7/31/2019 Ibogaine Therapy a Uncontrolled Experiment

1/2www.sciencemag.org SCIENCE VOL 308 15 APRIL 2005

On a snowy Presidents Day, an odd group ofactivists and scientists devoted to treatingaddiction gathered in an art gallery in theChelsea warehouse district of New York City.As an all-night, all-day rave throbbed nextdoor, panelists outlined the latest develop-ments in a decades-long movement to main-stream a West African plant alkaloid, ibo-gaine, that purportedly interrupts addictionand eliminates withdrawal.

Sustained by true believers who operatelargely outside the academic medical world,research on the vision-inducing drug is gaining

attention, despite its U.S. status as a bannedsubstance. The Food and Drug Administration(FDA) approved a clinical trial in 1993, but theNational Institute on Drug Abuse (NIDA)decided not to fund it after consultants raisedquestions about safety.

The plant extract can be neurotoxic at highdoses and can slow the heart. Yet a handful ofscientists continue to study it for its potential intreating addiction. The enthusiasts who gath-ered in New York reviewed efforts to tease apartits antiaddictive and hallucinatory components.

Although a PubMed search for ibogainepulls up some 200 articles on laboratory stud-ies, clinical reports cover just a few dozen

patients. Thats because patients seek treatmentclandestinely. Whether the FDA likes it or not,the fact of the matter is that hundreds, prob-ably thousands of people have been treatedwith ibogaine, said Stanley Glick, a physicianand pharmacologist at the Albany MedicalCenter in New York who has documented ibo-gaines antiaddictive potential in rodents. At themeeting, Kenneth Alper, a Columbia Univer-sity assistant professor of psychiatry, estimatedthat more than 5000 people have taken ibogainesince an organized (but unregulated) clinicopened in Amsterdam in the late 1980s. Boaz

Wachtel, an ibogaine advocate in Israel,believes that 30 to 40 clinics operate world-wide. Listed alongside heroin, LSD, and mari-juana on the U.S. Drug Enforcement Adminis-trations schedule I of banned substances, ibo-gaine is nevertheless legal in most of the world.

Theres basically a vast, uncontrolledexperiment going on out there, said FrankVocci, director of antiaddiction drug devel-opment at NIDA. The agency spent severalmillion dollars on preclinical ibogaine workin the 1990s before dropping it.

Ibogaines promoters yearn for the legiti-macy that a successful clinical trial can bring.They may soon get their wish. Later this

spring, neuroscientist Deborah Mash of tUniversity of Miami in Coral Gables, Floriwill launch a phase I safety trial in Miami.second safety and efficacy trial, of 12 heroaddicted individuals, is slated to begin this fat the Beer Yaakov Mental Health Center in TAviv. Both are being funded in an unusual faion: by anonymous donations$250,000 f

Mash, a smaller amount for the Israeli study

RestartingFor Mash, a tenured professor who runs Alzheimers brain bank and won attentionthe 1980s for research on how mixing alcohand cocaine damages the brain, the donatimarks a victory. The holder of a patent claon ibogaine, she has been trying for 12 yeto give the drug a scientific hearing. FDapproved Mashs phase I study in 1993, bshe abruptly halted the trial when NIDrejected her funding application.

Three years later, she moved offshore, ope

ing a fee-for-service clinic on the Caribbeisland of St. Kitts. The standard fee per patiof several thousand dollars is adjusted based ability to pay, according to Mash. Critiderided the unorthodox move as a money grabut Mash maintains that her motivations wscientific. You know, somebody ought to tit. Either the damn thing works or it doesnshe said in a telephone interview.

At the New York meeting, Mashs physiccolleague Jeffrey Kamlet presented snippetsdata from the 400 patients he and Mash helptreat at St. Kitts. (Patients took a single doseibogaine titrated to body weight and other fators.) He said that for up to 90 days posttrement, patients reported feeling wonderfuphysician evaluations also showed improvment in depression and drug-craving scorThe results mirror those from 27 cocaine- aheroin-addicted individuals treated with ibgaine at St. Kitts published by Mash in 2000theAnnals of the New York Academy of Scienc

However, Mash has not published the buof her data. Her explanation: She does nwant to stir up long-running controversiincluding a patent dispute with Howard Lsof, who discovered ibogaines antiaddictivalue as a young heroin addict in 1962.

Multiple effectsThere is no consensus on precisely hoibogaine works, although researchers hashown that it inhibits the reuptake of tneurotransmitter serotonin, among othactions. In this way, its like supersticklong-acting Prozac, said Kamlet, presideof the Florida Society of Addiction Mediciin Pensacola.

It can also have effects similar to those LSD or PCP. Like them, it jolts serotonin aglutamate systems and can cause hallucin

Ibogaine Therapy:A Vast,Uncontrolled ExperimentDespite potentially harsh side effects, an African plant extract is being tested in twopublic clinical trialsand many clandestine ones

Addict ion Research

Traditional high. Ibogaine is derived from a root bark used in the West African Bwiti religion as a wayto visit the ancestors.

CREDIT:LAURENTSAZY

Published by AAAS

7/31/2019 Ibogaine Therapy a Uncontrolled Experiment

2/2

N E W S F O C U S

15 APRIL 2005 VOL 308 SCIENCE www.sciencemag.org346

tions and feelings of depersonalization. InGabon, the Bwiti religion revolves aroundvisits to the ancestors induced by eatingroot bark from the shrub Tabernanthe iboga,the source of ibogaine. Many patients in theWest also report emotionally intense, some-times frightening visions: scenes from child-hood, or past mistakes and regrets replayedand somehow released. Debate rages overwhether these experiences are key to ibo-

gaines antiaddictive potential or simply apsychedelic side effect.Not every patient experiences visions, but

animal and human pharmacokinetic datareveal a common physiological response: Theliver converts ibogaine into its primarymetabolite, noribogaine, which fills opiatereceptors hungry for heroin or morphine.Mash believes that this dramatically reduces oreliminates withdrawal symptoms, and thatswhy [addicts] dont feel dope sick anymore.Ibogaine also stimulates nicotinic receptors inthe cerebellum, an action that, according toGlick, contributes to ibogaines long-lasting

antiaddictive properties by modulating thedopamine reward circuit in the midbrain.Besides tweaking neurotransmitters,

rodent studies suggest that ibogaine increasesquantities of a protein in the brain called glialcell linederived neurotrophic factor (GDNF).Researchers at the University of California,San Francisco, recently observed this effect inthe brains dopamine-producing areas. DoritRon and colleagues reported in the Januaryissue of theJournal of Neuroscience thataddicted rodents lose interest in opiates whengiven either ibogaine or GDNF. But afterinjecting an anti-GDNF antibody that scoops

the growth factor out of play, the team foundthat the animals go dope-crazy again.Ron goes further, suggesting that GDNF

maintains and possibly even repairs frazzleddopamine receptors. She reported last year intheJournal of Neuroscience that geneticallymodified mice producing excess GDNFgrow up to have denser dopamine connec-tions in the ventral tegmental area, where thedopamine reward pathway begins.

Mash and others suggest that the effects ofthe St. Kitts therapy lasted up to 3 monthsbecause unmetabolized ibogaine deposits infat, creating a slow-release reservoir, andbecause metabolized ibogaine can stay in cir-culation for weeks. But government agenciesare wary of ibogaine, in part because of itsmyriad effects. It slows the heart and, at veryhigh doses, can destroy neurons in the cere-bellum. FDA and NIDA cited these toxicityrisks repeatedly in the 1990s.

Glick has been trying to develop cleaner-acting derivatives. The best-studied,18-methoxycoronaridine (18-MC), exhibitsstrong action at nicotinic receptors but seemsto lack all of the actions that make ibogaineundesirable, said Glick. Mash and other ibo-

gaine supporters claim that the neurotoxicityrisks have been hyped. But the St. Kitts teamclosely monitors heart activity of volunteers,excluding any with irregular rhythms.

While Glick tries to line up funding forclinical studies of 18-MC, Mash is betting ona formulation of the metabolite noribogaine.She and the University of Miami won patentrights to noribogaine in 2002 after a long-running dispute with Lotsof, who holds a

patent claim on ibogaine. Mash hopes that,like 18-MC, noribogaine may offer antiaddic-tive effects without the scary trip.

Meanwhile, Vocci is disappointed that

Mash has not published her data from St. KittThis big case series, no one knows what make of it, he said. I would expect to seespectrum of responses. Even though its notcontrolled study, it would still give us some idwhether or not she has anything worth lookinat. If Mashs new trial does produce promisindata, ibogaine advocates will have a token legitimacy to point to. But the circle of trubelievers seems to be expanding, Wachtel say

because users insist that ibogaine works.BRIANVASTA

Brian Vastag, a writer in Washington, D.C., is woing on a book about ibogaine.

For 5 years, Daniel Nepstad has been slowlykilling trees throughout a hectare of hisbeloved Amazonian rainforest. In an elabo-rate experiment akin to an installation by theartist Christo, Nepstads team set up a1-hectare array of 5600 large plastic panelsthat diverted the rain and created an artificialdrought. The point of the $1.4 million experi-ment is to provide the most detailed look everat how tropical forests respond to such stress.

The good news, as Nepstad, an ecologistat the Woods Hole Research Center (WHRC)in Massachusetts, and colleagues havereported in recent papers, is that the forestis quite tough. Although thats no great

surpriseforests in the eastern Amazon halong experienced regular droughts from Nio eventsthe team is discovering clevtricks that the trees use to survive when tsoil becomes parched.

Whats worrisome is that when drouglasts more than a year or two, the alimportant canopy trees are decimateEveryone knows that a lack of water eventally kills plants. But by pushing the tropic

forest to its breaking point, researchers nohave a better idea of exactly how much puishment these forests can withstand.

These kinds of data will be indispensabfor predicting how future droughts mig

change the ecological structure the forest, the risk of fire, and hothe forest functions as a carbosink, experts say. Given thdroughts in the Amazon are prjected to increase in several climamodels, the implications for therich ecosystems is grim, says ecoogist Deborah Clark of the Univesity of Missouri, St. Louis, whworks at La Selva Biological Sttion in Costa Rica. The forests aheaded in a terrible direction, ssays. Whats more, t he pictuincludes a loss of carbon storathat might exacerbate globwarming.

Basement to atticNe pst ad got th e id ea fo r thexperiment while working in teastern Amazon in 1992 duri

Experimental Drought PredictsGrim Future for RainforestAn extraordinary research effort in the Amazon starved a tropical forest of rain and prvides a glimpse of the potential effects of climate change

Ecology

Parched. Thousands of panels prevented most rain fromreaching the forest floor.

Published by AAAS