Obviation of Opioid Withdrawal

Syndrome by Concomitant Administration

of Naltrexone in Microgram Doses:
Two Psychonautic Bioassays^

Jonathan Ott*

Abstract—Two psychonautic bioassays (self-experiments) in stepwise and abrupt cessation of long-

term daily oral ingestion habits of 800 mg of codeine phosphate are presented. Concomitant
administration of minute doses (about 0.5 meg) of the opioid antagonist naltrexone with each dose of
codeine was found in both cases to obviate the expected opioid withdrawal syndrome, resulting in
asymptomatic and uneventful transitions from physical opioid dependency states to exogenous opioid-
free metabolism. These experiments are analyzed in the context of a conjectured, rapid, iterative
reduction and complete elimination of opioid tolerance, once acquired. It was found that
coadministration of naltrexone with codeine phosphate obviated the development of both tolerance
and physical dependency over several months of four daily oral doses of 200 mg, allowing abrupt
("cold turkey"), asymptomatic and uneventful withdrawal. This points the way to the biochemical
substrate of opioid tolerance itself, and shows that this can easily and inexpensively be blocked,
even over months of iterative oral administration of substantial doses of opioid analgesics. Finally, it
suggests the opioid withdrawal syndrome is directly related to the physiology of opioid tolerance,
and can be prevented by blocking tolerance itself. Even when tolerance has been acquired, this can
be reduced stepwise over a matter of days, with no symptoms of opioid withdrawal syndrome.

Keywords—addiction, codeine, naltrexone, opioids, tolerance, withdrawal

Like progressive toleratice to their atialgesic atid eu-
phoric effects, the well-ktiowti opioid withdrawal sytidrome
is thought to be ati ineluctable sequel to cessatioti of ha-
bitual use of opioids, at high etiough dosage and for
sufficient duration. However, several classes of compotinds
are known in animal ttiodels to ameliorate and even to
tThe author is indebted to Richard Heffem for valuable advice and
consultation.
•Partner, Entheobotanica, Solothum, Switzerland.
Please address correspondence and reprint requests to Jonathan Ott,
Entheobotanica, Kronengasse, 11, Solothum CH-4502, Switzerland.
prevent the development of opioid tolerance, and also to
attenuate the allied withdrawal syndrome, a phenomenon I
recently dubbed "anti-Mithridatism"' (Ott 1997). Examples
of anti-Mithridatism are the use of dizocilpine, also known
as MK-801 (Trujillo & Akil 1991), and proglumide
(Watkins, Kinscheck & Mayer 1984). Based likewise on
animal models, it has lately been reported that nano- and
picomolar doses of naltrexone, coadministered with opio-
ids, could not merely enhance their analgesic potency, but
attenuate the withdrawal syndrome occasioned by their

Journal of Psychoactive Drugs 101 Volume 38(1), March 2006

Ott
withdrawal from dependent animals. This follows the in-
triguing discovery that the m-opioid receptors that mediate
analgesia exist as two types on nociceptive neurons (pain-
sensitive neurons): apart from the prototypical inhibitory
|i-receptors, there is a much smaller population of excita-
tory ^.-receptors, opioid binding to which produces
hyperalgesia (Crain & Shen 1996). In this innovative tech-
nique, which is currently undergoing clinical trials by Pain
Therapeutics, Inc. (using MorViva® and OxyTrex®),^
minute doses of the potent opioid antagonist naltrexone (ca.
1: 100,000 in relation to opioid doses, expressed as molar
equivalents of base) apparently block preferentially these
hyperalgesic, excitatory m-receptors, and in effect "unmask"
the true analgesic potency of opioids.
Being a long-time (ca. 25 years) daily user of medici-
nal opiates (chiefly morphine sulfate peroral, up to 300 mg/
day, and codeine phosphate peroral, up to 1.6 g/day), I am
well familiar with the opioid withdrawal syndrome, best
detailed in human studies by the U.S. Public Health Ser-
vice at the erstwbile federal "narcotics farm" prison in
Lexington, Kentucky (Kolb & Himmelsbach 1938; Small
et al. 1938). When I learned of this biphasic, mixed analge-
sic/hyperalgesic activity of opioids in animals, I at once
resolved to ascertain whether it were operative in human
beings. Using pharmaceutical codeine phosphate of known
dosage and unmixed with aspirin or other drugs, and stan-
dard solutions of pharmaceutical naltrexone hydrochloride
(Antaxone®, which allowed precise oral or sublingual ap-
plication of 0.5 meg doses, expressed as naltrexone base), I
began their concomitant administration. At roughly a 1:
100,000 (as molar equivalents) ratio of naltrexone base to
codeine base, peroral, there was approximately a 30% in-
crease in potency, as assessed by subjective (euphoric)
effects, in contrast to crude tests for analgesia in common
use by pharmacologists, despite the fact that I was then tak-
ing 800 mg/day codeine phosphate peroral, divided into four
doses of 200 mg each. I assert that an experienced opioid
habitue, who knows dosage amounts precisely, is able to
make rather good subjective assessments of potency—a
methadone-maintainee, for instance, would know soon
enough if a reduced or enhanced dose had mistakenly been
administered. So dramatic and incontrovertible was this
potentiation, that I at once reasoned it should follow that a
25% reduction in codeine dosage cum naltrexone would be
perceived as being equipotent with my habitual dose of
codeine neat. This proved to be a palpable hit: it was in-
deed equipotent. This suggested that the biochemical
substrate of opioid tolerance (which remains as inscrutable
as ever, despite exhaustive research) is amenable to phar-
macological readjustment in real time, as it were. It followed
inexorably, then, that in principle an opioid habitud could
stepwise rachet-down tolerance; indeed, reduce the dose to
zero, absent the opioid withdrawal syndrome. This also
proved to be true, as will be evident from my two self-
experiments.
Journal of Psychoactive Drugs
Obviation of Opioid Withdrawai Syndrome
ETHICS OF SELF-EXPERIMENTION
WITH PSYCHOACTIVE DRUGS
In peer-review of this article, the issue of ethics was
raised: specifically regarding the fact that this research "was
not conducted under the auspices of an Institutional Re-
view Board" (IRB), nor a physician's supervision. In a prior
article in this journal, I have already addressed the ethical
dimensions of purportedly "objective" pharmacological
research with animals, as opposed to "subjective" human
self-experimentation (Ott 2001). As far as the IRB is con-
cerned, such does not apply here, insofar as the research
was not conducted at any institution, nor involved any sub-
ject other than the experimenter.
EXPERIMENT 1: MAY-JUNE 2001
I am the subject, then aged 52 and in good health. I
was taking daily 800 mg codeine phosphate peroral as four
200 mg doses (Perduretas®), and had maintained tbis habit
for over a year, at times taking 1.0-1.6 g codeine phos-
phate daily. I resolved to reduce my habitual dose stepwise
over 14 days, with tbree plateaus (where a given dose is
repeated a second day). I followed a valuable practice: each
daily dose was taken a balf-bour later in tbe day, that is,
24.5 hours elapsed between doses (25 hours is probably
better). As bas been known since De Quincey's day, it is
unproblematic to reduce one's dose by one-balf, and so
tbe day before commencing, I simply prescinded (or elimi-
nated) two of my customary four doses, thus taking 400
mg. Table 1 shows tbe reduction schedule. Each codeine
dose was accompanied by 0.5 meg naltrexone base, ex-
cepting Day 1, wben the dose was 1.0 meg.
I experienced only tbe slightest withdrawal symptoms
on Day 1 (neck and shoulder tension starting 1.5 hours
before dose time) and on Day 2 (similar tension two bours
before dose time, and slight goose flesh 0.5 hours prior).
This was likely due to an overly abrupt initial reduction in
dosage. Apart from tbis, I passed a completely asymptom-
atic and uneventful witbdrawal, in the course of wbich I
ate, slept and worked normally. Althougb tbere was some
"clock-watcbing" up to Day 3, on Day 9 I forgot tbe time
and took my dose an hour late. Following merely 36 hours
of total abstinence (having been asymptomatic for 13 days
and after 10 days at doses beneatb 10% of the habitual),
on tbe morning of Day 15 and again that evening, I took
two 120 mg doses of codeine phosphate, wbich of course
gave good euphoric effects. Then on Day 16, 24 bours af-
ter tbe second dose of codeine, I conducted a
naltrexone-challenge test, by taking 25 mg naltrexone per-
oral, wbicb would bave precipitated withdrawal symptoms
bad I somehow been mistaken in my appraisals, or had the
prompt resumption of codeine intake for one day reestab-
lished physical dependence. Althougb I could indeed
perceive the "anti-opioid" nature of naltrexone, absolutely
102 Volume 38(1), March 2006
 Ott Obviation of Opioid Withdrawal Syndrome

TABLE 1
Codeine-Withdrawal Reduction-Schedule (Experiment 1)

Day Dose Total Reduction % Reduction

0 400 mg 50% 50%

1 160 mg 60% 60%

2 144 mg 64% 10%
3 120mg 70% 17%
4 120mg — — Week 1: 800 mg
5 96 mg 76% 20%
6 80 mg 80% 17%
7 80 mg — —

8 64 mg 84% 20%
9 48 mg 88% 25%
10 48 mg — —
11 40 mg 90% 17% Week 2: 256 mg
12 32 mg 92% 20%
13 24 mg 94% 25%
14 Omg 100% —

15 240 mg — —

16 Naltrexone (25 mg) Challenge

no withdrawal symptoms supervened. Out of curiosity, over
the next 72 hours, I made six "codeine-challenges" of
naltrexone. Doses of 160 mg codeine phosphate at two,
three, 24, 38, 64 and 72 hours post-naltrexone were taken.
Not until 64 hours was any opioid effect perceived, per-
haps 50% attenuated. At 72 hours, naltrexone blockade of
m-receptors had ceased, which agreed with my calculations
based on data showing an approximate four-hour tissue half-
life for naltrexone.
EXPERIMENT 2: JUNE 2002
I again maintained a habit of 800 mg/day codeine phos-
phate peroral for several months, always administering each
200 mg dose of codeine with 1.0 meg naltrexone orally or
sublingually. Given the above self-experiment, it seemed
lo me possible that not only might I develop no tolerance
to codeine-effects, but that such a habit could abruptly be
terminated without occasioning any withdrawal syndrome.
In this case, I merely dropped my daily dose to 200 mg
over three days by the simple expedient of daily prescinding
one of my habitual doses. On the fourth day and thence-
forth until this writing two months later, I abstained
completely from codeine or other opioid analgesic. Al-
though I felt weary on my first opiate-free day, I slept
normally and experienced not the slightest trace of any
opioid withdrawal syndrome.
I might add parenthetically that throughout the course
of four daily doses of 200 mg codeine phosphate, solid
euphoric effects followed each by some 30 minutes (the
pills were crushed in a mortar and partially dissolved in
hot water), suggesting tolerance was not developing. On
the other hand, absent naltrexone, this is normal in my ex-
perience—despite development of progressive tolerance,
a controlled user who knows dose precisely can stabilize at
a mid-level dose, experience pleasant, but not overwhelm-
ing, opioid euphoria, and maintain that situation indefinitely.
It is worth noting that exaggerated attention is focused on
uncontrolled users with no idea of dosage, nor indeed pu-
rity, much less identity, of their opioids. Meanwhile, the
United States, with roughly 4% ofthe world's population,
in 1994 consumed 700 tons or 50% of the world's licit
opium production, which is to say 13 times world per capita
consumption (International Narcotics Control Board, cf.
Marnell 1995). Most of this raw material for opiate phar-
maceuticals is converted to codeine, much simply extracted
and purified as morphine salts, some transformed to po-
tent, artificial opiate derivatives like oxycodone and
oxymorphone. Now, 700 tons of opium (even at a conser-
vative 10% morphine), represents 70 tons of morphine (or
70,000,000 g). Assuming a daily oral habit of 100 mg
(which I can attest certainly leads to physical dependency;
vide also Burroughs 1959, 1953), 36.5 g per year would
maintain one "addict," and 70 tons in principle could

Journal of Psychoactive Drugs 103 Volume 38(1). March 2006

Ott
support nearly two million such habits. This is certainly a
higher number than the total population of heroin users,
and surely there exist at least as many medicinal opioid
"addicts" as "junkies," whether by medical necessity or
personal choice.
COMMENTARY
The two experiments of opioid withdrawal described
here—completely novel in my long experience with such—
may well represent the first reports ever of truly
asymptomatic withdrawal of opioids following long-estab-
lished habituation to significant and multiple daily doses.
While of course no comparison can be made to intravenous
injection of street heroin in terms of analgesic potency in
human beings, 800 mg of codeine phosphate peroral is
equivalent to 240 mg of morphine sulfate or 120 mg of
oxycodone hydrochloride peroral (Beers & Berkow 1999).
What is being discussed here is the obviation, not of opioid
habituation per se, but of aspects of tolerance and physical
dependence, heretofore thought to follow like night, the day
of cessation of an opioid habit of such dosage-level and
duration as to constitute so-called "addiction." The term
"addiction" is used so loosely and tendentiously, and has
been subject to so many redefinitions and qualifications, as
to render it too imprecise for scientific use. The physical
withdrawal syndrome was once held to be the sine qua non
of addiction (Small et al. 1938) until a paradigm-shift oc-
curred in the 1980s. Whereas prior to this, negative
reinforcement (i.e., avoidance of the pain of withdrawal)
had been held to be the primary motor of addiction, posi-
tive reinforcement (rewarding effects) came to displace it,
and today the drugs considered to have the highest "addic-
tive liability" are the stimulants, notably cocaine,
amphetamines and nicotine, the withdrawal of which from
habitues occasions no physical withdrawal syndrome of
note. Despite politically-inspired efforts to conjure a
cocainic withdrawal syndrome, in my long experience and
based on observations and interviews of more than 100
habitues, nothing resembling the opioid withdrawal syn-
drome accrues on cessation of habitual use, irrespective of
its duration and dosage-levels. The same is true for nico-
tine, even after prolonged sublingual use exceeding 100 mg/
day of nicotine free-base (this will be the subject of another
report). "Mcofine-habituation" is often used carelessly to
describe "tobacco-smoking habituation." The so-called "to-
bacco-smoking withdrawal-syndrome" does not appear to
be based on physical dependency on nicotine (present at
low, nonpsychoactive levels in commercial tobacco; ca. 1.0
mg/cigarette). To obviate the physical withdrawal syndrome
of opioids, while it perforce removes negative reinforce-
ment aspects of the habit, nonetheless leaves intact any
positive reinforcement factors. As such, it should not be
mistakenly regarded as a cure for opioid habituation. Such
does not exist, nor likely ever will. Addiction is a synonym
for devotion, and devotion to a habit is in any case hardly a
Journal of Psychoactive Drugs
Obviation of Opioid Withdrawal Syndrome
disease, pursuant to ordinary understanding and use of the
term, irrespective of the possibility of medical manage-
ment of drug habits.
The nature and intensity ofthe opioid withdrawal syn-
drome, as well as its relative importance in sustaining
habituation, has been exaggerated wildly in films (e.g.. The
Man with the Golden Arm, Monkey on my Back) and lit-
erature (notably William Burroughs' Junkie and Naked
Lunch). Burroughs' "algebra of need" is a satisfactory lit-
erary device, but as mathematics does not add up to real
numbers. The physical withdrawal syndrome is not the sine
qua non of addiction. Perhaps it is more fruitful to view
opioid habituation as a sort of religious faith. Having once
had sufficient experience, the opioid habitue comes to ac-
quire a confirmed belief in an obdurate dogma of
diminishing dose-response; supported by hard physical
evidence (felt in the bones), as well as eyewitness-testi-
mony (what all the experts and fellow users say). Having
twice or thrice experienced total withdrawal from a state
of physical dependency on opioids, there is likewise in-
culcated in the user a fervent belief in the inevitability of
this pay-for-play purgatory: the more you take, the better
you feel; and the longer you feel better, the worse you'll
feel when you stop. These confirmed beliefs in inflexible
dogmas, at times attested and reconfirmed every single day,
are in my view keystones in the psychological arch but-
tressing opioid habituation. As Burroughs put it: "no
good . . . no bueno . . . hustling myself (Burroughs 1959:
213). Physical dependence on opioids and the allied with-
drawal syndrome are real and physiological, but
psychological or psychophysical factors are at least as
important in the long-term maintenance of opioid habitua-
tion.
Banishing the spectre ofthe dread opioid withdrawal
syndrome is in itself a major advance, but the real signifi-
cance of these findings, at least for me, as a trained scientific
researcher who approaches these matters in that spirit, is
this: in a flash, as it were, a single ingestion-experiment
(reducing the dose by 25%, with no reduction in intensity
of effects) can suffice convincingly to refute perhaps years
of daily evidence and supportive testimony for the dopers'
dogma of diminishing dose-response; as, in turn, a single
experience of asymptomatic and uneventful withdrawal can
render the heretofore inevitable Sword of Damocles emi-
nently forgettable. This is the crux of the case, but its
meaning to a given habitu6 is a matter of conjecture. In
my case, these dramatic refutations at once and forever
altered my personal psychology regarding opioid habitua-
tion, something now not worthy of much personal thought
or care. For another, however, a new dogma of play-and-
don't-pay might simply conduce to increased indulgence.
Moreover, what is being discussed here is oral inges-
tion of opioids, in which the euphoric reward is some 30
to 60 minutes removed from the act of ingestion. The closer
is the temporal connection between ingestion-behavior and
104 Volume 38(1). March 2006
 o«
associated reward, the more habituating is that behavior
(recall one can not become addicted to drugs per se, but
rather to the habit of ingesting them; until the twentieth
century, the substantive "addict" did not exist in English,
and "addiction" was used with linguistic precision, viz.,
addiction to a habit of ingesting one or another drug, or to
another behavior). In the case of intravenous drug injec-
tion, this reward delay is but a minute or so; following
inhalation of alkaloidal free-base vapors, about 30 seconds
merely. In this latter circumstance, ingestion-act and re-
lated reward become virtually contemporaneous, insofar
as one begins to feel the rewarding "rush" even before ex-
haling. To inhale vapors of free-base cocaine is directly to
confront crystalline craving. It is unclear, pending further
investigation, whether picomolar naltrexone combined with
injected or vaporized and inhaled opioids can block and
reverse tolerance or obviate the withdrawal syndrome, as
is the case with oral ingestion (although the animal research
on which the present report is based involved induced de-
pendency via injected morphine).
One final point is more than significant. During the
stepwise dose reduction in Experiment 1, very satisfactory
euphoric effects were experienced for the first five days,
although at the end of that period, my daily dose stood at
96 mg, or less than one-eighth of my habitual dosage! This
is unheard of in stepwise withdrawal. Significantly, that
dose, around 100 mg, constitutes the lowest dose that had
sufficed to produce euphoric effects for me, when I had
first used opioids some 30 years ago. This is to be expected,
were one indeed undoing and readjusting stepwise the bio-
chemical substrate of opioid tolerance, which appears to
be the case. While astonishing at the time, on subsequent
reflection this did not surprise me overmuch. There is ev-
ery reason to anticipate such rapid homeostatic plasticity
in an exquisitely sensitive and primary neural control
mechanism, which mediates vital physiological parameters.
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and Therapy. Whitehouse Station, New Jersey: Merck Research
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Burroughs, W.S. 1959. Naked Lunch. New York: Grove Press.
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Journal of Psychoactive Drugs
Obviation of Opioid Withdrawal Syndrome
such as setting and maintaining pain thresholds. Since
physical tolerance can be acquired from a single opioid
dose, it follows that a single dose could in principle dimin-
ish it. Certainly it is remarkable that one can reduce an
opioid habit to one-eighth its former level over five days,
while experiencing opioid euphoria from each successively
diminished dose. This is a dramatic first I'd have thought
next to impossible prior to having experienced it.
NOTES
1. Anti-Mithridatism: Mithridates VI of Pontus (120-
63 BC), together with his infamous physician Kratevas, on
the basis of human experimentation upon condemned con-
victs, who were poisoned, developed an all-purpose antidote
to poisoning, which was named the mithridatium or mith-
ridate. This was a type of theriac, and it happens that opium
was a chief, and later practically the sole, ingredient in
theriacs. Whereas a theriac was designed to prevent illness
(perhaps as an immunostimulant), repeated small doses of
toxins in the mithridatium were supposed to establish a pro-
gressive immunity to their toxicity.
2. Pain Therapeutics, Inc.; 250, E. Grand Street, Suite
70; San Francisco, CA, 94080. The company has already
released preliminary data on animal testing of these two
products: MorViva® in two formulations, both designated
PTI-555 (morphine sulfate 3 mg/kg + naltrexone 0.3 ng/
kg; and morphine sulfate 3 mg/kg + naltrexone 3 ng/kg)
and OxyTrex® likewise in two formulations, both desig-
nated PTI-801 (oxycodone 0.1 mg/kg + naltrexone 1 pg/
kg; oxycodone 0.1 mg/kg + naltrexone 1 ng/kg). Measur-
ing tail-flick latency in female mice, MorViva® showed
stronger analgesia and greater duration than 3 mg/kg mor-
phine sulfate neat; whereas OxyTrex® showed stronger
analgesia than 0.1 mg/kg oxycodone neat.
Ott, J. 1997. Pharmacophilia or the Natural Paradises. Vashon,
Washington: Natural Products Co.
Small, L.F.; Eddy, N.B.; Mosettig, E. & Himmelsbach, C.K. 1938. Studies
on Drug Addiction, with Special Reference to Chemical Structure
of Opium Derivatives and Allied Synthetic Substances and their
Physiological Action. Supplement No. 138 to the Public Health
Reports. Washington, D.C: U.S. Government Printing Office.
Trujillo, K.A. & Akil, A. 1991. Inhibition of morphine tolerance and
dependence by the NMDA receptor antagonist MK-801. Science
251:85-7.
Watkins, L.R.; Kinscheck, I.B. & Mayer, D.J. 1984. Potentiation of opiate
analgesia and apparent reversal of morphine tolerance by
proglumide. Science 224: 395-6.
105 Volume 38(1), March 2(X)6