ON ECSTASY, CONSENSUS IS ELUSIVE

Study Suggesting Risk of Brain Damage Questioned by Critics of Methodology

New research has escalated a decades-old scientific and political battle
over the risks inherent in the popular street drug known as Ecstasy.

A synthetic chemical cousin of "speed," Ecstasy already had a rap sheet as
long as its chemical name: 3,4-methylenedioxymethamphetamine, or MDMA.
Studies in animals have suggested it may be toxic to brain cells that help
regulate mood. It's been linked to memory impairment in some users. And
rarely the drug triggers a mysterious reaction in which the body becomes
radically overheated, causing sudden death.

If that weren't enough to make potential users think twice, Ecstasy is
highly illegal. The Drug Enforcement Administration (DEA) has placed it in
its most restrictive "schedule 1" category, meaning it has no medical value
and carries serious risks.

Last week, researchers added to the agony of Ecstasy by reporting in the
Sept. 27 issue of Science that, in monkeys, at least, even one night's
indulgence in the drug may increase the odds of getting Parkinson's
disease. Yet despite all the evidence against it, Ecstasy's popularity has
only grown in recent years, with about 10 percent of U.S. high school
students saying they've tried it in the past 12 months. That pattern is
testimony to the profound sense of peace and open-heartedness that Ecstasy
users say the drug delivers. But it is also the result of a deep distrust
of the evidence of Ecstasy's harm -- not only by youthful partygoers but
also by a cadre of scientists and others who have been arguing with
increasing fervor that much of the work, including the latest study, is flawed.

A close look at the evidence presented by both sides shows how difficult it
can be to judge the long-term significance of drug- induced changes in the
brain.

Ecstasy produces its pleasurable effects largely by making neurons secrete
massive amounts of serotonin, the same chemical that is the target of some
antidepressants. Studies in monkeys -- and less definitive studies in
people -- have suggested that Ecstasy can damage the tiny branching fibers
that allow those neurons to communicate with nearby cells, perhaps permanently.

George Ricaurte, a Johns Hopkins University neurologist who has led many
Ecstasy studies, said the evidence is overwhelming that the drug is
dangerous. "My belief and the belief of the vast majority of others is that
the [serotonin-producing] nerve endings are destroyed by the drug. It is a
pruning, if you will."

Others, however, strongly disagree. They say results in animals have varied
so much from species to species -- and the doses given the animals have
been so high -- that extrapolation to humans is unreliable. Moreover, they
say, human studies have rarely controlled for concomitant use of other
drugs (some scientists think the small memory decline seen in some Ecstasy
studies is actually due to participants' use of marijuana). And the few
human brain scan studies that have been published used old and
untrustworthy imaging technology.

"In my opinion . . . these studies are so flawed in terms of the technology
used that one cannot derive any conclusion from them at all," said Stephen
Kish, another leading Ecstasy researcher and chief of the human
neurochemical pathology laboratory at the Center for Addiction and Mental
Health in Toronto.

The newest study, led by Ricaurte and involving monkeys and baboons, sought
to more closely mimic human Ecstasy use by giving three consecutive doses
of the drug at three-hour intervals -- as if the animals were at an
all-night "rave." In contrast to previous human studies, brain scans found
evidence of damage not only to serotonin neurons but also to neurons that
produce dopamine.

Dopamine levels were down about 65 percent six weeks after the test. If
those reductions are permanent, Ricaurte said, users may be vulnerable to
early-onset Parkinson's (which is caused by reductions of about 90 percent)
when levels drop further as a natural result of aging. "The margin of
safety for MDMA appears to be extremely small, if present at all," he said.

Alan Leshner, former director of the National Institute on Drug Abuse
(NIDA) and chief executive of the American Association for the Advancement
of Science, which publishes Science, agreed. "This says even a single
evening's use is playing Russian roulette with your own brain," he said.

Critics, however, noted that the drug was given in human-equivalent doses
but was injected into the animals, a route that Ricaurte himself has shown
to be twice as potent as taking the drug orally. Adding to evidence that
the test involved overdoses, two of the 10 animals in the experiment died
quickly after their second or third dose and two others became so sick they
could not take the third dose.

"How come 40 percent of people who are doing this drug are not dying or
almost dying?" asked Rick Doblin, president of the Multidisciplinary
Association for Psychedelic Studies, a Sarasota- based organization that
funds research on therapeutic uses of mind- altering drugs.

Several experts said Parkinson's symptoms have never been associated with
Ecstasy users -- even those who have been taking it regularly for years.
Some called the new work the latest in a string of biased studies sponsored
by the federal government.

Federally funded research on Ecstasy is "an egregious example of the
politicization of science," said Charles Grob, a neuropsychiatrist at the
University of California at Los Angeles School of Medicine, in testimony
last year before the U.S. Sentencing Commission. "Much of the NIDA-promoted
research record . . . suffers from serious flaws in methodological design,
questionable manipulation of data, and misleading and deceptive reporting
in the professional literature and to the media."

Kish of Toronto said the one serious risk clearly linked to Ecstasy is
"malignant hyperthermia," an unpredictable onset of high fever and sudden
death. He said New York, a city estimated to have thousands of users,
experiences about one death a year linked to Ecstasy by itself and about
seven a year involving Ecstasy with other drugs. Leshner's Russian roulette
analogy only makes sense, he said, if one imagines a gun with one bullet
and "thousands and thousands and thousands of chambers."

To be sure, Kish said, that risk is not zero and needs to be taken
seriously. And the picture could get worse when definitive human brain
imaging studies are completed in the next year or so. New, high-tech
equipment being used in those studies should settle the question of
neuronal damage.

But if the results amount to something less than an indictment, then
scientists will have to consider whether the potential psychological
benefits might in some cases be worth the risks. That will require a new
batch of studies, looking not for damage but for evidence of healing.

Last fall, the Food and Drug Administration gave the green light to the
first such study, which would test Ecstasy's usefulness as an adjunct to
therapy for people with post-traumatic stress disorder as a result of
sexual or other violent assaults.

That study, sponsored by Doblin's organization and set to take place in
Charleston, S.C., is awaiting approval by the DEA.

Marsha Rosenbaum, a director at the New York-based Drug Policy Alliance,
warned that anti-drug advocates could harm their own cause by just saying
no to the possibility that some illicit drugs might be therapeutic.

"Like everyone, young people stop trusting you when you bend the truth to
scare them," Rosenbaum said in a statement. "Good science, not misguided
fear, is what helps us talk honestly and effectively with our teenagers
about drug use and their safety."