Source: Washington Post
Date: September 30 2002

On Ecstasy, Consensus Is Elusive

Study Suggesting Risk of Brain Damage
Questioned by Critics of Methodology

By Rick Weiss
Washington Post Staff Writer

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."

George Ricaurte
Ecstasy or speed?
Protect and survive
Ecstasy: 'neurological time bomb' or labelling error?
Dr Ricaurte's retracted "Ecstasy"/Parkinsonism paper

Go To Good Drug Guide
Fritz Haber
MDMA: hotlinks
Claudio Naranjo
MDMA: synthesis
The Good Drug Guide