Psychopharmacology

Development of Ibogaine as an Anti-Addictive Drug:
A progress report from the University of Miami School of Medicine

Deborah C. Mash, Ph.D., Julie K. Staley, Ph.D., John Pablo,M.S., Lionel Raymon, Pharm.D., Ph.D., Bonnie Levin, Ph.D., Frances M. Doepel, D.V.M., Richard Duoyon, M.D., W. Lee Hearn, Ph.D. and Juan. Sanchez-Ramos, Ph.D., M.D.
Departments of Neurology, Psychiatry and Pathology, University of Miami School of Medicine, Miami, FL 33101, USA
Pharmacokinetic Consultant: Nancy Sambol, Pharm.D., UCSF School of Pharmacy, San Francisco, CA, USA

The University of Miami Ibogaine Research Team has been working with ibogaine for the past three years in both preclinical and clinical studies. Ibogaine is a psychoactive indole alkaloid derived from the rain forest shrub Tabernanthe iboga.

Ibogaine is one of a dozen or more alkaloids found in the iboga shrub that grows in West Africa. The use of ibogaine for the treatment of drug dependence has been based on anecdotal reports from the International Coalition of Addict Self-Help (ICASH) and DASH (Dutch Addict Self-Help Group) that it may decrease the signs of opiate withdrawal and reduce drug craving for cocaine and heroin. Preclinical studies in animals have given additional support to the claim that ibogaine is an addiction interrupter. Studies by American and European scientists have shown that ibogaine reduces morphine and cocaine self- administration and blocks, albeit not completely, the signs of opiate withdrawal.

Clinical research with Ibogaine:
Questions and concerns affecting the pace of development?

While these initial reports were promising, clinical research and development of ibogaine as an anti-addiction drug has been very difficult for a number of reasons. First, all of the anecdotal reports of ibogaine's successes have come from individuals working outside the conventional medical establishment. Robert Sisko and his group from ICASH have provided the best information and follow-up on addicts who had used ibogaine to end their addictions to drugs and alcohol. Unfortunately, it has been very hard to obtain accurate post-treatment follow-up data to independently establish estimates of the percentages of successful ibogaine treatments. In addition, Howard Lotsof and his staff at NDA International had to stop treatments in the Netherlands following the death of one young woman who died after taking an ibogaine treatment for heroin addiction. This unfortunate loss of life has raised important questions about what is a safe dose range for ibogaine and opened up the possibility that there may be gender differences in the way the drug is metabolized.

The development of ibogaine has been hindered also by uncertainties raised by Mark Molliver, M.D. and his collaborators at Johns Hopkins University over the issue of drug neurotoxicity. Ibogaine is a centrally acting drug which at high doses produce tremors, loss of motor coordination and balance, and hallucinations. Using novel tools from the Neurosciences, Drs. Molliver and O'Hearn have shown that high doses of ibogaine can result in toxicity to cells located in the cerebellum, a part of the brain which controls balance and coordinated movements. This information raised considerable concern that taking ibogaine in a cocaine or heroin detoxification protocol might prove to be toxic to brain cells. In cooperation with Howard Lotsof and NDA International, Inc., we have conducted neurological and psychiatric evaluations on drug-dependent volunteers who had received ibogaine treatments offshore in either the Netherlands or more recently in Panama. These preliminary studies have shown that the neurobehavioral effects of high-dose ibogaine treatments are fully reversible. Although ibogaine's effects are transient and reversible, the chief concern of cytopathology (cell death) still remains unresolved. Our own studies in primates receiving multiple doses of ibogaine have failed to demonstrate any signs of cell death or other markers of neuronal toxicity. In addition, neuropathological evaluation was done on a female subject who came to autopsy for apparent natural causes. Although she had received four documented ibogaine treatments in 15 months, microscopic study of her brain showed no significant signs of pathology to the cerebellum or any other brain region. While these observations are encouraging, further studies are needed to rule out toxicity and to help guide our understanding of the long-term effects of ibogaine treatments on brain function.

If ibogaine is an addiction interrupter, how does it work?

While ibogaine has diverse effects on the brain and behavior, the pharmacological targets underlying the physiological and psychological actions of ibogaine are not completely understood. Ibogaine reportedly promotes long-term drug abstinence after only a single dose administration. As part of the original Phase 1 safety and pharmacokinetic clinical trial in ibogaine veterans, we have been searching for possible long-acting metabolites of ibogaine that might explain the persisting after-effects. We have recently demonstrated that ibogaine is O- demethylated to an active metabolite called noribogaine or 12- hydroxyibogamine1,2. Preliminary observations suggest that there may be considerable variability in the way that the drug is metabolized and that, in some individuals, the metabolite may persist in blood for a long time. In collaboration with investigators at the Addiction Research Center, we have demonstrated that the metabolite - noribogaine - targets the serotonin transporter and elevates serotonin in brain1. Our interpretation of these findings is that the putative anti-addictive effects of ibogaine may be due in part to a potent action of noribogaine on serotonergic systems which modulate mood, motivation and behavioral control. A persistent and targeted action of noribogaine on serotonin systems may help to explain how ibogaine treatments promote rapid behavioral changes which moderate long-term drug abuse and dependence.

What are the future directions for ibogaine research at the University of Miami?

The Drug Abuse Advisory Committee (DAAC) of the FDA recently reviewed the progress made by the Miami group. Per the recommendation of the DAAC and the reviewing staff of the FDA, permission has been granted to proceed with a dose escalation study of ibogaine in ibogaine-naive volunteers. The Miami group plans to proceed with caution and to involve a number of expert investigators in the development of a comprehensive protocol to fully assess the safety and metabolism of ibogaine. We will submit a grant to the National Institutes of Health to fund the Phase 1 study of ibogaine in cocaine-dependent male volunteers. The grant evaluation will take at least 9 months after the protocol is submitted in October 1995. In the interim, additional funds are now needed to keep the project alive and the clinical trial on track, while we await review of the grant proposal.

The Miami group is very grateful to MAPS for providing initial support for the Ibogaine Research Project when other sources of funds were not available. The research funds provided by MAPS went directly to support the clinical studies of ibogaine's metabolism in human patient volunteers and for preliminary studies which helped us to provide additional clinical and preclinical information to the FDA for their evaluation of the Phase 1 protocol. Our efforts to secure approval by the FDA were very labor intensive and costly. Our success is shared by those of you who support the efforts of MAPS to provide critical seed funding for research studies. This funding allows investigators to obtain important preliminary data to support grant applications for future funding by the Public Health Service.

Many more studies are needed to determine if ibogaine will be therapeutically useful for treating drug dependence. This work is in a very early stage of development. The clinical development of ibogaine will likely depend on the risk/benefit ratio and on the creative use of both pharmacokinetic and pharmacodynamic methods. We are very eager to continue with this important work. We hope that our efforts, together with the efforts of other scientific investigators throughout the United States and Europe, will lead to a better understanding of ibogaine's pharmacology and metabolism. We are optimistic that clinical and basic research studies with ibogaine will contribute to the development of novel, safe and successful treatments for drug addiction.

References

• Mash, D.C., Staley, J.K., Baumann, M., Rothman, R.P., and Hearn, W.L., Identification of a primary Metabolite of ibogaine that targets serotonin transporters and elevates serotonin. Pharmacol. Letters, 57: 45-50, 1995.
• Hearn, W. L., Pablo, J., Hime, G. and Mash, D.C. Identification and quantitation of ibogaine and an O-demethylated metabolite in brain and biological fluids using gas chromatography/mass spectrometry. In press - Jour. Anal. Toxicology, Volume 19, 1995.

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