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
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
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
What are the future directions for ibogaine research at the University of
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.
- 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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