The Ibogaine Dossier
The Ibogaine Dossier

NYU Conference on Ibogaine Nov 5-6, 1999

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The Ibogaine Dossier

Ibogaine in Drug Detoxification

From Preclinical Studies to Clinical Trials

Deborah C. Mash, Ph.D.
Associate Professor of Neurology and Molecular and Cellular Pharmacology
University of Miami School of Medicine

Proceedings of the Symposium on Maturational Issues in Behavioral Disorders, University of Limburg, Maastricht, The Netherlands (1995)

Ibogaine is a rain forest alkaloid found in the root of Tabernanthe Iboga (Apocynaceae family), a shrub that grows in West Central Africa. Ibogaine is used by native peoples in low doses to combat fatigue, hunger and thirst and at high doses for its hallucinogenic properties in religious rituals. The role of iboga (Ibogaine and associated alkaloids) in Bwiti initiation ceremonies has been studied by ethnologists in Gabon. The intoxication of iboga is characterized by four stages: the first three have been described in Freudian terms, while the fourth stage reflects the tribe's collective unconsciousness and has some similarities to the near death experience (NDE) (taken from Goutarel, 1992). Discussion of the CNS and cardiovascular actions of Ibogaine appeared in the literature since the early 1900's. In the 1950's, CIBA Pharmaceutical Company investigated Ibogaine as an antihypertensive agent, but were unconvinced of its commercial potential. The anti-addictive properties of Ibogaine were reported by Howard Lotsof in 1982. An informal self-help network had been providing Ibogaine treatments to addicts in Europe since 1987 (International Coalition of Addict Self-Help, ICASH series, and DASH focus group studies). Based on his own experience and that of six of his friends, Lotsof filed use patents for Ibogaine treatment of narcotic and psychostimulant addiction. The use of Ibogaine for the treatment of drug dependence has been based on anecdotal reports from addict self-help groups that it may decrease the signs of opiate withdrawal and reduce drug craving for cocaine and heroin. Preclinical studies have shown that Ibogaine reduces morphine self-administration, ameliorates signs of opiate withdrawal, and decreases cocaine preference.

Ibogaine and other indole alkaloids are centrally acting drugs that at high doses produce tremors and hallucinations. While Ibogaine has diverse CNS effects, the pharmacological targets underlying the physiological and psychological actions of Ibogaine are not completely understood. Ibogaine is not a substitute for narcotics or stimulants, it is not addicting and it reportedly promotes long-term drug abstinence after a single dose administration. At present, there is little information available on pharmacokinetics and metabolism of Ibogaine or on the identification of psychopharmacological targets underlying its putative anti-addictive properties. We are currently conducting an FDA approved Phase I safety and pharmacokinetic study of Ibogaine in male patient volunteers. In addition, we have attempted to characterize the neurobehavioral effects of high dose Ibogaine treatments in drug dependent patient volunteers that had received Ibogaine treatments offshore. Six subjects were treated with oral doses of Ibogaine ranging from 10 to 29 mg/kg. The patients were evaluated with a neurological battery that focused on cerebellar and extrapyramidal signs. Neurobehavioral deficits were assessed at baseline, during and after the Ibogaine treatment using the following rating instruments: the Brief Psychiatric Rating Scale (BPRS), the Addiction Research Center Inventory (ARCI) and the Physician Withdrawal Checklist (PWC). Studies of neuropsychological performance included psychiatric screening and profile of mood, measures of verbal fluency, mental arithmetic, conceptual reasoning, constructional praxis, motor skills, and verbal and visual memory. Blood and urine samples were assayed for Ibogaine and metabolites. We have identified a primary metabolite as 12-hydroxyibogamine (desmethyl Ibogaine). The time required to eliminate the majority of absorbed Ibogaine (>90%) was 24 h post-dose. The pharmacokinetic data demonstrate that the amount of 12-hydroxyibogamine in blood at 24 h was still quite appreciable suggesting that the metabolite may have a long half-life in humans. Ibogaine was found to have no significant neurobehavioral impairments over the dose range tested. Acute effects in patients included mild tremors and transient ataxia, and an overwhelming visual resurgence of repressed memories. These subtle "psychodysleptic" episodes induced by Ibogaine are not detected by currently available rating scales. The patients maintained an intact sensorium following Ibogaine administration as evidenced by the fact they interacted with the clinical staff, answered questionnaires appropriately, and showed no amnesia of current events. The time course for the appearance of lucid visions, mild tremors and ataxia was best correlated with the blood levels of the parent drug. These events last up to 8 hours and subside into a state of virtual relaxation 24 hr post-dose, although some patients experience mild insomnia for several days thereafter. Post Ibogaine neuropsychological profiles were highly variable, but did not reveal any obvious clinical impairments in performance on the measures tested as compared to baseline evaluations. The short-term reenactment of past traumatic experiences induced by Ibogaine can produce a dramatic catharsis or abreaction (i.e., discharge of fearful emotions).

The anecdotal reports from drug dependent individuals will require controlled clinical studies in order to validate the claims that either single or repeated Ibogaine administrations are effective for treating substance abuse disorders. However, Ibogaine's actions may target both an underlying neurochemical etiology and/or neural adaptations associated with chronic cocaine or opiate abuse, along with specific psychosocial problems as discussed above. As with most pharmacological agents, it is likely that Ibogaine would be indicated for use in conjunction with behavioral therapy approaches. This suggestion for drug development of Ibogaine as a pharmacotherapy for substance abuse is consistent with existing multidisciplinary strategies, ranging from molecular neuroscience to psychosocial and behavioral interventions. Drug dependence results from distinct but interrelated neurobiological processes, which include tolerance, sensitization and withdrawal. Recent studies from our laboratory have shown that Ibogaine and its primary metabolite interact with a number of distinct neuroreceptors and neurotransporters within particular cellular networks that are known to modulate the activity of dopaminergic-dependent and independent circuits. The multi-site actions of Ibogaine suggest that simultaneous modulation of two or more neural mechanisms (multi-target strategy) may be a more effective pharmacological treatment approach. Additional studies aimed at understanding the psychopharmacological targets underlying the putative anti-addictive properties of Ibogaine may provide significant leads for developing an effective treatment approach for the current drug abuse epidemic.

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