Introduction and History

Banzie (the members of the Bwiti, properly, "those of the chapel") ... say that eboga [sic] enables a man or woman to return to infancy and to birth - to life in the womb ... by returning initiates to the uterine condition, a condition in any case very close to life in the land of the dead [and so] restores them to their own integrity - their pristine conditions. (Fernandez, 1982).

     Ibogaine is a naturally occurring indole alkaloid found in a variety of tropical shrubs of the Tabernanthe genus, the most well known of which is Tabernanthe iboga (Shulgin and Shulgin, 1977). In the western world, extracts of iboga root, which contain some 12 known active alkaloids, including ibogaine, have been used medicinally for over a century (Popik, and Skolnick, 1999). Ibogaine was first extracted from the iboga root in 1901 by Dybowsky and Landrin (Goutarel, Gollnhofer, and Sillans, 1993), though its chemical structure was not determined until 1957 (Taylor, 1965). Complete synthesis of ibogaine from nicotinamide is possible by way of a 13 or 14 step process; however, this process is rarely used as a source of ibogaine, as extraction from the root is a considerably less work intensive means of obtaining the compound, and there are no known advantages to the synthetic method (Shulgin and Shulgin, 1977).
     The root of the Tabernathe iboga has been used for centuries by various indigenous cultures of western Africa, as first reported by French and Belgian explorers in the nineteenth century (Popik and Skolnick, 1999). Depending on the specific culture, the root is either chewed whole, or prepared in a mixture, with or without other psychoactive ingredients (Fernandez, 1982). These cultures use the iboga root as a catalyst for spiritual discovery, primarily involved in Bouti initiation rites. In these rites, the initiate must venture into the spiritual world, guided by those already initiated, in a complex ritual that is centred around the effects of ingestion of the iboga root. The effects of the ingested root propagate a voyage of self-discovery, which is heavily imbued with Jungian archetypes, involving a return to the womb and a journey through the domain of the tribal ancestors (Goutarel, Gollnhofer, and Sillans, 1993). Other preparations of the iboga root in smaller quantities are also used throughout western Africa as a stimulant, particularly before a hunt, and as an aphrodisiac (Lotsof, Della Sera, and Kaplan, 1995).
     Ibogaine was first introduced to the Western public in France in the 1930's, in the form of Lambarene, an extract of the Tabernathe manii plant. It was described as a mental and physical stimulant and contained about 8 mg of ibogaine (Popik and Skolnick, 1999). The drug was "...indicated in cases of depression, asthenia, in convalescence, infectious disease, [and] greater than normal physical or mental efforts by healthy individuals," and aroused a great deal of interest among post-war athletes. Eventually, Lambarene disappeared from the market, and the sale of ibogaine was prohibited in 1966 (Goutarel, Gollnhofer, and Sillans, 1993).
     In the 1960's, a Chilean psychiatrist named Claudio Naranjo began experiments to study the potential of ibogaine as a catalyst for the psychotherapeutic process. He found through case studies that, with a dosage range of between 3 and 5 mg/kg, ibogaine elicits an oneirogenic condition which facilitates long term memory retrieval and closure of unresolved emotional conflicts (Naranjo, 1974). The word "oneirogen" (from the Greek, meaning "dream") is used rather than "hallucinogen" in referring to ibogaine's psychological effects, because ibogaine is not truly psychomimetic; it does not produce loss of consciousness or any formal deterioration of thought (Goutarel, Gollnhofer, and Sillans, 1993). Naranjo noted, as did ethnographers who have studied the cultures of western Africa, that the imagery produced by ibogaine is largely Jungian in content. That is, it involves archetypes common to all humans, imagery that provides the basis for the human psyche. In a therapy session, this archetypal imagery is used as a medium for mitigating emotional insight in relation to memories most significant to the individual's condition (Naranjo, 1974). Indeed, from a psychological perspective, it would seem as though this relationship is likely to be a primary factor in ibogaine's therapeutic effects.
     Ibogaine was first reported to be effective in treating chemical addictions by H. S. Lotsof, when he introduced Endabuse (NIH 10567) (Popick and Glick 1996). He began studying the effects of ibogaine in treating individuals with addictive disorders with a series of focus group experiments in the early 1960's (Lotstof, Della Sera, and Kaplan, 1995). In 1985, Lotsof patented Endabuse for use in the interruption of opiate dependence disorders (U.S. patent 4,499,096), in 1986 for use in cocaine dependence disorders (U.S. patent 4,587,243), and in 1992 for poly-drug use dependence disorders (U.S. patent 5,152,994) (Lotsof, Della Sera, and Kaplan, 1995). Lotsof also developed a specific procedure for the use of Endabuse (aptly named the Lotsof ProcedureTM), which involves comprehensive short and long term physical, psychiatric, psychological, and social care of the patient (Lotsof, 1994).

Pharmacodynamics
     Ibogaine's physiological actions are particularly complex, and are still far from being fully understood. Structurally, ibogaine is a derivative of serotonin (Dhahir, 1971). It has specific affinities for many binding sites within the CNS, including NMDA (N-methyl-D-aspartate), kappa, opioid, sigma, and nicotinic receptors (Alper et al, 1999). It is known to act on many different neurotransmitter systems, sometimes in seemingly paradoxical ways (Popick and Glick, 1996), and does not appear to be a conventional dopamine or opioid agonist or antagonist or and amine uptake inhibitor (Alper et al, 1999). Noribogaine (12-hydroxyibogamine) is a metabolite of ibogaine created by the activity of liver enzymes, and is thought to be responsible for at least some of ibogaine's psychological effects, which goes to further complicate the study of ibogaine's pharmacodynamics (Mash et al, 2000).
     It has long been thought that dopaminergic pathways are involved in the reinforcement effects of addictive drugs, and ibogaine has been shown to have some unusual effects on this system. Ibogaine does not appear to affect binding at dopamine receptors, nor does it seem to consistently affect dopamine transport systems. However, under certain experimental conditions, ibogaine results in a reduction of dopamine concentrations and an increase in dopamine metabolites DOPAC (dihydroxyphenyl-acetic acid) and HVA (homovanilic acid) (Popick and Skolnik, 1999). Noribogaine is likely to be involved, at least in part, in ibogaine's dopaminergic effects, particularly that of reduced dopamine turnover for an extended period of time after administration; however, this relationship remains unclear (Mash et al, 2000).
     Like dopamine pathways, NDMA receptors have often been sighted as neural components implicated in addictive disorders. Ibogaine acts as an NDMA antagonist, a competitive inhibitor of [3H]MK-801 or [3H]TCP binding at receptor coupled NMDA ion channels (Sweetnam et al, 1995). In support of these findings, ibogaine produces a voltage dependent block of NDMA invoked currents in hippocampal cultures, and inhibits glutamate-induced cell death in neuronal cultures (Popik et al, 1995). NDMA antagonists acting at the glutamate, open channel, and glycine binding sites have been shown to suppress symptoms of morphine withdrawal in rodents, and attenuate drug self-administration (Trujillo and Akil, 1991).
     Ibogaine binds only mildly to opioid receptors, though its metabolite noribogaine has a considerably higher affinity for opioid receptor binding (Popick and Glick, 1996). Ibogaine has been reported not to affect [3H]carfentanil or [3H]enkephalin binding at mu or delta opioid receptors (Popick and Skolnick, 1999); however, Sweetnam et al (1995) demonstrated that it does inhibit radioligand binding to mu opioid receptors. In addition, ibogaine has been shown to inhibit other compounds from binding at opioid sites, including naloxone, an opioid antagonist (Popick and Skolnick, 1999). This may be related to the phenomena of reduced opiate withdrawal symptoms seen in addicts treated with ibogaine.
     As is the case with many tryptamines, ibogaine's effects on the serotonergic system are particularly complex. It has no effect on [3H]serotonin binding (Popick and Skolnick, 1999) and does not displace ligands acting at 5-HT1a, 5-HT1b, 5-HT1c, 5-HT1d, 5-HT2, or 5-HT3 receptors (Deecher et al, 1992). However, ibogaine does inhibit binding of 5-HT1a, 5-HT2a, and 5-HT3 ligands with low affinity (Repke et al) and inhibits radioligand binding to 5-HT2 and 5-HT3 receptors (Sweetnam et al, 1995). Furthermore, ibogaine's effects on the serotonergic system may have a role in its regulation of dopamine release (Popick and Skolnik, 1999). Clearly, there is need for much more research on ibogaine's effects on the serotonergic system, and on its pharmacodynamics in general.

Anti-addictive Properties
     As mentioned earlier, ibogaine was first introduced by H.S. Lotsof as an aide in breaking the addictive cycle. This claim has been supported by numerous empirical and clinical studies. Ibogaine has been shown to attenuate signs of morphine withdrawal in rats (jumping, rearing, digging, head hiding, chewing, teeth chattering, writhing, and penile licking), and to reduce self-administration of heroin, morphine, and cocaine (Glick, Rossman, and Steindorf, 1991). Similar results have been seen in experiments examining ibogaine's effects on morphine addicted rats and monkeys (Alper et al, 1999). Ibogaine has also been shown to reduce cocaine-induced motor stimulation in the mouse (Lotsof, Della Sera, and Kaplan, 1995).
     In humans, administration of ibogaine resulted in fewer self-reported cravings for both heroin and cocaine addicts, and reduced self-reported depressive symptoms (Mash et al, 2000). Sheppard (1994) found that ibogaine treatment seems to remove an addicted individuals desire to seek and use opiates, and that after treatment, several subjects who did use heroin again found the experience to be unsatisfying. Additionally, multiple reports have sighted that ibogaine reduces or eliminates opiate withdrawal symptoms within 1 to 2 hours with a complete resolution of symptoms within 24 to 48 hours (Alper et al, 1999). Judd (1994) observed that ibogaine has significant advantages over traditional treatment methods with respect to what she considers the three major obstacles in addiction treatment; fear of detoxification, lack of insight, and the inability of addicts to control their urges to use drugs.
     It is important to note that when using ibogaine in the treatment of addictive disorders, the methods involved are considerable different than those used in conventional addiction treatments. Often, only one treatment of ibogaine is necessary to break the addictive pattern, while sometimes multiple treatments are needed (Goutarel, Gollnhofer, and Sillans, 1993). In any case, ibogaine treatment involves a more intimate relationship between the patient and the clinician (or, more appropriately, the team of clinicians), involving a greater level of trust and compassion than is generally seen in typical addiction counselling (Lotsof, 1994). This is due to the deeply personal nature of the ibogaine experience, and the fact that at the dosage commonly used for addiction treatment ibogaine's psychotropic effects last approximately 24 - 38 hours (Sheppard, 1994).

Conclusion and Commentary
     Ibogaine represents a truly novel approach to the treatment of addictive disorders; one which involves a more holistic approach, involving simultaneous treatment from physiological, psychological, and even sociological perspectives. Though clinical research on this compound's anti-addictive properties is still in its infancy, at this stage there is significant evidence to suggest that ibogaine has the potential to address many obstacles that often prevent the successful treatment of addictions. As one patient stated, "ibogaine is a much more humane and dignified approach to detox [sic]" (Judd, 1994). If this notion proves to be true, ibogaine therapy would be a major step forward for addiction treatment, which at it's present state (particularly in the United States) is at best often ineffectual, and at worst seriously degrading to the addicted individual.
     This is not to insult the dedicated work of countless researchers and therapy providers, but is rather a statement to illustrate our current lack of understanding of the addictive process in general, and more specifically, the insurmountable difficulties that current approaches to addiction treatment inherently possess. With standard addiction treatment models, it typically takes 4 to 7 attempts on the part of the patient to reach sobriety, or even temporary abstinence ( Anderson, 1996). If ibogaine does prove to be safe and effective after further rigorous clinical investigations, and the previous findings are proven stable in their repeatability, ibogaine will truly represent the next step in the ever-present dilemma of the chemical addiction phenomenon.

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