E-fer madness

In one of the more embarrassing moments in drug research history, a study that "proved" how dangerous Ecstasy is was retracted after its authors realized they actually gave monkeys speed.

Published September 16, 2003 5:51PM (EDT)

In a bizarre turn of events, the results of the most widely publicized study on the effects of Ecstasy on the brain were recently retracted. Published in the journal Science in September 2002, the study found that Ecstasy dramatically damaged monkey brain cells and was even deadly in some instances. At the time the study was released, former National Institute for Drug Abuse (NIDA) director Alan Leshner called taking Ecstasy "playing Russian roulette with your brain." But critics scratched their heads, wondering how 40 percent of the test animals could die when so few humans actually OD on MDMA. Almost a year later, an investigation conducted by the study's own researchers has revealed that the monkeys were given speed, not the popular club drug. The lab animals, it seemed, were misdosed.

Although MDMA was invented in 1912 by the pharmaceutical company Merck, its value -- and its dangers -- began to be intensely debated only in the late '80s. From gray-haired professors to teen members of the harm-reduction organization DanceSafe, the pro-MDMA movement argues that when used safely, MDMA can be a miracle medicine for empathy and psychotherapeutic breakthroughs. Yet as it emerged from underground therapy circles and the London rave scene in the early '80s, it was subject to widespread use and abuse. In 1985, it was declared a Schedule 1 narcotic, a class of drugs deemed to have a high potential for abuse and no sanctioned medical use. Since that classification, Ecstasy use in America has increased each year. In 2000, the Drug Enforcement Administration seized 949,257 tablets, up from 13,342 in 1996.

In a two-part series this summer in Salon that brought on its own debate, I investigated the drug's appeal and downsides. My exploration was spurred by the now delegitimized report that appeared in the Sept. 27, 2002, issue of Science, the weekly peer-reviewed journal of the American Association for the Advancement of Science. One of the world's most esteemed research journals, Science published the results of a study called "Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ('Ecstasy')," aka the monkey study. Johns Hopkins neurologist Dr. George Ricaurte (working with three other researchers including Dr. Una McCann), aiming to mimic human Ecstasy habits, injected five monkeys with high doses of what he thought was MDMA every three hours. Some monkeys died; others experienced damage to the cells that secrete the brain chemical dopamine, damage that can cause symptoms similar to Parkinson's disease.

From NPR to the New Scientist the news spread, and the news was bad: Even one hit of the "club drug" can fry your brain, cause Parkinson's, or even kill you. Frightening facts for millions of Ecstasy users across the globe, but the reports were based on false data. The researchers had made a major error: They accidentally gave the monkeys methamphetamine -- aka speed -- not methylenedioxymethamphetamine (MDMA), commonly called Ecstasy. Speed is widely known to affect the brain's dopamine system, which in turn affects thinking and movement -- so Parkinson's-like symptoms would be expected.

How does one of the nation's most prestigious and well-funded research labs make such a colossal blunder? And how can such an error go undetected (or unacknowledged) for almost a year?

As detailed in the current issue of Science, where the study is officially retracted, Ricaurte explains that the labels provided by the lab's longtime supplier, Research Triangle Institute, were incorrect. Methamphetamine would be expected to produce the brain damage seen in the monkeys, the researchers said in their retraction. (If you've ever met a speed freak, that comes as no surprise.) When the researchers couldn't reproduce the data in subsequent studies (though this time they gave the animals oral doses, rather than injections as they had in the first study), they retraced their steps, finally realizing their mistake: A bottle of meth and a bottle of MDMA arrived in the same package and were evidently mislabeled.

"This is the kind of retraction nobody likes, but the only villain -- if there is one -- is the vendor that sent the compounds in mislabeled vials," says Donald Kennedy, editor of Science. "It is not unusual for experienced investigators to trust vendors they have worked with, and these authors had no reason to mistrust the labeling."

Research Triangle Institute did not return phone calls by press time. Neither Ricaurte nor McCann responded to repeated phone calls and e-mails from Salon. On Sept. 6, Ricaurte did tell the New York Times: "The laboratory made a simple, human error. We're scientists, not politicians. We're not chemists. We get hundreds of chemicals here. It's not customary to check them." According to the Baltimore Sun, Ricaurte's team is in the process of retracting another study -- which used the mislabeled vials -- linking MDMA to brain damage.

Johns Hopkins, which says it has no plans to take disciplinary action against the research team, released the following statement: "While it is unfortunate the labeling error occurred, this in no way undermines the results of numerous previous studies performed in multiple laboratories worldwide demonstrating the serotonin neurotoxic potential of recreational doses of MDMA in various animal species, including several primate species. The study results replicate what was previously published regarding the neurotoxic effects of methamphetamine use, and the researchers' efforts to investigate conflicting data in the laboratory are an excellent example of how science is self-correcting."

While it appears that a simple human mistake occurred, it's reasonable to ask why the study was published and so widely publicized without undergoing more fail-safe measures, which presumably would have exposed the egregious error. "The paper was peer-reviewed carefully by experienced, capable referees," says Science's Donald Kennedy. "The results and the presentation wouldn't have suggested that there was a problem, so I can't fault that process. And the authors did a hard thing: They discovered the problem and came right to us with the retraction."

While retractions in peer-reviewed journals such as Science are extremely rare and indeed newsworthy, the initial bad data takes on a life of its own. "One thing about retracted articles, they can be officially retracted, but the original article never goes away," says Michael Castleman, who has written on medicine and health for the past two decades. "The original study gets out on Medline [the medical research Web site] and other research hubs and will be quoted for 10 years. News of the study runs on Page 1, the correction runs on Page 17."

Looking back, none of the scientists I spoke with before the retraction could make sense of how MDMA could have killed the poor monkeys. "The abrupt deaths of two of the monkeys, the intense toxicity to most of the others, and the unexpected changes within the dopamine system, all seemed strange," says Dr. Alexander Shulgin, one of the drug's earliest researchers. The consensus among those who believe that MDMA's downsides have been overstated was that the dosage levels were unusually high -- researchers gave five monkeys high doses of "MDMA" every three hours -- exaggerating human use, rather than mirroring it.

For the past 20 years, Ricaurte has been considered one of the leading experts on MDMA and its effects. His research has been prominently featured on NIDA's Web site and cited in congressional testimony. He has received millions of dollars in funding for his research on MDMA and other drugs, research that has proved prominent in government's $54 million dollar effort in 1999 to educate the public about "club drugs." After the recent retraction, his critics make a dramatic charge: Ricaurte and his team were ardent to get their findings out to the public because the results were precisely the ammo the federal government needed for its War on Drugs.

"Ricaurte's got a long career of being funded by NIDA to say how dangerous MDMA is," says Dr. Julie Holland, an editor of "Ecstasy: The Complete Guide, A Comprehensive Look at the Risks and Benefits of MDMA," and the attending psychiatrist at the Bellevue Hospital Psychiatric Emergency Room. "He also should have known that no one else has been able to show dopamine damage from MDMA -- it should have occurred to him to question his results -- everyone else was suspicious of them. But instead of checking his work right away, they come up with a press release saying you're playing Russian roulette with the brain." Holland and others are calling for the release of the results from the oral replications -- the follow-up research that led to the study's retraction. "If Ricaurte can show neurotoxicity with those oral doses, then he'd silence his critics," says Holland. "If he can't, then that's interesting also."

The academic work of scientists in research labs around the country can have dramatic consequences for ordinary citizens. Ricaurte's findings were widely quoted when Congress was lining up support for the Illicit Drug Anti-Proliferation Act, also known as the Rave Act, which makes it easier to prosecute club owners and event promoters for the drug use of their customers. Congress passed the Rave Act on April 10, 2003. And tax dollars pay for public service announcements declaring that one hit of Ecstasy can destroy your brain.

"This study looks like high-class 'Reefer Madness,'" said Marsha Rosenbaum, director of the Safety First Project of the Drug Policy Alliance. "The government's trying to scare the kids out of experimentation and into abstinence, and it just doesn't work. The problem is that the kids after 20 years of these messages have become incredibly cynical about what we tell them about drugs. 'This is your brain on Ecstasy' turned out to be completely bogus -- so they roll their eyes and say, Who do they think they're kidding?"

Dr. Charles Grob, a professor of psychiatry at the UCLA School of Medicine, who 1994 conducted the first FDA-approved research study examining the effects of MDMA on human volunteers, has been a leading critic of the monkey study, as well as Ricaurte's earlier research of MDMA's effects on the brain. In 2000, he published an article in the journal Addiction Research examining what he felt were serious flaws in Ricaurte's research going back to the 1980s. "It's not that MDMA's without risk; that's not the case," says Grob. "But the neurotoxicity issue has been such an attention grabber that it's distracting us from more realistic concerns, such as people using the drug under adverse conditions, and the substitution of other drugs in pills passed off as pure MDMA."

To be sure, almost no one in the pro-MDMA movement says widespread pill popping is a good idea. What Grob and others believe is that with the rush to declare that MDMA fries your brain -- the neurotoxicity issue, an issue that clearly requires further research -- its therapeutic potential is being ignored. "It's certainly worth investigation," says Grob, "but we haven't been able to get to first base because everyone is so hyped up about neurotoxicity."

This fall, Rick Doblin, the founder of MAPS, a nonprofit organization that aims to develop MDMA into a FDA-approved prescription medicine, hopes to hit the home run of MDMA research. "It always shocked me that superimposed on MDMA -- which is a remarkably benign drug when used in therapeutic settings, with serious adverse effects quite rare even in uncontrolled recreational settings -- was an edifice of such fear and misinformation," he says. MAPS will examine the use of MDMA and psychotherapy for the treatment of patients with post-traumatic stress disorder (PTSD) in a clinic in Charleston, S.C. Doblin then plans to examine MDMA's use for alleviating anxiety, depression and pain in cancer patients at Harvard Medical School.

In the retraction, Ricaurte stands by what he believes are MDMA's considerable risks to the brain. Dr. Jean Lud Cadet, another leading expert on MDMA use and the brain, won't comment on the monkey study as he was not one of that study's researchers, but he remains steadfast in his belief that long-term Ecstasy use can lead to sleeping problems, depression and memory loss. Dr. Drew Pinsky, author of the book "Cracked," co-host of the radio show "Loveline," and director of the Department of Chemical Dependency Services at Las Encinas Hospital in Pasadena, Calif., points out some of the less deadly but nonetheless unfortunate side effects of prolonged MDMA use, explaining, "What we see clinically is a characteristic syndrome where very social people suddenly start isolating and soon they begin experiencing panic attacks and agoraphobia."

Where do we go from here? Somewhere between teenagers (or people who still think they are) doing too many doses at raves and "one hit of E can kill you" there may be acceptable therapeutic uses for MDMA. One thing is certain: After this mind-blowing blunder, everyone should heed that old raver adage -- mark your pills, people.

By Larry Smith

Larry Smith has written about his and other people's lives for ESPN magazine, the New York Times, Teen People, and other publications.

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