Introduction

Ibogaine, a monoterpene indole alkaloid that occurs in the root bark of Tabernanthe iboga Baill., is used for the treatment of substance use disorders (SUDs) (1 Alper KR, Lotsof HS, Kaplan CD. The ibogaine medical subculture. J Ethnopharmacol 2008;115:9–24.,2 Brown TK. Ibogaine in the treatment of substance dependence. Curr Drug Abuse Rev 2013;6:3–16.). It has been associated with controversy, and the medical and nonmedical settings of ibogaine use have been collectively designated as a “vast uncontrolled experiment” (3 Vastag B. Addiction research. Ibogaine therapy: a ‘vast, uncontrolled experiment’. Science 2005;308:345–346.), or “medical subculture” (1 Alper KR, Lotsof HS, Kaplan CD. The ibogaine medical subculture. J Ethnopharmacol 2008;115:9–24.). Ibogaine has been classified as a hallucinogen and illegal in the US since 1967, and is similarly scheduled in 9 of the 28 countries presently in the European Union. It is unregulated, i.e., neither officially approved nor illegal in much of the rest of the world. New Zealand, Brazil, and South Africa have classified ibogaine as a pharmaceutical substance and restrict its use to licensed medical practitioners.

Ibogaine is used most frequently for detoxification from opioids. A previous study on the known settings of ibogaine use as of 2006 found that approximately 3,400 individuals had taken ibogaine, 68% of whom did so for the treatment of a substance-related disorder, and 53% specifically for opioid detoxification (1 Alper KR, Lotsof HS, Kaplan CD. The ibogaine medical subculture. J Ethnopharmacol 2008;115:9–24.). A substantive effect of ibogaine in opioid detoxification is reported in studies of 33 individuals treated in nonmedical settings with single mean dosages of 19.3 ± 6.9 mg/kg (4 Alper KR, Lotsof HS, Frenken GM, Luciano DJ, Bastiaans J. Treatment of acute opioid withdrawal with ibogaine. Am J Addict 1999;8:234–242.), and 32 individuals treated in a medical setting with fixed dosages of 800 mg (5 Mash DC, Kovera CA, Pablo J, Tyndale R, Ervin FR, Kamlet JD, Hearn WL. Ibogaine in the treatment of heroin withdrawal. Alkaloids Chem Biol 2001;56:155–171.). Unpublished data include a series of 53 treatment episodes that was presented to the National Institute on Drug Abuse (NIDA) and influenced NIDA’s decision to undertake an ibogaine project from 1991 to 1995 (6 Alper KR. Ibogaine: a review. Alkaloids Chem Biol 2001;56:1–38.), and an academic thesis on a Web-based survey of 21 individuals who had used ibogaine (7 Bastiaans E. Life after ibogaine: an exploratory study of the long-term effects of ibogaine treatment on drug addicts. Doctorandus thesis. Faculty of Medicine Vrije Universiteit Amsterdam 2004. URL https://www.iceers.org/docs/science/iboga/Bastiaans%20E_Life_After_Ibogaine.pdf (accessed April 11, 2017).). The subjects in these unpublished case series were predominantly opioid users, and ibogaine appeared to be effective in opioid detoxification, and about one-third of subjects reported abstinence from opioids for periods of 6 months or longer following treatment. A retrospective study on 75 subjects, a subset available from a group of 195 individuals who have been treated or cocaine dependence, almost none of whom used opioids, reported a median relapse-free interval of 5.5 months following single doses of ibogaine of 7.5 to 20 mg/kg (8 Schenberg EE, De Castro Comis MA, Chaves BR, Da Silveira DX. Treating drug dependence with the aid of ibogaine: a retrospective study. J Psychopharmacol 2014;28:993–1000.). Published follow-up regarding drug use outcomes beyond detoxification in opioid use disorder (OUD) has been limited to a small number of case reports (9 Cloutier-Gill L, Wood E, Millar T, Ferris C, Eugenia Socias M. Remission of severe opioid Use disorder with ibogaine: a case report. J Psychoactive Drugs 2016;48:214–217.–11 Lotsof HS, Alexander NE. Case studies of ibogaine treatment: implications for patient management strategies. Alkaloids Chem Biol 2001;56:293–313.).

Consistent with its apparent effect in opioid detoxification in humans, ibogaine administered intraperitoneally or intracerebrally to animals reduces naloxone- or naltrexone-precipitated opioid withdrawal signs, in rats (12 Dzoljic ED, Kaplan CD, Dzoljic MR. Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats. Arch Int Pharmacodyn Ther 1988;294:64–70.–15 Parker LA, Burton P, McDonald RV, Kim JA, Siegel S. Ibogaine interferes with motivational and somatic effects of naloxone-precipitated withdrawal from acutely administered morphine. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:293–297.), mice (16 Frances B, Gout R, Cros J, Zajac JM. Effects of ibogaine on naloxone-precipitated withdrawal in morphine-dependent mice. Fundam Clin Pharmacol 1992;6:327–332.–19 Popik P, Layer RT, Fossom LH, Benveniste M, Geterdouglass B, Witkin JM, Skolnick P. NMDA antagonist properties of the putative antiaddictive drug, ibogaine. J Pharmacol Exp Ther 1995;275:753–760.), and primates (20 Aceto MD, Bowman ER, Harris LS, May EL. Dependence studies of new compounds in the rhesus monkey and mouse (1991). NIDA Res Monogr 1992;119:513–558.,21 Koja T, Fukuzaki K, Kamenosono T, Nishimura A, Nagata R, Lukas SE. Inhibition of opioid abstinent phenomena by Ibogaine. 69th annual meeting of the Japanese Pharmacological Society, March 20–23, 1996. Jpn J Pharmacol 1996;71:89.). Single dosages of ibogaine administered to rodents diminish self-administration of multiple abused substances including morphine (22 Belgers M, Leenaars M, Homberg JR, Ritskes-Hoitinga M, Schellekens AF, Hooijmans CR. Ibogaine and addiction in the animal model, a systematic review and meta-analysis. Transl Psychiatry 2016;6:e826.–25 Glick SD, Pearl SM, Cai J, Maisonneuve IM. Ibogaine-like effects of noribogaine in rats. Brain Res 1996;713:294–297.), heroin (26 Dworkin SI, Gleeson S, Meloni D, Koves TR, Martin TJ. Effects of ibogaine on responding maintained by food, cocaine and heroin reinforcement in rats. Psychopharmacology (Berl) 1995;117:257–261.), cocaine (24 Glick SD, Kuehne ME, Raucci J, Wilson TE, Larson D, Keller RW Jr., Carlson JN. 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.,25 Glick SD, Pearl SM, Cai J, Maisonneuve IM. Ibogaine-like effects of noribogaine in rats. Brain Res 1996;713:294–297.,27 Maisonneuve IM, Glick SD. Interactions between ibogaine and cocaine in rats - invivo microdialysis and motor behavior. Eur J Pharmacol 1992;212:263–266.–29 Sershen H, Hashim A, Lajtha A. Ibogaine reduces preference for cocaine consumption in C57BL/6By mice. Pharmacol Biochem Behav 1994;47:13–19.), amphetamine (30 Maisonneuve IM, Keller RW Jr., Glick SD. Interactions of ibogaine and D-amphetamine: in vivo microdialysis and motor behavior in rats. Brain Res 1992;579:87–92.), and alcohol (31 Rezvani AH, Overstreet DH, Lee YW. Attenuation of alcohol intake by ibogaine in three strains of alcohol-preferring rats. Pharmacol Biochem Behav 1995;52:615–620.), with normal responding for water. A notable aspect of these self-administration studies has been the observation of a treatment effect of a duration of 48 to 72 hours averaged for the entire sample, with sustained effects for longer time intervals in individual animals. Both ibogaine and its synthetic structural analog 18-methoxycoronaridine (18-MC) diminish an experimental correlate of drug salience, the sensitized response of dopamine efflux in the nucleus accumbens in response to morphine (32 Maisonneuve IM, Keller RW Jr., Glick SD. Interactions between ibogaine, a potential anti-addictive agent, and morphine: an in vivo microdialysis study. Eur J Pharmacol 1991;199:35–42.,33 Maisonneuve IM, Glick SD. Attenuation of the reinforcing efficacy of morphine by 18-methoxycoronaridine. Eur J Pharmacol 1999;383:15–21.) and nicotine (34 Maisonneuve IM, Mann GL, Deibel CR, Glick SD. Ibogaine and the dopaminergic response to nicotine. Psychopharmacology (Berl) 1997;129:249–256.,35 Glick SD, Maisonneuve IM, Visker KE, Fritz KA, Bandarage UK, Kuehne ME. 18-Methoxycoronardine attenuates nicotine-induced dopamine release and nicotine preferences in rats. Psychopharmacology (Berl) 1998;139:274–280.).

The mechanism of action of ibogaine is apparently novel, and unexplained by the receptor interactions of medications known to have clinical effects in opioid tolerance or withdrawal (6 Alper KR. Ibogaine: a review. Alkaloids Chem Biol 2001;56:1–38.,36 Antonio T, Childers SR, Rothman RB, Dersch CM, King C, Kuehne M, Bornmann WG, et al. Effect of iboga alkaloids on μ-opioid receptor-coupled G protein activation. PlosOne 2013;8:e77262.,37 Glick SD, Maisonneuve IM, Szumlinski KK. Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener. Alkaloids Chem Biol 2001;56:39–53.). As a small molecule that modifies opioid withdrawal and drug self-administration, ibogaine may offer an interesting prototype for drug discovery and neurobiological investigation. Ibogaine, its major metabolite noribogaine, and 18-MC do not act as orthosteric μ opioid receptor (MOR) agonists. Although ibogaine, noribogaine, and 18-MC bind with low micromolar affinity to the MOR, these compounds do not activate G proteins assessed by the binding of [35S]GTPγS in cells expressing the MOR (36 Antonio T, Childers SR, Rothman RB, Dersch CM, King C, Kuehne M, Bornmann WG, et al. Effect of iboga alkaloids on μ-opioid receptor-coupled G protein activation. PlosOne 2013;8:e77262.), and the dosages of ibogaine used for detoxification in the setting of severe physical dependence do not produce signs of overdose in opioid-naïve individuals (1 Alper KR, Lotsof HS, Kaplan CD. The ibogaine medical subculture. J Ethnopharmacol 2008;115:9–24.).

Ibogaine potentiates morphine analgesia without producing analgesia when administered alone (16 Frances B, Gout R, Cros J, Zajac JM. Effects of ibogaine on naloxone-precipitated withdrawal in morphine-dependent mice. Fundam Clin Pharmacol 1992;6:327–332.,38 Schneider JA, McArthur M. Potentiation action of ibogaine (bogadin TM) on morphine analgesia. Experientia 1956;12:323–324.–43 Sunder Sharma S, Bhargava HN. Enhancement of morphine antinociception by ibogaine and noribogaine in morphine-tolerant mice. Pharmacology 1998;57:229–232.), as might be expected of an allosteric MOR agonist. However ibogaine, noribogaine, and 18-MC do not potentiate the activation of G proteins by morphine or DAMGO (36 Antonio T, Childers SR, Rothman RB, Dersch CM, King C, Kuehne M, Bornmann WG, et al. Effect of iboga alkaloids on μ-opioid receptor-coupled G protein activation. PlosOne 2013;8:e77262.), indicating that these compounds do not act as allosteric MOR agonists. The reversal by ibogaine of analgesic tolerance to chronic morphine suggests that ibogaine may modify neuroadaptations associated with chronic exposure to opioids (39 Schneider JA. Assigned to Ciba Pharmaceutical Products Inc. Summit NJ. Tabernanthine, Ibogaine Containing Analgesic Compostions. US Patent no. 2,817,623. 1957.,43 Sunder Sharma S, Bhargava HN. Enhancement of morphine antinociception by ibogaine and noribogaine in morphine-tolerant mice. Pharmacology 1998;57:229–232.,44 Pearl SM, Johnson DW, Glick SD. Prior morphine exposure enhances ibogaine antagonism of morphine-induced locomotor stimulation. Psychopharmacology (Berl) 1995;121:470–475.).

Ibogaine is an NMDA receptor antagonist (19 Popik P, Layer RT, Fossom LH, Benveniste M, Geterdouglass B, Witkin JM, Skolnick P. NMDA antagonist properties of the putative antiaddictive drug, ibogaine. J Pharmacol Exp Ther 1995;275:753–760.,45 Skolnick P. Ibogaine as a glutamate antagonist: relevance to its putative antiaddictive properties. Alkaloids Chem Biol 2001;56:55–62.), and NMDA antagonists such as memantine diminish signs of opioid withdrawal in preclinical models and humans (46 Trujillo KA, Akil H. Inhibition of opiate tolerance by non-competitive N-methyl-D-aspartate receptor antagonists. Brain Res 1994;633:178–188.,47 Bisaga A, Comer S, Ward A, Popik P, Kleber H, Fischman M. The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology (Berl) 2001;157:1–10.), however 18-MC lacks significant affinity for the NMDA receptor and is equally effective as ibogaine in animal models of opioid withdrawal (12 Dzoljic ED, Kaplan CD, Dzoljic MR. Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats. Arch Int Pharmacodyn Ther 1988;294:64–70.–15 Parker LA, Burton P, McDonald RV, Kim JA, Siegel S. Ibogaine interferes with motivational and somatic effects of naloxone-precipitated withdrawal from acutely administered morphine. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:293–297.,37 Glick SD, Maisonneuve IM, Szumlinski KK. Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener. Alkaloids Chem Biol 2001;56:39–53.,48 Panchal V, Taraschenko OD, Maisonneuve IM, Glick SD. Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine. Eur J Pharmacol 2005;525:98–104.,49 Rho B, Glick SD. Effects of 18-methoxycoronaridine on acute signs of morphine withdrawal in rats. Neuroreport 1998;9:1283–1285.). Ibogaine has no significant affinity for the α 2 receptor or imidazoline I 2 site (50 Deecher DC, Teitler M, Soderlund DM, Bornmann WG, Kuehne ME, Glick SD. Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. Brain Res 1992;571:242–247.,51 Sweetnam PM, Lancaster J, Snowman A, Collins JL, Perschke S, Bauer C, Ferkany J. Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity. Psychopharmacology (Berl) 1995;118:369–376.), indicating that it does not act as an imidazoline α 2 adrenergic receptor agonist such as clonidine (52 MacInnes N, Handley SL. Characterization of the discriminable stimulus produced by 2-BFI: effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine and ibogaine. Br J Pharmacol 2002;135:1227–1234.).

The enhanced expression of glial-derived neurotrophic factor (GDNF) has been proposed to account for ibogaine’s effect on drug self-administration (53 He DY, McGough NNH, Ravindranathan A, Jeanblanc J, Logrip ML, Phamluong K, Janak PH, Ron D. Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption. J Neurosci 2005;25:619–628.). Ibogaine increases the GDNF expression in vivo and in cultured cells, and 18-MC reportedly does not (54 Carnicella S, He DY, Yowell QV, Glick SD, Noribogaine RD. But not 18-MC, exhibits similar actions as ibogaine on GDNF expression and ethanol self-administration. Addict Biol 2010;15:424–433.), but both compounds are equally effective in animal models of drug self-administration (37 Glick SD, Maisonneuve IM, Szumlinski KK. Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener. Alkaloids Chem Biol 2001;56:39–53.). Ibogaine’s action as an allosteric antagonist of the α3β4 nicotinic acetylcholine receptor (nAChR) is suggested to mediate its effect on drug self-administration (55 Glick SD, Maisonneuve IM, Kitchen BA, Fleck MW. Antagonism of α3β4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. Eur J Pharmacol 2002;438:99–105.), but does not appear to readily explain the prolonged effects that appear to persist beyond pharmacokinetic elimination (56 Pearl SM, Hough LB, Boyd DL, Glick SD. Sex differences in ibogaine antagonism of morphine-induced locomotor activity and in ibogaine brain levels and metabolism. Pharmacol Biochem Behav 1997;57:809–815.). Ibogaine’s major metabolite, noribogaine (57 Baumann MH, Rothman RB, Pablo JP, Mash DC. In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats. J Pharmacol Exp Ther 2001;297:531–539.,58 Glue P, Lockhart M, Lam F, Hung N, Hung CT, Friedhoff L. Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability. J Clin Pharmacol 2015;55:189–194.) has a longer half-life than the parent compound, and has been suggested to account for persistence of effects on drug self-administration and withdrawal (59 Mash DC, Ameer B, Prou D, Howes JF, Maillet EL. Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents. J Psychopharmacol 2016;30:688–697.), although in the animal model the effect of ibogaine in reducing drug self-administration appears to persist beyond the elimination of ibogaine and noribogaine from serum or brain tissue (56 Pearl SM, Hough LB, Boyd DL, Glick SD. Sex differences in ibogaine antagonism of morphine-induced locomotor activity and in ibogaine brain levels and metabolism. Pharmacol Biochem Behav 1997;57:809–815.).

There are no published prospective studies of ibogaine in the treatment of OUD reporting on drug use outcomes subsequent to detoxification. This study reports on outcomes up to one year following opioid detoxification with ibogaine.