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MAPS: Great ibogaine article from JAMA



Here's a great article on ibogaine, from the Journal of the American Medical
Association. The only change I'd make in the article is that it lets NIDA off
way too easily for deciding, at a 1995 meeting, not to fund ibogaine
research. That was a cowardly political decision that hide behind exaggerated
estimates of the risks of ibogaine.

Addiction Treatment Strives for Legitimacy

by Brian Vastag

Journal of the American Medical Association

Vol. 288 No. 24, pp. 3096-3101, December 25, 2002


Addiction Treatment Strives for Legitimacy


New York -- Some drugs are made in laboratories. Others, like

penicillin, are discovered by accident. And then there's ibogaine, a

sacramental substance from West Africa that some say interrupts heroin,

cocaine, and other addictions. Over the past 40 years, the tale of

ibogaine's flirtation with legitimacy boasts more twists than the roots

of Tabernanthe iboga, the shrublike source of ibogaine.


After riding the backpacks of Westerners to the radical 1960s New York

City underground, ibogaine rose from a counterculture star to a serious

project funded by the National Institutes of Health (NIH). In 1995,

after spending several million dollars on laboratory and animal studies,

the NIH decided not to pursue ibogaine development. Since then, patent

disputes have divided the drug's champions; a growing network of

informal clinics has sprung up; and pharmacologists have discovered that

ibogaine works on the brain in a manner unlike that of any other known

drug (see sidebar 1).


After all this, ibogaine and two of its derivatives appear closer to

legitimacy now than ever before. In 1998, a University of Miami Medical

Center researcher opened an ibogaine clinic on the Caribbean island of

St Kitt's. Although the US Food and Drug Administration (FDA) had

approved human trials with ibogaine, Deborah Mash, PhD, associate

professor of neurology and pharmacology at Miami, could not secure

funding for a stateside study. Instead, she solicited private investment

and won favor from the government of St Kitt's, where a team of

physician counselors and addiction specialists now collect data that

Mash hopes will cement support for US trials of ibogaine or its

metabolite, noribogaine.


Tabernanthe iboga, the West African source of ibogaine, used by some to

treat addiction.


Meanwhile, another pharmacologist, Stanley Glick, MD, PhD, director of

the Center for Neuropharmacology and Neuroscience at Albany Medical

Center, has painstakingly moved a derivative of ibogaine toward its own

clinical trial. After 12 years of basic research on scores of molecular

variations on the ibogaine theme, Glick recently forged an agreement

that represents his best chance for a clinical trial. Signed in November

2002, the contract obligates investors to raise $5 million within 2

years to fund the first human studies of 18-methoxycoronaridine (18-MC).


But even as ibogaine's supporters sniff success, they worry that the

drug's origins will continue to stunt its development. "It's been a

continuous battle for respect," said Glick. "Ibogaine has really become

notorious because it didn't originate in a lab, but in the

counterculture."


Mash is concerned that burgeoning unsanctioned use will compromise years

of laboratory and clinical work. "We've got this explosion of

underground clinics, and I'm scared that everything I work for is going

to go right down the toilet," Mash said in a recent telephone interview.

As an endowed, tenured professor, Mash has all the right credentials: a

29-page curriculum vitae listing 155 publications; a history of millions

of dollars in federal grants; a spot at the table of several National

Institute on Drug Abuse (NIDA) review committees; and a reputation as a

brilliant brain scientist.


And yet, Mash feels that ibogaine's tumultuous history (see sidebar 2)

has isolated her. "I'm the only one [doing clinical research]," she

said. "I figured, somebody ought to test the damn thing. You know,

either it works or it doesn't."


SCIENTISTS LOOK INTO USE


In 1999, Kenneth Alper, MD, PhD, assistant professor of psychiatry at

New York University School of Medicine, hosted the first serious

scientific conference devoted to ibogaine. He and Glick compiled the

proceedings into a thick volume (Alkaloids Chem Biol. 2001;56:1-330). In

the preface, Geoffrey Cordell, PhD, a pharmacology researcher at the

University of Illinois at Chicago, writes that while ibogaine probably

"won't save the world from addiction," it deserves a "prominent position

in the list of anti-addictive strategies" under study.


Animal data support Cordell's conclusion. Dozens of articles referenced

in the conference proceedings report reductions in self-administration

of morphine, heroin, cocaine, alcohol, and nicotine in rodents given

ibogaine. The effects last from 1 to 5 days, depending on dosage and

other variables. Noribogaine and 18-MC produced similar results.


That means the central hurdle for ibogaine's supporters is amassing

compelling human data. While unknowable scores of addicts continue

ingesting ibogaine hydrochloridea purified powder -- or ibogaa

whole-plant extract containing a dozen or more active alkaloids -- few

trained researchers witness the events.


"There's basically one big uncontrolled experiment going on out there,"

said Frank Vocci, PhD, head of antiaddiction drug development at NIDA.


Consequently, supporters have had to rely on anecdotal accounts. At a

pivotal 1995 NIDA meeting, Howard Lotsof, credited with discovering

ibogaine's purported antiaddictive potential, presented a collection of

case reports. He reported that 10 (19%) of 52 treatments led to

cessation of heroin or cocaine use for a year or longer; 15 (29%)

treatments led to 2 months or less of sobriety. The remaining treatments

were followed by sober periods between 2 months and 1 year. Despite

Lotsof's report, the NIDA peer review panel voted nine to four to reject

a clinical grant application from Mash.


She regrouped and eventually opened the Healing Visions clinic in St

Kitt's. In 2000, Mash and colleagues published the data from 27 cocaine-

or heroin-addicted patients treated at the center (Ann N Y Acad Sci.

2000:914;394-401). The researchers conclude that "self-reported

depressive symptoms and craving were significantly decreased" at 1 month

after stopping treatment with ibogaine. They also note that ibogaine

treatment "decreased participants' desire and intention to use heroin."

Mash is now analyzing safety and efficacy data for 257 patients.


SAFETY CONCERNS


At Healing Visions, patients receive what Mash calls "state-of-the-art

care," with round-the-clock monitoring and access to the latest

emergency equipment. But individuals who seek out ibogaine in other

settings receive no such supervision. "It's caveat emptor," said NIDA's

Vocci.


Vocci also said that safety was "not the main concern" at the pivotal

1995 NIDA meeting, which he chaired. However, that review panel did cite

safety issues. One reviewer wrote that the drug's toxicology profile was

"less than ideal," with bradycardia leading the list of worrisome

adverse effects.


In fact, between 1989 and 2000, three reports of patients dying after

taking ibogaine surfaced, sparking a swirl of questions about the drug's

safety. The first death, of a 40-year-old woman in France, apparently

stemmed from preexisting heart disease. A lack of medical information

hindered investigations into the other two deaths and led to conflicting

conclusions about whether ibogaine was to blame.


In a 1996 radio interview with WBAI in New York City, Mash said that, in

the French case, the patient "was very sick, she had a very sick heart

and she shouldn't have been given ibogaine under any circumstances. . .

." And in the second death, "we don't completely know the mechanism of

lethality, but it did appear to be respiratory collapse in this case.

The bottom line is that you need to be under medical supervision. . . .

Ibogaine is an important drug but it is not to be used outside the

medical establishment, not ever, ever, ever."


Despite Mash's warnings, unsanctioned ibogaine use appears to be

soaring. A sophisticated "underground railroad" of sorts has sprung up

in New York, spearheaded by Dana Beal, a long-time marijuana

legalization advocate. When heroin- or cocaine-addicted individuals

develop an interest in ibogaine, they often call Beal, who acts as

intake counselor.


During an interview in his home, the one-time headquarters of the

radical 1960s Yipster Times newspaper, Beal said that if he thinks

someone is a good candidate for ibogaine, he helps arrange a visit to an

informal clinic.


The best known operation, according to Beal, is in the Netherlands at

the Amsterdam home of Sara Glatt, who practices various types of

alternative medicine. Glatt has treated some 85 people during the last 3

years. When an addicted individual arrives, Glatt asks for a history of

heart problems or bad experiences with psychedelic drugs. Judging from

that information and the individual's weight, Glatt provides between 2 g

and 6 g of powdered iboga, the whole-plant extract that contains at

least a dozen active ingredients in addition to ibogaine.


Whereas Glatt charges upward of $1000 for her services, the newest

clinic, in Vancouver, British Columbia, offers free ibogaine. The

clinic's founder, Marc Emery, won 2000 of 140 000 votes in the 2002

Vancouver mayoral election running on a platform of open access to

ibogaine. He recently solicited an ibogaine e-mail list for feedback on

a proposed treatment regimen.


Lotsof, on the other hand, has already published a rigorous protocol

(Lotsof H, Wachtel B. Manual for Ibogaine Therapy: Screening, Safety,

Monitoring, and Aftercare, First Revision. Published online. Available

at http://www.ibogaine.org/manual.html. Accessed November 26, 2002). In

the preface to the first revision, Lotsof and coauthor Boaz Wachtel

write that the manual is "intended for lay-healers who have little or no

medical experience, but who are nevertheless concerned with patient

safety and the outcome of ibogaine treatments." The manual suggests

inclusion and exclusion criteria, ibogaine regimens and doses, and

considerations for posttreatment care. A naive physician would likely

accept it as a standard medical protocol.


Back in the realm of sanctioned drug development, Glick and Mash are now

focused on bringing their respective ibogaine derivatives into clinical

trials. "That's certainly the way to go now," said Vocci. Alper voiced a

similar opinion, saying that he views ibogaine as proof of concept that

the best hope for a therapeutic drug lies with ibogaine derivatives.

Glick, too, is certain that the FDA will never approve ibogaine. In

addition to safety concerns and the drug's social history, the

hallucinogenic effects of ibogaine (see sidebar 1) could be problematic.


After NIDA rejected ibogaine clinical trials, both Mash and Glick struck

out with the pharmaceutical industry, which has been traditionally cool

to antiaddiction drugs. The Pharmaceutical Research and Manufacturers of

America (PhRMA) reports that in 1999, for example, its roster of drug

giants had 10 antiaddiction agents in clinical trials. The same

companies had more than 400 cancer drugs in clinical development. When

asked to explain the disparity, Jeff Trewhitt, spokesman for PhRMA,

said, "We certainly don't know a reason, unfortunately."


But ibogaine researchers and others, including a spokeswoman for the

Substance Abuse and Mental Health Services Administration (SAMHSA), say

that addiction stigma and low profit potential are keeping companies

away.


Whatever the case, the dearth of pharmaceutical and other treatments

means that the societal costs of addiction will continue to climb.

SAMHSA reports that in 2000, illicit drug addiction cost the United

States $160 billion in medical care, lost productivity, and crime and

incarceration, up from $117 billion in 1997. Illicit drug addiction is

here to stay.


So too, it appears, is ibogaine.


An Odd Drug


Other hallucinations passed before my eyesburning skulls and faces, the

figures of women in black dresses stretching out long white arms toward

me from the edges of my visionbut when I tried to speak of them, they

disappeared. Meanwhile, the iboga was making me sick. I fought back

waves of nausea. I wanted to reach the deeper visionary state, but I was

also afraid of the drug.

Journalist Daniel Pinchbeck, in Breaking Open the Head: A Psychedelic

Journey Into the Heart of Contemporary Shamanism. New York, NY: Broadway

Books; 2002.


At low doses, ibogaine is a mild stimulant. At high doses, users report

deeply emotional visions, sometimes pleasant, sometimes harrowing.

Patrick Kroupa, who credits ibogaine with 3 years of sobriety after 15

years of addiction, said, "It was like dying and going to hell 1000

times."


Whatever the subjective experience, pharmacologists have spent decades

puzzling out the brain effects of ibogaine. Their conclusion: it's

unlike any other known drug. Kenneth Alper, PhD, assistant professor of

psychiatry at New York University School of Medicine, said that the drug

appears to work on "every neurotransmitter system we know about." It

binds to N-methyl-D-aspartate receptors and µ- and -opioid receptors;

all three play prominent roles in current theories of addiction.


Ibogaine also acts as an antidepressant by binding to serotonin

transporters, thereby increasing serotonin levels in the nucleus

accumbens. Evidence of impact on the dopamine and acetylcholine systems

is less compelling, but deserves consideration, said Alper (Alkaloids

Chem Biol. 2001;56:2-33).


Most recently, Stanley Glick, MD, PhD, published support for his theory

that ibogaine reduces drug-seeking behavior in rodents by blocking a3b4

nicotinic receptors (Eur J Pharmacol. 2002;438:99-105).


Meanwhile, Deborah Mash, PhD, a neuroscientist at University of Miami

Medical Center, is convinced that ibogaine is nothing but a short-acting

prodrug. It quickly metabolizes into noribogaine, she said, which boasts

a half-life so long that she has been unable to measure it. This

property, she believes, explains ibogaine's purported ability to block

drug cravings for weeks or months (Alkaloids Chem Biol.

2001;56:79-113).B.V.


(Return to text.)


A Brief History of Ibogaine


1885: First published description of religious use of Tabernanthe iboga

in Gabon appears in France; it reports that initiates of the Bwiti

religion eat rootbark to induce visions and "meet their ancestors."


1939: Sold in France as a stimulant until 1970.


1962: Howard Lotsof, a 19-year-old from Staten Island, receives ibogaine

from an LSD chemist and gives it to 19 other people. He later reports

that five of seven heroin and cocaine addicts in this group, including

himself, stop illicit drug use for up to 18 months and experience little

or no acute withdrawal.


1970: The US Food and Drug Administration (FDA) classifies ibogaine as a

Schedule I drug, making it illegal. Belgium also outlaws ibogaine, but

today it remains legal in the rest of the world.


1985: Lotsof receives a US patent for use of ibogaine in opioid

withdrawal. Additional patents describing ibogaine treatment for cocaine

and other addictions follow.


1989: Ibogaine addiction treatment begins in informal clinics in the

Netherlands. By 2002, informal clinics have opened in the United

Kingdom, Canada, Slovenia, and Mexico.


1991: After intense pressure from activists, the National Institute on

Drug Abuse (NIDA) begins funding preclinical toxicology and other

laboratory research on ibogaine.


1993: The FDA approves a US clinical trial of ibogaine sponsored by

University of Miami neuroscientist Deborah Mash, PhD.


1995: NIDA review committee rejects funding for Mash's clinical trial.


1999: Mash opens ibogaine clinic on Caribbean island of St Kitt's. By

late 2002, she has collected safety and efficacy data on 257 addicted

patients.


2002: Long-running legal dispute between Lotsof and Mash ends with the

University of Miami winning patents for noribogaine, a metabolite of

ibogaine. Stanley Glick, MD, PhD, director of the Center for

Neuropharmacology and Neuroscience at Albany Medical Center, signs

contract to bring ibogaine derivative 18-MC into clinical trials.B.V.


(Return to text.)

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