You are on page 1of 36

Drug and fikohol Dependence, 23 (1989) 183 - 218 183

Elseiver Scientific Publishers Ireland Ltd.

The Committee on Problems of Drug Dependence:


A legacy of the National Academy of Sciences.
A historical account
Everette L. Maya and Arthur E. Jacobsonb
“Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond,
VA 23298-0613 and bLaboratory of Medicinal Chemistry, National Institute of Diabetes, DigQShVQ and Kidney D~SQ~ZSQS,
National Institutes of Health, Bethesdo, MD 20892 Il7.S.A.)

(Received March 20th, 1989)

The history of The Committee on Problems of Drug Dependence is traced from its beginning (1929) as The Committee on
Drug Addiction to 1989, its sixtieth anniversary. A brief account of the etiology of The Committee from The Bureau of Social
Hygiene, established in New York City by John D. Rockefeller, Jr. in 1913 is also given.

Key words: physical dependence potential; abuse liability: narcotic analgesics and antagonists; agonist/antagonists; stimulants
and depressants; animal and human testing; drug addiction and evaluation.

Introduction tive Committee. It is hoped that the achieve-


ments of the CPDD since its inception (1929)
The purpose of this article is to review the will be well focused and that this history will
history of the Committee on Problems of Drug give insights into contributions of CPDD to
Dependence (CPDD). This history was solutions of drug-dependence problems.
undertaken on the recommendation of CPDD, Although the principal source of material for
acting on the suggestion of its Chairman, Dr. the period ending in 1971 was that of reference
Mary Jeanne Kreek, in order to summarize and 1, CPDD minutes, reports and proceedings
then update the detailed history presented in were consulted frequently, especially after
the volume ‘The National Research Council 1971.
Involvement in the Opiate Problem (1928-
1971) by Nathan B. Eddy, published by The Beginnings - The Committee on Drug
National Academy of Sciences [l]. Of particular Addiction
concern and interest are the years that fol-
lowed the termination of sponsorship by The The origin of the Committee on Problems of
National Research Council in 1976 and the tran- Drug Dependence is traceable to the Bureau of
sition years that culminated in the structuring Social Hygiene established m New York City in
of an incorporated committee affiliated with 1913 by John D. Rockefeller, Jr., to promote
several highly regarded scientific societies. The research in the general field of social hygiene
authors have been closely associated with with especial emphasis on criminology. How-
Committee activities since 1960 (E.L.M.) and ever, because of the increasing problem of
1974 (A.E.J.), principally as coordinators of the abuse of drugs*, particularly narcotics, and
testing program for evaluating the physical
dependence potential and abuse liability of *A special committee of investigation in 1919 arrived at a
analgesics and other compounds, and as figure of 100 000 addicts (including cocaine abusers) in the
members of the Board of Directors and Execu- United States.

0376-8716/89/)03.50 0 1989 Elsevier Scientific Publishers Ireland Ltd.


Printed and Published in Ireland
184

pressure from the public and the medical pro- time to address the latter problem, perhaps
fession, the Bureau was urged to get involved because the abuse of cocaine had waned consid-
in the area of drug abuse. Consequently, the erably following the introduction of the
Bureau of Social Hygiene established a ‘Com- (synthetic1 substitute, procaine.
mittee on Drug Addiction’, whose notable The DMS under the Chairmanship of Dr.
accomplishments have been previously set Ludwig Hektoen (pathologist), who succeeded
forth in a scholarly treatise, ‘The National Dr. White as chairman of DMS on June 30,
Research Council Involvement in the Opiate 1929, expanded the membership of the ‘Tempo-
Problem’, authored by Nathan B. Eddy and rary Advisory Committee on Drug Addiction’,
published by the National Academy of Sciences to include the following: Chairman, William
[ll. Charles White, Consultant Pathologist,
In 1928, the newly appointed Director of the National Institute of Health and Chairman,
Bureau of Social Hygiene, Lawrence B. Dun- Committee on Medical Research, National
ham, reassessed the Bureau’s involvement in Tuberculosis Association; Charles W. Edwards,
the drug-addiction problem and proposed to the Professor of Materia Medica and Therapeutics,
National Research Council, National Academy Chairman, Department of Pharmacology, the
of Sciences (NRC, NAS) that this body accept University of Michigan; Ludwig Hektoen, Path-
funds from the Bureau for the support of a ologist, Director, John McCormick Institute of
scientific investigation of narcotic drugs to be Infectious Diseases; Claude S. Hudson, Chief,
carried out under the auspices of the Division of Division of Chemistry, National Institute of
Medical Sciences (DMS). Health; Reid Hunt, Professor of Pharmacology,
Accordingly, Dr. Charles White, then Chair- Harvard Medical School; Frederick B. LaForge,
man of DMS, with the aid and advice of four Senior Chemist, Bureau of Entomology and
eminent members of the NRC, Drs. Claude Plant Quarantine, U.S. Department of Agricul-
Hudson and F.B. Laforge (chemistry) and Drs. ture; Torald Sollman, Dean, School of Medicine
Reid Hunt and Carl Voegtlin (pharmacology) and Professor of Pharmacology, Western
laid the groundwork for the formation of a new Reserve University; Walter L. Treadway,
‘Committee on Drug Addiction’ which first met Assistant Surgeon General, Division of Mental
on January 12,1929 as a ‘Temporary Advisory Hygiene, U.S. Public Health Service; Carl
Committee on Drug Addiction’. Dr. White was Voegtlin, Pharmacologist, Director, National
Chairman ex officio. The discussions of this Cancer Institute, National Institute of Health;
group centered on elaboration of a program Harry J. Anslinger, Commissioner, Bureau of
which would include: (1) the analysis of the Narcotics, U.S. Treasury Department and
chemical and biological literature of the addic- Lawrence Kolb, Assistant Surgeon General,
tion alkaloids; (2) the formulation of rules and Division of Mental Hygiene, U.S. Public Health
regulations for the legitimate use of alkaloids Service.
having addiction properties and the education This committee served without change until
of physicians and the public on the knowledge 1939. Its first meeting was held on November 3,
of these rules by means of medical schools, 1929 with secretarial assistance from Mrs. Dor-
scientific societies and drug-manufacturing othy Nicolson and Mrs. Mary Goodwyn, daugh-
firms and (3) the replacement of all present use ters of Chairman White.
of addicting alkaloids by substitutes having no
addiction properties. The discussions brought Early Scientific Program (1929-1939)
forth two subjects for research: (1) the
relationship between morphine and codeine (in- Ultimately, the Committee decided upon a
cluding possible dissociation of adverse and research plan that involved three components
beneficial effects) and (2) the cocaine addiction - chemical, pharmacological, and clinical. The
problem. Little, if anything, was done at that chemical effort, under the direction of Dr. Lyn-
185

don Small, a young, talented, Harvard-trained Pharmacology, Womens Medical College of


alkaloid chemist (who had also studied in Ger- Philadelphia, joined the staff later while Drs.
many for 2 years) was begun at the University Erwin E. Nelson and Ralph Smith of Dr.
of Virginia in the autumn of 1929. Small, with Edmund’s departmental staff complemented
his modest staff of pre- and post-doctoral stu- the efforts of Eddy’s group. Assistance was
dents, was concerned principally with chemical also provided by several pre-doctoral and medi-
modifications of the phenanthrene-type alkal- cal students.
oids (morphine, codeine, thebaine and neopinel The clinical arm of The Committee’s pro-
occurring in opium. A complementary program gram began to develop about 1934 under the
on total synthesis of structures vaguely resem- direction of Clifton K. Himmelsbach, M.D., a
bling morphine and congeners was directed by young commissioned officer of the Public
Erich Mosettig, Ph.D., a young organic chemist Health Service from The University of Virginia
‘drafted’ by Small from Professor Ernst Medical School. Himmelsbach, who was
Spaeth’s laboratory, University of Vienna, recruited by the aforementioned Dr. Treadway,
Austria. Mosettig also had a small group of pre- had received research training on tolerance and
and post-doctoral students, of which one of the physical dependence to morphine in rats at
authors (E.L.M.) was privileged to be a small Western Reserve University under Dr. Tarold
part from 1935 - 1939. Sollmann and later, at Michigan, with Eddy. Dr.
Nearly a year later (June, 19301, when the Himmelsbach began his studies with prisoner
need for pharmacological examination became addicts at the Penitentiary Annex of the Fort
pressing, Nathan B. Eddy, M.D., Cornell Uni- Leavenworth, Kansas, Prison. This unit was
versity, who had practiced medicine briefly but shortly thereafter transferred to Lexington,
who, at the time, was teaching physiology and Kentucky. Members of the Himmelsbach
pharmacology at the University of Alberta, research team included Drs. Edwin G. Wil-
Edmonton, Canada was appointed to direct the liams, Howard L. Andrews (later to spend
pharmacology program at the University of many productive years at NIHl, Fred W.
Michigan in the laboratory of Dr. Charles Oberst and Ralph R. Brown. Among the sub-
Edmunds (previously mentioned Committee stances tested by Himmelsbach (1934- 1935)
member). were codeine, isocodeine, pseudocodeine,
Eddy, who had spent the 2 previous years dihydrodesoxymorphine-D (desomorphine, a
working in the laboratory of Dr. Robert Gesell new substance from Small’s laboratory1 and
at the University of Michigan, was made Asso- dihydromorphine, all previously studied in
ciate Research Professor of Pharmacology. He animals by Eddy and his colleagues.
began ‘baseline’ animal studies of morphine and The achievements of the first decade of
codeine covering acute toxicity and effects on Committee sponsorship can be summarized as
pain, circulation, respiration, the G.I. tract and follows. Nearly 500 compounds (the majority of
the CNS as reflected in overall behavior (excite- them new) were supplied by Small, Mosettig
ment, sedation, convulsant action). Dr. Eddy’s and their colleagues for evaluation in animals.
staff at Michigan in 1932 included Drs. H.M. Three of the most promising ones, a totally syn-
Kruger, Charles I. Wright and R.H.K. Foster, thetic compound, a tetrahydroisoquinolino-
the first in physiology at Michigan and the phenanthrene, desomorphine and 5-methyl-
other two from the Universities of Rochester dihydromorphinone (metoponl were studied in
and Chicago, respectively. During his tenure at humans not only for dependence liability but
Michigan, Dr. Eddy also began one of his major also for pain relief. Metopon was judged to be
roles in the Committee, that of liaison, with vis- more potent (especially orally) than morphine
its to the University of Virginia and other cen- with less physical and psychological depen-
ters of activity. dence liability but manufacturing problems
Dr. Margaret Sumwalt of the Department of precluded its distribution for general clinical
186

usage. Nevertheless, important structure- ticularly Dr. Charles White and PHS Surgeon
activity relationships evolved and Himmels- General Thomas Parran, Small’s group and
bath’s basic studies for assessing tolerance and Eddy joined forces at the National Institute of
physical-dependence liability remain as a model Health (NIH) to resume their attempts to
of excellence. In addition to the studies in develop safe morphine and codeine substitutes
humans conducted at Fort Leavenworth and in close association with the PHS Hospital in
Lexington, clinical-efficacy trials were carried Lexington. In the meantime, the Committee on
out at University Hospital, the University of Drug Addiction held its last meeting on Janu-
Michigan by Drs. Boys, Logie and Becker (in ary 29,1939 and recommended to DMS that it
19381 under the supervision of Dr. Eddy, at The continue a Committee on Drug Addiction in an
Pondville Cancer Hospital in Massachusetts, advisory capacity (to PHS).
The Massachusetts General Hospital, at Walter Ultimately (early in 19401, an advisory com-
Reed Army Hospital (Washington, DC.1 and at mittee was appointed. It consisted of three
The Marine Hospital in Baltimore. In addition members of the 1929- 1939 committee: Charles
to Himmelsbach, a key individual in the efficacy White, Chairman, Harry J. Anslinger and
trials was Dr. Lyndon Lee, educated at the Lawrence Kolb. Dr. Small succeeded Dr. Kolb
University of Virginia and Duke University. in 1945 and Dr. Eddy was added as secretary in
Lee, after training with Himmelsbach, was 1946.
recruited principally to test metopon. While at Due to World War II, however, the efforts of
Pondville he conducted definitive clinical Eddy, Small and Mosettig were diverted to the
studies on morphine and desomorphine. He search for new antimalarials soon after the
remained active in the analgesics area for some combined move to NIH. Nevertheless, partly
40 years and maintained a liaison role with by dint of encouragement from Dr. Eddy and
CPDD from the vantage point of Veterans the Advisory Committee, partly due to the
Administration (VA) hospitals. emergence of totally synthetic analgesics (e.g.,
From 1929 - 1932, funds for Committee oper- pethidine, methadone and the morphinans)
ations ($50 OOO/yearl were supplied by the from Germany and Switzerland and partly
Bureau of Social Hygiene. For the remaining 7 because of sustained interest in metopon, clini-
years, a direct Rockefeller Foundation grant cal studies were continued at Lexington under
(again $50 OOO/yearl supported the work of the the direction of Himmelsbach. Dr. Himmels-
Committee. bath transferred to NIH in 1944 and was suc-
ceeded as director of the Lexington facility by
World War II hiatus Dr. Harris Isbell who had served as an intern at
the Lexington Hospital (1934 - 19351 and was a
Although successes with metopon, which staff member at NIB until 1944. In addition, Dr.
had definite advantages over morphine [l] and Abraham Wikler from the Staten Island Mar-
the totally synthetic isoquinolinophenan- ine Hospital joined the Lexington group as a
threne, codeine-like in analgesic potency and neurologist in 1940. Without a doubt, their fun-
essentially free of abuse liability (which how- damental finding that the synthetic analgesics
ever elicited unexpected human toxicity1 [l] (pethidine, methadone et al.) had dependence
gave cause for optimism, it was obvious that potential comparable to morphine was a prime
the goals set forth by the Committee in 1929 factor in the strict control of these early syn-
had not been attained by 1939. Thus, plans for thetics. These synthetics had, at first, been
continuation of the scientific program were publicized as having minimal abuse liability as
made as soon as it became apparent that Rocke- morphine-like narcotics [2].
feller funding would not be continued beyond Other notable contributions of the Advisory
1939. Committee and the chemical-pharmacological
Through the influence of several people, par- research group during the war years were: (1)
187

introduction of metopon, particularly for oral Drs. Isaac Starr, Professor of Therapeutic
use in chronic pain. Financial support (a meto- Research, University of Pennsylvania, School
pon fund) was provided by grants from the of Medicine and Nathan B. Eddy, Principal
American Cancer Society ($50001, Parke-Davis Pharmacologist and Medical Officer, NIH, were
and Company and Sharpe and Dohme ($2500 appointed Chairman and Secretary, respec-
each) to aid in the production and distribution tively. Other members of this new committee
of metopon; (21 preparation of a final report (by were as follows: Honorable Harry J. Anslinger,
Dr. White) of the Committee’s activities. This Commissioner of Narcotics, U.S. Treasury
report consisted of a very large number of Department; Drs. Raymond N. Bieter, Profes-
reprints and publications from the several par- sor and Head, Department of Pharmacology,
ticipating chemical, pharmacological and clini- University of Minnesota Medical School: Dale
cal laboratories and was published by the NRC C. Cameron, Senior Surgeon and Assistant
[3] and (31the publication of three detailed mon- Chief, Division of Mental Hygiene, U.S. Public
ographs, ‘The Chemistry of the Opium Alka- Health Service; Walter Palmer, Director, The
loids’ [4], ‘Studies on Drug Addiction’ [5] and Public Health Research Institute, City of New
‘The Pharmacology of the Opium Alkaloids’ [S]. York; Maurice H. Seevers, Professor and Head
It should be recorded here, too, that in June, of the Department of Pharmacology, The
1939, Small and Eddy were jointly the University of Michigan Medical School and
recipients of the first Scientific Award of the Lyndon F. Small, Chief, Laboratory of Chemis-
American Pharmaceutical Manufacturers Asso- try, National Institutes of Health. Drs. Starr
ciation. and Eddy continued in their respective roles
until June 30, 1960. Administrative details
A fresh start - The Committee on Drug were handled by members of the professional
Addiction and Narcotics (1947-1965) staff of NRC.
The first meeting of the newly appointed
With the rapid influx of totally synthetic committee was on October 2, 1947 at NAS,
agents from Europe after the war and in consid- Washington, D.C. Present at this meeting were
eration of ever-present problems of drug addic- liaison representatives from the Army, Navy,
tion in general, Dr. Lewis H. Weed, the FDA and the American Medical and Drug
Chairman of DMS, deemed it essential to form a Manufacturers Association. Also attending
new committee on drug abuse issues. His were Drs. Weed, S.D. Aberle, D.C. Leary, Hay-
actions were based on requests from Surgeons den C. Nicholson and Mr. John J. Lentz, Jr.,
General of the Army and Navy, inquiries from representing the NRC. It was the intent of the
commercial firms and increasing emphasis on CDAN to maintain association with these and
the work of the United Nations germane to other organizations with mutual concerns.
public health. A further stimulus was a report Later, liaison was established with the World
brought back from Germany by a governmental Health Organization (WHO) and the Addiction
committee headed by E.C. Kleiderer on Research Foundation of Toronto.
research done there from 1935-1944 toward At this time the supervised distribution of
the production of totally synthetic analgesics metopon was under way and would continue for
[7]. One of the most interesting compounds 1 year. Attention was also given to developing
described in the report was methadone (then a protocol for the international control of syn-
called amidone), which, its structural dissimilar- thetic narcotic drugs not covered by conven-
ities notwithstanding, mimicked morphine in tions then in force. The principles of the
almost every aspect of its pharmacological pro- protocol were comparable to those of the
file. Harrison Act (also known as the Opiates Act).
The new committee was named the Commit- The Committee endorsed these principles and
tee on Drug Addiction and Narcotics @DAN). the protocol (later known as the Paris Protocol
188

of 19481 was ratified by the U.S. It provided for bers of the American Pharmaceutical Manufac-
the same control of synthetic substances as for turers Association. Based on the replies
those of natural origin by the Geneva Conven- invitations were sent to 29 drug-manufacturing
tion of 1931. firms to a meeting with the chairman and secre-
From 1948- 1955, a total of 15 business-sci- tary of CDAN and Dr. Small. Seventeen
entific meetings of the CDAN were convened. accepted and sent representatives to Washing-
After 1955 (with the exception of 1960 when the ton, D.C., on July 1, 1949. At this meeting, it
Committee met in January and April), scientific was decided to invite representatives of inter-
meetings were held annually, a practice which ested firms to meet with CDAN whenever
has continued to the present. The NAS-NRC research reports were to be presented and to
published the proceedings of these meetings as request the Executive Committee of NRC to
‘minutes’ through 1968, as ‘reports’ through authorize CDAN to solicit, accept and adminis-
1974 and finally as ‘proceedings’ in 1975 and ter funds for research on analgesia and addic-
1976, when NRC relinquished sponsorship. The tion. Authorization for a sum of $50 000 was
1977 and 1978 proceedings were published by given by NRC July 26,1949 and, in September,
the Committee on Problems of Drug Depen- Dr. Detlev Bronk, Chairman of NRC wrote to
dence, Inc. Starting in 1979, the proceedings 26 drug firms inviting their support. There
have been published as part of the Research were 14 prompt replies. By the end of 1949,
Monograph Series of the National Institute on eight firms had contributed $18 500. Industrial
Drug Abuse (NIDA) and are archival. Before support increased gradually until 1970 when 51
1979 they were labeled non-archival firms (eight of them foreign) donated $198 225
The second and third meetings of the Com- for the year. Also discussed at the third meet-
mittee on Drug Addiction and Narcotics were, ing was the possibility of clinical trials of anal-
like the first, convened at NAS, Washington gesics in VA hospitals. These clinical studies
D.C., January 14,1948 and May 17.1948. At the were initiated some 15 years later and became
second meeting, such items as (1) efficacy and an important part of the activities of the CPDD.
control of methadone isomers; (21 the study of In addition a report on K-4710 (ketobemidone,
papaverine, a naturally occurring constituent ‘10720’1 from the ARC was presented and
of the opium plant; (31 evidence and time recorded in the minutes.
required to establish sufficient addiction liabil- The PHS hospital at Lexington, Kentucky
ity to initiate narcotics control: (41 testing of K- was chosen as the site for the fourth meeting of
4710 (ketobemidone, a new Demerol analog1 at CDAN, on October 15 and 16,1948 to show the
the Addiction Research Center (ARC); (51 clini- Committee the facilities of the hospital and
cal testing of methadone and its antipodes (at measures employed for evaluating physical
the Massachusetts General Hospital) and (61 dependence. Dr. Henry Beecher (Massachu-
testing of peyote at ARC and mescaline in setts General Hospital) was invited to attend
monkeys at the University of Michigan, were this meeting to describe his studies of analgesia
discussed. One scientific paper was also pre- and sleep in post-operative patients which was
sented - ‘The Addiction Liability of Some supported by a U.S. Army contract.
Drugs of the Methadone Series and of 6-Methyl- In line with the advisory functions of the
dihydromorphine’ by H. Isbell and Anna J. Committee, medical research programs of the
Eisenman. The major issue at the third meeting Army and VA were examined and recom-
was a discussion of three research proposals mendations made. The Committee also author-
seeking support from CDAN. Because of inter- ized a letter to the producer of ketobemidone,
est in supporting such types of proposals, Winthrop Stearns, Inc., that stated that this
efforts were made to establish a ‘research fund’ drug, based on the results of studies conducted
by contacting 100 members of the American at Lexington, ‘has addiction potentialities
Drug Manufacturers Association and 74 mem- which are highly dangerous’ and ‘that clinical
189

application is not advisable at this time.’ The agents with those of a placebo and the standard
Commissioner of Narcotics and the FDA were drug, morphine and (2) to evaluate the side
apprised of this recommendation which was effects in normal subjects of placebo, morphine
accepted by the producer. and the experimental agent, randomly
In November, 1949, March, 1950, January, administered at weekly intervals.
1951, June, 1951 and January, 1952, the fifth to During this period the Committee was asked
ninth meetings of CDAN were held at NAS, to review and make recommendations on such
Washington, D.C. Dr. Erwin E. Nelson who had matters as: (11 Armed Forces Medical Supply
attended the first two meetings as an FDA liai- List; (21 the replaceability of opiates by avail-
son representative was appointed to the Com- able synthetic analgesics; (3) the work of WHO
mittee in the fiscal year 1948-1949 and Dr. and its role in international control; (41 the dif-
Joseph N. Hayman, Jr., Dean of Tufts Medical ferences among isomers in the acetylmethadol
College replaced Dr. Palmer in 1949. and morphinan series; (51 the development of
The Committee was called upon frequently antagonistic capabilities of nalorphine [8], the
for evaluation and recommendations concern- first strong, specific opioid antagonist devel-
ing the efficacy and dependence-producing oped (at Merck and Company in the early
properties of such drugs as ketobemidone, 1940s); (61 the demonstration of the develop-
dihydrocodeinone (hydrocodone, Dicodid, Hyco- ment of tolerance and physical dependence to
dam, dihydrohydroxycodeinone (oxycodone, barbiturates; (71the mortality of opium addicts
Eucodal, Nucodan, Percodanl, ( + l-&hydr- in Taiwan; (81the status of national and interna-
oxy-N-methylmorphinan (Dromoranl and tional control of narcotics; (91 criteria for clini-
alphaprodine (Nisentil, NU-11961, a potent cal trial and (101 the physician’s handling and
Demerol (pethidinel analog. Based on results care of the drug addict. Opinions and recom-
from studies conducted at Lexington, all of mendations were rendered on all of these
these drugs were judged similar to morphine issues.
regarding dependence-producing properties. Meanwhile, chemical research by the Small-
The possibility of establishing a monkey col- Mosettig group at NIH was redirected toward
ony to perform preliminary studies on potential development of improved substitutes for
dependence-producing drugs at the University morphine and codeine and efforts to make the
of Michigan was first suggested by Dr. Seevers U.S. independent of products from opium. All
at the fourth meeting of the Committee, Octo- four of the above-mentioned acetylmethadol
ber, 1948. However, his formal proposal was optical isomers, along with the corresponding
not considered until 1950 at the sixth meeting. racemates, were prepared and evaluated at
The overall plan was to conduct studies in rhe- NIH [9], Michigan and, in some instances at
sus monkeys using procedures similar to those Lexington. Beginning about 1948, Eddy
employed at Lexington for the study of ‘addic- improved and refined the Wolff-MacDonald,
tion liability’ in humans. The first formal hot-plate method of testing for antinociception
reports from Dr. Seever’s project (partially [lo] and began coordinating the NAS-spon-
supported by the research fund) appeared in sored, drug-testing program. The coordination
the minutes of the ninth and tenth meetings, of the drug testing program of the CPDD has
both of which were held in 1952. persisted to the present at NIH.
By 1950, there were sufficient funds from the In addition to compounds submitted by the
pharmaceutical industry to partially support Small-Mosettig group, the pharmaceutical
studies by Dr. Henry K. Beecher (Mas- industry and later, universities and other
sachusetts General Hospital) whose objectives research institutions contributed compounds
were (11 to determine the potency of analgesic for preliminary testing by the hot-plate proce-
agents against post-operative pain by a double- dure for antinociception. When warranted, fur-
blind technique, comparing the effects of these ther testing at Michigan in monkeys was
recommended. More promising compounds vious 3 years (1951-19531. It was time, it
could then be considered for study in humans at seemed, to decide whether this type of program
Lexington and/or clinical trial for analgesic effi- was worthwhile and what changes, if any,
cacy. should be made in the Committee’s activities.
The tenth meeting of CDAN was held at the Overall, it was decided that its program was
University of Michigan, Department of Phar- sound but that rather than becoming a ‘screen-
macology, June, 1952 in order to observe the ing’ facility, the Committee’s efforts should be
addiction studies in monkeys. The effects of oriented toward research studies designed to
morphine, ketobemidone, Dromoran [( f l-3- contribute basic knowledge especially for the
hydroxy-N-methylmorphinan], methadone, iso- pharmaceutical industry.
methadone, 6-methyldihydromorphine and Concretely, it was suggested by Dr. Isbell
nalorphine were shown (in morphine-dependent that Dr. Beecher’s clinical trials include nalor-
monkeys) ‘live’ and on film. phine-morphine combinations and nalorphine
At this meeting, the Committee discussed alone as a control, This suggestion to use nalor-
the action of dextromethorphan (the O-methyl phine, the only clinically useful narcotic antago-
derivative of the analgesically inert deztro- nist known at the time, was based on the idea
isomer corresponding to Dromoranl and its that it might counteract the side effects of
potential as an antitussive agent (possible cod- morphine in humans. Dr. Isbell’s suggestion
eine substitute for cough). Also, an opinion ren- was, perhaps, promulgated by a discussion of
dered earlier by the Committee that all needs Dr. Eddy with the group at ARC in the late
for morphine and related opiates for sympto- 1940s about nalorphine. Dr. Eddy noted during
matic pain relief could be met by then-available that discussion ‘that if the antagonism were
synthetics, was reiterated in response to a really specific, the result of the administration
request from the Munitions Board in reference of nalorphine to a person in whom dependence
to the stockpiling of opium. of the morphine type had been established,
The ARC, Lexington, Kentucky was again should be the same as for abrupt withdrawal of
the site for CDAN’s eleventh meeting in Janu- morphine and an abstinence syndrome should
ary, 1953. Drs. Isbell, H.F. Fraser (who had emerge’. Nalorphine was not, prior to this time,
been transferred to ARC from NIH in 19491 and known to have analgesic action. The research
Wikler demonstrated: (1) the abstinence syn- (carried out by Drs. L. Lasagna and Beecher)
drome after prolonged administration of mor- resulted in the important finding that
phine and attempts to relieve symptoms with nalorphine itself was an effective analgesic for
synthetics; (2) the effects of prolonged adminis- humans with post-operative pain. Nalorphine,
tration of a new synthetic thiambutene (IC-501, then, became the first known narcotic agonist-
distantly isosteric with methadone; (3) induc- antagonist. It was not, however, clinically
tion of abstinence with eserine (physostigmine) useful for analgesia due to its side effects. The
in morphine-dependent, spinal dogs; (41 abrupt eventual utility of the original idea of Drs.
and nalorphine-induced withdrawal; (51 effects Eddy and Isbell to test a mixture of an analge-
of drugs and cycles of addiction and withdrawal sic and an antagonist is discussed later, in the
on the electroencephalogram; (61 effect of mor- ‘Animal testing’ section.
phine and of barbiturates on anticipatory anxi- The theme of the twelfth meeting, held in
ety associated with pain and (71 abstinence Boston in November, 1953 at the Massachu-
syndromes after withdrawal of barbiturates or setts General Hospital in the historic ‘Ether
alcohol. Dome’ (where anesthesia was first demon-
Committee meetings that included presenta- strated publicly), was analgesic testing in ani-
tion of research reports and participation of mals and humans. Attendance (761 was the
invited representatives from the pharma- largest yet and all attendees were entertained
ceutical industry had occurred over the pre- at dinner by two pharmaceutical firms. This
191

sponsorship gave rise to a discussion addiction to meperidine, possibly because of its


concerning propriety. With the understanding availability to them.
made known to the companies that no obliga- Three new compounds were considered at
tion was implied, it was considered acceptable the fourteenth meeting. One was the strong
to receive such amenities. analgesic, 14-hydroxydihydromorphinone (Oxy-
Current methods of analgesic testing were morphone, Numorphanl. The other two were
presented at this meeting along with the test- synthetics, propoxyphene and heptazone - the
ing of drug mixtures, especially those for latter closely, the former distantly related
cough. The discussion of drug mixtures which structurally to methadone.
could be useful as substitutes for codeine At this meeting in 1954, the Committee also
provided the stimulus for another symposium, adopted a resolution which, in effect, expressed
on antitussive action. The symposium was held disapproval of a proposal by the New York
during the thirteenth meeting in January, 1954. Medical Society to establish clinics to dispense
The initial half day of the thirteenth meeting narcotics to addicts (with precautions), which
was at the Merck Institute for Therapeutic would be in reality a quasi-legalization of their
Research in Rahway, New Jersey. The meeting distribution. This was an unequivocal rejection
continued in the afternoon at the Hoffman-La of maintenance therapy, an attitude that was to
Roche Research Laboratories, Nutley, New change some 15 years later, as is well known.
Jersey and concluded the following day at the For its fifteenth meeting, CDAN met again
New York Academy of Sciences. in Lexington, Kentucky, at the PHS Hospital in
In addition to the description of methods for January, 1955. Various aspects of treatment of
producing cough in animals developed at Merck addicts were discussed. Continued support of
and Roche, reports were presented by Drs. Seevers and Beecher was approved, as was a
Beecher and H.A. Bickerman, Columbia Univer- new grant for analgesic studies at Sloan-Ket-
sity, New York on their attempts to produce tering Memorial Institute, New York by Dr.
and measure cough in human volunteers. Also Raymond Houde. Also, an application from Dr.
presented were reports by Dr. Seevers (mon- Lyndon Lee at Wayne County Hospital, Detroit
key studies with coded compounds) and Dr. for clinical studies of analgesics was approved
Isbell on research at ARC. At this meeting in principle. These applications followed an
there was a discussion of research that the announcement in Science (November, 19541
Committee might support if more funds became that CDAN might have available limited
available. The studies mentioned were: (11 bar- resources for support of research on analgesia
biturate addiction studies; (2) patient response and addiction. Included in this announcement
(analgesic, subjective) to placebos; (3) difficulty was a request for information on basic research
of antitussive studies using volunteers and (4) being carried out in these areas, so that the
the psychological aspects of the use of anal- Committee might serve as a center for
gesics. exchange of information on current investiga-
The fourteenth meeting of the Committee tions in analgesia and addiction. Incidentally,
was another occasion for on-the-spot observa- this was the only meeting from 1930-1971 not
tion. This meeting was held on October 1 and 2, attended (due to illness1 by Dr. Eddy.
1954 at the Sterling-Winthrop Research Insti- From September, 1955 to February, 1965
tute, Rensselaer, New York, where factory meetings 16-27 (two in 19601 of CDAN were
production of Demerol was shown. Addiction to held (for dates and sites, see Appendix 3, Table
meperidine (Demeroll, as revealed by admis- 2 of Ref. 1). Changes in membership during this
sions to the hospital at Lexington, was period were as follows: Dr. Marshall Gates,
reported and the film, ‘The Slave,’ was pre- Chairman of The Department of Chemistry,
sented. It was noted that medical and paramed- University of Rochester succeeded Dr. Small
ical personnel were most susceptible to who died in 1957. Added to the Committee the
192

same year was Dr. Jonathan Cole, formerly a presented especially from 1961-1965. A sub-
member of the NRC professional staff and scription dinner became an established custom
Chief of the Psychopharmacology Center of along with an after-dinner speaker presenting a
The National Institute of Mental Health. Drs. lecture of general interest to the attendants.
Cameron and Nelson resigned in 1958 and were The research fund grew steadily from an
replaced by Drs. Ralph Smith (FDA), mentioned annual contribution of $39 000 in 1955 (one for-
previously and Henry Brill of the New York eign, 26 domestic firms contributing) to $85 349
State Department of Mental Health and Direc- (four foreign, 33 domestic) in 1965. This was
tor of The Pilgrim Psychiatric Hospital on Long supplemented by annual contributions from the
Island. Mr. Anslinger resigned from the Com- VA ($5000-$75001 and WHO ($20001beginning
mittee in 1959 and, although close liaison with in 1961. Consequently, grant applications and
The Bureau of Narcotics was maintained, he funding increased. These are all described in
was not replaced by anyone from the Bureau. detail on pp. 74-79 of Ref. 1. Most of the proj-
Dr. Starr, whose tenure as Chairman was the ects were funded for 1- 5 years, but support of
longest (13 years) ever, stepped down (but Drs. Seevers and Houde continued throughout
remained a Committee member until 19691.He the lo-year period and for many years beyond.
was replaced as Chairman by Dr. Eddy for 1 New, noteworthy drugs evaluated by CDAN
year only (19611, because he (Dr. Eddy) was during this period were propoxyphene (a dis-
made a professional associate of NRC and (offi- tant relative of methadone); the hexa-
cially) designated Executive Secretary of methyleneimines (e.g., ethoheptazinel; the
CDAN, duties which he had been performing benzimidazoles (e.g., etonitazenel; the 6,7-ben-
for several years. Dr. Cameron who served on zomorphans [ll] (which spawned, among others,
the Committee from 1947- 1958 and again in phenazocine, SKF 10047 and cyclazocinel; fen-
1961, became Chairman in 1962, a position he tanyl, and the antidiarrheal compound, diphen-
held until 1967 when he resigned to assume the oxylate. Also, dihydrocodeine, marketed in
office of Chief, Drug Dependence, WHO, Europe for many years as an antitussive agent,
Geneva, Switzerland. In this position he main- was tested clinically for analgesic efficacy by
tained close ties with the Committee until his Beecher and was found to be effective with min-
retirement from WHO (19751.Other new mem- imal side effects. Several of these drugs are in
bers of the Committee in the next 3 years were: medical use today and are controlled as narcot-
Everette L. May, Ph.D., Chemist, Chief, Sec- ics partly as a result of the findings and recom-
tion on Medicinal Chemistry, NIH; Isidor mendations of CDAN. Two drugs which were
Chein, Ph.D., Psychologist, New York Univer- not controlled at that time, dextropropoxy-
sity Graduate School of Arts and Sciences; phene (Darvonl, the (+ l-isomer of propoxy-
Francis N. Waldrop, Ph.D., Behavioral Scien- phene and pentazocine (Talwinl, the latter, the
tist, St. Elizabeth’s Hospital, Washington, D.C.; first agonist-antagonist to he used clinically,
Harris Isbell, M.D., Clinical Pharmacologist, were controlled later. In fact it was during this
Department of Medicine, University of decade that the basic laboratory research of
Kentucky Medical Center, who had retired Archer, Harris et al. [12] and the clinical studies
from PHS in 1963; and Robert Strauss, Ph.D., of Beecher, Keats, Lasagna et al. [13] paved the
Behavioral Scientist, University of Kentucky. way for the heightened interest in and the
Dr. Chein retired in 1964 after serving for 2 rapid development of the agonist-antagonist
years. type analgesics.
The decade from 1955 to 1965 was probably Specific opioid antagonists developed by the
among the most eventful in the Committee’s pharmaceutical industry and tested thoroughly
history. Growing awareness of and interest in, by CDAN from 1957 - 1965 were levallorphan,
the scientific sessions were reflected by an a nalorphine-like morphinan derivative; a ‘pure’
increasing attendance and diversity of reports antagonist, naloxone UV-allylnoroxymorphonel
193

and its orally effective, longer-acting, cyclo- University of Kentucky, while Dr. Fraser went
propylmethyl analog, naltrexone. These three to Eli Lilly. This would have been a crushing
compounds along with nalorphine have been of blow were it not for the appointment of Dr. Wil-
inestimable value in the dependence studies at liam Martin (who had joined ARC in 1957) with
Michigan and Lexington. They have also been M.S. and M.D. degrees from The University of
important drugs in clinical practice and have Illinois, to succeed Isbell as Director and the
stimulated a great deal of basic research in the hiring of Charles Gorodetzky (M.D., Boston
receptor area. Naltrexone was finally approved University School of Medicine, Ph.D., Univer-
for clinical use by the FDA in 1984. sity of Kentucky) and Donald R. Jasinski (M.D.
It was during this period, too, that seminal from The University of Illinois, Chicago) in 1963
analgesic-efficacy studies by Houde, Wallen- and 1965, respectively. These three maintained
stein, Rogers et al. [14] became models of excel- the splendid scientific tradition established by
lence and that clinical trials by the VA under their predecessors.
the direction of Dr. Lyndon Lee on potentially
The Committee on Problems of Drug
useful analgesics were begun. This period (1955
Dependence (1965-1976)
-1965) was also characterized by ack-
nowledgement of the importance of the monkey In 1964 the WHO Expert Committee on Ad-
colony at Michigan not only as a first-class diction-Producing Drugs met to discuss (among
‘screening’ facility but which was also rapidly other subjects) terminology relating to drug
developing into a laboratory of excellence in abuse. Objections to the term ‘addiction’ had
many aspects of basic research on analgesics, been expressed by Isbell (who preferred
their antagonists and the agonist-antagonists. ‘chronic intoxication’) as early as 1956 and by
Assisting Dr. Seevers in this effort were Seevers (1962) who alluded particularly to the
graduate students, Samuel Irwin and Gerald effects of amphetamines as psychotoxic. The
Deneau, who received their doctoral degrees in Expert Committee ultimately recommended
the Department of Pharmacology, University ‘drug dependence’ as a substitute for ‘drug
of Michigan. addiction’ and ‘drug habituation’ with a modify-
The Bureau of Narcotics and the FDA were ing phrase to indicate the drug type (e.g., mor-
increasingly seeking the advice and recommen- phine type, cocaine type, etc.). The CDAN
dations of CDAN on efficacy and abuse liability accepted this recommendation and officially
of potentially marketable drugs. From time to changed its name to Committee on Problems of
time resolutions and statements were issued by Drug Dependence (CPDD) on July 1, 1965, a
the Committee regarding narcotics control, title which more accurately reflected a broad-
treatment of addiction and replaceability of ening scope of interests.
codeine and other opiates by synthetics. The From 1966 to 1973 contributions from the
abuse of psychotropic substances such as the pharmaceutical industry increased from
amphetamines, tranquilizers, etc. was $101 850 to nearly $200 000 (51 domestic and
discussed from time to time but no research eight foreign firms), leveled at the latter figure
was sponsored by the Committee in this through 1973 and gradually declined there-
regard. In 1963 the Committee co-authored after. These funds were supplemented from
with The Council on Mental Health, American 1961-1970 by contractual and grant monies
Medical Association, a paper, ‘Narcotics in from the VA, Office of Civilian Defense, FDA
Medical Practice: The Use of Narcotic Drugs in and WHO (whose last contribution of $2000 was
Medical Practice and The Medical Management in 1966). From 1971-1976, contributions also
of Narcotic Addicts’ [15]. came from The Bureau of Narcotics and Dan-
Finally, some important changes in person- gerous Drugs (BNDD), The National Institute
nel at ARC should be noted. Drs. Isbell and of Mental Health and The National Institute on
Wikler retired in 1963 to accept positions at the Drug Abuse (NIDA).
194

Needless to say, the grants program flour- resources (to 19701 and on the grants program
ished during the halcyon funding years of 1966 (to 19721 are given in Tables 2, 3 and 4,
to 1973, principally in the clinical area. Investi- respectively, of Ref. 1.
gators included, in addition to the redoubtable During 1965- 1976 (especially the later
Ray Houde and his capable associates, Stanley years) CPDD continued to advise The Bureau of
Wallenstein and Ada Rogers, such outstanding Narcotics [later becoming the Bureau of
researchers as Henry K. Beecher, Louis Narcotics and Dangerous Drugs (BNDD), then
Lasagna, Arthur Keats, T.J. De Kornfeld, L.J. the Drug Enforcement Administration (DEA)]
Cass, F.F. Snyder, T.J. Kantor and the VA and FDA on various aspects of drug
study group (Lyndon Lee, Richard Paddock, dependence. It again aided The Council on
J.W. Belleville, William Forrest, Colin Brown Mental Health, AMA, in revising (1967, 1971)
et al.1 [16]. Those funded in the basic research [15] the 1963 statement on ‘Narcotics in Medical
areas included R. Aston, L.S. Harris, H.L. Practice’. Included were recommendations on
Grumbach, R.T. Harris and G.A. Deneau. Dr. the Nyswander - Dole ‘Methadone Mainte-
Deneau, Senior Investigator in Dr. Seevers nance’ program [18]. In collaboration with the
dependence studies in monkeys from 1954- AMA Committee on Alcoholism and Drug
1965, assisted by S. Weiss, established a dog Dependence, it drafted a resolution on mari-
colony dependent upon sodium barbital, for huana (see Ref. 1 therein, p. 1161 and provided a
assessing the abuse potential of hypnotics and task force which issued a report to FDA regard-
sedatives. Deneau set up a similar Beagle-dog ing the abuse potential and hazards of drug
colony at The Southern Research Institute in combinations (Ref. 1, p. 119). A ‘Statement on
Birmingham, Alabama and reported to the Testing for Dependence Liability in Animals
Committee through 1971[17]. and Man’ was prepared and made an Adden-
Noteworthy, too, is that (11 in 1969, CPDD dum to the Minutes of the 28th meeting in 1966.
held its first (joint) meeting with The Commit- At the request of The United Nations Division
tee on Alcohol and Drug Dependence, Council of Narcotics, this was published in The United
on Mental Health of the AMA at Palo Alto; (21 Nations Bulletin on Narcotics in 1969. A com-
in 1970 the first interim meeting of the execu- pletely revised statement was published in
tive committee was convened to allow more 1972 [19].
time for discussion of special problems and (31 In 1971 attention was again focused on
in 1971 CPDD met outside the United States replaceability of the narcotic analgesics and
for the first time (in Toronto, Canada at The antitussives from natural origin. The opinion,
Addiction Research Foundation). that opium was expendable, was again
At the first interim meeting, functions of expressed.
CPDD were redefined by Dr. R. Keith Cannan, In 1967 Dr. Eddy (who had retired from but
Chairman of DMS-NAS from 1953- 1967 and remained a consultant for NIH in 19601
Executive Secretary of CPDD from 1967- resigned as Executive Secretary and was suc-
1970. These functions included support of the ceeded by the aforementioned Dr. Cannan. Dr.
Annual Meeting and publication of its Eddy also relinquished management of the test-
proceedings, the screening and evaluation pro- ing program to one of the authors (E.L.M.1 but
grams and the grants program. CPDD also remained a member of CPDD until 1971 and a
functioned in an advisory role to The Bureau of consultant until his death in 1973. Executive
Narcotics. Secretary Cannan was succeeded by Mr. Duke
Peak attendance (459) at the annual scientific Trexler, an employee of NAS, in 1971. Mr.
meetings was reached in 1970 at The Hilton Trexler, assisted by an associate executive sec-
Hotel in Washington, D.C., February 16-18. retary, Dr. Ralph Smith who had for many
Complete and accurate information on time, years been associated with committee activi-
place and attendance of meetings (to 19711, on ties, served until the end of NAS sponsorship in
195

Table I. Members of the Committee on Problems of Drug Table III. Members of the Committee on Problems of
Dependence’ and Consultants in 1972. Drug Dependence and Consultants in 1974.

H. Frank Fraser, Chairman Leo E. Hollister, Chairman


D.C. Trexler, Executive Secretary (NRC) D.C. Trexler, Executive Secretary (NRC)
R.G. Smith, Associate Executive Secretary (NRC) R.G. Smith, Associate Executive Secretary (NRC)
Henry Brill Harris Isbell Jonathan 0. Cole Beny J. Primm
Jonathan 0. Cole Lewis J. Sargent Daniel X. Freedman Lee N. Robins
Daniel X. Freedman Cecil G. Sheps Raymond W. Houde Cecil G. Sheps
Leo E. Hollister Klaus R. Unna Donald R. Jasinski E. Leong Way
Raymond W. Houde E. Leong Way Milton H. Joffe Chris Zarafonetis
Milton H. Joffe Chris Zarafonetis
Consultants
Consultants Henry Brill Everette L. May
Nathan B. Eddy Everette L. May H. Frank Fraser Maurice H. Seevers
William R. Martin Maurice H. Seevers

‘At the time of the Annual Meeting for the denoted year. Table IV. Members of the Committee on Problems of
Drug Dependence in 1975.

1976. The members of the CPDD from 1972 to Leo E. Hollister. Chairman
D.C. Trexler, Executive Secretary (NRC)
1976 are listed in Tables I - V.
R.G. Smith, Associate Executive Secretary (NRC)
Regarding chairmanships, Dr. Henry Brill, a Daniel X. Freedman Jack H. Mendelson
member of CPDD since 1960, became chairman Louis S. Harris Beny J. Primm
in 1968, succeeded, as stated before, by Dr. Raymond W. Houde Herbert A. Raskin
Eddy for 1 year. Dr. H. Frank Fraser, well Arthur E. Jacobson Lee N. Robins
Donald R. Jasinski Cecil G. Sheps
known for his distinguished career at NIH,
Milton H. Joffe (deceased) Travis Thompson
ARC and Eli Lilly, also served for a single year, Everette L. May Klaus R. Unna
followed by Dr. Leo Hollister, a member of
CPDD since 1969. An outstanding medical
investigator from the VA Hospital, Palo Alto, Table V. Members of the Committee on Problems of Drug
Dr. Hollister functioned very effectively in this Dependence in 1976
capacity through the difficult transition years
Leo E. Hollister, Chairman
to be addressed below. D.C. Trexler, Executive Secretary (NRC)
R.G. Smith, Associate Executive Secretary (NRC)
Daniel X. Freedman Beny J. Primm
Table II. Members of the Committee on Problems of Drug Louis S. Harris Herbert A. Raskin
Dependence and Consultants in 1973. Raymond W. Houde Lee N. Robins
Arthur E. Jacobson Cecil G. Sheps
Leo E. Hollister, Chairman Donald R. Jasinski Travis Thompson
D.C. Trexler, Executive Secretary Everette L. May Klaus R. Unna
R.G. Smith, Associate Executive Secretary (NRC) Jack H. Mendelson
Jonathan 0. Cole Lee N. Robins
Daniel X. Freedman Lewis J. Sargent
Raymond W. Houde Cecil G. Sheps
Donald R. Jasinski Klaus R. Unna At the University of Michigan [20], the mon-
Milton H. Joffe E. Leong Way key-dependence studies were in the capable
Beny J. Primm Chris Zarafonetis charge of Dr. Julian Villarreal from 1967-
Herbert A. Raskin 1973. Dr. Villarreal a medical doctor from Mex-
ico City, Mexico, received the Ph.D. degree
Consultants
Henry Brill Everette L. May from the University of Michigan (in 1969) and
H. Frank Fraser Maurice H. Seevers had assisted Dr. Deneau for a year until the lat-
ter moved to Birmingham. From 1973- 1974,
196

Henry H. Swain, M.D. assisted him and became modality for heroin abuse. Their findings have
the principal investigator from 1974- 1978, been explored with enthusiasm and some
followed by James H. Woods, Ph.D., who is clinical success. The second event of especial
presently in charge of the group. note at the 1972 meeting was the convening of
At the thirty-fourth annual meeting of the first satellite conference at a CPDD annual
CPDD held on March 22- 24, 1972 at the Uni- meeting. This session on drug self-administra-
versity of Michigan, Ann Arbor, John E. Inger- tion (Chairman, Dr. James H. Woods of Dr.
soll, Director of BNDD, in his formal remarks to Seevers group) led to a CPDD-sponsored work-
Committee attendants stated, that ‘drastically shop held in February, 1973 on ‘Standardization
reducing the availability of heroin is our major of Self-Administration Techniques in Animals.’
objective,’ while generally implying that the The chairmen were Drs. Duncan McCarthy of
abuse of narcotics was reaching major propor- The Parke-Davis Company, Ann Arbor, Michi-
tions. Further emphasizing this, he called atten- gan and Woods. The proceedings of this work-
tion to the establishment of the White House shop were published in the first newsletter of
Special Action Office on Drug Abuse Preven- The International Study Group Investigating
tion, headed by Dr. Jerome Jaffe (an eminent Drugs as Reinforcers (ISGIDAR) in August,
investigator in drug abuse) and to the 1973. This group has continued to convene sat-
methadone maintenance program and treat- ellite meetings at each annual meeting of CPDD
ment programs that Jaffe was implementing. and undoubtedly helped pave the way for inclu-
Following the Michigan meeting, BNDD con- sion of the testing of stimulants and depres-
sidered the heroin-abuse problem so serious sants as a part of CPDD’s broadened interests
that this body negotiated a contract with NAS- and activities in 1988. Furthermore, several
CPDD to conduct a study concerning the use of distinguished members of ISGIDAR (Drs.
synthetic substitutes for the opiate narcotics in Woods, Schuster, Balster, Brady, Mello, Men-
medicine and the possibility of banning opium delson, Thompson, Griffiths et al.) eventually
production. Consultants chosen for this study became valuable members of the CPDD.
were Drs. Louis Harris and Joseph Cochin. tal- Early in 1973, Dr. Nathan Browne Eddy who
ented researchers in drug abuse and intimately had been the kingpin, the major driving force of
associated with CPDD activities. Their survey the Committee almost from its inception (and
(from December 1972 to March 19731ultimately especially from 19471, died peacefully in his
involved the AMA and the results were pub- sleep after a full workday of scientific and other
lished by The Drug Abuse Council, Inc., 1828 L. activities. It was fitting and timely, therefore,
Street, Washington, D.C. 20036, under the title, that at the May 21- 23,1973 annual meeting in
‘Synthetic Substitutes for Opiate Alkaloids: A Chapel Hill, North Carolina, Chairman Leo Hol-
Feasibility Study.’ The summary statement lister appointed an ad hoc committee (Seevers,
was as follows: ‘There is reason to believe that Brill and Fraser) to establish a Nathan B. Eddy
banning of opium production will not Memorial Award. This committee sent its rec-
significantly affect problems of narcotic abuse ommendations to Dr. Hollister on August 10,
even if adequate substitutes for the opium- 1973 providing for an annual award based on
derived drugs were available’. contributions to the drug abuse field either for
There were at least two other notable events ‘an unusually important discovery or for total
at the 1972 meeting. One was the presentation contributions over the entire career of the
of a paper by Dr. William Martin and Virginia recipient’. The award, to be presented at the
Sandquist of ARC, entitled ‘Long-Acting Nar- annual meeting, was to consist of a gold medal
cotic Antagonists.’ They suggested that such and a cash prize of $2500 plus travel expenses.
antagonists or depot preparations of antago- Also recommended were an International
nists might provide blockade of the usual Award Committee of six persons to be selected
heroin effects and thus could be a treatment by CPDD to serve a 3-year term and a goal of
197

$75 000 to be obtained through solicitations sion tests for dependence potential. The coordi-
from manufacturers, friends of Nathan Eddy nation of effort and agreement of results in
and attendees at recent and possibly future cases of deliberate duplication have been
CPDD meetings. The recommendations in remarkable and gratifying. In retrospect this
essence were accepted and appropriately the move was timely because it coincided with the
first Eddy awardee was Dr. Seevers at the gradual slowdown and ultimate cessation
annual meeting of CPDD, held in Mexico City, (December 31,19761 of human testing for abuse
March 14 - 17, 1974. The 1975 and 1976 recipi- potential at ARC. It was important to have a
ents of the award were ARC-University of more complete animal testing program to
Kentucky stalwarts, Harris Isbell and Abra- compensate for the lack of human data.
ham Wikler, respectively. The subsequent The last annual meeting of CPDD to be held
awardees are listed in Table XXV. at NAS was in May, 1975. Attendance (445) at
In executive session at the 1969 meeting in this meeting was the second largest in the his-
Palo Alto, it was noted that reports from Michi- tory of The Committee. In addition to the three-
gan on monkey-dependence studies were being day scientific program, four coordinate satellite
issued 8- 12 months after receipt of com- meetings were scheduled. At the executive
pounds. This lag was due not only to an increas- session (May 181,a goal of $100 000 was set as
ing rate of submission of compounds but also to principal for the Eddy award. At this session,
the more sophisticated and exhaustive tests also, the groundwork was laid for a conference
being made, in turn a reflection of changes in on prediction of abuse liability of stimulant and
the pharmacological profile of the new drugs, depressant drugs. Such a conference, convened
particularly the agonist-antagonists. at NAS April 19-21, 1976, was sponsored by
To ensure more prompt reporting and to CPDD, NAS-NRC, DEA, FDA and NIDA with
generally complement the Michigan program, a representatives of some thirty pharmaceutical
primate colony modeled after that at Michigan firms in attendance. Co-chairmen of the confer-
was ultimately established in 1973 at The Medi- ence were Drs. Travis Thompson and Klaus
cal College of Virginia (MCV) of Virginia Com- Unna of The University of Minnesota and Uni-
monwealth University under the direction of versity of Illinois, Chicago, respectively, both
Dr. Louis S. Harris (assisted by Dr. W.L. members of the Executive Committee of
Dewey, for many years a collaborator at Ster- CPDD. Participants were internationally recog-
ling-Winthrop Research Institute and The Uni- nized investigators in drug abuse. The
versity of North Carolina) who, a year earlier proceedings, titled ‘Predicting Dependence
had been appointed Chairman, Department of Liability of Stimulant and Depressant Drugs’,
Pharmacology at MCV. Dr. Mario Aceto, who were published by University Park Press,
had joined the MCV staff from Winthrop, was Baltimore, London, Tokyo, 1976. Co-editors
in charge of the day-to-day testing-research were Thompson and Unna. This was a valuable
operations and another MCV staff member Dr. supplement to the previously mentioned
Robert Balster, recruited from Duke Univer- publication (recently revised a second time)
sity in 1973, supervised self-administration ‘Testing for Dependence Liability in Animals
studies on drugs of special interest. Financially, and Man’ [19].
the MCV program was made possible because The death knell of NAS sponsorship of CPDD
first BNDD and then the National Institute of was sounded at its interim meeting at the NAS
Mental Health assumed support of the Michi- building, February 26, 1976. Chairman Hollis-
gan studies. Ultimately (starting in 19781,the ter made public the contents of a letter (dated
National Institute on Drug Abuse (NIDA) December 9.19751 written to him by Thomas J.
provided most of the financial support for both Kennedy, M.D., Executive Director of The
the Michigan and the MCV primate programs Assembly of Life Sciences, NRC-NAS. In
to which was later added (at MCVl rodent-infu- essence the letter stated that the Executive
198

Committee of the Assembly of Life Sciences reception and banquet dinner, scholarly
had voted to discontinue sponsorship of CPDD addresses were presented by Dr. Jerome Jaffe,
by approximately June 30, 1976. This decision then Professor of Psychiatry, College of
was based on the recommendation of a ‘Visiting Physicians and Surgeons, Columbia University,
Committee’ appointed by NRC-NAS to review New York and Dr. Robert L. DuPont, Director
various aspects of the Academy-Committee of NIDA.
structure. Among the last drugs to be tested at, ARC in
Despite the consternation caused by this humans were meptazinol, nalbuphine, bupren-
decision, the Committee began immediately to orphine, butorphanol, propoxyphene napsylate,
debate other possibilities for continuation of its propiram fumarate and tilidine. Most of these
activities, feeling unanimously that CPDD drugs were also tested for clinical efficacy by
‘serves an essential purpose in the national various CPDD grantees, principally by Ray
interest and the agencies that have provided Houde’s group and the VA. Most are now
support in the past have, in informal discussion, marketed.
expressed their wish to continue support’.
Post NRC - an independent, incorporated
Of the eight possibilities considered, incorpo-
committee (1976-1989)
ration of CPDD as a separate entity was
decided upon. Thus, it was declared that CPDD The two extraordinary events which
would be incorporated under the laws of the occurred late in 1976 deeply affected the future
District of Columbia, by June 30, 1976 if possi- course of the CPDD. The traumatic effects of
ble. This was not achieved, whereupon NAS the loss of the human testing facilities at the
agreed to extend sponsorship to February, Addiction Research Center (ARC) in Lexing-
1977. Along with incorporation would be solici- ton, Kentucky (due to a moratorium on prisoner
tation of a consortium of 8 - 10 highly regarded research declared by the Federal Bureau of
scientific societies with interest in drug abuse; Prisons) and the loss of NAS-NRC sponsorship
each society would name one of its members to colored the events of the following several
serve on a Board of Directors. years as well as the contemporary activities of
The NAS also agreed to publish the Proceed- the CPDD. These incidents heralded the begin-
ings of the Annual Meeting to be held in Rich- ning of a tumultuous decade in the life of the
mond, Virginia and to lend its good offices to Committee.
the solicitation of funds for the fiscal year 1977. Upon retrospective evaluation, it was real-
The NAS aided in every way possible the ized that the impact of the CPDD on the human
attainment of an orderly transition. testing facilities at Lexington had appreciably
At the last NAS-sponsored annual meeting lessened during the past several years, coinci-
of CPDD (hosted by The Medical College of dent with the ARC’s status as the intramural
Virginia, Virginia Commonwealth University) research arm of NIDA. NIDA had been man-
in June, 1976, three satellite meetings were dated to test only those compounds which were
held: Conference on Naltrexone, Chairman, Dr. of interest to the U.S. Government (not neces-
Julius Demetrios, Division of Research, NIDA, sarily compounds which might be marketed by
Rockville, Maryland; Drugs as Reinforcers, the pharmaceutical industry and for which the
Chairman, Dr. Charles R. Schuster, The Uni- CPDD perceived a need to determine abuse lia-
versity of Chicago; Session on Drugs as Dis- bility in human subjects with the thought that
criminative Stimuli, Chairman, Dr. John A. these new opioids might pose a public health
Rosecrans, MCV. There were over 400 in problem). Furthermore, the ability of the CPDD
attendance at this meeting. In addition to a to influence or even suggest which compounds
plenary session at which Dr. Abraham Wikler might be evaluated at the Lexington facility
gave the Eddy-Award address, some 52 scien- had lessened considerably since Dr. Eddy’s
tific papers were presented, Following a death. Thus, the CPDD, coincident with its
199

incorporation as a separate entity, began a ture into an Executive Committee and a Board
search for an alternative to the Lexington facil- of Directors. These two groups constituted the
ities. Corporation, and the offices of President of the
The activities of the Committee following Corporation and Chairman of the Board were
incorporation were complex and extensive. created. Although these could have been, in
These activities are grouped for purposes of principle, two separate individuals, in fact the
discussion into: (1) incorporation and reorgani- Chairman of the Board of Directors served as
zation, (21purposes and goals, (31animal testing, the President of the Corporation. New mem-
(41 human testing, (51 relationships with U.S. bers of the Executive Committee were elected
Government and international organizations, from a list of candidates selected by a subcom-
(6) funds and awards and (71 conversion to a mittee and each member of the Board of
membership organization. Directors was a representative of a profes-
sional society, appointed (with the concurrence
Incorporation and reorganization of the Executive Committee) by that society.
The first meeting of the wholly independent The professional organizations were called the
Committee on Problems of Drug Dependence, Affiliated Societies of the CPDD, Inc.
Inc., was held at the International Inn in Wash- Dr. Leo Hollister was elected Chairman of
ington, D.C., in February, 1977. The primary the Executive Committee and Dr. Theresa
objective was to organize the CPDD, Inc., and Harwood the Executive Secretary of the
to elect officers for the new corporation to meet Corporation, at the time of incorporation. Dr.
the legal requirements for the Committee to Hollister was succeeded as Chairman of the
act as an independent entity under a consor- Executive Committee in July, 1977, by Dr. Dan-
tium of professional societies. iel X. Friedman. Dr. Hollister then served (until
The initial and continuing reorganization of July, 1979) as the Chairman of the Board of
the CPDD will be presented in a simplified Directors. The members of the Committee and
manner. It may, even so, seem complex the initial four Affiliated Societies at the time
because, since incorporation in 1977, the CPDD, of incorporation are noted in Table VI.
Inc., had to modify its by-laws many times to
enable the organizational structure to best fit
its needs. The apparent complexity was
confounded by two facts: (1) The retention of Table VI. Members of the Committee on Problems of
the word ‘Committee’ in its name. After incor- Drug Dependence, Inc., and Affiliated Societies in 1977.
poration, the ‘Committee’ became in fact a Cor-
Leo E. Hollister, Chairman
poration, but the old word was retained. Thus, Theresa Harwood, Executive Secretary
an Executive Committee, various standing and Daniel X. Freedman Beny J. Primm
ad hoc committees and subcommittees of the Louis S. Harris Herbert A. Raskin
‘Committee’ were eventually formed; (21 The Raymond W. Houde Lee N. Robins
rapid evolution of the CPDD, Inc., in its Arthur E. Jacobson Cecil G. Sheps
Donald R. Jasinski Travis Thompson
attempt to increase the depth and the breadth Everette L. May Klaus R. Unna
of its views far beyond those encompassed by Jack H. Mendelson
the original CPDD, before incorporation. Pres-
ently, at least four new members are elected to Affiliated Societies
the Board each year (as noted below, the pre- American Psychiatric Association
American Society for Pharmacology and Experimental
sent-day Board is the combination of an Execu-
Therapeutics
tive Committee and a Board of Directors), and American Society for Clinical Pharmacology and Therapeu-
this serves to infuse new views and thoughts tics
into its actions. American College of Neuropsychopharmacology
The CPDD, Inc., in 1977, divided its struc-
200

During the next several years, the National Table VIII. Members of the Executive Committee and
Medical Association, the Society for Behavioral the Board of Directors of the CPDD, Inc., in 1979.
Medicine, the American Chemical Society, the
Joseph Cochin, Chairman
American Sociological Association, the Ameri- Leo E. Hollister, Executive Secretary
can Medical Association and the American Joseph V. Brady Arthur S. Keats
Psychological Association also became affili- Troy Duster Harold Kalant
ated with the CPDD, Inc. At the present time, Charles W. Gorodetzky Everette L. May
Louis S. Harris Jack H. Mendelson
all of these scientific organizations except the
Theresa Harwood John O’Donnell
American Sociological Association continue as Arthur E. Jacobson Charles R. Schuster
sponsors of the independent Committee. Each Jerome H. Jaffe Henry H. Swain
of the affiliated societies appointed a represen-
tative to an enlarged Board of Directors. Board of Directors
E. Leong Way, Chairman, American Society for Pharmacol-
Dr. E. Leong Way was elected as Chairman
ogy and Experimental Therapeutics
of the Board of Directors in 1978, replacing Dr. Daniel X. Freedman, American Psychiatric Association
Hollister who had officially retired as a member Keith F. Killam, American College of Neuropsycho-
of the CPDD, Inc. Dr. Keith F. Killam was pharmacology
elected as the Secretary and Treasurer of the Everette L. May, American Chemical Society
Board. Dr. Hollister returned to the Committee Edward C. Senay, American Medical Association
Beny J. Primm, National Medical Association
as the Executive Secretary of the corporation James A. Woods, American Psychological Association
in July, 1979, replacing Dr. Harwood. The Raymond W. Houde, American Society for Clinical Pharma-
members of the CPDD and the affiliated soci- cology and Therapeutics
eties, from 1977 to the present are listed in
Tables VI to XVIII. The Tables reflect the
membership at the time of the Annual Meeting
for the denoted year.

Table IX. Members of the Executive Committee and the


Board of Directors of the CPDD, Inc., in 1980.
Table VII. Members of the Executive Committee and the
Board of Directors of the CPDD, Inc., in 1978. Joseph Cochin, Chairman
Leo E. Hollister, Executive Secretary
Daniel X. Freedman, Chairman Joseph V. Brady Arthur S. Keats
Theresa Harwood, Executive Secretary Troy Duster Harold Kalant
Joseph Cochin Jack H. Mendelson Charles W. Gorodetzky Everette L. May
Louis S. Harris John O’Donnell Louis S. Harris Jack H. Mendelson
Arthur E. Jacobson Beny J. Primm Theresa Harwood Charles R. Schuster
Jerome H. Jaffe Herbert A. Raskin Arthur E. Jacobson Henry H. Swain
Donald R. Jasinski Lee N. Robins Jerome H. Jaffe
Arthur S. Keats Travis Thompson
Everette L. May Board of Directors
E. Leong Way, Chairman, American Society for Pharmacol-
Board of Directors ogy and Experimental Therapeutics
Daniel X. Freedman, American Psychiatric Association Daniel X. Freedman, American Psychiatric Association
Leo E. Hollister, American Society for Clinical Pharmacol- Keith F. Killam, American College of Neuropsycho-
ogy and Therapeutics pharmacology
Keith F. Killam, American College of Neuropsycho- Everette L. May, American Chemical Society
pharmacology Edward C. Senay, American Medical Association
Everette L. May, American Chemical Society Beny J. Primm, National Medical Association
Herbert A. Raskin, American Medical Association James A. Woods, American Psychological Association
E. Leong Way, American Society for Pharmacology and Raymond W. Houde, American Society for Clinical Pharma-
Experimental Therapeutics cology and Therapeutics
201

Table X. Members of the Executive Committee and the Table XI. Members of the Executive Committee and the
Board of Directors and Permanent Liasion of the CPDD, Board of Directors and Permanent Liaison of the CPDD,
Inc., in 1981. Inc., in 1982.

Joseph Cochin, Chairman Joseph V. Brady, Chairman


Leo E. Hollister, Executive Secretary Joseph Cochin, Executive Secretary
Joseph V. Brady Arthur S. Keats Martin W. Adler Theresa Harwood
Troy Duster Harold Kalant Sidney Archer Leo E. Hollister
Charles W. Gorodetzky Everette L. May William T. Beaver Jerome H. Jaffe
Louis S. Harris Jack H. Mendelson Richard J. Bonnie Harold Kalant
Theresa Harwood Charles R. Schuster Theodore J. Cicero Charles P. O’Brien
Arthur E. Jacobson Henry H. Swain Troy Duster Charles R. Schuster
Jerome H. Jaffe Charles W. Gorodetzky Henry H. Swain

Board of Directors BoaTd of Directors


E. Leong Way, Chairman, American Society for Pharmacol- E. Leong Way, Chairman, American Society for Pharmacol-
ogy and Experimental Therapeutics ogy and Experimental Therapeutics
Raymond W. Houde, American Society for Clinical Pharma- Raymond W. Houde, American Society for Clinical Pharma-
cology and Therapeutics cology and Therapeutics
Daniel X. Freedman, American Psychiatric Association Keith F. Killam. American College of Neuropsycho-
Keith F. Killam, American College of Neuropsycho- pharmacology
pharmacology Everette L. May, American Chemical Society
Everette L. May, American Chemical Society Jack H. Mendelson, American Psychiatric Association
Edward C. Senay, American Medical Association Beny J. Primm, National Medical Association
Beny J. Primm, National Medical Association Lee N. Robins, American Sociological Association
James A. Woods, American Psychological Association Edward C. Senay, American Medical Association
James A. Woods, American Psychological Association
Pemanent Liaison
Louis S. Harris Permanent Liaison
Arthur E. Jacobson Louis S. Harris
Arthur E. Jacobson

In order to gather scientists representing


the diverse scientific disciplines encompassed of the CPDD was, however, the prerogative of
by the CPDD’s continued emphasis on ‘physical the Executive Committee.
dependence potential and abuse liability’, and In the beginning, the Board of Directors and
its attempt to realize its goals and purposes, the Executive Committee of CPDD, Inc., were
the Executive Committee continued to expand assigned different roles. The Board of Directors
its membership, reaching a plateau of 18 voting had the responsibility of guiding the Executive
members by 1987. Although scientists elected Committee and suggesting new endeavors,
to the Executive Committee had been limited to while the Executive Committee was the imple-
a 3-year term under the auspices of the NAS, menting arm of the organization. This
the Incorporated Committee, in principle, separation in roles essentially disappeared
increased the term to four years and consecu- over the following decade as will he described
tive election to a second term was barred. below and the by-laws of the CPDD were modi-
At its inception in 1977, the members of the fied in 1987 to reflect the fact that, whether
Board of Directors were limited to a 5-year appointed or elected, individuals were function-
term of office. The ability of the sponsoring ally equivalent in their work on the Committee.
organization to reappoint its representative to The Incorporated Committee continued the
consecutive terms was, initially, unlimited. policy of holding two meetings a year, an
Acceptance of the representative suggested by interim meeting in December and a second
the affiliated society to the Board of Directors meeting in conjunction with the Annual Scien-
202

Table XII. Members of the Executive Committee and the Table XIV. Members of the Executive Committee and the
Board of Directors of the CPDD, Inc., in 1983. Board of Directors of the CPDD, Inc., in 1985.

Leo E. Hollister, Chairman Theodore J. Cicero, Chairman


Joseph Cochin, Executive Secretary Joseph &chin, Executive Secretary
Martin W. Adler Lloyd D. Johnston Martin W. Adler Lloyd D. Johnston
Sidney Archer Mary Jeanne Kreek Thomas F. Burks John Kaplan
William T. Beaver William R. Martin William L. Dewey Conan Kornetsky
Richard J. Bonnie Roger E. Meyer Loretta P. Finnegan Mary Jeanne Kreek
Theodore J. Cicero Charles P. O’Brien Marian W. Fischman William R. Martin
Marian W. Fischman Akira E. Takemori Roland R. Griffiths Roger E. Meyer
Roland R. Griffiths Julian E. Villarreal Leo E. Hollister Akira E. Takemori
Donald R. Jasinski Donald R. Jasinski

Board of Directors Board of Directors


Beny J. Primm, Chairman, National Medical Association Beny J. Primm, Chairman, National Medical Association
Joseph V. Brady, Society of Behavioral Medicine Joseph V. Brady, Society of Behavioral Medicine
Raymond W. Houde, American Society for Clinical Pharma- Raymond W. Houde, American Society for Clinical Pharma-
cology and Therapeutics cology and Therapeutics
Keith F. Killam, American College of Neuropsycho- Keith F. Killam, American College of Neuropsycho-
pharmacology pharmacology
Everette L. May, American Chemical Society Everette L. May, American Chemical Society
Jack H. Mendelson, American Psychiatric Association Jack H. Mendelson, American Psychiatric Association
Lee N. Robins, American Sociological Association Lee N. Robins, American Sociological Association
Edward C. Senay, American Medical Association Edward C. Senay, American Medical Association
E. Leong Way, American Society for Pharmacology and E. Leong Way, American Society for Pharmacology and
Experimental Therapeutics Experimental Therapeutics
James A. Woods, American Psychological Association James A. Woods, American Psychological Association

Table XIII. Members of the Executive Committee and


the Board of Directors of the CPDD, Inc., in 1984. Table XV. Members of the Executive Committee and the
Board of Directors of the CPDD, Inc., in 1986.
Leo E. Hollister, Chairman
Joseph Cochin, Executive Secretary Mary Jeanne Kreek, Chairman
Martin W. Adler Donald R. Jasinski Theodore J. Cicero, Past Chairman
Sidney Archer Lloyd D. Johnston William L. Dewey, Chairman-Elect
William T. Beaver Mary Jeanne Kreek Joseph Cochin (deceased), Executive Secretary
Richard J. Bonnie William R. Martin Martin W. Adler Donald R. Jasinski
Theodore J. Cicero Roger E. Meyer Thomas F. Burks Lloyd D. Johnston
William L. Dewey Charles P. O’Brien Richard A. Deitrich John Kaplan
Marian W. Fischman Akira E. Takemori Loretta P. Finnegan Conan Kornetsky
Roland R. Griffiths Marian W. Fischman Horace H. Loh
Roland R. Griffiths Akira E. Takemori
Board of Directors Leo E. Hollister
Beny J. Primm, Chairman, National Medical Association
Joseph V. Brady, Society of Behavioral Medicine Board of Directors
Raymond W. Houde. American Society for Clinical Pharma- Beny J. Primm, Chairman, National Medical Association
cology and Therapeutics Joseph V. Brady, Society of Behavioral Medicine
Keith F. Killam, American College of Neuropsycho- Raymond W. Houde, American Society for Clinical Pharma-
pharmacology cology and Therapeutics
Everette L. May, American Chemical Society Keith F. Killam, American College of Neuropsycho-
Jack H. Mendelson, American Psychiatric Association pharmacology
Lee N. Robins, American Sociological Association Everette L. May, American Chemical Society
Edward C. Senay, American Medical Association Jack H. Mendelson, American Psychiatric Association
E. Leong Way, American Society for Pharmacology and E. Leong Way, American Society for Pharmacology and
Experimental Therapeutics Experimental Therapeutics
James A. Woods, American Psychological Association James A. Woods, American Psychological Association
203

Table XVI. Members of the Executive Committee and the Table XVII. Members of the Board of the CPDD, Inc., and
Board of Directors of the CPDD, Inc., in 1987. affiliated societies in 1988.

Mary Jeanne Kreek, Chairman William L. Dewey, Chairman


Theodore J. Cicero, Past Chairman Thomas F. Burks, Chairman-Elect
William L. Dewey, Chairman-Elect Mary Jeanne Kreek. Past Chairman
Martin W. Adler, Executive Secretary Joseph V. Brady, Secretary/Treasurer
Mitchell B. Balter John Kaplan Keith F. Killam, Chairman, Advisory Council
William T. Beaver Sheppard G. Kellam Martin W. Adler, Executive Secretary
Thomas F. Burks Herbert D. Kleber Robert L. Balster Herbert D. Kleber
Richard A. Deitrich Conan Kornetsky Mitchell B. Balter Conan Kornetsky
Loretta P. Finnegan Horace H. Loh William T. Beaver Horace H. Loh
Marian W. Fischman Edward C. Senay Richard A. Deitrich Everette L. May
Roland R. Griffiths Akira E. Takemori Loretta P. Finnegan Donald E. McMillan
Donald R. Jasinski Kathleen M. Foley’ Nancy K. Mello
Louis S. Harris Jack H. Mendelson
Board of Directors Reese T. Jones Beny J. Primm
Keith F. Killam, Chairman, American Society for Pharma- John Kaplan Edward C. Senay
cology and Experimental Therapeutics Sheppard G. Kellam E. Leong Way
James A. Woods, Secretary-Treasurer, American Psychol-
ogical Association Affiliated Societies
Joseph V. Brady, Society of Behavioral Medicine American Chemical Society
Kathleen M. Foley, American Society for Clinical Pharma- American College of Neuropsychopharmacology
cology and Therapeutics American Psychiatric Association
Everette L. May, American Chemical Society American Psychological Association
Jack H. Mendelson, American Psychiatric Association American Society for Clinical Pharmacology and Therapeu-
Beny J. Primm, National Medical Association tics
E. Leong Way, American College of Neuropsycho- American Society for Pharmacology and Experimental
pharmacology Therapeutics
National Medical Association
Society of Behavioral Medicine

“Retired from Board in April, 1988. Replaced by Donald R.


Jasinski.
tific Meeting in the Spring or early Summer. In
order to facilitate the decision-making process
of the Committee on a daily basis, an executive
working group, or Action Committee, was for- the then Board of Directors (who were, now, to
mally constituted at an interim meeting in 1979. be appointed to a 4-year term by the affiliated
The President and the Executive Secretary of societies with the concurrence of the
the Corporation, and the Chairman of the Exec- membership of the Corporation), and the mem-
utive Committee, became the members of the bers of the Executive Committee, who contin-
Action Committee at that time. With the revi- ued to be elected to a I-year term. This
sion of the by-laws in 1985 (under the guidance definition clarified the positions of subcommit-
of a very active Rules Committee, with Dr. tee chairmen, some of whom were not members
Charles Gorodetzky as Chairman of that stand- of either the Executive Committee or the
ing subcommittee1 the Chairman, Chairman- Board of Directors, and the status of the Execu-
elect and Past-chairman of the Executive tive Secretary of the Corporation which, in
Committee, the Secretary/Treasurer and the 1986, became a salaried position. These
Chairman of the Board of Directors (later, the subcommittee chairmen and the Executive
Advisory Council) and the Executive Secretary Secretary of the Corporation were not, then,
of the Corporation became the constituents of voting members of the Corporation. The offices
the Action Committee. In 1985, the member- formerly titled Chairman of the Board of Direc-
ship of the Corporation was restated as being tors and President of the Corporation were
only those individuals who were members of combined, and the positions of Chairman of the
204

Table XVIII. Members of the Board of the CPDD, Inc., Table XX. Standing Committees and Liaison members of
and affiliated societies in 1989. the Committee on Problems of Drug Dependence, Inc., in
1984 and 1986.
William L. Dewey, Chairman
Thomas F. Burks, Chairman-Elect Committee Chaivmen
Mary Jeanne Kreek, Past Chairman Charles W. Gorodetzky, Rules
Joseph V. Brady, SecretaryfI’reasurer Louis S. Harris, Scientific Meetings
Keith F. Killam, Chairman, Advisory Council Arthur E. Jacobson, Drug Testing Program
Martin W. Adler, Executive Secretary
Robert L. Balster James M. Kulikowski Permanent Liuieon
Mitchell B. Balter Horace H. Loh Harold Kalant, Addiction Research Foundation (Toronto)
William T. Beaver Donald E. McMillan Howard McClain, Drug Enforcement Administration
Thomas J. Crowley Nancy K. Mello Heinz Sorer, National Institute on Drug Abuse
Richard A. Deitrich Jack H. Mendelson Edward C. Tocus, Food and Drug Administration
Loretta P. Finnegan Beny J. Primm
Louis S. Harris Kenner C. Rice
Donald R. Jasinski Edward C. Senay
Reese T. Jones Eric J. Simon
Sheppard G. Kellam E. Leong Way Table XXI. Standing Committees and Liaison members of
Herbert D. Kleber the Committee on Problems of Drug Dependence, Inc., in
1986.
Affiliated Societies
American Chemical Society Committee Chairmen
American College of Neuropsychopharmacology Charles W. Gorodetzky, Rules
American Psychiatric Association Louis S. Harris, Scientific Meetings
American Psychological Association Arthur E. Jacobson, Drug Testing Program
American Society for Clinical Pharmacology and Therapeu-
tics Permanent Liuiwn
American Society for Pharmacology and Experimental Jerome H. Jaffe, National Institute on Drug Abuse
Therapeutics Harold Kalant, Addiction Research Foundation (Toronto)
National Medical Association Howard McClain, Drug Enforcement Administration
Society of Behavioral Medicine Charles P. O’Brien, Veterans Administration
Boris Tabakoff, National Institute on Alcohol Abuse and
Alcoholism
Edward C. Tocus, Food and Drug Administration

Table XXII. Standing Committees and Liaison members


of the Committee on Problems of Drug Dependence, Inc., in
1987.

Table XIX. Standing Committees and Liaison members of Committee Chairmen


the Committee on Problems of Drug Dependence, Inc., in Theodore J. Cicero, Animal Testing Committee
1983. Marian W. Fischman, Human Testing
Charles W. Gorodetzky, Rules
Committee Chairmen Louis S. Harris, Scientific Meetings
Charles W. Gorodetzky, Rules Arthur E. Jacobson, Drug Testing Program
Louis S. Harris, Scientific Meetings
Arthur E. Jacobson, Drug Testing Program Permanent Liaison
Harold Kalant, Addiction Research Foundation (Toronto)
Permanent Liaison Howard McClain, Drug Enforcement Administration
Jerome H. Jaffe, Veterans Administration Charles R. Schuster, National Institute on Drug Abuse
Howard McClain, Drug Enforcement Administration Boris Tabakoff, National Institute on Alcohol Abuse and
Heinz Sorer, National Institute on Drug Abuse Alcoholism
Edward C. Tocus, Food and Drug Administration Edward C. Tocus, Food and Drug Administration
205

Table XXIII. Standing Committees and Liaison members members of the Executive Committee in the
of the Committee on Problems of Drug Dependence, Inc., in Corporation, to legitimize the corporate struc-
1988 and 1989. ture of the organization according to the laws of
Committee Chairmen
the District of Columbia, where the CPDD
Theodore J. Cicero, Animal Testing Committee incorporated. During that meeting in 1985, it
Marian W. Fischman, Human Testing was decided to limit the term of all subcommit-
Charles W. Gorodetzky, Rules tees to 1 year. A further change in the struc-
Louis S. Harris, Scientific Meetings ture of the Committee was initiated during the
Arthur E. Jacobson, Drug Testing Program
1985 Interim Meeting when Dr. Kreek
Permanent Liaison appointed Dr. Burks as chairman of a subcom-
Harold Kalant, Addiction Research Foundation (Toronto) mittee to examine the functions of the separate
Howard McClain, Drug Enforcement Administration Board of Directors of CPDD in relation to the
Charles R. Schuster, National Institute on Drug Abuse functions of the Executive Committee and the
Boris Tabakoff, National Institute on Alcohol Abuse and
Alcoholism
overall operations of the corporate organiza-
Francis J. Vocci, Food and Drug Administration tion of CPDD. Members of the Corporation
were polled for opinions in January, 1986, and
the responses were summarized at a meeting in
San Francisco on May 17, 1986, of Drs. Burks,
Executive Committee, Past-chairman, and Kreek, Killam and Gorodetzky. On this basis,
Chairman-elect were clarified with this revision specific recommendations for changes in the
of the by-laws. As a result of these modifica- CPDD, Inc., by-laws were made that would join
tions, in 1985 a 16-member Executive the Board of Directors and the Executive
Committee was defined, with the Past-chair- Committee into a combined Board of the CPDD,
man as a 17th member. Two appointed mem- Inc., all of whom would be voting members of
bers of the Board of Directors served as voting the Corporation. The Chairman of the former

Table XXIV. Site of the Annual Meeting of the Committee on Problems of Drug Dependence.

Year Date Place Annual


Scientific
Meeting No.

1972 May 22-24 Univ. of Michigan, Ann Arbor, MI 34


1973 May 21-23 Univ. of North Carolina, Chapel Hill, NC 35
1974 March 10 - 14 El Camino Real Hotel, Mexico City, Mexico 36
1975 May 19-21 National Academy of Sciences, Wash., DC 37
1976 June 7-9 Richmond Hyatt House, Richmond, VA 38
1977 July6-9 Hyatt Regency Hotel, Cambridge, MA 39
1978 June 3-6 Lord Baltimore Hotel, Baltimore, MD 40
1979 June 4-6 Holiday Inn, Center City, Philadelphia, PA 41
1980 June 16 - 19 Dunfey Hyannis Hotel, Hyannis, MA 42
1981 July 12- 15 San Franciscan Hotel, San Francisco, CA 43
1982 June27-30 Sheraton Centre Hotel, Toronto, Canada 44
1983 June 12- 15 Hyatt Regency Hotel, Lexington, KY 45
1984 June4-6 Chase Park Plaza Hotel, St. Louis, MO 46
1985 June lo- 12 Hyatt Regency Hotel, Baltimore, MD 47
1986 June 16- 18 Granlibakken Resort, Tahoe City, CA 48
1987 June 15- 19 Adam’s Mark Hotel, Philadelphia, PA 49
1988 June 29-July 1 Seacrest Resort, North Falmouth, MA 50
1989 June 19-22 Keystone Resort, Keystone, CO 51’

‘Sixtieth anniversary of the CPDD (1929- 1989).


206

Table XXV. Committee on Problems of Drug Dependence Jacobson, Drug Testing Program) and five liai-
award winners. son members. A complete list of the standing
subcommittees and the liaison members is
Nathan B. Eddy Memorial Award
1974 - Maurice H. Seevers
given in Tables XIX to XXIII. As noted pre-
1975 - Harris Isbell viously, in July, 1986, the office of Executive
1976 - Abraham Wikler Secretary became a paid position, and Dr. Mar-
1977 - William Ft. Martin tin W. Adler was elected to that position.
1978 - Hans W. Kosterlitz In 1987, two additional standing subcommit-
1979 - Eddie L. Way
1980 - Avram Goldstein
tees were created, the Animal Testing Commit-
1981 - Everette L. May tee (Dr. Cicero, Chairman1 and the Human
1982 - Vincent P. Dole and Marie Nyswander Testing Committee (Dr. Fischman, Chairman).
1983 - Eric J. Simon Thus, the changes in the makeup of the CPDD
1984 - Raymond W. Houde which were initially slow have come much more
1985 - Louis S. Harris
rapidly, a hectic pace compared with the early
1986 - Harold Kalant
1987 - Clifton K. Himmelsbach years of the CPDD, to the point where consider-
1988 - Albert Herz ation of the conversion of the CPDD to a mem-
1989 - Leo E. Hollister bership organization, an idea first introduced
by Dr. Adler during the Annual Meeting in
J. Michael Motion, Jr., Award
1982 - Robert Petersen
1984, and reformulated in ensuing years,
1984 - Kay Croker became an almost acceptable idea. At the 1988
1986 - Edward Tocus Annual Meeting (see Table XXIV for sites of
1988 - Marvin Snyder annual meetings from 1972 - 19891, the Board
overwhelmingly voted against the motion that
Joseph Cochin Young Investigator Award
1987 - Michael Bozarth
the CPDD should not change and that it should
1988 - Frank Porreca remain as a non-membership organization, but
1989 - Errol B. DeSouza the possible reformation of the CPDD as a
membership organization was left for further
consideration and discussion at future meet-
Board of Directors would become the Chairman ings. In anticipation of the goal of expanded
of the Advisory Council (Dr. Killaml. This membership, an alumni association composed of
Advisory Council was to be made up of the the former members of the CPDD was estab-
former members of the Board of Directors, lished as an affinity group at the Interim Meet-
those members appointed as representatives of ing in 1986, and Dr. Hollister was chosen as the
the Affiliated Societies. The report of the sub- first President of that group.
committee was presented for discussion at the Contributions to the Incorporated Commit-
June, 1986, Annual Meeting in Tahoe City by tee from pharmaceutical companies, to enable
Dr. Gorodetzky. In June, 1987, at the Annual the CPDD to meet its purposes and goals
Meeting, the Executive Committee accepted slowly diminished after the extraordinary year
the revision to the by-laws. At that point there of 1973. In 1977, 26 industrial groups contrib-
could be a maximum of 25 voting members of uted $144 900 but by 1985, the figure had
the combined Board, including the Chairman declined to $80 000. Contributions from
(Dr. Kreekl, chairman-elect (Dr. Dewey), Past- industrial groups have recently increased with
chairman (Dr. Cicero), Secretary/Treasurer the institution of a new CPDD stimulant/
(Dr. Woods), and the aforementioned Chairman depressant animal test program. However,
of the Advisory Council. There were, also, since 1978, NIDA has absorbed much of the
three standing subcommittees with chairs that considerable cost of both the animal testing
reported to the Board (Dr. Gorodetzky, Rules, activities for the opioid programs at the Uni-
Dr. Harris, Scientific Meetings, and Dr. versity of Michigan and the Medical College of
207

Virginia, and the Johns Hopkins University nurture, promote and carry out abuse liability
work on stimulants and depressants. NIH has research and testing, both at the preclinical and
absorbed the major costs of the work at NIH, clinical levels, (2) to sponsor an annual scien-
NIDDK (National Institute of Diabetes and tific meeting in fields related to drug abuse and
Digestive and Kidney Diseases), for the chemical dependency and (31to serve as advisor
coordination of the opioid program. Grants to both the public and private sectors, nation-
from the CPDD to the groups at UM, MCV, and ally and internationally (to our government, the
NIDDK have helped to supplement the U.S. World Health Organization, industry and aca-
Government funding and, presently, the CPDD demia). It has been noted that the annual
provides all of the funds to run the Committee’s scientific meeting has become one of the few
program on the determination of the physical forums where scientists from diverse disci-
dependence potential and abuse liability of plines can discuss problems of drug abuse and
stimulants and depressants at three universi- drug dependence at a rigorous academic and
ties (The University of Chicago, the Medical scientific level. It is evident that a marked
College of Virginia, and the University of Michi- change in the annual scientific meeting began
gan). The development of the stimulant/depres- about 1987 as evidence by the increased
sant program will be discussed more fully in number of symposia and the dramatically
the section on ‘Animal testing’. increased breadth of coverage. The duration of
the meeting has also increased, from an initial
Purposes and goals of the incorporated length of two and a half days to an anticipated
committee four days in 1989.
It is perhaps surprising that the overall
goals and purposes of the CPDD have endured Relationships with governmental
since the inception of the organization in 1929, organizations
although the emphasis on certain facets of the Although governmental representatives had
work of the Committee has changed, and a few been guests at CPDD meetings since its incep-
modifications of the original purposes have tion, formal liaison membership in the CPDD
been made. These purposes have expanded with governmental organizations was estab-
over the decades to meet current concerns of lished in 1979 with Edward Tocus, Heinz Sorer
drug abuse. and Howard M&lain as the appointed
The goals of the newly reorganized Commit- representatives of the FDA, NIDA and the
tee were noted at the November 9, 1978 meet- DEA, respectively. More recently, these agen-
ing to be: (a) to conduct an annual scientific cies were joined by the NIAAA and the
meeting; (bl to facilitate the screening of new Addiction Research Foundation in Toronto.
psychoactive agents that might be abused; (cl to Recent efforts, initiated in 1981 and discussed
facilitate communication between the animal at the 1982 Annual Meeting in Toronto by Dr.
testing facilities at Richmond and Ann Arbor Inayat Khan (presently Chief, Psychotropic and
and (dl to try to obtain means for testing depen- Narcotic Drugs, Division of Drug Management
dence liability in humans. and Policies, WHO) and fairly continuously
The Goals and Guidelines subcommittee, a thereafter, to enable the incorporated
committee which was initially formed to formu- Committee to become a Collaborative Center
late the Goals of the CPDD, Inc., for the 1978 with the World Health Organization, have
meeting, was reconstituted at times during the neared fruition.
ensuing 7 years to restudy the purposes of The efforts of the CPDD to serve as advisor
the CPDD, Inc. Thus, three goals of the Incor- to the public sector both nationally and interna-
porated Committee were articulated during the tionally have not lessened since it became inde-
December, 1985, Interim Meeting (Dr. Mary pendent, but with the institutionalization of
Jeanne Kreek, Chairman). The goals were: (1) to advisory committees to the various govern-
208

ment agencies concerned with drugs of abuse, ing that meeting the Committee noted that the
the efforts have been modified. Examples of the data obtained by the assessment of physical
contemporary CPDD approach to the advise- dependence potential and abuse liability in
ment of agencies are manifold. In 1984 the animals by the Drug Testing Program of the
CPDD published, in a NIDA research CPDD could be considered as a facet of preven-
monograph, an updated document, ‘Testing tion research, and these data could be used by
Drugs for Physical Dependence Potential and the FDA and the DEA to control the marketing
Abuse Liability’ [Zl] a revision of Ref. 19. The of new products on a national basis thereby
document was noted by Dr. Tocus to be valua- preventing the inadvertent introduction of
ble for the FDA as a model and guide for gath- substances adversely affecting public health.
ering data. Two years later, during the 1986 For example, methylenedioxymethamphet-
Interim Meeting, Dr. Tocus mentioned that the amine (MDMA), an illicit stimulant, was being
CPDD guidelines for testing presented in that used for patients by some psychiatrists and
document were used when guidelines were apparently was being abused by a number of
requested of the FDA by industrial groups. individuals. There was concern that the side
In addition, a number of meetings have been effects of MDMA were more devastating than
held under CPDD auspices to discuss issues of usually noted with amphetamine-like
interest to government groups. A special FDA/ substances. Thus MDMA was examined by the
NIDA/CPDD/pharmaceutical company meeting CPDD’s drug testing groups [22] at the request
was organized by Drs. Jaffe, Gorodetzky, Men- of NIDA. The results of the testing of this
delson and Hollister. This symposium entitled controlled-substance analog clearly indicated
‘Prediction of Human Abuse Potential of that this drug had significant abuse potential.
Drugs’ was held in Washington, DC., April 9, These data led to the emergency placement of
1978. In 1979, CPDD supplied a liaison (Dr. MDMA under Schedule I of the Controlled
Senayl to the subcommittee of the FDA Drug Substances Act by FDA.
Abuse Advisory Council to discuss the clinical During the post-NRC period, much greater
testing of neuropeptides and homologs, includ- emphasis has been given to drugs other than
ing opioid peptides. At the 1982 Annual Meet- opioids. Cocaine abuse has, once again, become
ing a committee was appointed to report to a difficult problem and a concern for govern-
NIDA on the domestic need for thebaine and ment organizations involved in drug abuse pre-
the justification of increased production of vention in the 1980s. New drugs, such as
hydromorphone (co-chaired by Drs. Archer and phencyclidine (PCP), are illicitly introduced to
Cochinl. In response to proposed congressional the public and abused from time to time, but
legislation concerning the use of animals in the older drugs, the opioids and various of the
research, in 1982 at the Interim Meeting in San stimulants and depressants, reach peaks of
Juan, the CPDD formed an Animal Legislation popularity followed by periods of decline in
subcommittee with Dr. Killam as Chairman, for their usage. This ongoing historical cycle has
support of a commission to study the use of been found, thus far, to be difficult to prevent.
animals in research, emphasizing the continued Research into the causes of the abuse, the
usefulness and necessity of these animals for nature and effect of these drugs in humans, and
this research. Several CPDD position papers the prevention of their introduction to the pub-
have been written and a great deal of discus- lic, continue to be among the main reasons for
sion has occurred at various CPDD meetings the continuance of the existence of the CPDD
since that time concerning groups which as an organization and its continuous coopera-
oppose the use of animals for research. tion with government organizations concerned
In 1983, Dr. Pollin, then Director of NIDA, with drug abuse. There has, of late, been
enunciated his desire to work closely with discussion in Congress on the legalization of
CPDD and to use its advice and assistance. Dur- certain of these drugs of abuse as one method of
209

dealing with their illicit supply. At the 1988 animal use, was examined by the drug-testing
Annual Meeting in Cape Cod, the members of groups of the CPDD at the behest of NIDA and
the Committee noted their disagreement with the FDA and was found to be 25 000 times as
the idea of legalization of opioids, cocaine and potent as morphine as an antinociceptive in
certain other abused substances, and suggested rodents [33]. It also, like the other potent fen-
that this be conveyed to Mr. Charles Rangell, tanyl analogues, could be antagonized by nalox-
Chairman of the House Select Committee on one. The CPDD noted during its discussion of
Narcotics, and to his Chief of Staff, Mr. Jurith, this drug that the introduction of carfentanil as
by Dr. Dewey. The CPDD’s stand on this issue a Schedule II drug could constitute a danger to
was summarized by Mr. Kaplan at that 1988 the public health by diversion of the licit sup-
meeting. He noted that although legalization ply: however, it was further noted, diversion
would be likely to cut the rate of crimes caused from licit suppliers is much less of a threat to
by these substances, public health problems the public than synthesis of this extremely
would increase. potent drug by illicit manufacturers.
The increased prevalence of licit and illicit The post-NRC period has also been one
use of stimulants and depressants by the public which has seen a great deal of interaction
during this period induced the CPDD to initiate between the CPDD and the WHO. The CPDD
its new testing program on determination of has sent a representative to many of the
the dependence potential and abuse liability of Expert Committee on Drug Dependence and
these classes of compounds. This program is Program Planning Working Group (PPWG)
discussed more fully below, but the meetings held during this time in Geneva, at
considerable concern of the CPDD with these the behest of Dr. Khan, of the WHO. Dr. L.
classes of abused substances should be noted in Harris was the CPDD representative to
regard to CPDD initiatives and relationships the International Conference on Drug Abuse
with government organizations. Thus, during and Illicit Trafficking which was held in Vienna
the Interim Meeting in 1986, in Washington, in June, 1987. This has allowed CPDD input
D.C., a consensus meeting (with ASPET) was into important policy and decision-making
planned on cocaine research. The document activities of the WHO with respect to interna-
(‘Scientific Perspectives on Cocaine Abuse’) tional control of drug abuse, prevention, identi-
relating to this meeting was produced for pre- fication and prediction of drug-abuse liability,
sentation to ADAMHA (Alcohol, Drug Abuse and in the control of existing clinical, drug-
and Mental Health Administration) and its abuse related problems. Further, cooperation
components, including NIDA, and was pub- with the WHO has been manifested by the
lished [23]. CPDD’s testing of many of the stimulants and
As a further example of the cooperation of depressants which were being considered for
the CPDD with government organizations dur- scheduling by WHO. The scientific data
ing the post-NRC period, the Drug Testing obtained from the drug-testing groups of the
Committee of the CPDD has tested a number of CPDD has been noted by Dr. Khan to be of
fentanyl derivatives [24-351 which were syn- great value to the WHO for their scheduling
thesized under contract by NIDA at the re- responsibilities under the Psychotropic Con-
quest of the DEA, or obtained directly from the vention since few, if any, other groups are able
DEA. Some of these fentanyl derivatives were to provide such scientific data to them within a
found to be among the most potent opioids ever reasonable time.
tested and to have dependence potential of the Although the WHO has not been able to pro-
morphine type. Even the most potent of them, vide consistent funding for this testing, in 1979
fortunately, could be antagonized by a conven- a $12 000 grant from the United Nations Fund
tional dose of naloxone. Lately, a fentanyl ana- for Drug Abuse Control was given to the CPDD
logue, carfentanil, introduced by a company for through WHO to test khat (Cutha edulis,
210

Forsk.1, a plant which was known to contain WHO for international control was organized
various bioactive components such as cathine as an adjunct to the Annual Scientific Meeting
(( + l-norpseudoephedrinel, cathinone (u-amino- of the CPDD in June, 1984, in St. Louis. As
propiophenonel and other, more complex, alka- noted by Drs. James H. Woods and Charles R.
loids. It was noted in the Bulletin on Narcotics Schuster in their foreword [39] to the published
[36] that questions related to Catha edulis were symposium in Drug and Alcohol Dependence
first raised at the international level in 1935 at [40], the CPDD ‘thought it would be helpful to
the League of Nations. The effect caused by all parties concerned, WHO, the United
chewing the leaves and stem tips of the khat Nations Commission on Narcotic Drugs, phar-
plant, a plant with mild stimulant and euphoric maceutical companies, and the academic com-
properties, had become a concern for various munity to have an open forum for discussion of
African and Mid-Eastern countries (e.g., Kenya, the complex issues that go into decision-making
the Yemen Arab Republic1 and for the WHO, on the international control of dependence-pro-
who feared that its use would spread to other ducing substances. To the extent that pertinent
continents. The CPDD provided funding, information is made more open to the scrutiny
obtained from the WHO grant for these tests, of all, decisions to control substances with
to Dr. Knoll in Hungary, to the Medical College abuse liability may be more informed.’
of Virginia and to The University of Chicago, During the Third World Conference on Clini-
and to Dr. Yanagita in Japan and Dr. Halbach, cal Pharmacology and Therapeutics in Sweden
formerly of WHO. Work on the isolation and in 1986, the CPDD collaborated with Dr. Khan
characterization of the bioactive alkaloids was and the WHO in the organization of a sympos-
undertaken at NIH by Dr. Henry M. Fales ium entitled ‘Drug Dependence: Benefit-Risk
(Chief, Laboratory of Chemistry, NHLBI), an Ratio Assessment of Agonist-Antagonist
expert in mass spectrometry, and by Drs. May Analgesics’. Several members of the CPDD or
and Jacobson at NIDDK (then NIAMDD). Dr. their close associates (Drs. Harris, Woods, and
K. Szendrei, a Hungarian chemist (presently on Lasagna) spoke at this symposium, and the
the staff of the United Nations Division of Nar- papers which were presented were published
cotic Drugs, Vienna), who was at that time [41] in Drug and Alcohol Dependence, edited by
attached to the UN staff in Geneva, brought Drs. T. Yanagita and C. Johanson.
the khat plant to Dr. May’s laboratory at NIH
for the purpose of this investigation and was Animal testing
instrumental in the characterization of several It is interesting to remember that from its
bioactive constituents of the plant. initiation the pharmacological testing facilities
In response to the request of the WHO for under the auspices of the Committee have not
information about agonist-antagonists to be only served as a ‘screening’ facility, but have
discussed at the PPWG in Geneva, the CPDD had a distinct research orientation. This con-
sponsored the Innisbrook Symposium on Nar- cept and implementation of a screening facility
cotic Antagonist Analgesics which was held in biased towards research led, for example, to
Tarpon Springs, Florida, in February, 1983, the testing of combinations of opioids and their
with Dr. Harris as Chairman. A CPDD position antagonists. Drs. Beecher and Houde initiated
paper was prepared for the WHO. Papers on the testing, for pain-relief efficacy, of various
the subjects encompassed by the Symposium ratios of mixtures of morphine and nalorphine
were published in Drug and Alcohol Depen- in the early 1950s. Dr. Harris Isbell studied the
dence [37] in 1985 as an up-to-date review of the effects of these mixtures on non-tolerant
field, edited by Drs. Schuster and Harris. former morphine addicts at the Addiction
A symposium to discuss the scientific evi- Research Center in Lexington, Kentucky [42].
dence on the abuse liability of 28 stimulants and Various ratios of morphine and SKF 10 047
hallucinogens [38] under consideration by the were tested at the University of Michigan in
211

1962 [43]. Although the results from the work Eddy, although the beneficiaries of the
were not immediately applied, it should he program, the nature and number of tests which
noted that there is now at least one such combi- are carried out, and the groups which have run
nation which has recently been introduced and the testing procedures under the auspices of
successfully marketed. Pentazocine (Talwinl the CPDD have changed considerably over the
had been found to be abused by a segment of decades. This program has served, and contin-
the addict population in some geographic areas ues to serve, to alert individuals and govern-
from about 19’7’7to the early 1980s. especially in ment organizations to the possibility of public
combination with an antihistamine, tri- health problems and issues arising from the
pelennamine. To eliminate the intravenous marketing, licit or illicit, of new compounds
abuse of pentazocine, Sterling-Winthrop refor- which affect the various opioid-receptor sys-
mulated it with naloxone, a narcotic antagonist. tems. The individual laboratories in the
This was reported to the CPDD by Drs. George consortium that examine compounds under the
Goldstein and Frank Rosenberg at the Interim auspices of the Committee are noted below.
Meeting in December 1982. At the Annual
Meeting in 1984, Dr. Glenda Treadway noted Constituency of the opioid testing program
that a special symposium would be presented The Drug Testing Program on opioid-like
during that meeting sponsored by Winthrop- compounds serves three distinct audiences:
Breon, a subsidiary of Sterling Drugs, called (11University researchers who seek to deter-
‘Talwin NX One Year Later’ with several mine whether, and how well, their new com-
members of the CPDD making presentations pounds interact with an opioid receptor. These
(Drs. Jasinski, Harris, and Senayl. It was noted in vitro data, and data obtained from rodent
at that meeting that the parenteral abuse of antinociceptive and narcotic antagonist assays,
pentazocine had diminished appreciably since are utilized for qualitative or quantitative
the introduction of Talwin NX. structure-activity relationship studies. Oc-
The idea of combining a narcotic antagonist casionally, when a sufficient amount of sample
with an agonist, which resulted in the success- is received, data from single-dose suppression
ful combination of pentazocine and naloxone in and precipitated-withdrawal assays are
Talwin NX, might be attributed to the exten- obtained for this constituency.
sive early work of researchers who tested mix- (21 Pharmaceutical firms that wish to deter-
tures of agonists and antagonists in animals mine the physical dependence potential and
and humans in testing facilities run under the abuse liability of their compounds as part of
auspices of the CPDD. That work illustrates their preclinical work with compounds which
the type of accomplishment which resulted have the ability to interact with opioid recep-
from the CPDD’s ‘screening’ of analgesics in a tors. The FDA has, on occasion, requested such
research-oriented mode, and epitomizes the far- data from industrial firms prior to marketing in
reaching consequences of such research. The order to prevent public health problems and to
ostensibly simple screening/research effort of facilitate scheduling.
the testing groups associated with the CPDD (31 Government organizations, such as the
has continued since that time, resulting in a DEA and the WHO, who desire sufficient in
number of valuable contributions to the field by vivo data for scheduling purposes, nationally or
these groups. Their work continues to be pub- internationally.
lished annually in the Proceedings of the
Annual Scientific Meeting of the CPDD. Procedures used in the opioid testing program
Compounds have been, and continue to be,
Opioid testing program tested in a ‘blind’ fashion. Only the Chairman of
The original purposes of the program have the Drug Testing Program (Dr. A. E. Jacobson,
not been modified since its inception by Dr. NIDDK, NIH), who assigns an NIH coded num-
212

ber to the compound, is aware of the name and a new procedure 1473 initiated by Dr. Woods
structure of the tested compound before the (UM) for the study of the antinociceptive effect
data gathered under CPDD auspices are of opioids in the monkey. (f) Primary physical
released for publication. At the Annual Meet- dependence (carried out both at MCV and UM).
ing in July, 1977, the incorporated Committee (3) In vitro determination of the binding
decided to place a three-year time limit on the affinity of opioids by displacement of [SH]etor-
confidentiality of the data obtained under phine from rat cerebral membrane
CPDD auspices. Within the next few years a preparations, and the electrically stimulated
further decision was made requiring the sub- mouse vas deferens assay (carried out at UM by
mission of spectroscopic and analytical informa- Drs. Fedor Medzihradsky and Charles B.
tion with each compound, to enable the Smith, respectively).
Chairman of the Drug Testing Program to ver-
ify that the compound appeared to have the Testing for s timulunts and depressants
assigned structure and was sufficiently pure The suggestion presented to the Executive
for testing. The purity of submitted samples is Committee by Dr. James H. Woods (American
evaluated, before and after testing them, Psychological Association representative) in
through thin-layer chromatography by Dr. 1980 that the CPDD support a screening facil-
Everette L. May (at MCV). ity for testing sedative and stimulant drugs for
All but one of the rodent studies are carried abuse potential was passed in principle that
out at the Medical College of Virginia (MCV) of year, and the mechanism for doing so was left
Virginia Commonwealth University, presently to a subcommittee (Drs. Woods, Jacobson,
under the direction of Drs. Mario Aceto and Jaffe, and Schuster).
Louis Harris, with E.R. Bowman and E.L. May. After several years of preliminary testing of
The hot-plate assay is carried out at NIH, facilities and procedures, the Drug Testing
NIDDK by M. Mattson and A. E. Jacobson. Program of the incorporated Committee was
The various animals and assays which are expanded to include stimulants and depres-
used are as follows: (1) Studies using rodents: (a) sants and, in 1988, the CPDD accepted com-
Antinociceptive assays in mice using hot-plate pounds in the new program submitted from the
[44] tail flick [45] and phenylquinone [45] proce- pharmaceutical industry as well as from inter-
dures; fb) Narcotic antagonist assay in mice, national organizations such as the WHO. The
using the tail flick antagonism vs. morphine [45] initial laboratories involved in the stimulant/
procedure; (cl Rat continuous infusion proce- depressant group were The University of Chi-
dures (modification of the procedure of Teiger cago, under the direction of Dr. Chris Johanson
[46]). These include substitution for morphine (succeeded by Dr. William Woolverton in 1987),
and, occasionally, a primary physical depen- the Medical College of Virginia with Drs. Louis
dence determination. Harris and Graham Patrick, and The Johns
(2) Studies in the rhesus monkey. (a) Single Hopkins University, with Drs. Joseph Brady,
dose suppression in morphine withdrawn mon- Roland Griffiths and Nancy Ator. More
keys (carried out at MCV). (b) Precipitated recently, the University of Michigan joined this
withdrawal in non-withdrawn monkeys (at program, under the direction of Dr. Gail Win-
MCV). (cl Self-injection in monkeys trained on ger. Dr. Edward Cone, in the Intramural
codeine (at the University of Michigan (UM), Research group at NIDA, initially collaborated
under the direction of Dr. Gail D. Winger and, in these testing facilities by obtaining solubility
occasionally, at MCV under the direction of Dr. and stability data on the drugs. The CPDD
Robert L. Balster). (d) Drug discrimination in presently offers evaluation of compounds in the
monkeys (at UM), under the direction of Dr. stimulant or depressant classes using the fol-
Charles P. France. (e) Antinociceptive assay - lowing methodology,
213

(11Initial screening tests, to provide potency would be carried out under CPDD auspices in a
estimates and the physical dependence poten- manner similar to preclinical studies. A new
tial of the examined compound, are carried out committee was formed to evaluate the feasibil-
at the Medical College of Virginia under the ity of this approach. Dr. Charles P. O’Brien, the
direction of Drs. G. Patrick and L. Harris. The chairman of this Human Testing Committee in
procedures include: (al an assessment of activ- June, 1983, reported on the results of a ques-
ity in an inverted screen test, and spontaneous tionnaire that was sent out to investigators
locomotor activity in mice; (b) assessment of asking whether they would be interested in
physical dependence potential by substitution participating in a human testing program. The
in pentobarbital-dependent rats using continu- feasibility of this approach was questioned by
ous intraperitoneal infusion; (cl primary physi- several CPDD members, due to the limited
cal dependence determination in rats, by financial resources of the CPDD and a variety
infusion. of other reasons. Although Dr. Schuster’s
(21 Self-administration studies are carried suggestion at that meeting that the CPDD
out at the University of Michigan under the might serve as a consulting body and endorse
direction of Dr. Gail Winger. The reinforcing particular centers rather than accept funds
properties of an intravenously administered directly for fee-for-service was not immediately
drug is determined by self-administration in acted on at that time, it was the harbinger of
rhesus monkeys. future thinking and decisions on the subject.
(31 Drug discrimination studies are obtained At the Interim Meeting in 1983 in San Juan,
at The University of Chicago under the direc- Dr. Mendelson suggested that the CPDD initi-
tion of Dr. W. Woolverton. The discriminative ate an action meeting between interested drug
stimulus properties of drugs are determined in firms, federal representatives, and the CPDD
rhesus monkeys trained to discriminate pento- Human Testing Committee for exploration of
barbital or D-amphetamine from saline, through the next step. Dr. O’Brien noted, during the
intragastric infusion. Annual Meeting in St. Louis in 1984, that a
(41 Drug discrimination in baboons by oral number of centers had indicated their interest
administration (under the direction of Drs. in human testing (Duke University, University
Roland Griffiths and Joseph V. Brady, The of Pennsylvania, The University of Chicago,
Johns Hopkins University) is carried out for The Johns Hopkins University, and Harvard’s
particular compounds, when necessary. McLean Hospital). In 1985, at the Interim Meet-
ing in Maui, Dr. Marian Fischman was given
Human testing the mandate to determine which testing
procedures are available for behavioral as well
With the loss of the Lexington facilities in as related metabolic and neurologic-neuroendo-
1976, the question of assessment of drugs in crine testing, and the validation of the various
humans has been discussed at almost every procedures. Dr. Loretta Finnegan was asked to
subsequent CPDD meeting. Dr. D. Jasinski concurrently review current attitudes and
noted, at the CPDD, Inc., Annual Meeting in polices of institutional review boards with
July, 1977, that he hoped better ways for nar- respect to including males, females, adolescents
cotic evaluation would emerge out of necessity. and elderly people as test subjects. The
In July, 1979, a grants program was initiated to Chairman of the Executive Committee, Dr.
improve methodology for clinical screening and Kreek, noted that it was important to develop a
to facilitate the evaluation of pharmacological list of valid tests which could be suggested for
substances with respect to their abuse poten- use, and a list of where those tests could be
tial in humans. In December, 1982, Dr. J. Woods performed. Such a document would be an
presented the case for human studies which important resource for government, academia
214

and industry. Dr. Kreek further noted that it young, recently deceased administrator at
would be more plausible for companies to make NIDA who represented excellence in science
their arrangements with individual investiga- administration. The J. Michael Morrison, Jr.,
tors, once an appropriate site was identified, award for outstanding service as an administra-
rather than CPDD undertaking the actual tor was established as a biennial award, and
testing and acting as an advocate for the drug consists of a plaque and travel expenses to
to the FDA and DEA. Lastly, she noted that attend the Annual Scientific Meeting of the
CPDD might support the testing of a few, CPDD. The first such award was given to Dr.
initial, model compounds to validate proce- Robert Petersen, of the National Institute of
dures. At the Interim Meeting in 1986 Dr. Mental Health (ADAMHA), in 1982 (Table XXV
Fischman suggested the organization of a lists subsequent awardeesl.
conference involving the CPDD, regulatory The second new award, to honor the memory
authorities, the WHO, NIDA and the IFPMA, of Dr. Joseph Cochin, a former Executive
and a publication reviewing human testing. The Committee member, Chairman, and Executive
objectives of the conference were elaborated Secretary was established in 1986, and named
by Dr. Fischman at the Interim Meeting in 1987 the J. Cochin Young Investigator Award. The
and included educating participants concerning creation of the Cochin award was suggested by
what human testing can offer, the kinds of data Dr. Kornetsky at the 1985 Interim Meeting in
which are collected and the current status of Maui. He noted that Dr. Cochin had been very
research. This meeting entitled ‘Testing for supportive of young investigators and that this
Abuse Liability of Drugs in Humans’ was held award would be a fitting memorial to Dr.
on November 5-6,1988, at the Scanticon Con- Cochin. The first award was given in 1987 to
ference Center in Princeton, and it was co- Dr. Michael Bozarth (then at Concordia Univer-
chaired by Drs. M. Fischman and N. Mello. The sity, Canada) (Table XXV). The award was
conference was jointly sponsored by the CPDD, established to recognize research contributions
NIDA, and the FDA, and it was attended by a in any facet of the field of drug abuse and is
group of about 80 individuals representing the given annually to an investigator who has not
various constituencies for which the meeting attained his or her 40th birthday by July 1 in
was conceived. The publication on the confer- the year of the award. The awardee receives an
ence [47] discussed the history of testing proce- inscribed plaque and travel expenses to attend
dures in humans and the current state of the the Annual Meeting of the CPDD. Both the
field. Discussion was centered around the con- Cochin and Morrison awards, as well as the
clusions which can be drawn from such testing, aforementioned Eddy award, are now adminis-
and those areas which require further research. tered by a separate Awards Committee com-
posed of a number of national and international
Funds and awards experts in the field who are not members of the
CPDD, as well as a few CPDD members and the
Two new awards, as well as Travel Fellow- contemporary Eddy awardee.
ships, were instituted during the post-NRC Lastly, in 1983, the CPDD established travel
period. In 1981, Dr. Adler suggested the fellowships to attend its annual meeting. As
establishment of an award for administrators in suggested by Dr. Kreek, the CPDD agreed to
the alcohol, drug abuse and mental health grant ten such awards (extended to twelve in
fields. Although many awards have been 1987, including two foreign scientists working
established for scientists, the CPDD felt that in the U.S.1 to young researchers who obtained
individuals who pursued science administration their Ph.D. degree or who have completed their
perform a valuable service and should be hon- medical residency within the previous five
ored with their own award. This award was years and give promising evidence of future
named J. Michael Morrison, Jr., in honor of a careers in the scientific areas encompassed by
215

the CPDD. The initial awards were made for plans continuation of two formal meetings of
the 1984 Annual Meeting in St. Louis by a sub- the Board each year, one in conjunction with
committee on grants and fellowships. Dr. Hol- the annual scientific meeting and an interim
lister appointed Dr. Mary Jeanne Kreek as meeting in conjunction with the American
Chairman of this subcommittee, with Drs. W. College of Neuropsychopharmacology. Meet-
Martin, L. Robins and R. Griffiths. The Travel ings of the executive working group (or Action
Award for each grantee was limited to $750 Committee), Animal Testing Program, and
plus waiver of the registration fee for the meet- other committees occur as required during the
ing. year.
The recent impact of AIDS in association
Possible future changes in the Incorporated with parenteral drug abuse, the advent of
Committee and conclusion opioid and amphetamine-like controlled-sub-
stance analogs and the epidemic of cocaine
The broadening scope of the CPDD in abuse have placed new responsibilities on
response to the national crisis caused by chemi- CPDD to serve as a scientific advisory group to
cal dependence in the 1980s was exemplified by government agencies, the pharmaceutical
significant changes in organization and struc- industry, and to scientific and professional
ture of the membership, active consideration of organizations affected by drug abuse and chem-
conversion to a scientific society to expand ical dependence. The CPDD has responded by
membership, and increasingly close relations expansion of preclinical and clinical drug-test-
with NIDA and other governmental agencies. ing programs, by organizing conferences
As previously noted, at the Annual Meeting of directed at specific drug-related topics, and by
the CPDD in June, 1988, the members of the increased interactions with NIDA, DEA. FDA,
Board voted in a manner consistent with a fun- and the WHO. One relatively new area of con-
damental change in the nature of the CPDD. It cern for the CPDD is the abuse of alcohol.
was decided to no longer reject the Although alcohol is undoubtedly the most
reconstitution as a membership organization, widely abused substance in the United States
so that the CPDD could continue to increase its and in many other countries, the CPDD did not
responsiveness to the concerns of scientists in begin to include alcohol in its activities until its
the many different fields of research which incorporation in 1976 (although a joint meeting
address drug abuse. was held with The Committee on Alcohol and
The CPDD had changed incrementally over Drug Dependence, Council on Mental Health of
the 50 years of its existence, slowly at first and the AMA in 1969, as noted previously). During
then with increasing rapidity during the past the post-NRC period the membership of the
twelve years. Initially a small, closed group Committee has been chosen in part to reflect
concerned with a search for a better analgesic, recognition of the problem. In 1987 the Annual
the CPDD has attempted to meet the chal- Scientific Meeting in Philadelphia was held as a
lenges brought about by the discovery of joint meeting with the Research Society on
multiple opioid receptors and their endogenous Alcoholism (RSA) and symposia, such as
ligands in human brain and tissue, as well as by ‘Effects of Alcohol and Drugs on Fetal Develop-
the social problems caused by the wide-spread ment’, ‘Psychiatric Aspects of Alcohol and
abuse of other psychotropic drugs. Continuity Drug Abuse. Drug and Alcohol Interactions’,
of CPDD activities was ensured through the and Self-Administration Models in Alcohol and
office of the Executive Secretary of the Corpo- Drug Abuse’, were arranged to elucidate con-
ration, Dr. M. Adler at Temple University, and temporary research in the field. Papers from
by providing orderly transitions of leadership these symposia were published as part of the
of the Chairman-elect, Chairman and Past- Proceedings of the 49th Annual Scientific Meet-
chairman as members of the Board. The CPDD ing [48].
216

At the Interim Meeting in San Juan in sie Robinson, office-staff member of the
December, 1988, a new area of potential inter- Department of Pharmacology and Toxicology,
est for the CPDD, the effect of narcotics on the Medical College of Virginia, Virginia Common-
immune system, was broached by Drs. K.C. wealth University for typing a substantial por-
Rice and A.E. Jacobson. This was stimulated by tion of the manuscript and especially for her
the accumulating evidence in the scientific patience and dedication in making many
literature that opioids affect immune function, revisions.
and these data were summarized at a recent
NIDA Technical Review [49]. An ad hoc References
committee was appointed by Dr. Dewey, with
Dr. Rice as Chairman, to examine the feasibility
1 N.B. Eddy, The National Research Council Involve-
of testing various opioid receptor agonists and ment in The Opiate Problem, 1928-19’71, National
antagonists for their immunosuppressive (or Academy of Sciences, Washington, D.C. 1973.
immunostimulantl properties as an expansion 2 For publications from The Addiction Research Center
of the Drug Testing Program in the 1990s. New (Himmelsbach, Isbell, Frazer, Wikler, Andrews, Mar-
tin, Gorodetxky, Jasinski, Cone et. al.1 see Annotated
challenges, such as those associated with con-
Bibliography of Papers from The Addiction Research
trol of drug use in the workplace and percep- Center, 1935- 1975, National Institute on Drug Abuse,
tions by the public of widespread corruption of U.S. Department of Health, Education and Welfare,
the legal system resulting from illegal drug Public Health Service, Alcohol, Drug Abuse and Men-
traffic and use, face CPDD as we enter the tal Health Administration, DHEW Publication No.
(ADM) 7’7- 434, Rockville MD 1978.
1990s. The CPDD can be expected to maintain
3 National Research Council: Report of Committee on
and expand its vital leadership role in the scien- Drug Addiction, 1929- 1939 and Collected Reprints,
tific evaluation of problems resulting from drug 1929 - 1941. Chemical Pharmacological and Clinical
abuse and in providing advice concerning re- Studies, 1581 pp.
sponses to those problems. L.F. Small and R.E. Lutz, Chemistry of The Opium
Alkaloids. Public Health Rep., Suppl. 103 (1932).
L.F. Small et al., Studies on Drug Addiction. Public
Acknowledgements Health Rep., Suppl. 138 (19381.
H. Krueger, N.B. Eddy and M. Sumwalt, The Pharma-
We would like to acknowledge, and thank, cology of The Opium Alkaloids. The Public Health
Dr. Mary Jeanne Kreek, for it was at her urg- Rep., Suppl. 165 (2 Vols.l(l9421.
7 E.C. Kleiderer et al., Pharmaceutical Activities of the
ing that this historical account was undertaken. I.G. Farbenindustrie Plant, Hoechst am Main, Office of
We express our gratitude to Dr. Clifton K. Publication Board, Department of Commerce, Report
Himmelsbach and William R. Martin (men- No. PB-981, Washington, DC, 1945.
tioned frequently in this history) for their help- 8 J. Weijlard and A.E. Erickson, J. Am. Chem. Sot., 64
ful discussions, correspondence and reference (19421869; K. Unna, J. Pharmacol. Exp. Ther., 79 (1943)
27.
material. The authors would also like to thank 9 N.B. Eddy, E.L. May and E. Mosettig. J. Org. Chem.,
various members of the Committee for their 17 (19521321.
enthusiastic response to this paper and for 10 N.B. Eddy, C.F. Touchberry and J.E. Lieberman, J.
their many suggestions for its improvement. Pharmacol. Exp. Ther., 98 (19501121; See also Appen-
Special thanks are due to Drs. Martin W. Adler, dix 4, pp. 205-209 of Ref. 1.
11 N.B. Eddy and E.L. May. Synthetic Analgesics, Part
Joseph V. Brady, Thomas F. Burks, Marian W. II-B, 6,7-Benzomorphans, Pergamon Press, London,
Fischman, Charles W. Gorodetzky, Louis S. 1966.
Harris, and James A. Woods who, with their 12 S. Archer et al., J. Med. Chem., 7 (19641 123. See also
knowledge of the history of the CPDD gained Appendix 4, pp. 211- 215 of Ref. 1.
13 See Appendix 4, pp. 196 - 201; 245- 248; 249- 250 of
through close association with the Committee
Ref. 1.
over many years, helped us recall the events of 14 R.W. Houde, S.L. Wallenstein and A. Rogers, Clin.
the past several decades and untangle a convo- Pharm. Ther.. 1 (19601 163. See also Appendix 4, pp.
luted history. Heartfelt thanks are due to Sus- 215-220 of Ref. 1.
217

15 Council on Mental Health (A.M.A.), J. Am. Med. 30 A.E. Jacobson, Biological evaluation of compounds for
Assoc., 186 (19631976;202 (19671209;218 (19711578. their physical dependence potential and abuse liabil-
16 See Appendix 4. pp. 209-211; 252; 203-205; 201- ity. XI. Drug testing program of the Committee on
203; 245; 269 - 270 of Ref. 1. Problems of Drug Dependence, Inc. (19871, in: L.S.
17 See Appendix 4, pp. 196; 205; 211; 248-249 of ref. 1. Harris (Ed.), Problems of Drug Dependence: 1986,
18 V.P. Dole and M.E. Nyswander. J. Am. Med. Assoc., Natl. Inst. on Drug Abuse Res. Monogr. Ser. 81, Wash-
193 (19541646; M.E. Nyswander. Hospital Practice, 2 ington, D.C., U.S. Govt. Print. Off., 1988, pp. 469,480-
(19671No. 4. 481.
19 Committee on Problems of Drug Dependence, Bulletin 31 M.D. Aceto, E.R. Bowman, L.S. Harris and E.L. May,
on Narcotics, XXV (1972125. Dependence studies of new compounds in the rhesus
20 M.H. Seevers et al., see Appendix 4, pp. 256-269 of monkey, rat and mouse, 1987, in: L.S. Harris (Ed.),
Ref. 1. Problems of Drug Dependence: 1987, Natl. Inst. on
21 The Committee on Problems of Drug Dependence, Drug Abuse Res. Monogr. Ser. 81, Washington, D.C.,
Inc., in: J.V. Brady and S.E. Lucas (Eds.1, Testing U.S. Govt. Print. Off., 1988, pp. 485-542.
Drugs for Physical Dependence Potential and Abuse 32 J.H. Woods, F. Medzihradsky, C.B. Smith, G.D. Win-
Liability, Natl. Inst. on Drug Abuse Res. Monogr. Ser. ger and D.E. Gmerek, Evaluation of new compounds
52, U.S. Govt. Print. Off., Washington, DC, 1984. for opioid activity: 1987 annual report, in: L.S. Harris
22 A.E. Jacobson, Biological evaluation of compounds for (Ed.), Problems of Drug Dependence: 1987, Natl. Inst.
their physical dependence potential and abuse liabil- on Drug Abuse Res. Monogr. Ser. 81, Washington,
ity. X. Drug testing program of the Committee on D.C., U.S. Govt. Print. Off., 1988,pp. 543-588.
Problems of Drug Dependence, Inc. (19861, in: L.S. 33 A.E. Jacobson, Biological evaluation of compounds for
Harris (Ed.), Problems of Drug Dependence: 1986, their dependence liability. XII. Drug testing program
Natl. Inst. on Drug Abuse Res. Monogr. Ser. 76, Wash- of the Committee on Problems of Drug Dependence,
ington. D.C., U.S. Govt. Print. Off., 1987, pp. 374-375, Inc. (19881,in: L.S. Harris (Ed.), Problems of Drug
and references therein. Dependence: 1988, Natl. Inst. on Drug Abuse Res.
23 Consensus document by ASPET and the Committee Monogr. Ser., Washington, D.C., U.S. Govt. Print. Off.,
on Problems of Drug Dependence, The Pharmacolo- 1989, pp. 392- 420.
gist, 29 (1987120. 34 M.D. Aceto et al., Dependence studies of new com-
24 A.E. Jacobson, Biological evaluation of compounds for pounds in the rhesus monkey, rat and mouse (19881,in:
their physical dependence potential and abuse liabil- L.S. Harris (Ed.), Problems of Drug Dependence: 1988,
ity. IX. Drug testing program of the Committee on Natl. Inst. on Drug Abuse Res. Monogr., Washington,
Problems of Drug Dependence, Inc. (19851, in: L.S. D.C., U.S. Govt. Print. Off., 1989, pp. 468-515.
Harris (Ed.), Problems of Drug Dependence: 1985. 35 J.H. Woods et al., Evaluation of new compounds for
Natl. Inst. on Drug Abuse Res. Monogr. Ser. 67, Wash- opioid activity, in: L.S. Harris (Ed.), Problems of Drug
ington, D.C., U.S. Govt. Print. Off., 1986, p. 397. Dependence: 1988. Natl. Inst. on Drug Abuse Res.
25 M.D. Aceto, L.S. Harris and E.L. May, Dependence Monogr., Washington, D.C., U.S. Govt. Print. Off.,
studies of new compounds in the rhesus monkey, rat 1989,pp. 421- 467.
and mouse (19851,in: L.S. Harris (Ed.). Problems of 36 Bull. Narc., XXX11 (19801l-99.
Drug Dependence: 1985, Natl. Inst. on Drug Abuse 37 Mixed Agonist-Antagonist Analgesics. C.R. Schuster
Res. Monogr. Ser. 67, Washington, D.C., U.S. Govt. and L.S. Harris (Eds.1,Drug Alcohol Depend., Vol. 14
Print. Off., 1986, pp. 399-452. (Special issue) 1985, pp. 221- 431.
26 J.H. Woods et al., Evaluation of new compounds for 38 Report of the Committee on Problems of Drug Depen-
opioid activity (19851,in: L.S. Harris (Ed.), Problems of dence Consensus Committee, Drug Alcohol Depend.,
Drug Dependence: 1985, Natl. Inst. on Drug Abuse 17 (19861279- 295.
Res. Monogr. Ser. 67, Washington, D.C., U.S. Govt. 39 J.H. Woods and C.R. Schuster, Drug Alcohol Depend.,
Print. Off., 1986, pp. 453- 489. 17 (19861105- 106.
27 See pp. 372-373 and 387 in Ref. 22. 40 Stimulants and Hallucinogens, C.R. Schuster, J.H.
28 M.D. Aceto, E.R. Bowman, L.S. Harris and E.L. May, Woods and H. Halbach (Eds.1,Drug Alcohol Depend.,
Dependence studies of new compounds in the rhesus Vol. 17 (Special issue) 1986, pp. 107- 278.
monkey, rat and mouse (19861,in: L.S. Harris (Ed.), 41 Drug Dependence: Benefit-Risk Ratio Assessment of
Problems of Drug Dependence: 1986, Natl. Inst. on Agonist-Antagonist Analgesics, C.E. Johanson and T.
Drug Abuse Res. Monogr. Ser. 76, Washington, D.C., Yanagita (Eds.1,Drug Alcohol Depend., Vol. 20 (Special
U.S. Govt. Print. Off., 1987. pp. 392-447. issue) 1987,pp. 289- 409.
29 J.H. Woods et al., Evaluation of new compounds for 42 H. Isbell, Work of the NIMH Addiction Research Cen-
opioid activity: 1986 annual report, in: L.S. Harris ter, Public Health Service Hospital, Lexington, KY,
(Ed.), Problems of Drug Dependence: 1986, Natl. Inst. Appendix I, Bull. Drug Addiction and Narcotics,
on Drug Abuse Res. Monogr. Ser. 76. Washington, National Academy of Sciences-National Research
D.C., U.S. Govt. Print. Off.. 1987. DD. 448-484. Council, Publ., 1954, pp. 840 - 852; see also L. Lasagna
218

and H.K. Beecher, Studies and Speculations on the 46 L.A. Dyhstra and J.H. Woods, 3. Pharmaeol. Methods,
Antagonism of Morphine by Nalorphine (N-Allylnor- 16 (19851263.
morphine) in Man, ibid, Appendix J, pp. 873-889. 47 Testing for Abuse Liability of Drugs in Humans, in: M.
43 G.A. Deneau and M.H. Seevers, Bull. Drug Addict. Fischman and N. Mello (Eds.1, Natl. Inst. on Drug
Narc., Natl. Acad. Sci.-Natl., Res. Council Publ., Abuse Res. Monogr., Washington, D.C., U.S. Govt.
Addendum 2, (19621l-26. Print. Off., 1989, in press.
44 L. Atwell and A.E. Jacobson, Lab. Animal, 7 (1978142. 48 Problems of Drug Dependence: 1987, in L.S. Harris
45 W.L. Dewey et al., J. Pharmacol. Exp. Ther., 1’75(19701 (Ed.), Natl. Inst. on Drug Abuse Res. Monogr. Ser. 81,
435; W.L. Dewey and L.S. Harris, J. Pharmacol. Exp. Washington, D.C., U.S. Govt. Print. Off., 1988.
Ther.. 179 (19711652. 49 Natl. Inst. on Drug Abuse, Tech. Rev., 1988.