The ibogaine medical subculture
Introduction
Ibogaine is the most studied of the iboga alkaloids (Bartlett et al., 1958), a group of naturally occurring and synthetic indole alkaloids, some of which reportedly reduce opioid withdrawal symptoms and drug self-administration in humans (Luciano, 1998, Alper et al., 1999, Mash et al., 2001) or preclinical models (Glick et al., 2001). Presently in the setting of homes, hotel rooms and private clinics in North America and Europe, individuals in increasing numbers are taking ibogaine in what has been termed “a vast uncontrolled experiment” (Vastag, 2005).
The ritual eating of iboga has been a psychopharmacological sacrament in the Bwiti religion for several centuries, and was likely practiced among Pygmies in much earlier times (Fernandez, 1982). In Gabon and elsewhere in West Central Africa, ibogaine is ingested in the form of scrapings of Tabernanthe iboga root bark. The ritual aim of eating iboga has been conceptualized as “binding”; the binding across time through ancestral contact, or binding participants socially on the basis of a common shared experience of a distinctive consciousness and system of belief (Fernandez, 1982, Fernandez and Fernandez, 2001). In the colonial era Bwiti became a context of collective psychological resistance to the anomie and demoralization related to the strain on indigenous community and family institutions. Bwiti offered a dignified realm of spiritual endeavor, “the work of the ancestors” and social cohesion. Following Gabonese independence in 1960, Bwiti has remained constellated with national identity and contemporarily retains significant social and political importance (Swiderski, 1988, Samorini, 1995).
Iboga has not commonly been used to treat addiction in the traditional African Bwiti context. Iboga has been sought as a treatment for some somatic conditions, in particular for infertility (Fernandez, 1982). In the colonial era the indigenous community experienced a crisis due to a sharp decline in fertility caused by venereal disease stemming from prostitution and the separation of men from their families by the large-scale physical relocation of indigenous workers. The possibility of an objective basis for the use of iboga in this setting is suggested by evidence associating iboga alkaloids with antimicrobial activity or effects on cell-mediated immunity. Iboga alkaloids are reportedly active against Candida albicans in the intact animal (Yordanov et al., 2005). In vitro studies indicate reversal of multidrug resistance in human cancer cells (Kam et al., 2004) and activity against Mycobacterium tuberculosis (Rastogi et al., 1998), human immunodeficiency type 1 virus (Silva et al., 2004), and the tropical parasite Leishmania amazonensis (Delorenzi et al., 2002).
The first observation of ibogaine as treatment for substance-related disorders in 1962 involved a network of lay drug experimenters who ingested a variety of hallucinogens and systematically recorded their experiences (Lotsof and Alexander, 2001). Withdrawal symptoms were unexpectedly absent in heroin-dependent individuals who had taken ibogaine. Common to various sociological definitions of the term “subculture” is a system of beliefs, norms and values apart from a superordinate culture (Clarke, 1974, Dowd and Dowd, 2003). The ibogaine subculture has elicited wariness from the “superordinate culture” of conventional clinical medicine (Kleber, 2001), and has been invoked regarding the null hypothesis that ibogaine's reported effect in opioid withdrawal is not pharmacologically mediated, but is instead accounted for by suggestion and ritual (Sharpe and Jaffe, 1990). The ibogaine subculture is also significant as the setting of case report evidence that influenced the decision of the National Institute on Drug Abuse (NIDA) to pursue its ibogaine project (Alper, 2001), and the Food and Drug Administration (FDA) to approve a clinical trial (Mash et al., 1998).
Ibogaine is unscheduled in most of the world, with the exception of the US, Belgium, Denmark, France, Sweden, Switzerland, and Australia where it is illegal. Ibogaine has not been popular as a recreational drug regardless of its legal status (Kleber, 2001), and apparently only two arrests involving ibogaine are known to have occurred in the US (Ranzal, 1967, Lane, 2005). Iboga alkaloids reportedly are not self-administered, and do not produce withdrawal signs following chronic administration in animals (Aceto et al., 1992). As of late 2006, ibogaine hydrochloride (HCl) was available for $400–$500 USD per gram (ethnogarden.com, 2006), and the dosage typically used for opioid withdrawal is in the range of 1–2 g. Purity on the order of 97–98% has been reported on certificates of analysis for supplies of ibogaine HCl used in the subculture. Ibogaine is also available as Tabernanthe iboga extract or dried root bark.
Ibogaine, either as Tabernanthe iboga root bark or ibogaine HCl is the only iboga alkaloid that has reportedly been administered to humans, with apparently only one exception, a study in which 12 normal volunteers were evaluated with some brief neuropsychological tests after receiving the naturally occurring iboga alkaloid ibogaline (Schmid, 1967). Ibogaine HCl has been typically administered as a single oral dose in the range of 10–25 mg/kg of body weight. Patients physically dependent on opioids have described significant attenuation of withdrawal symptoms within several hours of ingesting ibogaine, with subsequently sustained resolution of the opioid withdrawal syndrome (Alper et al., 1999, Mash et al., 2001). The advantages attributed to ibogaine are higher tolerability relative to other standard treatments for acute opioid withdrawal, and an interval of diminished drug craving that may last days to months following a treatment. Individuals also take ibogaine in search of psychological or religious insight, typically at dosages lower than those used in the treatment of opioid withdrawal.
There are no randomized controlled clinical trials of ibogaine, and the available clinical data is limited mainly to two open label case series. One series from the US and the Netherlands included self-reported outcomes of a consecutive series of 52 treatments involving 41 different individuals, some of who were treated on multiple occasions mainly for the indication of dependence on opioids or stimulants (Alper, 2001). Thirty-six percent of the treatments were associated with self-reported intervals of 6 months or longer of abstinence from the primary drugs of dependence for which treatment had been sought. A subset of 33 individuals were treated for the indication of opioid withdrawal with a single dose of ibogaine averaging 19.3 mg/kg (Alper et al., 1999). Twenty-five of these patients had full resolution of opioid withdrawal without drug seeking behavior that was sustained throughout a 72-h period of post-treatment observation, and another four individuals denied withdrawal symptoms but expressed their preference to continue to use heroin. The other series, from a clinic in St. Kitts consists of 32 patients treated with a fixed dose of 800 mg of ibogaine HCl for the indication of withdrawal from heroin (Mash et al., 2001). Physician-rated structured instruments indicated resolution of withdrawal signs and symptoms at 24 h after the last use of opioids (an interval of abstinence commonly associated with significant withdrawal symptoms) that was sustained during subsequent observation for 1 week following ibogaine administration.
An unpublished Dutch doctorandus thesis (Bastiaans, 2004) presents data obtained from 21 subjects who responded to a Web-based questionnaire adapted from the European Addiction Severity Index a mean of 21.8 months after they had taken ibogaine for treatment of a substance-related disorder. Seventeen of the 21 patients (81%) identified opioids as the primary drug of dependence for which they had sought treatment. Five individuals reported stopping the use of all substances following treatment with ibogaine, and another nine reported stopping the use of their primary drug while continuing to use alcohol or cannabis. Nineteen patients reported stopping their use of their primary drug for at least a week following treatment, suggesting frequent resolution of acute opioid withdrawal.
Research utilizing animal models has involved the iboga alkaloids ibogaine (Alper, 2001) and its desmethylated metabolite noribogaine (Baumann et al., 2001), and a synthetic congener, 18-methoxycoronaridine (18-MC) (Maisonneuve and Glick, 2003). Eleven of the 13 published preclinical studies of iboga alkaloids in opioid withdrawal indicate a significant attenuation of opioid withdrawal signs in the rat (Dzoljic et al., 1988, Sharpe and Jaffe, 1990, Maisonneuve et al., 1991, Glick et al., 1992, Cappendijk et al., 1994, Rho and Glick, 1998, Parker et al., 2002, Panchal et al., 2005), mouse (Frances et al., 1992, Popik et al., 1995, Layer et al., 1996, Leal et al., 2003), and primate (Aceto et al., 1992). Iboga alkaloids are also reported to reduce the self-administration of morphine (Glick et al., 1991, Glick et al., 1994, Glick et al., 1996, Maisonneuve and Glick, 1999, Pace et al., 2004), cocaine (Cappendijk and Dzoljic, 1993, Glick et al., 1994), amphetamine (Maisonneuve et al., 1992), methamphetamine (Glick et al., 2000, Pace et al., 2004), alcohol (Rezvani et al., 1995, Rezvani et al., 1997, He et al., 2005) and nicotine (Glick et al., 1998, Glick et al., 2000), and to diminish dopamine efflux in the nucleus accumbens (NAc), which is regarded as a correlate of drug salience (Berridge, 2007), in response to opioids (Maisonneuve et al., 1991, Glick et al., 1994, Glick et al., 2000, Taraschenko et al., 2007b) or nicotine (Benwell et al., 1996, Maisonneuve et al., 1997, Glick et al., 1998).
Initially, ibogaine's mechanism of action was hypothesized to involve antagonism at the N-methyl-d-aspartate-type glutamate (NMDA) receptor (Skolnick, 2001). However, 18-MC, which has negligible NMDA receptor affinity, also reduces opiate withdrawal and drug self-administration in the animal model (Glick et al., 2001). Antagonism of the α3β4 nicotinic acetylcholine receptor (nAChR) is a possible mechanism of action, as indicated by a series of studies of iboga alkaloids and nicotinic agents (Fryer and Lukas, 1999, Glick et al., 2002a, Glick et al., 2002b, Pace et al., 2004, Taraschenko et al., 2005). The α3β4 nAChR is relatively concentrated in the medial habenula and interpeduncular nucleus, where 18-MC's antagonism of α3β4 nAChRs diminishes sensitized dopamine efflux in the NAc (Taraschenko et al., 2007a, Taraschenko et al., 2007b).
Ibogaine's mechanism of action has frequently been suggested to involve the modification of neuroadaptations related to prior drug exposure (Rabin and Winter, 1996b, Popik and Skolnick, 1998, Alper, 2001, Glick et al., 2001, Sershen et al., 2001, Levant and Pazdernik, 2004). Ibogaine may modulate intracellular signaling linked to opioid receptors, and potentiates the morphine-induced inhibition of adenylyl cyclase (AC) (Rabin and Winter, 1996b), an effect that is opposite to the activation of AC that is classically associated with opioid withdrawal (Sharma et al., 1975). In animals, ibogaine enhances the antinociceptive effect of morphine or other μ opioids without by itself having an effect on nociception (Schneider and McArthur, 1956, Schneider, 1957, Frances et al., 1992, Bagal et al., 1996), and inhibits the development of tolerance to morphine antinociception (Cao and Bhargava, 1997). Prior exposure to morphine potentiates ibogaine's diminution of sensitized dopamine efflux in the NAc in response to morphine (Pearl et al., 1996) or ibogaine's enhancement of morphine antinociception (Sunder Sharma and Bhargava, 1998), suggesting an effect on neuroadaptations related to opioid tolerance or dependence.
Increased glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area has been suggested to mediate decreased ethanol consumption following the administration of ibogaine to rats (He et al., 2005, He and Ron, 2006). GDNF enhances the regeneration of dopaminergic function (Ron and Janak, 2005) and is increased by antidepressant treatment (Hisaoka et al., 2007). The hypothesis that GDNF may mediate improvement in hedonic functioning and mood in chronic withdrawal from addictive substances is appealing, but does not appear likely to explain efficacy in acute opioid withdrawal.
Although designated as a hallucinogen, ibogaine's use in opioid withdrawal distinguishes it from other compounds that are commonly termed “psychedelics”, namely the serotonin type 2A receptor agonist classical hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and mescaline, or the serotonin releasing substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA). In contrast with ibogaine, there is no preclinical or case report evidence that suggests a significant therapeutic effect of classical hallucinogens or MDMA in acute opioid withdrawal. Ibogaine's effects in opioid withdrawal do not appear to involve serotonin agonist or releasing activity (Wei et al., 1998, Glick et al., 2001). Serotonergic neurotransmission does not appear to play a significant role in mediating the expression of the opioid withdrawal syndrome, which remains unchanged even after extensive lesioning of the raphe (Caille et al., 2002).
The phenomenology of the subjective state produced by ibogaine has been attributed with the quality of a “waking dream” and distinguished from the state associated with classical hallucinogens (Goutarel et al., 1993, Lotsof and Alexander, 2001). The visual phenomena associated with ibogaine tend to occur with greatest intensity with the eyes closed, and to be suppressed with the eyes open, and often involve a sense of location within an internally represented visual or dream landscape, in contrast to an alteration of the visual environment experienced with the eyes open while awake which is often reported with classical hallucinogens. The occurrence of an atropine-sensitive electroencephalogram (EEG) rhythm in animals treated with ibogaine (Schneider and Sigg, 1957, Depoortere, 1987) suggests a waking neurophysiological state with an analogy to rapid eye movement sleep (Goutarel et al., 1993, Alper, 2001).
A previous publication provides a history and description of the ibogaine subculture in the U.S. and Europe from its origin in 1962 until early 2001 (Alper et al., 2001). The major objectives of this study are the qualitative analysis of observational and textual data (Bailey, 1994, Malterud, 2001) to provide an updated description as well as a typology of the ibogaine medical subculture, and the systematic collection of quantitative data regarding treatment and the purpose for which individuals took ibogaine.
Section snippets
Methods
The Institutional Review Board of the New York University School of Medicine approved this research.
Typology
As indicated in Table 1, four types of scenes were identified and classified on the basis of the features of treatment setting, provider credentials and provider set; “medical model”, “lay provider/guide”, “activist/self-help” and “religious/ceremonial”.
A medical subculture, distinct from other drug subcultures
The clinical focus on the treatment of opioid withdrawal distinguishes the ibogaine subculture from subcultures associated with psychedelic or other illegal drugs. The reason for taking ibogaine was more frequently to alleviate the symptoms of opioid withdrawal than to pursue spiritual or psychological goals. In the US, the expansion of the ibogaine subculture coincides temporally with a substantial increase in the public health impact of opioid use disorders (Compton and Volkow, 2006). The
Conclusions
The estimated number of participants in the ibogaine subculture increased fourfold relative to the prior estimate of 5 years earlier, an average yearly rate of growth of approximately 30%. The existence and expansion of the subculture indicates a demand for new treatment, which is sought regardless of medical risk, inconvenience, expense, and in some cases legal prohibition. Across a diversity of settings, most individuals who took ibogaine did so for the treatment of a substance-related
Conflict of interest statement
We declare that we have no conflict of interest. Howard Lotsof was awarded multiple patents on the use of ibogaine in substance-related disorders, which he divested in 1998.
Acknowledgements
The authors gratefully acknowledge Geoffrey Cordell, Ph.D., James W. Fernandez, Ph.D., Renate L. Fernandez, Ph.D., Marc Galanter, M.D., and Stephen Sifaneck, Ph.D. for their review and helpful comments regarding this paper.
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