THE BIOLOGY OF . . . ADDICTION - THE END OF CRAVING

A Controversial New Drug Seems To Stop Addiction Cold

The rats in Stanley Glick's lab are junkies. They spend their days and
nights lounging around in steel cages, twiddling their claws, waiting for
the next hit. Each rat has a small plastic tube protruding from the base of
its skull. Once a day, for an hour, each tube is connected to an infusion
pump that controls a syringe containing a common addictive substance:
morphine, cocaine, nicotine, or methamphetamine. The rats are trained to
pull levers for water, but for one hour each day they can use the same
system to mainline as much of the drugs as they want. And they want. "Just
about any drug that humans abuse, animals will self-administer," Glick says.

Glick gets the rats addicted only to get them back on the wagon later with a
substance called 18-methoxycoronaridine (18-MC, for short). The new drug may
be the miracle pill that addicts have always needed: A single dose of it can
remarkably diminish both withdrawal symptoms and craving. By revealing its
mechanism, Glick, director of the Center for Neuropharmacology and
Neuroscience at Albany Medical College in New York, offers a new
understanding of the brain's pleasure zones.

Eighteen-MC is a synthesized derivative of ibogaine, an extract of the bark
of the root of the African iboga shrub. For centuries the Bwiti tribe of
West Africa has used the root for initiation ceremonies and, in smaller
amounts, to stay awake during long hunts. The drug's story as an
anti-addictive began in 1962, when college dropout and heroin addict Howard
Lotsof obtained a dose from a chemist friend. "What happened is indelibly
ingrained in my mind," Lotsof says. "I was living with my parents. I felt my
feet hit the ground, and I realized I had no desire to use opiates."

In 1986 Lotsof created a company called NDA International and began to
supply ibogaine to a clinic for addicts in Holland. The clinic found that
ibogaine works in three stages. First the addict has about four hours of
waking dreams in which he seems to confront inner demons. This is followed
by an eight-to 10-hour "cognitive evaluation period," during which the user
analyzes the waking dream. Then comes a sleepless day or two, which Lotsof
calls the "residual stimulation phase."

The clinic treated about 30 addicts and reported impressive results: After a
single dose, a majority stayed off drugs for several months or more. But
Lotsof was unable to find funding for follow-up studies-and they were
needed: One of the patients died of unknown causes, and a study at Johns
Hopkins University showed that high doses of ibogaine cause brain damage in
rats. Lotsof's lack of scientific degrees, as well as his history of drug
use, also raised questions.

"The personalities involved are, for lack of a better word, peculiar," says
Glick. He is lanky, has a closely trimmed beard, and wears a white lab coat
over black pants as if to match his Holstein-style rats. The closest he has
ever gotten to drug culture is playing trumpet in a jazz band called
SwingDocs. "Certainly in the beginning everybody thought that Lotsof was an
absolute lunatic, and I was included. But when you hear the same things
enough times from enough people who have taken ibogaine, you've got to
believe that there is at least something there that is worth investigating."

In 1991 Glick and his colleagues began to look for a synthetic derivative of
ibogaine without the drug's side effects. The search eventually led to
Martin Kuehne, a chemist at the University of Vermont who is an expert on
the anticancer drug vincristine. Vincristine is structurally similar to
ibogaine, and Kuehne knew how to tinker with the compound to produce
derivatives. Glick tested 15 or so of the derivatives on rats before zeroing
in on 18-MC.

"Withdrawal is related to the rapidity with which the drug disappears from
the nervous system," Glick says. "It really reflects the change from the
drug state to the nondrug state." To test 18-MC's effect on withdrawal,
Glick gave the rats a continuous supply of morphine. He then administered an
opiate antagonist that removes morphine from the neurons in the brain and
causes immediate withdrawal symptoms. The rats given 18-MC suffered few if
any withdrawal symptoms. Unlike people who take ibogaine, who may tremble as
well as hallucinate, the animals seemed normal.

Hallucinogens like ibogaine raise serotonin levels in the brain; 18-MC
doesn't. At the same time, 18-MC counteracts the increase in dopamine levels
that opiates create. When Glick's addicted rats received 18-MC, their
dopamine levels plummeted. The next time the rats were offered their daily
hour of fun, they just said no. "Here's a drug that supposedly decreases
craving, that supposedly decreases self-administration, and it also appears
to block a key neurochemical correlate," Glick says. "But the real question
is how exactly it is doing this. And this question plagued us for several
years."

Activities in the brain occur at synapses, where neurons and receptors
almost touch. Neurons fire off chemicals known as neurotransmitters (of
which serotonin and dopamine are two), and neurotransmitters find their way
to particular receptors. By using a technique that isolates receptors,
called patch-clamp electrophysiology, Glick's colleague Mark Fleck
discovered that 18-MC blocks only one kind of receptor effectively (ibogaine
blocks several, which accounts for its many side effects). Receptors of this
kind are clustered in two very specific parts of the brain, which are
connected by a channel called the habenulo-interpeduncular pathway.

Since the 1960s, scientists have known that the brain's primary reward
circuit is the mesolimbic dopamine pathway. When rats are rigged with
electrodes that allow them to stimulate this pathway by pressing a lever,
they develop an instant and insatiable craving. "It's an amazing
phenomenon," Glick says. "The rats wake up and as soon as they find the
lever, they just go nuts pressing it. They'll do it to the exclusion of food
and water." When Glick went back and examined similar studies done in the
1980s, he discovered that rats would behave the same way if they were
allowed to stimulate another area of the brain -- the medial habenula. As it
happens, the medial habenula is also part of the habenulo-interpeduncular
pathway. "What we believe is that we've found an alternate reward system
that has been ignored for 15 years," Glick says.

The two pathways are tightly connected, and the secondary reward system
seems able to modulate the activity of the primary pathway. When 18-MC binds
to a receptor in the alternate circuit, it sends a signal to the main
circuit that dampens its responsiveness. When the rats in a later study had
18-MC injected directly into this secondary pathway, they all but stopped
administering morphine to themselves -- at least for a day, and sometimes
for a few weeks.

Despite the mounting evidence that 18-MC is a simple and clean way to end
addiction, Glick, like Lotsof, has had trouble raising funds to test the
drug on humans. The problem, he says, is guilt by association. In 1995 the
National Institute on Drug Abuse hired a panel of nine academics and nine
members of the pharmaceutical industry to review all the existing ibogaine
research. After hearing presentations from Lotsof and others, 16 of the
panel members reportedly voted to end trials of ibogaine in humans.
Unfortunately, Glick says, 18-MC was tarred by the same brush. "I keep
fighting the same battles over and over again," he says. "People lump 18-MC
with ibogaine, and I'm constantly making the same point -- that we've got
something that is a hell of a lot better."

In the meantime, Glick gets about three calls a month from addicts and their
families. "They're desperate for anything that will help," he says. "They've
tried everything. They always want to know when can I give them 18-MC, and
it's really hopeless. I'm just not in the position to do that yet."

SIDEBAR:

On the Caribbean island of St. Kitts, neuropharmacologist Deborah Mash of
the University of Miami has been running clinical trials of ibogaine on
addicts. Of the 272 patients she has treated, none have had major side
effects, and almost all have been drug-free at least a month.

RELATED WEB SITES:

Read summaries of current ibogaine findings in the Ibogaine Dossier:
www.ibogaine.org .