IBOGAINE: A BRIEF HISTORY

INCLUDING RESEARCH CONDUCTED IN 1995 & 1996

Ibogaine, a naturally occurring alkaloid found in Tabernanthe iboga and other plant species of Central West Africa, was first reported to be effective in interrupting opiate narcotic dependence disorders in U.S. patent 4,499,096 (Lotsof, 1985); cocaine dependence disorders in U.S. patent 4.587,243 (Lotsof, 1986) and poly-drug dependence disorders in U.S. patent 5,152,994 (Lotsof, 1992). The initial studies demonstrating Ibogaine's effects on cocaine and heroin dependence were accomplished in a series of focus group experiments by H. S. Lotsof in 1962 and 1963. Additional data on the clinical aspects of Ibogaine in the treatment of chemical dependence were reported by Kaplan (1993), Sisko (1993), Sanchez-Ramos & Mash (1994), Sheppard (1994), Judd (1994) and Mash et al. (1995).

Prior to Ibogaine's evaluation for the interruption of various chemical dependencies, the use of Ibogaine was reported in psychotherapy by Naranjo (1969, 1973) and at the First International Ibogaine Conference held in Paris (Zeff, 1987). The use of Ibogaine-containing plants has been reported for centuries in West Africa in both religious practice and in traditional medicine (Fernandez, 1982; Gollnhofer & Sillans 1983, 1985) Overviews of the history of Ibogaine research and use were published by Goutarel et al. (1993) and Popik et al. (1995)

Claims of efficacy in treating dependencies to opiates, cocaine, and alcohol in human subjects were supported in preclinical studies by researchers in the United States, the Netherlands and Canada. Dzoljic et al. (1988) were the first researchers to publish Ibogaine's ability to attenuate narcotic withdrawal. Stanley D. Glick et al. (1992) at Albany Medical College published original research and a review of the field concerning the attenuation of narcotic withdrawal. Maisonneuve et al. (1991) determined the pharmacological interactions between Ibogaine and morphine, and Glick et al. (1992) reported Ibogaine's ability to reduce or interrupt morphine self-administration in the rat. Woods et al. (1990) found that Ibogaine did not act as an opiate, and Aceto et al. (1991) established that Ibogaine did not precipitate withdrawal signs or cause dependence.

Cappendijk and Dzoljic (1993) published Ibogaine's effect in reducing cocaine self-administration in the rat. Broderick et al. (1992) first published Ibogaine's ability to reverse cocaine-induced dopamine increases and later, on Ibogaine's reduction of cocaine-induced motor activity and other effects (1994). Broderick et al.'s research supported the findings of Sershen et al. (1992), that Ibogaine reduced cocaine-induced motor stimulation in the mouse. Sershen (1993) also demonstrated that Ibogaine reduced the consumption of cocaine in mice. Glick (1992) and Cappendijk (1993) discovered in the animal model that multiple administrations of Ibogaine over time were more effective than a single dose in interrupting or attenuating the self-administration of morphine and cocaine, supporting Lotsof's findings in human subjects (1985).

Popik et al. (1994) determined Ibogaine to be a competitive inhibitor of MK-801 binding to the NMDA receptor complex. Popik's findings were supported by Mash et al. (1995). MK-801 has been shown to attenuate tolerance to opiates (Trujillo & Akil 1991) and alcohol (Khanna et al. 1993). MK-801 has also shown a blockade of "reverse tolerance" of stimulants (Karler et al. 1989). Ibogaine's effects on dopamine, a substance hypothesized to be responsible for reinforcing pleasurable effects of drugs of abuse, and the dopamine system were found by Maisonneuve et al. (1991), Broderick et al. (1992) and Sershen et al. (1992). Ibogaine binding to the kappa opiate receptor was reported by Deecher et al. (1992). Both Ibogaine and its principal metabolite, desmethyl ibogaine were shown to target serotonin transporters and to elevate serotonin levels by Mash et al. (1995). The possibility of an endogenous substance that may mimic Ibogaine was suggested to be norharman by Cappendijk et al. (1994). Thus we begin to see a broad spectrum of mechanisms by which Ibogaine may moderate use of substances so diverse as opiate narcotics, stimulants and alcohol.

Studies not previously discussed have been accomplished concerning both Ibogaine and its principal metabolite desmethyl ibogaine (12-hydroxyibogamine or noribogaine) as well as, studies that have demonstrated the complexity of addiction via the interaction of various neurohormonal systems that are effected by Ibogaine or desmethyl ibogaine. Schechter and Gordon (1993) determined that Ibogaine from the three principal sources of the drug; Sigma Chemical, The National Institute on Drug Abuse and NDA International, Inc. (ENDABUSE, NIH 10567) would allow pre-clinical work using any research samples from the above suppliers to be comparable. Sershen et al. (1994) reviewed the effects of Ibogaine on serotonergic and dopaminergic interactions in the striatum of mice and rats and then (1995) published on Ibogaine actions on kappa opioid and 5-HT induced changes on dopamine release. Pearl et al. (1995), continuing research of the Albany Medical College Ibogaine working group published on the effects of prior morphine exposure to enhance Ibogaine's effects in reducing morphine-induced locomotor stimulation. Rezvani et al. demonstrated that Ibogaine would reduce alcohol intake in alcohol-preferring rats (1995) adding to previous pre-clinical demonstrations that Ibogaine would reduce the self-administration of opiates and cocaine thus supporting Lotsof's clinical findings that Ibogaine was effective for attenuating opiate, stimulant and alcohol self-administration. Hough et al. added significant understanding to the actions of Ibogaine in the publication of data on tissue distribution of Ibogaine from intraperitoneal and subcutaneous injections. The paper concluded that the persistence of the Ibogaine in fat may contribute to Ibogaine's long duration of action and that Ibogaine is subject to substantial "first pass" effect after IP dosing, but not after SC dosing. Responding to the concern of neurotoxicity in rats found by O'Hearn et al. (1993), Molinari et al. (1994) published that Ibogaine at therapeutic doses in the rat did not produce neurtoxicity, supporting Mash's (1995) data that Ibogaine did not demonstrate neurotoxicity from multiple administrations at therapeutic doses in monkeys or humans.

Concerning desmethyl ibogaine (noribogaine), Pearl et al. (1995) provided an important insight into the mechanisms of actions of that drug in a radioligand-binding study that showed desmethyl ibogaine to bind to all opiate receptors. Rezvani et al. (1995) published data showing noribogaine, like Ibogaine, to also reduce alcohol intake in rats. Inherent in a review of the papers herein discussed and in discussions with the researchers, a significant understanding of the actions and interrelated actions of ibogaine and noribogaine are provided.