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Executive Summary

The hallucinogenic drug ibogaine causes degeneration of the cerebellum when administered to rodents either orally or intraperitoneally at high doses, Johns Hopkins researcher Mark Molliver, MD, reported to FDA's Drug Abuse Advisory Committee Aug. 25. "Ibogaine at high doses -- 100 mg/kg -- given i.p. produces neuronal injury, it disrupts the cytoskeleton of neurons, causes increases in several markers, it causes silver screening signs of degeneration, as well as ultra-structural evidence of degeneration," Molliver told the committee. "We found consistently that the neurotoxic effect after oral administration was at least as great as after [i.p.], probably greater," he added. Ibogaine, a drug derived from the root of the west African shrub tabernanthe iboga, is in development in the U.S. as a treatment for addiction. Preclinical research on ibogaine has been conducted at several universities, as well as the National Institute for Drug Abuse. Anecdotal reports of the use of ibogaine by heroin addicts suggests that the compound "interrupts" addiction for months or even years at a time. Used in western Africa for centuries as a stimulant and hallucinogen, ibogaine emerged in the U.S. in the 1960s as a recreational drug. A Schedule I DEA controlled substance, ibogaine has been illegal in the U.S. since 1967. The discovery of the alleged efficacy of ibogaine in treating addiction is attributed to Howard Lotsof, who is now the president and founder of NDA International, the Staten Island-based company which holds the patents on the use of ibogaine (Endabuse) to treat a variety of chemical dependency disorders. NIDA's Medications Development Division met with Lotsof in April 1991 and decided to embark on a drug development program with ibogaine. It took 16 months for NIDA to secure a supply of ibogaine, and animal studies began in August 1992. Researchers at the University of Miami also have been conducting preclinical studies with ibogaine and submitted an IND to FDA earlier this year. The work at Miami is being done under an R&D agreement with NDA International, which is supplying the researchers with ibogaine in exchange for the use of their data. The company has an exclusive manufacturing agreement with a Belgian firm, Omnichem S.A. This spring, as NIDA and FDA were both considering moving ibogaine forward into human studies, Molliver reported his initial findings of neurotoxicity. NIDA and FDA agreed in April that additional toxicology data on the drug was necessary before clinical trials could proceed. About 20 activists from the AIDS Coalition to Unleash Power (ACT-UP) gathered at FDA's Parklawn building on July 6 to protest the delay in clinical trials. FDA convened the Aug. 25 advisory committee meeting to examine the ibogaine preclinical data that has been accumulated to date, as well as some limited human data, and to solicit the panel's recommendation as to whether there is adequate safety information to being Phase I studies. The reports on the use of ibogaine in humans come from a clinical program being conducted by the International Coalition for Addict Self-Help, which has taken more than 20 addicts to the Netherlands for treatment. FDA Pilot Drug Staff Acting Director Curtis Wright, MD, advised the committee of its role: "The question is, if you were a researcher wishing to conduct research with this drug, could you tell a...prospective subject what the risks were, and once you had done that, would you know how to dose the patient, and how to follow the patient to ensure that those risks that might be prevented were prevented...The question is, do we know enough to proceed, would a reasonable scientist proceed?" Molliver reported to the committee that the neurotoxic effect which he found at high doses of ibogaine also appeared at lower doses (down to 25 mg/kg). The usual human dose is 16-18 mg/kg orally. The effect is clearly dose-related, Molliver said, but he found that "at 25 mg/kg, we do see consistent but small degrees, very minor degrees of toxicity." Molliver determined that the neurotoxic effect of ibogaine works indirectly on the Purkinje cells -- the major output cells of the cerebellum -- through the interior "olive." Molliver's hypothesis is that ibogaine acts on the olive to increase glucomate release, and that the glucomate then overstimulates the Purkinje cells, effectively "driving them to their deaths." Molliver correlated his hypothesis with the behavioral effects observed after ibogaine administration: immediate tremor and ataxia (one to three minutes), profound hypotonia (five to 30 minutes), recurring tremor and ataxia (30 minutes to 12 hours), followed by gradual recovery (12 to 24 hours). Molliver explained to the committee that he believes that during the first 12 hours after ibogaine administration, the drug is "having an active pharmacological effect causing excess activity of Purkinje cells with prolonged excitation." During the next 12 hours there is Purkinje cell degeneration, following which the behavioral effect is "terminated...because these cells are dead and they can no longer generate action." Molliver pointed out that while he has found that a number of pharmacological treatments can modify the toxic effect of ibogaine, the issue is, "can one protect the animals against the toxicity and prevent the loss of the Purkinje cells, or does the loss of Purkinje cells underlie a reduction in addictive behavior, if indeed that's what occurs with ibogaine?" He added: "I think that is a crucial question to look for in further research, because if the Purkinje cell loss is essential, then one is making a pharmacologically surgical lesion. If it is not essential, then it is a side effect, and it could be eliminated, perhaps." Molliver has not yet completed similar neurological studies in rabbits and monkeys to determine whether the same toxicity will be found in other species; however, he suggested that "it's very likely" that the same mechanism occurs. Preclinical studies in primates conducted by University of Miami researcher Deborah Mash, PhD, did not reveal neurotoxicity; however, her studies did not include the sophisticated methods used by Molliver. Members of the committee were split in the weight they have to Molliver's data and the amount of risk they were willing to permit clinical trial volunteers to undertake. Several panel members were concerned that there is not enough information to adequately apprise participants of the risks. "I'm not in favor of holding the drug up before clinical trials for an unreasonable length of time until every last question has been answered," explained committee member Laura McNicholas, MD/PhD, University of Pennsylvania. "But I do think we need some answers before we proceed with a clinical trial." Former committee member and FDA consultant George Bigelow, PhD, Johns Hopkins Medical Center, argued that the risk/benefit balance for ibogaine data leans toward proceeding with studies. Addiction "is a disorder with high toxicity and high mortality," he said. "I don't think we risk very much by proceeding cautiously through a small scale controlled clinical evaluation." He added: "We have really quite a lot of data about the drug...I don't think anyone presented us data showing persistent irreversible functional impairment." George Ricaurte, MD/PhD, Johns Hopkins University, also a former committee member, contended that "usually, when we formulate an issue in terms of a risk/benefit ratio, we've heard a lot about potential benefit, we've heard a lot bout potential risk ...Given the preclinical information that we've heard today -- which, while substantial, is not by any means complete -- it seems today that a great deal more information is needed in terms of defining the risk on the basis of preclinical studies in rats and monkeys." The committee came to no conclusion about proceeding to human studies and decided that there is not yet enough data on ibogaine to make a decision regarding all Phase I trials. The panel went into closed session to discuss the details of the proposed Miami protocol, and concluded that, with changes, the study could proceed. The Miami researchers agreed to limit the participation in their human study to volunteers who already have used ibogaine. Between six and nine subjects will be involved, and dosing in the study will be no higher than 25 mg/kg. The researchers will also continue to look at primate data using Molliver's methods.

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