Obviation of Opioid Withdrawal Syndronte by Concomitant Adntinistration of Naltrexone in Microgrant Doses: Two Psychonautic Bioassayst

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 tolerance to their analgesic and eu­ prevent the development of opioid tolerance, and also to phoric effects, the well-known opioid withdrawal syndrome attenuate the allied withdrawal syndrome, a phenomenon I is thought to be an ineluctable sequel to cessation of ha­ recently dubbed "anti-Mithridatism" 1 (Ott 1997). Examples bitual use of opioids, at high enough dosage and for of anti-Mithridatism are the use of dizocilpine, also known sufficient duration. However, several classes of compounds as MK-801 (Trujillo & Akil 1991), and proglumide are known in animal models to ameliorate and even to (Watkins, Kinscheck & Mayer 1984). Based likewise on tThe author is indebted to RichardHef fern for valuable advice and animal models, it has lately been reported that nano- and consultation. picomolar doses of naltrexone, coadministered with opio­ *Partner, Entheobotanica, Solothurn, Switzerland. ids, could not merely enhance their analgesic potency, but Please address correspondence and reprint requests to Jonathan Ott, Entheobotanica, Kronengasse, II, Solothurn CH-4502, Switzerland. attenuate the withdrawal syndrome occasioned by their

Joumal of Psychoactive Drugs 101 Volume 38 (I}, March 2006 Ott Obviation of Opioid Withdrawal Syndrome withdrawal from dependent animals. This follows the in­ ETHICS OF SELF-EXPERIMENTION triguing discovery that the m-opioid receptors that mediate WITH PSYCHOACTIVE DRUGS analgesia exist as two types on nociceptive neurons (pain­ sensitive neurons): apart from the prototypical inhibitory In peer-review of this article, the issue of ethics was 11-receptors, there is a much smaller population of excita­ raised: specifically regarding the fact that this research "was tory IJ.-receptors, opioid binding to which produces not conducted under the auspices of an Institutional Re­ hyperalgesia (Crain & Shen 1996). In this innovative tech­ view Board" (IRB), nor a physician's supervision. In a prior nique, which is currently undergoing clinical trials by Pain article in this journal, I have already addressed the ethical Therapeutics, Inc. (using MorViva® and OxyTrex®),2 dimensions of purportedly "objective" pharmacological minute doses of the potent opioid antagonist naltrexone (ca. research with animals, as opposed to "subjective" human I: I 00,000 in relation to opioid doses, expressed as molar self-experimentation (Ott 200 I). As far as the IRB is con­ equivalents of base) apparently block preferentially these cerned, such does not apply here, insofar as the research hyperalgesic, excitatory m-receptors, and in effect "unmask" was not conducted at any institution, nor involved any sub­ the true analgesic potency of opioids. ject other than the experimenter. Being a long-time (ca. 25 years) daily user of medici­ nal opiates (chiefly morphine sulfate peroral, up to 300 mg/ EXPERIMENT 1: MAY-JUNE 2001 day, and codeine phosphate peroral, up to 1.6 g/day), I am well familiar with the opioid withdrawal syndrome, best I am the subject, then aged 52 and in good health. I detailed in human studies by the U.S. Public Health Ser­ was taking daily 800 mg codeine phosphate peroral as fo ur vice at the erstwhile federal "narcotics farm" prison in 200 mg doses (Perduretas®), and had maintained this habit Lexington, Kentucky (Kolb & Himmelsbach 1938; Small for over a year, at times taking 1.0- 1.6 g codeine phos­ et al. 1938). When I learned of this biphasic, mixed analge­ phate daily. I resolved to reduce my habitual dose stepwise sic/hyperalgesic activity of opioids in animals, I at once over 14 days, with three plateaus (where a given dose is resolved to ascertain whether it were operative in human repeated a second day). I fo llowed a valuable practice: each beings. Using pharmaceutical codeine phosphate of known daily dose was taken a half-hour later in the day, that is, dosage and unmixed with aspirin or other drugs, and stan­ 24.5 hours elapsed between doses (25 hours is probably dard solutions of pharmaceutical naltrexone hydrochloride better). As has been known since De Quincey's day, it is (Antaxone®, which allowed precise oral or sublingual ap­ unproblematic to reduce one's dose by one-half, and so plication of 0.5 meg doses, expressed as naltrexone base), I the day before commencing, I simply prescinded (or elimi­ began their concomitant administration. At roughly a I: nated) two of my customary four doses, thus taking 400 I 00,000 (as molar equivalents) ratio of naltrexone base to mg. Table I shows the reduction schedule. Each codeine codeine base, peroral, there was approximately a 30% in­ dose was accompanied by 0.5 meg naltrexone base, ex­ crease in potency, as assessed by subjective (euphoric) cepting Day I, when the dose was 1.0 meg. effects, in contrast to crude tests for analgesia in common I experienced only the slightest withdrawal symptoms use by pharmacologists, despite the fact that I was then tak­ on Day I (neck and shoulder tension starting 1.5 hours ing 800 mg/day codeine phosphate peroral, divided into four before dose time) and on Day 2 (similar tension two hours doses of 200 mg each. I assert that an experienced opioid before dose time, and slight goose flesh 0.5 hours prior). habitue, who knows dosage amounts precisely, is able to This was likely due to an overly abrupt initial reduction in make rather good subjective assessments of potency-a dosage. Apart from this, I passed a completely asymptom­ methadone-maintainee, for instance, would know soon atic and uneventful withdrawal, in the course of which I enough if a reduced or enhanced dose had mistakenly been ate, slept and worked normally. Although there was some administered. So dramatic and incontrovertible was this "clock-watching" up to Day 3, on Day 9 I forgot the time potentiation, that I at once reasoned it should follow that a and took my dose an hour late. Following merely 36 hours 25% reduction in codeine dosage cum naltrexone would be of total abstinence (having been asymptomatic for 13 days perceived as being equipotent with my habitual dose of and after 10 days at doses beneath 10% of the habitual), codeine neat. This proved to be a palpable hit: it was in­ on the morning of Day 15 and again that evening, I took deed equipotent. This suggested that the biochemical two 120 mg doses of codeine phosphate, which of course substrate of opioid tolerance (which remains as inscrutable gave good euphoric effects. Then on Day 16, 24 hours af­ as ever, despite exhaustive research) is amenable to phar­ ter the second dose of codeine, I conducted a macological readjustment in real time, as it were. It followed naltrexone-challenge test, by taking 25 mg naltrexone per­ inexorably, then, that in principle an opioid habitue could oral, which would have precipitated withdrawal symptoms stepwise rachet-down tolerance; indeed, reduce the dose to had I somehow been mistaken in my appraisals, or had the zero, absent the opioid withdrawal syndrome. This also prompt resumption of codeine intake for one day reestab­ proved to be true, as will be evident from my two self­ lished physical dependence. Although I could indeed experiments. perceive the "anti-opioid" nature of naltrexone, absolutely

Journalof Psychoactive Drugs 102 Volume 38 (I), March 2006 Ott Obviation of Opioid Withdrawal Syndrome

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

Day Dose Total Reduction %Reduction

0 400 rng 50% 50%

I 160 rng 60% 60% 2 144 rng 64% 10% 3 120 rng 70% 17% 4 120 rng Week I : 800 rng 5 96 rng 76% 20% 6 80 rng 80% 17% 7 80 rng

8 64 rng 84% 20% 9 48 rng 88% 25% 10 48 rng II 40 rng 90% 17% Week 2: 256 rng 12 32 rng 92% 20% 13 24 rng 94% 25% 14 0 rng 100%

15 240 rng

16 Naltrexone (25 rng)C hallenge

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

Journalof Psychoactive DntRS 103 Vo lume 38 (1), March 2006 Ott Obviation of Opioid Withdrawal Syndrome support nearly two million such habits. This is certainly a disease, pursuant to ordinary understanding and use of the higher number than the total population of heroin users, term, irrespective of the possibility of medical manage­ and surely there exist at least as many medicinal opioid ment of drug habits. "addicts" as "j unkies," whether by medical necessity or The nature and intensity of the opioid withdrawal syn­ personal choice. drome, as well as its relative importance in sustaining COMMENTARY habituation, has been exaggerated wildly in films(e.g., Th e Man with the Golden Arm, Monkey on my Back) and lit­ The two experiments of opioid withdrawal described erature (notably William Burroughs' Junkie and Naked here-completely novel in my long experience with such­ Lunch). Burroughs' "algebra of need" is a satisfactory lit­ may well represent the first reports ever of truly erary device, but as mathematics does not add up to real asymptomatic withdrawal ofopioids following long-estab­ numbers. The physical withdrawal syndrome is not the sine lished habituation to significant and multiple daily doses. qua non of addiction. Perhaps it is more fruitful to view While of course no comparison can be made to intravenous opioid habituation as a sort of religious faith. Having once injection of street heroin in terms of analgesic potency in had sufficient experience, the opioid habitue comes to ac­ human beings, 800 mg of codeine phosphate peroral is quire a confirmed belief in an obdurate dogma of equivalent to 240 mg of morphine sulfate or 120 mg of diminishing dose-response; supported by hard physical oxycodone hydrochloride peroral (Beers & Berkow 1999). evidence (felt in the bones), as well as eyewitness-testi­ What is being discussed here is the obviation, not of opioid mony (what all the experts and fellow users say). Having habituation per se, but of aspects of tolerance and physical twice or thrice experienced total withdrawal from a state dependence, heretofore thought to follow like night, the day of physical dependency on opioids, there is likewise in­ of cessation of an opioid habit of such dosage-level and culcated in the user a fervent belief in the inevitability of duration as to constitute so-called "addiction." The term this pay-for-play purgatory: the more you take, the better "addiction" is used so loosely and tendentiously, and has you feel; and the longer you feel better, the worse you'll been subject to so many redefinitions and qualifications, as feel when you stop. These confirmed beliefs in inflexible to render it too imprecise for scientific use. The physical dogmas, at times attested and reconfirmed everysingle day, withdrawal syndrome was once held to be the sine qua non are in my view keystones in the psychological arch but­ of addiction (Small et al. 1938) until a paradigm-shift oc­ tressing opioid habituation. As Burroughs put it: "no curred in the 1980s. Whereas prior to this, negative good ...no bueno ...hust ling myself' (Burroughs 1959: reinforcement (i.e., avoidance of the pain of withdrawal) 213). Physical dependence on opioids and the allied with­ had been held to be the primary motor of addiction, posi­ drawal syndrome are real and physiological, but tive reinforcement (rewarding effects) came to displace it, psychological or psychophysical factors are at least as and today the drugs considered to have the highest "addic­ important in the long-term maintenance of opioid habitua­ tive liability" are the stimulants, notably cocaine, tion. amphetamines and nicotine, the withdrawal of which from Banishing the spectre of the dread opioid withdrawal habitues occasions no physical withdrawal syndrome of syndrome is in itself a major advance, but the real signifi­ note. Despite politically-inspired efforts to conjure a cance of these findings, at least for me, as a trainedscie ntific cocainic withdrawal syndrome, in my long experience and researcher who approaches these matters in that spirit, is based on observations and interviews of more than 100 this: in a flash, as it were, a single ingestion-experiment habitues, nothing resembling the opioid withdrawal syn­ (reducing the dose by 25%, with no reduction in intensity drome accrues on cessation of habitual use, irrespectiveof of effects) can suffice convincingly to refute perhaps years its duration and dosage-levels. The same is true for nico­ of daily evidence and supportive testimony for the dopers' tine, even after prolonged sublingual use exceeding 100 mg/ dogma of diminishing dose-response; as, in turn, a single day of nicotine free-base (this will be the subject of another experience of asymptomatic and uneventful withdrawal can report). "Nicotine-habituation" is often used carelessly to render the heretofore inevitable Sword of Damocles emi­ describe "tobacco-smoking habituation." The so-called "to­ nently forgettable. This is the crux of the case, but its bacco-smoking withdrawal-syndrome" does not appear to meaning to a given habitue is a matter of conjecture. In be based on physical dependency on nicotine (present at my case, these dramatic refutations at once and forever low, nonpsychoactive levels in commercial tobacco; ca. 1.0 altered my personal psychology regarding opioid habitua­ mg/cigarette ). To obviate the physical withdrawal syndrome tion, something now not worthy of much personal thought of opioids, while it perforce removes negative reinforce­ or care. For another, however, a new dogma of play-and­ ment aspects of the habit, nonetheless leaves intact any don't-pay might simply conduce to increased indulgence. positive reinforcement factors. As such, it should not be Moreover, what is being discussed here is oral inges­ mistakenly regarded as a cure for opioid habituation. Such tion of opioids, in which the euphoric reward is some 30 does not exist, nor likely ever will. Addiction is a synonym to 60 minutes removed fromthe act of ingestion. The closer for devotion, and devotion to a habit is in any case hardly a is the temporal connection between ingestion-behaviorand

Journal of Psychoactive Drugs 104 Volume 38 (I), March 2006 Ott Obviation of Opioid Withdrawal Syndrome

associated reward, the more habituating is that behavior such as setting and maintaining pain thresholds. Since (recall one can not become addicted to drugs per se, but physical tolerance can be acquired from a single opioid rather to the habit of ingesting them; until the twentieth dose, it follows that a single dose could in principle dimin­ century, the substantive "addict" did not exist in English, ish it. Certainly it is remarkable that one can reduce an and "addiction" was used with linguistic precision, viz., opioid habit to one-eighth its former level over five days, addiction to a habit of ingesting one or another drug, or to while experiencing opioid euphoria fromeach successively another behavior). In the case of intravenous drug injec­ diminished dose. This is a dramatic first I'd have thought tion, this reward delay is but a minute or so; following next to impossible prior to having experienced it. inhalation of alkaloidal free-base vapors, about 30 seconds merely. In this latter circumstance, ingestion-act and re­ NOTES lated reward become virtually contemporaneous, insofar as one begins to feel the rewarding "rush" even before ex­ I. Anti-Mithridatism: Mithridates VI of Pontus (120- haling. To inhale vapors of free-base cocaine is directly to 63 BC), together with his infamous physician Kratevas, on confront crystalline craving. It is unclear, pending further the basis of human experimentation upon condemned con­ investigation, whether picomolar naltrexone combined with victs, who were poisoned, developed an all-purpose antidote injected or vaporized and inhaled opioids can block and to poisoning, which was named the mithridatium or mith­ reverse tolerance or obviate the withdrawal syndrome, as ridate. This was a type of theriac, and it happens that opium is the case with oral ingestion (although the animal research was a chief, and later practically the sole, ingredient in on which the present report is based involved induced de­ theriacs. Whereas a theriac was designed to prevent illness pendency via injected morphine). (perhaps as an immunostimulant), repeated small doses of One final point is more than significant. During the toxins in the mithridatium were supposed to establish a pro­ stepwise dose reduction in Experiment 1, very satisfactory gressive immunity to their toxicity. euphoric effects were experienced for the first five days, 2. Pain Therapeutics, Inc.; 250, E. Grand Street, Suite although at the end of that period, my daily dose stood at 70; San Francisco, CA, 94080. The company has already 96 mg, or less than one-eighth of my habitual dosage! This released preliminary data on animal testing of these two is unheard of in stepwise withdrawal. Significantly, that products: MorViva® in two formulations, both designated dose, around 100 mg, constitutes the lowest dose that had PTI-555 (morphine sulfate 3 mg/kg + naltrexone 0.3 ng/ sufficed to produce euphoric effects for me, when I had kg; and morphine sulfate 3 mg/kg + naltrexone 3 ng/kg) first used opioids some 30 years ago. This is to be expected, and OxyTrex® likewise in two formulations, both desig­ were one indeed undoing and readjusting stepwise the bio­ nated PTI-801 (oxycodone 0. 1 mg/kg + naltrexone I pg/ chemical substrate of opioid tolerance, which appears to kg; oxycodone 0.1 mg/kg + naltrexone 1 ng/kg). Measur­ be the case. While astonishing at the time, on subsequent ing tail-flick latency in female mice, MorViva® showed reflection this did not surprise me overmuch. There is ev­ stronger analgesia and greater duration than 3 mg/kg mor­ ® ery reason to anticipate such rapid homeostatic plasticity phine sulfate neat; whereas OxyTrex showed stronger in an exquisitely sensitive and primary neural control analgesia than 0.1 mg/kg oxycodone neat. mechanism, which mediates vital physiological parameters,

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Journal of Psychoactive Drugs 105 Volume 38 (1), March 2006