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.

[sidebar 1]

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 u- 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).

[sidebar 2]

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.