NYU Conference on Ibogaine Nov 5-6, 1999

Search the Web!

Ibogaine, A Putatively Anti-Addictive Alkaloid

Piotr Popik and Stanley D. Glick
Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland (P.P.),
Department of Pharmacology and Neuroscience, Albany Medical College, Albany, NY 12208 USA

Contents

Reprinted with permission from Prous Science.
This article appeared in Drugs of the Future 1996,21(11):1109-1115.
If your browser does not fully support the FONT-tag, the greek mu may appear as a regular M (e.g. in mg)

Synthesis

Ibogaine was first isolated and identified in the beginning of this century (1-4); the structure of this and related alkaloids (figure 1) was first established about 60 years later (5-7). Total synthesis from nicotinamide was reported using a 13- or 14-step sequence (8,9). The ¹³C-NMR spectra of several iboga alkaloids were published by Wenkert et al., (10).

Introduction

Ibogaine (NIH 10567, Endabuse^TM) is among psychoactive indole alkaloids isolated from the shrub, Tabernanthe iboga. Preclinical studies demonstrate that ibogaine reduces self-administration of both cocaine and morphine, as well as attenuates the symptoms of morphine withdrawal. Several anecdotal observations in man (11-19) seem to support the notion that ibogaine may have anti-addictive properties.

Source and chemistry

Ibogaine has a m.p. of 153° at 0.01 mm Hg and pK_a = 8.1 in 80% methylcellosolve. The absorption maxima in methanol are 226 and 296 nm (log e₂₂₆ = 4.39; log e₂₉₈ = 3.93). Ibogaine crystallizes from alcoholic solutions into small, reddish prismatic needles; it is levorotatory [a]_D = -53° (in 95% ethanol) and is soluble in ethanol, methanol, chloroform and acetone, but insoluble in water. Ibogaine hydrochloride (f.p. 299°C, [a]_D = -63° (ethanol), [a]_D = -49° (H₂O)) is soluble in water, ethanol and methanol, is slightly soluble in acetone and chloroform and is practically insoluble in ether (20). Alkaloids which are structurally similar to ibogaine include harmaline, tabernanthine, ibogamine, iboxigaine, gabonine, iboquine, kisantine and ibolutenine.

Mechanisms of action

Despite several years of intensive research, the mechanism of anti-addictive action of ibogaine has not been unequivocally defined. This is perhaps due to the fact that the neurochemical and molecular basis of drug addiction is by itself poorly understood. The recently identified antagonistic activity of ibogaine on N-methyl-D-aspartate (NMDA) receptors as well as its agonist activity at opioid receptors are highly regarded as a possible mechanisms of these anti-addictive actions. However, it should be mentioned that ibogaine interacts with several neurotransmitter systems, including serotonin uptake sites and sigma sites, and that at least some of ibogaine's actions have been attributed to a long-lasting metabolite, possibly O-desmethylibogaine (other names: noribogaine or 12-hydroxyibogamine) - see figure 1 for chemical structures.

Several lines of evidence suggest that NMDA receptors are involved in mediating the effects of abused drugs. NMDA antagonists acting at the glutamate, open channel (MK-801) and glycine binding sites suppress symptoms of morphine withdrawal in rodents (21-23) as well as attenuate drug self-administration, sensitization to the behavioral effects of psychostimulants and rewarding effects of drugs of abuse (for review see (24)). Several studies indicate that ibogaine is a competitive inhibitor of [³H]MK-801 or [³H]TCP binding (K_i ~1 mM) to NMDA receptor coupled ion channels (25,26). Consistent with these neurochemical studies, ibogaine produced a voltage dependent block of NMDA evoked currents in hippocampal cultures (K_i, 2.3 mM at -60 mV) as well as inhibited glutamate-induced cell death in neuronal cultures, indicating its antagonistic activity at the NMDA receptors. Moreover, in drug-discrimination studies, ibogaine substituted as an interoceptive cue in mice trained to recognize MK-801 (dizocilpine) in a drug discrimination paradigm (25).

Ibogaine binds to opioid receptors with an affinity of 2-4 M (27,28), and its metabolite O-desmethylibogaine has an affinity of ~ 1 M (28). Increasing evidence suggests that agonists can modulate the reinforcing effects of drugs. It has been reported that agonists decrease morphine and cocaine self-administration in rats (29) and attenuate the rewarding effects of both morphine (30) and cocaine (31) in a conditioned place preference paradigm. In addition, agonists were found to prevent sensitization to the conditioned rewarding effects of cocaine (32). Kappa agonists, as well as an NMDA antagonist, mimic the inhibitory effect of ibogaine on morphine-induced locomotor hyperactivity in rats (33). The combination of a antagonist and an NMDA agonist has been reported to antagonize ibogaine's effects on nucleus accumbens dopamine release, on morphine-induced hyperactivity, and on morphine self-administration (33).

Ibogaine has been reported to produce hallucinations or fantasies in man. Several s receptor ligands (e.g. cyclazocine and N-allylnormetazocine [SKF 10,047]) also produce psychotic symptoms in humans (34), while the major effect of s receptor antagonists in humans is attenuation of hallucinations (both drug-induced and illness-related) (35). Ibogaine inhibited the binding of [³H]pentazocine (a s₁ receptor ligand), to high (IC₅₀ ~86 nM) and low (IC₅₀ ~5.6 mM) affinity sites in mouse cerebellum (36). In other studies, ibogaine had a relatively high affinity for s₂ receptors (K_i = 90.4 and 250 nM) and a significantly lower affinity for s₁ receptors (K_i = 9310 nM) (37). Nonetheless, since the physiology and pharmacology of the s receptor is not well understood, the significance of these findings remains unclear.

Pharmacokinetics and metabolism

An adequate understanding of ibogaine's pharmacokinetics is not yet established. It is not entirely clear how ibogaine is absorbed, distributed, metabolized and excreted. Dhahir (38) as well as Zetler et al., (39) reported that the half life of ibogaine is approximately one hour in rodents; ibogaine could not be detected in the brain and other tissues 12 hours after administration. However, the assay used by these investigators lacked desired specificity and sensitivity. Gallagher et al. (40) have developed a highly sensitive and specific method to quantify ibogaine in plasma and tissues. The method utilizes organic extraction and derivatization with trifluroacetic anhydride, followed by gas chromatography for separation and mass spectrometry (GCMS) for detection. Using this GCMS method, Hough et al. (41) studied the tissue distribution of ibogaine after i.p. and s.c. administration in rats. The results indicated that ibogaine is subject to a significant "first pass" effect after i.p. dosing and that there is a marked propensity for ibogaine to be deposited in adipose tissue; ibogaine levels in fat were very high for at least 12 hours after administration. It was suggested that a single administration of ibogaine may provide a long-acting depot-like time course of action (41).

Little is known about the metabolism of ibogaine. Dhahir (38) showed that 4-5% of injected ibogaine is excreted unchanged in the urine of rats. Recent evidence suggests that ibogaine is metabolized to at least one active metabolite. It has been shown that, following ibogaine administration in humans, a metabolite can be detected in plasma (42). This metabolite, called O-desmethylibogaine (noribogaine or 12-hydroxyibogamine), is a result of ibogaine O-demethylation and has also been detected in plasma and in the brain of ibogaine-treated rats (43,44). Behavioral and neurochemical studies in rats (45) have established that O-desmethylibogaine is pharmacologically active and produces several effects (e.g., decrease in morphine and cocaine self-administration, reduction in the locomotor stimulant effect of morphine) that mimic those of ibogaine. Other studies (46), however, failed to demonstrate inhibition of the morphine withdrawal syndrome by O-desmethylibogaine (the putative metabolite of ibogaine) or by O-t-butyl- O-desmethylibogaine (an ibogaine analog designed to resist O-dealkylation) (figure 2). Thus, it appears that various "anti-addictive" effects of ibogaine and its metabolite may involve different neurotransmitter pathways. While a report of one human patient (42) indicated that O-desmethylibogaine persisted in plasma at high levels for at least 24 hours after oral ibogaine administration, it is not clear if this response was typical or atypical; recent reports (43,44) indicate that levels in plasma as well as in brain progressively decline from five to 24 hours after ibogaine administration (i.p.) in rats, although levels in brain may still be high enough (2-5 M) at 24 hours to mediate pharmacological effects.

Toxicology

The LD₅₀ of ibogaine has been determined in guinea pig (82 mg/kg i.p.) and rat (327 mg/kg intragastrically and 145 mg/kg i.p.) (38,47). Dhahir (38) reported no significant pathological changes in rat liver, kidneys, heart and brain following chronic ibogaine treatment (10 mg/kg for 30 days or 40 mg/kg for 12 days, i.p.). Similarly no evidence of neurotoxicity in African green monkeys given ibogaine in doses of 5-25 mg/kg p.o. for 4 consecutive days has been found (48). However, O'Hearn and Molliver (49) reported that repeated administration of ibogaine (100 mg/kg i.p.) to rats caused the degeneration of a subset of Purkinje cells in the cerebellar vermis. This degeneration was accompanied by a loss of the microtubule-associated protein 2 (MAP-2) and calbindin. Others (50) found that the neurotoxic effects of ibogaine on rat cerebellum strongly depend on the dose, and that at the dose (40 mg/kg, i.p.) most commonly used in behavioral studies, no toxicity occurs (51). It should be mentioned that both ibogaine as well as O-desmethylibogaine were recently found to possess significant behavioral effects at even much lower doses (0.25 - 2.5 mg/kg) than those typically used (e.g., 40 mg/kg) (52).

Animal studies

GENERAL

In male mice at one, but not 24 hours after injection, ibogaine (40 mg/kg i.p.) decreased locomotor activity (53). The same dose inhibited locomotion in rats during the first hour after injection (but not later), while one week later locomotor activity was increased (54). At the typical dose of 40 mg/kg, ibogaine has been found to attenuate memory (55). At much lower doses (0.25 - 2.5 mg/kg), however, ibogaine as well as O-desmethylibogaine facilitated memory retrieval (52). In mice, ibogaine is tremorigenic both when given intracerebrally (ED₅₀ 127 nmol/g brain, ~46 mg/g with a latency to tremor of about one minute) (56) and systemically (ED₅₀ 12 mg/kg s.c.) (39). Zetler et al., (39) also established the tremorigenic structure-activity relationship of several ibogaine-like compounds, with the descending order of potency: tabernanthine > ibogaline > ibogaine > iboxygaine > O-desmethylibogaine.

"ANTI-ADDICTIVE"

Ibogaine (40 mg/kg, i.p.) inhibits the self-administration of psychostimulants such as cocaine in rodents. Cappendijk and Dzoljic (57) trained male Wistar rats to intravenously self-administer cocaine; a single dose of ibogaine decreased cocaine intake by 40-60% for several days, while repeated ibogaine administration at one-week intervals produced a 60-80% decrease in cocaine self-administration which was sustained for several weeks. Similar effects were found in mice that developed a preference for cocaine in the drinking water. Thus, ibogaine administration (two weeks after the beginning of a choice period, 2 doses of 40 mg/kg, 6 hours apart) diminished cocaine preference for five days (58). Recently, Glick et al., (59) demonstrated that ibogaine and several iboga alkaloids reduced cocaine self-administration in rats in a dose-related fashion.

Sex and species of animals are noted here as they may influence the ability of ibogaine to modulate psychostimulant-induced hypermotility. Sershen et al., (60) found that ibogaine (40 mg/ kg i.p. 2 or 18 hrs prior to amphetamine) enhanced amphetamine (1 mg/kg) -induced hypermotility in female rats, but reduced it in male mice. In other studies, an amphetamine-induced increase in locomotor activity was potentiated in female rats pretreated with ibogaine (40 mg/kg, i.p.) 19 hrs earlier (61). An inhibitory effect of ibogaine on amphetamine metabolism has been proposed (62). However, like amphetamine, cocaine-induced hypermotility in female rats was potentiated by ibogaine (63) and ibogaine administration had no effect on brain cocaine levels (64). Broderick et al., (65,66) reported that ibogaine (20-40 mg/kg i.p.) administered to male rats for four days reduced cocaine (20 mg/kg) -induced hypermotility. Ibogaine (40 mg/kg i.p.) administration reduced also cocaine- (25 mg/kg s.c.) induced hypermotility in male mice (53), a finding in agreement with the amphetamine-ibogaine interaction (60), (see above).

Ibogaine dose dependently (2.5-40 mg/kg) reduced intravenous morphine self-administration in female Sprague-Dawley rats both immediately after injection and the next day (67). In some animals, a reduced morphine intake was observed for several days, while some rats needed several doses of ibogaine to achieve a prolonged reduction. Similar effects were demonstrated for the other iboga alkaloids (59). However, Dworkin (68) found that ibogaine alters morphine self-administration in male Fisher rats only on the day it was administered.

In morphine-dependent animals, the opioid antagonist naloxone induces a withdrawal syndrome, characterized (in rats) by increased rearing, digging, jumping, salivation and "wet-dog" head shaking. Ibogaine dose-dependently reduced the frequency of some of these withdrawal symptoms (rearing, digging, head hiding, chewing, teeth chattering, writhing, penile licking) after i.c.v. (4-16 mg) (69) and i.p. administration (40 and 80 mg/kg in rats) (70,71). In morphine-dependent monkeys, ibogaine (2 and 8 mg/kg s.c.) partially suppressed the total number of withdrawal signs (70). Popik et al., (25) found that ibogaine inhibits the morphine withdrawal syndrome in mice in a dose-related fashion. This effect was reversed by combining ibogaine treatment with glycine, which is consistent with the hypothesis involving NMDA receptors in ibogaine's effects. Layer et al. (46), however, failed to demonstrate inhibition of morphine withdrawal syndrome by O-desmethylibogaine (the putative metabolite of ibogaine) or by O-t-butyl- O-desmethylibogaine (an ibogaine analog designed to resist O-dealkylation).

Ibogaine seems to interfere with drug-seeking behavior produced by not only psychostimulants (cocaine) and opioids (morphine) but also by alcohol and nicotine. It has been reported that ibogaine decreases alcohol consumption in alcohol-preferring rats (72) and interferes both with neurochemical and behavioral effects associated with administration of nicotine (73). Thus, the ability of ibogaine to modify drug-seeking behavior evoked by all of addictive substances is consistent with the same effects of NMDA antagonists in preclinical models (for review see [24]) as well as with the claims of its "universal" anti-addictive effects based on observations in humans. Nonetheless, several recent studies implicate a significant role for opioid agonist actions in mediating ibogaine's effects on morphine and cocaine self-administration (33) while ibogaine- and O-desmethylibogaine-induced inhibition of serotonin uptake (42) has been linked to ibogaine's effects on alcohol intake (72,74).

Clinical studies

Numerous psychotropic actions of ibogaine have been reported. These actions appear to depend on both the dose and setting.

Ibogaine or the total iboga extract (4-5 mg/kg) given orally, elicits subjective reactions which last for approximately 6 hours. Fifty percent of subjects are reported to experience dizziness, incoordination, nausea, and vomiting (11,75,76). Typically in these studies, the drug elicited a state of drowsiness in which the subject did not want to move, open the eyes, or attend to the environment.

The psychoactive properties of ibogaine and related compounds were studied in detail by Naranjo (75,76), who explored the possibility of using ibogaine to facilitate psychotherapy. He used the term "oneirophrenia" to describe the ibogaine-induced state. Such an "oneirophrenic" state differs from the psychotomimetic state by the absence of all psychotic symptoms, yet having in common the prominence of primary process thinking. Naranjo, observing at least 40 sessions conducted with 30 patients, reported that the psychic state produced by ibogaine might be described as similar to a dream state without loss of consciousness. Thus, at doses of 4-5 mg/kg, subjects experienced an enhancement of fantasy without experiencing changes in the perception of the environment, delusions, depersonalization, or formal alterations of thinking. Ibogaine's fantasies (often described as a "movie run at high speed" or "slide show" [11]) were reported as rich in archetypal contents, involving animals and/or the subject himself with or without other individuals. The fantasies evoked by ibogaine were easy to manipulate by both the subjects and the psychotherapist. The patients were able to respond to the questions of the therapists. It was concluded that ibogaine could act as a psychological catalyst which could compress a long psychotherapeutic process into a shorter time (75,76).

No double-blind, placebo controlled clinical trials with ibogaine in the treatment of drug addiction have been conducted. Such studies are obviously needed.

Conclusions

The preclinical pharmacological effects of ibogaine may be summarized as follows: a decrease in self-administration of psychostimulants, morphine and alcohol, reduction of morphine withdrawal syndrome, a decrease in locomotor activity, memory retrieval facilitation, cardiovascular effects and tremor. Ibogaine decreases the hypermotility and dopamine turnover elicited by stimulants in male mice and rats, but has opposite effects in female rats. Neurochemical effects of ibogaine on mesolimbic and mesocortical dopamine systems can be summarized as follows: high doses decrease extracellular dopamine concentrations and increase concentrations of dopamine metabolites; low doses do not affect dopamine concentrations but decrease dopamine metabolite concentrations. Ibogaine may also affect the activity of voltage-dependent sodium channels, opioid k, s and NMDA receptors, and serotonin transporters (see table 1). In addition, high doses of ibogaine appear to be toxic to Purkinje cells in the rat cerebellum. In humans, it has been reported that ibogaine reduces craving and attenuates opioid dependence. Ataxia, nausea, vomiting and hypertension have also been observed. It also has been reported that ibogaine will produce tremors, hallucinations or "fantasies" and apprehension, increase strength and appetite, and possibly increase libido.

The pharmacological profile of ibogaine, including its putative "anti-addictive" effects, is likely to result from actions at multiple loci. For example, the effects of ibogaine on voltage-dependent sodium channels could explain its tremorigenic actions, while an anti-cholinesterase activity may explain its effects on blood pressure as well as stimulation of digestion and appetite. The neurochemical basis(es) for the putative "anti-addictive" actions of ibogaine remains unclear. Based on its neurochemical profile, ibogaine may produce "anti-addictive" actions through multiple effects at k receptors, s receptors, or serotonin transporters (see [36] for a review). Alternatively, ibogaine, or an unidentified active metabolite might act at pathways which have not been previously linked to addictive processes.

While these hypotheses all merit further investigation, at present, there are converging lines that link the NMDA-antagonist action of ibogaine to its putative "anti-addictive" properties. NMDA antagonists (acting at either glutamate, glycine, polyamine, or, open channel site) attenuate morphine withdrawal, attenuate drug self-administration, the sensitization to the behavioral effects of psychostimulants and rewarding effects of drugs of abuse (for review see [24]).

From the reports of human heroin addicts who have taken ibogaine, it appears that several features of the ibogaine experience are important in interrupting addiction. Thus, Dutch addicts who used ibogaine described the experience as having a dream with full consciousness, together with anxiety and the recall of memories (11,17). After this experience, the addicts did not feel compelled to use heroin. While these insights are intriguing, they are at present without heuristic value. Further studies are required to determine the importance of such experiences in the treatment of drug abuse. In conclusion, the claimed "anti-addictive" properties of ibogaine require rigorous validation in humans, after careful assessment of its neurotoxic potential. It remains to be established if an ibogaine metabolite, producing less side effects, could be of therapeutic value.

Acknowledgments

References

1 Dybovsky, J. and Landrin, E. Sur l'Iboga, ses proprietes excitantes, sa composition et sur l'alcaloide noveau qu'il renferme, l'ibogaine. C. R. Acad. Sci. (Paris), 1901, 133: 748-50.

2 Haller, A. and Heckel, E. Sur l'ibogine, principe actif d'une plante du genere Tabernaemontana, originarie du Congo. Compt. Rend. Soc. Biol. 1901, 133: 850-3.

3 Lambert, M. and Heckel, E. Sur la racine d'Iboga et l'ibogaine. C. R. Acad. Sci. 1901, 133: 1236-8.

4 Landrin, A. Etude botanique, pharmacologique, et chimique (Tabernanthe iboga). Bull. Sc. Pharmacol. 1905, 11: 319

5 Taylor, W.I. The iboga and voacanga alkaloids. In R.H.F. Manske (Ed.) The Alkaloids. Volume XI. Chemistry and Physiology, Academic Press, New York, London, 1968, pp. 79-98.

6 Taylor, W.I. The iboga and voacanga alkaloids. In R.H.F. Manske (Ed.) The Alkaloids. Volume VIII. Chemistry and Physiology, Academic Press, New York, London, 1965, pp. 203-235.

7 Taylor, W.I. Iboga alkaloids. II. The structures of ibogaine, ibogamine and tabernanthine. J. Am. Chem. Soc. 1957, 79: 3298-9.

8 Buchi, G., Coffen, D.L., Kocsis, K., Sonnet, P.E. and Ziegler, F.E. The total synthesis of iboga alkaloids. J. A. C. S. 1966, 88:13: 3099-109.

9 Rosenmund, P., Haase, W.H., Bauer, J. and Frische, R. Ibogamin, ibogain und epiibogamin. Chem. Ber. 1975, 180: 1871-95.

10 Wenkert, E., Cochran, D.W., Gottlieb, H.E. and Hagaman, E.W. 13C-NMR. Spectroscopy of naturally occurring substances. XLV. Iboga alkaloids. Helv. Chim. Acta, 1976, 59: 2437-42.

11 Lotsof, H.S. Ibogaine in the treatment of chemical depencency disorders: clinical perspectives. Bull.MAPS, 1995, 5: 16-27.

12 Lotsof, H.S. Rapid method for interrupting or attenuating poly-drug dependency syndromes. U. S. Patent, 1992, 5,152,994:

13 Lotsof, H.S. Rapid method for interrupting or attenuating the nicotine/tobacco dependency syndrome. U. S. Patent, 1991, 5,026,697:

14 Lotsof, H.S. Rapid method for attenuating the alcohol dependency syndrome. U. S. Patent, 1989, 4,857,523:

15 Lotsof, H.S. Rapid method for interrupting the cocaine and amphetamine abise syndrome. U. S. Patent, 1986, 4,587,243:

16 Lotsof, H.S. Rapid method for interrupting the narcotic addiction syndrome. U. S. Patent, 1985, 4,499,096:

17 Kaplan, C.D., Ketzer, E., de Jong, J. and de Vries, M. Reaching a state of wellness: Multistage explorations in social neuroscience. Social Neuroscience Bulletin, 1993, 6: 6-7.

18 Sisko, B. Interrupting drug dependency with ibogaine: A summary of four case histories. Bull.MAPS, 1993, IV: 15-24.

19 Sheppard, S.G. A preliminary investigation of ibogaine: Case reports and recommendations for further study. Journal of Substance Abuse Treatment, 1994, 11(4): 379

20 Stecher, P.G., Windholz, M. and Leahy, D.S. The Merck Index. An Encyclopedia of Chemicals and Drugs. Merck & Co., Inc. Rahway, N.J.,USA, 1968, pp. 1-1713.

21 Trujillo, K.A. and Akil, H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science, 1991, 251: 85-7.

22 Rasmussen, K., Fuller, R.W., Stockton, M.E., Perry, K.W., Swinford, R.M. and Ornstein, P.L. NMDA receptor antagonists suppress behaviors but not norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal. Eur. J. Pharmacol. 1991, 197: 9-16.

23 Cappendijk, S.L., de Vries, R. and Dzoljic, M.R. Excitatory amino acid receptor antagonists and naloxone-precipitated withdrawal syndrome in morphine-dependent mice. Eur. Neuropsychopharmacol, 1993, 3: 111-6.

24 Trujillo, K.A. and Akil, H. Excitatory amino acids and drugs of abuse: a role for N-methyl-D-aspartate receptors in drug tolerance, sensitization and physical dependence. Drug and Alcohol Dependence, 1995, 38: 139-54.

25 Popik, P., Layer, R.T., Fossom, L., Benveniste, M., Getter-Douglas, B., Witkin, J.M. and Skolnick, P. NMDA antagonist properties of the putative anti-addictive drug, ibogaine. The Journal of Pharmacology and Experimental Therapeutics, 1995, 275: 753-60.

26 Sweetnam, P.M., Lancaster, J., Snowman, A., Collins, J., Perschke, S., Bauer, C. and Ferkany, J. Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine's putative anti-addictive activity. Psychopharmacology, 1995, 118: 369-76.

27 Deecher, D.C., Teitler, M., Soderlund, D.M., Bornmann, W.G., Kuehne, M.E. and Glick, S.D. Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. Brain Res. 1992, 571: 242-7.

28 Pearl, S.M., Herrickdavis, K., Teitler, M. and Glick, S.D. Radioligand - binding study of noribogaine, a likely metabolite of ibogaine. Brain Res. 1995, 675: 342-4.

29 Glick, S.D., Maisonneuve, I.M., Raucci, J. and Archer, S. Kappa opioid inhibition of morphine and cocaine self-administration in rats. Brain Res. 1995, 681: 147-52.

30 Funada, M., Suzuki, T., Narita, M., Misawa, M. and Nagase, H. Blockade of morphine reward through the activation of kappa-opioid receptors in mice. Neuropharmacology, 1993, 32: 1315-23.

31 Suzuki, T., Shinozaki, H., Masukawa, Y., Misawa, M. and Nagase, H. The role of mu- and klappa-opioid receptors in cocaine-induced conditioned place preference. Japanese Journal of Pharmacology, 1992, 58: 435-42.

32 Shippenberg, T.S., LeFevour, A. and Heidbreder, C.A. k-Opioid receptor agonists prevent sensitization to the condition rewarding effects of cocaine. The Journal of Pharmacology and Experimental Therapeutics, 1996, 273: 545-54.

33 Glick, S.D., Maisonneuve, I.M., Pearl, S.M., Mann, G.S. and Visker, K.E. Mechanism of action of ibogaine: interaction between kappa agonist and NMDA antagonist effects. NIDA Res. Monogr. 1996, (in press)

34 Haertzen, C. Subjective effects of narcotic antagonists. In M.C. Braude, L.S. Harris, E.L. May, J.P. Smith and J.E. Villarreal (Eds.) Narcotic antagonists. Raven Press, New York, 1974, pp. 383-398.

35 Snyder, S.H. Neurotransmitters and CNS disease. Schizophrenia. Lancet, 1982, 2: 970-4.

36 Popik, P., Layer, R.T. and Skolnick, P. 100 years of ibogaine: Neurochemical and pharmacological actions of a putative anti-addictive drug. Pharmacological Reviews, 1995, 47: 235-53.

37 Mach, R.H., Smith, C.R. and Childers, S.R. Ibogaine possesses a selective affinity for sigma(2) receptors. Life Sci. 1995, 57: PL57-62.

38 Dhahir, H.I. A comparative study of the toxicity of ibogaine and serotonin. Dissertation Abstracts International, 1971, 32/04-B: 2311

39 Zetler, G., Singbarth, G. and Schlosser, L. Cerebral pharmacokinetics of tremor-producing harmala and iboga alkaloids. Pharmacology, 1972, 7: 237-48.

40 Gallagher, C.A., Hough, L.B., Keefner, S.M., Seyed Mozaffari, A., Archer, S. and Glick, S.D. Identification and quantification of the indole alkaloid ibogaine in biological samples by gas chromatography-mass spectrometry. Biochemical Pharmacology, 1995, 49: 73-9.

41 Hough, L.B., Pearl, S.M. and Glick, S.D. Tissue distribution of ibogaine after intraperitoneal and subcutaneous administration. Life Sci. 1996, 58: PL119-22.

42 Mash, D., Staley, J.K., Baumann, M.H., Rothman, R.B. and Hearn, W.L. Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. Life Sciences, 1995, 57: PL45-50.

43 Pearl, S.M., Hough, L.B., Boyd, D.L. and Glick, S.D. Sex differences in ibogaine antagonism of morphine and ibogaine brain levels. NIDA Res. Monogr. 1996, (in press)

44 Jackson, J., Carter, A., Mash, D.C., Rothman, R.B. and Baumann, M.H. Neuroendocrine and behavioral actions of ibogaine and its metabolite 12-hydroxyibogamine. NIDA Res. Monogr. 1996, (in press)

45 Glick, S.D., Pearl, S.M., Cai, J. and Maisonneuve, I.M. Ibogaine-like effects of noribogaine in rats. Brain Res. 1996, 713: 294-7.

46 Layer, R.T., Skolnick, P., Bertha, C.M., Kuehne, M.E. and Popik, P. Modification of the expression of morphine dependence by ibogaine derivatives: relation to NMDA antagonist actions. Eur. J. Pharmacol. 1996, 309: 159-65.

47 Delourme-Houde, J. Contribution a l'etude de l'iboga [Tabernanthe Iboga H. Bn]. Ann. Pharm. Fr. 1946, 4: 30-6.

48 Sanchez-Ramos, J. and Mash, D. Ibogaine research update: Phase I human study. Bull.MAPS, 1994, 4: 11

49 O'Hearn, E. and Molliver, M.E. Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Neuroscience, 1993, 55: 303-10.

50 Molinari, H.H., Maisonneuve, I.M. and Glick, S.D. Dose dependence of ibogaine neurotoxicity. Soc. Neurosci. Abstr. 1994 20(1) 1236

51 Molinari, H.H., Maisonneuve, I.M. and Glick, S.D. Neurotoxicity of ibogaine: a re-evaluation. Brain Res. 1996, (in press)

52 Popik, P. Facilitation of memory retrieval by the "anti-addictive" alkaloid, ibogaine. Life Sciences, 1996, (in press)

53 Sershen, H., Hashim, A., Harsing, L. and Lajtha, A. Ibogaine antagonizes cocaine-induced locomotor stimulation in mice. Life Sciences, 1992, 50: 1079-86.

54 Maisonneuve, I.M., Rossman, K.L., Keller, R.W., Jr. and Glick, S.D. Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats. Brain Res. 1992, 575: 69-73.

55 Kesner, R.P., Jackson-Smith, P., Henry, C. and Amann, K. Effects of ibogaine on sensory - motor function, activity and spatial learning in rats. Pharmacology Biochemistry and Behavior, 1995, 51: 103-9.

56 Singbarth, G., Zetler, G. and Schlosser, L. Structure-activity relationship of intracerebrally injected tremorigenic indole alkaloids. Neuropharmacology, 1973, 12: 239-44.

57 Cappendijk, S.L.T. and Dzoljic, M.R. Inhibitory effects of ibogaine on cocaine self-administration in rats. Eur. J. Pharmacol. 1994, 241: 261-5.

58 Sershen, H., Hashim, A. and Lajtha, A. Ibogaine reduces preference for cocaine consumption in C57BL/6By mice. Pharmacology Biochemistry and Behavior, 1994, 47(1): 13-9.

59 Glick, S.D., Kuehne, M.E., Raucci, J., Wilson, T.E., Larson, D., Keller, R.W. and Carlson, J.N. Effects of iboga alkaloids on morphine and cocaine self-administration in rats - relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Res. 1994, 657: 14-22.

60 Sershen, H., Harsing, L.G., Jr., Hashim, A. and Lajtha, A. Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats. Life Sciences, 1992, 51: 1003-11.

61 Maisonneuve, I.M., Keller, R.W., Jr. and Glick, S.D. Interactions of ibogaine and D-amphetamine: in vivo microdialysis and motor behavior in rats. Brain Res. 1992, 579: 87-92.

62 Glick, S.D., Gallagher, C.A., Hough, L.B., Rossman, K.L. and Maisonneuve, I.M. Differential effects of ibogaine pretreatment on brain levels of morphine and (+)-amphetamine. Brain Res. 1992, 588: 173-6.

63 Maisonneuve, I.M. and Glick, S.D. Interactions between ibogaine and cocaine in rats: in vivo microdialysis and motor behavior. Eur. J Pharmacol, 1992, 212: 263-6.

64 Glick, S.D., Rossman, K., Wang, S., Dong, N. and Keller, R.W., Jr. Local effects of ibogaine on extracellular levels of dopamine and its metabolites in nucleus accumbens and striatum: Interactions with D-amphetamine. Brain Res. 1993, 628: 201-8.

65 Broderick, P.A., Phelan, F.T. and Berger, S.P. Ibogaine alters cocaine-induced biogenic amine and psychostimulant dysfunction but not [³H]GBR-12935 binding to the dopamine transporter protein. In L. Harris (Ed.) NIDA Research Monograph No. 119. Problems of Drug Dependence, U.S. Government Printing Office, Washington, D.C. 1992, pp. 285

66 Broderick, P.A., Phelan, F.T., Eng, F. and Wechsler, R.T. Ibogaine modulates cocaine responses which are altered due to environmental habituation - in vivo microvoltammetric and behavioral studies. Pharmacology Biochemistry and Behavior, 1994, 49: 711-28.

67 Glick, S.D., Rossman, K., Steindorf, S., Maisonneuve, I.M. and Carlson, J.N. Effects and aftereffects of ibogaine on morphine self-administration in rats. Eur. J. Pharmacol. 1991, 195: 341-5.

68 Dworkin, S.I., Gleeson, S., Meloni, D., Koves, T.R. and Martin, T.J. Effects of ibogaine on responding maintained by food, cocaine and heroin reinforcement in rats. Psychopharmacology, 1995, 117: 257-61.

69 Dzoljic, E.D., Kaplan, C.D. and Dzoljic, M.R. Effect of ibogaine on naloxone precipitated withdrawal syndrome in chronic morphine dependent rats. Arch. Int. Pharmacodyn. 1988, 294: 64-70.

70 Aceto, M.D., Bowman, E.R. and Harris, L.S. Dependence studies of new compounds in the rhesus monkey, rat and mouse. NIDA Res. Monogr. 1990, 95: 578-631.

71 Glick, S.D., Rossman, K., Rao, N.C., Maisonneuve, I.M. and Carlson, J.N. Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor. Neuropharmacology, 1992, 31: 497-500.

72 Rezvani, A.H., Overstreet, D.H. and Leef, Y.W. Attenuation of alcohol intake by ibogaine in three strains of alcohol-preferring rats. Pharmacol. Biochem. Behav. 1995, 52: 615-20.

73 Benwell, M.E.M., Holtom, P.E., Moran, R.J. and Balfour, D.J.K. Neurochemical and behavioural interactions between ibogaine and nicotine in the rat. Br J. Pharmacol. 1996, 117: 743-9.

74 Rezvani, A.H., Mash, D., Overstreet, D.H., Hearn, W.L. and Lee, Y.W. Suppressing effect of 12-hydroxyibogamine, the primary metabolite of ibogaine, on alcohol intake in rats. Alcoholism - Clinical and Experimental Research, 1995, 19: 15A

75 Naranjo, C. Psychotropic properties of the harmala alkaloids. In AnonymousEthnopharmacologic search for psychoactive drugs, U.S. Public Health Service Publication 1645. Washington,D.C. Government Printing Office, 1967, pp. 385

76 Naranjo, C. The healing journey. New approaches to consciousness. N.Y.Pantheon, New York, 1973,

77 Repke, D.B., Artis, D.R., Nelson, J.T. and Wong, E.H. Abbreviated ibogaine congeners. Synthesis and rections of tropan-3-yl-2-and-3-indoles. Investigation of an unusual isomerization of 2-substituted indoles using computational and spectroscopic techniques. Journal of Organic Chemistry, 1994, 59(8): 2164-71.

78 Codd, E.E. High affinity ibogaine binding to a mu opioid agonist site. Life Sci. 1995, 57: PL315-20.

79 Popik, P., Layer, R.T. and Skolnick, P. The putative anti-addictive drug ibogaine is a competitive inhibitor of [³H]MK-801 binding to the NMDA receptor complex. Psychopharmacology, 1994, 114: 672-4.

80 Whitaker, P.M. and Seeman, P. Hallucinogen binding to dopamine / neuroleptic receptors. J. Pharm. Pharmacol. 1977, 29: 506-7.

81 Bowen, W.D., Vilner, B.J., Williams, W., Bertha, C.M., Kuehne, M.E. and Jacobson, A.E. Ibogaine and its congeners are sigma(2) receptor-selective ligands with moderate affinity. Eur. J. Pharmacol. 1995, 279: R1-3.

Figure 1.

Figure 2.

Mice were rendered morphine dependent and withdrawal was precipitated with naloxone, as described (46). The number of jumps was recorded during a 10 min test. Asterisk denote significant (p<0.05) effect toward placebo treatment. Data partially presented in (46).