanced
knowledge of the nature of the responses that are to be expected. The
double-blind study, in other words, is not possible.
A logical outgrowth of this situation is the frequent incidence of selfexperimentation. The quintessence of informed consent is to be found in a
clinical study where the designer and author of the experimental protocol is
also the experimental subject. Alles (1959) first used the term "doubleconscious" to emphasize this resolution to the problems concerning this area
of research. He explained: "Might as well call this [a] 'double-conscious'
technique, because I not only made the compound, but I weighed it out,
dissolved it in water, and knew that I took it at [a] particular time. I was
entirely on my own resources in observing what was happening." The use of
a restricted group of subjects, drawn largely from the research team itself,
circumvents many of the problems discussed earlier associated with paid or
otherwise rewarded volunteers.
An important feature in the clinical evaluation of psychotomimetic drugs
is the influence of the immediate environment within which the experiment
is conducted. This "setting" not only plays an important role in establishing
the attitude and tone of the subject's interpretation of the events that are
occurring, but it can constitute a rich source of sensory clues. A consistent
source of such "catalysts" is especially desirable in the comparison of two
different drugs in a single subject. The hospital environment with its white
walls, institutional sounds and smells, and Constant associations with illness
and medical authority has on occasion contributed a psychotic note to the
drug experiment. For these reasons, many researchers prefer to conduct
their drug evaluations in more unconventional settings such as the outdoors
or in a person's home, and with the availability of sensory stimuli that are to a
subject's own liking. On the other hand, Elkes et al. (1955) have expressed
concern for the occasionally severe or delayed response seen, and have urged
the use of a hospital environment with trained personnel and emergency
facilities. These variables can promote or suppress the expression of a
psychotomimetic episode and can certainly contribute to the diverse statements of drug potencies that are found in the literature.
256
The legal problems associated with this area of research cannot be

ignored. Many of the psychotomimetic drugs, for the very reasons that they
are known drugs of abuse and have no accepted medical utility, are classified
as Schedule I drugs in the Controlled Substances Act. Medical research with
these requires the presentation of an exacting protocol to several government
and academic agencies for approval. It is maintained that these complications
were not intended to restrict research in these areas but were merely to
maintain some control over drug abuse possibilities; but these requirements
certainly have had a dampening effect on research. Most of the materials to
be discussed in this chapter are not included in any drug legislation, for they
have never been implicated in any social problem. Work with this broader
group of compounds must still recognize the public health and pharmacy
laws, but is not an immediate concern of the narcotics law agencies.
1.4.4. "Street" Information

Much of the exploration and use of the psychotomimetic drugs has
taken place not in the clinic under the control of attending research scientists
but in the paramedical areas of social drug use and noninstitutional research.
The sources and identities of the drugs that are used can only be poorly
documented. Some are certainly stolen, or diverted, from legitimate channels, and as such are of potentially firm identity and purity, although there
can be misrepresentation in distribution. Many, however, are privately or
clandestinely prepared.
Some of these preparations are entirely for purposes of exploration
motivated by personal curiosity. The ready availability of chemicallaboratories in the academic and industrial world can provide the facilities, and the
volume of production is usually small since the use of the drug is generally
restricted to the synthesist and his immediate acquaintances. Many structural
variations are explored by intellectual curiosity. The investigator may be a
student who is following an unrelated line of study; he may be an amateur
chemist who is professionally employed in an unrelated field; he may be a
physician who feels that to reveal this form of research would bring criticism
from his peers.
Many preparations are, however, manufactured in frankly illicit laboratories. These can be production operations, motivated by the economics of
drug sales rather than by the subtleties of drug effects. Here, the encouragement.s for structural variation are largely intentional changes designed to
circumvent the exacting letter of the law that defines a restricted drug, or to
compensate for the unavailability of some preferred starting material.
From either source, new compounds can be introduced into experimentation as potential psychotomimetics. In these circumstances, these drugs are
evaluated immediately in human subjects without any preliminary animal
toxicology, and often without exact knowledge of the structure or the purity
of the sample. Often the synthetic variations are taken from the scientific
257
literature, but if a novel compound is designed and prepared it may well

remain unrecognized in the literature since there is neither an accepted
procedure for presentation of nor a desire to publish any findings.
On occasion samples of such preparations are obtained in amount and
in consistency sufficient to allow identification of the drug present and its
connection to examples of documented use. Also, there is a sizable body of
legitimate scientific information concerning the activity or the lack of activity
of potential psychotomimetic drugs that has never been published for the
reasons mentioned. Where appropriate, and in those cases where the
information is felt to be reliable, these observations will be included in this
compilation.
1.5. Classes to Be Considered

The several score of, known psychotomimetic drugs based on the
phenethylamine substructure will be organized and presented in this section
in a manner that emphasizes their chemical character. This represents the
"S" of the SAR, or structure-activity relationship.
A structure-activity study is a comparison of the chemical structures of a
class of compounds with one another, and a correlation of these differences
with observed differences of drug potency and drug effect. The chemical
structure or formula is one of the few incontestable factual properties known
and usually forms the framework of all relationship presentations. One of
the underlying reasons for most of the studies made with the psychotomimetic drugs is the desire to explore the relationship of their action to
endogenous mental illness. Their structures, compared with the naturally
occurring biochemicals and neurochemicals, may explain their action or may
indicate unexpected biochemical transformations, which can be involved with
spontaneously expressed psychological problems. At the first approximation,
it is usually assumed that the more potent a compound is, the more closely its
structure will resemble some natural feature that is responsible for mental
aberration. This assumption is faulted for a number of reasons. Relative
potencies of compounds will reflect many other properties than just their
absolute potency at some hypothetical site of action. Relative differences of
absorption rate will exist. Even within a closely related series of compounds,
differences in biotransformations are to be expected; many of these aspects
are considered in detail with these compounds by Castagnoli in Chapter 7.
The compound may serve well or poorly as a substrate to some enzyme
system that has no bearing whatsoever on its relationship to native biochemicals. The tissue distribution of a drug may reflect its physical properties more
than its metabolic vulnerability or inertness.
As has been stated above, only one of the two major families of
psychotomimetic drugs will be considered here in great detail; this is the
phenethylamine group, with the logical extensions to the alpha-methyl
258
homologs, the homologs related to the chemical structure of amphetamine. This family has been employed in the discussions on metabolism as the
presentation basis for the many aspects of biotransformation presently
known. It will be used here as the basis for illustrating the many nuances of
dependency known between minor chemical change and resulting change in
the nature of the psychological intoxication that results from these changes.
The second large family of psychotomimetics are best generalized as the
indoles. Although they will not be considered in detail, they should be briefly
presented in summary, for reference purposes.
The principal subdivision of the indole psychotomimetic drugs contains
the substituted tryptamines. Most of those which have been studied are
unsubstituted on the aromatic ring. One principal structural variation has
been the manipulation of the identity of the substituent on the basic
tryptamine nitrogen. N,N-Dimethyltryptamine (DMT) is the prototypic example, and human studies are known for the N,N-diethyl, N,N-dipropyl,
N,N-diisopropyl, N,N-di-(n)-butyl, and N-mono-(t)-butyl homologs. The compounds with short-chain substitutions are only active parenterally, but the
branched-chain counterparts are orally active. The substitution of a hydroxyl
group at the 4-position yields, with the simplest member DMT, the natural
alkaloid psilocin. This base, and its naturally occurring phosphate ester
psilocybin, are orally active tryptamines and have also served as the basis of a
series of homologs. The addition of a methoxy group to the 5-position
generally maintains the route of application requirements of the 5-H
counterpart, but increases the potency by a factor of 5 to 10. Fuller details on
the structure-activity relationships known about the tryptamine psychotomimetics may be obtained from recent reviews and compilations describing
them (Brimblecombe and Pinder, 1975; Shulgin, 1976a).
The second of the three indole subdivisions of the psychotomimetic
drugs is a small but potentially very important branch. This involves the
tricyclic carbolines and is best represented by the natural base harmaline.
These materials were first introduced into human psychopharmacological
study by the South Indian native use of the plant extract Ayahuasca.
Botanically, there is a continuing stream of new compounds being uncovered
in this area of native drug use. A very close connection has been established
between the carbolines and the tryptamines in plant biosynthesis. In human
biochemistry, these connections are also becoming understood with the
widely recognized facile formation of the pyridine ring from normally
occurring indoles such as serotonin. For a review of the structures and the
psychopharmacology of the known active carboline psychotomimetics, see
Schultes and Hofmann (1973) and Naranjo, (1967, 1973).
The third, and most socially significant group of the indolic psychotomimetic drugs, incorporates the various amides of lysergic acid. One of these,
the diethylamide LSD, is considered symbolic for the entire family. It was the
major factor in the rapidly developing social drug scene in the 1960s, and
although many closely related analogs are known to be active in man, with
259
similar qualitative and quantitative effectiveness, LSD still maintains its

position as the single most widely recognized psychotomimetic drug. For a
comparative discussion of the several psychoactive homologs and analogs of
LSD, reference should be made to Hofmann (1959, 1968), Isbell et al. (1959),
and the papers by Abramson (1959; Abramson and Rolo, 1967).
2. THE PHENETHYLAMINES
Most of the drugs that are known today have had their origins in the
family of chemicals known as the alkaloids. These are basic, nitrogencontaining organic chemicals from the plant kingdom, and they represent a
bewildering array of structural variations. A consistent theme found through
most of the alkaloids is the separation of the nitrogen atom from an aromatic
system, by two carbon atoms:
C-C-N
This relationship can be found in most of the known families of alkaloids

and has been the mainstay of the thousands of synthetic drugs that have
been based upon some alkaloid model. It may be complexly substituted, or
convoluted by additional ring forms or three-dimensional bridging, but it is
usually there to be found.
The simplest aromatic system encountered is the benzene ring, and one
of the largest classes of psychotomimetic drugs are the substituted phenethylamines. 3,4,5-Trimethoxyphenethylamine (mescaline, 1) will be considered
as a prototype chemical, and variations on its structure will be the basis of the
classification of this section.
2.1. Variations of Ring Substitution

2.1.1. Mescaline
a. History. The story of mescaline (1) has its origins in the use of the
cactus Lophophora williamsii, or Anhalonium lewinii. This dumpling cactus,
known natively by the name peyote or peyotl, has been involved in North
CHaO~NH2
CHaO~
OCHa
( I) Mescaline
260
American Indian practices for centuries before Columbus, with its appearances in the funerary art of some 2000 years ago (Furst, 1972). The first
description of peyote was made by Hernandez (1651), who called it peyote
zacatecensis. His observations of its appearance, actions, and scarcity are
beautifully concise, and have been quoted by Schultes (1972):
The root is nearly medium size, sending forth no branches or leaves above
the ground, but with certain wooliness adhering to it ... It appears to have a
sweetish and moderately hot taste. Ground up and applied to painful joints,
it is said to give relief. .. This root. .. causes those devouring it to foresee
and predict things ... or to discern who has stolen from them some utensil
or anything else, and other things of like nature ... On which account, this
root scarsely issues forth, as it it did not wish to harm those who discover it
and eat it.
All written record of pre-Spanish culture was lost, and the only sources
of the native rituals of its use are to be found in the more remote desert and
mountain areas where there was sufficient cultural isolation to maintain some
of the original history. For descriptions of the northward migration of peyote
culture in the late nineteenth century, reference should be made to the
writings of Slotkin (1956) and La Barre (1969) and the review of Marriott
and Rachlin (1971).
b. Cactus Sources. The best known botanical origin of mescaline is the
aforementioned peyote cactus L. williamsii, which is found throughout the
Rio Grand area of Texas and Northeastern Mexico, and well south into the
state of Chihuahua. A related species, L. diffusa, occurs yet further south in
the state of Queretaro (Bravo, 1967), but it has been reported to contain only
traces of mescaline (Todd, 1969). Heffter (1898) reported analyses of A.
lewinii and A. williamsii and found great variation in mescaline content. It is
now felt that the L. diffusa species was actually at hand, and these
chemotaxonomic problems have been largely resolved (Braun, 1975).
A large number of cacti have been considered to be psychoactive, and
collectively they have been referred to as the "peyote complex." This is in
part due to their physical resemblance to L. williamsii, and in part to the
reputation of toxic effects associated with their use. Included are examples of
the genera Ariocarpus, Astrophylum, Aztekium, Dolichothele, Obregonia, Pelecyphora, and Solisia. There has been a recent flurry of analytical research into
the alkaloid content of these plants, and a large number of compounds have
been reported that are either present in L. williamsii or can be biosynthetically related to them. Mescaline itself, however, has only been reported in the
hatchet cactus Pelecyphora asilliformis (Neal et al., 1972).
A Peruvian counterpart to the peyote complex of psychoactive cacti is
the group referred to as the "San Pedro complex." These are largely
members of the genus Trichocereus. Mescaline is a major component of T.
pachanoi (Agurell, 1969a), which is employed in the folk-medicine "cimora"
for both healing and for devination. The reports in the scientific literature
identifying mesc~ne in the cactus Austrocylindropuntia (Opuntia) cylindrica
261
(Poisson, 1960; Turner and Heyman, 1960) were based on misidentified

specimens of T. pachanoi (Agurell, 1969a). Eight additional species of
Trichocereus have been reported as containing mescaline, in six as a major
alkaloid (see Table I) and in two (T. cutcoensis and T. fulvilanus) as minor
components. The Uruguayan cactus Cereus peruvianus, which is believed to
have narcotic properties, was reported to contain only tyraminelike alkaloids
(De Vries et al., 1971). It may be that the native usage actually involved T.
pachanoi (Braun, 1975).
c. Congener Alkaloids. Brief mention should be made concerning the
alkaloids that are found in company with mescaline in the peyote cactus.
Many of these can be classed as less-complexly substituted phenethylamines. These are interesting in their probable roles as biosynthetic precursors
of mescaline (Paul, 1973). A number of these are recognized pharmacologically active drugs: tyramine (2) (McLaughlin and Paul, 1966); hordenine (3)
(McLaughlin and Paul, 1965); and epinine (4) (Lundstrom, 1971a,b). Others
are recognized biochemicals normally found in the body: dopamine (5)
(Lundstrom, 1971a) and 3,4-dimethoxypheniethylamine, DMPEA (6)
(Lundstrom and Agurell, 1968). The amounts present in peyote appear to be
too small to contribute to the intoxication syndrome that follows plant
ingestion.
More interesting from the point of view of contribution to the psychopharmacological effects of the cactus peyote are the tetrahydroisoquinolines
that are present. At the present time there are some 25 reported as being
identified in the plant (see Kapatia and Fayez, 1973). The theoretical interest
in several of these compounds comes from their possible in vivo formation by
the closing of the amino group of a phenethylamine with some aliphatic
aldehyde. This process has been suggested as a reasonable procedure for the
TABLE
Occurrt'nCl' (if M estaline in Cacti

Cactus
Lophophora williamsii
L. diffusa (Anhalonium williamsii)
Trichocereus pachanoi
T. bridgesii
T. macrogonus
T. terscheckii
T. werdermannianus
T. cuzcoensis
T. fulvilanus
T. taquimbalensis
T. validus
Stetsonia caryne
P elecyphora aselliformis
Locale
Texas, Chihuahua
Queretaro
Peru
Bolivia
S. America
Argentina
S. America
Peru
S. America
S. America
S. America
Argentina
San Luis Potosi
Reference
Heffter (1898)
Todd (1969)
Poisson (1960), Agurell (1969a)
Agurell (1969a)
Agurell (l969a)
Reti and Castrill6n (195 I)
Agurell (1969b)
Agurell et al. (I 971 )
Agurell et al. (I 97 I)
Agurell et al. (I 97 I)
Agurell et al. (1971)
Agurell et al. (1971)
Neal et al. (1972)
262
~NH2
HO~
(2) Tyramine
(3) Hordenine
HO~NHeHa
HO~NH2
H~
(4) Epinine
HO~
(5) Dopamine
eHaO~NH2
CHaO~
(6) DMPEA
generation of alkaloid-like compounds in mammalian species, through the

interaction of the phenethylamines and the corresponding phenylacetaldehydes to generate tetrahydropapaveroline (7) and morphinelike compounds
HO~
HO
:~~eHO
HO
N ~..~H2
HoN
OH
HO
HO
HO
(5) Dopamine
and
3,4-dihydroxyphenylacetaldehyde
(7) Tetrahydropapaveroline
(Davis and Walsh, 1970). These structural manipulations have been discussed
in the chapter on biotransformations.
In peyote, four of the tetrahydroisoquinoline alkaloids that accompany
mescaline are known to produce some central activity in man, and may
HO
N",
eHa
HO
Morphine (for comparison)
263
conceivably contribute to the psychopharmacology of the plant. These are all

condensation products (in effect) of a phenethylamine and acetaldehyde.
Pellotine (peyotline, 8) is the major alkaloid reported by Heffter (1898)
in the A. williamsii now believed to be L. diffma (see above). Although there
appears to be no reports of field work that describes the use of this latter
species, its morphological similarity to active peyote would suggest that it
might have played a role in Indian religious rites. The psychopharmacological action of pellotine in man is one of sedation rather than intoxication,
however. At low levels (15-30 mg) there is a calming effect and the
observation of the production on an uneventful sleep in patients with
dosages of 50 mg subcutaneously Golly, 1896). Heffter (1898) reported that
at levels of as much as 240 mg (total dose) there is a dizziness and a
generalized tiredness but no indications of sensory distortions.
Anhalonidine (9) appears to produce a heavy-headedness and sedation
CH.O
~N-CH.
CH.O~r
OH
CH.
(8) Pellotine
W1
CH.O
N-H
CHaO
OH
CH.
(9) Anhalonidine
similar to that of pellotine, but is about one fourth as potent. Dosages of

between 100 and 250 mg produced a marked sedation, but again without
any reported sensory changes. Lophophorine (10) in animal studies is the
most toxic of the components of peyote, and in man an oral dose of 20 mg
provoked vasodilation, an immediate headache, and a warm flushed feeling
(Heffter, 1898). A 50-mg dose produced a marked slowing of the heart with
a compensatory rise in blood pressure, but no suggestion of mescaline-like
effects (Dixon, 1899). Anhalonine (ll) has been evaluated in a single
oW-
CH.O
CR
'cH;O
,CH.
(10) Lophophorine
CH.O
'
~ ~
CH~
N-H
CH.
( II) Anhalonine
experiment with an oral dose of 100 mg and this led to an uneventful

tiredness without any observed central effects of a sensory nature (Heffter,
1898).
d. Dose and Route. Mescaline is usually administered at a dosage level of
between 300 and 500 mg, in the form of the sulfate salt (equivalent to 225375 mg as the free base). Dosages at the higher limit are often administered
in two portions, spaced about an hour apart, to lessen the abruptness of
onset, and to minimize the nausea that is usually produced by the drug. The
264
drug has been administered by a number of routes (oral, subcutaneous,

intramuscular, and intravenous) without changes in the dose requirement for
intoxication, although with the intravenous route the first effects are noted
immediately (Hoch, 1951). With this route, the period of maximum intoxication occurs somewhat sooner than usual (1.5-2 hr following the drug's
administration) but the overall time period is largely the same as that seen
with other routes of administration.
e. Psychopharmacological Syndrome. Many books, reviews, and research
reports have appeared with extensive detail of the mescaline-induced intoxication syndrome. Reference should be made to Beringer (1927) and Rouhier
(1926) for a body of clinical detail thav will outline the variability of the
individual response to the drug. A generalized profile of effect has been
constructed from a number of separate descriptions (Shulgin, 1973a):
At a nominally active dosage level of 350 mg (orally, as the sulfate)
there is a generally predictable chronology of events. The first signs of
change are largely physical. At about a half hour following ingestion there is
an onset of nausea, often accompanied with active vomiting. There is
occasionally the development of diarrhea. A mild tachycardia and rise in
blood pressure is often seen during this initial phase, but this may be
associated with anxiety and apprehension. The initial indication of sensory
change is noted in about one hour. The development of central effects ends
the "physical distress" phase of the intoxication and this "sensory" phase
continues to develop to a plateau of intensity during the next two to three
hours. The physical changes noted during this period are minor. There is a
cardiovascular quieting with the pulse rate and blood pressure dropping
below their initial base levels, and a constant, extensive, but reactive,
mydriasis. A gradual diminution of the central intoxication over the
following few hours leads to a complete recovery, generally within twelve
hours. There is consistently an excellent recall of the impressions and events
that occurred during the experiment.
Whereas this time pattern and sequence of events is quite predictable
from one person to another and from one occasion to another, the content
and the direction taken by the subject'S imagination as directed by his
interpretive capacities are completely unpredictable and are unique to each
experience.
Some sensory changes are regularly noted and can be expected to
contribute to the overall impact of the drug'S effects. There is a shimmering
and intensification of the visual field, far more intense than what one might
expect from the mydriasis-induced photophobia. There is an intensification
of color perception, and extreme amplification of minor differences in both
color and texture. Frequently observed is the generation of patterned
imagery, sometimes in a grid structure, sometimes with undulating shapes,
but usually with some color contribution. There is a benign empathy shown
to both inanimate and living things, especially to small things.
There is still no satisfactory answer to the question of the action of

mescaline being possibly different from the reported effects of the entire
peyote cactus. Thus far, there have been no reports that have compared the
chemical with the plant in a single study. The two substances are usually used
in quite different ways: the chemical is administered as a single acute bolus,
265
to an isolated individual, in a clinical setting that can provide overtones of

social improperness. On the other hand, the sacramental use of peyote
involves consumption over an extended period of time, in a group situation,
and is unquestioned as an accepted ritual. Some of these factors surely
contribute to the reported differences in the induced intoxication state.
2.1.2. 2,3,4-Trimethoxyphenethylamine
2,3,4-Trimethoxyphenethylamine (12, 2,3,4,-TMPEA) is a positional
isomer of mescaline first prepared by Slotta and Heller in 1930. Direct
OCH 3
CH30yNH2
7'1
~
CH 3 0
(12) 2,3,4-TMPEA
pharmacological comparisons of the drug with mescaline in conditioned

response assays showed the two to be essentially equivalent in terms of both
dosage and nature of response (Winter, 1973) although it was much more
rapidly oxidized in mouse brain homogenate preparations (Seiler and
Demisch, 1971).
A single report exists concerning the activity of this isomer of mescaline
in man. The following is translated from the report of Slotta and Muller
(1936):
We have discovered that the intoxicating action depends to a remarkable
degree upon the position of the three methoxy groups. Mescaline, the 3,4,5trimethoxy-beta-phenethylamine, produces in the normal subject a much
stronger overall intoxication than in the schizophrenic patient, whereas
2,3,4-trimethoxy-beta-phenethylamine has quite the opposite effect. It has
little action in healthy individuals, being almost without intoxicating properties, but it is very potent in the schizophrenic. The metabolic conversion
products of the "reciprocal" mescaline will be further studied as soon as the
study of the metabolism of the proper mescaline is complete.
The dosage employed of the 2,3,4-trimethoxy isomer is not given, but

the mescaline dosages were 400 mg and it can be presumed that a similar
amount had been used in the "reciprocal" mescaline experiments. The
promised further studies have not as yet appeared.
2.1.3. 2,4,5- Trimethoxyphenethylamine

This positional isomer of mescaline, 2,4,5-trimethoxyphenethylamine
(13, 2,4,5-TMPEA) was first synthesized by Jansen (1931) and compared
directly with mescaline. Pharmacological studies in both frogs and cats led to
the conclusion that the two compounds were qualitatively similar. In this
266
study, unspecified amounts of 2,4,5-TMPEA

were administered (by injection) to the author, and finally a control test was
carried out with an equal quantity of mescaline. The action of both these
substances agreed only to a limited extent with the effects described for
mescaline by, for example, Beringer (1927). It must be remembered,
however, in this connection, that the quantities used by Beringer were
larger than the doses administered in these experiments. Nevertheless it
may be concluded, that the pharmacological action of beta-2,4,5-trimethoxyphenylethylamine agrees to a large extent to that of mescaline. However
the new compound had more unpleasant secondary effects (nausea) and did
not bring about the euphoric state caused by mescaline.
It is not possible to estimate from this quotation the potency of 2,4,5TMPEA. The smallest dose unit reported by Beringer was 300 mg, so that
CHa0x:L'NH2
~I
CHaO
OCHa
(13) 2,4,5-TMPEA
lesser amounts than this were presumably employed in this experiment. A

more recent study (Dittrich, 1971) found that an acute oral dosage of 300 mg
was indistinguishable from placebo, with no report of any such "secondary"
effects. Although not centrally active itself, 2,4,5,-TMPEA appeared to
potentiate the action of mescaline when employed as pretreatment 45 min
prior to the administration of mescaline. Smythies et ai. (1967a) had reported
that 2,4,5-TMPEA did not appear to be hallucinogenic in rat model studies,
in substantial agreement with the acute study of Dittrich. However, these
animal studies suggested that 2,4,5-TMPEA should have an inhibitory action
against mescaline (Smythies, 1967b) rather than the potentiating action
found.
This compound is the trimethyl ether of the extremely interesting
neurological poison 6-hydroxydopamine and one should expect to uncover
valuable information by further exploring this amine in clinical studies.
2.1.4. 4-Methoxyphenethylamine
Interest has been directed toward the simpler methoxylated phenethylamines for a number of years. Ernst (1962, 1965) had observed that the
lower homologs of mescaline, 4-methoxyphenethylamine (14, MPEA) and
(14) MPEA
267
DMPEA (6) produced a mescalinelike catatonia in mice, a property that is

absent in the corresponding phenols. Michaux and Verly (1963) reported
that the mono-methoxy compound (14) was the most biologically active of
these methoxylated phenethylamines. MPEA (14) as well as DMPEA (6) has
been found as a component of human urine (Sen and McGeer, 1964).
(6) DMPEA
Brown et at. (1968) have studied the effects of MPGA in man. Sixteen
normal subjects were given MPEA at dose levels of approximately 400 mg
orally, employing mescaline as a standard in the same subjects, and at the
same dose. All of the subjects reacted as expected to the mescaline administration, and none of them showed any response whatsoever to MPEA.
2.1.5. 3,4-Dimethoxyphenethylamine
3,4-Dimethoxyphenethylamine (6, DMPEA) has been the center of
controversy for over a decade. The initial report of the occurrence of this
compound in the urine of schizophrenic patients (Friedhoff and Van Winkle,
1962) has been confirmed by several independent investigators. The findings
of Perry et at. (1964) that DMPEA was not present in the urine of
schizophrenic patients has also been confirmed by several independent
investigators. Dietary factors have been implicated (von Studnitz and Nyman,
1965), a cyclic nature of the appearance of DMPEA has been observed
(Kalbhen and Braun, 1973), and the application of radioimmunoassay
techniques has indicated that small, erratic levels may be present in all
human subjects (Knoll and Wisser, 1976). This last analytical technique is
extremely sensitive but appears to show some cross reactivity to normal
urinary metabolites (Riceberg and Vunakis, 1975).
DMPEA has received additional attention because of its close chemical
relationship with the known neurotransmitter dopamine (5). The processes
of enzymatic O-methylation may give rise to DMPEA in the intact individual
and this latter compound, with its resemblance to mescaline, is an attractice
candidate for the role of an endogenous psychotogen.
This point has been evaluated by the direct measurement of DMPEA as
a psychotomimetic in man. A series of studies in normals and in schizophrenic patients showed that oral dosages between 400 and 1000 mg were
without either central or peripheral effects (Friedhoff and Hollister, 1966;
Shulgin et at., 1966; Charalampous and Tansey, 1967; Hollister and Friedhoff, 1966; Brown et at., 1968). It was only at a remarkable 1500 mg that
subtle changes in behavior were observed (Vojtechovsky and Krus, 1967),
and these were compared to the stimulant effects of caffeine.
268
2.1.6. Homopiperonylamine
3,5-Methylenedioxyphenethylamine (15, homopiperonylamine) contains
the methylenedioxy group that is characteristic of several of the alkaloids
0:;20~NH2
~ I
~
"'0
(IS) Homopiperonylamine
present in peyote. This compound, and the 5-methoxy analog homomyristoylamine (18) are biosynthetically related to a large number of plant
products. The three-carbon homologs (to be discussed later) of these two
bases have been shown to be effective psychotomimetics in man and so with
their dose resemblance to the known peyote alkaloids prompted their
evaluation as potential psychotomimetics. A single report exists concerning
trials with homopiperonylamine (15) (Alles, 1959), and it was found to be
without the slightest peripheral or central effects following two separate
assays of 200 mg.
2.1.7. 3,5-Dimethoxy-4-ethoxyphenethylamine
Literally hundreds of alkoxylated analogs and homologs have been
synthesized, and many have been explored in biochemical and pharmacological studies. However, 3,5-dimethoxy-4-ethoxyphenethylamine (16, escaline)
and the two following entries (17, 18) are the only analogs of mescaline,
differing only in the identity of the substituent group on the ether oxygens,
that have been assayed as psychotomimetics in man. Acute studies with (16)
have shown it to be active orally in the range of 40-60 mg (Nichols and
Shulgin, unpublished data). It differs from mescaline in that the onset of
action is quicker (within the first hour) and there is no nausea noted, but
otherwise the time course, and much of the qualitative content, is quite
similar. The effectiveness of this base and of the 4-propoxy-homolog (17; see
Section 2.1.8) is 5 to 10 times more than that of mescaline itself and
approaches that seen for the 2,4,5-trisubstitution patterns in the substituted
phenylisopropylamines. This suggests that the bases that are trioxygenated
and presumably indifferent to monoamine oxidase attack may be active
independently of whether they are 3,4,5-trisubstituted or 2,4,5-trisubstituted,
269
and of whether they do or do not carry an alpha-methyl group adjacent to

the nitrogen atom.
2.1.8. 3,5-Dimethoxy-4-(n)-propoxyphenethylamine
This immediate homolog of (16) is also orally active in man, and some
5-10 times more potent than mescaline. 3,5-Dimethoxy-4-(n)-propoxyphenethylamine (17, proscaline) shows threshold activity at 15 mg orally and is
active in the range of 40-80 mg (Nichols and Shulgin, unpublished data).

The trivial names of proscaline (for 17) and escaline (for 16) are suggested by
the fact they are related to mescaline by the replacement of a propoxy and
an ethoxy, for the methoxy-group of mescaline in the 4-position. The
significance of the unusually high activity of this 3,4,5-trisubstituted amine is
discussed above.
2.1.9. Homomyristylamine
3-Methoxy-4,5-methylenedioxyphenethylamine (18, homomyristylamine, lophophine) is of interest both for biosynthetic and for structural analogy
~2 ~ I
~~
NH2
OCH a
(18) Homomyristylamine
reasons. The compound, although not yet detected per se in the peyote
cactus, is a logical intermediate in the biosynthesis of several of the
methylenedioxy-substituted tetrahydroisoquinolines known to be present.
Although supporting evidence has not been sought, (18) can theoretically
participate in the ring-closure reactions with acetaldehyde to form anhalonine (11) and (after N-methylation) lophophorine (10). Furthermore, (18) is
the two-carbon analog of the well-established psychotomimetic MMDA (51,
Section 3.2.4). The compound has been clinically assayed and is an active
psychotomimetic with a threshold level observed at 250 mg (Shulgin, 1976a);
thus it has somewhat less than twice the potency of mescaline. Qualitatively it
is similar to mescaline in action, with mood elevation progressing into a
euphoric state and an enhancement of visual perception, especially in the
270
realm of color. Unlike mescaline, there is little if any nausea and there is no
visual distortion.
2.1.10. 2-Methoxy-3,4-methylenedioxyphenethylamine
This isomer of homomyristylamine (19, 2-methoxy-3,4-methylenedioxyphenethylamine) has the ethylamine side-chain relocated to a position
OCHa
/0.~NH2
I
"0
CH 2
(19)
adjacent to the methoxyl group. It has been titrated to levels in excess of 60

mg orally, acutely. Although there is a pleasant mood elevation reported at
this dosage, there are no effects that can be described as psychotomimetic.
The reported potency has therefore been recorded as being less than five
times that of mescaline (Shulgin et al., 1969).
2.1.11. 2,5-Dimethoxy-4-methylphenethylamine
Most of the development of the substitution requirements for activity
within the benzenoid psychotomimetics has occurred in studies of compounds with the three-carbon side-chain. The investigation of (20, 2,5-
dimethoxy-4-methylphenethylamine) as well as of the halo analogs (21) and

(22) (Sections 3.1.12 and 3.1.13), was an outgrowth of the recognition of the
ring substitution patterns, which afforded highly active psychotomimetic
drugs. The corresponding phenylisopropylamines (69, 82, 86) are discussed
in Section 3.4, on the three-carbon psychotomimetics.
The base (20) was first reported in the literature by Ho et al. (l970a) in a
synthetic chemical study of a number of methylated homologs of DOM (69).
Upon evaluation in man, (20) has been found to be of lower potency that
DOM. Orally, 6 mg achieves a threshold effect, and 10-15 mg is usually
sufficient to produce an intense intoxication, although twice this amount can
be required in a few refractory subjects. Onset of subjective effects is noted
unusually rapidly (20-30 min) and these become maximum at 1.5-2 hr.
They then rapidly subside. The subjective description of the induced
271
intoxication is different from the more characteristic "psychotomimetic"

reports associated with DOM. Rather than showing signs of stimulation, the
subject
becomes passive and relaxed and is aware of an integration of sensory
perception with emotional state ... There is a considerable euphoria with an
increased body awareness and an increased receptiveness of visual, auditory, olfactory, and tactile sensation. The integration of sensory and
emotional states induces in most subjects a feeling of security and an ability
to cope with incidents and experiences that might have led, with drugs such
as LSD, to a state of anxiety and possible panic (Shulgin and Carter, 1975).
Six hours following the start of the experiment, the subject is alert, relaxed,
and content, with no residual subjective signs of intoxication (Shulgin and
Carter, 1975).
2.1.12. 2,5-Dimethoxy-4-bromophenethylamine
The ethylamine analog of DOB (82) is 2,5-dimethoxy-4-bromophenethylamine(21). It was prepared and assayed in normal subjects (Shulgin and
CH30~NH
~
2
Br
~I
OCH 3
(21)
Carter, 1975) following reasoning analogous to that discussed for (20). With
a threshold dosage of about 4 mg and an effective dose range of 8-10 mg, it
is the most potent of the known ring-substituted phenethylamines. The
duration of action (6-8 hr) is somewhat longer than that reported for (20),
and at equivalent dosages (based upon threshold values) somewhat less
intense. With increasing dosage levels, the intensity but not the duration of
the intoxication increases, unlike the homologous phenylisopropylamine (82;
Section 3.5.4), where higher dosages led to prolonged residual subjective
responses.
2.1.13. 2,5-Dimethoxy-4-iodophenethylamine
2,5-Dimethoxy-4-iodophenethylamine (22) has been prepared by the
iodination of N-(2,5-dimethoxyphenethyl)-phthalimide with ICI followed by
CH30~NH
~
2
I
~I
(22)
OCH3
272
the regeneration of the free amine with hydrazine (Braun et at., 1977). Bodydistribution kinetics with 131I-Iabeled material and 123J-Iabeled material
(Braun and Shulgin, 1976) have been compared with the considerably more
potent homolog (86) (Sargent et at., 1977). In limited human titrations of
(22), threshold central effects are clearly noted at oral levels of 8 mg, but
appear to be of short duration. Effective intoxication levels have not yet been
explored.
2.1.14. Structure-Activity Generalizations

These 13 compounds, all with the intact two-carbon chain and varying
only in the position and the identity of ring substituents, are all that have
been assayed in human subjects as psychotomimetics. A great number of
additional analogs and homologs are known in the scientific literature. As an
example, the complete collection of methoxylated phenethylamines (from the
mono- to the penta- and with all possible orientation patterns) have been
prepared and studied biochemically by Clark et at. (1965). They report that
compounds with high degrees of methoxylation serve less well as substrates
for enzymatic deamination, but that mescaline (1) was the only isomer (of the
20 studied) that showed an enzymatic deamination that was completely
inhibited by semicarbazide. The active 2,3,4- and 2,4,5-isomers (12, 13) and
the inactive 3,4-dimethoxyphenethylamine (6) were not similarly affected.
A number of in vivo studies have compared mescaline with these and
the other analogs discussed here (with DMPEA, 6, see Bueno, 1975; Carlini
et at. , 1967; Smythies and Levy, 1960; with 2,3,4-trimethoxyphenethylamine,
12, Winter, 1973). The 3- and 4-monomethoxyphenethylamines have been
compared to DMPEA and homopiperonylamine (15) (Epstein et at., 1932)
and have been found to be excitants in most species studied. At the other
extreme it was only the tetra(2,3,4,5)-methoxy- and pentamethoxyphenethylamine analogs that equaled or exceeded mescaline in behavior-influencing
potency studies in rats (Smythies et at., 1967a). The mono-, di-, and
trisubstituted isomers (other than mescaline) were inactive. Actual brain-level
analyses in rats support this, with both mescaline and pentamethoxyphenethylamine entering the CNS more quickly than 2,4,5-trimethoxyphenethylamine (13) (Cohen et at., 1974). A number of methylated and halogenated
analogs of mescaline have been studied in the cat and have been found to be
highly active centrally (Benington et at., 1958). No animal model covering the
simple substituted phenethylamine psychotomimetics can be considered
seriously at the present time until more of the known isomers have been
assayed clinically.
A single generalization can be made: If the methoxy-group in the 4position of the phenethylamine is replaced with another substituent (higher
alkoxy, methyl, halo) there is an unquestioned increase in potency. It appears
that the 2,4,5-orientation pattern is more effective than the 3,4,5-orientation
273
pattern, but too few examples of direct comparison presently exist to

establish this as a generality in the two-carbon phenethylamines.
2.2. Nitrogen-Substituted Phenethylamines

2.2.1. N-Methylmescaline
N-Methylmescaline (23) has been detected as a minor component in
peyote (Spath and Bruck, 1937), but human trials of the compound at levels
CH"O~NHCH"
CHaO~
OCH a
(23) N-Methylmescaline
in excess of those conceivably encountered in peyote consumption (i.e., 25

mg) have produced neither central nor peripheral effects (Shulgin, 1967,
unpublished data). This suggests that (23) does not contribute to the plant's
overall pharmacological toxicity.
2.2.2. N,N-Dimethylmescaline
N,N-Dimethylmescaline (24, trichocerine) has never been observed in
peyote, although the 3-O-demethylated homolog is present and has been
CHaO,yN(CHa)2
~I
CHaO
OCH a
(24) Trichocerine
studied in biosynthetic schemes (Lundstrom, 1971b). The compound has

been reported as the major component of the mescaline-containing cactus
Trichocerius terscheckii (Reti, 1939; Reti and Castrill6n, 1951). The fact that
both animals and man can, with impunity, drink the fluids from the crushed
pulp of this plant has prompted a study into the psychopharmacological
properties of trichocerine.
Ludueiia (1935, 1936) in a single acute experiment consumed 550 mg of
the trichocerine hydrochloride and noted no effects of a sensory nature, only
a slight gastric heaviness. Vojtechovsky and Krus (1967) have reported that
this base has less than one-half the potency of mescaline in humans. At doses
of up to 800 mg, with one exception, all responses were weaker than those
274
noted for a 400 mg challenge of mescaline. A 400 mg trial with trichocerine

via the perlingual route showed a moderate psychodysleptic effect with a
one-hour latency (mescaline required two hours with this mode of absorption). The duration of symptoms was proportionally shorter.
2.2.3. N-Methylhomopiperonylamine
Both the N-monomethyl (N-methylhomopiperonylamine, 25) and the
N,N-dimethyl homologs of piperonylamine (15) have been studied clinically
/
0~NHCH3
,;:?'
"'0
CH 2
(25)
as antitussive agents (Brown, 1958). Acute dosages of 30 mg appear to be

pharmacologically effective, but there is no mention of central side-effects
that might be prodromal to psychotomimetic activity.
2.2.4. N -A cetyl-3, 4-dimethoxyphenethylamine

In conjunction with the study of the presence of DMPEA (6) in human
urine, it was observed that exogenously administered chemical was converted
III part to N-acetyl-3,4-dimethoxyphenethylamine (26). This compound is
CH30~NHCOCH3
CH 3 0
(26)
pharmacologically active (Friedhoff and Schweitzer, 1968) and has been

studied in man, where it is in part 4-O-demethylated (Schweitzer and
Friedhoff, 1968). In studies of this de methylation as a possible biochemical
measure to distinguish schizophrenic from normal patients, loading doses
were administered (Tozman et al., 1972). Oral administration of up to 500
mg of the amine salt produced no reported toxic consequences.
2.2.5. N-Acetylmescaline
N-Acetylmescaline (27) has been reported as a trace component of
peyote (Spath and Bruck, 1938). It is also a trace metabolite of mescaline in
man, appearing in the urine between the fifth and seventh hour following
mescaline administration, and accounting for about 0.1 % of the administered
drug (Charalampous et al., 1966). This research group has explored the
action of N -acetylmescaline (27) in normal humans and found it to be largely
275
CH'O~NHCOCH'
CHaOY
OCHa
(27)
without effects in the dose range 30.0.-750. mg, orally. At the highest dose
explored, there was a report of a mild degree of drowsiness one hour
following administration of the chemical.
Peyote is known to contain a number of additional N-methylated and Nacylated derivatives of substituted phenethylamines (see Kapatia and Fayez,
1973), and a great number in addition are known in the chemical synthetic
literature. Several of these basic N -alkyl phenethylamines are known to be
pharmacologically active in man and have entered the drug literature as
clinical pharmaceuticals, but they have not been studied as, nor are they
thought to be, psychotomimetics. Most of these compounds have less than
three substituents in the aromatic ring and are generally classified as
bronchodilators or stimulants.
2.2.6. 3,4,5-Trimethoxyphenylacetic Acid

Although 3,4,5-trimethoxyphenylacetic acid (28) is not a nitrogensubstituted phenethylamine, it is a major (-30.%) metabolite of mescaline in
CHaO
VCOOH
CHaOY
OCHa
(28)
man (Charalampous et at., 1964), and interest in this compound stems from a
desire to determine if it is an active biotransformation product, or whether its
generation should be classified as a detoxification. Trials with 40.0. mg orally
led to a 75% recovery of unchanged compound in urine, but to no
observable effects (Slotta and Milller, 1936). Trials in the dose range 350.750. mg also failed to produce either physiological or psychological changes
(Charalampous et al., 1964).
2.2.7. f3-(3,4,5-Trimethoxyphenoxy)-ethylamine
In a study of structural analogs of mescaline, Carlsson et al. (1963)
prepared the ethanolamine ether 13-(3,4,5-trimethoxyphenoxy)ethylamine
(28.1) and the N,N-dimethyl homolog. Again, neither compound is strictly a
N-substituted derivative of mescaline, but their close structural similarity, and
the fact that they have been assayed in man, makes their inclusion here
276
desirable. The toxicity of (28.1) was determined in the mouse to be 500 mg/
kg (LD50' Lp.). In a series of human trials (from 10 to 300 mg dosages), (28.1)
was found to be without central effects (mescaline was the control drug, at a
420-mg dose).
2.2.8. {3 (3,4,5 -Trimethoxyphenoxy )-N,N-dimethylethylamine

The N,N-dimethyl homolog of (28.1) is ~-(3,4,5-trimethoxyphenoxy)
N,N-dimethylethylamine (28.2). It bears the relationship to (28.1) that
trichocerine (24) does to mescaline. The LD50 of (28.2) in the mouse was 250
mg/kg i.p. Human trials were conducted over the dose range 10-400 mg,
without the appearance of any central effects. Mescaline, at 420-mg total
dose, served as the control (Carlsson et al., 1963).
3. THE PHENYLISOPROPYLAMINES
The substitution of a methyl group alpha- to the nitrogen atom in
phenethylamine gives rise to the compound amphetamine, a powerful CNS
Phenethylamine
Amphetamine
stimulant as well as a peripherally active adrenergic agent. The cardiovascular and stimulatory properties were first reported by Alles (1933). The
application of this excitatory property in clinical problems of narcolepsy was
initiated by Prinzmetal and Bloomberg (1935). The protracted action and the
oral activity of amphetamine is associated with the proximity of the methyl
group to the amine function, effectively interfering with enzymatic deamina-
277
tion. The three-carbon chain in general increases toxicity, increases stimulation to the CNS, and decreases the purely "sympathomimetic" nature of the
two-carbon chain counterpart (Gunn et al., 1939). There is also the introduction of an asymmetric center, permitting the preparation and study of optical
isomers. By far, the largest subfamily of phenethylamine psychotomimetics
known are the alpha-methyl phenethylamines, or phenylisopropylamines. As
will be indicated they are, as psychotomimetics, in general more potent than
their two-carbon counterparts, they are long-acting, and they are orally
effective.
One form of psychotogenic action is known that is directly ascribable to
the use of amphetamine itself. This is the "amphetamine psychosis" that
results form the chronic use of large doses of amphetamine (Monroe and
Drell, 1947; Connell, 1958). As the symptoms of stimulation become lost due
to the development of tolerance, there is revealed a psychotic state, clinically
similar to spontaneous schizophrenia (Bell, 1965). The amount of drug
required to evoke this response varies widely from individual to individual
(Griffith et at., 1970) but it seems not to depend upon any previous history of
predisposition to mental illness (Angrist and Gershon, 1970). This "amphetamine psychosis" has been observed following the chronic abuse of related
sympathomimetic stimulants (Greenberg and Lustig, 1966; Angrist et at.,
1970a). The psychotropic syndrome that follows chronic drug exposure lies
outside this review and will not be included within the concept of psychotomimetic action.
A caution is appropriate concerning the popular custom of referring to
this family of a-methyl phenethylamines as "psychotomimetic amphetamines." The name amphetamine designates one unique chemical and there
can be no justification for its use in the plural (Shulgin, 1976b). The
pharmacologist will consider the stimulant action of amphetamine and will
associate it with other sympathomimetics or anorexogenics. A forensic
chemist will consider the legal classifications and will probably limit his
grouping to the two proscribed drugs amphetamine and methamphetamine.
The synthetic chemist will envisage the phenyl ring and the three-carbon
chain with the nitrogen on the beta-carbon, whether the compound is
biologically active or not. The term will be avoided in this chapter, and the
inoffensive substitute "phenylisopropylamines" will be used for this family.
Nonetheless, many of the compounds to be discussed in this section have
commonly encountered code-names that include a final "A" from this oftenused family designation.
These phenylisopropylamines will be grouped in five subsections, according to substitution patterns:
3.1. Methoxylated phenylisopropylamines, with varymg position and
varying number of methoxyl groups.
3.2. Methylenedioxy phenylisopropylamines, with or without methoxyl
groups in addition.
278
3.3. Phenylisopropylamines with alkoxy substituents in addition to, or

instead of, methoxyl groups.
3.4. Phenylisopropylamines with alkyl groups on the aromatic ring, with
or without methoxyl groups in addition.
3.5. Phenylisopropylamines with a halo group or a sulfur on the
aromatic ring, with methoxyl groups in addition.
3.1. Methoxylated Phenylisopropylamines

3.1.1. 4-Methoxyphenylisopropylamine
4-Methoxyphenylisopropylamine (29, p-methoxyamphetamine, PMA) is
the simplest of the methoxylated phenylisopropylamines to be classified as a
(29) PMA
psychotomimetic drug. In animal toxicology and pharmacology studies it has

been found to be a highly toxic stimulant, showing prolonged cardiovascular
effects in the dog at only 0.2 mglkg (Cheng et ai., 1974). In the rat behavioral
studies employing the Bovet-Gatti proftle procedure (Smythies et ai., 1967a)
PMA appeared to be a potent hallucinogen, second only to LSD (Smythies et
ai., 1967c). Para-hydroxylation of amphetamine is a major metabolic pathway
in the rat (see Chapter 7 on biotransformation) and it was felt that the
psychotogen effects following high doses of amphetamine might be due
to some O-transmethylase that could relate amphetamine metabolism to
PMA toxicity. Analyses of the urines of experimental subjects in which the
amphetamine psychosis had been induced by protracted chronic amphetamine exposure showed no trace of PMA (Angrist et ai., 197Ob). It has been
shown that upon the intentional administration of PMA to human subjects
there is a small erratic excretion of the base in unchanged form (Schweitzer
and Freidhoff, 1970; Schweitzer et ai., 1971). 4-Methoxyphenylisopropylamine has been isolated from monkey brain and CSF following amphetamine
administration (Andreoli, et ai., 1973). The free hydroxyl counterpart of (29)
has been employed therapeutically under the brand name Paredrine as a
sympathomimetic in patients with heart block or postural hypotension
(Anon., 1973a). Cumulative daily doses of 400 mg are known, and acute
dosages of 80 mg produce no central effects related to alertness or mood
(Alles, 1959). A recent study in man describes the intravenous administration
(acutely) of 2 mg, again without the report of any central effects (Severs et ai.,
1976). It would appear that PMA is not a contributary agent in the
mechanism of the generation of the amphetamine psychosis.
279
PMA (29) is a treacherous drug to study in human subjects, and its

indiscriminate use has been implicated in a number of tragic accidents. The
compound has an unusually steep dose-response curve in man. At dosages
of 40 mg or less, it is without either peripheral or central effects. Yet at 6080 mg, the effective dose for the induction of a psychotomimetic syndrome
(Shulgin et al., 1969), there have been incidents of precipitous hypertention
and cardiovascular stimulation (Angrist, 1969, personal communication). The
psychotomimetic state is realized quite suddenly about an hour following
ingestion of the drug, and the plateau of central intoxication is passed within
the second hour. The somatic effects can persist longer, with blood-pressure
elevation. Paresthesia can still be reported four hours following administration.
In early 1973, a flood of PMA appeared in the illicit drug market, first
in Canada and then in the United States primarily in the Midwest and the
South. A number of deaths have been connected with the use of the drug
(Cimbura, 1974) and the procedures for scheduling PMA as a controlled
substance were quickly and successfully put into motion (Anon., 1973b). The
toxic symptomology associated with overdosage were agitation, respiratory
depression, choking, hypertention, extreme hyperthermia, and convulsions.
One death occurred 2.5 hr following a parenteral administration, but in the
surviving cases the symptomatic crisis was passed at about 8 hr following
drug use. No accurate dosages could be determined in these cases, but based
upon forensic analysis of evidence associated with hospitalization and autopsy
it appears as if as little as 150 mg might be fatal in man. This would
represent an extraordinarily small therapeutic index of about 2.5.
The positional isomers of PMA have been studied in experimental
animals and appear to be less potent than, and pharmacologically distinct
from, PMA (Tseng et al., 1976; Menon et al., 1976). They have never been
clinically explored in man, but since they are positional isomers of PMA they
are explicitly included in the Federal Drug Schedules. Their physical and
chromatographic characteristics have been compared for possible forensic
use (Bailey et al., 1974a).
3.1.2. 3, 4-Dimethoxyphenylisopropylamine
The most interesting of the six possible dimethoxyphenylisopropylamines is the 3,4-isomer (30, DMA, 3,4-DMA, 3 ,4-dimethoxyamphetamine) ,
since it has the substitution pattern of the neurotransmitters dopamine and
norepinephrine, and it is the immediate homolog of DMPEA (6). Unfortu-
(30) 3,4-DMA
280
nately there have been no clinical studies reported that concern this chemical
as a possible psychotomimetic, and very litde is known about its intoxicating
character. Alles conducted self-experiments in 1962 and "on the basis of
threshold effects judged this compound to be two or three times less active
than MDA" (Fairchild et al., 1967). Some details are provided in an
unpublished work reported by Fairchild (1963): "Oral doses from 10 to 120
mg were without peripheral or subjective effects, except for a slight gastrointestinal discomfort at the higher dose. When 160 mg was ingested a 20 mm
of mercury increase in blood pressure occurred within 45 minutes, which was
accompanied by a slight mydriasis, lacrimation, and gastro-intestinal uneasiness."
The only account of hallucinogenic effects ascribable to 3,4-DMA (30) is
in an Army Chemical Center report (Fairchild, 1963). This group authorized
the study of DMA with several psychiatric patients in the New York State
Psychiatric Institute:
One patient received 0.004 mM/kg of the hydrochloride salt intravenously
(perhaps 70 mg) and exhibited only a slight increase in psychiatric symptoms; a comparable dose in a second individual also elicited only insignificant changes. When one of these two patients was reinjected at a later date
with approximately 0.04 mM/kg of 3,4-DMA (perhaps 700 mg Lv.) a
definite "mescaline-like" state was induced. The symptoms included colored
hallucinations of geometric figures and occasional structured forms. The
other individual experienced visual distortions, notable after-imagery, feelings of unreality, and paranoid ideas. Marked mydriasis and gross body
tremors also occurred but apparently no hallucinations were experienced.
From these various comments one may assume that the effective dose of 3,4DMA is approximately that of mescaline, or perhaps 300-400 mg.
3.1.3. 2, 4-Dimethoxyphenylisopropylamine
There is only a single report of the human effectiveness of 2,4dimethoxyphenylisopropylamine (31, 2,4-DMA, 2,4-dimethoxyampheta-
o:(H.
CH 3 0
OCH 3
(31) 2,4-DMA
mine) as a psychotomimetic compound (Shulgin et al., 1969). The potency of

five times that of mescaline is based upon acute trials of approximately 60
mg (as the hydrochloride salt, orally), which led to a short-lived intoxication
with a considerable component of amphetamine-like stimulation. The euphoria phase peaked at about two hours following administration of the
281
drug, and had largely receded in another hour. Nothing is known of either
its metabolism or excretion in the body.
3.1.4. 2,5-Dimethoxyphenylisopropylamine
This third positional isomer of dimethoxyphenylisopropylamine (32,
2,5-DMA, 2,5-dimethoxyamphetamine) has a potency in man of some eight
'CX:"
CHaO
NH2
OCHa
(32) 2.S-DMA
times that of mescaline (Shulgin et al., 1969), being effective as an intoxicant

at an oral dose of about 50 mg. At this level the drug's effects are closer to a
stimulant than a psychotomimetic. There is a sudden onset of action just over
an hour following ingestion, which is characterized by vertigo, a closed visual
field, and slight muscular incoordination (Shulgin, 1963, unpublished data).
Over the following 2 hr there is a modest central intoxication, which is
accompanied by a slightly elevated blood pressure and extreme hyperactivity.
The syndrome is dissipated at 5 hr.
2,5-DMA appeared in the illicit drug market in 1970 both in Canada
(Bailey et al., 1974b) and in the United States (Shaler and Padden, 1972). It
was initially misrepresented as mescaline or MDA, but was eventually called
by the code name DMA. (In the forensic literature the unprefixed term
DMA refers to the 2,5-isomer; in the medical and scientific literature, DMA
is assumed to stand for the 3,4-isomer.) Seized capsules were found to
contain 200 mg of the hydrobromide salt of a high degree of purity (De Zan,
1971) and this must be assumed to have been the dosage employed. This is
equivalent to some 170 mg of the hydrochloride, and represents a regimen
that has not been studied under controlled clinical conditions.
Although 2,5-DMA has no medical utility and has thus been classified as
a Schedule I drug by the Drug Enforcement Administration, there is a
considerable demand for it as a chemical in the photographic industry. The
manufacturing quota for it, for a single year's production, is 45,000,000 g as
the free base (Anon., 1976), and this magnitude of commercial production,
in addition to the inexpensive availability of the synthetic precursor 1-(2,5dimethoxyphenyl)-2-nitropropene, may have accounted for its appearance in
high purity and broad availability in the period prior to its legal proscription.
The drug has been only rarely seen in the last two years, although it cannot
be determined if this is due to effective security control of manufacture, or to
an unpopularity of the nature of the intoxication.
The remaining three positional isomers of the dimethoxyphenylisopropylamines are of unknown action in man. They have been studied and
282
compared spectrophotometrically (Bailey, 1972) and chromatographically

(Bailey et at., 1974b).
3.1.5. 3,4,5- Trimethoxyphenylisopropylamine

3,4,5-Trimethoxyphenylisopropylamine (33, TMA, trimethoxyamphetamine) is the first psychotomimetic drug that evolved from the systematic
application of the principles discovered in studying the relationships between

chemical structure and biological activity. Armed with the known structure of
mescaline, the proclivity of most phenethylamines to be of only fleeting
activity centrally (due to facile deamination), and the effectiveness of a
methyl group alpha- to the nitrogen as a stabilizing factor in central activity,
Hey (1947) synthesized TMA. His favorable impressions on the euphoric
properties of the compound encouraged the Canadian group of Peretz and
co-workers (1955) to explore its psychopharmacological nature and to
evaluate its potential as a psychotomimetic. In their initial studies of the
compound, dosage levels of 50-100 mg were administered to normal
subjects. In about an hour a transient headache developed, followed by
nausea of short duration, without vomiting. This latter symptom was
successfully avoided by pretreatment of the subject (30 min) with 50 mg
Dramamine. During the second hour the subjects commented upon a
sudden onset of giddiness, followed by an increase in movements and
communicativeness, and a decrease in inhibitions. There was a slight loss of
motor coordination, hyperreflexia, and a modest rise in heart rate without a
change in blood pressure. This phase remained for the ensuing three or four
hours, and then fell off rather rapidly. At these levels the experience was
described as pleasant, and there were no complaints of anxiety or discomfort
aside from the slight initial nausea. The interpretation of their studies at
somewhat higher levels is complicated by the use of a stroboscope as a visual
irritant or a precipitating stimulus for the generation of hallucinations. At
100-125 mg, there was the generation of structured visualization as well as of
geometric patterns, often with considerable coloration, when the subject was
exposed to the stroboscope at various photic rates. Only occasional image
formation (eyes closed) and perceptual distortion (eyes open) were observed
without this device.
At the dose range 200-275 mg, there were profound psychic changes
produced, which varied from individual to individual (Shulgin et at., 1961).
Visual experiences were noted at the end of the second hour following
283
ingestion, and involved distortion of color, texture, form, and spatial

relationships. The sensory changes were, in general, less extensive than those
observed from effective dosages of mescaline. Auditory and tactile sensations
were intensified, and both paresthesia and synesthesia were noted. There was
none of the enhanced capacity for empathy characteristically reported with
mescaline. Emotional responses elicited during the period of maximum
intoxication (3-5 hr from the start of the experiment) were striking in their
intensity. "Anger, hostility, and megalomaniac euphoria dominated the
subject'S thoughts and conversation. Actual acts of hostility were not observed
but it was felt that, in at least two subjects, provocation would have
precipitated homocidal violence." There was a consistent report of eyesclosed imagery, but recollections of past experiences appeared not to be
enhanced, and there was some impairment of intellectual performance. Once
the plateau of intoxication has passed, a return to the normal state was rapid,
and subsequent recall of events was excellent. The effective level of TMA
appears to lie in the range 160-200 mg orally, and the drug has quantitatively about twice the potency of mescaline.
3.1.6. 2,4,5-Trimethoxyphenylisopropylamine
This geometric isomer of TMA was first synthesized by Bruckner (1933)
and its Psyc!:lOtomimetic properties were first observed some 30 years later
(Shulgin, 1964a). 2,4,5-Trimethoxyphenylisopropylamine (34, TMA-2, 2,4,5CHa0Y"lrYNH2
~O(,HC:Ha
OCHa
CHaO
(34) TMA-2
trimethoxyamphetamine) was the second of the six possible positional

isomers found to be psychotomimetic, and was thus called TMA-2. The
remaining isomers (see below) have been numbered in order of their
progressive position of substitution. As with TMA (33), TMA-2 is not known
to occur in nature. The two most commonly encountered essential oils with a
trimethoxysubstitution pattern are elemicin (35) (and its conjugated rearrangement product isoelemicin, 36) with the 3,4,5-pattern seen in TMA, and
the2,4,5-trimethoxyphenylpropene asarone (37). The elemicin group, along
with safrole and myristicin will be discussed in conjunction with nutmeg
CHaO~
CHaOY
OCHa
(35) Elemicin
CH'Ol0
CHaOY
OCHa
(36) Isoelemicin
(37) Asarone
284
intoxication (see Section 3.2). Asarone is widely distributed in the plant

kingdom. It is a major component of Acorus calamus from a number of
different geographical origins (Guenther, 1952). Its common name is sweet
calamus or sweet flag. It is used as a medicine by the indians of northern
Canada (Hoffer and Osmond, 1967) where it is known by the name rat-root,
and is claimed to have intoxicating properties similar to those of LSD. The
conversion of asarone to TMA-2 is easily realized chemically but has not been
demonstrated as occurring metabolically.
There is a theoretical interest in TMA-2 stemming from the recognition
of 6-hydroxydopamine (38) as a potent disrupting agent within the adrenergic nervous system. The two compounds have an identical oxygen substitution, and TMA-2 (34) has been shown to be partially demethylated in vivo
(Mitoma, 1970; Sargent et al., 1976). The totally demethylated product from
TMA-2 is 2,4,5-trihydroxyphenylisopropylamine (39), which has been exHO~NH2
H0Y'lrYNH2
HO
0nOHH tCHH 3
HO
00u
OH
(38)
(39)
plored as an antihypertensive agent, but which exhibits no mental effects at

dosages as high as 200 mg (Stone, 1963).
Threshold effects of TMA-2 are evident at dosages of 10 mg as the
hydrochloride salt, and the effective oral dose is twice this amount. The drug
is therefore some 20 times more potent than mescaline and is the most active
of the six trimethoxylated phenylisopropylamines. A generalized presentation of the intoxication state has been presented (Shulgin, 1976c):
The first indications of intoxication usually noted are signs of physical
disturbance such as nausea, paraesthesia, and a modest reflexive mydriasis.
The central sensory changes appear in the second hour and are characterized by some exaggeration of visual input (especially in the appreciation of
colors and contrasts of lighting) and of empathy with irrational objects in
one's environment. These preludes lead to a plateau, from three to about
six hours following administration, which is an impressive altered state of
consciousness virtually free of the distortions and portentousness so common with LSD. The experience disssipates gradually, and is usually completed in 8-10 hours. A sharp dose-response curve exists for TMA-2 in that
several additional toxic symptoms have been reported at 25-30 mg levels.
There can be a pervasive nausea throughout the entire experimental
period, accompanied by actual vomiting, apparent fainting, and brief but
repeated periods of amnesia. Peripheral vision can be lost (this, apparently,
of hysterical origin) and the accompanying fear of being irreparably severed
from reality has led to situations that have proven difficult to manage.
TMA-2 has been coadministered with other psychotomimetics in experimental psycholytic therapy (Naranjo, 1967, personal communication). Mixtures of 20 mg TMA-2 with 250 mg ibogaine, or with 250 mg harmaline,
285
have led to long-lived periods of intoxication (16 hr) complicated by severe

motor agitation.
This positional isomer of the trimethoxyphenylisopropylamines (40,
TMA-3, 2,3,4-trimethoxyphenylisopropylamine, 2,3,4-trimethoxyamphetaOCH 3
CH30~NH2
CH 30
AJ
tH3
(40) TMA-3
mine) is the only one for which no psychotomimetic activity has been
observed. A number of acute trials have been carried out at dosage levels of
up to 100 mg as the hydrochloride salt (Shulgin, 1964a; Naranjo, 1967,
personal communication). At this highest level there were signs of peripheral
toxicity, but since there were no indications whatsoever of central disruption
further study was discontinued. All of the other trimethoxyphenylisopropylamines had clearly shown some form of sensory or interpretive changes at
or below this level; thus it may be stated that TMA-3 is the least active of
these isomers, if active at all. In a structure-activity review (Shulgin et at.,
1969) the compound was stated to be of activity of less than twice that of
mescaline, and this has been occasionally interpreted in animal correlations as
indicating the presence of activity but of a low order of potency. Neither
statement is exact; the active level of TMA-3, as a psychotomimetic in man, is
not known.
TMA-4 (41, 2,3 ,5-trimethoxyphenylisopropylamine, 2,3 ,5-trimethoxyamphetamine) and the following isomer TMA-5 are extremely scarce
OCH 3
CH 30 A N N H2
CH 3
OCH 3
(41) TMA-4
compounds, and the extent of the known pharmacology has been obtained
on the milligram quantities originally synthesized (Shulgin, 1966a). No
peripheral or central effects were noted in several experiments including
dosage levels of up to 50 mg. In a single experiment, 80 mg (of the
286
hydrochloride salt) in a drug-sophisticated subject led to an impressive

introspective state without any complaint of physical distress. The intensity of
intoxication was equated to 50 ILg LSD 'and to 120 mg TMA (Naranjo, 1967,
personal communication). If this represents the effective level, then TMA-4
has about four times the potency of mescaline (Shulgin et al., 1969).
As discussed in Section 3.1.8, TMA-5 (42, 2,3,6-trimethoxyphenylisopropylamine, 2,3,6-trimethoxyamphetamine) was available for clinical assay in
OCH 3
CH30WNH2
H3
OCH 3
(42) TMA-5
only small quantities, and there is a corresponding uncertainty concerning

the accuracy of the quantitative potency assigned to it. There are initial signs
of activity at an oral dosage of 20 mg; these threshold effects include mild
mydriasis, increased heart rate, piloerection, and other closely associated
prodromal indicators of central activity. A single experimental subject, at 30
mg, underwent a protracted LSD-like session that was adjudged to be similar
to the effects produced by 75 mg LSD (Naranjo, 1967, personal communication). With the assumption that this dose represents a valid effective
exposure, the drug can tentatively be called a psychotomimetic, and appears
to be some ten times more potent than mescaline. The original published
value (l3X; Shulgin et ai., 1969) implies more accuracy than in fact exists. A
satisfactory ranking of both TMA-4 and TMA-5 requires much further
experimentation.
The symmetrical, sixth isomer of trimethoxyphenylisopropylamine is
TMA-6 (43, 2,4,6-trimethoxyphenylisopropylamine, 2,4,6-trimethoxyamphe-
~NH2
CH 30
MorjH
OCH3
(43) TMA-6
tamine). This base was first synthesized over 20 years ago (Benington et al.,
1954) and its psychotomimetic properties were discovered 10 years later
(Shulgin, 1964, unpublished data). A threshold of central activity is apparent
at an oral dose of 20 mg, and the dosage range for a fully developed
287
TABLE 2
Human Potencies of the Six Trimethoxyphenylisoprojrylamines
Code
Orientation of
methoxyl groups
Activity
(mescaline = I)
2,4,5
2,3,6
2,4,6
2,3,5
3,4,5
2,3,4
20
10
10
4
2
<2
TMA-2
TMA-5
TMA-6
TMA-4
TMA
TMA-3
psychotomimetic intoxication state is 30-40 mg. There is a visually entertaining aspect to the experience, although its extended action (maximum effects
can persist into the sixth hour) can be both tiring and anxiety-provoking.
Naranjo (1967, personal communication) has investigated TMA-6 with 13
subjects in the 40-80 mg range and has found that these higher doses lead to
erratic results. With several patients there was neither a prolongation nor an
intensification of effects; and with at least one, there was the generation of a
convincing psychotic episode. The recorded potency of TMA-6 (ten times
that of mescaline; effective dose about 30 mg) can be used in quantitative
comparisons with confidence (Shulgin et at., 1969).
This family of all possible isomers of a single drug, varying widely as it
does in comparative human potencies, constitutes an excellent model against
which to challenge physical or biological assays for potential psychotomimetic
activity. In the several studies that have been reported comparing the human
activity of members of this series to physical-chemical properties (Sung and
Parker, 1974) and in in vivo animal screens (Uyeno, 1968; Uyeno et at., 1968)
there are promising correlations. The best present values for relative human
potencies of these six isomers are given in Table 2.
3.1.11. 2,3,4,5-Tetramethoxyphenylisopropylamine
Only one substituted phenylisopropylamine with more than three methoxyl groups has been established as being psychotomimetic. This is 2,3,4,5tetramethoxyphenylisopropylamine (44, 2 ,3,4,5-tetramethoxyamphetamine).
OCHa
CHaO~NH2
~ I
CHaO
OCHa
(44)
CHa
288
A threshold level of central activity is evident at a 30 mg dose orally, and a

relatively long-lived disinhibited intoxication is produced by a 50-mg dosage.
Compound (44) has been recorded as having six times the potency of
mescaline (Shulgin et ai., 1969), but additional studies will be needed to
establish the qualitative nature of its action.
Although a good correlation has been shown to exist between fluorescence spectra of methoxylated phenylisopropylamines (reflecting molecular
orbital energy) and psychotomimetic potency, this isomer (44) and the 2,4,6trimethoxy analog (43) show a disproportionately feeble fluorescence. Arguments of unusual metabolic protection may be considered in the explanation
of the biological activity of these latter two compounds (Antun et ai., 1971).
Another potential distinction of these highly methoxylated phenylisopropylamines is the possibility of intramolecular association between an amine
hydrogen and an ortho-Iocated methoxyl oxygen that may be undergoing
steric displacement from the plane of the benzene ring by interaction with its
neighboring methoxyl group (Chothia and Pauling, 1969). The evaluation of
the two remaining tetramethoxyl- and the pentamethoxyl-substituted phenylisopropylamines would certainly help resolve these questions.
3.2. Methylenedioxyphenylisopropylamines
A second major substitution system found in the alpha-methyl phenethylamine psychotomimetics is the methylenedioxy group. In plants, compounds with this five-membered ether ring are frequendy found in close
conjunction with the dimethoxy- or the methoxy hydroxy-substituted counterparts. The best known and most thoroughly studied of these essential oils
are safrole (45, a structural analog of methyleugenol 46) and myristicin (47,
similarly analogous to the already discussed elemicin, 35). Just as there is a
close biosynthetic connection between these compounds in plant sources,
there is a close interrelationship in the pharmacology of the correspondingly
substituted phenylisopropylamines.
CHaO~
CHa~
(45) Safrole
iH~~
"'O~
OCHa
(47) Myristicin
"
(46) Methyleugenol
CHao~
~ I
I
~
CHaO
OCHa
(35) Elemicin
289
There is an extensive literature describing the use of parts or extracts of

the plant Myristica fragrans as an intoxicant. Reference should be made to
the recent review of Forrest and Heacock (1972) concerning the chemical
composition of the plant, to Weil (1967) concerning its psychotomimetic
potential, and to Shulgin (1966b) for a discussion concerning the implication
of a major essential oil myristicin (47) as a contributing factor to this
intoxication. The hypothetical conversion of safrole (45) to MDA (48) and of
myristicin (47) to MMDA (51) by the canonical addition of ammonia to the
olefinic group (Shulgin et al., 1967) has received some support from recent
liver homogenate studies, which indicate chromatographically that substituted phenylisopropylamines can be formed from these olefins (Braun and
R~
Kalbhen, 1972, 1973). This could result from the possible formation of a
beta-keto intermediate, the corresponding phenylacetone, which is known to
be formed metabolically in turn from MDA (Midha, 1974). Oswald et al.
(1969, 1971a,b) have found that rats and guinea pigs metabolize both safrole
and myristicin via an alpha-keto intermediate, to form amination products
through the addition of dimethylamine, pyrrolidine, or piperidine. The
pharmacological role that such metabolites might play in an explanation of
the intoxicating nature of nutmeg is still only speculative. None of them have
been identified as metabolic consequences of human ingestion of nutmeg or
mace spices. The phenylisopropylamine analogs have been well explored
pharmacologically, however, and will be discussed below under each specific
chemical entry.
3.2.1. 3,4-Methylenedioxyphenylisopropylamine
3,4-Methylenedioxyphenylisopropylamine (48, MDA, 3,4-methylenedioxyamphetamine) is the simplest and the best studied of the methylenedioxyphenylisopropylamines. It was first synthesized by Mannich and Jacobsohn (1910) and first explored in animal studies by Gunn et al. (1939). It was
290
/O~NH2
C~~AJ
CH 3
(48) MDA
found to be the most effective stimulant of a large group of similarly

substituted amphetamine derivatives (including amphetamine).
The initial human trials with MDA were directed toward possible
therapeutic relief of Parkinson's disease (Loman et al., 1941) but it was found
to be detremental. Biniecki and Muszynski (1953) observed the analeptic
properties of MDA and the levorotatory isomer was clinically explored at
Smith Kline and French, Co., as an appetite-suppressing drug (Cook and
Fellows, 1961) and as an antidepressant. The compound was found to be
equivalent to amphetamine as an anorexogenic agent, but at higher doses
(up to 120 mg/day) had central stimulant properties that were found to be
objectionable, although hardly classifiable as psychotomimetic (Doughty,
1964, personal communication).
These central effects were explored further by Alles (1959), who
following ingestion of 126 mg of the racemate described his subjective
changes as follows:
Forty-five minutes (after ingestion) an abundance of curling grey
smoke rings was readily observed in the environment whenever a relaxed
approach to subjective observation was used. Visually, these had complete
reality. When I concentrated my attention on the details of the curling grey
forms by trying to note how they would be affected by passing a finger
through their apparent field, they melted away. Then, when I relaxed
again, the smoke rings were there.
Awareness of the body and of its functioning became subject to a
detached special consideration, and the reality of the place of detached
observation for a time seemed clearly transposed out of the body and to a
place above and to the right rearward. I was compelled to turn my head
several times and look-at what part of me could be up ther~bserving
the situation.
Additional central sensory intensities were noted (such as an extreme

auditory acuity, and tactile confusion) but there was a complete absence of
color distortion so characteristic of other psychotomimetics. Several recent
clinical studies of MDA have especially explored these symptomatic peculiarities in an effort to evaluate the potential value of the drug in psychotherapeutic medicine. Naranjo et al. (1967) employed doses of the racemate of
from 40 to 150 mg. Turek et al. (1974) used a fixed dose of 75 mg of the
levo-isomer. Yensen et al. (1976), again employing the levo-isomer, explored
the dosage range from 40 to 200 mg. A comparison of these studies indicates
that the levo-isomer is largely responsible for the activity of the drug, a
conclusion in keeping with a single study that has been made (Marquardt,
1977, personal communication) directly comparing the levo-isomers with the
racemate with the dextro-isomers. The pharmacologically equivalent dosages
291
needed for the three optical forms are 70, 125, and 225 mg, respectively.
There also appears to be a considerable stimulant content associated with the
less potent dextro- (or S) isomer.
At the small, but effective dose level of 150-mg racemic MDA (or 75 mg
of the levo- (or R) isomer) the effects are noted within the first hour, and
reach their peak quite quickly (in an additional one-half to one hour). The
return to the predrug psychological baseline may be quite slow, however,
taking as much as an additional 8 hr. The subjective effects generally noted
are quite unlike those commonly associated with psychotomimetic drugs.
There is litde perceptual phenomena, depersonalization, or disturbances of
thought, which usually characterize these latter drugs. There is a minimal
loss of ability to concentrate on and perform relatively complex visual-motor
tasks. Rather, there is an intensification of feelings, a facilitation of selfinsight, and the creation of a state of mind that allows increased introspectiveness and insight. There are few objective signs noted of the intoxication
state. A small but significant rise in systolic blood pressure occurs in the
second to third hour following administration, and a small, insignificant
increase in pulse rate during the same period. These latter effects may be
due to the dextro- (or S) isomer, since they were noted only in the studies that
employed the racemic mixture and not in the levo-isomer studies.
Studies with medium dose levels of the levo-isomer (125-150 mg)
appeared to be better suited for psychotherapeutic application (Yensen et al. ,
1976). There was much more of a tendency to remain within the experience
rather than describe it as it was taking place, although communication was
fully possible between subject and observer. Externally, the behavior of
patients experiencing these doses of MDA more closely resembled that of a
similar population under the effects of LSD (200-300 p,g). Visions were
reported with greater frequency than had been observed with the lower
doses. High doses of MDA (again, the levo-isomer, at 200 mg) appeared
externally identical to high-dose LSD sessions (300-400 p,g). Patients seemed
to be absorbed in the unfolding of inner experiences; visions were reported
frequendy and transcendental-mystical experiences increased in frequency
and intensity. There were no reports of distressful physiological problems
even with the high dosages employed.
The one possible positional isomer of MDA is 2,3-methylenedioxyphenylisopropylamine. Although it has been listed as an isomer of MDA and as
such is a Schedule I drug in the Federal Law Schedule (Anon., 1970), it is at
present completely unexplored pharmacologically.
3.2.2. N-Methyl- 3, 4-methylenedioxyphenylisopropylamine

There are only two N -alkyl derivatives of the phenylisopropylamines
that have been found to be psychotomimetic in man. Since they are both
homologs of MDA, it is appropriate to enter them here, rather than to make
a separate section for them. The first is N-methyl-3,4-methylenedioxyphenyl-
292
isopropylamine (49, MDM, MDMA, 3,4-methylenedioxymethamphetamine),

which is structurally analogous to MDA in exactly the same way that
methamphetamine is analogous to amphetamine. Two trivial codes have
been employed for (49), MDM for the methylenedioxy (MD) and M for the
~~~HCH'
O~
CH 3
(49) MDM
nitrogen substituent, and MDMA, in which the final MA represent methamphetamine. The compound was first reported in the chemical literature by
Biniecki and Krajewski (1960) although it was known earlier, having been
studied toxicologically by the Army Chemical Center in the I 950s. These
studies have recently appeared (Hardman et al., 1973). The compound has
had an occasional and erratic appearance in the illicit drug market (Gaston
and Rasmussen, 1972; Helisten, 1976, personal communication).
MDM has a higher threshold level than does MDA (48) but otherwise it
is very similar in potency. Within the effective dose range (100-150 mg
orally) the effects are first noted very quickly, usually within one half-hour
following administration. With most subjects the plateau of effects is reported
to occur in another one-half to one hour. The intoxication symptoms are
largely dissipated in an additional two hours except for a mild residual
sympathomimetic stimulation, which can persist for several additional hours.
There are few physical indicators of intoxication, and psychological sequelae
are virtually nonexistent. Qualitatively the drug appears to evoke an
easily controlled altered state of consciousness with emotional and sensual
overtones very reminiscent of low levels of MDA (Shulgin and Nichols,
1977).
3.2.3. N-Ethyl-3, 4-methylenedioxyphenylisopropylamine

The second of the N -alkyl phenylisopropylamines known to be psychotomimetic is the ethyl homolog of MDM (49). This is N-ethyl-3,4-methylenedioxyphenylisopropylamine (50, MDE, N-ethyl-3,4-methylenedioxyamphe0X)'t.NHCH2CH3
CH 2
'\
CH
(50) MDE
tamine). The compound has made a brief appearance apparently as a

synthetic substitute for MDA (Helisten, 1976, personal communication), but
it remains substantially undescribed in the scientific literature. MDE has a
potency very similar to that of MDM, with 100-125 mg representing an
293
effective dose. The buildup of intoxication is rapid, occurring between onehalf and one hour following ingestion, and the effects are already receding
before the end of the second hour. Psychopharmacologically this compound
is similar to, but slightly faster acting and shorter lived than MDM (Shulgin,
1977, unpublished data). A number of closely related N -methyl homologs of
known psychotomimetics have recently been prepared for forensic purposes
(Bailey et al., 1975).
3.2.4. 3 -Methoxy-4,5 -methylenedioxyphenylisopropylamine

The first prepared and first described positional isomer of methoxymethylenedioxyphenylisopropylamine was the 3,4,5-substituted compound
MMDA (51, 3-methoxy-4,5-methylenedioxyphenylisopropylamine, 3-methoxy-4,5-methylenedioxyamphetamine).
Three spearate lines of structure-activity relationship reasoning led to
the preparation and study of MMDA. First, a comparison of 3,4-dimethoxyphenylisopropylamine (DMA, 30) with the methylenedioxy counterpart
(MDA, 48) indicated that the replacement of two adjacent methoxyl groups
with the five-membered heterocyclic ring diether leads to an unmistakable
increase in potency. And similarly, the addition of the third methoxyl
function to the amphetamine skeleton (compare DMA, 30, with TMA, 33)
also increases potency. Second, a large number of natural alkaloids found in
peyote are isoquinolines vicinally substituted with a methoxyl and a methylenedioxy group in the aromatic ring. The possible biosynthetic precursor of
these compounds, and the immediate phenethylamine homolog of MMDA
(homomyristylamine, 18) has already been discussed. Third, in the natural
essential oils, there is a close parallel between elemicin (35) and myristicin
(47), both present in the psychopharmacologically active plant nutmeg.
3-Methoxy-4,5-methylenedioxyphenylisopropylamine was synthesized
and code-named MMDA, concurrently and independently in two different
C'~~I
,,~
NH2
CH 3
OCH 3
(51) MMDA
laboratories (Alles, 1962, personal communication, see Fairchild, 1963;

Shulgin, 1964b). The effective dose of MMDA, as the hydrochloride salt, is
120-150 mg and has therefore slightly less than three times the potency of
mescaline. A recent monograph has reviewed the known pharmacology and
psychopharmacology of MMDA (Shulgin et al., 1973) from which the
following generalized description of the objective and subjective symptomology is taken:
294
In human subjects, the first symptoms appear within 30-60 minutes

following administration. Moderate mydriasis was constant, and slight to
moderate dizziness was noted by most of the subjects (N = 20). Frequent
somatic sensations were those of heat or cold, or trembling. On one occasion
(250 mg), a pendular nystagmus was observed in all directions of gaze, and
on two occasions a difficulty in focusing was reported. Nausea was present
in three subjects for a brief interval, and in one it led to actual vomiting.
The psychological effects were mild, so long as the experience was
allowed to develop spontaneously. The phenomena most frequently reported were the accentuation of feelings (anxiety, euphoria, loneliness,
loving warmth), the visualization of images (with eyes closed), a state of
drowsiness and muscular relaxation, and an overestimation of elapsed time.
The imagery was generally realistic, and related to everyday perception of
people, landscapes, or objects. The effects usually reached a peak after the
first hour following the initial symptoms, diminishing during the second
hour, and had disappeared by the end of the fifth hour.
The psychotherapeutic potential of MMDA has been recently explored

at great length by Naranjo (1973), who reports numerous patient situations,
and compares MMDA with several other psycholytic therapeutic drugs
(MDA, harmaline, and ibogaine). There are, as of the present time, no
reported studies on the human pharmacokinetics or metabolism of MMDA.
3.2.5. 3 -Methoxy-4,5 -ethylenedioxyphenylisopropylamine

Although not strictly a methylenedioxy derivative, 3-methoxy-4,5-ethylenedioxyphenylisopropylamine (52, MEDA) is the six-membered ring homo-
NH2
H2r/~1
:::::,....
CH
H 2C
'--0
OCH 3
(52) MEDA
log of MMDA and is logically mentioned here. It was reported (Shulgin,

1964b) to be of "marked decrease in psychotropic effectiveness" in comparison with MMDA (51). Acute trials have been extended to oral levels of 200
mg, without indications of central effects. This is three times the level at
which initial threshold effects are reported for MMDA, indicating that there
is a decrease in psychotomimetic effectiveness with the relief of strain of the
heterocyclic ring (from five atoms to six). The seven-membered homolog 3methoxy-4,5-trimethylenedioxyphenylisopropylamine has been described
(Shulgin, 1964b) but it too has not yet been shown to be psychotomimetic.
3.2.6. 2-Methoxy-4,5 -methylenedioxyphenylisopropylamine

2-Methoxy-4,5-methylenedioxyphenylisopropylamine (53, MMDA-2, 2methoxy-4,5-methylenedioxyamphetamine) has been given the identifying
295
suffix "2" to allow direct structural comparison with TMA-2 (34), which has
an identical substitution pattern. And like the TMA-2, MMDA-2 is the most
potent of the methoxy methylenedioxyphenylisopropylamines that have as
yet been evaluated as psychotomimetic drugs (Shulgin, 1964a).
~~~:H2
"O~OC~H
(53) MMDA-2
Most subjects experience threshold effects following oral administration

of 15-20 mg of the amine hydrochloride. An effective psychotomimetic
intoxication is reported with dosages of 30-50 mg, indicating a drug potency
some ten times that of mescaline. The qualitative nature of the psychotomimetic syndrome for most subjects is similar to that reported for MDA. Rather
than the anxiety and restlessness common with TMA-2 (the methoxyl
counterpart), there is a highly humored empathy and pleasant relaxed state,
which persists for 2 to 4 hr. With subjects who appear to have a lower
sensitivity to psychotomimetic drugs, the effects have been reported to be
paradoxically quite unpleasant. Physical complaints include stomach cramping and intermittent nausea extending well into the period normally free of
somatic distress. The psychological effects in this latter subgroup are
generally reported as unpleasant and acutely distressing. As with the
remaining isomers to be discussed, this drug will have to be much more
extensively studied before its psychopharmacological character can be considered established.
3.2.7. 2-Methoxy-3, 4-methylenedioxyphenylisopropylamine

There are two positional isomers in the methoxy methylenedioxy series
of substituted phenylisopropylamine series that can correspond to the
substitution pattern seen in TMA-3 (40). To maintain a consistency of
nomenclature between the two parallel families of compounds, the isomers
within the 2,3,4-substitution patterns (54, 2-methoxy -3,4-methoxlenedioxy-
(54) MMDA-3a
phenylisopropylamine, MMDA-3a, 2-methoxy-3,4-methylenedioxyamphetamine; and 55 to be discussed below) the first has been suffixed as MMDA3a and the second as MMDA-3b. There cannot be a 2,4,6-isomer that would
correspond to TMA-6 (43).
296
The initial report that described MMDA-3a clinically and pharmacologically (Shulgin, 1964a) described it as being similar to mescaline in that there
was hallucinatory synthesis and total recall, but that it was effective at 16 mg
of the hydrochloride salt taken orally. Subsequent clinical study has shown
(Shulgin et al., 1969) that in most subjects perhaps twice this quantity is
needed to achieve a consistency of imagery (and related phenomena such as
slowing of subjective time and a generalized empathy), thus prompting a
reassessment of the dosage to be accepted as effective as twice this. MMDA3a has therefore some ten times the potency of mescaline, but is qualitatively
very similar. A note of caution should be added here, in that two subjects (in
a study of nine patients) developed a delayed psychotic state, with one
unsuccessful suicide attempt.
3.2.8. 4-Methoxy-2,3 -methylenedioxyphenylisopropylamine

4-Methoxy-2,3-methylenedioxyphenylisopropylamine (55, MMDA-3b, 4methoxy-2,3-methylenedioxyamphetamine) is the second of the two possible
(55) MMDA-3b
methoxy methylenedioxy substitution arrangements in the phenylisopropylamine series with the three oxygens substituted adjacent to one another and
adjacent to the aliphatic side chain. A single study of its psychotomimetic
effectiveness has appeared (Shulgin et al., 1969). Threshold activity grossly
similar to that reported for MDA (48) was reported at oral doses of 60 mg of
the amine hydrochloride, which would presumably extrapolate to an intoxicative potency of about three times that of mescaline. The qualitative nature
of MMDA-3b at such levels must await further clinical studies.
3.2.9. 6-Methoxy-2,3-methylenedioxyphenylisopropylamine
Equally sparse human pharmacology has been reported for 6-methoxy2,3-methylenedioxyphenylisopropylamine (56, MMDA-5, 6-methoxy-2,3-

TABLE
Human Potencies
Code
297
of the Six Methoxy Methylenedioxyphenylisopropylamines

Orientation of the
methoxyl and
methylenedioxy
groups
2,
2,
6,
3,
4,
5,
MMDA-2
MMDA-3a
MMDA-5
MMDA
MMDA-3b
MMDA-4
Activity
(mescaline = I)
(4,5)
(3,4)
(2,3)
(4,5)
(2,3)
(2,3)
10
10
10
3
3
methylenedioxyamphetamine) the methylenedioxyanalog of TMA-5. Its oral

activity is realized at dosages of 30 mg (LaBerge, cited in Shulgin, 1973),
which would suggest a potency perhaps ten times that of mescaline.
The sixth possible positional isomer within the MMDA series is the
compound 2,3-methylenedioxy-5-methoxyphenylisopropylamine, MMDA-4,
which would correspond in structure to 2,3,5-trimethoxyphenylisopropylamine, TMA-4 (41). At present, there has been no reported successful
synthesis of this compound and, of course, no pharmacological evaluation.
The human potencies of these MMDA isomers are ranked in Table 3.
3.2.10. 2,5 -Dimethoxy-3, 4-methylenedioxyphenylisopropylamine

There are six aromatic substitution patterns theoretically possible for the
dimethoxymethylenedioxy groups, and three possible orientations for trimethoxymethylenedioxyphenylisopropylamine. A number of these products
have been synthesized (see Dallacker, 1969, for leading references). Only two
of these compounds have been established as being psychotomimetic in man.
The first, 2,5-dimethoxy-3,4-methylenedioxyphenylisopropylamine (57,
Ha
C~~ ~ I
NH2
CHa
OCHa
(57) DMMDA
DMMDA, 2,5-dimethoxy-3,4-methylenedioxyamphetamine), bears a relationship to the natural essential oil apiole (2,5-dimethoxy-3,4-methylenedioxy-lallylbenzene, a major constituent of parsley seed oil, and commonly called
parsley camphor) in exactly the same manner that MMDA is related to
myristicin. Threshold effects are evident at oral dosages of 20 mg, and twice
298
this amount provokes a psychotomimetic intoxication. There is an abrupt

precipitation of effects approximately one hour following drug administration (there is no preliminary notice in the form of nausea, muscular tremors,
etc.) and the chronology and subjective nature of the experience closely
follow that of LSD. The maximum intensity of the subjective effects occurs
from 2 to 4 hr following ingestion, with extensive interpretive distortion,
subjective time lengthening, and inappropriate paranoia, followed by a gende
recovery that is largely complete at 8 hr. (Shulgin and Sargent, 1967). The
compound thus has some ten times the potency of mescaline.
3.2.11. 2,3 -Dimethoxy-4,5 -methylenedioxyphenylisopropylamine

The second of the isomers that has been studied in man IS 2,3dimethoxy-4,5-methylevedioxyphenylisopropylamine (58, DMMDA-2, 2,3-
/OW
C~2
o ~
NH2
CHa
OCHa
OCHa
(58) DMMDA-2
dimethoxy-4,5-methylenedioxyamphetamine). Its substitution pattern is that

of the essential oil dillapiole, a major component of dill oil. Limited clinical
trials have shown that threshold responses are elicited by the oral administration of 30-50 mg of the amine hydrochloride (Shulgin and Sargent, 1967)
with the prodromal indicators of an intoxication similar to that of MDA. If
the effective dose proves to be twice this, DMMDA-2 may be quantitatively
ranked as having about five times the potency of mescaline. Neither of the
dimethoxymethyledioxyphenylisopropylamines has been studied metabolically.
3.3. Alkoxyphenylisopropylamines
Almost all aliphatic ether groups that are found in living processes
involve the methyl group. In the biosynthetic pathways that are now quite
well understood, there are a number of trans methylase processes known to
provide a methyl group to a hydroxy function. In the metabolic chemistry of
norepinephrine and epinephrine there is an O-methylation (through the
action of the enzyme system catechol-O-methyl transferase, COMT). This is
considered to be a possible origin of DMPEA (6) if the latter can be
established as being of endogenous origins. Interest in the specific function
of the methoxyl groups per se in the substituted phenethylamines stems from
two possible interpretations of research in the area.
299
a. Processes of O-Methylation. One of the principal motives for the

research directed to the study of the structure-activity relationships in the
area of the psychotomimetics is that there might be an endogenously
produced chemical, normally not present or at least not present in sufficient
quantity to be effective, which becomes generated or mobilized in examples
of spontaneous schizophrenia. It is hoped that some indication of the
responsible chemical might become apparent by the comparison of hypothetically generatable natural phenolic biochemicals to known active methoxylated psychotomimetics. Positions that might be the sites of in vivo methylation would be just those positions that would be found to have a structural
specificity for a methoxyl group in the exogenous drug.
h. Processes if O-Demethylation. The complement of the above argument,
of the generation of a psychotomimetic-like drug by unexpected methylation
within the body, is the generation of a product that resembles a normal
biochemical by the demethylation of an administered drug. As has been
discussed in the section on biotransformation, there is extensive evidence that
several of the known psychotomimetics [such as mescaline (1), TMA-2 (34)
and DOM (69)] can and do undergo metabolic demethylation in biological
systems. Two experimental challenges to this latter process have been
explored. One is to replace the methyl aspect of the methoxyl group with
another chemical group that may present the body with a dealkylation
problem of considerably different ease, and if the demethylation is an
enzymatic demethylase process there might be considerable substrate specificity shown. The other is to replace the entire methoxyl group with a
different functionality, one that cannot participate in the same metabolic
transformations as can the OCHa In either case it has been hoped that the
pharmacological consequence of such a chemical maneuver at a given point
of substitution would reflect the importance of that position in any explanation for the mechanism of action of the drug in question.
Both approaches have been followed. Section 2 discussed the replacement of adjacent methoxyl groups with the more labile methyledioxy
counterparts. Section 3 will outline the few homologous ethers that have
been studied in man. Sections 4 and 5 will itemize the alkyl, and the halo and
sulfur substitution products (substitution in place of a methoxyl group) but
products that (mostly) still have methoxyl groups present.
3.3.1. 4-Benzyloxy-3,5-dimethoxyphenylisopropylamine
Of the many phenylisopropylamines with variations of the ether function that are known, only one with the 3,4,5-trisubstitution pattern is known
to be psychotomimetic in man. This is 4-benzyloxy-3,5-dimethoxyphenylisopropylamine (59). In a clinical study with seven subjects, there was a variable
threshold level noted at 30-50 mg, and dosages of 150 mg produced an
intense experience (Naranjo, 1967, personal communication). Frequently
reported were instances of imagery, mainly of reminiscences of past events,
300
CHSO~H2
V.
~O
: I
CHs
OCHs
(59)
and a continuous intellectual turmoil that seemed to persist for several hours.
Direct comparisons with the methoxy counterpart (TMA, 33) indicated that
on a weight basis it was distinctly more potent, although the subjects
comparing the two drugs found them largely indistinguishable.
3.3.2. 4-Ethoxy-2,5 -dimethoxyphenylisopropylamine

All seven of the theoretically possible ethyl homologs of TMA-2 (34)
have been chemically prepared and characterized (Shulgin, 1968), but only
the three monoethoxy examples have been evaluated as psychotomimetics in
man. In this series the Ms and the Es have been generated into code names
based upon the first letter of the alkoxy group located in the 2-, 4-, and 5positions, respectively.
The para-ethoxy homolog of TMA-2 is 4-ethoxy-2,5-dimethoxyphenylisopropylamine (60, MEM, 4-ethoxy-2,5-dimethoxyamphetamine). The
threshold and effective levels of MEM are quantitatively similar to those

reported for TMA-2, i.e., 12 and 20 mg, respectively (Naranjo, 1967,
personal communication). In a study employing nine subjects with dosages
ranging from 15 to 40 mg, there were consistent reports of color intensification, wavering and flickering in the visual field, and a relatively long-lasting
euphoria. There were indications of extrapyramidal tremors, paresthesia,
and a slight mydriasis. The effects are quite slow to be apparent (up to 2 hr)
and the overall experience is quite lengthy. Qualitatively, the subjective
reports likened MEM as being more like MDA than the homolog TMA-2.
3.3.3. 2-Ethoxy-4,5-dimethoxyphenylisopropylamine
The ortho-ethoxy homolog of TMA-2 (34) is 2-ethoxy-4,5-dimethoxyphenylisopropylamine (61, EMM, 2-ethoxy-4,5-dimethoxyamphetamine).
Acute trials have been conducted to levels (30 mg of the hydrochloride salt,
orally) more than twice those which precipitate threshold effects with either
301
CH30XXJ;NH2
CH 30
H3
OCH2CH3
(61) EMM
MEM (60) or TMA-2 (34) (Shulgin, 1968). No effects either central or

peripheral were noted, indicating that EMM would be less than half as
potent as these latter drugs as a psychotomimetic, if indeed it had that action
at all.
3.3.4. 5-Ethoxy-2,4-dimethoxyphenylisopropylamine
5-Ethoxy-2,4-dimethoxyphenylisopropylamine (62, MME, 5-ethoxy-2,4dimethoxyamphetamine) was found to be without activity in man at acute
CH3CH20~NH2
.
~
CH 30
~ I
CH 3
OCH3
(62) MME
dosage trials of 30 mg of the hydrochloride salt, orally. This is over twice the
threshold dose of MEM (60) and TMA-2 (34), indicating that the compound,
if it proves to be psychotomimetic, will have less than half the potency of
either of these two latter drugs (Shulgin, 1968). Neither the three diethoxy
homologs (EEM, EME, or MEE, see Section 3.3.2) nor the triethoxy homolog
(EEE) ~ave been clinically evaluated as of the present time.
3.3.5. 4-(n)-Propoxy-2,5-dimethoxyphenylisopropylamine
An unpublished study of the 4-propoxy homolog of TMA-2 (63, 4-(n)propoxy-2,5-dimethoxyphenylisopropylamine, MPM, 4-(n)-propoxy-2,5-di-
methoxyamphetamine) indicates that it has threshold activity at an oral dose

level of about 15 mg, as the hydrochloride. It is then approximately as
effective, certainly not much less so, than the two lower homologs MEM (60)
and TMA-2 (34). The two higher homologs, 4-(n)-butoxy-2,5-dimethoxyphenylisopropylamine and 4-(n)-amyloxy-2,5-dimethoxyphenylisopropyla-
302
mine (MBM and MAM, respectively) were without any central effects at
similar dosages (12 and 16 mg, respectively, orally, as the hydrochloride
salts). Too little is known of this homologous series at the present time to
generalize as to structure-activity relationships.
3.4. Alkylphenylisopropylamines
The principal psychotomimetic drugs that are alkyl-substituted phenylisopropylamines contain two methoxyl groups in addition. The several
amphetamine homologs with aromatic methylation that have been explored
clinically have for the most part been investigated as stimulants, as analgesics,
or as appetite-suppressing agents. However, in the last few years there have
been a number of reports of 4-methylphenylisopropylamine (4-methylamphetamine, 64) appearing as an abuse drug in the illicit market in North
Carolina (Keaton, 1973), in Pennsylvania (Cordova, 1974) and in Canada
(Bailey et ai., 1974a). As several isomers and homologs of these simple
aliphatic substituted amphetamine derivatives have been clinically studied in
man, they are included in this section along with the analogs containing
methoxyl groups.
3.4 .1. 4-Methylphenylisopropylamine

The sporadic appearance of 4-methylphenylisopropylamine (64, ptolylisopropylamine, 4-methylamphetamine, Aptrol) in the illicit market (see
(64)
references above) may be due to its possible pharmacological effectiveness as

a stimulant and as a physically and emotionally disruptive drug. It has been
clinically studied as an anorexogenic by Smith Klein and French Laboratories
under the name Aptrol. At 75 mg doses, in normal subjects, this effect is
generally recognized, without any expression of central complications. Marsh
and Herring (1950) have observed nausea, sweating, and blood pressure
elevation at higher levels. At about 150-mg dosages orally (as the sulfate)
there were overt signs of toxicity (gastric distress, salivation, coughing,
vomiting), which effectively masked any expression of central stimulation
common with amphetamine. This behavioral display is completely compatible with that found in rats with the Bovet-Gatti analysis (Beaton et ai., 1968)
wherein 4-methylphenylisopropylamine, unlike 4-methoxyphenylisopropylamine, appeared to be a weak stimulant rather than a hallucinogenic. The
303
decrease in pressor effectiveness found in the phenylisopropylamine series by

the addition of the 4-methyl group (64 vs. amphetamine) parallels dog
studies with the corresponding phenethylamines (Hambourger and Jamieson, 1936).
As of the present time, there are no reports of the dosages available in
illicit use, nor of the pharmacological effects experienced.
3.4.2. 2-Methylphenylisopropylamine
Only limited studies have been made in the human evaluation of 2methylphenylisopropylamine (65, o-tolylisopropylamine, 2-methylampheta-
~NH2
(J
CH
(65)
mine) and these have been directed toward its evaluation as a potential
anorexogenic agent (Marsh and Herring, 1950). Although there were some
indications of pressor effectiveness at as little as 40 mg orally (as the sulfate),
at 150-mg dosages these changes were no more than those induced by less
than half this dosage of control amphetamine, and were less than those
induced by similar doses of either the 3- or 4-positional isomers (compounds
66 and 64). The only evidence of mood change was an increase in
talkativeness at this highest level.
3.4.3. 3-Methylphenylisopropylamine
The meta-isomer of the tolylisopropylamines (66, 3-methylphenylisoproH3C~NH2
CH 3
(66)
pylamine, m-tolylisopropylamine, 3-methylamphetamine) has been clinically

explored as a possible anorexogenic agent by Marsh and Herring (1950).
Orally administered doses of (66) (as the sulfate) of up to 150 mg produced a
cardiovascular response similar to the 4-methyl isomer (64) at similar
dosages, but the subjects seem to be relatively free of the distressful sideeffects produced by this latter drug. Some slight evidence of central nervous
system stimulation was reported.
304
3.4.4. 3, 4-Dimethylphenylisopropylamine
Interest has been directed toward 3,4-dimethylphenylisopropylamine
(67, xylopropamine, Perhedrin, Esanin) as either an analgesic or an anorexo-
genic agent. At acute dosages of 10 mg orally (as the sulfate) there was some
relief in experimental subjects to electrically induced pain (via electrodes to
tooth ftllings), without any central changes noted that could be considered in
any way as being stimulant or psychotomimetic (Harris and Worley, 1957).
No cardiovascular effects are noted in man until levels of about 100 mg are
administered (Marsh and Herring, 1950), and at 150-mg dose levels there is
a relatively short-lived toxicology picture of nausea, vomiting, and reported
collapse.
3.4.5. 2,5-Dimethylphenylisopropylamine
A single report has been published concerning the effects of 2,5dimethylphenylisopropylamine (68) in man (Marsh and Herring, 1950). In
H3C
NH2
~3
~CH3C}l
(68)
studies directed toward the possible anorexogenic effectiveness of homologs

of amphetamine, they found that even at levels of 150 mg (of the sulfate,
orally), (68) had very little obvious activity on either the cardiovascular system
or the central nervous system of man.
A number of positional isomers of the Ar-polymethylated phenylisopropylamines have been chemically described [the 2,4-di- (Anon., 1959); 2,4,6tri- (Buu-Hoi and Petit, 1960); 3,4,5-tri- (Benington et at., 1958)]. These
chemicals have been explored pharmacologically in experimental animals but
there are no reports of their action in man.
3.4.6. 2,5-Dimethoxy-4-methylphenylisopropylamine
In contrast to the relative cardiovascular and central inactivity of the
simpler methylated homologs of amphetamine, it is now known that the
addition of methoxyl groups to the aromatic ring can result in compounds
305
that are not only highly potent, but which are psychotomimetic as well. The
first member of this family, and one of the most completely studied, is 2,5dimethoxy-4-methylphenylisopropylamine (69, DOM, STP).
CHaO~NH2
HaC
~()rH~Ha
OCHa
(69) DOM, STP
The rationale for its synthesis and pharmacological study was based
upon the suspected participation of the aromatic 4-position in the mechanism
of action of several of the phenethylamine psychotomimetics. The replacement of the potentially labile methoxyl ether with a hydrolytically stable but
oxidatively vulnerable methyl group (compare TMA-2, 34, with DOM, 69)
led to a compound with a severalfold increase in human potency, and one
with a considerably extended course of action. Threshold effects can be
recognized at oral levels between 1 and 2 mg. There is a generalized
awareness of minor physical disturbances (muscular tremor, facial flushing,
paresthesia) that occur about an hour following these low levels of the drug's
administration, and marginal sensory amplification (pleasure from sights and
smells, a relaxed contentment), which give indications of the long chronology
to be expected with increased dosage.
DOM was first synthesized and its psychotomimetic properties discovered in 1963 (Shulgin, 1963, unpublished data). Its initial appearance within
the drug abuse population occurred in San Francisco in mid-l 967, with the
distribution of thousands of tablets, leading to a pandemonium of acute toxic
reactions (Smith, 1969). The weight of DOM in the dosage unit distributed
was 10 mg, although initially a small distribution was made of units of twice
this quantity (Meyers et at., 1968). Two controlled clinical studies with normal
subjects were quickly conducted (Snyder et at., 1967), which were directed
both toward a characterization of the drug at low doses (Snyder et at., 1968;
Faillace et at., 1970; Weingartner et at., 1971) as well as toward a study of the
nature of the intoxication induced by higher doses (Hollister et at., 1969).
There appears to be a dose-dependent biphasic response to the drug. At
dosage levels between 2 and 5 mg, the Snyder group reported their subjects
to be substantially free of objectively observed physiological change, and of
perceptual distortion. There were clear indications of abnormal responses
that depended upon intact cognition and the interpretation of visual signals,
but there were no indications of effects that they could call either hallucinogenic or psychotomimetic. The peak of central activity in these studies was
between 3 and 4 hr on the average.
In studies involving higher dosages (to 14 mg, acutely, orally) the
Hollister group observed extensive somatic as well as perceptual and psychic
changes (see Hollister et at., 1969, for details and chronology). At the time of
306
the extensive street appearance of DOM, it was thought that chlorpromazine,

rather than ameliorating the drug's action, actually aggravated the psychotic
aspects of the intoxication. This point was specifically challenged by the
administration of therapeutic amounts (50-200 mg) of chlorpromazine to
experimental subjects concurrently with large doses of DOM. There were no
instances of complete reversal of the toxic syndrome, but the sedating action
appeared generally to attenuate some aspects of the intoxication.
Two studies have been made of the development of tolerance to DOM
by repeated exposure. Hollister et ai. (1969) administered gradually increasing doses to his subjects until a total of 12 mg had been administered on a
single day (4 mg, t.i.d.); on the following day the subject was challenged with
a single 12-mg dose. Angrist et ai. (1974) administered 6 mg per day for
three consecutive days. Both groups reported the development of a high
degree of tolerance, as judged both by objective measurement and by
subjective evaluation.
The pharmacology of the individual Rand S isomers of DOM has been
studied. Animal behavioral tests (Benington et ai., 1973) as well as in vitro
studies of serotonin agonism activity (Dyer et ai., 1973) have indicated that
the R or levorotatory isomer should be the major contributor to the
psychotomimetic activity of the racemate. Human studies (Shulgin, 1973b)
have reported this same conclusion.
The biotransformation fate of DOM has been investigated in several
systems. The major metabolite observed is the benzyl alcohol resulting from
the oxidation of the 4-methyl group. In in vitro preparations, this hydroxylation product is the major derivative observed, although there is evidence of a
minor metabolic process involving O-demethylation (Weinkam et ai., 1976).
If there were bis-O-demethylation of DOM, the product would be a
hydroquinone that is known to spontaneously air-oxidize to a potentially
bioactive indole (Zweig and Castagnoli, 1974). The hydroquinone was found
(Zweig and Castagnoli, 1975) but appeared not to be further oxidized in the
in vitro system employed. Body distribution of DOM and its metabolites has
been studied in a number of animal species (Idanpaan-Heikkila et ai., 1969,
1970; Idanpaan-Heikkila and McIsaac, 1970; Ho et at., 1971a).
Metabolism of DOM in the intact organism has been studied in three
species. In the rat some 10% is excreted in the urine unchanged (Tacker et
ai., 1969) and the majority of the administered compound was oxidized at
the 4-position to the hydroxymethyl analog and to the corresponding
carboxylic acid (Ho et ai., 1971b). Traces of the corresponding phenylacetone
were noted (this is a major product in amphetamine metabolism, see Chapter
7) but indications of beta-hydroxylation and of N -acetylation were looked for
but not found. In the rabbit, DOM is converted mainly to the 4-carboxylic
acid (Matin et ai., 1974) with less than 2% being excreted unchanged. This
latter, however, interestingly shows an enrichment in the active R isomer.
And in man there is a report of the urinary excretion of between 5 and 20%
307
of the administered dose as the unchanged base (Snyder et al., 1968), as

determined by an unspecified spectrofluorometric method.
3.4.7. 2,6-Dimethoxy-4-methylisopropylamine
The only positional isomer of DOM (69) that has been explored as a
psychotomimetic in man is 2,6-dimethoxy-4-methylphenylisopropylamine
(70, Z-7). Its threshold of central activity is realized at 10-15 mg orally, as the
hydrochloride, indicating that (70) may be slightly more potent than the
m
OCH3
::P
H3 C
NH2
CH 3
OCH3
(70) Z-7
methoxy counterpart TMA-6 (43). The duration of action is also slightly

longer (up to 8 hr). Insufficient clinical studies have been completed to assign
a probable full activity dosage requirement as yet.
A theoretical complication is introduced into the understanding of the
mechanisms of action of the psychotomimetic drugs by the activity of
compounds such as (43) and (70). One of the arguments advanced to explain
the increase in biological activity associated with the 2,4,5-ring substitution
pattern has been the theoretical ease with which such compounds can
undergo oxidation to para-quinones and possible subsequent indole formation [the prerequisite intermediate hydroquinone in the example of DOM
(69) has actually been isolated from in vitro preparations (Zweig and
Casta311oli, 1975)]. However, compounds with the 2,4,6-orientation are
incapable of such oxidation without the introduction of an oxygen into the
aromatic nucleus. A major step toward uncovering a common mode of action
of the 2,4,5- and the 2,4,6-trisubstituted psychotomimetics will be taken when
and if it can be shown that the metabolic disposition of the latter system
involves an additional oxidation step and that the resulting phenols (or their
methyl ethers) are biologically active.
A large number of substitutional and positional isomers of the methoxy
methyl phenylisopropylamines have been synthesized and chemically characterized, These can be thought of as manipulations and rearrangements of
the DOM structure, and should represent the raw material from which an
explanation of the mechanism of action will come. Several examples of
promising animal pharmacology have been observed with some of these
analogs. Ho et al. (1970b) have reported that 3-methoxy-4-methylphenylisopropylamine (71; DOM missing the ortho-methoxyl group and thus unable
to form a benzoquinone) was equivalent to DOM itself in both the nature
and the duration of this action. This compound has apparently been seen in
308
TABLE 4
Isomers of Methoxy Methyl Phenylisopropylamine
3~NH.
'V6
CH 3
Disubstituted
OCH 3
OCH 3
OCH 3
OCH 3
CH 3
Trisubstituted
CH 3
CHa
OCH 3
OCH 3
OCH 3
Horii and Inoi (1957)

Ho et at. (1970b)
Horii and Inoi (1957)
Morishita et at. (1956)
Carlsson et at. (1970)
Ho et at. (197Ob)
Wenner (1951)
Carlsson et al. (1970)
CH 3
CH3
CH 3
OCH 3
OCH 3
CH 3
CH 3
CH3
OCH 3
OCH3
CH3
OCH 3
OCH 3
CH3
OCH 3
CH 3
OCH 3
CH3
OCHa
CHa
O-CH.-O
CHa
CHa
Reference
OCH 3
OCH 3
Burger and Foggio (1956)

Anderson et at. (1977)
Shulgin (1970b)
Anderson et at. (1977)
Shulgin (I 970b )
Ho et at. (197Ob)
Sugasawa and Hino (1954)
a street sample seized in Italy, where it had been considered hallucinogenic,

with the code initials MMA (De Zorsi and Cavalli, 1974). Anderson et al.
(1977) have found that both 2,4-dimethoxy-5-methylphenylisopropylamine
(72) and 4,5-dimethoxy-2-methylphenylisopropylamine (73) (DOM with its
CH30Y'!{YNH.
H3C
AJ
(71)
CHa
H3 CY ' ! { Y N H . CHa0Y'!{YNH.
~()rJ..lCHa
OCHa
CHaO
(72)
~rJ..l_CHa
CHa
CHaO
(73)
substituents interchanged to preclude the formation of a benzoquinone by

simple demethylation) are inactive in the rabbit hyperthermia assay of
Aldous et al. (1974). Table 4 itemizes these analogs with their leading
references.
3.4.8. 2,5-Dimethoxy-4-ethylphenylisopropylamine
One of the most satisfactory correlations between animal pharmacology,
biochemistry, and human psychopharmacology is to be found in the small
309
homologous family of 4-alkyl-substituted-2,5-dimethoxphenylisopropylamines. The second member of this series is the base 2,5-dimethoxy-4ethylphenylisopropylamine (74, DOET). Originally all members of this
CH 30
NH2
nJu
CHaCH.
OCH 3
(74) DOET
homologous 4-alkyl series of phenylisopropylamines had three-lettered

codes, an initial DO indicating "desoxy" or the loss of oxygen followed by the
first letter of an alkyl group introduced. Thus the code for (74) was originally
DOE, but when this was recognized as a well-established abbreviation for
methamphetamine (deoxyephedrine) the additional letter T was added.
As with DOM (69), threshold effects of DOET are dearly apparent in
the 1-2 mg range, when administered orally to normal experimental
subjects. In a series of studies employing a 1.5-mg dose (with an active
placebo control of IO mg amphetamine), Snyder and co-workers have
reported a generalized chronology of onset at 1-1.5 hr, a peak of effect at 34 hr, with subjective symptoms largely subsided after 6 hr (Snyder et al.,
1968, 1969; Weingartner et al., 1970). Subjectively the effects are consistently
different from the psychotomimetic syndrome observed with higher levels of
DOM. There was the generation of a mild euphoria, feeling of enhanced
self-awareness, eyes-dosed imagery, and changes in the cognitive processes in
areas such as free association. In a study involving a range of dosages (from
0.75 to 4 mg) these symptoms appeared consistently, but at no dose level
were there indications of hallucinations or of disruptive psychotomimetic
toxicity (Snyder et al., 1971). It would appear that the induced behavior
changes, at least over this range, are dose independent. In a study of the two
optical isomers of DOET, independently and in comparison with the
racemate, the R or levo-isomer is perhaps twice as effective as the DLracemate, which in tum is twice as effective as the S or dextro-isomer (Snyder
et al., 1974). There are many problems involved in any attempt to interrelate
potencies of two compounds such as DOM (with a narrow range of benign
effectiveness, 2-5 mg, and above this level the production of a dysphoric and
LSD-like state rather abruptly) and DOET (which shows a largely doseindependent subjective intoxication syndrome over the same range, i.e., up
to 4 mg). No hallucinogenic effects have been reported with the oral use of
DOET, but then there are no reports of oral use exceeding 4.0 mg.
Comparing the effective threshold levels of the two drugs (at which level the
induced effects are largely indistinguishable both in nature and in duration)
it would appear that DOET is slightly more potent and should be considered
as having some one hundred times the potency of mescaline. This would
arbitrarily place its effective dose (of the racemate) at about 4.0 mg.
310
The metabolism of DOET has been studied. In the rat, the principal site
of oxidation appears to be the ethyl group in the 4-position (Ro, 1975) with
approximately half of the administered dose being excreted as the betahydroxymethyl analog, and some 18% as the 4-carboxymethyl oxidation
product (Tanseyet al., 1975). These were excreted, in part, in conjugated
form. Some 14% of the administered amine was excreted unchanged. In
human studies there was between 10 and 40% of the free base excreted in
unchanged form, with the greatest concentration occurring in the 3-6 hr
collection period (Snyder et al., 1969). Limited studies on the kinetics of body
distribution of DOET (Ro, 1975) indicate that it is taken up (in the rat) into
tissue more rapidly and to a higher level than is DOM, but that DOM is
retained longer and is more slowly metabolized. The biochemical and
behavioral animal studies of DOET and the related homologs discussed here
are entered below DOAM (77).
3.4.9. 2,5 -Dimethoxy-4-propylphenylisopropylamine

The immediate homolog of DOET, by the elongation of the alkyl chain
at the aromatic 4-position, is 2,5-dimethoxy-4-phenylisopropylamine (75,
DOPR). In analogy with DOET, this compound was initially encoded DOP,
and the last letter added at a later time. A potential ambiguity exists in the
literature with the use of this code. The term DOP was employed in a study
of a compound thought to be the 4-isopropyl isomer (Kulkarni, 1973). It is
now known that the compound employed in this study was in fact the npropyl isomer, and that therefore both DOP and DOPR in the literature
refer to compound (75). Recently the isopropyl isomer has been prepared
(Aldous et al., 1974) and in animal studies appears to have reduced potency.
Nothing is known of its human psychopharmacology.
DOPR (75), as with the two higher homologs (76) and (77), has not been
pharmacologically characterized to the same extent as have the methyl and
ethyl counterparts (69) and (74). The rat behavioral studies of Morin et al.
(1975) as well as the biochemical studies of Shulgin and Dyer (1975) both
indicate that the propyl substitution should produce the greatest potency of
the entire series of 4-alkyl substituted 2,5-dimethoxyphenylisopropylamines
(see Fig. 1). In humans, threshold effects are regularly noted in orally
administered doses of less than 1 mg, but the effects observed with doses in
the 1-2 mg area are generally less extreme than those noted with equal dose
a
3.0
2.0
1.0
100
80
80
60
60
40
40
20
20
012345
120
100
311
012345
012345
rlW1BER OF CARBON ATOr4S
FIG. l. Comparison of the in vitro and the in vivo assay of a homologous series of
psychotomimetics (4-alkyl-2,5-dimethoxyphenylisopropylamine). (a) Disruption of rat behavior. Response to control saline/response to test compound; confidence limits 3% (see
Morin et ai., 1975). (b) Serotonin agonist effectiveness. ED 25 of mescaline/ED25 of test
compound; confidence limits from reference (see Shulgin and Dyer, 1975). (c) Human
psychotomimetic effectiveness. Effective dose of mescaline/effective dose of test compound;
confidence limits 25% (see Shulgin and Dyer, 1975).
level administrations of DOET in control experiments. This suggests that the

drug is less effective and should be quantitatively equated with DOM
(Shulgin and Dyer, 1975) (see Fig. 1). There is not sufficient information
available to determine if the effects of DOPR should qualitatively be classified
with DOM or with DOET.
3.4.10. 2,5 -Dimethoxy-4-butylphenylisopropylamine

The four-carbon homolog in this series, 2,5-dimethoxy-4-butylphenylisopropylamine (76, DOBU), appears in the animal behavior tests (see DOAM,
CH3
-7"X J Q O NH2
~ I
CH 3CH 2CH 2C 2
CH 3
OCH 3
(76) DOBU
77) to be a highly potent compound, although somewhat less active than the
three-carbon counterpart. The compound shows clear threshold effects in
man in the 1-2 mg area, acutely and orally, and is effective at dosage levels
slightly more than twice those required for DOM (69). It has been assigned
(Shulgin and Dyer, 1975) a relative potency 36 times that of mescaline,
although the qualitative nature has not yet been adequately investigated. As
312
with the 4-propyl countei part (75) there seems to be a sympathomimetic

stimulatory component associated with the effective dosage.
3.4.11. 2,5-Dimethoxy-4-amylphenylisopropylamine
The last member of this series of homologs is 2,5-dimethoxy-4-amylphenylisopropylamine (77, DOAM). As will be seen below, it has been
studied both in behavioral tests and in biochemical systems, and in both it

appears to be of substantially reduced potency compared with its two
immediately lower homologs. limited human evaluation has provided the
same results. Threshold effects are noticed at levels of 5-10 mg orally, and
the compound has a stated effective potency of only 10 times that of
mescaline (Shulgin and Dyer, 1975). No qualitative description of its intoxication syndrome at effective levels can be made from the limited experimental
data available.
As mentioned above, throughout this series both in vivo and in vitro
assays have been surprisingly consistent and in good agreement with the
reported human values of activity. In the modified Discrimination Sidman
Avoidance Schedule animal behavioral test (which was mentioned earlier)
Morin et al. (1975) have found the propyl homolog (75) to be the most
effective compound in disrupting behavior, followed closely by the n-butyl
homolog (76). The 4-methyl and 4-ethyl compounds (DOM, 69 and DOET,
74) were intermediate in effectiveness, and the 4-H and the 4-n-amyl
compounds (2,5-DMA, 32, and DOAM, 77) were ineffective. In an in vitro
assay for serotonin agonism, these same compounds were ranked in almost
precisely the same way (Shulgin and Dyer, 1975). The n-propyl homolog was
the most effective agonist, with the other homologs dropping away on either
side. The human effectiveness of this family is seen to be greatest at the ethyl
compound, with the methyl (DOM, 69) and propyl (DOPR, 75) being
equipotent within experimental variability; the remaining isomers are significantly less potent as psychotomimetics. These data are shown in Fig. 1.
3.4.12. 6-(2-Aminoporpyl)-2,2-dimethyl-5-methoxy-2,3-dihydrofuran
In a synthetic study of 4-alkyl-substituted 2,5-dimethoxyphenylisopropylamines, a number of compounds were prepared in which the 4-alkyl and the
5-alkoxy groups were tied together in a furan or a pyran ring, thus showing
313
a passing resemblance to the heterocyclic structure of tetrahydrocannabinol

(Shulgin, 1971). The title compound (78) has been assayed as a psychotomi-
(78)
metic and is at least one order of magnitude less potent than the isosteric
analogs DOET (74) and DOPR (75). There are no detectable effects noted
following oral administration in excess of 10 mg, acutely.
3.5. Halo- or Sulfur-Substituted Phenylisopropylamines

The last subdivision of the variously substituted phenylisopropylamine
psychotomimetics contains those compounds, largely with methoxyl groups
which are substituted in addition with atoms other than carbon or oxygen.
The introduction of the halogen into the phenylisopropylamine nucleus
has generally been inspired by an effort to interfere with metabolic attack. In
the case of the simplest unsubstituted compounds such as amphetamine and
methamphetamine, there was a desire to interfere with the known oxidative
attack at the aromatic para position. It was hoped to create a molecule that
might have some of the pharmacological virtues of amphetamine (anoxia,
alerting) without the dependence problems. In the case of the more highly
substituted phenylisopropylamines, the effectiveness found to follow the
replacement of a para-methoxy group with a para-methyl group [increase in
potency comparing TMA-2 (34) with DOM (69)] might be yet further
enhanced by replacing this latter group with a metabolically refractory halide
atom. The substitution of sulfur atoms in the aromatic nucleus was made to
study the effects of isosteres (Le., the replacement of a methoxy with a
thiomethoxy group). Both lines of study have led to compounds of pharmacological interest.
3.5.1. 4-Chlorophenylisopropylamine
The simplest of the halogenated phenylisopropylamines is 4-chlorophenylisopropylamine (79, para-chloroamphetamine, 4-CA). It and the NNH2
CI
~,
(79) 4-CA
314
methyl homolog (80) are highly active compounds in experimental animals,

producing a remarkably long-lasting depletion of brain serotonin levels
(Pletscher et al., 1963) and a decrease in tryptophane hydroxylase activity
(Sanders-Bush et al., 1972).
Considerable clinical application of 4-CA has been made, and it has been
found effective as an antidepressant when used chronically at levels of 75
mg/day (van Praag et at., 1971; van Praag and Korf, 1976). There are very
few side effects noted and the drug is tolerated very well. However,
indications of raphe-nucleus degeneration (Yunger et al., 1974) and related
neurotoxicity (Harvey and McMaster, 1976) in experimental animals have
discouraged further clinical study.
An unusual aspect of 4-CA metabolism is the reported conversion of the
CI
NH2
~,
HO
NH.
~,
CI
4-CA
""
"-.,.
(79.1 )
drug to oxygen-containing products. A phenolic product was identified by

Parli and Schmidt (1975) as being 3-chloro-4-hydroxyphenylisopropylamine.
This would seem to invoke the NIH shift as an explanation for the migration
of the chloro atom. Even more remarkable is the report (Sherman and Gal,
1976) of the isolation of 3,4-dimethoxyphenylisopropylamine following the
intraventricular injection of 4-CA. This represents the formation in vivo of a
weak but accepted pressor and psychotomimetic. When the mechanism of its
formation is understood, a chemical link may be at hand tying the simpler
phenylisopropylamine stimulants to the methoxylated psychotomimetics.
There were no reports from the clinical studies of 4-CA that suggested any
psychotomimetic action.
315
3.5.2. 4-Chloro-N-methylphenylisopropylamine
The N-methyl homolog of 4-chlorophenylisopropylamine (80, parachloromethamphetamine, p-CMA, Ro 4-6861, S-33) was also found to be a
~NHCH3
CI
CH 3
(80) p-CMA
potent and long-lasting depleter of brain serotonin (Fuller et ai., 1965). It has
been compared with methamphetamine in normal subjects (Verster and van
Praag, 1970) and has been evaluated clinically in comparison with 4-CA (79)
as an antidepressant (Deniker et ai., 1971; van Praag et ai., 1971; van Praag
and Korf, 1976). Typical dosages were between 60 and 90 mg/day, administered chronically for several weeks. There appeared to be no physical or
psychic dependence developed, no cardiovascular complications, and no
sleep or appetitite problems. There was no mention made of mental
disturbances that might be considered psychotomimetic.
The alpha-alpha dimethylphenylethylamine homo logs of p-CMA have
been explored clinicaly as anoxerics. 4-Chloro-alpha-alpha-dimethylphenethylamine is used therapeutically under the name of Chlorphentermine; the
ortho-isomer is known as Clortermine.
3.5.3. 4-Bromo-N-methylphenylisopropylamine
The bromo-counterparts of the chlorophenylisopropylamine have been
studied, but have not found extensive clinical evaluation. The primary amine
4-bromophenylisopropylamine (4-bromoamphetamine) is, like the 4-chloroanalog 4-CA (79), a long-term depleter of serotonin in the brain (Fuller et ai.
(1975). The 4-fluoro analog, while still effective biochemically, is not of as
long a duration of action. The N-methyl homolog of 4-bromo-phenylisopropylamine has demanded interest from a separate point of view, however.
This compound, 4-bromo-N-methylphenylisopropylamine (81, V-Ill, p-
0&,
NHCH 3
Br
(81) V-Ill
bromomethamphetamine), has been found to give pharmacological profiles

in a large number of animal species, which are indistinguishable from those
316
shown by LSD and other psychotomimetics (Knoll et ai., 1970). Although

much of the literature appearing over the period from 1965 to 1975 refers to
(81) as a psychotomimetic, it had apparently never been clinically assayed in
man. It is now known that the compound "has no psychotomimetic effect
whatsoever in humans" (Knoll, 1974, personal communication). The high
pharmacological potency of (V-Ill) in the biochemicaty of serotonin and its
apparent enhancement of learning and memory in experimental animals
have maintained an active interest in it in the research area.
3.5.4. 4-Bromo-2,5 -dimethoxyphenylisopropylamine

The addition of methoxyl groups to the nucleus of 4-bromoamphetamine leads to compounds that have proven to be not only psychotomimetic
in man, but to be among the most potent phenylethylamine derivatives yet
reported in the scientific literature. The first of this family of compounds to
be reported was 4-bromo-2,5-dimethoxyphenylisopropylamine (82, DOB, 4CH30~NH2
M()r~_H3
OCH
Br
(82) DOB
bromo-2,5-dimethoxyamphetamine), which has the substitution pattern of so

many of the psychotomimetics discussed earlier, the 2,5-dimethoxy orientation with an additional substituent at the 4-position. DOB (82) shows an
active threshold effect at oral dosages of about 0.4 mg and exhibits its full
psychotomimetic activity over the range 0.8-2.0 mg (Shulgin et ai., 1971). At
these higher levels (up to 2 mg) there appeared
to be an increase of both intellectual and emotional stimulation, whereas
perceptual enhancement seemed not to be dose-dependent. There was an
increase in the level of fluency and attention, while maintaining full
communication capabilities. This compound is thus similar to 3,4-methylenedioxyamphetamine (MDA) except that here the subjects were more active
and had greater contact with the environment. The sense of added
significance in ordinary events and motivation towards introspection were
similar to that of the hallucinogens such as mescaline, but with a complete
lack of imagery or perceptual distortion.
Studies of DOB in rats in a conditioned avoidance response (Barfknecht

and Nichols, 1971) showed it to be the most active (in a mescaline-like
profile) of a number of positional isomers of bromo-methoxy phenylisopropylamines. In a study of the optical isomers, the R form (the psychotomimetically active absolute configuration found with DOM) had greater potency
than the S isomer, but these observations were made very near to the lethal
level (Benington et ai., 1973). A number of studies have been made of the
317
human body distribution and clearance kinetics of DOB, employing the drug
labeled with radioactive bromine (Kalbhen et at., 1974; Sargent et at.,
1975a,b). The radioisotope shows an accumulation in human lung tissue and
brain and is being evaluated as a potential diagnostic tool. The R isomer was
compared directly with the racemate, and there were no significant differences reported in their distribution or kinetics.
3.5.5. 5 -Bromo-2, 4-dimethoxyphenylisopropylamine

A positional isomer of DOB (82) is which the bromo atom has been
relocated to the aromatic 5-position and the hydroquinone-like orientation of
the oxygens disrupted has been synthesized and evaluated in man as a
psychotomimetic (Sepulveda et at., 1972). The compound 5-bromo-2,4dimethoxyphenylisopropylamine (83) shows some cardiovascular activity
even below 70 mg (orally, acutely, in human subjects) and generates an

intoxication resembling that of MDA at dosages of 100 mg as the hydrochloride. There is an onset delay of about 1 hr, and the duration of action is
about 6 hr. The metabolism of the compound is at present completely
unstudied.
3.5.6. 2 -Bromo-4,5 -methylenedioxyphenylisopropylamine

A second brominated aromatic ether studied by the Cassels groups
(Sepulveda et al., 1972) is 2-bromo-4,5-methylenedioxyphenylisopropylamine
(84). This is the bromination product of MDA (48) and can be considered
the bromo analog of MMDA-2 (53). At dosages of 350 mg orally in man
(weight-equivalent to those needed of mescaline, but slightly more potent
with consideration of molarity) there was the generation of amphetamine-like
c~~YI0u:H2
'\O~Br
CH
(84)
responses, indicating central activity but with no detail reported to indicate

that this activity was psychotomimetic in nature. This can only be resolved
with additional clinical study.
318
3.5.7. 4-Bromo-3,5-dimethoxyphenylisopropylamine
4-Bromo-3,5-dimethoxyphenylisopropylamine (85) has been prepared
(Barfknecht and Nichols, 1971) and found to be centrally active in man
CHao)O&NH2
Br
"""" I
CHa
OCHa
(85)
(Nichols et al., 1977). Threshold effects are first noted in the dose range 3-6
mg, and at 10 mg orally there are indications of both mental (psychotomimetic?) and physical (central analgesia) effects. The action of the drug
appears to be complex, and a single assignment of its character will have to
await additional studies.
A number of additional brominated methoxylated phenylisopropylamines are known chemically, but have not as yet been studied in man. 2Bromo-5-methoxyphenylisopropylamine and 2-bromo-4,5-dimethoxypheny1isopropylamine have been found to be inactive in the rat response screening
(Barfknecht and Nichols, 1971), which showed DOB (82) to be highly potent.
The study of the fluorescence of several isomers (Antun et at., 1971) has
been correlated to animal activity. In a chemical study of the bromination
products obtained direcdy from the several known dimethoxyphenylisopropylamines, Bailey et al. (1976) have prepared a number of heretofore
unknown isomers. The listing of the currendy known brominated methoxylated phenylisopropylamines is presented in Table 5 with appropriate
references.
3.5.8. 4-1odo-2 ,5-dimethoxyphenylisopropylamine

Unlike the bromination products of the methoxylated phenylisopropylamines, the analogs that contain iodine in the aromatic nucleus must be
made indirecdy. The only iodinated analog known to be psychotomimetic
(and also the only iodinated organic molecule known to be psychotomimetic)
is 4-iodo-2,5-dimethoxyphenylisopropylamine (86, DOl, 4-iodo-2,5-di-
x:a:.
CHaO
NHa
OCHa
(86) DOl
319
TABLE 5
Brominated Alkoxylated Phenylisopropylamines
VY.
I
~
4::::::""
NH.
CHa
Rz
Ra
R4
Disubstituted
Br
Rs
Ra
Barfknecht and Nicholas (1971)

Barfknecht and Nichols (1971)
OCHa
Br
OCH~
Trisubstituted
Br
OCHa
Br
Br
OCHs
OCHa
OCHa
Br
OCH 3
Br
Br
Br
OCHs
OCHa
Tetrasubstituted
Br
OCHa
OCHa
Br
OCHa
OCHa
OCHa
O-CHr-O
Br
OCHs
Br
OCHa
Br
OCHa
OCHa
OCHa
O-CHr-O
OCHs
Br
OCHa
Reference
Bailey et al. (1976)

Sepulveda et al. (1972)
Shulgin et al. (1971)
Sepulveda et al. (1972)
OCHa Bailey et al. (1976)
Cassels (1976, personal communication)
Br
Br
methoxyamphetamine). It has been prepared from the 4-amino analog by the

Sandmeyer reaction (with the aliphatic amine function blocked by the acetyl
group) (Coutts and Malicky, 1973) or from the 4-hydrogen analog by the
action of iodine monochloride (with the amine function blocked with the
phthalic acid ir.:ide group) (Braun et al., 1977). The compound has been
prepared with radioisotopic iodine (both 1311 and 123J; Braun et al., 1977) and
its distribution studied in experimental animals (Sargent et al., 1977). Human
clinical trials have shown the compound to have both the potency and the
duration of action of the brominated counterpart (DOB, 82).
The corresponding chloro analog (4-chloro-2,5-dimethoxyphenylisopropylamine) has been synthesized (Coutts and Malicky, 1973) and found to be
equivalent to both the bromo (82) and the methyl (69) analogs, but it has not
been reported to be psychotomimetic in man. The 4-fluoro analog has not
been synthesized.
320
3.5.9. 4-Thiomethyl-2 ,5-dimethoxyphenylisopropylamine

Sulfur analogs of several of the indolic psychotomimetics have been
synthesized and pharmacologically investigated (of DMT, Harrison et at.,
1974; of 5-methoxy-DMT, Bosin et at., 1976; of portions of the LSD
molecule, Campaigne and Knapp, 1970). A recent report has described the
preparation of the 4-thio analog of TMA-2 (Nichols and Shulgin, 1976). This
base, 4-thiomethoxy-2,5-dimethoxyphenylisopropylamine (87, para-DOT) is
CH 3 0
NH2
XX:&'
CH 3 S
OCH 3
(87) para-DOT
the only one of the three possible positional isomers found to be psychotomimetic. In man, the potency of 87 lies intermediate to the two analogs, which
have a methoxy group (TMA-2, 34) or a methyl group (DOM, 69) at the 4position instead of the methyl-thio group (Shulgin and Nichols, 1977). Its
threshold and active levels in normal experimental subjects lie between 5 and
15 mg, administered orally. The chronology of the induced intoxication
resembles TMA-2 (34). Initial effects are noted at just over one hour
following administration with the maximum effect reached at about the end
of the second hour. The plateau is maintained for about 1.5-2 additional
hours, and are completely dissipated by the end of the sixth hour. Qualitatively there were few visual effects reported with para-DOT (87), but in other
aspects many of the conceptual and interpretively disruptive aspects of LSD
intoxication were induced. With dosed eyes, there was an easy visualization
of hypnogogic images, which, although not of voluntary origin as to subject
matter, could be terminated at will.
There are two positional isomers of para-DOT: one has the sulfur in the
2-position of the aromatic ring (2-thiomethyl-4,5-dimethoxyphenylisopropylamine, ortho-DOT) and the other in the 3- (or 5-) position (5-thiomethyl2,4-dimethoxyphenylisopropylamine, meta-DOT). Both compounds have
been described chemically Uacob et at., 1977) but neither has yet been
reported as being psychotomimetic.
3.5.10. 4- Thioethyl-2,5 -dimethoxyphenylisopropylamine

A number of homologs of para-DOT (87) have been synthesized,
containing a variety of alkyl and aryl groups on the sulfur atom in the 4position (Shulgin, 1977, unpublished data). The immediate ethyl homolog 4thioethyl-2,5-dimethoxyphenylisopropylamine, 88) is about twice as potent as
321
the S-methyl counterpart 87, but has similar chronological and qualitative
properties. Threshold effects are apparent at 2 mg orally, and at effective
dosages of about 5 mg there is the first appearance of central effects at
approximately 0.5 hr following administration. Quantitatively the intoxicative
state develops over the following 1.5 hr. The psychological syndrome is
largely dissipated after 8 hr, but some residual physical stimulation can
persist and has interfered with sleep in some subjects. The body kinetics and
metabolic fate of (88) have not been studied.
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WEINGARTNER, H., SNYDER, S. H., and FAILLACE, L. A., 1971, DOM (STP). A new
hallucinogenic drug: Specific perceptual changes,]. Clin. Pharmacol. 11: 103-111.
WEINKAM, R.]., GAL,]., CALLERY, P., and CASTAGNOLI, N., JR., 1976, Application of chemical
ionization mass spectrometry to the study of stereoselective in vitro metabolism of 1-(2,5dimethoxy-4-methylphenyl)-2-aminopropane, Anal. Chern. 48:203-209.
WENNER, W., 1951, Hydroxyphenylisopropylamines containing nuclear methyl groups,].
Org. Chern. 16:457-460.
WINTER, ]. C., 1973, A comparison of the stimulus properties of mescaline and 2,3,4trimethoxyphenylethylamine,]. Pharm. Pharmacol. 185: 10 1-107.
YENSEN, R., DILEO, F. B., RHEAD, ]. C., RICHARDS, W. A., SOSKIN, R. A., TUREK, B., and
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YUNGER, L. M., McMASTER, S. E., and HARVEY, ]. A., 1974, Neurotoxic effects of pchloroamphetamine and 5-hydroxyindoleacetic acid in brain, Pharmacologist 16:244.
ZWEIG, ]. S., and CASTAGNOLI, N., JR., 1974, Chemical conversion of the psychotomimetic
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1:359-371.
7
DRUG METABOLISM: REVIEW OF
PRINCIPLES AND THE FATE OF ONERING PSYCHOTOMIMETICS
Neal Castagnoli, Jr.
Interest in the metabolic fate of compounds foreign to the body (xenobiotics)

has intensified dramatically during the past decade. Research efforts are
derived today from a variety of disciplines and any attempt to review the
entire field is likely to require a "team of experts." Fortunately, a number of
books that cover various aspects of drug metabolism have appeared recently.
The most chemically oriented is the Testa and Jenner monograph (1976),
which provides an excellent description of biotransformation processes with
much fine molecular detail. The Chemical Society, London, publishes a good
review series entitled "Foreign Compound Metabolism in Mammals" (Hathway, 1975). A bibliographic survey, "The Fate of Drugs in the Organism"
(Hirtz, 1976), has recorded 9000 references (through about 1972) dealing
with various aspects of drug metabolism. Two textbook-type publications
(Goldstein et al., 1974; La Du et al., 1971) are mainly concerned with the fate
and mechanism of action of small molecules. The more traditional textbooks
in medicinal chemistry contain good chapters on drug metabolism (McMahon, 1970; Daniels and Jorgensen, 1977). Biologically oriented material
will be found in the series "Concepts in Biochemical Pharmacology," particularly Part 2 (Brodie and Gillette, 1971) and Part 3 (Gillette and Mitchell,
1975). The publications of the proceedings of a number of symposia provide
first-rate discussions of specific topics. Two symposium publications focus on
in vitro aspects of microsomal oxidations (Estabrook et al., 1973a; Gillette et
al., 1969). Applications of mass spectrometry techniques to problems in drug
metabolism are compiled in two volumes (Frigerio and Castagnoli, 1974,
1976). Biological aspects of drug hydroxylation (Shugar, 1969), the metaboNeal Castagnoli, Jr. Department of Pharmaceutical Chemistry, School of Pharmacy,
University of California, San Francisco, California.
335
336
NEAL CASTAGNOLI,jR.
lism of organic molecules contammg nitrogen (Bridges et al., 1972),

and drug metabolism in man (Vessell, 1971) are additional topics of recent
symposia.
Research publications and review articles on drug metabolism will be
found in numerous journals. In recent years the following new journals in
this area have appeared: Drug Metabolism and Disposition, Chemico-Biological
Interactions, Xenobiotica, European Journal of Drug Metabolism and Pharmacokinetics, Drug Metabolism Reviews, and Journal of Pharmacokinetics and Biopharmaceutics. These journals join an already impressive list where drug
metabolism articles appear. Some of the journals where drug metabolism
articles are frequently published include the following: Biochemical Pharmacology, Journal if' Biological Chemistry, Science, Nature, Biochemistry Journal,
Journal if' Pharmacology and Experimental Therapeutics, Journal if'Medicinal
Chemistry, Molecular Pharmacology, Journal if' Pharmaceutical Sciences, Journal
of Pharmacy and Pharmacology, Life Sciences, European Journal of Pharmacology, Biochimica-Biophysica Acta, Pharmacology Reviews, Proceedings of the
National Academy if' Science, British Journal of Pharmacology, Experientia,
Pharmacology, Annual Review of Pharmacology, Annals of the New York
Academy of Sciences, Arzneimittel-Forschung.
An important development in the area of foreign compound metabolism has been the recognition that the biotransformations of small molecules
do not necessarily lead to metabolites that are less active than the parent
compound. Hydroxylated metabolites, for example, of THC (Gill et al.,
1973), glutethimide (Aboul-Enein et al., 1975), and diazepam (Schwartz and
Postma, 1968), contribute to the pharmacological effects of the parent drugs.
The anticancer agent cyclophosphamide must be metabolically activated by
carbon hydroxylation before it can exert its therapeutic effects (Takamizawa
et al., 1975; Colvin et al., 1973). The subject of active metabolites was recently
reviewed by Garattini et al. (1975). In addition to the formation of pharmacologically active metabolites, many compounds are biotransformed to highly
chemically reactive species that covalently bond to macromolecules, causing
toxic reactions (Mitchell et al., 1975; Gillette et al., 1974; Gillette, 1974)
including malignant transformations (Weisburger and Weisburger, 1973;
Miller, 1970; Miller and Miller, 1966).
Thus the traditional view that biotransformation processes result in the
"detoxification" of foreign substances must be modified to take into account
the large body of knowledge relating to the formation of toxic metabolites.
The present chapter, which is concerned with the metabolic fate of the onering psychotomimetics, will attempt to evaluate the significance of biotransformation processes with regard to the mechanisms of action of these
compounds. Particular attention is given to the possible formation of
chemically reactive metabolites that may contribute to the neurotoxicity of
the parent drug. In order to facilitate this discussion, a brief description of
the basic principles of biotransformation processes is presented, which is
followed by a detailed discussion of the metabolism of amphetamine,
DRUG METABOLISM: REVIEW OF PRINCIPLES
337
mescaline, and aryl-substituted I-phenyl-2-aminopropanes. Chapter 9 provides a detailed description of the psychopharmacological properties of these
compounds.
l. PRINCIPLES OF DRUG METABOLISM

Unlike many enzyme-catalyzed reactions, the enzyme systems responsible for the majority of foreign compound transformations are relatively
nonspecific. In general, one of the basic requirements for good substrate
properties is lipophilicity. Within a series of structurally related molecules,
the more lipophilic molecules will tend to be more extensively metabolized
(Hansch, 1972).
The relationship of lipophilicity to metabolic susceptibility is due at least
in part to the lipoidal characteristics of the membranes that house the
responsible enzyme systems. Although extrahepatic sites of drug metabolism
are well documented (Dajani et at., 1975; Estabrook et at., 1973b; Testa and
Jenner, 1976, pp. 419-454), the liver is the major organ of metabolism.
Primarily through the elegant early structural work of Claude (1969) and
later by Fouts (1971) among others and the pioneering metabolic studies by
the NIH group (Brodie et at., 1955, 1958), it was learned that the drug
metabolizing lipoidal microsomal fraction isolated from liver homogenates in
the lOO,OOOg pellet was derived from the endoplasmic reticulum of the intact
hepatocyte. In order to undergo metabolism by the enzymes embedded in
the endoplasmic reticulum (or in the microsomes), a drug must partition
from the aqueous cytosol (or incubation medium) into the lipoidal environment of the endoplasmic reticulum (microsomes). Although there are a
number of important soluble enzymes that act on foreign compounds [e.g.,
carbonyl oxido-reductases (Bachur, 1976; Hutson, 1975a; McMahon, 1971;
Gillette, 1971; Leibman, 1971) and hydrolytic enzymes (Testa and Jenner,
1976; Hutson, 1975b; La Du and Shady, 1971)], the majority of metabolic
conversions is effected by the complex of membrane-bound enzyme systems
located in the endoplasmic reticulum.
Extensive chemical, biochemical, and pharmacological investigations
have focused on the characterization of the foreign compound metabolizing
enzyme systems of the liver. Efforts to solubilize and purify these enzymes
have been partially successful (Sato et at., 1973; Cooper et at., 1973; Fujita
and Mannering, 1973; Bleecker et at., 1973; Comai and Gaylor, 1973; Lu et
at., 1973) and one can anticipate that the next few years will see significant
advances in the characterization of the enzymes and the molecular mechanisms involved in drug metabolism. In most of the in vitro studies reviewed
below relatively crude liver preparations have been employed. Even so, a
large body of information has accumulated. The discussion that follows
focuses on those principles of drug metabolism that will help the reader to
338
NEAL CASTAGNOLI,jR.
better appreciate the events associated with the metabolism of highly lipid
soluble drugs, which include all of the psychotomimetic agents to be
considered in Section 2.
In general, biotransformation reactions may be considered under three
headings: (1) oxidation-reduction reactions, (2) hydrolytic reactions, and (3)
conjugation reactions. In terms of structural alterations that may be associated with the biological properties of psychotomimetics, the oxidative transformations reviewed below are of special interest.
Metabolic oxidations of foreign compounds are catalyzed primarily by
the so-called mixed-function oxidase (or mono-oxygenase) enzyme complex
of the liver endoplasmic reticulum (Coon et at., 1973; Estabrook et at.,
1973c). Fundamentally, the oxidations follow the stoichiometry given by
Eq.(1)
R-H
+ NADPH + O 2 + H+ = ROH + NADP+ + H 2 0
(1)
where R-H is the substrate and NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate. The substrate undergoes a twoelectron oxidation, while molecular oxygen suffers a four-electron reduction.
Studies with 1'02 (Mason, 1957) established that one atom of O 2 becomes
attached to the substrate while the second atom is found in the water formed
in the reaction-hence the name "mixed-function" oxidase. The mechanistic
details whereby molecular oxygen becomes "activated" remain incompletely
understood. The key macromolecule associated with the activated oxygen is a
protoporphyrin IX iron-containing protein (similar to the oxygen-carrying
blood pigment hemoglobin) known as cytochrome P450 (Omura and Sato,
1964).
A simplified depiction of the sequence of events thought to be associated
with the cytochrome P450 electron transport system is given in Fig. 1. The
PtstRH
6;
+-+
Ptst RH
62~
pt.~
RH
O2
FIG. 1. Simplified depiction of the electron transport system associated with the cytochromeP <so-catalyzed oxidation of foreign compounds.
339
sequence of events is initiated by the binding of drug, RH, to the oxidized

(+3) form of P450 to give p15~RH. A NADPH-dependent flavoprotein,
NADPH-cytochrome Pt5~ reductase, transfers an electron to form P15~RH,
which then may bind a mole of O 2 to form a species that is depicted as
O 2 P15~RH. A second electron, perhaps derived from the second reducing equivalent of NADPH, then leads to the formation of the oxidized drug
ROH and a mole of water. As the details of this cycle become better defined
it will be possible to predict more rationally the metabolic fate of foreign
compounds and to appreciate more fully the consequences of the interactions of substrates (and metabolites) with the mixed-function oxidase system.
These interactions can lead to enhanced enzyme activity (Estabrook et at.,
1973d; Gram et at., 1967; Gelboin, 1971; Vesell et at., 1976; Michalopoulos et
at., 1976; Gielen and Nebert, 1971), inhibition of enzyme activity (Estabrook
et at., 1973e; Mannering, 1971; Bobik et at., 1975; Cooper et at., 1954; Fouts
and Brodie, 1955, 1956), and even destruction of the P450 system (De Matteis,
1973; Levin et at., 1973; Rentsch and Johnston, 1976).
Particularly important with regard to understanding the mechanisms of
drug metabolism is the molecular nature of the P45o-activated oxygen. A
variety of chemical studies have attempted to model mixed-function oxidase
reactions but with only marginal success (Ullrich and Staudinger, 1969, 1971;
Hamilton, 1964; Brodie et at., 1954; Groves and Van der Puy, 1974; Chang
and Dolphin, 1976). Various oxidation states of oxygen including the
hydroxyl radical He): (Locke and Mayer, 1974), a potential hydroxonium
ion HQ: + (Jerina et at., 1971), oxene :<) (Daly et at., 1972), and superoxide
radical anion O2- (Moro-oka and Foote, 1976) have been proposed as species
that may approximate P45o-activated oxygen. Since the P450 -bound oxygen is
almost certainly ligated to the iron of the porphyrin molecule (Lipscomb and
Gunsalus, 1973), model oxidations that are not dependent on an ironoxygen complex must be viewed with caution.
Whatever the nature of the P45o-activated oxygen system, it is capable of
carrying out a wide variety of oxidations on an essentially infinite number of
lipid-soluble substrates. The compilation of reaction types that follows will
provide the reader with some appreciation of the broad scope of biotransformations attributed to the cytochrome P450 mixed-function oxidase system.
1.1. Aromatic Hydroxylation

In a formal sense, this reaction leads to the substitution of an aromatic
hydrogen atom with a hydroxyl group as illustrated in reaction (2) with the
conversion of naphthalene (1) to a-naphthol (2). Perhaps more is known
about the mechanism of this conversion than any other mixed-function
oxidase-catalyzed reaction. Two important aspects of aromatic hydroxylation
reactions are that molecular oxygen (02) is the source of the newly introduced
phenolic oxygen atom (Mason, 1957) and that the reaction in most instances
340
NEAL CASTAGNOLI,jR.
proceeds with a migration to an adjacent carbon atom of the proton located

at the carbon atom bearing the hydroxy group-the so-called NIH shift
Gerina and Daly, 1974; Boyd et al., 1972; Kasperek and Bruice, 1972). The
reaction pathway is depicted in reaction (3) with the deuterium(D)-labeled
substrate naphthalene-l-d(3).
(2)
The first step in the overall conversion is the oxidation of 3 to the arene
oxide 4 Gerina et al., 1970), which presumably via the protonated ringopened species 5 undergoes the hydride (deuteride in the case of 5) shift to
the eneone 6. The direction of ring opening in general will be determined by
the stability of the resultant carbonium ion. Due to the greater C-D vs C-H
bond energy (Wiberg, 1955), intermediate 6 preferentially loses a proton
instead of a deuteron to yield the final product 7.
D
o)
::::::,...
#'
r0-:;?'
-+
:;
~ I
H+
------+
~~
-+~D-+
(3)
~
6
An appreciation of this pathway has had far-reaching significance in

leading to an understanding of the molecular basis of polycyclic aromatic
hydrocarbon toxicity and carcinogenicity (Daly et al., 1972), which very likely
are associated with covalent bonding of the chemically reactive (Harvey et al.,
1975; Keller and Heidelberger, 1976; Beland and Harvey, 1976) arene oxide
(illustrated by 4) to nucleic acids (Alexanderov et al., 1976; Weinstein et al.,
1976; Grover and Sims, 1973). Arene oxide metabolites of benzo(a)pyrene
(Grover et al., 1972; Kinoshita et al., 1973) and related carcinogenic aromatic
hydrocarbons (Sims et al., 1973; Grover et al., 1971, 1974; Grover, 1974;
Selkirk et al., 1971) have been detected. The evidence supports the concept
that these electron-deficient, highly chemically reactive species (sometimes
classified as proximate carcinogens) react with nucleophilic functionalities of
macromolecules to cause structural perturbations that are responsible for the
341
malignant transformations and cytotoxicity associated with the parent hydrocarbons (Miller and Miller, 1966; Heidelberger and Iype, 1967).
In addition to undergoing spontaneous rearrangement to phenolic
products and reactions with macromolecules, arene oxides may be attacked
by water, a reaction catalyzed by a microsomal epoxide hydrase (Oesch,
1973; Oesch et at., 1974; Jerina et at., 1970) to form a dihydrodiol. The trans1,2-dihydrodiol 8, for example, has been characterized as a metabolite of
naphthalene (Oesch et at., 1971; Holtzman et at., 1967). A third reaction
pathway available to arene oxides is conjugation with glutathione (Hutson,
1975c), which after dehydration and modification of the side chain leads to
the mercapturic acid 9 Gerina et at., 1970; Boyland, 1962).
A wide variety of aromatic-containing drugs also has been shown to

follow the arene oxide pathway (Horning et at., 1976). The metabolic
formation of such chemically reactive intermediates should prove of great
interest in terms of the toxicology and pharmacology of clinically useful
drugs .
.l.2. Aliphatic Epoxidations

Somewhat related to arene oxide formation is the formation of epoxides
(11) from olefins (10). This oxidation, which is illustrated in reaction (4), is
responsible for an important step in the biosynthesis of cholesterol, namely,
the conversion of squalene to squalene-l,2-epoxide. Although not a P450catalyzed reaction, this is a typical mixed-function oxidase system, which
requires molecular oxygen and NADPH (Ono and Bloch, 1975). Epoxidations of drugs include carbamazepine (Frigerio et at., 1972), protriptyline
(Sisenwine et at., 1970; Hucker et at., 1974), cyproheptadine (Frigerio et at.,
1976), cyclobenzaprine (Belvedere et at., 1975), tetrahydrocannabinol (Mechoulam et at., 1972) and diethylstilbesterol (Metzler, 1976). Epoxides are often
converted to 1,2-glycols 12 (Maynert et at., 1970).
OH OH
-+
"I
1/
/c-c",
12
-+
conjugates
(4)
342
NEAL CASTAGNOLI,jR.
1.3. Allylic and Related Oxidations

A number of centrally active compounds contain allylic groups 13 that
are susceptible to mixed-function oxidation to the corresponding allylic
alcohols 14. Pentazocine (Pittman, 1970; Pittman et ai., 1969), aI-tetrahydrocannabinol (Mechoulam et ai., 1976), and hexobarbital (Bush and Weller,
1972; Kupfer and Rosenfeld, 1973) are examples of eNS-active drugs that
undergo allylic oxidation. Reaction (5) illustrates the oxidation of an allylic
methyl group together with the possible subsequent oxidations of the
carbinol 14 to the corresponding aldehyde 15 and carboxylic acid 16.
Although microsomal preparations can oxidize some alcohols (Orme-Johnson and Ziegler, 1965) it is generally believed that in vivo oxidations of
alcohols are achieved mainly by the soluble enzyme alcohol dehydrogenase
(Theorell, 1967). Similarly, aldehydes are converted to the polar (ionizable)
carboxylic acids by a soluble aldehyde oxidase (Rajagopalan et ai., 1962) or
aldehyde dehydrogenase (Racker, 1949).
allylic methyl
!
""
/CH a
/C=C",
------+
(5)
15
In an analogous fashion [ reaction (6)], methyl groups attached to an

aromatic moiety, e.g., 17, may undergo a sequence of three two-electron
oxidations to form the corresponding alcohols 18, aldehydes 19, and
carboxylic acids 20 (Parke, 1968). The process is often referred to as benzylic
oxidation. In the event that the benzylic carbon atom is substituted, such as in
ethylbenzene (21), the compound undergoes a four-electron oxidation
[reaction (7)] via the carbinol 22 to the ketone 23 (McMahon et ai., 1969b; EI
a :1 a a:1
CH
'
->
17
~H'DH
18
21
CHO
->
<2
er
19
CH
22
(6)
20
OH
CHa
CODH
'
<2
ct'CH'
23
(7)
343
Masry et at., 1956; Smith et at., 1954). Further oxidation of the carbonyl
group of 23 would involve a high-energy process leading to carbon-carbon
bond cleavage, a conversion that apparently occurs infrequently as a mixedfunction oxidase process (see the section on amphetamine metabolism for an
important exception to this generalization).
A special case of benzylic hydroxylation is the conversion of dopamine
(24) to norepinephrine (25) by the membrane-bound enzyme dopamine-~
hydroxylase (Kaufman and Friedman, 1965). This conversion is not a P450catalyzed reaction but belongs to the general category of mixed-function
oxidations. In this case ascorbic acid (26) serves as the cofactor that provides
the additional two electrons for the overall four-electron reduction of
oxygen. The net reaction is shown in (8) with ascorbic acid undergoing
conversion to dehydroascorbic acid (27) in a fashion analogous to the
conversion of NADPH to NADP+ in the P 45o-catalyzed reactions. One of the
potentially important metabolic pathways of amphetamine involves its oxidation first to p-hydroxyamphetamine and then, via dopamine-~-hydroxylase,
to p-hydroxynorephedrine (see Section 2).
-l;;HO~
OH
HOm
/~ I
HO
24
NH2
HO
CH~H
26
H 20
+0
0
2
HO~
0)-\0
~H2 + H0-V~O
HO
25
(8)
CH 2 0H
27
A final example of hydroxylation of carbon attached to an Sp2 hybridized carbon is the conversion of amides (Kiese and Lenk, 1973) and cyclic
amides (lactams) such as glutethimide (Keberle et at., 1962, 1963) and
diazepam (Sadee et at., 1971) to carbinolamides. In some instances, cyclic
amines are converted to lactams, which subsequently undergo a-hydroxylation. For example, nicotine (28) is first oxidized to the pyrrolidinone
derivative cotinine (29), which is then hydroxylated to the carbinol amide
trans-3-hydroxycotinine (Dagne and Castagnoli, 1972).
1.4. Oxidations of Carbon Attached to Heteroatoms

Cytochrome P45o-catalyzed oxidations at carbon atoms attached to nitrogen and oxygen include the important oxidative N- and O-dealkylations. The
generally accepted pathway for N-dealkylation is illustrated in reaction (9),
344
NEAL CASTAGNOLI,jR.
which shows the initial oxidation product of amine 31 to be the carbinolamine 32. Except in rare instances (Gorrod, 1976; Sadee et ai., 1971) the HOC-N moiety is unstable and spontaneously fragments to give the products,
the dealkylated amine 33 and an aldehyde or ketone 34. A continuing
mechanistic controversy concerns the initial site of attack by the P450activated oxygen (McMahon et ai., 1969a; Faulkner and Smith, 1972; Bickel,
1969) with some authors debating the role of an N -0 intermediate (Willi and
Bickel, 1973; Beckett and Belanger, 1975a; Gorrod et ai., 1975; Beckett,
1976).
'"
CH-N /
R'/
'"
31
-+
01
R I
/
"'C...C'N
R'/
'"
32
-+
R"
/c=o
R'
34
+HN
(9)
'"
33
When 31 is a primary amine, then the conversion is described as

oxidative deamination. Monoamine oxidase (MAO) catalyzes the oxidative
deamination of a variety of monoamines including the biogenic amines
(Tipton et ai., 1976). This important enzyme is associated with the mitochondria and not the endoplasmic reticulum.
The oxidation of cyclic amines such as the conversion of nicotine (28) to
cotinine (29) shown in Fig. 2 probably proceeds by an analogous pathway via
the intermediate carbinolamine 35, which is then further oxidized by a
soluble oxidase to the lactam cotinine (McKennis et ai., 1964). Details
concerning the actual species undergoing the second two-electron oxidation,
i.e., the carbinolamine 35 or its tautomeric ring open aminoaldehyde 36, are
not known. Recent studies have revealed that compound 35 is in equilibrium
with the iminium ion 37, which can be trapped with cyanide ion to form the
a-cyanoamine 38 (Murphy, 1973). Similarly, microsomal N-demethylation [a
specific example of the conversion shown in reaction (9)] of nicotine to
nornicotine (42) in the presence of cyanide ion has been shown to lead to Ncyanomethylnornicotine (41) via the methyleniminium intermediate 40.
Compound 40 presumably is formed by ionization of the metabolically
formed carbinolamine 39 (Nguyen et ai., 1976). Evidence for oxidative
metabolic attack at C-5 of cotinine to form !:)-hydroxycotinine (43), which is in
equilibrium with the ketoamide 44, has also been reported (McKennis et ai.,
1962). Finally, norcotinine (45) has been identified as a nicotine and cotinine
metabolite (Turner, 1969). Reactions summarized in Fig. 2 describe the
important carbon oxidative pathways of nicotine and have been reviewed to
illustrate the scope of metabolic transformations involving carbon-nitrogen
bonds. The significance of these pathways with regard to the pharmacological and toxicological properties of nicotine is not known. The formation of
electron-deficient, chemically reactive species such as the iminium ions 37
and 40 opens the possibility of covalent interactions with macromolecules.
345
DRUG METABOLISM; REVIEW OF PRINCIPLES
X)
Py
CH 3
37
1
H)()
py
H)()
pY
Py
CH 2CN
NH
CH 3
36
42
O~/\
Py
'cONHCH 3
HO",/\
.ANA
Py
I
44
H 0CN
Py
41
~~
H)(-\HQ..
CH 3
CH 3
29
38
H~H H)(Ao
py
N
Py
CH 3
CH 3
43
30
45
FIG. 2. Oxidative metabolism of nicotine (28) illustrating various types of oxidative attack on
carbon attached to nitrogen (28 - 39. 28 - 35, and 29 - 43), the formation and trapping
of iminium species (37 and 40), and oxidation of carbon a to a lactam carbonyl (29 - 30).
Further studies will be required to evaluate the biological significance of

transient intermediates involved in aliphatic amine metabolism.
Oxidative 0- and S-dealkylation are additional mixed-function oxidase
transformations involving attack at carbon followed by cleavage of the
heteroatom-carbon bond. The process is illustrated by oxidative O-demethylation of an aryl methyl ether (46) in reaction (10). The conversion presumably proceeds via the hemiacetal 47, which analogous to the carbinolamine 32
spontaneously fragments to yield the phenol 48 and formaldehyde.
o
ArOCH 3
46
-+
ArO'" CH2~H
47
-+
II
ArOH + H-C-H
(10)
48
O-Demethylation of foreign compounds is not the reverse of the catecholamine-O-methyltransferase (COMT) catalyzed transmethylation pathway (Kopin, 1972). A limited number of mechanistic investigations concerning
structure-activity relationships (Schmidt et al., 1973; Beckett and Morton,
1966; McMahon, 1966) and isotope effects (Foster et al., 1974; Mitoma et al.,
1967) have been published for O-demethylation. This conversion is particu-
346
NEAL CASTAGNOLI,jR.
larly important in the metabolism of psychotomimetic amines since many

known psychotogens bear aryl O-methyl groups. Some of the potential
pharmacological consequences of oxidative O-demethylation will be considered in Section 2.
1.5. Oxidations and Reductions of Nitrogen-Containing Moieties

Extensive studies on the metabolic oxidations of aromatic amines and
amides and a variety of other nitrogen functionalities bonded to an unsaturated group link these transformations to the cytotoxic and carcinogenic
properties of the parent compounds (Weisburger and Weisburger, 1973;
Miller and Miller, 1969; Bridges et at., 1972; Shugar, 1969). For example,
carcinogens such as 2-aminonaphthalene (Radomski and Brill, 1970), related
aromatic amines (Radomski and Brill, 1971), and 2-acetylaminofluorene
(Miller et at., 1964; Thorgeirsson et at., 1973) and related polycylic Narylacetamides (Fries et at., 1973) appear to cause malignant transformations
via their metabolically formed N-oxidation products. The hepatotoxicity
(Jollow et at., 1974a; Mitchell et at., 1973a,b) and nephrotoxicity (Calder et at.,
1973) of substituted acetanilides similarly are associated with metabolic Noxidation. The covalent binding of these toxic substances to macromolecules
has been shown to depend on metabolic activation (Davis et at., 1976; Jollow
et at., 1973; Potter et at., 1973, 1974). Although the exact details of the
molecular interactions of metabolically formed aromatic N-hydroxylamines
remain obscure, it seems reasonable to invoke the formation of an ArN-OR
species in which OR is a good leaving group such as an O-sulfate or O-acetyl
derivative (Miller, 1970; Bartsch et at., 1972, Lhoest et at., 1976; King and
Phillips, 1972). Nucleophilic moieties present on macromolecules may then
form covalent bonds by displacement of the OR group of the activated
hydroxylamine causing structural alterations and cellular dysfunction. Figure
3 summarizes this postulated pathway with the secondary aromatic amine 49.
<
R'
)-N(
H
-->
o-/~
\
R'
53
<--
Q/
~
SR
o-/~
~ J N + eOR
1 52
1 50
49
SR
N'bR
R'
RSe
<------
'
Q.=N/R
H
51
FIG. 3. Metabolic N-oxidation of aromatic amines leading to reactive intermediates that have
been postulated to be responsible for cytotoxicity and carcinogenicity.
347
N-Oxidation followed by esterification generates the reactive intermediate

50, which then either via heterolytic ionization to the nitrenium ion 52
followed by nucleophilic attack by RSH or by a concerted nucleophilic attack
on 50 forms intermediate 51. Intermediate 51 will then rearrange to the
stable adduct 53.
Methemoglobinemia caused by aromatic amines is also thought to result
from an N-oxidation pathway (Kiese, 1966; Vehleke, 1973; Eyer et al., 1974).
Again, precise molecular details are incomplete although the responsible
metabolic events may be quite complex. For example, Kisese and co-worker
(Kiese and Renna, 1976) have examined the pathway involved in methemoglobin formation by N,N-dimethylaniline-N-oxide (54). Apparently compound 54 is converted to a purple dye, compound 55, which oxidizes
hemoglobin by accepting two electrons to form the leuko compound 56 as
shown in reaction (11).
54
55
<t-~-< (OU
CH 3
(11)
N(CH 3)2
56
More recently, the potential pharmacological and toxicological significance of aliphatic amine N-oxidation has received attention (Bickel and
Gigon, 1971; Gorrod, 1973a; Gorrod and Jenner, 1975; Fuller et al., 1974).
While aliphatic amine metabolic N-oxidation is well established (Beckett and
Gibson, 1975; Caldwell et al., 1975; Beckett and Shenoy, 1973; Beckett et al.,
1973a; Beckett and Belanger, 1974b,c, 1975b; Israili et al., 1973) the
subsequent fate of the chemically unstable hydroxylamines and the importance of these compounds in metabolic oxidative N-dealkylation and deamination are not thoroughly understood (Tyler et al., 1973; Beckett, 1974;
Beckett and Belanger, 1974a,b, 1976; Beckett et al., 1973a,b). Of particular
interest is the recently published evidence that N-hydroxy compounds such
as N-hydroxyamphetamine (57) form strong complexes with cytochrome P450
akOH UY-o
CH 3
CH 3
57
58
58a
348
NEAL CASTAGNOLI,jR.
(Franklin, 1974a,b,c; James and Franklin, 1975). The "difference" electronic

spectrum of cytochrome-P45o-N-hydroxyamphetamine is shown in Fig. 4a.
This difference or binding spectrum is obtained by plotting the difference in
absorptivities of the reference cell containing all components of the P450
system against the sample cell, which contains the "substrate" as well. When
NADPH (the required cofactor for the mixed-function oxidase system) is
added to both reference cell and sample cell, a new chromophor absorbing at
455 nm (Fig. 4b) is generated, which is due to the interaction of the
presumably oxidized N-hydroxy compound and cytochrome P450' The fact
that mixed-function oxidase capability is lost with the formation of the 455nm complex suggests a chemical modification of one of the essential P450
ligands (James and Franklin, 1975). The details of this complexation remain
unclear, although one author has speculated that the hydroxylamine may be
converted to a nitroso species 58, which theoretically could react with a
sulfhydryl group present at the P450 active site (Mansuy et ai., 1976). Covalent
modification of P450 could account for the observed spectral properties and
loss of enzymatic activity. The 455-nm complex also forms with the parent
primary amine although the relative rates of formation suggest that the Nhydroxy compound is an obligatory intermediate. Further characterization of
the 455-nm absorbing complex should provide interesting structural and
mechanistic information on the role of metabolic oxidations of hydroxylammes.
Amine oxidative metabolism also may involve non-P450 enzymes. Ziegler
and co-workers (Gold and Ziegler, 1973; Ziegler et ai., 1973; Ziegler and
Mitchell, 1972) have demonstrated aromatic N-hydroxylase activity from
preparations isolated from liver microsomal fractions. Although it does not
utilize cytochrome P450, this microsomal N-oxidase system appears to be a
typical mixed-function oxidase process requiring molecular oxygen and
NADPH as the second two-electron donor.
One of the exciting possibilities concerning the involvement of a nonP450 metabolizing system is that tissues with low P450 content may be capable
of transforming xenobiotics. Metabolic activation of parent amines by enzymes present in the brain conceivably could utilize non-P450 enzymes such as
the N-oxidase system characterized by Ziegler in the liver.
A final comment on the metabolism of nitrogen-containing compounds
concerns the reductive transformations of systems such as the nitroso, azo,
and nitro groups (Testa and Jenner, 1976, pp. 123-131; Gillette, 1971). A
number of toxic nitroaryl compounds are known to undergo metabolic
reduction, again by enzymes systems mainly localized in the endoplasmic
reticulum of the liver. Several reports document that reduction of these
systems is responsible for the formation of carcinogenic metabolites (Wang et
ai., 1975; Poirier and Weisburger, 1974). It is quite likely that the same
species can be formed metabolically either by oxidation of the amine or by
reduction of the corresponding nitro compound. A particularly well-documented example of the metabolic reduction of a carcinogenic agent is that of
349
0.004
0.002
I:
co
-eg
500nm
.0
<I:
<1
-0.002
-0.004
-0.006
0.3
0.2
0.1
.,
U
I:
500nm
co
.0
~
.0
<I:
<1
-0.1
-0.2
-0.3
FIG. 4. (a) Binding spectrum of N-hydroxyamphetamine obtained by recording differences

in absorptivity of a sample cell containing microsomal preparation and N-hydroxyamphetamine, while reference cell contains microsomal preparation only. (b) Same as (a) only
NADPH has been added to both sample cell and reference cell.
350
NEAL CASTAGNOLl,jR.
4-nitroquinoline-N-oxide (59). Apparently the 4-nitro group is reduced in

the liver to the 4-hydroxyamino compound 60, which after loss ofOH e then
serves as an electron-deficient species that may undergo nucleophilic attack
by DNA and other biopolymers, eventually leading to malignant transformations (Sugimura et at., 1966).
59
60
In many of the above discussions, attention has been focused on the

"metabolic activation" of foreign compounds. Obviously, a majority of the
metabolic transformations achieved by the body are designed to "detoxify"
foreign substances. A major route by which the body eliminates foreign
compounds is via excretion in the urine. The kidney in general can readily
eliminate polar compounds, but many of the substances that enter the body
are relatively nonpolar. Hence, mixed-function oxidase enzymes functionalize these substances by introducing in one way or another polar groups.
Particularly important in terms of detoxification pathways is the so-called
second phase of drug metabolism, namely, conjugation reactions (Testa and
Jenner, 1976, pp. 312-328; Dutton, 1971; Roy, 1971; Weber, 1971; Axelrod,
1971; Hutson, 1975c). Once a nonpolar molecule becomes "functionalized"
by the various oxidative, reductive, or hydrolytic transformations, then these
polar groups, such as hydroxy, amino, or carboxy, undergo conjugation
reactions to form products that are in general highly polar and readily
eliminated by the kidney. The major conjugates formed in mammalian
systems are glucuronides, sulfates, and various peptides; these are illustrated
by the general formulas 61, 62, and 63, respectively. In general co~ugates
are considerably more polar than the parent metabolites and consequently
are more readily excreted. The role of glutathione (64) in detoxification
pathways may be particularly important. Chemically reactive species including carcinogenic arene oxides may be "trapped" by glutathione to form
highly polar molecules, such as compound 65. As discussed earlier, the
glutathione adducts undergo further transformations and eventually are
excreted as "mercapturic acids," such as 66 (Boyland, 1971). Recent studies
(Mitchell et at., 1975) have shown that depletion of liver glutathione increases
the susceptibility of animals to the toxicity of compounds such as bromobenzene Oollow et at., 1974b) and acetaminophen (Mitchell et at., 1973b)
emphasizing the importance of conjugation reactions in the detoxification of
foreign and perhaps endogenous toxins.
351

H
HO
OR
62
61
~~COOH
=HSG
63
64
( CH"Cl)n
~
S~NyCH3
o
65
OH
66
2. METABOLISM OF ONE-RING PSYCHOTOMIMETICS

This section will attempt to review the relevant literature concerning the
metabolic fate of amphetamine, mescaline, and certain ring-substituted 1phenyl-2-aminopropanes. Particular attention will be given to primary oxidative metabolic events (as opposed to co~ugative pathways) since oxidative
biotransformations are more likely to reveal information of value with regard
to the mode of action of these drugs. Little or no consideration is given to the
clinical, pharmacological, toxicological, and pharmacokinetic aspects of psychotomimetics, these areas being beyond the scope of this chapter. The
discussion is limited to the one-ring psychotomimetics. The following citations may prove useful to readers interested in other well-known psychotomimetic drugs. An excellent review on the chemistry and biochemistry (including metabolism) of cannabis recently appeared (Mechoulam et al., 1976). A
recent monograph on lysergic acid diethylamide (LSD) contains a brief
chapter on its metabolism (Sankar, 1975). In addition to the fairly wellestablished aromatic oxidation pathway (Freter et al., 1957), metabolic Ndealkylation of LSD has also been reported (Niwaguchi et aI., 1974a,b). N,NDimethyltryptamine is reported to undergo metabolic hydroxylation and N-
352
NEAL CASTAGNOLI,jR.
demethylation (Szara and Axelrod, 1959). Finally, although not itself a

psychotomimetic, tryptamine may be metabolized in the brain to N-methylated compounds with psychotomimetic activity (Saavedra and Axelrod,
1972). The somewhat outdated but still interesting article by Giarman and
Freedman (1965) on the biochemical aspects of psychotomimetic drugs also
should be consulted.
2.1. Amphetamine (Benzeneethaneamine, a-Methyl)*

Of the several drugs to be considered in this section, the metabolic fate
of amphetamine has been the most extensively investigated. This drug
differs from the other compounds to be discussed in this section since its
pharmacological properties are more those of a CNS stimulant than a
psychotomimetic (Haefely et at., 1976; Innes and Nickerson, 1975; Knoll,
1970). Nevertheless, long-term abuse of amphetamine leads to a syndrome
that at times is difficult to distinguish clinically from psychotic disorders
(Connell, 1958; Ellinwood, 1971; Griffith et at., 1970; Jonsson and Gunne,
1970; Davis and Janowsky, 1973). A summary of the current views regarding
amphetamine metabolism will prove instructive in terms of evaluating the
significance of metabolite formation with regard to the pharmacological
actions of this drug and also in terms of contrasting the extensive body of
knowledge available on amphetamine with the information available on the
metabolic fate of the less well-studied but structurally related psychotomimetic agents.
Structurally amphetamine (67) is a relatively simple organic molecule,
which bears a single chiral (asymmetric) center. The absolute configuration
has been established as R(-) and S(+), structures 67a and 6Th, respectively.
CH 3
~
67a
CH 3
()XH.
67b
The pharmacological properties of amphetamine are sensitive to the configuration about the asymmetric side chain with the (S)-(;!nantiomer in general
possessing the greater CNS stimulant activity (Alles, 1939; Segal, 1975;
Taylor and Snyder, 1970; Holmes and Rutledge, 1976). Some evidence has
been published that suggests that the (R)-enantiomer may possess psychotomimetic properties (Angrist and Gershon, 1971; Angrist et at., 1971). This
issue is of some interest since the (R)-enantiomers of a number of related
psychotomimetic compounds have been shown to be more active than their
* The currently used Chemical Abstracts nomenclature for key compounds in this section will
be included to aid readers in literature searches.
353
(S)-antipodes (Shulgin, 1973; Benington et al., 1973). It should be noted that

the absolute configuration of LSD-25 at the chiral center corresponding to
that of amphetamine is also R (Leemann and Fabbri, 1959).
According to the various oxidative pathways discussed in Section 1, one
might predict a priori that amphetamine would undergo aromatic hydroxylation to p-hydroxyamphetamine (68), benzylic hydroxylation to norephedrine
(69), oxidative deamination to phenyl-2-propanone (70), and N-oxidation to
N-hydroxyamphetamine (57). All of these pathways are well documented. In
addition to these metabolites, p-hydroxynorephedrine (71), phenyl-2-propanone oxime (72), I-phenyl-2-propanol (73), benzoic acid (74), and perhaps 1phenyl-2-nitropropane (75) as well as conjugates of some of these compounds have been well characterized as in vivo and/or in vitro metabolites of
amphetamine. These pathways, which have been discussed at length in a
number of articles (Smith and Dring, 1970; Dring and Caldwell, 1973; Dring
et al., 1966, 1970; Gorrod, 1973a,b; Williams et al., 1973), are summarized in
Fig. 5. The discussion that follows will review some of the more important
findings concerning these pathways with particular regard to stereochemical
parameters, species variations, and mechanistic considerations. Readers interested in methods of analysis (Keller and Ellenbogen, 1952; Beckett and
Rowland, 1964, 1965; Beckett and Tucker, 1966), drug interactions (Lewander and jonssan, 1973; Lal et al., 1970; Consolo et al., 1967; Creaven et al.,
1970), distribution Uori and Caccia, 1974; Fuller and Hines, 1967; Cho et al.,
1975a) and the pharmacokinetics of amphetamine and metabolites (Groppetti and Costa, 1969; Beckett et al., 1969; Beckett and Rowland, 1965; Vree
et al., 1972; Rowland and Beckett, 1966) should consult the cited references.
In one of the classical studies on drug metabolism Axelrod (1955)
CH.
~,
HO
HO
68
~CH.
NH,
71
Ok,
OkOH
CH.
CH.
s:~
~
~ UlaH
69/1J
1
~
CJ en: CJ',
57
CH.
CH,
NH,
72
70
CH.
CH.
74
73
75
FIG. 5. Metabolic pathways of amphetamine (67) exclusive of conjugate formation.
354
NEAL CASTAGNOLI,jR.
examined the metabolic fate of amphetamine in liver preparations of the

rabbit. In a series of elegant experiments, he was able to establish that rabbit
liver microsomes in the presence of NADPH, O 2 , and a NADPH-generating
system convert (R)-amphetamine (67a) to phenyl-2-propanone (70). In an
attempt to rationalize the absence of deaminating activity of rat microsomal
preparations, Axelrod coincubated rat and rabbit microsomes with amphetamine and observed a marked inhibition of enzyme activity. When the rat
microsomes were preheated (2 min, 100") an increase in enzyme activity was
observed. Apparently heat-labile inhibiting and heat-stable stimulating factors
were influencing the course of the deamination of (R)-amphetamine. A
comparison of the rates of deamination of (R)- vs (S)-amphetamine showed a
marked stereoselectivity for the (R)-enantiomer. More recently Hewick and
Fouts (1970) reported an analogous stereoselective preference of the rabbit
microsomal system (obtained from phenobarbital pretreated animals). Of
interest in this regard was the higher affinity of (S)-amphetamine for
microsomal P450 (as measured by the magnitude of the binding spectra of the
two enantiomers).
Studies on the in vitro metabolism of amphetamine by rabbit liver
preparations have been concerned with possible intermediates formed in the
deamination reaction. The classical view held for this biotransformation
(Brodie et al., 1958) involves a-carbon hydroxylation to the carbinolamine 76
(analogous to the general structure 32, p. 344), which spontaneously cleaves
to phenyl-2-propanone (70) and ammonia. Since mixed-function oxidation
reactions in general are known to proceed with the incorporation of
molecular oxygen (McMahon et al., 1969a,b; Mason et al., 1955; Holtzman et
al., 1967; Kaufman et al., 1967; Sadee et al., 1971), the carbinolamine oxygen
and therefore the phenyl-2-propanone oxygen should be enriched with lib
if Ilb2 were employed in the incubation (Fig. 6).
This pathway was challenged by the report (Hucker et al., 1973) that
rabbit liver microsomes convert amphetamine to phenyl-2-propanone oxime
(72). The oxime could result from oxidation of the hydroxylamine or from
dehydration of the carbinolamine 76 to the imine 77 followed by oxidation to
72. Should the hydrolysis of phenyl-2-propanone oxime be an obligatory step
in the overall oxidative deamination of amphetamine, then the oxygen atom
of phenyl-2-propanone would be derived from water (Fig. 6). Parli et al.
(1971, 1973) investigated this question by means of Ilb2 and were able to
demonstrate that the ketone 70 isolated was enriched to the extent of 2531 % of the theoretical lib, thus precluding a hydrolytic pathway as the
exclusive route to phenyl-2-propanone. Beckett and Al-Sarraj (1972) have
stated that N-hydroxyamphetamine is not metabolized by microsomal enzymes. Incubation of oxime 72 with rat liver preparations leads to I-phenyl2-nitropropane (75) as the major metabolite (36.9%) although phenyl-2propanone (9.4%) was also identified (Coutts et al., 19700). The situation is
complicated by the instability of N-hydroxyamphetamine (57), which will
undergo spontaneous oxidation to the oxime (Beckett and AI-Sarraj, 1973).
355
VI:
CH 3
67
FIG. 6. Postulated intermediates and oxygen-labeling patterns in the deamination of

amphetamine in the presence of 1'b2 and H/'b.
In an attempt to characterize the stereochemical parameters of amphetamine

metabolism, Gal et al. (1976) working under carefully controlled conditions
showed that rabbit liver preparations converted racemic amphetamine and
the individual enantiomers to N-hydroxyamphetamine (57), phenyl-2-propanone (70), and I-phenyl-2-propanol (73) in varying amounts depending on
the stereochemical makeup of the amphetamine substrate. Oxime formation
from (R)-amphetamine was reported to be significant only after one hour. In
view of these results a likely explanation for the incorporation of the 1'b
derived from water in phenyl-2-propanone is via hydrolysis of the imine 77
that could form by dehydration of the carbinolamine 76 or from some
reactive N-oxidation species (Beckett and Belanger, 1975a). Whatever the
final outcome of this controversy, the importance of metabolic N-oxidation
of l-phenyl-2-aminopropanes is now well established. Examples in addition
to amphetamine include phentermine (76a) (Cho et al., 1972; Beckett and
Belanger, 1974a,b,c), chlorphentermine (76b) (Caldwell et al., 1975), 1phenyl-2-alkylaminopropanes (77, R = methyl, ethyl, propyl, etc.) (Beckett et
al., 1974a; Coutts et al., 1976b), norephedrine (69) (Beckett et al., 1974b), and
J3,J3-difluoroamphetamine (78) (Fuller et al., 1973). In all cases, N-oxidation
proved to be a singificant in vitro metabolic pathway leading to a variety of
N-oxidation products (hydroxylamines, nitrones, oximes, amine-N-oxides).
Thus, although N-oxidation may not be involved in the formation of
oxidative deamination products in this series, it is clear that this is an
important pathway for aliphatic as well as aromatic nitrogen functionalities.
The possible significance of the 455-nm-absorbing complex formed
between substrate and cytochrome P450 (see Section 1) and amphetamine
356
NEAL CASTAGNOLI, .JR.
NH2
~H'
76aR=H
76b R=CI
~CH3
()
kH2
78
metabolism should be considered at this time. The rat normally does not
extensively deaminate amphetamine (Axelrod, 1955; Dring et ai., 1970;
Ellison et ai., 1966; Alleva, 1963). Liver microsomes obtained from phenobarbital pretreated rats, however, will deaminate amphetamine (Parli and
McMahon, 1973; Fuller et ai., 1973) and significant levels of the 455 nm
absorbing complex are observed Games and Franklin, 1975). On the other
hand, with the metabolically susceptible (R)-enantiomer, significant 455-nmcomplex formation and oxidative deamination occur even with microsomes
derived from untreated rabbits Games and Franklin, 1975). It is possible
therefore that oxidative deamination and the potential for forming the 455
nm complex are related.
The in vivo metabolic fate of amphetamine has been shown to be species
dependent (Smith and Dring, 1970; Debackere and Massart-Leen, 1965;
Ellison et ai., 1966; Williams, 1974; Williams et ai., 1973). Basically, either phydroxylation dominates, as in the rat, or side chain degradation takes place,
as in the rabbit and man. The extent to which the side chain is modified
varies with the species---the rabbit, for example, excretes relatively large
amounts of an acid-labile precursor to phenyl-2-propanone for which the
enol sulfate structure 78 (Dring et ai., 1968) has been proposed. One of the
major urinary metabolites found in man (Dring et ai., 1970) is benzoic acid
74 or its glycyl conjugate hippuric acid (79). It is generally assumed that
benzoic acid formation results from the oxidation of phenyl-2-propanone
(Caldwell et ai., 1972b). Williams et ai. (1973; Williams, 1974) have reported
the in vivo conversion of phenyl-2-propanone to benzoic acid in the rabbit.
This pathway is potentially important since at one stage or another hydroxylation of the benzylic carbon atom is likely to be involved. Should benzylic
hydroxylation precede the deamination step, then substances related to
norephedrine (69) would be formed. Amphetamine and p-hydroxyamphetamine undergo ~-hydroxylation in several species (Dring et ai., 1970; Sever
et ai., 1973a,b, 1976; Sjoerdsma and Von Studnitz, 1963; Carlsson and
Lindquist, 1962) including man, although these compounds represent minor
urinary metabolites compared to benzoic acid and hippuric acid (Caldwell et
357
at., 1972b). The conversion presumably occurs in noradrenergic neurons

(Costa and Groppetti, 1970) and has been shown to be stereospecific both in
terms of substrate requirement [only the (S)-enantiomers are oxidizied] and
in terms of product formation [the absolute configuration of p-hydroxynorephedrine (71) and presumably norephedrine (69) possessing the (IR,2S)erythro configurations] (Goldstein et at., 1964; Goldstein and Anagnoste,
1965). The stereospecific formation of 71 has been suggested to be a key
factor in the development of tolerance to (S)-amphetamine (Brodie et at.,
1970) and could be responsible for the behavioral differences observed with
the two enantiomers (Taylor and Snyder, 1970). Beckett et at. (1974a,b) have
reported that rabbit liver homogenates convert norephedrine to the Noxidation products 80 and 81 and the oxidative deamination products 82
and 83. The authors did not examine the incubation mixture for benzoic
acid. Benzyl alcohol (84) was observed as an in vitro metabolite of phenyl-2propanone oxime (Coutts et at., 1976a). Therefore, a,,B-carbon-carbon bond
cleavage of an N-oxidation product of amphetamine metabolism has been
established. Chemically feasible reaction sequences leading eventually to
benzoic acid via an intermediate possessing a good leaving group on
nitrogen, such as the oxime sulfate ester 85 or hydroxylamine sulfate ester
86, are outlined in Fig. 7 together with some of the known conversions
related to these postulated transformations. Should benzaldehyde (87) be
formed in vivo, as proposed in Fig. 7, it would be expected to undergo rapid
oxidation to benzoic acid or reduction to benzyl alcohol. The participation of
such pathways in the metabolism of amphetamine would imply a quantitatively more significant role of phenylpropanolamines such as norephedrine
than indicated by the low levels of norephedrine and p-hydroxynorephedrine detected in human urine.
The second quantitatively most important in vivo metabolic pathway of
amphetamine is p-hydroxylation. Urinary aromatic hydroxylation metabolites
of amphetamine have been detected in a number of species (Dring et at.,
1970; Ellison et at., 1966; Caldwell et at., 1972b) and are the major pathway
in the rat with 60, 48, and 63% of the administered dose (110 mg) of (R,S)-,
(S)-, and (R)-amphetamine, respectively, appearing as p-hydroxyamphetamine or a hydrolyzable conjugate of p-hydroxyamphetamine (Dring et at.,
1970). In view of this extensive in vivo hydroxylation of amphetamine, it was
very surprising that microsomal preparations from the rat displayed only
weak aromatic hydroxylating capability with amphetamine as substrate
(Dingell and Bass, 1969; Daly et at., 1967). Recently, this question has been
reinvestigated and the microsomal hydroxylation of amphetamine to phydroxyamphetamine clearly documented (Rommelspacher et at., 1974; Cho
et at., 1975b). Kinetic studies revealed that the reaction proceeds only at low
(nm) substrate concentrations with substrate inhibition occurring at I'm
concentrations. Jonsson (1974) established the Michaelis-Menton kinetic
constants as Km = 2.4 X 10-5 M, Vmax = 3.7 nmole X mg protein- 1 X 10
min- 1 for (R)-amphetamine and Km = 1.1 X 10-6 M, V max = 2.8 nmole X
///
78a
OS02 0H
79
\
\
57
""NOH
CHa
87
CHa
,
H ""NH
80
\
\
\
\
OH
I
83
OH
CHa
."-~.
l' ~?-S020H
0 .. ",N N
H
82
~HO
"",H CHa
.;?'
~HO
",H a
CH
"
i,,---------/
HO""H CHa
69
H ""NH 2 - - -
","H CH a
,
~------------------j
84 CHO
((
11
~ I
.;?'
r y C H 20H "
'"
ryCOOH
74
\ oi H~?-S020H
,,"HN
'7
81
cJto:
HO
67b
CJ'H
(n
\72
V
~CHa
70
HO
~
I
~
FIG. 7. Metabolic pathways of (S)-amphetamine (67b) involving the oxidation of the benzylic carbon atoms and eventually leading to benzoic acid, a
major urinary metabolite of amphetamine in man. Solid lines represent established conversions; dashed arrows are speculative conversions.
~CONHCH2COOH
~CHa
//
H ""'NH 2 -----+
~CHa
Vb+- V
~CHa
......
Q
c"
~
::.:
t-<
r"o
Ut
00
359
mg protein- 1 X 10 min- 1 for (S)-amphetamine. The larger V max for (R)amphetamine vs (S)-amphetamine determined in vitro is consistent with the
in vivo results, which show that 63% of an administered dose of (R)amphetamine is excreted as the p-hydroxylated metabolite vs only 48% for
(S)-amphetamine. A similar result was obtained by Gunne and Galland
(1967) with (R,S)-amphetamine, that is the RlS ratio of urinary p-hydroxyamphetamine was found to be greater than 1 (1.22 in the 0-4 hr urine and
1.09 in the 0-24 hr urine). These authors suggest that the enantiomeric
difference resulted from the stereospecific metabolism by ,8-hydroxylation of
(S)-p-hydroxyamphetamine.
The above discussion has attempted to focus on those aspects of
amphetamine metabolism that may contribute to an understanding of its
pharmacological properties. The liver has been the major organ for in vitro
investigations, and one may presume that with the exception of neuronal ,8hydroxylation the liver is primarily responsible for the in vivo biotransformations of this drug. Published results (Mitra and Guha, 1973) describing the
"dehydrogenation" of amphetamine by brain tissues have been seriously
questioned because of the nonspecificity of the assay (Marckel and Harrison,
1974). Attempts to identify "proximate psychotogens" such as p-methoxyamphetamine (88) in patients suffering from "amphetamine psychosis" have, for
the most part, been unsuccessful (Friedhoff and Schweitzer, 1971; Angrist et
al., 1971; Andreoli et al., 1973). Variations in human metabolism by naive
individuals vs amphetamine users have been observed (Sever et al., 1973b;
Gunne and Anggard, 1973).
It may be concluded that in the nearly 50 years that have passed since
the first description of the human pharmacological properties of amphetamine (Alles, 1933) much has been learned about this drug's metabolic fate in
mammals. The importance of biotransformation processes in determining
the biological properties of amphetamine, however, remain controversial.
2.2. Metabolism of Mescaline (Benzeneethaneamine,

3,4,5-Trimethoxy)
Mescaline (89) is the only known naturally occurring one-ring psychotomimetic. From an historical standpoint, this compound is the most important of the "phenylalkylamine" psychotomimetics (see Chapter 6) even
though it has proved to be one of the less potent. Unlike amphetamine,
which causes psychotic behavior in man usually only after long-term abuse,
the ingestion of 300-500 mg (~20-30 ILmole/kg) of mescaline causes
profound behavioral alterations which usually begin within a few hours.
In part because of the relatively high doses required and the apparent
lack of a correlation between the time of onset and duration of effect with
the time of maximum levels of drug in the brain of animals, some workers
have suggested that a metabolite of mescaline may be responsible for the
360
NEAL CASTAGNOLI,jR.
psychotomimetic effects of the parent drug (Harley-Mason et al., 1958;

Mokrasch and Stevenson, 1962; Smythies, 1963; Friedhoff and Goldstein,
1962). To date, no definitive evidence has been presented to confirm or rule
out the formation of a proximate psychotogen derived metabolically from
mescaline.
Figure 8 summarizes those metabolic conversions of mescaline that are
reasonably well established. Other than mescaline itself, the most commonly
encountered metabolite is 3,4,5-trimethoxyphenylacetic acid (91), which has
been observed in man (Charalampous et al., 1964, 1966; Friedhoff and
Hollister, 1966), rat (Musacchio and Goldstein, 1967), monkeys (Taska and
Schoolar, 1972), rabbits (Slotta and Muller, 1936), and cats (Neff et al., 1964).
Brain homogenates also have been reported to convert mescaline to 91
(Demisch and Sellar, 1975). This compound possesses no mescaline-like
properties in man (Slotta and Muller, 1936; Charalampous et al., 1966).
Amine oxidases that will act on mescaline have been observed in several
tissues including plasma (Tabor et al., 1954; Blaschko et al., 1958). This
enzyme presumably catalyzes the conversion of mescaline to 3,4,5-trimethoxyphenylacetaldehyde (90), an unstable intermediate that is either further
oxidized to the acid 91 or reduced to 2-(3,4,5-trimethoxyphenyl)ethanol (92).
Based on evidence first reported by Bernheim and Bernheim (1938),
mescaline oxidase appears to be similar to but not identical with "diamine
oxidase" (Zeller et al., 1958; Huszti and Borsy, 1966) and is distinct from
CH30~NH'
HO~
OC::
R=CH,NH,
1 98 : R=COOH
~HR~'------~
~
CH30~
OCHa
F7:
CH 30
CH30~
OH
~CH'OH
HO~
CH,o
CHaO
CH30~R
NH,
CH30~
OCH,
'ICHaO~CHO
CH30~
OCHa
94: R=H
95: R=COCH 3
1
CH 3 0
~HCOCHa
CHaO~
~
OCH,
CHaO
~COOH
CH,o~
OCHa
93
FIG.
92
8. Summary of metabolic pathways for mescaline (89).
91
361
monoamine oxidase. Recent evidence based on inhibition studies with

aminoacetonitrile suggests that the rabbit oxidatively deaminates mescaline
by a Cu +2-containing "pyridoxal" amine oxidase and not the flavin-containing
monoamine oxidase found in the mitochondria (Riceberg et at., 1975). It
should be noted that no consideration has been given to the possibility that
N-oxidation of mescaline is involved in its deamination. Considering the
evidence that amphetamine and a variety of related aliphatic amines undergo
metabolic N-oxidation (see above), it would not be surprising if mescaline
were to be a substrate for the mammalian N-oxidase enzyme systems. As
shown in reaction (12), the hydroxylamine 99 could be further oxidized to
the oxime 100 followed by hydrolysis to the aldehyde 90. A second possible
N-oxidation sequence to the aldehyde 90 would involve dehydration of 99 to
the imine 101 followed by rehydration to the carbinolamine 102 and loss of
ammonia. These reaction pathways are analogous to those already discussed
under amphetamine metabolism and in Section 1.
CH30~_N_O_H_ _C~~,o'(lT'CHO
CH30~
OCH 3
CH30~
OCH 3
100
CH'O~_N_H_2_C_H->,30Yl1~NHOH
CH30~
OCH 3
(12)
CH,o~
OCH 3
89
\99
CH,o~1o/_N_H_C_H->3~YLI NH2
CH,o
~
OCH 3
101
CH 30
OH
OCH 3
102
Some consideration has been given by Friedhoff and Goldstein (1962) to

the potential importance of the trimethoxyphenylacetaldehyde 90 as a
proximate psychotogen. These workers monitored gross behavioral changes
caused by mescaline and 2-(3,4,5-trimethoxyphenyl)ethanol (92) in rats
pretreated with either an amine oxidase inhibitor, which was found to have
no potentiating effect, or an aldehyde oxidase inhibitor, which was found to
potentiate the activities of both mescaline and its carbinol metabolite 92. Such
effects are reminiscent of the increased toxicity observed following ethanol
ingestion after treatment with disulfuram (Hald and Jacobsen, 1948). Studies
by Browne and Ho (1975) suggest, however, that the parent amine is
responsible for mescaline's CNS activity since several mescaline metabolites
failed to mimic mescaline in an operant discrimination test.
362
NEAL CASTAGNOll,jR.
The acetylation of mescaline to form the N-acetyl compound 93 also has

been reported in a number of animal species (Charalampous et ai., 1966;
Taska and Schoolar, 1972; Musacchio and Goldstein, 1967). This metabolite
has been found in the brain of mice (Shah and Himmich, 1971) and rats (Ho
et ai., 1973). Related ring-substituted 2-phenylethylamines have been shown
to undergo N-acetylation by the melatonin-forming enzyme located in the
pineal gland of the brain (Hartley and Smith, 1973). Since the aromatic
nucleus of mescaline is electron rich, cyclization of N -acetylmescaline to the
dihydroisoquinoline 1M via the intermediate carbinolamine l04a could
(13)
104
104a
93
occur (reaction 13). Analogous processes leading to tetrahydroisoquinolines

have been reported in plants (Kapadia et at., 1970) although the conversion
in mammalian systems has not been demonstrated. It should be pointed out
that a number of tetrahydroisoquinolines derived from catecholamines
(Davis and Walsh, 1970; Cohen and Collins, 1970; Sandler et ai., 1973;
Walsh et ai., 1970; Greenberg and Cohen, 1973) and pyridoindoles derived
from indolealkylamines (Wyatt et at., 1975; Mandel et at., 1974) have been
reported to be formed in mammals. It is not clear, however, if these
compounds are metabolically derived or artifacts due to the chemical
reactivity of the precursor molecules.
The one-ring psychotomimetics all possess alkoxy (methoxy, methylenedioxy) functionalities. Considerable interest has focused on metabolic pathways involving oxidative cleavage of these groups to form the corresponding
phenolic compounds. Also of in\erest has been the possible in vivo methylation of phenolic groups present, for example, on dopamine (105) to form
aberrant metabolites such as 3,4-dimethoxyphenylethylamine (106), which
could function as endogenous psychotogens (Friedhoff and Van Winkle,
1962).
HO
yYl
~H2
HO
105
106
In the case of mescaline, five O-demethylated metabolites have been

characterized, namely, compounds 94-98 shown in Fig. 8 (Daly et at., 1962).
Of special interest is the bis-O-demethylation of mescaline to form the 0-
363
hydroquinone (catechol) derivatives 97 and 9S. As will be discussed in more

detail below, hydroquinones are relatively unstable molecules that tend to
auto-oxidize to chemically reactive, electron-deficient quinones. These reactive substances may then form covalent bonds with nucleophiles present on
macromolecules. In an early study by Block (1953, 1958) on the metabolism
of 1't'>labeled mescaline, incorporation of the It label into liver proteins was
observed. Details regarding the pathway leading to this incorporation are
lacking. One possible pathway is analogous to that reported for the incorporation into protein of the potent sympatholytic agent 6-hydroxydopamine
(107), which most likely involves quinone intermediates (Saner and Thoenen,
1971).
Another important consequence of the susceptibility of catechols to
undergo oxidation to quinones is the possible formation of cyclic species such
as adrenochrome (lOS) from epinephrine (109) (Axelrod, 1964). Adrenochrome has been associated with the psychotomimetic activity of LSD (Hoffer
et ai., 1959) and related molecules have been examined as potential endogenous psychotogens. As with almost all attempts to derive psychopharmacological correlates from metabolic events, this area remains unresolved (Blaschko,
1972). During the past several years however, extensive studies on the
neurodegenerative effects of 6-hydroxydopamine (Kostrzewa and Jacobowitz, 1974; Malmfors and Thoenen, 1971), which may be formed in vivo from
dopamine (Senoh et ai., 1959), have led to a renewed interest in the oxidative
pathways of catecholamines as being possibly linked to eNS disorders (Stein
and Wise, 1971).
Mescaline is oxidized by enzymes present in a number of tissues
(Blaschko et ai., 1958; Riceberg et ai., 1975) including brain (Ho et ai., 1973).
With regard to the possible participation of drug metabolic processes in the
psychotomimetic effects of this drug, the recent series of papers by Seiler and
Demisch (1974a,b) describing the in vivo and in vitro metabolism of mescaline
by mouse brain are of some interest. These workers present evidence (based
on 14(:02 production in vivo and gas chromatographic-mass spectrometric
data) for the metabolic formation of 3,4,5-trimethoxybenzoic acid (110) from
HO
HO
OH
H2
107
109
108
CH30VCOOH
CH 3 0
~I
OCH 3
110
364
NEAL CASTAGNOLI,jR.
mescaline by an enzyme system in the mouse brain. As was pointed out when
discussing the metabolism of amphetamine, side chain cleavage to benzoic
acid is likely to involve benzylic oxidation to /i-hydroxylation products that
could be pharmacologically active. Further study in this area would seem
appropriate.
2.3. The Metabolism of Ring-Substituted

I-Phenyl-2-aminopropane Psychotomimetics
Shulgin et al. (1969) in an effort to evaluate the pharmacological
consequences of combining the dominant structural features of mescaline,
the trimethoxyphenyl moiety, with the dominant structural feature of
amphetamine, the phenylisopropylamino unit, have synthesized a variety of
I-phenyl-2-aminopropanes. Although variations in the side chain substituents
have been examined, the major focus of Shulgin's work has concerned arylsubstituted derivatives (see Chapter 6 for a review). The 2,4,5-trioxysubstitution pattern led to maximal potency; furthermore it was found that the 4position could be an alkyl, alkoxy, or halo group without sacrificing activity.
The alkoxy groups at the 2 and 5 positions, however, appear to be essential
for high potency in this series. The 4-methyl compound III (Matin et al.,
1974) and 4-bromo compound 112, (Nichols et al., 1973) are two of the most
potent one-ring psychotomimetics known. As with amphetamine, these
molecules bear a chiral center. The R-enantiomers ilIa and 1l2a are the
more potent isomers (Aldous et al., 1974; Shulgin, 1973; Benington et al.,
1973). These compounds display activities approximately 100-400 times that
of mescaline.
The metabolism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane
(benzeneethaneamine,a,4-dimethyl-2,5-dimethoxy,. DOM, Ill) has been examined in some detail. Idanpaan-Heikkila and McIssac (1970) have determined the tissue distribution of tritium-labeled III in mice and Ho et al.
(1971) in rats and monkeys. Additionally, Ho et al. (1971) and Matin et al.
(1974) have characterized a number of urinary metabolites of III (Fig. 9).
Both in vitro (McGraw et al., 1977) and in vivo (Matin et al., 1974)
studies on III have shown that the S(+)-enantiomer (ilia) is metabolized
more rapidly than the R( - )-enantiomer when racemic drug is administered.
The individual isomers, however, are metabolized by rabbit liver microsomes
at approximately the same rate, suggesting an enantiomeric interaction in
which the (S)-isomer inhibits the metabolism of the (R)-isomer. Similar results
have recently been described for amphetamine (Gal et al., 1976). This
stereochemical selectivity is reflected in the enantiomeric composition of the
metabolites formed in vitro from racemic III (Weinkam et al., 1976). In all
cases except one, the SIR ratio of the metabolites of racemic III is greater
than l. The single exception involves the microsomal N-oxidation of III to
117. Gas chromatographic-mass spectrometric analysis of this metabolite
365
,--------,----,--- X)Q:,--~.
CH,O
CH,
CH,
OCH,
CH,O
):JC'fOH
CH,
III
OCH,
117
CH,~CH,
H 0 ' Y Y YCH ,
M". NH,
M"I'~H'
CH,
CH,
CH 3
OCH,
OH
119
11K
H 0 ' Y Y YCH ,
M"u
CH,
OH
NH ,
CH'0YjrYCH,
AA"I'~H,
OCH,
HOCH,
120
1113
CH,O
CH,
X)Q:,
HOOC
OCH,
CH'O~CH'
CH,
CH,O
CH,
X)C}.
CH,
114
FIG.
111~cH'
OCH,
116
9. Metabolic pathways for amine III (DOM).
employing selected ion recording established that the R/S ratio ranged
between 2.4 and 6.3 under conditions when 6-8% of 111 incubated was
isolated in the postincubate as 117 (Gal et at., 1976).
The quantitatively most important metabolic pathway of 111 involves
oxidation of the C-4 methyl substituent. The amino acid 114 that has been
identified in the urine of rabbits and rats represents about half the dose of
111 administered. The hydroxymethyl compound 113 is the major rabbit
liver microsomal metabolite (Weinkam et ai., 1976) and has been detected in
the brains of monkeys although in very low amounts (Idanpaan-Heikkila and
McIssac, 1970).
Oxidative deamination of 111 to form the 2-propanone metabolite 115
appears to be a minor metabolic pathway in all species studied. Particularly
interesting in this regard is the very low yields of 115 observed in rabbit liver
preparations (Weinkam et at., 1976) since this is a major pathway for
amphetamine (Axelrod, 1955). This ketone or its carbinol reduction product
116 has been detected as rat and rabbit urinary metabolites, but again in
small amounts. No evidence could be obtained in rabbits for side chain
cleavage of 111 to 2,5-dimethoxy-4-methylbenzoic acid (121), its glycyl
conjugate 122, or its aldehyde precursor 123 or the diacid 124 (Matin et at.,
1974).
Attempts to characterize the J3-hydroxy and N-acetyl compounds 125
and 126, respectively, in rat urine were unsuccessful (Ho et at., 1971b). As
366
NEAL CASTAGNOLI,jR.
CHa0Y'lr.><CHa
MI"\~U""NH2
ROCHa
Il1b: R=CH a
112b: R=Br
lila: R=CH a
112a: R=Br
CH,XX
COOH
CHa
OCHa
CHaO
CONHCH 2COOH
XX
CHa
OCHa
121
122
CHaOyyCHO
CHaOyyCOOH
CHa
OCHa
123
HOOC
OCHa
124
already mentioned, N-oxidation of 111 to the hydroxylamine 117 has been

observed in rabbit liver microsomal preparations. Although the air oxidation
of 117 to the oxime 127 was found to proceed rapidly in pH 7.4 buffer, no
evidence could be obtained for its presence in the incubation mixture.
Furthermore, denatured (boiled) microsomes protected the hydroxylamine
against this air oxidation, suggesting the presence of an inhibitory substance.
An analogous inhibition of the oxidation of I-hydroxyaminonaphthalene
(128) has been reported by Ziegler et al. (1973).
OH
CHaOroCHa
CHa
NH2
OCHa
125
128
The third general metabolic pathway for 111 is oxidative O-demethylation of the methyl phenyl ether groups. All three possible O-demethylated
metabolites, compounds 118-120, have been characterized in rabbit liver
367
homogenates (Zweig and Castagnoli, 1975, 1977). The p-hydroquinone 120 is

an analog of the sympatholytic agent 6-hydroxydopamine (107) and has been
shown to possess some of the neurodegenerative properties of 6-hydroxydopamine (Butcher, 1975). Similar to 6-hydroxydopamine (Blank et ai., 1972),
hydroquinone 120 undergoes facile oxidation to form the quinone 129 (Fig.
10), which cyclizes to the iminoquinone 130 (Zweig and Castagnoli, 1974). In
the absence of nucleophiles, 130 is relatively stable at pH 7.4. As the pH is
raised, however, proton rearrangements take place, eventually leading to the
indole 132 via the indolinine 131.
In view of the ease with which the hydroquinone 120 undergoes
oxidation at pH 7.4, it is somewhat surprising that this compound survives
the one hour pH 7.4 incubation. This stabilization may be analogous to the
inhibition by liver constituents of hydroxylamine auto-oxidation. It should
prove of interest to determine the nature and significance of the protection
of these substances from air oxidation.
Reports on the metabolism of a number of other ring-substituted
psychotomimetic I-phenyl-2-aminopropanes have appeared. The 4-ethyl
analog 133 of DOM is reported to undergo metabolic oxidation to the
carbinol 134 and the phenylacetic acid 135 in the rat (Tansey et ai., 1975).
The slower rate of metabolism of 133 compared to III is consistent with the
greater potency of the ethyl analog (Snyder et ai., 1968).
OCH 3
OCH 3
~CH3
CH 3
NH,
HO
OCH 3
i/H,
COOH OCH 3
134
135
In an attempt to determine if metabolic factors are associated with

differences in psychotomimetic potency, Mitoma (1970) examined the tissue
distribution (rats) and in vitro O-demethylation (rats and rabbits) of the three
Y1rY
H0
Mrm
CH 3
O~CH3
CH 3
NH2
------>-.
OH
AAn
CH 3
120
NH2
------+
0
129
O~_----+~OYY) ._----+.HO~
~/''cH3
CH3
130
FIG.
~rCH3
CH 3
131
~N/'t:H3
CH3
132
10. Oxidative cyclization of p-hydroquinone metabolite derived from DOM.
368
NEAL CASTAGNOLI,jR.
possible 1-(trimethoxyphenyl)-2-aminopropanes, 136-138. The 2,3,4-trimethoxy isomer 138 is reported to be inactive in man (Shulgin, 1964) and
animals (Uyeno et al., 1968) as a psychotogen. No dramatic differences were
observed in brain levels or in the extent of in vitro O-demethylation as
measured by formaldehyde production. A more detailed analysis of the in
vivo (rat) O-demethylation of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane
(137), the most potent of the three isomers, was recently described (Sargent
et al., 1976). The methyl carbon atom of each of the three methoxy groups
was independently labeled with I t and the rates of lt02 formation
measured. According to these data, the C-4 methoxy group is more
extensively cleaved (21.3%) than the C-2 (8.1 %) or the C-5 (13.7%) groups.
Characterization of the phenolic metabolites resulting from these O-demethylation transformations was not reported.
Beckett and Midha (1974) have examined the metabolism of 1-(4methoxyphenyl)-2-aminopropane (139) by liver preparations of rabbit,
guinea pig, and rat. Four side-chain oxidation products, the N-hydroxy
derivative 140, oxime 141, phenyl-2-propanone 142, and phenyl-2-propanol
143 were characterized. The chemical lability of the N-hydroxy compound
140 was discussed and the authors suggest that the oxime 141 may not be a
true metabolite but rather an artifact resulting from the air oxidation of 140.
No comment was made on the possible formation of phenolic metabolites
although it is likely that the isolation procedures followed would not have
revealed such compounds.
In addition to methoxy substituents, substitution of the phenyl ring of
amphetamine with a methylenedioxy group leads to psychotomimetic activity
(Naranjo et at., 1967). The in vitro metabolic fate of 1-(3,4-methylenedioxy-
ro 0
CH
CH 30
NH2
OCH 3
CH 3 0
136
CH
NH2
CH'O~CH'
~ I
NH2
CH 3 0
OCH 3
137
CH 3
CH 3 0
OCH 3
~,
138
CH 3
CH 30
~CH'
~OH
~ I
CH 3 0
140
139
142
141
143
NOH
369
phenyl)-2-aminopropane (144) has been examined by two laboratories.

Oxidative O-dealkylation of 144 by the microsomal mixed-function oxidase
derived from rats has been shown (Marquardt and DiStefano, 1974) to yield
the putative false neurotransmitter (Muscholl, 1972) a-methyldopamine
(146). In terms of the general principles discussed in Section 1, oxidative
attack on 144 would lead to the unstable formate ester 145, which would
rapidly hydrolyze to a-methyldopamine and formic acid. In a separate study,
Midha (1974) examined by gas-chromatography-mass-spectrometry the neutral and basic extracts of guinea pig and rabbit liver homogenate incubations
of the methylenedioxy compound 144. He was able to characterize the
phenyl-2-propanone 147 and its oxime 148 as major metabolic products.
CHa
<X)k,
HOx:n:CHa
::::::,....
144
HO
NH 2
HOOCH
'46
H 0 y Y T C Ha
NH2
O-C-H
<
145
O~CH3
~
I
o
147
Thus, both side chain oxidation and oxidative O-dealkylation have been
demonstrated for 144 although in different species.
3. CONCLUSION
Psychotomimetic drugs deserve careful study since an understanding of
their mechanisms of action must eventually contribute to the deciphering of
the complex events associated with mental disorders. In a more strictly
academic sense, the dramatic alterations in potencies of these substances,
which are associated with seemingly minor structural variations, pose an
interesting challenge to investigators working in this area. The possibility that
metabolic transformations of the parent drugs may be responsible for these
differences in biological activity is worthy of study. It is clear that metabolites
370
NEAL CASTAGNOLI,jR.
are not necessarily "detoxification" products. Often, chemically reactive

species are generated and these may covalently interact with biologically
important molecules, leading to altered structures and functions. Psychotomimetic amines undergo analogous metabolic conversions to those identified
with xenobiotic toxicities--aromatic oxidation, N-oxidation, hydroquinone
formation. In reviewing the metabolic fate of the one-ring psychotomimetic
amines, particular emphasis has been given to pathways that may lead to
biologically and chemically active molecules. It must be stated, however, that
efforts on the part of various researchers to link the pharmacological
properties of these molecules to structural changes they suffer in vivo have
not yielded definitive results. On the other hand, with the possible exception
of amphetamine, relatively little detailed information on the metabolic fate of
psychotomimetics is available and one can anticipate that the molecular
events associated with their modes of action are complex. Technological
advances will continue to provide increasingly sophisticated avenues to better
explore small molecule-macromolecule interactions. Well coordinated, interdisciplinary research programs will continue to cross-fertilize new approaches
to the study of these drugs. Hopefully these efforts will lead to a clearer
understanding of the pharmacological significance that metabolic transformations can play in psychotomimetic activity and toxicity.
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PSYCHOTOMIAIETIC DRUGS IN MAN

Leo E . Hollister
1. INTRODUCTION
Few drugs have had more scientific or social impact than the psychotomimetics. Few have been so peculiarly potent in their actions and so uniquely active
in humans. While we may surmise that animals may be thinking strangely or
perceiving erroneously or having marked alterations in mood, only man's
symbolizing ability lets us know for certain the degree to which relatively
small amounts of psychotomimetics may profoundly alter mental functions.
Therefore it would appear to be worth considering the pharmacology of
these drugs in humans to see if we can grasp a few elusive clues concerning
its mode of action.
During the past few years, a number of reviews of psychotomimetic
drugs have appeared, covering various aspects of their types, their pharmacologic actions in animals, and their effects in man (Freedman, 1969; Cohen,
1971; Brawley and Duffield, 1972). One multiauthored volume concerned
itself primarily with lysergic acid diethylamide (LSD) (Sankar, 1975), while
another concerned itself with psychotomimetics in general (Radouco-Thomas
et ai., 1974). The subject does not lack interest, although a variety of
constraints on human research with these drugs has virtually limited recent
literature to accounts of experiences resulting from their illicit use.
While any definition of the term psychotomimetic drugs is bound to be
arbitrary, one can limit the field somewhat if the following criteria are used:
1. In proportion to other effects, changes in thought, perception, and
mood should predominate.
Leo E. Hollister Veterans Administration Hospital, and Stanford University School of
Medicine, Palo Alto, California.
389
390
LEO E. HOlLISTER
2. Intellectual or memory impairment should be minimal with doses

producing the above mental effects; with large doses these may
occur.
3. Stupor, narcosis, or excessive stimulation should not be an integral
part of the action.
4. Autonomic nervous system side-effects should be neither disabling
nor severely disconcerting.
5. Addictive craving should be minimal.
Even with criteria such as these, drugs admissible to the list may vary,
depending upon the investigator. Indeed, one can scarcely get any agreement upon the term used to describe this class of drugs, since many
objections to the most likely used term, psychotomimetics, can be offered. The
following terms are often submitted: hallucinogens, phantasticas, psychotogens,
dysleptics, and psychedelics. Nevertheless, psychotomimetic enjoys a broader
use and has seniority over most of the alternatives, as well as being about as
accurate a designation as any of them.
2. CHEMICAL BASIS FOR CLASSIFICATION

Basing a classification on chemical structures, one can separate seven
groups of these drugs:
1. Lysergic acid derivatives, of which LSD is the prototype.
2. Phenethylamine derivatives of which 3,4,5-trihydroxyphenethylamine (mescaline) is the prototype.
3. Indolealkylamines, such as 4-phosphorodimethyltryptamine (psilocybin).
4. Other indolic derivatives, such as the harmine alkaloids or ibogaine.
5. Piperidyl benzilate esters, such as N -ethyl-3-piperidyl cyclopentylphenyl glycolate OB-329 Ditran).
6. I-Phenylcyclohexyl compounds, such as phenylcyclidine (Semyl).
7. A miscellaneous group of varying chemical structures.
Because the first three groups are virtually identical in their clinical effects,
they are often lumped together as the LSD-mescaline-psilocybin group.
3. CLINICAL EFFECTS OF PSYCHOTOMIMETIC DRUGS

Descriptions of clinical syndromes vary considerably, depending on the
use of volunteer subjects or psychiatric patients, types and doses of drugs,
PSYCHOTOMIMETIC DRUGS IN MAN
391
setting of the clinical experiment, and expectations of the subjects or

experimenters. In a sense, these drugs provide an experimental situation in
which the results can almost be foreordained by the above variables. Even if
this were not the case, one is faced with a verbal barrier that makes trying to
describe a drug experience as elusive as trying to describe the fragments of a
dream.
3.1. LSD Reaction

The description of the first known reaction to LSD, that unplanned
experiment of Albert Hofmann, still stands as a landmark in careful,
objective reporting (Hofmann, 1961). What Hofmann described then, and
what objective investigators have since repeatedly elaborated upon, have been
three characteristic types of symptoms: somatic, perceptual, and psychic. In
repeated laboratory experiments, our subjects have reported a basic clinical
syndrome that might be described as follows:
1. Somatic symptoms---dizziness, weakness, tremors, nausea, drowsiness,
paresthesias, and blurred vision.
2. Perceptual symptoms-altered shapes and colors, difficulty in focusing on objects, a sharpened sense of hearing, and rarely, synesthesias.
3. Psychic symptoms-alterations in mood (happy, sad, or irritable at
varying times), tension, distorted time sense, difficulty in expressing
thoughts, depersonalization, dreamlike feelings, and visual hallucinations.
Physiological effects are relatively few. Dilated pupils, hyperreflexia,

increased muscle tension, incoordination, and ataxia are common physical
signs. Effects on pulse rate, respiration, and blood pressure are so variable
that they probably represent varying levels of anxiety of subjects rather than
true physiologic effects. Changes in appetite and salivation are inconstant,
being increased in some subjects, decreased in others.
The clinical syndrome tends to follow a sequential pattern with somatic
symptoms presenting first, perceptual and mood changes next, and finally
psychic changes, although there is considerable overlap between these
phases. Between the range of 1 to 16 ILg/kg, the severity of psychophysiological effects of LSD in a given subject are proportional to the dose (Klee et al. ,
1961). Specific types of reaction, such as paranoid ideation, are more likely a
matter of personal predisposition than a function of dose.
Two studies have used questionnaire data to obtain some description of
the clinical effects of LSD (Hollister and Hartman, 1962; Linton and Langs,
1962). One study used a single dose of 100 ILg of LSD; the other, doses of 1
ILg/kg. In general, there was good agreement between the two studies,
considering that the experimental settings were different, the subjects were
392
LEO E. HOllISTER
chosen differently, and the questionnaires constructed and administered

differently. Somatic symptoms most frequently reported were dizziness,
weakness, nausea, paresthesias, and tremors. Perceptual alterations were
visual (blurring, changed shapes, heightened color contrasts), auditory (hearing more acute), and kinesthetic (body looked and felt strange). Psychic
symptoms were silliness, distorted time sense, difficulty in expression and
concentration, depersonalization or dreamlike state, and loss of control of
thoughts. Perhaps of most interest are some of the symptoms not often
reported: synesthesias, paranoid ideas, sexual feelings, hallucinations other
than visual, and any type of disorientation. The peak of symptoms in both
studies occurred between three and five hours after the drug was given.
3.2. LSD Homologs

A number of clinical comparisons have been made between LSD and
closely related lysergic acid derivatives. One comparison between 2,3-dihydrolysergic acid diethylamide and LSD revealed that the former compound
induced LSD-like autonomic and mental changes in man, but was less potent
and slower in onset than LSD (Gorodetzky and Isbell, 1964). As the analog
has only 1125 the pyretogenic action of LSD in rabbits, it was postulated that
the latter test might correlate reasonably well with clinical potency in
psychotomimetic actions. Acetylation or methylation of the LSD molecule on
the pyrrole nitrogen produces two analogs, I-acetyl lysergic acid diethylamide and I-methyl lysergic acid diethylamide. These three compounds were
tested in both patients and normal subjects (Malitz et al., 1960). About 1.52.0 times as much of the analogous drugs were required to produce
essentially the same clinical reactions with the analogs as with LSD.
Replacement of the diethylamine side chain of LSD with a morpholine group
results in a compound that has pharmacological and clinical effects generally
similar to those of LSD; potency was probably somewhat less (Gogerty and
Dille, 1957).
In summary, it appears that alterations in the basic structure of LSD
mayor may not materially change the quality of the clinical effects, but
generally tend to reduce potency. LSD is still the most potent compound in
the series, as well as one of the most potent known to man.
3.3. Mescaline
Except for the fact that the effective dose of mescaline is a one or two of
orders of magnitude more than for LSD, there is really little to choose
between the two drugs insofar as the clinical effects are concerned. Just as
with LSD, there are prominent somatic symptoms, perceptual alterations,
and psychic effects. Physiological effects are largely manifested by mydriasis,
393
increased deep tendon reflexes, some degree of ataxia and incoordination,

and little if any circulatory effects. Nausea and vomiting with mescaline has
been somewhat more common in our studies than with the other drugs, but
one always has uncertainties regarding the equivalence of the doses. Despite
the fact that nausea and vomiting have been known to occur frequently with
these drugs, it is often difficult for subjects to accept such simple explanations of the symptom; several of our psychologically minded subjects have
attributed their nausea to role rejection. These kinds of extrapolations from
the basic observations account in part for the diversity of clinical descriptions,
but as mentioned earlier a common basic syndrome is produced by these
drugs in almost every circumstance and in most subjects.
A number of mescaline homologs with psychotomimetic activity have
been tested. The amphetamine analog, trimethoxyamphetamine, produces
euphoria and a loosening of emotional restraint in doses of 0.8-1.2 mglkg
(Peretz et at., 1955). Doses about twice as large evoke visual hallucinations;
other symptoms reported are nausea, headache, giddiness, incoordination,
and increased deep tendon reflexes. Doses on the order of 2.8-3.5 mg/kg
evoke tremors, paresthesias, amplified and distorted colors, textures, forms
and spatial relationships, increased auditory acuity, and occasional synesthesias (Shulgin, 1964). Psychic effects from large doses seem to be somewhat
antisocial, with anger and hostility accompanying euphoria and impaired
intellectual functions. The span of action is similar to that of mescaline,
lasting about seven hours; the peak of urinary excretion of the drug occurs
between two and five hours after a dose, with 20-35% being excreted
unchanged.
Other amphetamine homologs have become popular as street drugs.
Most widely used has been 2,5-dimethoxy-4-methylamphetamine (DOM or
"STP"). Our studies of the drug showed it to have properties very similar to
that of mescaline, although it was about 40 to 50 times as potent (Hollister et
at., 1969a). Our report of rapid tolerance to the drug was subsequently
confirmed (An grist et at., 1974). 3,4-Methylenedioxamphetamine (MDA),
first discovered by Gordon Alles, was found by self-experimentation to be a
psychotomimetic resembling mescaline. It is more potent by three- to
fourfold (Thiessen and Cook, 1973). Human studies of 3-methoxy-4,5methylenedioxamphetamine (MMDA) are scanty, but such as exist suggest
that it, too, resembles the other amphetamine homologs (Shulgin et at.,
1973).
3.4. Psilocybin
In general, effects of psilocybin strongly resemble those of LSD and
mescaline. As with the former drugs, psychotic symptoms were infrequent.
None of the subjects experienced paranoid delusions or hallucinations of
smell, taste, or feeling. A few described auditory hallucinations, these being
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LEO E. HOllISTER
either misinterpretations of meanings of environmental sounds or of actually

hearing fantasied conversations. Neither type of auditory experience contained accusatory material. Occasional subjects reported changes in the body
image, the extremities appearing larger than normal. These changes were
concurrent with other visual effects. Only rarely did subjects have difficulty
in maintaining temporal or spatial orientation, these symptoms being brief
and transient.
Changes in blood pressure or pulse rate were minimal. No decreases in
blood pressure were noted, and in no instance did the blood pressure either
rise or fall beyond physiologic levels unless it had been abnormal on the
control measure. Pulse rate was not changed appreciably in either direction,
remaining within physiologic limits or close to the control values in all drug
trials. Dilatation of the pupils was almost constantly encountered after
effective doses. Average dilatation over a 2-hr period was 3 mm. When
dilatation was extreme, the pupillary reaction to light was often sluggish with
hippus. Deep tendon reflexes were increased, often becoming clonic in
character.
A psilocybin analogue with highly potent psychotomimetic effects, N,Ndimethyltryptamine (DM1), when administered intramuscularly in doses of 1
mglkg, produces a brief but intense LSD-like experience. Mental effects
consist of anxiety, hallucinations (usually visual), and perceptual distortions.
Pupillary dilatation, increased systolic and diastolic blood pressure, and
increased deep tendon reflexes are common attendant effects. Because the
material is most active by parenteral injection, the onset is rapid, within 1530 min, but brief, subsiding completely in one to two hours. Intravenous
injection produces an even more precipitous reaction, large doses producing
delirium within minutes (Rosenberg et al., 1964). In many respects the action
of this drug simulates that of bufotenin, the 5-hydroxy derivative. Curiously,
placement of the hydroxy group at the 6-position on the ring makes for a
compound that has been found by several investigators to be essentially
inactive.
3.5. Piperidyl Benzilate Esters

Early reports of the clinical effects of the piperidyl benzilate esters (JB318, JB-329) suggested that they were analogous to those of LSD. Further
studies have indicated that these central anticholinergics produce a clinical
syndrome different from LSD and kindred drugs in a number of respects
(Davis et al., 1964; Ostfeld et al., 1959). Peripheral anticholinergic effects are
more 'prominent among many of the somatic effects common to the other
drugs. Thought processes are much more severely disrupted: disorganization, incoherent speech, confusion, disorientation, and memory loss are
striking and comparatively long-lasting. They characteristically wax and
wane, typical of a true delirium. Tactile, auditory, and visual hallucinations
395
may occur, the latter being less intense than those from comparably
disturbing doses of LSD, mescaline, or psilocybin. Mental states produced by
the piperidyl benzilates are reminiscent of those from other centrally acting
anticholinergics, such as scopolamine or, more recently, benactyzine. These
are classical deliria, so there is little wonder that chronic alcoholics react to
JB-329 with a delirium tremens syndrome. The analogy of LSD to delirium
tremens is less striking.
Usual doses of the piperidyl benzilates range between 5 and 15 mg.
Mental disturbance may be quite prolonged at the upper range of dosage,
lasting well over 24 hr, with mild residual confusion even for days. Unlike
the LSD-type drugs, this experience is perceived by most subjects as
frightening and distinctly unpleasant. Few subjects claim increased insight;
indeed, with larger doses, subjects are unable to remember parts of the
experience. Psychologic testing of any sort may be completely impossible if
the delirium becomes severe enough.
3.6. Phencyclidine
Of all socially used psychotomimetic agents, phencyclidine is the most
different. In recent years, its rate of illicit use has risen rapidly, along with
some indications that it is one of the most dangerous of drugs of this type.
It was one of a series of phenylcyclohexamines developed as potential
anesthetic agents. This particular one was never approved for human use,
but became commercially available for "veterinary use only" in 1967 under
the name Sernylan. Subsequently a related compound, ketamine, was
approved for human use as an anesthetic. Because of the primary use of
phencyclidine in veterinary medicine, one of the popular epithets for it has
been "hog," although it has many other synonyms in the street: "PCP,"
"peace pill," "angel dust," "angel mist."
Early investigative experience with the drug indicated that it was most
unpleasant. When given to psychiatric patients, many refused to take another
dose. Preoccupation with death was common, as were body image distortions
and estrangement from the environment (Ban et ai., 1961). Some investigators were impressed with its ability to dissociate interoceptive sensory input
from consciousness, likening it to exteroceptive sensory deprivation, a
currently fashionable model for schizophrenia (Luby et ai., 1959). One would
scarcely have imagined that such a drug would attain a high degree of
popularity as a social drug.
Because of markedly different effects at varying dose levels, phencyclidine is a bit difficult to categorize, although most would regard it as a
psychotomimetic with some central stimulating action. Ataxia is one of the
earliest manifestations of intoxication, before obtundation of consciousness.
Low doses might also be accompanied by drowsiness, numbness, and mild
euphoria. Larger doses may lead to coma or convulsions. Between these
396
LEO E. HOlLISTER
extremes, many of the phenomena of other psychotomimetic agents are

experienced: illusions of color, depersonalization, disturbances of body
image, and mental confusion. In the latter respect, the drug impairs mental
functions far more in relation to its other effects than do drugs of the LSD
class. Aside from ataxia, nystagmus, muscular incoordination, double vision,
flushing, profuse sweating, and vertigo sufficient to evoke nausea or vomiting may be encountered. Overdoses produce marked hypertension, which
can produce a fatal hypertensive crisis (Eastman and Cohen, 1975). Ketamine, the related compound, retains some of the same psychotomimetic
effects. This anesthetic has fallen into disfavor because of the hallucinogenic
side effects. Judging by an account of the experimental use of the drug, it is
quite similar to phencyclidine (Johnstone, 1973).
Phencyclidine poisoning is frequendy encountered in emergency clinics.
In addition to symptoms and signs already mentioned, miotic pupils,
increased deep tendon reflexes, and in severe cases, spasticity and opisthotonus are seen. Respiratory depression and hypertension are most lifethreatening. Removal of the drug by emetics or lavage, hydration, and a
quiet environment are basic treatment procedures. Diazepam may be used to
treat spasticity and agitation (Liden et ai., 1975).
3.7. Miscellaneous Drugs

One of the rare studies of harmine found that the threshold dose of the
material given orally was 300 mg. Higher oral doses, around 900 mg,
induced nausea, vomiting, tremors, buzzing noises, waviness of the environment, sinking sensations, a feeling of bodily vibration, and numbness. Many
of these physical and perceptual changes are similar to those from LSD.
When a dose of 150-200 mg was administered intravenously over a 20- to
30-min period, about half the subjects experienced visual hallucinations. On
the basis of these data, one might conclude that harmine is somewhat like
LSD in its clinical effects (Pennes and Hoch, 1957).
When the author was studying Ditran, it was virtually impossible to get
someone to volunteer to take a second dose. Thus, centrally acting anticholinergics were unlikely candidates for becoming popular social drugs. Compared to the vast amount of such drug use, they are not very popular. Yet
the syndrome of agitation, hallucinations, mydriasis, and urinary retention
should call attention to their possible use. Stramonium, which may be taken
as a tea prepared from over-the-counter tramonium cigarettes used for
treating asthma, is a common offender (Teitelbaum, 1968; Muller, 1967;
Hussain, 1971). Scopolamine was also available in a number of proprietary
sleeping medications that lent themselves to abuse, but these have now been
removed from the market (Stroo, 1967). Legitimate anti-Parkinson drugs
such as benztropine methanesulfonate, trihexyphenidyl, or others with
anticholinergic properties are increasingly abused, as are some antihistamines
397
with sedative and anticholinergic actions (Malcolm and Miller, 1972). The
central anticholinergic syndrome evoked by these drugs can be readily
reversed by physostigmine (Duvoisin and Katz, 1968).
Nutmeg, which is readily available on grocery shelves, is periodically
abused. As vomiting and severe abdominal pain may follow an excessive
dose, getting the right amount is important. Feelings of depersonalization
and unreality, changes in perceptions and visual illusions and hallucinations
are the presumed desired effects (Painter et al., 1971; Fras and Friedman,
1969). Some of the effects may be long-lasting, persisting for a week
(Panayotopoulos and Chisholm, 1970).
Catnip use has never caught on and one wonders if it was not another
hoax such as the smoking of banana skins. Its effects were said to mimic
those of marihuana, with euphoria, silliness, relaxation, e~oyment of music,
and increased flow of thoughts (Jackson and Reed, 1969).
4. PSYCHOLOGICAL EFFECTS IN EXPERIMENTAL

STUDIES
Generalizations about the effects of psychotomimetics on psychological
functions of man are difficult, and almost all studies have used LSD. Doses
have been for the most part small, necessitated by the actual inability to test
subjects with any reasonable degree of confidence at high dose levels. Testing
under even moderate doses of drugs is complicated by poor motivation of
the subjects, who often view the whole procedure with disdain. Nonetheless,
the range of doses used is sufficiently broad to lead at times to contradictory
results. A second difficulty has been the fact that studies have often used
mixed groups of "normal" volunteers or psychiatric patients, making interpretations of results difficult. Finally, individual experiments are limited in
the number of tests that can be performed, making a consistent pattern of
testing difficult.
4.1. Intellectual Functions

Usually, even moderate doses of any of these drugs severely impair most
intellectual functions. Immediate memory is impaired, whether measured by
ability to draw geometric figures from memory, remembrance of digits or
paired words, or many other devices. A dose of 1 ILg/kg of LSD-25 markedly
impairs the ability of subjects to repeat a numerical series backwards and
forwards (Orsini and Benda, 1959). Simple problem-solving, such as simple
addition or serial subtraction, tests of spatial relation abilities, attention and
concentration, recognition and recall, and color-naming and color-reading,
are also impaired. LSD-25 produced more errors and slower reactions in a
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LEO E. HOLLISTER
word-association test than were present in control tests; it also abolished the
differential response to traumatic and nontraumatic stimuli (Weintraub et al.,
1959).
4.2. Perceptual Functions

As visual phenomena are almost constantly experienced with psychotomimetic drugs, their study is more relevant. A dose of 50-100 p.g of LSD
intravenously raised the absolute visual threshold, the effect being greater on
photopic (central, bright, color) than scotopic (peripheral, dim, no color)
thresholds (Carlson, 1958). It was felt that these changes occurred independently of mydriasis, inattention, or other extraneous factors and were consistent with inhibition of cortical synaptic transmission. However, somewhat
opposite results were obtained in another study: the inten~ity threshold for
light was decreased (cone dark adaptation inhibited, rod dark adaptation
facilitated) as well as a decrease in threshold for electrical flicker in the
electroretinogram. Critical flicker fusion threshold was increased (Takashina,
1960). Retinal function tested by the electroretinogram and dark adaptation
curve in subjects treated with LSD and JB-318 revealed significant changes in
retinal function in those subjects who experienced hallucinations (Krill et al.,
1960). Thse changes were considered to be compatible with a mild toxic or
hypoxic effect on the retina. None of these studies throws much light on the
mechanism of the frequently reported clinical sign of increased contrast
between light and dark, nor the apparent wavering or undulation of viewed
objects.
Time sense is markedly altered by these drugs, although clinically it
seems that some subjects think it passes more slowly than usual while others
think the reverse. The same paradox has been found experimentally. At
doses of 1-2 p.g/kg of LSD, time intervals were overestimated by normal
subjects, who thought that real time was passing more slowly than normal
(Aronson et al., 1959). On the other hand, another study revealed underestimation of intervals of 10 and 30 sec by normal persons under the drug;
these subjects perceived real time as passing more rapidly. Their errors were
attributed to reduced attention and enhanced indifference, the usual problems of this type of research (Benda and Orsini, 1959). When I-sec time
intervals were measured, schizophrenic patients overestimated these, but not
normal subjects treated with LSD (Boardman et al., 1957).
4.3. Psychomotor Functions

Simple reaction time was significantly prolonged by doses of 1 p.glkg of
LSD as well as by an intravenous dose of phencyclidine (Orsini and Benda,
1959). An opposite effect of these two drugs has been noted in the rotary
399
pursuit test; this skill was increased under LSD but decreased under
phencyclidine (Rosenbaum et al., 1959). A dual pursuit test, in which two
pointers, one horizontal and one vertical, must be kept fixed on a moving
object, revealed significant impairment under LSD, which cleared after five
hours; this would be a time when all mental effects of the drug might be
waning and the results were interpreted as due mainly to difficulty in
concentration during the early learning period (Silverstein and Klee, 1960).
A dose of 1 /Lg/kg of LSD caused a moderate deterioration both in the time
required as well as the accuracy of a test of mirror-image drawing (Orsini
and Benda, 1960).
4.4. Projective Tests

Rorschach responses have been regarded as similar to those of schizophrenics by some observers, while appearing to others to be more like those
from an acute exogenous psychosis. Some consider that basic personality
factors are simply exaggerated by the drug, responses correlating quite well
with the type of clinical reaction (Delay et al., 1954). Almost every observer
has commented upon the increased tendency toward concrete thinking that
occurs under the drugs.
4.5. Other Psychological Effects

Although much speculation has been made concerning enhancement of
creativity by LSD, few solid data are at hand. Examples of paintings or
drawings done before and after LSD show some remarkable changes, but it
is difficult, at least for amateurs, to interpret them (Berlin et al., 1955). There
is little evidence that a more disciplined form of art is improved, such as
writing a sonnet or sonata. The whole question of long-term effects on
artistic expression is virtually impossible to measure.
LSD was found to enhance the type of primary suggestibility involved
with hypnotic states to a degree similar to that of trance induction itself
(Sjoberg and Hollister, 1965). Unfortunately, the secondary type of suggestibility, which is related to social conformity, has not yet been tested, although
clinical evidence suggests that it, too, may be enhanced.
While there is little argument that the personality characteristics of
subjects affect the type of response to LSD to varying extents, it is dubious
that LSD may be used profitably for uncovering latent schizophrenic
symptoms. It is very likely no more sensitive than many other techniques,
with the disadvantage of probably increasing false positive results (Sedman
and Kenna, 1965). The latter would be especially true when high doses of
drug are used. On the other hand, ability to tolerate well the effects of the
drug would certainly not be construed as positive evidence of emotional
400
LEO E. HOLLISTER
stability; such increased tolerance has been noted frequently in psychotics,

psychopaths, and alcohol or drug addicts (Krus et al., 1963).
5. ELECTROENCEPHALOGRAPHIC AND
NEUROPHYSIOLOGICAL STUDIES
A number of studies have revealed essentially no detectable effects on
the scalp EEG in human subjects given substantial doses of drugs. Negative
EEG studies have been reported in patients who have been given up to 6ILgi
kg of LSD, or doses of LSD ranging between 50 and 400 ILg, as well as
mescaline in doses of 500 to 1000 mg.
Most reports of changes attributable to the drugs emphasize their
mildness. Abnormalities in as many as 7 of 12 subjects given very modest (40
to 60 ILg) doses of LSD have been reported, possibly reflecting conceptual
differences in the ranges of normal among different EEG readers (Gastaut et
al., 1953). The change most frequently reported has been a slight increase in
alpha rhythm or a desynchronizing pattern. One investigator saw EEG
changes only during the clinical appearance of visual phenomena, there
being a suppression of the alpha rhythm with the appearance of visual
hallucinations (Shirahashi, 1960). Low-voltage fast activity with frequent
irregularity in the pattern has been reported from both mescaline and LSD
(Fin, 1959; Ruiz, 1958). In this regard, the increased frequency produced by
the psychotomimetics resembles the changes produced by other eNS stimulants. A similarity between the EEG effects of LSD and amphetamine has
been described, both producing significant decreases in voltage output, but
the changes from LSD appearing more slowly and lasting longer (Murphree
et al., 1962).
Only a few studies of depth tracings have been made in humans. Both
LSD and mescaline had a pronounced quieting effect on the spike and
sharp-wave foci of two epileptic patients; the existing paroxysmal activity of
three chronic schizophrenic patients was increased (Schwarz et al., 1956).
Subcortical paroxysmal activity was induced by LSD and mescaline in
hippocampal, amygdaloid, and septal regions by both LSD and mescaline
(Monroe et al., 1957). These changes were associated with behavioral
manifestations of anxiety and hallucinatory psychosis; they were blocked by
administration of chlorpromazine but not by reserpine.
The desynchronizing action of LSD is evident in interactions with drugs
having the opposite EEG effect. Synchronization and slowing caused by
chlorpromazine was reversed by 20-80 ILg of LSD administered intravenously (Flugel and Bente, 1957). An oral dose of 60 ILg was adequate to
abolish the paroxysmal theta waves produced by reserpine. EEGs previously
slowed by barbiturates, chlorpromazine, reserpine, reserpine, and chlorpro-
401
mazine in combination, convulsive therapy, or epilepsy were accelerated by

20-150 p,g of LSD (Bente et al., 1963).
Thus in the human, it appears that ordinary doses of psychotomimetics
have a slight but definite effect of desynchronization. They resemble other
CNS stimulants in producing this nonspecific effect. Except for an occasional
report linking the appearance of EEG changes with clinical symptoms, there
has been little relevance of the former to the latter.
6. PHYSIOLOGICAL EFFECTS
The clinical syndrome from these drugs has been studied at various
levels of sophistication, but agreement is fairly substantial about certain
physiological changes. Almost every observer has commented upon the
pupillary dilatation and increase in deep tendon reflexes seen with LSD. The
Lexington group has carefully measured blood pressure and pulse rates and
has found a significant, although not striking, increase in systolic blood
pressure and pulse rate following LSD at doses as low as 0.5 p,g/kg as well as
from mescaline, psilocybin, and dimethyltryptamine (Rosenberg et al., 1963).
Changes in blood pressure are not great and often variable. LSD caused a
slight increase in body temperature. Increased salivation and slight ataxia
have been described from LSD (Forrer and Goldner, 1951). Areas of color
vision in the visual fields were increased by mescaline, which also produced
ataxia; no cardiovascular changes of consequence were noted (Feigen and
Alles, 1955).
Endocrinological effects in man are not very clear. Data from a few
chronic schizophrenics indicated no change in urinary excretion of epinephrine or norepinephrine following small doses of LSD. The same doses
increased excretion of catecholamines in manic-depressive patients, and
increased epinephrine excretion while decreasing norepinephrine excretion
in involutional patients, both of whom showed more clinical reactions
(Elmadjian et al., 1958). We have found that LSD 2 p,g/kg orally produced a
small, early rise in epinephrine excretion, but that over a longer period of
time (8 hr), the excretion rates did not differ from a control period. Total
metanephrines and vanillylmandelic acid (VMA) excretion were unchanged.
Doses of 200-300 P,g of LSD reduced 24-hr urinary excretion of dopamine
and serotonin, but not norepinephrine, or the metabolites of these neurotransmitters, homovanillic acid, 5-hydroxyindoleacetic acid, or vanillmandelic
acid (Messiha and Grof, 1973). It is very difficult to draw conclusions about
what may be happening in the brain by what comes out in the urine. An
antidiuretic action of LSD has been twice demonstrated, using different
techniques; it is not seen in all subjects but in those in whom it is observed, it
may be profound (Kies et al., 1957). Excretion of 17-hydroxy- and 17-
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LEO E. HOLLISTER
ketosteroids by subjects taking 1.5-2 JLg/kg of LSD is not much changed,

although a significant increase in excretion of 17-ketogenic steroids was
noted during the first 8 hr after the drug. No effects were noted on serum
protein-bound iodine levels within the first 4 hr after the drug (Hollister et
at.,
1970).
Although increased serum creatine phosphokinase (muscle isoenzyme)

and aldolase have been observed in acute psychotic conditions such as
schizophrenia, no such elevations were found following administration of
LSD or N,N-dipropyl-tryptamine to 36 normal subjects (Meltzer et at., 1970).
Apparently, drug-induced psychoses differ from natural ones in respect to
levels of muscle enzymes.
7. KINETICS OF LSD IN MAN

Humans given doses of 2 JLglkg intravenously had blood specimens
taken that were analyzed for LSD using a spectrofluorometric technique.
After equilibration had occurred in about 30 min, the plasma level was
between 6 and 7 ng/ml. Subsequently, plasma levels gradually fell until only a
small amount of LSD was still present after 8 hr. The half-life of the drug in
humans was calculated to be 175 minutes. Performance scores on simple
arithmetic tests showed considerable impairment during the period of
maximal levels followed by improvement as the plasma levels of drug
dropped (Aghajanian and Bing, 1964).
Subsequent pharmacokinetic analysis of these data indicated that plasma
concentrations of LSD were explained by a two-compartment open model.
Performance scores were highly correlated with concentration in the tissue
("outer") compartment, which was calculated at 11.5% of body weight. The
new estimation of half-life for loss of LSD from plasma, based on this model,
was 103 min (Wagner et at., 1968).
8. ADVERSE REACTIONS-PSYCHIATRIC
The clinical manifestations of adverse psychiatric effects of LSD have
been reviewed elsewhere (Sarwer-Foner, 1972). In general, not much new
has been added over the years. The acute panic reaction is still most
common, but of much greater concern has been the prolonged psychosis.
The latter is still, fortunately, uncommon. Of 57 patients admitted to a
poisoning treatment center in Scotland with reactions due to LSD, only 16
were considered to require psychiatric help. Most were treated with sedation.
Men predominated, the mean age being 20 years. Most had previously taken
other drugs, including LSD. The majority were from lower social classes, in
403
distinction to the common notion that use of these drugs is limited to the
literati (Forrest and Tarala, 1973). Another review of the complications from
LSD makes the special point that when the drug was administered to
psychologically normal subjects under secure conditions, lasting adverse
effects did not occur (McWilliams and Tuttle, 1973). Probably true, but if
that were the way the drug was usually taken, there would be no problem.
The characteristics of 12 patients with an acute drug-induced psychosis
were compared with those of 26 patients with acute psychoses unrelated to
drug use. Not surprisingly, the former group had more of the characteristics
associated with "reactive" or schizophreniform psychoses than those associated with true schizophrenia (Bowers, 1972a). A study of the formation of
cerebrospinal fluid metabolites of serotonin (5-hydroxyindoleacetic acid) in
these subjects revealed a lesser formation in those who had been exposed to
LSD, consonant with the idea that the clinical effects of the drug are
mediated through an action on this neurotransmitter (Bowers, 1972b). Longterm psychoses, in contrast to the acute reactions, may be difficult to
distinguish from true schizophrenia. These aspects were carefully studied in
19 such patients. Thought disorder, auditory hallucinations, aggressive
behavior, paranoid delusions, and regression were the most frequent symptoms in the drug-induced group, such symptoms resembling those which
may occur in true schizophrenia. The major distinguishing features of the
drug-induced psychosis were regression to childhood was common, grandiose delusions of a philosophical nature prevailed, visual hallucinations and
perceptual disturbances were observed. The wide spectrum of symptoms,
compatible not only with schizophrenia, but also with affective and neurotic
disorders, was most striking. Such psychoses may require treatment with
antipsychotic drugs in much the same way as true schizophrenia, but their
stay in the hospital was brief (mean, less than six weeks) (Dewhurst and
Hatrick, 1972). Electroconvulsive therapy (ECT) was found to shorten the
course more than drug treatments alone. ECT has also been found to be
effective when other types of treatment have failed (Muller, 1971). Not to be
outdone, one patient who failed to respond either to chlorpromazine or to
ECT improved when given imipramine (Fookes, 1972). Treatment, therefore, is based on the type of psychosis as determined by its clinical
presentation. It is more likely that patients who have prolonged psychotic
reactions to LSD are either latent or actual schizophrenics than that the drug
can cause the disorder de novo.
Acute panic reactions to LSD, which are usually of only a few hours
duration, may be handled in two ways. One may "talk the patient down,"
provided staff or friends are available, or one may simply sedate the patient
and allow him to sleep off the effects of the drug. In the latter case, recent
experience suggests that diazepam or some similar drug is preferable to the
antipsychotics (Barnett, 1971). The latter produce such lasting and noxious
side effects that the treatment may ultimately prove to be more disagreeable
than the illness.
404
LEO E. HOLLISTER
"Flashbacks" or acute, unpredictable recurrences of phenomena experienced under LSD, have always been a mystery. Because they may occur
months later with completely lucid intervals, most of us have subscribed to a
psychological theory of causation. They may, of course, be triggered by other
drugs that alter consciousness, such as marihuana or, in one unusual case,
biperiden given to prevent phenothiazine-induced extrapyramidal reactions
(Tec, 1971). Biperiden, being a potent anticholinergic, especially when
combined with phenothiazines, may be hallucinogenic in its own right.
Although it is difficult to see why it should be effective, haloperidol
eliminated flashbacks in four of eight patients treated over a four-week
period and reduced their frequency in the other four patients (Moskowitz,
1971). A more intriguing possibility is that flashbacks could represent some
long-lasting temporal lobe seizure. They are paroxysmal, brief, and "deja vu"
phenomena, which are part of temporal lobe epilepsy. EEG confirmation
could not be obtained, but treatment on one patient with diphenylhydantoin
was said to be beneficial. When the drug was discontinued without the
patient'S knoweldge, attacks returned within 48 hr (Thurlow and Girvin,
1971). Such experiments in what is usually a self-limited disorder can not be
considered as proof of efficacy for any treatment.
A slightly different sequel to LSD use are "trailing phenomena." These
are visual illusions in which objects appear to move in discrete, discontinuous
fashion, as though exposed to a stroboscopic light. They may persist for as
long as a year following the last dose of the drug (Asher, 1971). Their cause
is unknown, with as many theories as for the cause of flashbacks. In one
patient who had both conditions, a small dose of trifluoperazine alleviated
trailing but did not ameliorate the flashbacks (Anderson and O'Malley,
1972).
Homicides under the influence of LSD continue to be reported. In one
tragic case, the homicide occurred soon after the patient had been discharged from psychiatric care following a previous homicidal assault (Kleptisz and Racy, 1973). Another patient, with marked homicidal impulses,
developed a fairly long-lasting psychosis following use of LSD. While still
psychotic, he killed a stranger upon impulse. While recovering from a bullet
wound inflicted by a policeman in the fray, his psychosis cleared quickly and
he remained free of psychosis for several years (Reich and Hepps, 1972).
During the past several years the author has encountered several instances of
persons accused of homicide who claimed that it was perpetrated under the
influence of some hallucinogenic drug. Some of these instances strain one's
credulity and suggest that this type of plea is often misused.
An obsessive neurosis was precipitated by use of morning glory seeds,
which contain a material similar to LSD. This unusual reaction was not
responsive to psychotherapy, drugs or ECT but responded to behavioral
modification (Solyom and Kingstone, 1973). All the evidence suggests that
hallucinogens may unmask a variety of psychiatric disorders, but aside from
their acute effects, they probably directly cause none.
405
9. ADVERSE EFFECTS-PHYSICAL
9.1. Chromosomes, Dysmorphogenesis, and Carcinogenesis
Few areas of scientific inquiry are clouded with more emotion and suffer
from poorer experimental or epidemiological techniques than the controversy about the effect of LSD on chromosomes. It has left a blot on human
cytogenetics as a discipline.
Chromosome breaks and gaps are subject to different definitions and to
different interpretations when read on slides. Some are to be expected as
artifacts of the preparation. Consequently, reports on the prevalence of such
alterations due to LSD vary greatly. In various studies they have either been
the same or more frequent than seen on control preparations, or occur with
the same frequency as those from other commonly used drugs. These
considerations apply whether or not the tests were done in vitro, or used cells
from exposed subjects. At the present time, the bulk of evidence, as reviewed
extensively by two observers, suggests that the burden of proof is still on
those who allege that the frequency and severity of chromosomal breaks
encountered from LSD exposure is of clinical significance (Dishotsky et ai.,
1971; Long, 1972). Rather than dismiss the matter out of hand, one should
take the stance that harm has not been disproved and try to determine better
ways to settle the issue (Berlin and Jacobson, 1972).
Evidence for altered development of the embryo in patients exposed to
LSD is somewhat more persuasive, but such alterations might be due to
many coincidental factors other than the drug itself. From 148 pregnancies
in 140 women who had used LSD, 83 liveborn children were delivered, 8
having major congenital defects. This prevalence seems to be higher than
normal. Even more striking is the fact that 65 abortions occurred, 12 of
which were spontaneous. Four intact embryos from 14 therapeutic abortions
were found to have gross anomalies Uacobson and Berlin, 1972). One of the
factors that may cause such changes could be an alteration in protein
synthesis induced by LSD. In vitro studies showed marked inhibition of
immunoglobulins from T - and L-Iymphocytes cultured in the presence of the
drug. It was hypothesized that the indole moiety of LSD might substitute for
that of tryptophan in protein synthesis, making peptide formation impossible
beyond that point (Maugh, 1973). Remarkably enough, no clinical evidence
for impaired immunity after LSD has been reported.
The case for carcinogenesis is less certain, again for the obvious reasons
that controlled epidemiological studies are virtually impossible. Two patients
who had testicular choriocarcinomas had taken heavy doses of LSD for
months before the appearance of their tumors. As these are germinal
tumors, their importance may extend beyond the fate of the affected
individual (Levick and Levick, 1971).
Such difficult questions will not be easily resolved. Until they are, one
406
LEO E. HOLLISTER
should counsel prudence about the use of any hallucinogen in repeated

doses by any individual who might spawn offspring. We may have the right
to hurt ourselves if we so desire, but this right does not extend to inflicting
lifelong misery on others.
9.2. Miscellaneous Other Types

Although hyperthermia can be regularly produced in animal pharmacologic tests with LSD, such reactions in man are rare. Measuring body
temperatures during experiments with LSD, the author has never been able
to show a rise greater than expected with diurnal variation. Larger doses may
do the trick. One IS-year old man, in a severely disturbed state from a dose
of LSD of unknown quantity, had a fever that reached 41.3C. He was
treated with chlorpromazine (which in this particular instance would be
highly appropriate) and cooling soaks (Friedman and Hirsch, 1971). Eight
young patients, all of whom had "snorted" material thought to be cocaine but
that proved to be LSD, were admitted simultaneously to a single hospital.
Five were comatose on admission, three being in respiratory arrest, which
required assisted ventilation. Fever developed in four (ranging from 100.S to
107.0~). Transient hypertension was noted in four, reaching the level of
230/130 in one. All had a disturbance in blood coagulation manifested by the
inability to form clots and absence of clot retraction. The latter might have
been associated with some deficiency in platelet function, as both platelet
counts and prothombin time were in the normal range (Klock et ai., 1974).
Subjective visual disturbances including diploplia, persistent after-images
and "seeing over my nose all the time" were found in three young users of
LSD. Ocular examinations were normal and reassurance was apparently
successful (Raine, 1972). More serious damage can occur when subjects
under the influence of LSD gaze at the sun. Two cases of solar retinopathy
were reported in young patients who did this (Schatz and Mendelblatt, 1973).
Some cases reported in press accounts have been hoaxes, but the danger is
real.
An unusual instance of occlusion of the internal carotid artery with left
hemiplegia occurred some hours. after a 20-year old woman took an oral
dose of LSD. The most likely cause was believed to be vasoconstriction
secondary to the effects of the drug, as other reports of focal arterial
occlusions in the brain preceded this one (Lieberman et ai., 1974). Ergot
alkaloids can be potent vasoconstricting agents but LSD is not especially so.
Two cases of retroperitoneal fibrosis followed exposure to LSD in middleaged men. In one instance the drug had been used extensively, but in the
other only one exposure was claimed. The most common cause for this
disorder is chronic use of methysergide, a homolog of LSD (Aptekar and
Mitchinson, 1970).
An unusual case of angioneurotic edema and urticaria was reported in a
407
patient whose employment was the chemical and physical analysis of synthetic and ergot-derived lysergic alkaloids (Nava, 1972). While it is not certain
that LSD was the allergen, the other frequent evidence of allergy in drugusing populations suggests that it may be a contributing factor. Interferon
production was markedly inhibited in mice treated acutely with peyote,
hashish, and mescaline. The effect persisted for several days (Lefkowitz et al.,
1973). Thus, hallucinogenic drugs could conceivably alter host resistance to
viral infection, but such extrapolations to man can not be made at this time.
10. THERAPEUTIC USES

Few reports on the use of psychotomimetic drugs as therapy would meet
criteria for an adequate therapeutic evaluation. Difficulties include poorly
defined samples of patients, vague goals of treatment, lack of comparison
groups, excessive claims, and unorthodox investigators. These drugs are
presumed to exert their benefits through facilitation of insight psychotherapy, or by producing abreaction, a psychedelic (mind-manifestating) experience, or a religiomystical experience, and as "crisis" therapy. Evidence that
psychotomimetics function in these ways in any constructive fashion, or
better than other less disruptive drugs, is not at hand. Nonetheless, these
drugs have been used therapeutically in a variety of psychiatric disorders.
10.1. Psychoneuroses
As most psychoneuroses are treated with some form of psychotherapy,
the addition of LSD or kindred drugs is based on the putative facilitation of
psychotherapy they may offer. Progressive weekly doses of 25-200 ILg were
used in 36 psychoneurotics, 20 of whom had previous psychotherapeutic
intervention. After an average of ten treatments, 14 patients were considered
recovered; results were poorer when the number of treatments was fewer.
Only one patient refused treatment after the first dose (Sandison et al.,
1954). Repeated administration of LSD in doses of 40-200 ILg was of great
benefit to 8 of 22 neurotics; discussion of the LSD experience on the day
following treatment was considered to be an especially important part of the
treatment program (Giberti and Gregoretti, 1955). Fifty patients, chiefly
psychoneurotics with prior psychoanalytic therapy, were given doses of 2550 ILg, increasing to a maximum of 450 ILg; five were cured, 14 markedly
improved, 27 slightly improved, and only 4 unimproved. During a two-year
follow-up period, only 9 patients relapsed (Martin, 1957).
The role of LSD in treating ordinary cases of anxiety is more accepted
than its use in treating obsessive-compulsive neuroses. Some of the latter
were included in 23 neurotic patients who received doses ranging from 25 to
408
LEO E. HOLLISTER
500 p,g orally or intravenously over a period of a few weeks to four months;
the number of treatments varied from 1 to 25: Twelve were improved, 9
were unchanged, and 2 were considered to be worse (Lewis and Sloane,
1958). Sixteen patients with compulsive states were treated with 50- to 100p,g doses of LSD over one to eight sessions. Compared to previous treatment,
13 were improved; further improvement was subsequently noted from
individual or group psychotherapy (David, 1960). Polypharmacy was practiced in a night hospital where 50 patients, mostly psychoneurotics, were
given LSD in 40- to 200-p,g doses combined with 5-10 mg of methamphetamine; after 4 to 6 hr the sessions were interrupted by chlorpromazine or
thioridazine. Recovery was obtained in 7, great improvement in 8, and
moderate improvement in all but one (Ling and Buckman, 1960).
The only controlled trial so far reported found LSD to be no more
effective than standard psychotherapy or abreaction with intravenous sodium
hexobarbital and methamphetamine (Robinson et al., 1963). An ambiguous
report on phencyclidine found it usually helpful in promoting a free flow of
emotionally charged material when given twice weekly to five chronically
obsessive patients in doses of 5-15 mg orally. Effects at these doses were
neither severe nor long-lasting (Davies, 1961).
More recent studies still show the same divergence of opinion between
the clinical impressions of advocates of therapy versus those who conduct
some sort of controlled trial. Anecdotal evidence was put forth to assert that
psychedelic psychotherapy could effect personality change in patients who
were specially prepared for the procedure and strong believers in it (McCabe
et al., 1972). The same group compared LSD treatment against "conventional institutional treatment" of chronic, severe neurotics and concluded that
high doses of LSD had a superior short-term impact over conventional
treatment (Savage et al., 1973). A controlled trial used 28 patients randomly
assigned to two psychotherapy groups, one of which received five LSD
sessions and the other five placebo sessions over a 13-week period. Both
groups improved to a modest extent with no differences between them.
Twenty patients followed for 18 months still showed little differences
between the LSD and placebo groups; such as there were favored the
placebo group (Soskin, 1973).
10.2. &hizophrenic Reactions

After being treated with LSD at weekly intervals 7 of 14 schizophrenic
patients were improved. Doses were 50 to 100 p,g, followed in two hours by
50 mg of chlorpromazine, rather modest amounts of each drug (Sandison
and Whitelaw, 1957). Twelve schizophrenics were treated orally with LSD in
doses of 60-250 p,g given from one to ten times. LSD was considered to be
valuable in accelerating the development of an acute psychotic episode,
which could then be managed by electroconvulsive therapy Qost, 1957). A
PSYCHOTOMIMETI,C DRUGS IN MAN
409
similar procedure selected "therapy resistant" schizophrenic patients on the

basis of clinical response and a hypersynchronous EEG and treated them
with LSD and Ditran for periods of one to three months. When they became
more psychotic, they were then treated with antipsychotic drugs, to which
they now seemed to be more amenable (Itil et al., 1969). This procedure is
somewhat analogous to hoping that a common cold, which cannot be treated
specifically, will progress to pneumococcal pneumonia, which can. Ten
chronic schizophrenic patients treated with 1-2 JLg/kg oral doses of LSD
weekly for five weeks showed no marked improvement (Jovanovic et al.,
1960). A similarly negative report followed a trial of mescaline in doses of
500-750 mg given to 24 chronic schizophrenics. The majority developed
some inner feelings of tension without emotional outbursts; a minority
showed some aggravation of underlying symptoms. It was concluded that
mescaline was not a clinically effective agent (Merlis, 1957).
Because Ditran is even more disturbing than LSD or mescaline, there
has been some interest in its use in this desperate situation. A single dose of
15 mg was said to produce some improvement in 12 of 39 schizophrenics of
undifferentiated type. The criteria of change were not stated (Karn et al.,
1961). Single, or sometimes multiple, doses of 30 mg of Ditran intramuscularly were given to 103 hospitalized psychiatric patients, 27 of whom received
concomitant ECT. Results were spectacular: 8-9 patients were considered to
be improved to the point of discharge, while 17 were actually discharged and
working. Results were equally impressive in schizophrenics (20 of 29 improved) and depressions (29 of 37 improved). Addition of ECT added
nothing to treatment with the drug alone (Finkelstein, 1961).
In general, little enthusiasm persists for the treatment of schizophrenic
reactions with psychotomimetic drugs. The large number of effective antipsychotic drugs available seems to be clearly superior to any other treatment.
Here, no therapeutic vacuum exists.
10.3. Depressions
Treatment of depressions by any means is difficult to evaluate, as many
depressions remit spontaneously. Despite the availability of a proven effective
treatment, such as ECT, and a variety of antidepressant drugs with varying
degrees of efficacy, the treatment of each case of depression must usually be
empirical and is often frustrating. Consequently, any treatment of promise
has to be looked at.
LSD, initially administered in 25-JLg doses with weekly or biweekly
increments to 100-150 JLg was given to 29 patients with depressive states or
borderline schizophrenic reactions. The number of treatments averaged 5,
ranging from 1 to 15. Improvement was noted in 16 of 22 patients who
could be followed for from 6 to 17 months. Daily doses of 20-100 JLg orally
for one month were given to 15 patients with psychotic depressions. Three
410
LEO E. HOLLISTER
recovered, 4 improved, 4 were unchanged, and 4 did not complete treatment. It was concluded that LSD offered no advantage over usual methods
for treating depression (Savage, 1952).
The highly beneficial effects of single doses of Ditran in treating
depressions, mentioned above, would seem to be confirmed by a report of
the recovery of 16 of 25 depressed patients given single doses of 10-20 mg,
usually 15 mg, orally. Five relapsed during a follow-up period of three
months, but the remainder maintained their remissions (Bercel, 1961). Such
reports as these indicate that a further look at this drug for treating
depression is in order. Yet, if we had to hazard a guess on the mechanism of
the apparently beneficial response, based on our studies of this drug in
normal subjects, it would be that the patients feared they might receive a
second dose.
10.4. Alcoholism
Alcoholics were treated with LSD in single doses of 200-400 JLg, or
mescaline in doses of 500 mg, and administration of the drug was followed
by a prolonged interview. Complete abstinence or minimal drinking was
obtained in 6 cases, definite reduction in drinking in 6, and no change in 12;
although some patients were transiently improved, no patient was made
worse. It was thought that alcoholics with character disorders or some degree
of psychopathy did best on this treatment, while those with psychotic
symptoms did not benefit (Smith, 1958). Single doses of 200 JLg of LSD were
given to 68 chronic alcoholics, 26 of whom attained sobriety during an
average follow-up period of 38 weeks. Prior to treatment, psychodynamic
personality factors had been elicited, and these were used as the basis for
therapeutic intervention during the LSD state (O'Reilly and Funk, 1964).
Doses of 400-1500 JLg were used along with psychotherapy in 61 alcoholics
followed for 3-18 months. Thirty were much improved, while 16 showed
some degree of improvement (MacLean et al., 1961). It has been alleged that
a "favorable" environment provides better therapeutic results from LSD in
alcoholics; presumably the more intense the experience, the better the effect
(Chwelos et al., 1959). Only symptomatic improvement (relief of nightmares,
impotency, and depression) was claimed for 10 of 20 alcoholics treated with
LSD.
Some reservations have been raised. An attempt to replicate the work of
the Saskatchewan group, which has reported the most outstanding results,
using a situation as nearly similar as possible, revealed no increase in sobriety
following an LSD therapeutic intervention, even if as many as three massive
doses were given. Despite the failure to show a clinical response, many
patients seemed to experience the transcendental religious experience that
has been considered central to this form of treatment (Van Dusen et al.,
1964).
411
In recent years, controlled evaluations of LSD in alcoholics have been

made by different groups employing somewhat different techniques. For
short periods alcoholics respond favorably to any intervention, so that
without some sort of control or comparison group almost any treatment
looks good. One study compared a large single dose of dextroamphetamine
with one of LSD, with little psychotherapeutic intervention. LSD produced
slightly better results early on the follow-up period, but by six months there
were no differences between the two treatment groups (Hollister et al.,
1969b). Another study compared three LSD treatment procedures against
"no therapy." None of the treatments was superior to any other (Ludwig et
al., 1969). LSD given with and without a therapist was compared with
sodium amobarbital-amphetamine abreactive treatment and routine clinic
care. At the end of a year, all groups were improved, but equally so
(Johnson, 1969). No benefits from LSD treatment of alcoholics or neurotics
were found in still another controlled study (Denson and Sydiaha, 1970).
One group, which uses psychotomimetics to produce a "peak experience,"
still claims success with their treatment, but without adequate control or
comparison groups (Kurland et al., 1971). Recently, they have turned their
attention to dipropyltryptamine, which has a shorter span of action (Grof et
al., 1973).
A number of follow-up studies of patients who had been treated with
LSD for alcoholism come to identical conclusions. Over the long term, the
drug had little evidence of any sustained or meaningful beneficial effect
(Bowen et al., 1970; Faillace et al., 1970; McGlothlin and Arnold, 1971;
Bryce, 1970).
A recent claim that LSD helps rehabilitated narcotic addicts when used
in the same fashion as for alcoholics has not been tested elsewhere (Savage
and McCabe, 1973).
11. PSYCHOTOMIMETICS AND MODEL PSYCHOSES

The revival of interest in chemical theories of psychosis during the past
generation has several sources. First, the rapid advance in chemical techniques has made possible many studies completely unthinkable prior to their
development. Second, the production of abnormal mental states by various
psychotomimetic drugs convincingly proved that chemicals can markedly
alter normal mental functions. This change is especially striking with LSD, in
that such minute quantities have such enormous effects. Third, the introduction of drugs that ameliorate naturally occurring psychoses has suggested to
many that, if a chemical treatment is effective, a chemical cause must
underlie the disorder. Finally, the demonstration of specific enzymatic
defects in a number of illnesses associated with mental deficiency (phenylketonuria, galactosemia, maple-sugar urine disease) or specific chromosomal
412
LEO E. HOLLISTER
defects in others (21-trisomy or 21-13 translocation in mongolism) has

reemphasized the importance of chemical factors in brain function.
12. CONDITIONS FOR ENDOGENOUS PSYCHOTOGENS

At the outset it would be well to clarify that, for any chemical theory of
the cause of psychosis (and we are talking in this context exclusively of
schizophrenic reactions) to be tenable, a number of conditions must be met:
1. The chemical that causes the mental disorder must be endogenous,
consisting either of too little or too much of some normal material or
being an abnormal metabolite of it.
2. The production of the offending chemical (or its failure to be
produced) must be continuous and prolonged, or it must act indirectly by producing irreversible enzyme inhibition or structural
damage. Many instances of schizophrenia lasting over a half-century
can be documented, making this disorder the epitome of chronic
infirmities.
3. The quantitative bases for production of the abnormal material must
be realistic. At present one is inclined to think that any chemical toxin
must be produced in extremely small amounts. Most have been
extremely elusive to detection by available chemical techniques, nor
can they be demonstrated clinically by such gross techniques as
exchange transfusions. On the other hand, some postulated materials, such as various epinephrine metabolites, would have to be
present in extraordinarily large amounts in order to have clinical
effects; the total amount of catecholamine substrate available in the
body would be inadequate to provide such amounts, even assuming
total conversion of the material.
4. The toxic material should be one for which tolerance did not
develop, or one that would produce irreversible enzymatic changes.
Most known psychotomimetic substances have been shown to evoke
tolerance quite readily.
5. The effects of the material must be highly specific, affecting only the
central nervous system. Schizophrenics are often remarkably healthy,
with few of the gross alterations of sympathetic nervous system
functions that are characteristic of psychotomimetics. Quite possibly
only specific brain areas are involved, requiring a higher degree of
specificity than is known for most postulated substances. Further,
even after prolonged exposure of the nervous structures to this
chemical, none of the classic histopathologic or histochemical changes
of toxic injury should be demonstrable; at least none have been
shown convincingly yet.
413
Some would add that the reversibility of the psychotic syndrome by

known antipscyhotic drugs should be added as a criterion, but in view of the
fact that most studies of psychotomimetics are done in normals, for whom
the antipsychotic drugs are noxious, this criterion is not wholly reliable.
13. CONCEPT OF ENDOGENOUS PSYCHOTOGENS

An original and provocative hypothesis for a chemical basis fof schizophrenia was proposed in 1952 (Osmond and Smythies, 1952). The suggestion was made that mescaline or some related compound might be easily
synthesized in the body from normal precursors if the process of biological
transmethylation was altered. Dopamine, the immediate precursor of norepinephrine, if methylated at the hydroxy positions on the ring, could become
3,4-dimethoxyphenylethylamine, a compound previously reported to produce catatonic states in animals (Fig. 1). Acting on the basis that if such
excessive methylation occurred in schizophrenia it could be countered by
administering a methyl acceptor, schizophrenics were treated with nicotinamide in huge doses. Although promising results have been reported by the
group proposing the hypothesis, this treatment is not generally considered to
be effective. An opposite test of the hypothesis involved the feeding of the
amino acid methionine, a methyl donor, in large amounts. It was postulated
that by increasing transmethylation, schizophrenics would be made worse,
which was the case in about one-third the patients treated (pollin et al., 1961).
This finding has been confirmed by others (Brune and Himwich, 1962).
Finally, a short time later, in 1962, a spot was found on paper chromatograph:c examination of the urine of schizophrenics that did not occur as
often in normals, and was tentatively identified as 3,4-dimethoxyphenylethy-
3-methyoxytyramine
dimethoxyphenethylamine
FIG. l. Possible metabolic conversion of dopamine to dimethoxyphenethylamine (DMPEA).

Solid arrow is major metabolic pathway; dashed arrow is a minor pathway.
414
LEO E. HOllISTER
lamine (Friedhoff and Van Winkle, 1962). Thus, it appeared that things had
come full cycle: this compound, postulated as a possible endogenous psychotogen a decade earlier, was excreted by schizophrenics. Unfortunately, this
material is inactive in man when given in doses comparable to mescaline by
mouth (Hollister and Friedhoff, 1966).
The same group that proposed the above hypothesis had an alternative
possibility (Hoffer and Osmund, 1959). It was suggested that adrenaline may
not be metabolized properly under stress and, instead of following the usual
route of catabolism, might be transformed into a cyclized indolelike quinone
with psychotomimetic effects. This compound, adrenochrome, was reported
to be found in blood and urine by the same group that proposed the theory,
but by no one else (Fig. 2). Furthermore, it is not even certain that
adrenochrome has psychotomimetic activity or exists in a stable form.
As it would only require the N -dimethylation of serotonin to produce
bufotenin, it was logical to assume that this pathway might be a source of an
endogenous psychotogen (Fig. 3). Rabbit lung was demonstrated to possess
the required methylating enzyme, lending encouragement to this hypothesis
(Axelrod, 1961). Later, enzymes were found in blood and in brain that would
form dimethyltryptamine and N-methyltryptamine (Saavedra and Axelrod,
1972; Wyatt et ai., 1973a). An attempt to find bufotenin in the urine of 15
nonpsychotic patients was unsuccessful, but the material was found in
amounts of around 400 Jg/liter in 25 of 26 hallucinating schizophrenics
(Fischer et ai., 1961). Confirmation of these findings was soon forthcoming;
A "bufotenin-like" substance was found in 9 of 12 urine samples from five
schizophrenic patients and none of three mentally deficient patients (Brune
et ai., 1963). However, it has been pointed out that the technical methods
used by these workers were not highly specific. Using a method claimed to be
superior to previous ones, no bufotenin could be found in five normals or 21
schizophrenic patients (Siegel, 1965). At the moment, therefore, the possibility that bufotenin functions as an endogenous psychotogen is highly doubtful.
epinephrine
adrenochrome
FIG. 2. Possible conversion of epinephrine to adrenochrome. This is a highly doubtful

occurrence. Epinephrine is only present in the brain in small amounts.
CDII
415
CH2-yH-NH2
COOH
N
H
tryptophan
tryptamine
N,N-dimethyltryptamine
5-hydroxytryptamine (serotonin)
5-hydroxydimethyltryptamine
FIG. 3. Metabolic pathways of tryptophan that lead to N,N-dimethyltryptamine or 5hydroxydimethyltryptamine (bufotenin); O-methylation would convert latter to 5-methoxydimethyltryptamine, a substance also postulated as an endogenous psychotogen.
More recently, attention has shifted from bufotenin (which is a poor

candidate on clinical grounds) to N,N-dimethyltryptamine or 5-methoxyN,N-dimethyltryptamine. Both of these substances have been found in the
urine of schizophrenic patients (Narasimhachari et at., 1971). With newer
methods, however, these findings have not been confirmed, at least for
dimethyltryptamine (Wyatt et at., 1973b; Bidder et at., 1974). The failure of
dimethyltryptamine to evoke tolerance in cats allows it to meet one of the
criteria for an endogenous psychotogen (Gillin et at., 1973).
Melatonin is a naturally occurring derivative of serotonin that has been
isolated from the pineal gland. Its functions are uncertain; it may be involved
in pigment deposition, acting as a lightening factor, and may be a regulator
of circadian rhythms. The removal of a molecule of water from melatonin
results in its conversion of lO-methyoxyharmalan, which has been demonstrated to have antiserotonin actions, similar in degree to LSD (Fig. 4). It is
also reported to disrupt conditioned avoidance responses in animals (McIsaac, 1961). A pathway for conversion of melatonin to this harminelike
derivative has been demonstrated, providing a basis for an endogenous
psychotogen. This provocative hypothesis has not yet been confirmed or
416
LEO E. HOLLISTER
HO~ICH 2CH 2NH-C-CH 3
~)
H
0",,CH3
N-aoel,'",<olo";"
(,
O~CH2CH2NH-C-CH3
0~)
5-methoxy-N- acetelyserotonin
(melatonin)
10-methoxyharmalan
FIG. 4. Normal formation of melatonin by action of hydroxyindole-O-methyltransferase.
Further condensation of molecule by dehydration and cyclization of side-chain could form
the beta-carboline, lO-methoxyharmalan, a harmine-like material. Other such side-chain
cyclizations have been described, but these may be artifacts.
refuted, but the basic reasoning is subject to the same cautions mentioned
earlier for any postulated chemical basis for psychosis.
14. MODEL PSYCHOSIS

Following a study some years ago, the author concluded that the
differences between schizophrenia and the LSD "psychosis" were so great in
kind that anyone who claimed to be a clinical psychiatrist ought to be able to
make the distinction (Hollister, 1962). More recently, observations of young
psychotics experiencing their first break suggest a greater resemblance than
formerly thought. So many of these patients have had prior exposure to LSD
that it is difficult to determine how much of their symptoms are like those of
LSD or how much exposure to this drug has modified their schizophrenic
symptoms. One suspects the latter, for eidetic hallucinations and oneiric
states were rare manifestations of schizophrenia in the past, although now
they are frequently reported.
For many years, most astute clinicians thought that the best druginduced model of schizophrenia was produced by abuse of amphetamines, a
view that is still strongly supported. The fact that the amphetamine-induced
psychosis may work through biochemical mechanisms currently fashionable
in the etiology of schizophrenia has made this model much more attractive
417
(Snyder, 1973). Amphetamine-like materials, such as beta-phenethylamine,

are present in the brain and presumably could go awry. We have not heard
the last of the model psychosis by any means, although it is safe to predict
that the model drug may change periodically.
15. PATTERNS OF SOCIAL USE

During the 1960s, the extensive advertising freely given psychotomimetic drugs by the press raised the possibility that everyone might ultimately
become an "acid-head." With diminished press coverage and less frequent
untoward reactions to these drugs coming to medical attention, it is easy to
conclude that their use has decreased. Perhaps this is true but, judging by the
samples of drugs submitted for analysis from street sales, psychotomimetic
drugs are still abundant.
The revolt of the young against the product of science and their faith in
things that were natural or "organic" led them to embrace mescaline as their
favorite psychotomimetic. Few of them ever saw that drug, for virtually all
the material purveyed as mescaline (and psilocybin, for that matter) was LSD.
So despite changing fashion, LSD remains the major psychotomimetic drug.
It is being rivaled by phencyclidine, however. The illicit synthesis of this drug
is apparently accomplished with as much ease as that of LSD, so supplies are
abundant.
Drug users seldom stick to a single drug (almost all alcoholics are
smokers) and this practice holds with the newer social drugs. Psychotomimetics are seldom used as the sole social drug, but rather in a matrix of drug use
that may include most, if not all, other illicit and licit drugs. The fact that
they now cause so little trouble is probably because a better product is
available. Even though street drugs are often mislabeled, they are not far
from being what they purport to be, either in kind of drug or in amount.
Undoubtedly many of the previous bad trips were simply from marked and
inadvertent overdoses.
It would be comforting to think that eventually these drugs would be
replaced by the currently fashionable psychomystical techniques for altering
consciousness and that they might again become mere curiosities of the
laboratory. Viewing man's long search for drugs that alter consciousness, this
hope is very likely to be vain.
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WEINTRAUB, W., SILVERSTEIN, A.
NICOTINE AND SMOKING

Ellen R. Gritz and Murray E. Jarvik
Tobacco's but an Indian weed
Grows green at morn, cut down at eve
It shows a decay, we are but clay
Think of this when you smoke tobacco
The pipe that is so lily white
Wherein so many take delight
Is broke with a touch, man's life is such
The pipe that is so foul within
Shows how man's soul is stained with sin
It doth require to be burst with fire
The ashes that are left behind
Do serve to put us all in mind
That unto dust return we must
The smoke that does so high ascend
Doth shows man's life must have an end
The vapor's gone, man's life is done
-18th Century American Ballad
What defines the allure of tobacco? Does it symbolize sin and man's frailty as
the ballad suggests? Or, as the psychoanalyst theorizes, does it represent an
autoerotic behavior related to breast-feeding?
How do teenagers join the ranks of the smoker? What provokes the
Ellen R. Gritz Veterans Administration Hospital Brentwood, and Department of Psychiatry, University of California, Los Angeles, California. Murray E. Jaruik Veterans
Administration Hospital Brentwood, and Departments of Psychiatry and Pharmacology,
University of California, Los Angeles, California.
425
426
ELLEN R. GRITZ AND MURRAY E.JARVIK
experimentation process? Why is the habit maintained? Does the repeated

practice of smoking produce an addictive affinity between smoker and
cigarette and among smokers?
What of those who seek to abandon the use of tobacco? What miseries
do they suffer and what hope can we offer?
These topics of initiation, maintenance, and cessation of smoking will be
our prime considerations in this chapter.
l. THE INITIATION OF THE SMOKING HABIT

Historically, the use of tobacco has caught on dramatically whenever and
wherever introduced (Brecher, 1972; Wagner, 1971). The Indians of Central
and North America were the first to burn tobacco, although we do not know
the exact date of origin of the practice. A Mayan carving dating from the
fifth century A.D. in the Yucatan peninsula of Mexico depicts a priest
drawing smoke through a long tube, which most likely contained tobacco
(Modell and Lansing, 1967). Columbus, Verrazzano, and Cartier, early
explorers, observed and sampled the Indian weed, but the introduction of
tobacco to European civilization is credited to Andre de Thevet. In 1556 or
1557 he planted seeds of Brazilian tobacco in France. John Hawkins brought
tobacco to England from Florida in 1565; its use was popularized greatly
after Sir Walter Raleigh and Thomas Hariot introduced the native Virginia
clay pipe (Morison, 1971). Hawkins reported that for the Indians, tobacco
smoke "satisfieth their hunger, and therwith they live foure or five dayes
without meat or drinke, and this all the Frenchmen used for this purpose"
(Morison, 1971, p. 428). Moreover, Hariot recorded that tobacco was a
panacea for "grosse humors," "of so precious estimation amongest" Indians
that "they thinke their gods are marvelously delighted therwith" (Morison,
1971, p. 668).
Sailors proceeded to carry the leaves and seeds of tobacco around the
world to establish local supplies on their long voyages, and managed to
spread the custom to the native populations. Tobacco use was so readily
adopted by the masses that the combination of great demand and scarcity of
supply forced the price out of the comfortable reach of many.
Control of such a popular indulgence was attempted through religious
and civil channels. As early as the 16th century smoking inside a church was
prohibited by the Spanish-American priests of the Roman Catholic faith.
Two popes (Urban VIII and Innocent X) issued formal prohibitions of
smoking in the seventeenth century, forcing the devout to switch to snuff,
which could be used covertly. Concurrently, Sultan Murad IV in Turkey
tortured and killed violators of the Moslem ban on smoking. Similar
situations existed in the European states, Russia, Japan, and colonial outposts.
427
Economic sanctions (such as those imposed by King James I of England)

commonly took the form of severe taxation when tobacco use was permitted,
or fines and property confiscation for violation of the use and possession
laws. However, it was impossible to stem the spread of the habit; Japan
succumbed to legalizing cultivation and use in the early 17th century, and
while the growing of tobacco was prohibited in England in 1652, this move
was made primarily to support the growth of the industry in the infant
colonies. Ironically enough, James I, one of the greatest critics of tobacco use
(Counterblaste to Tobacco) became the father of the tobacco industry in
America. By the 17th century tobacco was worldwide, firmly embedded for
at least the next 400 years.
The modern history of the cigarette industry dates from the late
nineteenth century, when the manufacture of a new flue-cured tobacco
(Virginia type or Bright) made cigarettes eminently inhalable. These cigarettes were much milder in nature, easier to become accustomed to, and
600
500
400
U>
Z
300
...J
...J
200
100
1880 1890 1900 1910 1920 1930 1940 1950 1960
FIG. l. Production of cigarettes, 1880 to 1968. [From Brecher, 1972, p. 230; obtained from
James L. Hedrick, Smoking, Tobacco and Health, prepared for National Clearinghouse for
Smoking and Health, U.S. Department of Health, Education and Welfare, Public Health
Service, March 1969 (revised), p. 4.]
428
ELLEN R. GRITZ AND MURRAY E. JARVIK
therefore more suitable to introduce to women and teenagers. In 1913, the

"blended cigarette," a mixture of flue-cured Virginia and air-cured Burley
and Turkish tobaccos was introduced, combining inhalability with flavor and
aroma (Wagner, 1971). Since then, supported by all the powers of the
tobacco and advertising industries, sales of cigarettes have risen steadily (see
Fig. 1), although the per capita intake remained stable at around 11
cigarettes per day as of 1970 (Brecher, 1972).
Approximately 80% of the cigarette brands surveyed in 1972 delivered
between 1.00 and 1.74 mg nicotine (see Fig. 2). This dosage range of nicotine
is probably optimal for the vast majority of smokers, judging from the
distribution of commercial producers. The Report of the Surgeon General's
Advisory Committee on Smoking and Health (1964) caused a very temporary drop in cigarette purchases. Indeed, the sum total of the education
campaigns of the American Cancer Society, the National Clearinghouse for
Smoking and Health, and various medical and lay antismoking groups have
not been able to markedly decrease the proportion of the population that
smokes. We are able to present the latest (1974) epidemiological information
for the United States.
Teenage smoking patterns surveyed between 1968 and 1974 (DHEW,
50
CIGARETTES ~
LITTLE CIGARS
45
III
40
<I
35
CD
30
a:
...0
....
(!)
<I
~
z
....
u
a:
....
Q,
25
20
15
10
5
0
__ I
., ., ,....,
(1)
Mg NICOTINE
ciI
0
0
ci
CIGARETTES
LITTLE CIGARS
,.,
ci
I
0(')
ci
I
to
ci
(1)
II)
I<'i
.r
ui
(1)
(1)
I
0(')
,...
(1)
".;
.,1
<'!
I
0
0
(1)
I<'i
.r
(1)
I
0(')
., I
(1)
,...
CD
,.,
.,
0(')
.,ori
~
n
.,
(1)
0
~
to
N
N
<'!
I
<i-
~
I
FIG. 2. Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by
nicotine content. [From United States Department of Health, Education and Welfare, 1973.
Taken from (I) U.S. Department of Health, Education and Welfare: Tar and Nicotine
Content of Cigarettes. Washington, Federal Trade Commission, May, 1972, DHEW Publication No. (HSM) 72-7510, and (2) Federal Trade Commission: Report of Tar and Nicotine
Content of the Smoke of 25 Varieties of Small Cigars, Federal Trade Commission News, 1-0703,
July 3, 1972.]
429
AGE
15-16
12-13-14
40
17-18
30
I-
~ 20
0::
1&.1
a..
10
'68 '70 '72 '74
FIG. 3. Percentage of current regular smokers-teenage girls, 1968-1974. (From DREW,

1972, 1974.)
1974) reveal little change in the percentage of teenage boys who smoke, but a
gradual increase in that of female smokers (see Fig. 3). In 1968, about half as
many girls as boys smoked, but by 1972 this difference was practically
obliterated. This change may be the consequence of increased acceptance of
female smoking and the women's liberation movement, as well as the
"unisex" trend among teenagers. Recruitment to the smoking population is
gradual: in 1974 approximately 4.5% of those aged 12-14 smoked, 19% of
those aged 15-16, and 28.5% of those aged 17-18.
Family and peer associations with smoking strongly influence the
teenager's behavior (see Fig. 4), corroborating the findings of earlier studies
AGE
15-16
SMOKERS'
REPLIES
AT LEAST ONE OF
FOUR BEST FRIENDS
IS A REGULAR
SMOKER
NON-SMOKERS
REPLIES
17-18
. . . .~
SMOKERS
REPLIES I---~
NONE OF FOUR BEST

FRIENDS IS A REGULAR
SMOKER
Em
NON-SMOKERs'
REPLIES
10
20
30
40
50
60
70
80
90
NONE OF FOUR BEST

FRIENDS HAS EXPERMENTED
FIG. 4. The influence of peer behavior on smoking: smoking behavior of "four best friends"
in teenage girls. (From DREW, 1972, 1974.)
430
EllEN R. GRITZ AND MURRAY E. JARVIK
(see also Russell, 1971). Teenagers with parents or older siblings who smoke
are far more likely to smoke than those in nonsmoking households. Similarly,
teenage smokers congregate together; nonsmokers infrequently have close
friends who smoke. Smoking tends to be less prevalent in intact families than
in one- or no-parent homes and is also negatively correlated with the level of
education achieved by parents. Consistent with this pattern, high school
students preparing for college educations are less likely to smoke than those
who are not.
Part of the 1974 survey sampled teenage opinion on smoking. Teenagers overstimate the prevalence of smoking in their own group: 37%
estimated that 40-50% of teenagers smoked, and an additional 37% place
the estimate at 60-100%. Although all teenagers are well aware of the health
hazards of smoking and of the harmful environmental effects, those who
smoke see more positive effects of smoking than those who do not (cf. Horn,
1969). Nonsmokers place more credence in the social desirability stereotype
of smoking as well as the show-off, overly cool, "bad" image of the teenage
smoker than do the smokers themselves. Earlier studies from the 1960s
(Russell, 1971) also identified the male teenage smoker as tough, precocious,
adventurous, and masculine. Teenage smokers seem to have more conflict
with authority than do nonsmokers in degree of objection to parental
restrictions, yet express less confidence in the extent to which they can
control their own lives.
It is unfortunate that the adult pattern of cognizance of the health
hazards of smoking combined with rationalizations of smoking, including the
ability to quit at any time, are already clearly recognizable in the teenage
smoker. Also present are the expected role ambiguities and problems with
authority characteristic of adolescence. The teenage smoker paradoxically
believes in his ability to give up smoking while he feels less self-determination, and more likely to get "hooked" on something (even cigarettes) than the
nonsmoker. This is a serious problem related to drug experimentation in
youth.
The latest national survey of the U.S. adult population (Gallup, 1976)
described the overall incidence of cigarette smoking as follows:
l. Of all adults over the age of 18, 37% smoke (41.6% of the men,
32.8% of the women).
2. The proportion of adults smoking remains fairly constant until the
age of 50, when it drops significantly (18-34 years, 43.6%; 35-39
years, 40.7%; 50 or over, 24.7%).
3. When classified by occupation, manual laborers had the highest
proportion of smokers (43.2%), followed by professional and business
people (36.7%), clerical and sales personnel (36.2%), farmers
(28.4%), and those not in the labor force (23.2%).
4. Larger communities clearly had a higher percentage of smokers than
smaller ones, just over 41 % in populations exceeding 250,000 and
just over 32% in populations under 250,000.
431
5. Family income bore little relationship to smoking, except in the lowest

category (less than $5000/year), where smoking was slightly less
prevalent.
6. There were no regional differences in smoking incidence.
Smoking habits have not altered substantially from earlier surveys of the
United States and other Western nations (Brecher, 1972; Russell, 1971).
Almost all smokers try their first cigarette as teenagers. The proportion of
smokers in the adult population remains constant until the age of 50, when it
begins to decline precipitously. This is due to a combination of factors that
are difficult to define in cross-sectional research of this type, especially since
fewer members of the older population may have originally smoked
(women). The general decline in health and the loss of some smokers
through severe disease or death are likely involved.
In 1976, 620 billion cigarettes were smoked in the United States, an
increase of 2.1% over 1975 (607.2 billion), and an increase of 14.4% over
1970 (542 billion) (New York Times, January 2, 1977; Brecher, 1972). The
continual rise of cigarette sales in this country provides an excellent example
of the entrenchment of the smoking habit.
2. WHY DO PEOPLE KEEP SMOKING?

2.l. Do People Smoke for Nicotine?
However complex the reasons for beginning to smoke, once having
begun people keep smoking. Nicotine, the active alkaloid in tobacco, is the
ingredient sought by smokers, snuffers, and chewers of tobacco. The
evidence for this statement derives from the body of literature that measures
"titration" or self-regulation of nicotine intake by smokers. It has been shown
that smokers try to maintain a constant level of nicotine in their bodies,
perhaps in order to maintain a certain level of arousal, or other physiological
and psychological states. Titration of nicotine intake further constitutes
support for a dependence-producing property of the drug.
While referring to titration as the maintenance of a constant level of
nicotine in the body, it has not been possible to objectively estimate such a
quantity until very recently. Nicotine in smoke figures (Federal Trade
Commission, 1975) and butt analyses (Ashton and Watson, 1970; Kozlowski
et al., 1975) provided rough estimates of nicotine intake, but could not cross
the crucial inhalation barrier. More recently, estimates of nicotine intake
were made indirectly from the measurement of nicotine and its metabolites
excreted in the urine (Beckett et al., 1971; Gorrod and Jenner, 1975), and
directly from the measurement of plasma nicotine levels (see Fig. 5) (Russell
et al., 1975; Langone et al., 1973). The earlier studies, which did not use
432
60
50
40
PLASMA
NICOTINE
(ng Iml )
30
20
10
0
Smoking Period
Time (hours)
FIG. 5. Effects of smoking five consecutive cigarettes on plasma nicotine concentration.

(From United States Department of Health, Education and Welfare, Public Health Service,
1973, p. 16. Taken from Isaac and Rand, 1972.)
physiological measures of body nicotine levels, suffer from some ambiguity

of interpretation.
Perhaps the most cited early study was that of Johnston (1942), who
noted that the injection of nicotine was pleasant to smokers and most
unpleasant to nonsmokers. Although not a test of titration, the Johnston
study demonstrated that nicotine may have reinforcing value for smokers
that is not immediately apparent to nonsmokers. In a subsequent controlled
study, it was shown that the intravenous administration of nicotine over
several hours cut down but did not eliminate smoking, compared to a
placebo infusion (Lucchesi et al., 1967). Thus high blood levels of nicotine do
influence the choice of a cigarette, but do not totally determine it.
Judging from a series of experiments performed in our own laboratories, physiological responsiveness to nicotine does seem to be a small, but
operative factor in cigarette smoking:
Jarvik et al. (1970) were able to demonstrate a significant decrease in the
number of cigarettes smoked when subjects ingested nicotine orally (10 mg
nicotine tartrate, five times a day), compared to lactose placebo.
433
Similarly, when subjects were pretreated (preloaded) with nicotine prior

to smoking, dose-related effects occurred (Kozlowski et ai., 1975). Latency to
smoke and number of puffs taken on a cigarette in the experimental
condition were used as measures of nicotine regulation. Longer latencies to
smoke followed the high-nicotine than the low-nicotine cigarette preload, and
fewer puffs were taken on the subsequent cigarette following high-nicotine
gum preloading than low-nicotine gum preloading.
Since nicotine itself can reduce smoking in an experimental situation,
one would predict that a nicotine antagonist, by blocking the nicotine
receptor sites, would increase the number of cigarettes smoked by subjects.
(In a chronic experiment it could lead to extinction.) Stolerman et ai. (1973b)
showed that subjects increased the number of cigarettes smoked when
mecamylamine hydrochloride was administered orally in a graded doseresponse study. In 2-hr sessions, doses of 7.5 to 17.5 mg mecamylamine
hydrochloride significantly increased the mean number of cigarettes smoked
and the mean number of puffs taken, when compared to placebo. Physical
discomfort (dizziness, visual disturbances) precluded the use of higher doses
for most subjects. Pentolinium, a quaternary compound that does not easily
cross the blood-brain barrier, was without consistent effect.
Measuring the level of nicotine in the blood plasma is the most accurate
and sensitive measure of titration that is currently available. We still cannot
measure the level of nicotine in the brain, which is presumably the site of
reinforcement. Using the naturalistic setting of subjects' own offices, blood
samples were obtained after smoking high- or low-nicotine cigarettes for an
entire afternoon (Russell et ai., 1975). Although significantly fewer of the
high-nicotine cigarettes were smoked compared to subjects' own brands,
plasma nicotine levels remained about the same in both conditions. However,
in the low-nicotine condition, there was not a corresponding increase in the
number of cigarettes smoked, nor were plasma nicotine levels anywhere near
normal. The authors speculate that the unusually low nicotine content of that
experimental cigarette and the high resistance of the filter were too
discouraging to subjects. Over a longer time period, subjects might adjust
their smoking patterns in ways previously discussed, or might stop smoking.
The aversive lettuce cigarettes used by Goldfarb et ai. (1970) were not even
terrible enough to lower the smoking rate by more than 50% over a threeweek period. The smoking habit is apparently extremely resistant to extinction.
Although not frequently demonstrated, increased smoking has been
reported with cigarettes very low in nicotine content (Ashton and Watson,
1970; Frith, 1971). There are serious methodological and statistical problems
with these reports. In the Ashton and Watson study, significantly more puffs
were taken on low- than on high-nicotine cigarettes, both in easy and difficult
driver-simulation tasks. However, butt analysis did not reveal effective
titration in the difficult driver-simulation task. This result conflicts with the
former; also, nicotine presented to the mouth is only an estimate of the
434
effective absorbed dose. Differences in puffing style on high- and lowresistant filters could be expressed in depth of inhalation or duration of
draw, as well as number of puffs.
Frith (1971) attempted to demonstrate that subjects increased the
number of cigarettes smoked as the nicotine content of the cigarettes
decreased, using high, medium, and low levels of nicotine. The number of
subjects smoking more or less than his own experimental mean (an average
of the three conditions) for each type of cigarette was analyzed by a
non parametric statistical test. It would have been preferable to know the
number of cigarettes smoked by subjects in each condition.
In addition to methodological and statistical complications in the interpretation of titration data, some of the behavioral measures used may not
have the requisite sensitivity. Physical manipulation of cigarette composition
or size, such as enriching lettuce cigarettes with nicotine or shortening
cigarettes, have not always resulted in observable titration. There are many
aspects of smoking that probably have secondary reinforcing value (lighting,
handling, inhaling), which would diminish the probability of radically altering smoking behavior and lengthen extinction.
Two studies in which secondary reinforcement or behavioral stereotypy
may have masked a titration effect were performed in our laboratory.
In the first study, when lettuce cigarettes were modified by adding 0, 2,
and 3 mg nicotine, no differences among the numbers smoked during three
one-week intervals were observed (Goldfarb et al., 1970). The aversive taste
of the cigarette may have served as an overall depressant of smoking;
however, the 10-20 cigarettes smoked daily by subjects indicated some
nicotine-seeking and/or secondary reinforcement effects.
In the second example, whole cigarettes, cigarettes cut in half (proximal
cigarettes), and cigarettes lined at half the length (so that only the distal end
would be smoked) were used in three one-week trials. A small but nonsignificant increase in cigarettes smoked occurred in the two half-cigarette conditions compared to control (Goldfarb and Jarvik, 1972); subjects would have
to double the number smoked in order to demonstrate perfect titration.
We now know that other compensating behaviors may also occur, such
as increasing the number of puffs or depth of inhalation, and have
incorporated these measures into more recent research (Gritz et at., 1976a).
U sing a gas chromatograph assay of urinary nicotine to provide a measure of
nicotine intake, we were able to demonstrate titration when smokers were
required to smoke equal numbers of whole and half (proximal and distal)
cigarettes. Excretion of urinary nicotine was not significantly different in the
proximal and whole cigarette conditions; in the distal condition, the rod
filtration effect may have accounted for the lesser amount of excreted
nicotine. However, the proportion of available nicotine extracted in the two
half cigarette conditions was approximately equal, and greater than in the
whole cigarette condition. Subjectively, whole cigarettes were given ratings of
435
greatest strength and greatest satisfaction, followed by proximal and then

distal cigarettes.
We may conclude from the body of the literature presented here that
smokers do attempt to regulate nicotine intake. Titration is difficult to
demonstrate because of the highly overlearned motor aspects of smoking,
secondary reinforcing effects, and the effect of other variables such as social
interaction.
Nicotine regulation does not appear to be very precise, but chronic
determinations of physiological levels of nicotine have not been made in
naturalistic settings. Neither has anyone ascertained whether nicotine levels
in the blood or derivative states such as arousal level are the critical variables
to measure. Perhaps different people smoke for different reasons as
Tomkins (1966) and Horn (1970) claim, but their hypotheses need validation.
This brings us to a discussion of the panoply of effects exerted by
nicotine on the body and brain. Some of these may be reinforcing and thus
important in the maintenance of the smoking habit.
2.2. Effects of Nicotine on Physiological and Psychological

Functions
2.2.1. Physiological Effects of Nicotine
When a cigarette smoker inhales the smoke from his cigarette it starts a
chain of physiological events that somehow culminate in what he must regard
as a pleasurable experience. Let us trace the possible course of events. There
is generally very little time lag between lighting a cigarette and taking the
first puff. This puff consists on the average of 35 to 40 ml of smoke, which in
most cases is drawn all the way into the alveoli of the lung. This is in contrast
to cigar smoke and pipe smoke, which is only taken into the mouth and nose
and not into the lungs. A certain proportion of smokers say they do not
inhale (see Fig. 6). Certain cigarette tobaccos resemble cigar tobacco and
therefore result in less inhalation. Thus, the smoke from French cigarettes,
Gauloises, have a higher pH and are not inhaled as much. Consequently, the
incidence of lung cancer is lower in France than in the United States, but
cancers of the oral cavity are more frequent.
When the smoke passes down the trachea and bronchioles it exerts
characteristic effects. First it produces irritation of the oral cavity, the
nasopharynx, larynx, trachea, bronchi, and bronchioles. The cilia lining the
respiratory tract lose their ability to function, and the secretions change in
character. Chronic bronchitis occurs much more frequently in smokers than
nonsmokers. A wide variety of bronchopulmonary pathological changes can
be attributed to smoking. Cigarette smoke causes changes in mucociliary
436

NONE
8.7
SLIGHT
INHALATION
13.5
MODERATE
INHALATION
48.7
10.8
17.7
23.0
30.0
41.1
31.9
DEEP
INHALATION
23.9
40
50
17.4
12.1
9.2
60
70
80
AGE
FIG. 6. Depth of inhalation among cigarette smokers by age. (From United States Department of Health, Education and Welfare, Public Health Service, 1973, p. 185. Taken from
Hammond, 1966.)
function and structure, and perhaps more importantly, in alveolar surfactant,

macrophage activity, and alveolar transport mechanisms, all of which contribute to the development of emphysema in susceptible smokers. It is not
surprising to find changes in pulmonary function among smokers, but it may
be surprising to note that even young asymptomatic smokers have changes in
pulmonary function detectable by sensitive tests. Thus, for example, Seely et
al. (1971) showed that teenage smokers show changes in maximum expiratory flow and volume, reflecting small airway obstruction. They conclude
that the functional decrement is probably caused by a toxic effect of cigarette
smoke on airways.
There are a wide variety of substances in cigarette smoke that may be
responsible for harmful effects (Surgeon General's Report, 1972). In Tables
1-3 are listed the compounds in smoke judged to be "most likely," "probable," and "suspected" contributors to the health hazards of smoking. Clearly,
carbon monoxide, nicotine, and "tar" are the most prominent suspects, and
nicotine has the strongest pharmacological effects.
Experiments with lettuce cigarettes incriminate nicotine as the prime
agent responsible for cardiovascular effects. Herxheimer et al. (1967) found
that lettuce cigarettes did not produce changes in pulse rate and blood
pressure, while nicotine aerosol spray did.
Once the smoke reaches the alveoli of the lungs, the nicotine, carbon
monoxide, and coal tar derivatives are rapidly absorbed into the blood
stream of the pulmonary circulation. They quickly reach the left heart and
thence are pumped to the rest of the body and the brain. Nicotine is almost
completely extracted from the brain in one pass (Oldendorf, 1976) and thus
is able to affect the central nervous system almost instantaneously. We are
most interested in the reinforcing effect of nicotine (or smoke), but unfortu-
437

TABLE
Compounds in Cigarette Smoke Judged Most Likely to Contribute to the Health Hazards of
Smoking"
Compound
Carbon monoxide
Nicotine
Tare
Concentrations in
cigarette smoke
(/Lg/cigarette)
Primary phase
classification b
5,240-21,400
200-2,400
3,000-33,000
G
P
P
From United States Department of Health, Education and Welfare, Public Health Service (1973,
p. 143).
G, gas; P, particulate.
'Tar is defined as the total particulate matter collected by a Cambridge filter (CM-113) after
subtracting moisture and nicotine and includes the class of compounds known as polycyclic aromatic
hydrocarbons (PAH). PAH are generally accepted as being responsible for a substantial portion of
the carcinogenic activity of the total tar. Although tar from different cigarettes varies in its
carcinogenic potential as measured by the bioassay methods in current use, it remains the most
practical single "indicator" of total carcinogenic potential. Special mention should be made of beta
naphthylamine, which is a known human urinary bladder carcinogen for which there is no known
safe level of exposure and which has been reported present in tobacco smoke in very low
concentrations (0.022 g/cigarette).
a
nately there are few hard data available. However, the physiological effects of
nicotine on the rest of the body are well known.
Nicotine is a potent and versatile drug that has been studied since the
beginnings of pharmacology a hundred years ago. It is well known that
nicotine mimics certain actions of acetylcholine, which are therefore called
nicotinic actions. These include transmission across autonomic ganglia and at
the neuromuscular junction. In low concentrations, nicotine stimulates and
later depresses the activity of these receptors. An important effect of nicotine
is to cause release of catecholamines from the adrenal medulla and other
sites. This action is so pronounced that it tends to overshadow the other
TABLE 2
Compounds in Cigarette Smoke Judged as Probable Contributors to the Health Hazards of Smoking"
Concentration in
cigarette smoke
Compound
Acrolein
Cresol (all isomers)
Hydrocyanic acid
Nitric oxide
Nitrogen dioxide
Phenol
a
(/Lg/cigarette)
45-140
68-97
100-400
0-600
0-10
9-202
Primary phase
classification b
G
P
G
G
G
P
From United States Department of Health, Education and Welfare, Public Health Service (1973,
p. 144). G, gas; P, particulate.
438
ElLEN R. GRITZ AND MURRAY E. JARVIK

TABLE 3
Compounds in Cigarette Smoke Judged as Suspected Contributors to the Health Hazards
Smoking a
Compound
Concentrations in
cigarette smoke
(lLg/cigarette)
Acetaldehyde
Acetone
Acetonitrile
Acrylonitrile
Ammonia
Benzene
2,3-Butadione
Butylamine
Carbon dioxide b
Crotononitrile
Dimethylamine
DDT
Endrin
Ethylamine
Formaldehyde
Furfural
Hydrogen sulfide
Hydroquinone
Methacrolein
Methyl alcohol
Methylamine
Nickel compounds
Pyridine
180-1440
88-650
140-200
10-15
60-330
12-100
43-200
3
23,100-78,000
4
10-11
0-0.77
0.06
10-11
20-41
45-110
12-35
83
9-11
90-300
20-22
0-0.58
25-218
of
Primary phase
classification C
G
G
G
G
G
G
G
P
G
G
P
P
P
G
G
P
G
P
G
G
G
P
P
From United States Department of Health, Education and Welfare, Public Health Service (1973.
p.145).
Co. is included because of the hazard it may represent to those with CO. retention, such as those
with advanced COPD.
C G, gas; P, particulate.
effects of nicotine. It is largely responsible for the cardiovascular effects

including the increase in pulse rate, blood pressure, and peripheral vasoconstriction. It also results in a mobilization of free fatty acids and a decrease in
appetite.
The central nervous system actions, which are probably more important,
are less well understood. Nicotine depresses spinal reflexes (Domino and von
Baumgarten, 1969) but has an arousing effect upon the electroencephalogram. It excites respiration through stimulation of the carotid body. There
are evidently numbers of nicotinic synapses in the brain. For example,
synapses in the supraoptic nucleus of the hypothalamus, which control
antidiuretic hormone, are nicotinic. Pharmacological analysis of the central
actions of nicotine has been extensively performed with a variety of blocking
agents: mecamylamine, a central and peripheral nicotine blocker; hexame-
439
thonium, a peripheral blocker; and scopolamine, a central blocking agent for

muscarinic, but not nicotinic, synapses.
The assumption has long been made that cigarette smoking, and
particularly nicotine, will cause activation of the electroencephalogram. In
fact, Knapp and Domino (1962) demonstrated a short-lasting stimulant effect
on the brain-stem-activating system of different animals. This appears to be
direct action upon the brainstem reticular formation. Two studies in humans
(Ulett and ltil, 1969; ltil et at., 1971) demonstrated that chronic cigarette
smokers who were deprived of smoking for 24 hr showed an increase in slow
activity in the EEG. They interpret this as a physiological withdrawal effect
analogous to drug addiction and indicative of either increased arousal under
the influence of cigarettes or decreased arousal without cigarettes.
It is of some interest to determine whether nicotine can influence the
reinforcement centers in the brain. Wise and Stein (1970) have already
shown that activity in this system can be influenced by catecholamines. Thus,
self-stimulation is facilitated by amphetamine (Olds and Domino, 1969).
However, nicotine appears to depress self-stimulation in the hypothalamic
reward systems, an effect that can be reversed by either scopolamine or
mecamylamine. The picture is puzzling and not at all dear-cut. It becomes
even more difficult to understand when we consider that there is some
evidence (still to be confirmed) that nicotine is weakly self-administered by
monkeys when made available by the intravenous route (Deneau and Inoki,
1967).
It is conceivable that a substance or activity might be reinforcing without
directly affecting the reinforcement centers in the brain. If self-stimulation
worked to amplify the reinforcing effect of some activity controlled by a
different part of the brain, then it would not be affected by nicotine. Let us
say, for example, that nicotine facilitated cognitive activity in the cortex. It
might be that the pleasure derived from thinking more dearly would
reinforce the act of smoking and perhaps indirectly stimulate the reinforcement centers.
2.2.2. Psychological Effects
Nicotine is a drug with complex actions. As we have seen, it acts on both
central and peripheral nervous systems, and can directly affect organ
systems. Since we are primarily interested in psychological variables, we will
concentrate on the central and relevant peripheral actions of nicotine.
Psychoactive effects ranging from stimulant to depressant have been
reported in the animal literature (Hutchinson and Emley, 1973; Miller, 1973)
as well as the human (Heimstra, 1973; Eysenck, 1973; Ryan, 1973). In each
case, the arousal level of the organism is involved. The results of various
studies can best be understood in light of shifts along the activation/arousal
continuum. In addition, care must be taken to distinguish acute from chronic
440
effects, especially when making comparisons to human smoking, and to

specify task contingencies when reporting facilitative or disruptive effects.
It will be difficult, if not impossible, to integrate the range of results
reported in the literature using a single hypothesis, but a most challenging
concept has been put forth by Nelsen (in press). She and her colleagues
(Nelsen and Goldstein, 1972, 1973; Nelsen et ai., 1973, 1975) propose that
the chronic administration of nicotine facilitates motivated, well-learned
vigilance task performance, while acute administration may impair it. They
have explored the effects of acute and chronic administration of nicotine on
vigilance task performance in rats. Both behavior and electrical activity in the
reticular activating system, limbic system, and cortex were monitored.
The electroencephalographic studies in the rat revealed a biphasic
stimulation-sedation pattern after acute nicotine administration (100 J.l.g/kg,
s.c.). However, both activation and sedation phases were markedly diminished following chronic nicotine administration (lOO J.l.g/kg, t.i.d. for three
weeks). The development of tolerance was further supported by the EEG
effects of a single dose given 3 weeks after cessation of chronic dosage. These
closely resembled the effect of chronic, rather than acute dosage (see also
Stolerman et ai., 1973a).
The hippocampus may exert greater influence on cortical activation
than the reticular formation during chronic nicotinization (Nelsen et ai.,
1973). No change in reticular formation activity occurred over time, but
amplitude levels and mean variability of electrical activity at the cortical and
hippocampal recording sites decreased. The authors further hypothesize that
enhanced hippocampal activity, manifested as a shift toward desynchronization (lesser theta activity) facilitates goal-directed behavior while reticular
activity is more general, more drive-oriented.
In the vigilance task used in these experiments, clear differences existed
between acute and chronic nicotine effects. The presentation of a stimulus
light afforded food-deprived rats limited time access to a lever-press task and
food reward. Behavior of the well-trained rats was depressed after the initial
dose of nicotine (100 J.l.g/kg, s.c.), but by the fourth week of chronic nicotine
injections (100 J.l.g/kg, t.i.d.) performance was facilitated over saline controls.
This facilitation of behavior was independent of a practice effect, and
separable from tolerance to the initial disruption of behavior. When electrical
stimulation of the reticular formation was introduced to disrupt ongoing
responding (Nelsen et at., 1975), the administration of nicotine either
attenuated the task disruption effect or antagonized it completely in some
instances.
Furthermore, in other studies of the effect of chronic nicotine treatment
on acquisition of the vigilance task (Nelsen and Goldstein, 1973), nicotine
paradoxically impaired acquisition but facilitated performance during postacquisition phases compared to saline treatment. In summary, although
nicotine may impair vigilance task performance in rats by an acute disrupting
441
action, chronic administration produces facilitation of behavior in which

arousal is an important element.
It has long been debated whether the principal psychological effect of
smoking is one of stimulation or sedation. Since nicotine can both stimulate
and depress the central nervous system, this question may have two answers.
However, much effort has been devoted to characterizing the situation along
a continuum of arousal in which people choose to smoke (Frith, 1971;
Tomkins, 1966; Russell, 1971; Myrsten et al., 1975).
It is possible to identify some people who fall on the extremes of the
arousal continuum with regard to their smoking behavior. In one experiment (Myrsten et al., 1975) a questionnaire was used to select subjects who
smoked only in boring, monotonous situations (low arousal) or only in tense,
stressful situations (high arousal). Performance on a vigilance task while
smoking was significantly affected both by task difficulty and by type of
smoker. Using two vigilance-type sensorimotor tasks, one far more demanding and complex than the other (low and high arousal) performance while
smoking improved for low-arousal smokers in the low-arousal task, and for
high-arousal smokers in the high-arousal task. Furthermore, performance
while smoking was impaired for each group on the inverse arousalproducing task; there was no difference between groups on either task in a
nonsmoking situation. In this study, 16 subjects were chosen from the 90
light smokers (fewer than 15 cigarettes/day) screened. Such results are
intriguing demonstrations of nicotine-arousal interactions on selected subject
samples.
In other experiments on light smokers in which arousal level was
manipulated through task difficulty, smoking facilitated performance compared to the nonsmoking condition on a boring, simple reaction-time task, as
well as on a difficult and stressful one (Frankenhaeuser et al., 1971; Myrsten
et al., 1972). These effects were achieved by prolonging attentiveness and
counteracting the deterioration in performance which usually occurs over
time in such tasks.
In all of the studies conducted by Frankenhaeuser and her colleagues,
smoking increased physical measures of arousal, such as catecholamine
excretion and heart rate, over nonsmoking levels. Subjective reports of
arousal, well-being, and mental efficiency rarely differed significantly between conditions. Perhaps smoking is less under the control of verbal than
nonverbal cues, such that mood-related effects are difficult to identify, except
under extreme conditions such as smoking deprivation.
For most people, smoking behavior occurs in situations widely differing
in arousal value. This is especially true as the daily number of cigarettes
increases and the functionally autonomous aspects of the habit become
ingrained. Fuller and Forrest (1973) used both heavy and light smokers to
examine the smoking/arousal interaction. They compared number of puffs
and estimated nicotine intake (butt analysis) in high arousal (watching a
442
stressful fIlm) and low arousal (lying down) conditions. Heavy smokers
significantly reduced their smoking rate while watching the fIlm, suggesting
self-regulation of arousal level. However, the estimate of nicotine intake
obtained by butt analysis revealed approximately the same nicotine delivery
in both high- and low-arousal conditions. This latter result implies titration of
nicotine intake, not arousal level. The situation is further complicated by
increased smoking rate in both groups in the low arousal condition, when
idle.
Both external and internal stimuli influence an organism's arousal level.
It will probably be very difficult to formulate simplistic relations between
smoking and anyone selected variable. We do know that smoking affects
arousal-we do not know whether people smoke to maintain a given arousal
level, to change that level, or automatically, by some internal cue system, to
adjust a physical blood level of nicotine.
Smoking is alleged to facilitate concentration and the ability to work;
how does it affect cognitive processes such as learning and memory?
Stimulant drugs, such as amphetamine, have been shown to affect cognitive
and psychomotor performance by reversing fatigue and raising arousal
levels, rather than by directly facilitating the learning process (Weiss and
Laties, 1962). Nicotine has stimulant properties and may produce facilitating
effects through similar mechanisms.
In the animal literature, the few "learning" studies conducted using
nicotine suggest a definite effect on arousal level but do not firmly establish
an effect on cognitive processes. Experimental design is crucial in such
experiments, since pretrial drug administration can alter arousal levels as well
as affect learning and memory processes. Posttrial administration eliminates
the "performance" confound and mainly affects consolidation mechanisms
and long-term memory processes. The work of Nelsen and her associates was
described earlier in this chapter; initial disruption of vigilance task performance and later facilitation during chronic drug administration involved both
arousal and attention mechanisms. Bovet-Nitti (1969) obtained facilitation of
a simultaneous visual discrimination task with pretrial i~ections of nicotine in
three out of four strains of inbred mice. An arousal effect is especially likely
since the strain whose performance was impaired had the highest level of
responding, suggesting hyperarousal by nicotine. Garg (1969) reported a
suggestion of facilitation of maze-learning but not of an escape-avoidance
task with posttrial administration of nicotine.
The human literature is equally unclear regarding the locus of the
"cognitive" effect of nicotine. Smoking impaired nonsense syllable learning
compared to a nonsmoking session; arousal level, as measured by heart rate,
was elevated by smoking. Recall scores 45 min later, when the effect of a
single cigarette had worn off, were higher in the smoking than the
nonsmoking condition (Andersson, 1975).
It is unusual to find studies of the effects of nicotine on nonsmokers or
occasional smokers. In one such study (Frith, 1968), nicotine (0.1 mg
443
administered sublingually in tablet form) facilitated one measure of pursuit

rotor learning, although not the overall score. A stimulant effect in nonsmokers is surprising. Besides the irritating qualities of sublingual nicotine, hand
steadiness is impaired by nicotine. One would expect exacerbation of such
effects in nontolerant subjects. Much more research is needed in this area;
while nicotine most likely can alter human arousal levels, it is still questionable whether learning processes are susceptible.
2.3. Is Nicotine Addicting?

The term "addiction" has been used in so many contexts and with such
negative overtones of helplessness, coercion and depravity that its use would
best be avoided. However, since cigarette smoking is so frequently called an
addiction (see Brecher, 1972), it will be discussed here using the definition
supplied by Jaffe (1975, p. 285). Addiction is
a behavioral pattern of compulsive drug use characterized by overwhelming
involvement with the use of a drug, the securing of its supply, and a high
tendency to relapse after withdrawal. It is possible to be physically dependent
on drugs without being addicted and to be addicted without being physically
dependent.
Smoking certainly fits within the framework of this definition. The next
edition of the DSM III issued by the American Psychiatric Association will
probably include compulsive tobacco use as a classifiable disorder. Whether
all smokers or only those who have tried unsuccessfully to quit-estimated at
50% (McAlister, 1975)-will be included under this rubric is not yet clear.
Tolerance and physical dependence are usually considered closely
associated with compulsive drug use. These two phenomena are tissue
changes also produced by a variety of drugs not used compulsively by man
and involve a wide variety of mechanisms Gaffe, 1975). For the smoker,
tolerance develops to some of the effects of nicotine, primarily those
manifested by beginning smokers and associated with acute nicotine poisoning. These include nausea, vomiting, pallor, abdominal pain, headache,
dizziness, and weakness (Volle and Koelle, 1975). That tolerance does not
develop to all of the effects of nicotine (and other constituents of tobacco) is
demonstrated by long-term toxicity data. The chronic use of tobacco is
associated with a number of extremely serious diseases, fully expounded by
the Surgeon General's Reports (1964-1973), but briefly classified as lung
cancer, smokers' respiratory syndrome, Buerger's disease, coronary artery
disease and cerebral disorders, and tobacco amblyopia. In addition, complications of pregnancy and low infant birth weight are linked to heavy smoking.
The issue of physical dependence upon nicotine is a difficult one to deal
with. Both physical and psychological changes occur with the cessation of
smoking, although varying widely among individuals. Physiological changes
have been observed: a decrease in heart rate and blood pressure (Knapp et
444
al., 1963; Weybrew and Stark, 1967); a significant decrease in urinary

epinephrine and norepinephrine excretion, an increase in skin temperature,
and improved hand steadiness (Myrsten and Elgerot, 1974). These changes
may reflect an overall decrease in arousal level from the state of chronic
nicotinization, or may be actual rebound phenomena characteristic of altered
CNS excitability occurring in a true withdrawal syndrome. The literature is
replete with anecdotal withdrawal symptoms reported by exsmokers (see
Surgeon General's Report, 1964; Russell, 1971; Brecher, 1972; Larson and
Silvette, 1968, 1971; Horn, 1970; Guilford, 1966). Gritz and Jarvik (1973)
and Shiffman and Jarvik (1976) showed that the desire to smoke (craving)
and abstinence symptomatology varied according to time of day and length
of deprivation, decreasing over time. It is reasonable to conclude that a wide
variety of dysphoric symptoms occur after quitting smoking, associated with a
lowering of arousal level.
3. CESSATION OF CIGARETTE SMOKING: WHY DO

PEOPLE STOP SMOKING AND HOW DO THEY DO IT?
It is no longer possible to deny the body of evidence describing the
harmful physical effects of smoking; these are reviewed annually in the
Surgeon General's Report (see, for example, U.S. Public Health Service,
1964, 1973). There are still some individuals who claim that the health
hazards are greatly exaggerated, but they remain in a dwindling minority.
Continual bombardment of the public with press releases of the latest
medical, environmental, and statistical facts regarding smoking and health
has forced such information upon even the deafest ears. In addition,
increasingly militant antismoking groups and a veritable plethora of smoking
cessation treatment centers encourage open consideration of quitting. It has
been variously estimated that from 50 to 77% of current smokers would like
to abandon the habit, although a maximum of 25% do stop permanently
(Gallup Poll, 1974; Russell, 1971).
For a given individual, it would seem that the subjective cost-benefit
ratio of smoking has to exceed a critical level before cessation will occur. The
difficulty in shaping such behavior is that the benefit involves immediate
gratification (within seconds of smoking), still poorly defined, whereas the
cost involves future punishment (after 20 to 60 years) with an unknown level
of probability. Under these circumstances, risk-taking behavior is greatly
enhanced; one of the greatest factors involved is the cognitive appraisal of
the future consequences of smoking. Not surprisingly, Horn (1969) has
found that smokers perceive the dangers of smoking to be less than
nonsmokers or ex-smokers.
The simplest possible example of a situation that exceeds the subjective
445
cost-benefit ratio for smoking is that of a heavy cigarette smoker who

experiences an acute life-threatening illness that he can associate with
smoking. A myocardial infarction, removal of a lung, or the onset of
emphysema is sufficiently frightening to motivate a decision to stop smoking.
When he actually stops, he may feel a great craving for a smoke, but
suppresses this desire. Thus an intellectual factor, a probability judgment, or
a form of induction helps him to mold his behavior. Yet for most individuals,
intellectural considerations are far from sufficient to break the smoking
habit.
The use of drugs to treat cigarette smoking or any other habit has been
fraught with great difficulties. Whether a habit involves drug seeking or not,
the factors that are involved in b~eaking it are very complex. While the
smoking habit is probably primarily a nicotine-seeking habit, it is more than
that. In order to extinguish a habit of such complexity, one needs to combine
extinction of the longing for nicotine with extinction of the secondary
reinforcing components of the habit. These consist of sensory factors such as
the taste, smell, and sight of a cigarette, motor factors such as lighting,
handling, and stubbing of a cigarette, and social factors such as peer support
and situation-bound smoking. All of these factors represent stimuli to which
the reinforcing value of a cigarette (nicotine) may be conditioned, so that
they in themselves are capable of delivering pleasure (secondary reinforcement).
Curing any type of drug habit is extremely difficult and permanent
success is limited (Hunt and Matarazzo, 1973). Nevertheless, a significant
minority (about 20%) of individuals addicted to opioids, alcohol, barbiturates,
and amphetamines manage to stop the habit for periods greater than a year.
Just about every variety of the "psycho-" therapies has been tried on
smokers trying to quit, with some degree of success reported. Quitting
smoking could easily be a side effect of any therapy that reduces tension,
frustration, anger levels, or compulsive behaviors. Among the more prominent types of therapy specifically applied to smoking have been psychotherapy, group therapy, hypnosis, and behavior therapy. Most of the smoking
clinics offering programs to the general public combine one or more of the
above treatments with information, exhortation, and/or fear-indoctrination.
Pharmacotherapy will be evaluated here in great detail. The effectiveness of
various classes of drugs will be compared with placebo and nondrug
treatments.
Psychoanalysts treat smoking as a manifestation of oral behavior, specifically related to a deprivation of breast-suckling (Roazen, 1975; Menninger,
1973). Freud himself considered smoking an addiction and reported great
suffering and craving every time he stopped. Even knowing that his
progressive jaw cancer was exacerbated by his cigar smoking, and probably
caused by it, he was unable to give up the habit. He suffered 16 years of
recurrent lesions, eventually necessitating the removal of his entire jawbone.
(Brecher, 1972). This sad case history is not meant to indicate that psycho-
446
analysis is ineffective in the treatment of smoking; anecdotal success has been

reported but no systematic evaluations have been made.
Hypnosis and individual and group psychotherapy have all been systematically employed to treat cigarette smoking. Their use in controlled studies
with comparison to various drug treatments will be discussed later.
Behavior therapy, utilizing the principles of Skinnerian (operant) conditioning, has been widely acclaimed (see references below), but also strongly
criticized (Shapiro, 1976). Analysis of hierarchies of behavior in which
smoking occurs, gradual reduction and elimination of situational smoking by
disruption and interference, and substitution of other behaviors constitute
the "stimulus control," positive-reinforcement behavior modification treatments. These have been employed with varying degrees of success (Marston
and McFall, 1971).
Overt and covert aversive conditioning techniques comprise the negatively reinforcing forms of treatment. Smoking a cigarette is paired with
some noxious stimulus, such as an emetic, hot smoke, or electric shock.
Another form of aversive conditioning is "oversmoking," in which the
smoker puffs at an unusually rapid rate (every 6 seconds in one treatment)
until brought to the point of sickness (Lichtenstein et al., 1973). This
treatment can be repeated daily for a given number of sessions or until a
decrease or cessation of smoking occurs. These aversive conditioning procedures carry with them some dangers for individuals with respiratory or
cardiac conditions, those who may be most in need of them (Hauser, 1974).
Covert conditioning usually consists of imagining the horrible medical
consequences of cigarette-related diseases whenever the desire to smoke
arises. It is worth noting that punishment often produces complete suppression of behavior, but is followed at some later time by a spontaneous
reinstatement of that behavior.
As recently evaluated by McAlister (1975), combining positive-reinforcing techniques with group support, contingency contracts, and posttreatment
contact has proved most promising in the behavior modification field. Longterm follow-up studies are still needed to verify preliminary reports of high
abstinence rates (over 50% at the end of one year). To date, the one year
total abstinence rate in formally evaluated treatments has not exceeded 30%
(see Fig. 7; Hunt and Bespalec, 1974). Claims of higher abstinence rates have
been made by various private treatment centers, but none have been
formally evaluated by an external agency.
Voluntary disclosure of success rates is critical to the evaluation of
smoking cessation programs. One of the major drawbacks to progress in this
area has been variation in definition of success criteria and lack of follow-up
procedures. Attempts are being made (American Cancer Society, personal
communication) to rectify this situation, but for the present one can only
attempt to correct for distortions in the reported statistics.
As an excellent example of unbiased disclosure, the Stanford Research
Institute (1976) has evaluated termination and follow-up "success" (total
447
100
90
80
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70
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60
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50
40
II:
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30
20
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FIG. 7. Relapse rates after treatment for smoking. (From Hunt and Bespalec, 1974.)
abstinence) for a four-week educational "stop smoking" clinic (n = 4S7). The

termination success rate (percentage of clients not smoking at the last session
attended) was 41.7%. This proportion fell successively at 6-, 12-, and ISmonth follow-ups to 30, 22, and IS%, respectively. The rate of smoking for
40% of those who resumed the habit averaged at least a pack a day, implying
complete recidivism in a substantial number of individuals. The IS-month
abstinence rate rose in proportion to the number of clinic sessions attended
(one to nine), reaching a high of 67% for those attending all nine sessions. As
stated above however, the overall success rates were much lower when
calculated on the basis of all who began the program. The Stanford Research
Institute concluded that the cost-effectiveness of such a program is unfortunately quite high.
The main advantage of pharmacotherapy is that drugs can be used to
alter the smoker's physiological and psychological functioning (the internal
stimulus milieu), while extinction and the substitution of new behaviors is
taking place. Nonspecific therapy aims at the symptomatic relief of dependence. Thus, an opioid addict or amphetamine user might be treated with a
tricyclic antidepressant for depression or a benzodiazepine for anxiety. There
is no direct relationship between the therapeutic drug and the drug habit,
although their actions may converge on the same psychological symptoms.
Specific therapy aims at somehow occupying the critical receptor sites or
interacting with some of the biochemical consequences of the drug's action,
using either agonists or antagonists. Methadone is a good example of the
448
therapeutic use of an agonist (a like-acting drug). This synthetic form of

heroin (opioid) is distributed to several hundred thousand former heroin
users in the U.S. Methadone serves as a legal substitute for heroin; it does
not eliminate opiate dependence. It is orally effective, long lasting, and in
large doses can block the effect of intravenously administered heroin. Thus it
enables the user to extinguish some of his drug-taking behavior while he
leads a more normal life. Many of the effects of methadone are similar to
heroin and the methadone-maintained patient is by no means physiologically
equivalent to the drug-free patient (Martin et at., 1973; Gritz et at., 1975).
The degree of success of a substitute depends again upon the change in
the cost-benefit ratio as perceived by the patient. Thus, the cost term of the
equation, the incentive to stop, is not as great as the reward value of the
drug. Even if methadone is considerably less reinforcing than heroin, the net
cost-benefit ratio is favorable because the rewards of working, noninvolvement with police, and clinic attention may compensate for the rewards of
heroin. Any drug substitute that produces less reinforcement than cigarette
smoking itself is apt to be considerably less acceptable.
There are practically no drugs available that mimic the range of actions
of nicotine. Lobeline is said to have some actions similar to nicotine, but it is
difficult to document these claims. The quaternary nicotinelike substances, of
course, do not get into the brain and are therefore unlikely substitutes. They
would, however, mimic some of the peripheral actions of the drug but clearly
could not be expected to be more reinforcing than nicotine itself.
An alternate form of drug treatment for a dependence is a specific
antagonist. If an individual is so dependent upon a drug that he cannot stop
taking it, one way to change his behavior is to make the drug unavailable to
him or to his receptors. He can be placed in a drug-free environment such as
a jail, and can be detoxified. Therapeutic communities exist where smoking,
drinking, and drug-taking are prohibited, of which Synanon is the best
example. Certain religious groups such as Seventh Day Adventists and
Mormons prohibit smoking. If, however, an individual wants to return to his
accustomed environment, then a chemical antagonist will provide a barrier
against the drug for him. Narcotic antagonists are the most highly developed
example of this class of drugs. Naloxone or naltrexone block the actions of
heroin with little other activity (Martin et at., 1973; Gritz et at., 1976b). As
long as the antagonist is in his body, the narcotic addict cannot experience
the effects of heroin and he will diminish his heroin-seeking behavior
accordingly (Altman et at., 1974).
There are several rather specific nicotine-blocking agents available, some
acting only peripherally (e.g., hexamethonium, pentolinium) and others that
have access to the brain as well as the periphery (e.g., mecamylamine). While
it appears that blockade of the central effects of nicotine does impair the
pleasure of a cigarette, it would be ideal if a "pure" nicotine antagonist could
be found. Thus, naloxone is virtually a pure opioid antagonist and has no
actions of its own other than antagonism. However, nicotine antagonists all
449
block the nicotine actions of acetylcholine and therefore produce the

unpleasant effects of ganglionic blockade. If a substance could be found that
would selectively block nicotine but spare acetylcholine, we would have a
much more useful therapeutic agent. If the nicotine receptors of a heavy
smoker could be blocked, let us say for six months, it would be expected that
he would gradually give up smoking with the removal of primary reinforcement via the pharmacological action of cigarettes. The secondary reinforcing
value might persist longer, but in the absence of empirical data, it is difficult
to predict how long a smoker would go on smoking what is essentially a
nicotine-free cigarette.
A survey of the literature summarizing research through the early 1970s
and of papers published after 1970 reveals very few systematic attempts to
test the efficacy of any therapeutic agent as an antismoking aid except
lobeline.
Among the drugs mimicking the action of nicotine and thus serving as a
substitute for the nicotine contained in tobacco are two: nicotine and lobeline.
Since nicotine is the chemical constituent of tobacco that we believe produces
the craving for cigarettes described by smokers, it is also the most likely
chemical to be a successful replacement for cigarettes when delivered
independently of tobacco. It is surprising that there have not been more
attempts to use nicotine as an antismoking aid, but its toxicity might be an
important factor.
The recent development of a nicotine-containing chewing gum in
Sweden (Ferno, 1973) has provided a chance to test the use of nicotine in this
manner. Gum provides an oral source of nicotine more socially acceptable
and neater to use than snuff or chewing tobacco. For an initial test of the
nicotine-containing gum (4 mg), a one week double-blind comparison was
made with a placebo gum in a smoking clinic setting. Subjects were instructed
to substitute gum for cigarettes as much as possible and to chew as much
gum as desired.
Results after one week showed tobacco consumption in the active gum
group to be significantly less than in the placebo gum group, with heavy
smokers benefitting most. The nicotine gum group chewed fewer gums than
the placebo group, indicating the effectiveness of the nicotine content (or else
its unpleasant taste). However, the reduction in smoking for both groups is
more striking than the difference between them. The mean tobacco consumption of patients in the active treatment group fell from 24.3 to 1.6 gl
day, and in the placebo group from 24.8 to 3.9 g/day. The performance of
the placebo group was very impressive, considering the supplement of
nicotine given to the active treatment group. Measures of blood level of
nicotine would be very informative. The similarity between the reported
abstinence syndromes in both groups (irritability, impaired concentration,
depression, headache, nervousness, and fatigue) is equally interesting. Much
greater symptomatology would have been expected in the placebo group.
The active treatment group did show significantly more heartburn than the
450
EUEN R. GRITZ AND MURRAY E. JARVIK
placebo group, as well as irritation of the oral cavity and hiccups. From the
results of this first week, we may conclude that the nicotine gum supplement
provided a small, but significant advantage over the placebo gum in terms of
actual tobacco consumption, consistent with the results of Jarvik et al. (1970).
The size of the placebo effect was quite marked, especially since subjects were
not even enjoined to abstain totally.
A second phase of the study involved six months of treatment in which
all patients were offered free choice of gums containing 0, 1, 2, or 4 mg of
nicotine. By the end of the study (26 weeks), there was no difference between
the initial treatment groups. All subjects chewed about the same number of
pieces of gum during the follow-up phase, but more than 50% of the subjects
dropped out. Both tobacco and gum consumption declined over time in the
remaining subjects. The follow-up results suggest that as a long-term
supplement, nicotine does not show markedly more promise than other
treatment approaches, for only a total of 22-28 (25%) patients were abstinent
after 26 weeks, 52 patients (59%) had relapsed entirely, and 18 patients
(16%) fell somewhere in between. No reported actual follow-up was made
after treatment ceased, which is usually the period of greatest recidivism. We
have devoted so much consideration to this study because we feel it is an
important trial of the substitution of pure nicotine for tobacco over a
substantial time period.
A recent clinical study of nicotine gum (2 mg) designed as a doubleblind, placebo controlled crossover, yielded substantially the same results as
those described above (Russell et al., 1976). When subjects chewed the gums
without trying to stop smoking, fewer cigarettes were smoked in the nicotine
gum than in the placebo gum condition and COHb levels were lower. Plasma
nicotine levels also suggested regulation of nicotine intake in the nicotine
gum condition. Once subjects tried to stop smoking, there was no advantage
of chewing nicotine over placebo gum; both groups cut down drastically. Yet
sui:?jective report revealed that of the 30 smokers who achieved abstinence
during the two-week treatment period, nicotine gum was preferred by 23,
compared to only 4 of the 13 who could not stop smoking (p < 0.02). Over
one year of follow-up however, only 10 subjects remained totally abstinent,
which is 23% of the original sample, or 26% of those completing treatment.
Russell attributes a small, significant role to nicotine per se, in achieving
abstinence, combined with many hours of daily chewing and placebo effect
for the belief in the efficacy of nicotine gum. He relates his findings on
plasma nicotine levels and COHb to the titration hypothesis.
One other clinic has reported use of the same nicotine gum, in 2- and 4mg strengths (W. M. Fee, personal communication). In this complex fourweek study, the effect of nicotine gum was compared to that of avena sativa
(oat extract, to be further discussed), ascorbic acid (2 glday), and a placebo.
Hypnotherapy was concurrently employed. The preliminary analysis on a
very small number of subjects showed immediate success rates ranging from
40 to 65% among treatments, with no significant differentiation. The most
451
surprising result to come out of this study so far was that ten subjects who
had claimed to be abstinent after four weeks of treatment showed high
nicotine concentrations in their urine, even when all patients knew their
urine samples were being analyzed before and after treatment. A result like
this casts a serious shadow of doubt over the reliability of self-report
measures of abstention from or reduction in smoking.
Lobeline, alleged to closely resemble nicotine in peripheral and central
actions, has been the most widely tested substitute for the nicotine in
cigarettes. The Indian tobacco plant (Lobelia infiata) provides the source for
this alkaloid, which primarily acts as a respiratory stimulant, but also causes
circulatory changes, nausea, and vomiting in large doses (Merck Index,
1968). It also has irritating effects in the mouth and gastrointestinal tract. As
these effects appear to resemble those of nicotine, it has been hypothesized
that lobeline would also satisfy the craving for nicotine in patients quitting
the smoking habit. This hypothesis was made in the 1930s and only recently
systematically examined. Davison and Rosen (1972) present an excellent
evaluative summary of the use of this drug through 1972.
In their own double-blind study, Davison and Rosen (1972) sought to
overcome the design deficiencies of much of the preceding research by
utilizing independent control groups, an active placebo, and follow-up data
on both placebo and drug groups. They were also interested in the
psychological aspects of the treatment situation, such as the subjects' perception of the situation, the "activity" of the placebo, the effects of motivation
and willpower, and the optimization of treatment gains in the follow-up
period.
Experimental procedure involved a baseline week of recording the
number of cigarettes smoked normally, followed by four weeks of medication
with either lobeline sulfate (0.5 mg cherry-flavored lozenge, Nikoban) or
identically flavored placebo lozenge, following the distributor's recommended schedule of decreasing the quantity used over a period of four
weeks. AU subjects were urged to abstain totally from smoking from the
beginning of the experiment and to keep records of cigarettes smoked; no
form of therapy was given.
Results showed no difference between the lobeline and placebo groups
at any time over the four-week treatment period either in terms of mean
daily cigarette consumption or percentage reduction in smoking. About onethird of the subjects in each group cut down 85-100% by the end of week 4.
A slight increase in number of cigarettes smoked across all subjects did occur
in the posttreatment week, with no difference between original placebo 01
drug groups.
From the questionnaire data collected before the study, it was found that
the most successful subjects were those who had smoked the shortest length
of time and who had attempted to stop the fewest number of times
previously. Neither the subjects's hypothesized strength of willpower nor his
conviction that he would be helped by the drugs correlated with treatment
452
effect. Not even the subject's desire to stop smoking before the study related
to actual reduction in smoking. The correlations regarding duration and
strength of the smoking habit are frequently reported in the literature, but it
is interesting that apparent level of motivation does not correlate with
observed performance in this study.
The authors commented that the lobeline lozenges were more irritating
to the throat than the placebo lozenges, despite attempts to mask the lobeline
"burr." They believed that this irritation contributed to the reduction in
smoking for drug subjects, although the differences between groups was not
significant. Furthermore, it is unlikely that lobeline actually satisfies the
smoker's craving for cigarettes (in doses of 0.5 mg/2 hr, Nikoban, or 5 mgl5
hr, Bantron), since there has been no direct evidence for this action (cf.
Lucchesi et at., 1967; Jarvik et at., 1970; Brantmark et at., 1973).
We also examined several of the papers comparing lobeline to an
antacid placebo (true double-blind) and also chose to review reports comparing lobeline to other active drugs, usually in much more complex experimental settings.
The utilization of a placebo that will not be distinguishable from the
active drug, i.e., an active placebo, is often almost impossible; this is especially
true in the case of lobeline, where the active drug has a truly aversive taste,
causes throat irritation, and frequently produces gastrointestinal side effects.
Since there is an unusually large placebo effect in the area of smoking
deterrent drugs, patients discovering differences between treatment measures may become discouraged if they believe that they are not being given
"real" drug therapy.
It is frequently difficult to detect whether a study described by the
author as double blind was any more than single blind, that is, to the
experimenter. For example, Colledge (1965) reports that in a one-month
double-blind comparison of Lobidan (lobeline sulfate 2 mg, magnesium
carbonate 125 mg, tribasic calcium phosphate 190 mg) and placebo, the
active drug aided patients to cease or reduce their smoking more than
placebo. This is the type of therapeutic report that misleads readers avidly
seeking an "antismoking pill." The 33% dropout rate, small sample sizes, lack
of report of side effects with either Lobidan or placebo, admission that many
subjects did not take the tablets in either group for the entire trial, and total
lack of follow-up are all considerations that make scientific evaluation of the
effectiveness of the Lobidan tablets difficult in this study.
Similarly, in another ostensibly double-blind study (Rosnick, 1965) in
which Nikoban pastilles were superior to undescribed placebo pastilles in
reducing cigarette consumption, subjects using the Nikoban reported "epigastric fulness" while placebo subjects did not. No report was made of the
number of pastilles actually used in either group, or of any follow-up.
When careful attempts were made to compare Lobidan to the antacid
base alone (Scott et at., 1962; Merry and Preston, 1963), many patients
453
stopped smoking during the initial placebo period and the subsequent
comparison of Lobidan to placebo yielded no differences.
Even when lobeline was compared to placebo in three different forms
(lozenges, synthetic and natural lobeline pills) in a series of withdrawal clinics
(Leone et al., 1968), it was at no time significantly different from placebo as a
smoking deterrent. The pastilles were particularly unpleasant in taste or
aftereffect upon smoking, but this was also noted by some placebo users. The
use of lobeline and placebo, both in tablet and lozenge form, fell over time at
the same rate, following curves of decreased cigarette consumption. As usual,
there was a rapid decrease in cigarette use for the first two weeks of the clinic
followed by a slow upward drift to about 50% of baseline. A nine-month
follow-up showed 20% of subjects still abstaining, compared to the eightweek treatment success of 60% abstinence.
The smoking withdrawal clinics of Ejrup (1963; see also reviews of
Keutzer et al., 1968; Bradshaw, 1973; Hunt and Bespalec, 1974) have the
highest initial success rates, about 76%, after a ten-day treatment involving
lobeline and therapy. High doses of lobeline are given, up to 55 mg/day by
injection, as well as meprobamate and anticholinergics, upon occasion. Over
6000 patients were treated between 1958 and 1963 and the six-month followup rates vary around 40-50% abstention. Although placebo was occasionally
used, no comparisons are reported with lobeline treatment. It is possible that
the national prominence of these clinics provide a strong placebo effect. No
comparable success has been reported in this country.
A number of studies have been performed between 1966 and 1974
comparing lobeline to other active drugs as well as to placebo. In each of
these studies, at least one form of psychotherapy was employed in addition to
drug therapy. None of these studies showed a superiority of anyone
medication over another and often groups receiving only medication fared
worse than groups involving the intervention of a human therapist.
In the study by Hammet and Graff (1966), chlordiazepoxide 10 mg t.i.d.
and lobeline 2 mg t.i.d. were compared in a design also involving group
psychotherapy or hypnotherapy. Only 24 out of 37 (65%) of the patients
finished the ten-week course. The hypnosis group reported the greatest
initial success rate (100% completion and abstinence), 55% of the group
therapy section completed the treatment abstaining, but the drug groups
averaged only 31 % completion and abstention. Three-month follow-up rates
dropped about 10% for each group, except that all lobeline patients
relapsed. The confound of therapist intervention, ranging from none at all
to individualized hypnosis sessions, plus the invalid designation of the
persons who decided not to enter the clinic as a control group, make the
results uninterpretable.
In a series of smoking clinics, Ross (1967) studied the effectiveness of
placebo, lobeline alone, lobeline plus amphetamine, amphetamine alone, and
amphetamine plus phenobarbital. Confusing as this initially appears, overall
454
results were simple-medication always helps in the short term (even

placebo), but not over the long-term. At six months, the success rate dropped
to 16%, with no advantage of medications.
Schauble et al. (1967) found educational therapy in antismoking clinics
to be a useful adjunct to lobeline or amphetamine, but only in males. No
drug differences were reported, nor were formal statistical tests made.
Wilhelmsen (1968) reported treatment of over 400 patients in a smoking
clinic, using individual therapy and a variety of drugs-injections of lobeline,
methylscopolamine, tranquilizer, or a lozenge tasting like tobacco and coffee
(Tobalin). Although an abstinence rate of over 60% after two weeks was
reported, half of these subjects had relapsed after one year, regardless of
treatment, making these results comparable to others in the literature (Hunt
et al., 1971).
When placebo, buffered lobeline sulfate 2 mg, dextroamphetamine, and
imipramine were compared in a ten-week treatment program (Jacobs et al.,
1971) that involved both group and individual therapy, no advantage was
found among drugs or between therapy type. Although the antidepressant
imipramine was selected to alleviate withdrawal depression, the incidence of
anticholinergic side effects appeared to be high, and this implied that the
desired mood elevation was not seen in these normal patients. Amphetamine
was selected to simulate nicotine's peripheral action as well as to energize.
However, the central effect of amphetamine is much stronger than that of
nicotine, and it can produce dependence. Finally, lobeline was chosen to
mimic the sympathomimetic actions of nicotine, a questionable concept we
have dealt with previously.
The most recent comparison of lobeline with another drug, in this case
chlordiazepoxide, was made in a ten-week factory clinic; treatment primarily
involved group discussions with medical personnel (Heyden et al., 1974).
Since patients were allowed to refuse or to choose between medications, there
can be no scientific evaluation of results. All patients tended to stop taking
medication as the treatment progressed, as well.
From this brief summary of the literature, it appears that the polydrug
comparisons involving lobeline and other agents have been poorly designed,
conducted, and reported. Although not even a suggestion of a positive effect
emanates from the variety of psychoactive agents tested, this may be partially
due to design considerations working to confound and obscure drug effects,
rather than to maXimize them.
We found very few articles in the smoking cessation literature investigating effects of common psychotherapeutic agents. The use of both stimulant
and sedative psychoactive drugs to diminish smoking can be seen as attempts
to replace certain of the reported effects of smoking and to counteract or
minimize the psychological and physical discomforts of abandoning the habit.
Stimulants presumably substitute for similar actions of nicotine and prevent
the oft-reported lassitude and weight gain accompanying smoking abstinence. Arguments have been set forth for the use of various minor
455
tranquilizers, based on the hypothesis that the smoker often needs some aid
in relaxing, an effect cigarettes are purported to produce. Tranquilizers and
sedatives reduce nervousness, insomnia, and dysphoria characteristic of
abstinence.
As far back as 1941, clinicians were administering stimulants on a
chronic basis to treat smoking. Miller (1941) gave large doses of benzedrine
for 3-6 months and found that some patients were able to abstain and some
to reduce their consumption. Patients treated with placebo did not cut down
their smoking, suggesting to Miller that ampetamine was responsible for this
effect. In 1964, Whitehead and Davies performed two double-blind trials
involving chlordiazepoxide, methylphenidate, and placebo. In neither trial
were there differences between drugs, nor was the success rate very high.
Rosenberg (1972) ran a two-week smoking clinic in Copenhagen, where he
started to follow Ejrup's methodology, but omitted the lobeline. Although no
placebos were used, he found it effective to administer chlordiazepoxide to
ease withdrawal and to repeatedly measure the patient's carbon monoxide
levels as a measure of the severity of his problem and the rate of
improvement. Frightening the patient with measures of his high carbon
monoxide levels is probably an effective short-term method of reducing
smoking!
Fee (1972; Fee and Benson, 1971) has reported extensive experiences
with smoking clinics in Scotland, in which both drugs and therapies have
been varied. We reported ealier on his experience with lobeline, nicotine
chewing gum, avena sativa, ascorbic acid, and placebo. The only other drug
he has tried, also unsuccessfully, is fenfluramine hydrochloride, an antiobesityagent.
The very best study of an experimental nature, using a smoking clinic
milieu, is that of Schwartz and Dubitzky (1967, 1968). These researchers
recruited 288 patients, using stratification and random assignment to treatment condition, from among the Kaiser Permanente Health Group population. The study was completely double-blind, and included nontreatment
controls and all placebo-drug combinations within treatment group types
(individual or group counseling). The barbiturate-like agent, meprobamate
(Equanil) 400 mg, was compared to a matched placebo.
Immediately following the eight-week treatment period, the overall
success (85% reduction in smoking) rate was 33% for treated subjects and
11 % for untreated controls. The four counseling/pill combination treatments
showed significantly greater rates of success than did the controls. The drug
alone and therapy alone (no drug) treatments were not significantly more
effective than controls at a final 1i-year follow-up; comparison of success
between treatment and control groups was significant, but not very impressive (19.8% to ILl %). The prescription-placebo group, which had a success
rate of 25%, comparable to the individual counseling/placebo group (30.6%)
and group-counseling/placebo (27.8%), was the cheapest, simplest treatment
employed. Success rates for the tranquilizer groups ranged from 8.3 to
456
19.4%. We consider this the best designed, reported, and analyzed study in a
smoking clinic setting and find the results representative of the by now
predictable pattern in smoking abstention trials.
In addition to those commonly used, a variety of little-known drugs are
constantly being reported. Schmidt (1966) and Scharfenberg et al. (1967)
have used dihydrochlorothiazide (Urodiazin), a saluretic, which promotes
excretion of sodium and chloride ions by the kidney. Results in both trials
indicated some immediate benefit from the drug compared to placebo, but
no follow-ups were made. Schmidt (1974) reported a double-blind trial in
over 5000 smokers using a variety of drugs, of which the most efficacious
were Tabex (laburnum, a poisonous Eurasian plant, alleged to be a nicotine
substitute), Niperlen (a silver-lactate derivative), and Atabakko (a compound
of caffeine and theobromine). The immediate result was 50-57% success
among various drug groups vs 35% in the placebo group; at three-month
follow-up the respective success rates had fallen to 40 and 25%. These
figures are not substantially different from others reviewed here.
One other preparation deserves review in this discussion of miscellaneous pharmacological agents-avena sativa, an extract of oats, first described by Anand (1971). Anand's sample consisted of 26 patients and
volunteers in an inpatient hospital. After four weeks of treatment, mean
cigarette consumption in the active drug group had dropped significantly,
and 5/13 of the patients had stopped smoking totally. In the placebo group,
no patients stopped smoking and the mean rate had not dropped at all. The
lack of placebo result is very surprising, and one wonders whether the
placebo resembled the active mixture, i.e., whether the trial was blind.
Gekeler et al. (1974) conducted a blind trial with 50 patients in each
group in which they devised a placebo visually identical to the avena sativa
solution and found an equal effect in both groups, 35-37% quitting after 8
weeks. Recruitment of subjects, distribution of medication, and assessment of
results were all conducted by mail. The reliability of the questionnaire
assessment method must be subjected to scrutiny at some point, in this type
of research. Fee (personal communication) found no effect with avena sativa
in his recent small scale clinic. Our overall assessment is that this oat
derivative probably has no therapeutic value aside from the all pervasive
placebo effect.
Despite the inability of medical research to discover a drug that will
discourage people from smoking, several diseases are reported to induce an
aversion to the taste of cigarettes. These are viral hepatitis, for which the
cigarette aversion is almost a diagnostic sign, and most recently reported, the
Hong Kong flu. Any systemic febrile disease results in a loss of desire to
smoke-also loss of appetite and sexual drive.
Some of the newest and most intriguing studies involving smoking deal
only indirectly with the problem of cessation, but do indicate important
pharmacological actions of nicotine hitherto unmeasured, and of possible
therapeutic use. Smokers required higher doses of propoxyphene, Darvon
457
(but not aspirin), to obtain a given level of dental analgesia Uick, 1974). The
plasma levels of phenacetin in smokers were much lower than in nonsmokers
after a 900-mg oral dose (Pantuck et al., 1974). Drowsiness after administration of the benzodiazepines, diazepam, and chlordiazepoxide (but not after
the barbiturate phenobarbital) was much greater in nonsmokers than in
smokers and also significantly correlated with age and dose (Boston Collaborative Drug Surveillance Program, 1973). Similarly, greater drowsiness was
induced in nonsmokers than in smokers by chlorpromazine; a highly
significant trend was found across all doses tested (Swett, 1974). Induction of
microsomal drug-metabolizing enzymes by chronic nicotine use is hypothesized to increase the metabolism of these drugs.
Several reviewers have synthesized comparisons of the various forms of
treatment for smoking. In particular, Bernstein (1970), Keutzer et al. (1968),
Bradshaw (1973), Hunt et al. (1971), and Hunt and Bespalec (1974) provide
excellent overall reviews of methodology with critiques of individual studies
and the entire field of research.
Bradshaw compared results from four different types of clinical approaches (34 studies in all, conducted between 1955 and 1969): medication
(all lobeline), nonmedication (psychotherapy), medication and nonmedication, and behavior therapy. He included only studies in which total abstention was used as a success criterion, since relapse rates are much higher in
those who only cut down during treatment. When compared to no-treatment
controls, medication, nonmedication, and behavior therapy were all significantly better, but no further differences could be found. The mean success
rates for the four conditions were, respectively, 7.3, 36.8, 44.6, and 45.0%.
Of course, lobeline was the only medication reviewed, but we have not found
any other preparations to be significantly different. Bradshaw further
summarized recidivism rates across treatment modalities and found that one
to three months after treatment, 30% of patients were still abstinent, while
four to six months after treatment, only 16% of patients were still abstinent.
These figures are similar to those reported by Hunt and Bespalec
(1974), who compared six forms of treatment. Their composite curves
summarize 89 studies (through 1973) in which follow-up data were reported
(see Fig. 7). The curves describing complete abstinence asymptote at 20-30%
from four to seven months onward. The percentage reduction in smoking
base rate asymptotes at around 40%. When follow-up success rates are
compared among various types of treatments, hypnosis appears to be most
promising, but small sample sizes and individual therapy are costly ways to
treat smoking, as noted by the authors. The newer articles reviewed by us in
this paper substantiate the same recidivism curves derived by Hunt and by
Bradshaw.
A comparison of relapse rates for heroin addiction, alcoholism, and
smoking is quite intriguing (see Fig. 8; Hunt et al., 1971). The curves are so
similar as to make one wonder whether a specific treatment should be sought
for all drug dependencies. The degree of physical dependence produced by
458
100
90
80
.--- .. HEROIN
-SMOKING
0-----<> ALCOHOL
70
(j)
a::
w
60
50
(j)
m
<t
f-
40
w
a::
w
n.
30
20
10
2 weeks 1 2 3 4 5 6 7 8 9 10 11 12
MONTHS
FIG. 8. Relapse rate over time for heroin, smoking, and alcohol. (From Hunt et ai., 1971.)
heroin and alcohol is certainly greater than that produced by nicotine, yet the
recidivism rates are about the same. What underlying similarities govern
abandonment of any "bad habit," whether it be an inability to stop smoking,
taking drugs, or compulsive overeating? Reinforcement on both physiological
and psychological levels may be a key factor to examine.
Analysis of the reinforcing components, both primary and secondary, of
complex drug dependencies is one side of the coin. The other side is the
study of extinction, of how to bring the behavior down to a operant level. In
the case of heroin dependence, methadone, a legally obtained opioid,
partially replaces heroin in pharmacological action. Unfortunately, many
"ex-addicts" maintained on methadone still occasionally shoot heroin and
misuse other drugs, such as alcohol, barbiturates, and amphetamines.
Furthermore, the attempt to wean patients from methadone itself is infrequently made, so that the drug dependency becomes lifelong. With alcohol,
long-term maintenance on disulfiram or diazepam is most common, but
often also accompanied by misuse of other drugs. Only strong peer group
pressure and support provided by agencies such as Alcoholics Anonymous or
Synanon has resulted in drug-free maintenance of the exalcoholic.
In our examination of cigarette smoking, our main concern in this
review, we have found that placebo and pharmacotherapy are equally
effective in the short run in helping smokers cease smoking or cut down
sizably on the daily number of cigarettes. Combined with some form of
psychotherapy, the initial success rates are even higher. We must entertain
459
the possibility that neither specific agents, substitutes for nicotine and
nicotine antagonists, nor nonspecific agents, various psychoactive drugs
alleviating the discomfort of withdrawal or producing pleasurable effects of
their own, can ever be "successful" in the manner used.
We are convinced that much more emphasis must be placed on
maintenance of abstinence. High immediate success rates have been obtained
with just about every form of smoking cessation therapy employed, and high
relapse rates almost certainly follow. Concentration on techniques developed
for the continued alteration of behavior, combined with more intensive study
of successful exsmokers, may yield information that can be applied to those
who only manage to abstain for a few weeks or months at present.
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INDEX
Abuse of
amphetamine, 119
cocaine, 109
diethylpropion, 127
ephedrine, 128
high dose, 144
phenmetrazine, 124
Acepromazine, 47
Acetylcholine (Ach), 59, 67, 68,75-76
nicotine mimics, 437
Acetylcholinergic transmission, 59
N-Acetyl-3,4-dimethoxyphenethylamine,
274
N-Acetylmescaline, 274-275
Acid-head, 417
Acarus calamus, 234, 284
Acrolein, 437
Activity-structure generalizations, 257, 272
Additives in food, 177
Adenosine monophosphate, cyclic, 74
Adenylate cyclase, 73-74
Adrenalin, 124
hypothesis, 414
Adrenochrome, 363
conversion of epinephrine to, 414
Aguacol/a, 232
Alcohol dehydrogenase, 342
Alcoholics treated with LSD, 410
Alcoholism, 410-411
Aldehyde dehydrogenase, 342
Alkaloids, 259-263
Alkocyphenylisopropy1amine, 298-302
Alkylphenylisopropylamine, 302-313
Amanita muscaria, 220,222,245
Amfonelic acid, 49, 50,61,74
Amine
biogenic (see also separate compounds), 2-12
cyclic, 344
oxidative metabolism, 348
465
6-(2-Aminopropyl)-2,2-dimethyl-5-methoxy2,2-dihydrofuran, 313
Aminorex, 19,20
Arninoxaphen, 19
Amitryptyline, 46,184,185
AMP, see Adenosine monophosphate
Amphetamine, 1-98,106,111-124,258,276,
351-359
abuse, 120-121,352
activity-structure relationship, 1-39
bacteria in, 117
behavior due to, 41-98
benzedrine, 112-115, 197
inhaler, 137
chlorinated derivatives, 9-11
dependence, 113, 116
dextro-, 127, 151, 175, 178, 200
first synthesized in 1887, 111
metabolic pathways, 351-358
murders due to, 143
and narcolepsy, 148
and obesity, 149
production in U_S_A_ (1958-1970), 119
and psychosis, paranoid, due to, 30, 113119, 121, 135, 137, 139, 277
and schizophrenia, 118, 130, 137,139,141,
416
and sexual maladjustment, 143
sulfate, 100,114
use, clinical, 43
Amphetarninics, 186, 197
Anadenanthera peregrina, 231
Anesthetics, 245
Anhalonidine, 263
Anhalonium lewinii, 259
Animals, behavioral effects
pretreated with drugs which modify catecholaminergic neurotransmission processes, 44-5 8
466
Anorexia nervosa, 18, 187-189
Anticholinergics, 183
Anticonvulsants in children, 201-203
Antidepressant, tricyclic see also separate
compounds, 46, 61,78,169,181,188
Apomorphine, 55, 56, 75
Aptrol,302
Arbol de los brujos, 225
Arecoline, 59
Arene oxide, 341
Arhuaca Indians
first to use coca, 101
Ariocarpus, 260
As~one,234,283,284
Assaultiveness, 143
Astrophylum, 260
Atarax, see Hydroxyzine
Atropa belladonna, 224
Atropine, 59
Austrocylindropuntia cylindrica, 260
Ayahuasca, 230
plant extract, 258
Aztekium, 260
Banisteriopsis snuffs, 230, 245
B~biturate, 47, 244
Behavior
disorders of mentally ret~ded, 173-176
hyperkinetic children, 148-149
modification, 177
peer and smoking, 429
repetitious, 142
stereotyped, 9, 142, 152
tests in animals, 253
therapy, 173
Belladonna, 224
Benadryl,169
Benzedrine, see Amphetamine
Benzene ethaneamine, 352-359
Benzodiazepine,47
Benzoic acid, 358
major urinary metabolite of amphetamine
in man, 358
Benzoyl ecgonine, methyl ester of, 107
Benzphetamine, 18-20
Benztropine, 61, 70, 78
4-Benzyloxy-3 ,5-dimethoxyphenylisopropylamine, 299-300
Betel nut, 244
Biotransformation, oxidative, 351
Biperidin, 404
Bleph~ospasm, 186
BOL, see Bromolysergic acid diethylamide
(bromo-LSD)
INDEX
Bovet-Gatti profile procedure, 253, 278,302
Box of Skinner, 71
Brew of witches, 224
4-Bromo-2,5-dimethoxyamphetamine, 316
4-Bromo-2,5-dimethoxyphenylisopropylamine
(DOB),316-317
4-Bromo-3,5-dimethoxyphenylisopropylamine,
318
5-Bromo-2,4-dimethoxyphenylisopropylamine,
317
2-Bromolysergic acid diethylamide (BOL),
252
p-Bromomethamphetamine, 316
2-Bromo-4,5-methylenedioxyphenylisopropylamine, 317-318
4-Bromo-N-methylphenylisopropylamine, 315316
Bronchitis, chronic
in smokers, 435
Brugmansia, 225
Brunfelsia, 233
Bufotenine, 231,414,415
Button of peyote, 220
Butyrophenone, 47, 170
Cactus (see also Peyote)
aguacolla, 232
San Pedro, 232
Trichocereus pachanoi, 232
Caffeine, 109, 127, 178,244
Calea zacatechichi, 229
Cannabis, 220, 223
Cannulation, push-pull, 67
C~bamazapine(Tegretol), 202
~bamazepine(Tegretol), 202
used in treatment for psychomotor epilepsy,
202
C~boline,tricyclic, 258
C~bon monoxide, 437
~bon
oxidation of attached heteroatoms, 343-346

340, 346
C~cinogenesis, 4-5, 407
C~cinogenicity, 340
Catatonia in mouse, 267
Catecholamine, 44, 48, 58, 60, 62-73, 83, 84
blocking, 76
in brain identified: dopamine,44
epinephrine, 44
norepinephrine, 44
drugs which deplete, 48
release, 58, 65-73, 83-84
synthesis, 49-54, 62-63
uptake, 46, 65-67
C~cinogen,
467
INDEX
Catecholaminergic receptor, 47-48

transmission, 45-58
Catechol-O-methyltransferase(COMT), 44,298
Catha edulis, 99
Cathidine, 100
Cathine, 100, 101
Cathinine, 100
Catnip, 397
Central nervous system
and stimulant use, 129-148
Cerebrospinal fluid (CSF), 67,72,73
Cerebroventricular perfusion, 68, 80
Cereus peruvian us, 261
Channa of Hottentots, 233
CheWing khat, 99
Chicha, 231
Children
epileptic, 201-203
anticonvulsants for, 201-203
and hyperactivity, 201
hyperactive
and epileptic, 201
and mentally retarded, 180
psychotic, treatments for
electroshock, 168
megavitamin,172
tranquilizer, major, 172-173
p-Chloramphetamine, 9,11,19,20,42,314
p-Chlorbenzphetamine, 20
Chlordiazepoxide, 169, 174, 183, 184, 193,
244
p-Chlormethamphetamine, 8, 315
4-Chloro-2,5-dimethoxyphenylisopropylamine,
320
p-Chloro-Il-methylbenzylamine, 8
p-Chloro-N-methylphenethylamine, 8
p-Chlorophenylalanine,58
4-Chloro-N-methylphenylisopropylamine, 315
Chlorphentermine, 19
4-Chlorophenylisopropylamine, 314-315
Chlorpromazine, 47, 63, 136, 169, 172, 174,
180,188,189,195,198,199,306
in treatment for amphetamine poisoning, 141
Chloprothine, 174
Cholesterol biosynthesis, 341
Chromosome, 405-407
Cigar, li ttIe
nicotine content of brands, 428
Cigarette (see also Nicotine, Smoking)
adult incidence of smoking in the U.S.A.,
430
blended, 428
industry, 427
lettuce, 436
Cigarette (cont'd)
nicotine content of 130 brands, 428
production in the U.S.A. (1886-1968),427
tramonium, 396
Cimora, 232
Coca (see also Cocaine), 99-105,109,220
Coca-Cola (1888), 110
Cocaine, 66,80, 104-111,124,244
anesthetic, local, 105
clubs, 110
Freud's interest in, 107
isolation from Peruvian coco leaves, 104,107
self-administration, 18
Coffee, 244
Cohoba powder of Taino Indians, 231
Coleus blumei, 228
C. pumila, 228
Color distortion, 248
COMT, see Catechol.Q-methyltransferase
Conocybe, 225
Coriaria thymifolia, 233
Cresol,437
Cryogenine, 229
CSF, see Cerebrospinal fluid
Cults see also separate entries
jurema, 230
peyote, 228
San Pedro, 232
Cyclopropane ring, 28
Cylert (see Pemoline)
Cyproheptadine, 188
Cytisine, 229, 234
Cynsuscanarien~, 234
Cytochrome-P45o electron transport system,
338
Cytomel, 171
D, see Dopamine
Dj3H, see Dopamine j3-hydroxylase
Datura, 224, 232
D. suaveolens, 230
Deamination, oxidative, 344
Decarboxylase of L-amino acid, 53
Dehydration, 144
Demethylation of foreign compound, 345
Dependency
on stimulant, 151
without psychosis, 116
Deprenyl, 29, 30
Depression, 146, 150-151,409-410
and demoralization, 151
withdrawal, 146
Desfontania spinosa, 233
Desipramine, 46, 66, 80,184
468
INDEX
3,5-Dimethoxy-4(n )-propoxyphenethylamine,
269
proscaline,269
2,5-Dimethoxy+propylphenylisopropolamine
Dexphenmet~ne,123
Dextroamphetamine, see d-Amphetamine
(DOPR), 310-311
N-Dialkylation, 24, 25
N,N-Dimethylmescaline, 273-274
Diazepam(Valium), 169, 181, 186, 190,244
trichocerine, 273
2,4-Dichloroamphetamine, 9
N,N-Dimethylphenethylamine, 3
Diethyldithiocarbamate, 51,53
N,N-Dimethyltryptamine, 230, 231, 258,415
Diethylpropion, 18,20,124,126-128
identical with nigerine, 231
3,4-Dihydroxyphenylacetic acid (DOPAC), 61
Diphenhydramine (Benadryl), 169, 182
DihydroxyphenyIaIanine (dopa), 44, 49, 55,
Diphenylhydantoin(DPH), 182, 202
64,71,118,144,171
a,a-Diphenyl-2-piperidine ethanol, 17
Dihydroxypheny1serine (DOPS), 52
a,a-Diphenyl-4-piperidinemethanol, 17
5,6-Dihydroxytryptamine, 8
Disability
5,7-Dihydroxytryptamine, 58, 59
of learning, 196
Dilapidation
of reading, 196
striking in stimulant abusers, 144
Disulfiram, 51-53
2,5-Dimethoxy-4-amylphenylisopropylamine
Ditran, 396, 409
(DOAM),312-313
for treating depression, 410
2,5-Dimethoxy-4-bromopheny1ethylamine,
DMA, see Dimethoxyphenylisopropylamine
271
DMPEA, see Dimethoxyphenethylamine
2,5-Dimethoxy-4-butylphenylisopropylamine
DMT, see Dimethyltryptamine
(DOBU),312
DOAM, see 2,5-Dimethoxy-4-amylphenyl3,5-Dimethoxy-4-ethoxyphenylethylamine,
isopropylamine
268-269
DOB, see 4-Bromo-2,5-dimethoxyphenylescaline, 268
isopropylamine
2,5-Dimethoxy-4-ethylphenylisopropylamine
DOBU, see 2,5-Dimethoxy-4-butylphenylisopropylamine
(DOET), 308-310
DOET, see 2,5-Dimethoxy-4-ethylphenyl2,5-Dimethoxy-4-iodophenethylamine, 271isopropylamine
272
2,5-Dimethoxy-4-methyIamphetamine (DOM), Dolichothele, 260
30,34,42,305-306,364,365,393
DOM, see 2,5-Dimethoxy-4-methylamphet2,3-Dimethoxy-4,5-methy1enedioxyamphetamine
Dopa, see Dihydroxyphenylalanine
amine,298
2,5-Dimethoxy-3,4-methylenedioxyamphetDOPAC, see 3,4-Dihydroxyphenylacetic acid
Dopamine, 5-8,44,45,48-59,61-78,80-85,
amine, 297
261,267,343,413
2,3-Dimethoxy-4,5-methylenedioxyphenylDopamine ,,-hydroxylase, 44, 63, 83, 343
isopropylamine (DMMDA-2), 298, 298
DOPR, see 2,5-Dimethoxy-4-propylphenyl2,5-Dimethoxy-3,4-methy1enedioxyphenylisopropylamine
isopropylamine (DMMDA), 297-298
OOPS, see Dihydroxyphenylserine
2,6-Dimethoxy-4-methylisopropylamine, 307Double-conscious technique, 255
308
2,5-Dimethoxy-4-methylphenethylamine, 270- DPH, see Diphenylhydantoin
271
Dreams, frightening, 189
2,5-Dimethoxy-4-methylphenylisopropylainine, Drug
281-282,304-307
addiction, 101
3,4-Dimethoxyphenylethylamine (DMPEA),
adverse reaction due to, 389, 402-407
261,262, 267,413-414
anorexic effects, 18-26
in urine of schizophrenics, 267, 413
classification, 390
2,4-Dimethoxyphenylisopropylamine(2,4clinical effects, 390-397
DMA),280-281
culture, 247
3,4-Dimethoxyphenylisopropylamine, 279metabolism, 335-387
280,304
principles of, 337-351
Detoxification via urinary excretion, 350
Dexamphetamine, 124
Dexedrine, 197
469
INDEX
Drug (cont'd)
model psychosis due to, 416-417
pharmacologically active, 261
psychological effect, 397-400
psychomimetic, 243-333, 389-424
psychotomimetic, 30-34
psychotropic, 171-172, 200
and schizophrenia, 413-416
screening, 252-254
as stimulant, 12-18, 133-146, 179
therapy, 183-184,407-411
treatment, 167-217
trial, 178
use
social,417
therapeutic,407-411
withdrawal,146-148
Drynimal, 122
Dysmorphogenesis, 405-407
Dystonia, acute, 190, 193, 194
Ebena, 232
ECT, see Electroconvulsive therapy
Eidetika, 246
Electroconvulsive therapy, 188, 403
Elemicin, 283, 288
Emepronium, 183
Emphysema in smokers, 436
Enuresis, 182-185
Enzymes, mixed-function oxidase, 350
Ephedra vulgaris, 99
Ephedrine, 4,5,49,50,99,106,128-129,
244
oldest known stimulant, 128
potent bronchodilator, 128
stereotyped behavior in rats, 129
Epilepsy (see also Carbamazepine, Diphenylhydantoin),201-202
Epinephrine, 44
Epinine, 261, 262
Epoxidation, aliphatic, 341
Epoxide hydrase, 341
Ereiba leaves; 234
Erythrina, 234
Erythroxyline, 104
Esanin, 304
Escaline, 268
Ethanol,244
Ethics, medical, 255
Ethosuximide, 202
recommended drug for epilepsy, petit mal,
202
2-Ethoxy-4,5-dimethoxyamphetamine, 300
2-Ethoxy-4 ,5-dimethoxyphenylisopropylamine, 300-301
4-Ethoxy-2,5-dimethoxyphenylisopropylamine, 300
5-Ethoxy-2,4-dimethoxyphenylisopropylamine, 301
N-Ethyl-3,4-methylenedioxyamphetamine,
292
N-Ethyl-3,4-methylenedioxyphenylisopropylamine, 292-293
Euphorica, 245
heroin,245
morphine, 245
opium, 245
Excitancia, 243-244
Exocytosis, 83
Feeding tube, 188
Fenfluramine, 19,20, 22, 25, 42
FLA-63, 52, 53
"Flash," 136
"Flashbacks," 404
Fluorescence, 288
Fluphenazine, 170, 188
Fly agaric, see Amanita muscaria
Food additive, 177
Fornication, 109
Freud and cocaine, 107
Functions, intellectual
and psychological effects in experiments,
397-400
perceptual, 398
psychomotor, 398-399
Galbulimima belgraveana, 234
Gastritis in khat eaters, 100
Gilles de la Tour syndrome, 185-187
Gomortega keule, 234
Gustavia poeppigiana, 232
Haight-Ashbury, a speed-freak community,

121
Hall's open field test, 253
Hallucination
auditory, 221
haptic,109
Hallucinatoria, 245
Hallucinogen, 220, 246
African, 223
enable man to fly through space, 221
in primitive societies, 220
INDEX
470
Haloperidol, 47,48, 141, 170,174, 181,186187,195,404
for multiple tics, 186
Harmaline, 230, 258
Harmine, 230, 396
Harrison Tax Act (1914), 110
Heimia salidfolia, 229
Henbane, 224
Heroin, 245
Hexenkraut, 224
Hexobarbital, 342
5-HIAA, see 5-Hydroxyindoleacetic acid
Homalomema, 234
Homomyristoylamine, 268, 269
Homopiperonylamine, 268
Homovanillic acid, 61, 68, 82, 132
Horas de la pastora, 227
Hordenine, 261, 262
Hormone secretion, antidiuretic
a syndrome of inappropriate secretion, 82
Hospitan, 116
Hottentots
use of channa(or kanna), 233
5-HT, see 5-Hydroxytryptamine
5-HTP, see 5-Hydroxytryptophan
Hualhual, 234
Hung-up being, 141
HVA, see Homovanillic acid
Hydrocarbon, polycyclic aromatic
carcinogenicity of, 340
Hydrocyanic acid, 437
4-Hydroxy-d,l-amphetamine,6
m-Hydroxyamphetamine, 5
N-Hydroxyamphetamine. 349
p-Hydroxyamphetamine, 19,42,51,82
6-Hydroxydopamine(6-0HD), 8, 54-56, 266,
284
-induced lesion, 57
5-Hydroxyindoleacetic acid (5-HIAA), 8-12,
74,75,82,83,132
Hydroxylation, 2, 4
aromatic, 339-341
para-, 9, 46, 356
ring, 5, 6, 15
5-Hydroxy-N,N-dimethyltryptamine, 231
p-Hydroxynorephedrine. 51, 60, 82
5-Hydroxytryptamine, 46, 48, 49, 53, 58, 59,
68,74,75,83
5-Hydroxytryptaminergic transmission, 58-59
5-Hydroxytryptophan (5-HTP), 49
Hydroxyzine (Atarax), 169, 174, 181, 183
Hyoscyamus niger, 224
Hyperactivity, 176-182
most common psychiatric disorder in U.S_
children, 176
stimulant drug treatment required, 178
Hyperphagia, 147
Hypersomnia, 147
Hyperthermia, 253, 406
and LSD, 406
Hypnosis, 244
Hypnotica, 244
Ibogaine, 223
Imipramine (Tofranil, Imavate, SK Pramine),
46,149,151,169,184,185,190-194
for hyperactive children, 149
for school-phobic children, 192
Incontinence, urinary, 182
Indians
Arhuaca, 101
Quehua, 104
Taino, 231
and tobacco use, 426
Indole, 258
Inebriantia, 244
Inhalation of cigarette smoke
depth in relation to age, 436
Insulin, 188
Intercourse, sexual
marathon, 143
Intoxication, 246
negative features of, 247
peyote, see Peyote
social,244
Iochroma, 233
4-Iodo-2,5-dimethoxyamphetamine, 319
4-Iodo-2,5-dimethoxyphenylisopropylamine,
318-320
Ipomoea violacea, 227
Iprindole, 46
Iproniazid, 45
Isoelemicin, 283
Isotoma longiflora, 232
Jurema cukt, 230, 231
Justicia pectoralis var. stenophylla, 232
Kaempferia galanga, 234
Kanna of Hottentots, 233
Ketamine, 395
Khat, 244
chewing of, 99
food-stimulant, 99
INDEX
471
Melatonin, 415-416
Memory, 397
Mentally retarded patient, 175-176
Mephentermine, 2, 3
Meprobamate, 169,174, 183,195, 244
Mescaline, see 3,4,5-Trimethoxyphenethylamine
Lactam, 343
Mesembryanthemum, 233
Lagochilus inebrians, 233
mint, 233
M_ expansum, 233
M_ tortuosum, 233
Latue,225
Latus pubi/lora, 225
Metabolite, toxic
Learning disorders, 196-200
formation, 336
Metaraminol, 5, 6, 12, 78,80
Lethargy, 147
Methamphetamine, 2-4, 14, 15, 19,49,50,61,
Leukotomy, 188
62,111-124,302
Lewiris classification, 243-245
abuse epidemic in Japan, 116-117
Librium,169
first synthesized, III
Liothyronine, 171
mental disorders continue for decades after
Lipophilicity, 337
withdrawal, 117
Lithium, 171
Liver, 337, 359
Methaqualone, 244
Lobelia tupa, 233
Methemoglobinemia, 347
Lobeline, 233
Methionine, 413
Lophophine, 269
Lophophora diffusa, (see also Peyote),
feeding in large amount as a methyl donor,
413
228,260
Methoxamine, 7
L_ williamsii, 228, 229, 259, 260
Methoxylation, 5, 7, 33
Lophophorine, 263, 269
(The following entries are in alphabetical order,
most toxic compound of peyote, 263
but are arranged according to chemical
Lycoperdon marginatum, 229
stru cture. )
L_ mixtecorum, 229
p-Methoxyamphetamine, 278
Lysergic acid diethylamide (LSD), 32, 169,
1-( 4-Methoxyphenyl)-2-aminopropane, 368
227,250-253,258,259,286,400-410,
2-Methoxy-3,4-methylenedioxyphenylethyl417
amine, 270
in alcoholics, 411
2-Methoxy-3,4-methylenedioxyamphetamine,
homologs, 254, 392
reaction, 391-392
295
2-Methoxy-3,4-methylenedioxyphenylisopropylin schizophrenics, 407
symptoms, 391
amine, 295-296
Mahuang, 99
31,294
Mandragora efficinarum, 224
2-Methoxy-4,5-methylenedioxyphenylisoprolylMandrake, 224
amine, 294-295
in black magic, 224
3-Methoxy-4,5-ethylenedioxyphenylisopropylMAO, see Monoamine oxidase
amine, 294
Maquira sclerophylla, 234
Maraba,234
293-296, 393
Marijuana, 245
3-Methoxy-4,5-methylenedioxyphenethylMasturbation, 144
amine, 269
MDA, see 3,4-Methylenedioxamphetamine
3-Methoxy-4,5-methylenedioxyphenylisopropylMecamylamine hydrochloride, 433
amine, 293-294
Mecloqualone, 244
3-Methoxytryptamine, 61,413
Megavitamin treatment for psychotic children, 4-Methoxy-2,3-methylenedioxyamphetamine,
172
296
Khat (cont'd)
d-norpseudoephedrine in, 100
Kola, 244
Kwashi,234
472
4-Methox y-2,3-methylenedioxyphenylisopropylamine, 296, 297
Methoxyphenanrlne, 7
4-Methoxyphenylethylamine, 266-267
4-Methoxyphenylisopropylamine, 278-279
4-Methyamphetanrlne, see Methamphetamine
5-Methoxy-N,N-dimethyltryptamine, 231,
232,415
296
6-Methoxy-2,3-methylenedioxyphenylisopropylamine, 296-297
10-Methoxyharmalan, 415-416
a-Methylation, 2, 3, 5, 15,31
2-Methylamphetamine, 303
3-Methylphenylisopropylamine, 303
a-Methyldopamine, 6
Methyleugenol, 288
N-Methylhomopiperonylamine, 274
N-Methylmescaline, 273
N-Methyl-3,4-methylenedioxyphenylisopropylamine, 291-292
N-Methylphenethylamine, 3
Methylphenidate, 16-18,49,50,52,59,61,
62,73,74,106,124-126,149,151,175,
178,181,183,197
abuse, 126
psychosis after abuse, 126
4-Methylphenylisopropylamine, 302-303
Methyl-a-phenyl-2-piperidine acetate, see
Methylphenidate
a-Methyl-p-tyrosine (MT), 5, 6, 49, 50, 51,54,
64,72,83,84,136,352-359
3,4-Methylenedioxyamphetamine (MDA), 289,
292,393
3,5-Methylenedioxyphenethylamine, 268
Methylenedioxyphenylisopropylamines, 288298
2,3-Methylenedioxyphenylisopropylamine,
291
3,4-Methylenedioxyphenylisopropylamine,
289-291
Methysergide, 172, 250
Microsome, 337
Mimosa expansum, 233
M. hostilis, 230
Mind-altering agent, history of, 219-241
Mint, 227
MMDA, see 3-Methoxy-4,5-methylenedioxyamphetamine
INDEX
Monoamine oxidase, 8, 42, 45-46, 344
inhibitors, 26-30,45-46, 184, 193
Morning glory, 227
seeds, 404
Morphine, 245, 262
MPEA, see 4-Methoxyphenylethylanrlne
MT, see a-Methyl-p-tyrosine
Mushroom
genera, 225
hallucinogenic, 225
ikons, 225
sacred,226
Myristicin, 288-289
Mysoline, 202
Nandrolone, 188
Naphthalene, 339-341
conversion to a-naphthol, 339
a-Naphthol, 339
Narcolepsy, 112, 148
treatment with amphetamine, 112, 148
Natema, 230
Navane, 171
NE, see Norepinephrine
NeOTtn'mondia macTostibas, 232
Neuroleptics, 47, 50
Neuron, catecholaminergic, 54-58
Neurosis, obsessive, 404
Neurotransmission, catecholaminergic, 44-58
Neurotransmitter in brain, 60
Niacinanrlde, 172
Nicotine and smoking, 425-464
Niemann's isolation of cocaine, 104
Nigerinine,231
Nightmare, 189-190
Nightshade, a deadly plant, 224
NIH shift, 340
Nitric oxide, 437
Nitrogen dioxide, 437
NM, see Normetanephrine
Norepinephrine (NE), 2-7,44,45, 54-56, 6068,71,72,76-84,343
Normetanephrine (NM), 33, 61
d-Norpseudoephedrine, 100
Nortriptyline, 184
N-oxidation, 347, 355
of aliphatic amine, 347
of aromatic amine, 346
Nut
betel,244
kola,109
Nutmeg, 289
abuse of, 397
INDEX
Nyakwana, 232
Obesity, 149-150
treatment with amphetamine, 149
Obregonia, 260
O-dealkylation, oxidative, 369
O-demethylatioJl, 299, 368
6-0HD, see 6-Hydroxydopamine
Ololiuqui, 225, 227
sister of, 224
O-methylation, 299
Opium, 245
Ospolot, 203
Overdose of drug and death directly related
to it, 146
Oxazepam, 183
Oxazolidinone, 17
Oxidase, mixed-function, 338, 345
Oxidation, metabolic, 338, 342-343, 346-351
Oxidative pathway, 353
Oxygen, P450 -activated, 339
Oxytremorine, 59
Panaeolus, 225
Pancratium trianthum, 234
Panic reaction, acute, 402
Paredrine, 278
Pargyline, 45
Parica, 232
Parkinson's disease, 150
drugs for, 396
Pedilanthus tithynaloides, 232
Pelecyphora, 260
Pellotine, 260
Pemoline(Cylert), 17-18, 175, 178, 197
Pentazocine, 342
Pentolinium, 433
Pentylenetetrazol, 200
Perhedrin, 304
Pernettya, 233
Per-Vitin, 112
widely issued to German troops, 115
Peyote (see also Lophophorine), 221, 228,
245,259,260,275
Aztecs knew it, 228
"buttons," 220, 226
cactus, 225
complex, 260
cult,228
dried heads, 226
false, 229
first description in 1651, 260
hallucinations, visual, 228
473
Peyote (cont'd)
intoxication, 228
leader, 229
Peyotline, 263
Phantastica, 245
Phencyclidine, 395-396,417
Phendimetrazine, 19, 20
Phenelzine, 29, 193
Phenethylamine, 2, 14,41,45,257,259-276
derivatives, 12-17,41,42,83
methoxylated,272
nitrogen-substituted,273-276
release of norepinephrine, 3, 4, 6, 7
ring substitutions, 259-273
skeleton, 15
Pheniprazine, 29, 42, 45
Phenmetrazine, 18-20,49,50,61,64,74,83,
106, 123-125, 127, 132, 183
discovered in, 1954, 123
rapidly replaced amphetamine as stimulant
of choice, 123
Phenol,437
Phenomenon, visual, 398
Phenoxybenzamine, 136
Phentermine, 2, 14, 18,20
~-Phenethanolamine, 4, 5
Phenobarbital, 182, 199,201-202
for grand mal epileptic seizures in children,
201
Phenol,437
Phenothiazines (see also Chlorpromazine,
Fluphenazine, Thioridazine, Trifluoperazine), 47,169-170,180-181,186
Phentolamine, 47, 48
I-Phenyl-2-aminopropane, 351, 367
metabolism of ring-substituted, 364-369
Phenylisopropylamine, 2,22,27-28,30,254,
276-321
derivatives with anorexic activity, 19, 21-26,
29
with stimulatn activity, 13-16
Phenylpropanolamine, 4, 5, 7
Phenyl-2-propanone, 356
converted to benzoic acid, 356
Philopon, 116
Physostigmine, 59
Pimozide, 47, 48,136
Pinde, 230
Pinocytosis, reverse, 83
Pipe of Virginia clay, 426
Piperidinoglycolates, 253
Piperidyl benzilate ester, 394-395
INDEX
474
Pipiltzintzintli of ancient Aztecs, 227
Pipradrol, 16-18,49,50,68, 74
Piptadenia parviflora, 233
P. peregrina, 231
Placebo, "active," 249
Plants, lJook of, by Abraham Crowley in 1662,
101
Plant preparations, early use, 99-106
Preludin, 125
Primadone, 202
Prisoners, use of, in drug experiments, 251
Procaine synthesis, 108
Prochlorperazine, 199
Projective test, 399
Propantheline, 183
Propanolol, 47, 48,136
4-( n )-Propoxy-2 ,5-dimethoxyamphetamine,
301
4-( n )-Propoxy-2,5-dimethoxyphenylisopropylamine,301
Proscaline, 269
Protriptyline, 46
Psilocin, 226, 258
Psilocybe aztecorum, 226
P. Yungensis, 226
Psilocybin, 226, 249, 250,393-396
"Psychedelic," 246
Psychiatry for children, 167-217
"Psychodynamic," 248
Psycho mimetic drugs, see Drug
Psychoneurosis, 407-408
treated with psychotherapy, 407
Psychopharmacology, clinical, 243
pediatric,167 in, 1937, 148
started with Bradley's report in 1937,
148
Psychosis, model of, 137-141,411-412,416417
induced by amphetamine, 30, 113-119,
121, 135,137,139,141,277,
359
cocaine, 109
drug, 403
phenmetrazine, 124
psychomimetics, 411-412
prolonged, 402
theories, 168-173,411-412
toxic,76[
Psychotherapy, 177,182-183,188
psychedelic, 408
for recurrent nightmares, 190
Psychotica, 246, 248
Psychotogen, endogenous
concept in schizophrenia, 413-416
conditions for, 412-413
Psychotomimetics, 254
definition, 243-247
fluorescence of, 25 4
metabolism, 351
of ring-substituted, 364-369
and model psychosis, 411-412
synonyms for the term, 246-247
Psychotria viridis, 230
"Psychotropic," 243
Pteridine cofactor, 63
Puffball, 229
Lycoperdon marginatum, 229
L. mixtecorum, 229
"Punding," 142
Quechua Indians, 104
Rat-proof, 284
Reaction time, 398
Reinforcement, secondary, 434
Reserpine, 48, 50, 67,73,175,199
Response, individual
variability of, 249-250
Retardate, mental
lives in an institution, 173
Retardation, mental, mild, 196
behavior disorders of, 173-176
psychomotor disorder, 147
Rhynchosia, 234
Ritual, social, 244
drinking as, 244
Rivea corymbosa, 227
Ro 4-6861, 315
Rorschach responses, 399
"Rush," 136-137
intensity is dose-related, 136
S-33, 315
Safrole, 288, 289
Salvia divinorum (Hojas de la pastoral, 227
San Pedro
cactus, 232
complex, 260
cult, 232
SAR, see Structure-activity relationship
Schizophrenia, 118, 126, 129, 139, 168, 170
amphetamine-induced (see also Amphetamine
psychosis), 416
in animals, 43
chemical reactions, 408-409
chronic, 401
dopamine hypothesis for, 152
drug-induced,416
hypothesis of a chemical basis for, 413
thought disorder, 125
475
INDEX
Schizophrenia (cont'd)
treatment, 172, 176
with huge doses of nicotinamide, 413
School phobia, 191-194
Scopolamine, 396
Sebil,231
Sedative, 183
Seizure (see also Epilepsy), 200-203
Self-experimentation, 255
Self-stimulation, 48, 55
Sernylan, 395
Serotonin, 8-12, 132, 252,403,415
Serranos, 104
Sexuality, 143-144
Sinicuichi, 229
Skinner box, 7I
Sleep, 147
disorders, 189-190
Smoke of cigarette, 437
compounds contributing to health hazards,
437
Smoking, 425-464
banana skins, 397
reasons for starting, 426-444
teenage patterns, 428-430
Snuff,232
cocaine, lIO
Society, primitive, and hallucinogens, 220
So/isia, 260
Soma of Northern India is Amanita muscaria,
222
Somnabulism, 189
Sophora secundiflora, 229
Speed-freak, 143
at Haight-Ashbury, 121
Spiramide,47
Squalene, 34
Squalene-l,2-epoxide, 34
Stenophylla, 232
Stereotypy, 141-142
behavioral, 434
Stimulant, 169, 175, 177-180,183,197-198
attention improved by, 198
and central nervous system, 99-165
clinical considerations, 179
effectiveness, 177
problems due to, 151-153
psychomotor, 81-83
types, 178
uses
athletic, 133-134
medical, 148-151
STP,305,393
Stramonium, 396
Stropharia, 225
Structure-activity study of psychomimetic

drugs, 248-333
Stuttering, 194-196
Sulthiame, 203
Superfusion, surface-cup, 67
Supersensitivity, 130-131
dopaminergic, 130
Synaptosome, 5
Syndrome, psychiatric, 117
psychotomimetic, 247-248
Tabaco del diablo, 233
Tabernantheiboga, 223
Taino Indians, 231
Tea, 244
khat, 100
Tegretol, 202
Teonanacatl, 226
Tesguino, 224
Tetrahydroharmine, 230
Tetrahydroisoquinolines, 261
2,3,4,5-Tetramethoxyamphetamine, 287
2,3,4,5-Tetramethoxyphenylisopropylamine,
287-288
Theine, 104
4-Thiomethyl-2,5-dimethoxyphenylisopropylamine, 320-321
Thioridazine(Meilaril), 170, 174, 175, 180,
188, 195, 198
impairs learning, 198
Thioxanthene, 171, 174
Thyroid preparation, 171
Tic, 185-187
haloperidol for multiple, 186
Time sense, 398
Tlitlitzin, 227
TMA, see Trimethoxyphenylisopropylamine
Tobacco, 244
control, 426
introduction into
England, 426
Europe, 426
France, 426
tar, 437
Tolerance, 82, 83, 131-133, 250
Tolyisopropylamine, 303
Toxicity
and carcinogenicity, 340
physical, 144-146
of polycyclic aromatic hydrocarbon, 340
2,4,5-T, PEA, see 2,4,5-Trimethoxyphenethylamine
Trailing phenomenon, 404
Tranquilizer (see also separate compounds)
major, 198-199
476
Tranquilizer (cont'd)
minor, 169-172, 174-175, 183
Tranylcypromine, 28, 29, 42,45
Trichocereus pachanoi, 232, 260
T. terschekii, 273
Trichocerine, 273-274
p-Trifluoromethylamphetamine, 9
3-(p-Trifluoromethylphenoxy)-N-methyl-3phenylpropylamine, 12
Trifluoperazine, 170, 174, 188
Trifluperidol, 170
Triiodothyronine, 171
I-Trimethoxy-2-aminopropane, 368
Trimethoxyamphetamines, 30-34, 282, 275286,393
3,4,5-Trimethoxyphenethylamine (Mescaline),
5, 7, 30, 229, 246, 248, 259-268, 272,
275,351,363,392-393,409,417,
acetylation, 362
cactus sources, 260-261
species listed, 261
congener alkaloids, 261-263
dose, 263-264
history, 259-260
metabolism, 359-364
metabolites, demethylated, 362
oxidation, 361
pathway, metabolic, 360
route, 263-264
syndrome, psychopharmacological, 264-265
/3-3,4,5-Trimethoxyphenoxyethylamine, 275276
/3-3,4,5-Trimethoxyphenoxy-N,N-dimethylethylamine, 276
Trimethoxyphenylacetaldehyde, 361
3,4,5-Trimethoxyphenylacetic acid, 275, 360
2,3,5-Trimethoxyphenylisopropylamine (TMA),
295-296
derivatives, 282-287
Tryptamine, 221, 230-232, 253
substituted, 258
INDEX
Tryptophan, 82, 132
metabolic pathways, 415
Tryptophan hydroxylase, 8
Tupa, 233
Tyramine,5,6,30,69,70, 261,262
Tyrosine, 44, 64, 71-73
Tyrosine hydroxylase, 44, 62, 63, 71
U-14,624, 52-54
Users, high dose
of drugs usually have disturbed backgrounds,
135
V-ll1, 136
Valium, see Diazepam
Vesicle
mobilization of storage material, 84
Vilca, 231
Violence, 142-143
Virginia clay pipe, 426
Virola calophylla, 232
V. elongata, 232
V. theiodora, 232
Wake-amine, 116-117
Witches' brew, 224
Withdrawal effects, 146-148
Wyosoccan, 224
Xenobiotics, 335
Xylopropamine, 304
V-maze, 472, 477
Yaje, 230
Yakee, 232
Yopo, 231
Z-7, 307
Zarontin, 202
Zedrine, 116
Zingiberaceae, 234

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Handbook

Biochemical Principles and Techniques in Neuropharmacology

SECTION II: BEHAVIORAL PHARMACOLOGY IN ANIMALS

Principles of Behavioral Pharmacology

SECTION III: HUMAN PSYCHOPHARMACOLOGY

Neuroleptics and Schizophrenia

PLENUM PRESS NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

1978 Plenum Press, New York

Softcover reprint of the hardcover 1st edition 1978

Underlying the design of the Handbook of Psychopharmacology is a prejudice

3. General Pharmacological Actions ......................

4.1. Drugs Which Enhance Catecholaminergic

Introduction-Early Use of Plant Preparations.. . . . .. . . .

9.5. Depression ....................................

8.1. Characteristics, Occurrence, and Outcome . . . . . . . . .

RICHARD EVANS SCHULTES

Psychotomimetic Drugs: Structure-Activity Relationships

1.3. Quantitative Differences . . . . . . . . . . . . . . . . . . . . . . . . .

Drug Metabolism: Review of Principles and the Fate of One-Ring

1. Principles of Drug Metabolism. . . . . .. . .. . .. . . . .. . . . . . .

Psychotomimetic Drugs in Man

3. Clinical Effects of Psychotomimetic Drugs ..............

2.2. Effects of Nicotine on Physiological and

AAIPHETA1\IIINES: STRUCTUREACTIVITY RELATIONSHIPS

H. Bielt and B. A. Bopp

1977. B. A. Bopp Abbott Laboratories, North Chicago, Illinois.

BIEL AND B. A. BOPP

2. EFFECTS ON BIOGENIC AMINES

a Burgen and Iversen (1965).

Uptake of NE by rat heart"

Effects of Methylatian on the Inhibitian of Norepinephrine Uptake and the Release

Burgen and Iversen (1965).

Uptake of NE by rat heart a

AMPHETAMINES; STRUCTURE-ACTIVITY RELATIONSHIPS

ethylamine, amphetamine, and methamphetamine were all considerably more

" Burgen and Iversen (1965).

Uptake of NE by rat hearta

Burgen and Iversen (1965).

Uptake of NE by rat heart"

H. BIEL AND B. A. BOPP

stimulatory effects while dopamine was implicated in causing stereotyped

AMPHETAMINES: STRUCTURE -ACTIVITY RELATIONSHIPS

of Alterations in the Side Chain on the Serotonin-Depleting Activity of Chlorinated

trast to the relative actiVities of the optical isomers of amphetamine as

BIEL AND B. A. BOPP

Effects of the Position of the Chlorine on the

Fuller and Molloy (1974); serotonin in rat brain 6

of Ring Substitution on Serotonin-Depleting Activity of

AMPHETAMINES.' STRUCTURE -ACTIVITY RELATIONSHIPS

substituted compound had only a slight effect on both the 5-hydroxyindole

Effects of Substitutirm on the Side Chain or Amino Group

Fuller and Molloy (1974) and Fuller et at. (1973. 1974a);

H. BIEL AND B. A. BOPP

3. CENTRAL STIMULATORY EFFECTS

AMPHETAMINES: STRUCTURE-ACTIVITY RELATIONSHIPS

may be metabolized too rapidly, or may be sufficiently similar in structure to

Effects of Alterations in the Side Chain on Stimulant Activity of

BIEL AND B. A. BOPP

Effects of Substitutiun on the Amino Group on Stimulant Activity of

Van der Schoot et at (1961); effect on spontaneous locomotor activity of

AMPHETAMINES: STRUCTURE-ACTIVITY RELATIONSHIPS

H. BIEL AND B. A. BOPP

der Schoot et at. (1961); effect on spontaneous