February 27, 2004 - The Chronicle of Higher Education (US)

Ecstasy Agonistes

A Retracted Study On A Controversial Substance Raises Questions About The Reliability Of Government-Sponsored Research On Drugs

By Thomas Bartlett

Until recently, Ecstasy had been very good to George A. Ricaurte. An associate professor of neurology at the Johns Hopkins University, Dr. Ricaurte is the nation's most prominent researcher on methylenedioxymethamphetamine, or MDMA, the chemical name for Ecstasy, a drug that produces feelings of intense euphoria, heightened sociability, and enhanced sensations like touch. His research in the mid-1980s was the first to suggest that the drug might be damaging to the serotonin system, which is important in regulating mood, sleep, appetite, and other functions. He has also received nearly $10-million in federal funds in the last seven years, and some of his research results have become key building blocks in the government's much-ballyhooed "war on drugs."

In an article published in the September 27, 2002, issue of the journal Science, Dr. Ricaurte (pronounced ri-CAR-tay) launched another salvo in support of that war. His article warned of new dangers attached to the use of Ecstasy, including the risk of severe brain damage and debilitating neurological diseases, such as Parkinson's-even from just one night of using the drug.

It was sensational and frightening news. Within days, Dr. Ricaurte's findings were printed in scores of newspapers around the world and repeated on television.

But that particular alarm about Ecstasy turned out to be false.

A serious and almost unbelievable mistake-the primates in the study were injected not with Ecstasy, but with methamphetamine-negated both the study and its startling results.

Almost exactly a year later, Dr. Ricaurte retracted the article.

That is the way science works.

A scientist makes a mistake, discovers it, and issues a retraction. End of story.

But this was not just any article, and Dr. Ricaurte is not just any researcher. His previous work had already attracted plenty of critics. Many of them are leading researchers themselves, who contend that Dr. Ricaurte's studies have been flawed and biased.

Specifically, some accuse him of overstating the dangers of Ecstasy to please his government backers.

The fallout from the mistake has brought not only Dr. Ricaurte's reputation into question, but also that of the National Institute on Drug Abuse, which has supported his research for years. "It kind of gives science a black eye because people start to question whether NIDA has an agenda," says Glen R. Hanson, a professor of pharmacology and toxicology at the University of Utah and a former director of NIDA.

The retraction has prompted some, like Charles S. Grob, a professor of psychiatry and pediatrics at the University of California at Los Angeles School of Medicine and a longtime critic of Dr. Ricaurte's work, to urge a second look. "The whole thing about Ricaurte really demands a thorough, objective re-evaluation of the whole record of MDMA research going back 15 years," he says.

At the least, say some researchers, future Ecstasy studies may be ignored or viewed more skeptically by the public. "An Ecstasy user is not going to believe any statement by a scientist," says Stephen J. Kish, head of the human-neurochemical-pathology laboratory at Canada's Center for Addiction and Mental Health. "Whether they did before, I'm not certain, but it's now going to be much more difficult."

Holes in the Research

It is not surprising that Dr. Ricaurte's 2002 claims inspired such a strong reaction.

The drug, first synthesized by the German pharmaceutical company Merck in 1912, has been used by millions of people for more than 20 years, and inspired a popular music and fashion subculture. Many former and current users wondered if the damage had already been done. But the 2002 study was not the first time that his work had landed in the public spotlight. Another article by Dr. Ricaurte, published in 1998, became the centerpiece of a provocative anti-Ecstasy campaign paid for by NIDA. In the study, Dr. Ricaurte scanned the brains of Ecstasy users and compared them with nonusers' brain scans.

In the advertising campaign, two of those images were combined into a single image that the drug-abuse agency used on its Web site and printed on posters and postcards.

The left half of the image is labeled "plain brain" and appears healthy and vibrant.

The image on the right, which is labeled "brain after Ecstasy" is much darker. An entire chunk of the organ is missing, as if the drug had eaten away part of the gray matter.

The compelling campaign seemed to prove that Ecstasy could cause severe, long-term brain damage. But was its message-based on Dr. Ricaurte's research-accurate?

A German study published last year using similar methods arrived at a very different result.

As in Dr. Ricaurte's study, a radioactive marker was used to tag serotonin neurons in the brains of human subjects, using Positron Emission Tomography, or PET, scans.

Recent users of Ecstasy and nonusers were scanned.

Instead of finding massive reductions in the number of serotonin neurons, as Dr. Ricaurte reported, the loss was small-about 4 to 5 percent.

And when the German researchers looked at those who had not used the drug recently, they found no decrease at all. There were no holes.

"I've been on record saying [Dr. Ricaurte's study] was terribly flawed and should not have been published," says Mr. Kish, who is also a professor of psychiatry and pharmacology at the University of Toronto. In November Mr. Kish published an article that highlights the contradictory results of the two studies.

In it, he also argues that there is little evidence that Ecstasy leads to Parkinson's disease.

Others, like Marc Laruelle, an associate professor of psychiatry and radiology at Columbia University and a specialist in PET scans, agree that Dr. Ricaurte's study was inaccurate.

In December The New York Times reported that two of Dr. Ricaurte's former subjects said they had been encouraged by a research assistant to lie about their past drug use and that they were mistreated during experiments. Dr. Ricaurte has defended his methods and called the use of heroin by a subject days before being tested "unfortunate." He stands by his 1998 article and says that improvements in technology account for the large discrepancy between the two studies.

But even Dr. Ricaurte has doubts about the "brain after Ecstasy" image used by NIDA. He says he mentioned once to an official at the drug-abuse institute that the image was of "poor quality" but didn't pursue the matter.

Asked why he didn't insist that it be corrected, Dr. Ricaurte at first says it was not his concern. When pressed, he concedes, "Maybe I should have picked up the phone and complained."

The image, once featured prominently on NIDA's Web site, has been removed.

Monkeys and Mistakes

The risks that Dr. Ricaurte examined in his retracted 2002 article in Science were different from those he had explored before.

While the bulk of previous research had focused on serotonin, this new study examined MDMA's effect on dopamine, a neurotransmitter linked to emotion and movement, among other functions.

For years, studies had suggested that MDMA affected only serotonin neurons.

Many researchers felt sure that it did not damage dopamine neurons. Dr.

Ricaurte decided to test that notion.

In his retracted article, he describes how five squirrel monkeys were given three doses-with three hours between each dose-of what turned out to be methamphetamine.

One of the monkeys had trouble walking after the second dose, so researchers did not administer a third. Another monkey died within hours of receiving the third dose, a victim of hyperthermia, or overheating.

Brain scans of the three monkeys that had tolerated the drug without apparent difficulty showed massive reductions in dopamine neurons.

Dr. Ricaurte later performed the same experiment on five baboons, again apparently mistakenly administering methamphetamine instead of MDMA. As in the first experiment, one of the primates died and the others suffered severe damage to their dopamine systems.

The project took about two years, according to Dr. Ricaurte. He argues that researchers who say he rushed his results into publication before thoroughly testing them are "uninformed." In an e-mail message, Dr. Ricaurte wrote, "We reject the notion that, due to our experience and knowledge of the literature, we should have concluded that there was some sort of error."

Such explanations have done little to satisfy critics.

Dr. Hanson, who was interim director of NIDA at the time of the study, was suspicious of the results from the beginning. "I had a chance to talk to him, and I said, 'George, we never see this. Where is this coming from?'" Dr. Hanson says. "And he said, 'Well, the dosing paradigm is different and there are some subtle differences and maybe there is just this little window that you don't see unless you do it exactly right.'"

Dr. Hanson was not persuaded. "I just said I really need to see this in more animals," he says. "And you always like to see it done in another lab."

Because of Dr. Hanson's doubts, the drug-abuse institute, which had given Dr. Ricaurte $1.3-million to carry out the research, did not publicize his results.

There was no press release, no mention on its Web site. Dr. Hanson says that while some have used the study to accuse NIDA of bias, "the irony is we totally stepped back from it because we wanted to see it replicated somewhere else."

One of the red flags for Dr. Hanson and others was the deaths from hyperthermia of two of the 10 primates cited in the article.

Deaths from hyperthermia do occur among Ecstasy users, but they are extremely rare. The drug can affect the body's ability to regulate temperature, and there is a risk of hyperthermia, albeit a small one, in people who are exercising vigorously or who are dehydrated. A recent British study of Ecstasy-related deaths in that country showed that most of those who died while on Ecstasy were taking it with another drug.

Dr. Ricaurte scoffs at the suggestion that the deaths of the two primates should have alerted him to a problem.

He says that Ecstasy is known to cause hyperthermia and that because the sample size was small, the high mortality rate was not significant. Dr. Ricaurte also points out that the paper made it through the peer-review process at Science. If the flaws were so obvious, he contends, "Science wouldn't have published the paper."

Donald Kennedy, editor in chief of Science and a former president of Stanford University, says that the publication of the flawed article does not mean that there was a breakdown in the peer-review process.

How, he argues, could peer reviewers have known about the drug mix-up? "Sometimes in science, mistakes get made and you discover ... a paper that on balance, with perfect hindsight, you wish you hadn't published," he says.

Alan I. Leshner, chief executive officer of the American Association for the Advancement of Science, which publishes Science, agrees with Mr. Kennedy's assessment. Mr. Leshner is a former director of NIDA, and some have speculated that he had a hand in getting Dr. Ricaurte's paper published -- a charge Mr. Leshner denies.

He says he was not even aware of the paper before it was published. He calls the retraction "unfortunate" but doesn't believe it should end Dr. Ricaurte's career. "I don't think he should be tarnished for a mistake that he very rapidly retracted," says Mr. Leshner.

Researchers like Mr. Kish, however, are less willing to let Science or Dr. Ricaurte off the hook. "How could Science accept an article purporting to show that Ecstasy causes dopamine neuron damage in monkeys without having mentioned in the article that two human studies have been conducted in which there was no evidence that Ecstasy caused the same type of brain damage?" he says.

Dr. Ricaurte says he was aware of the studies showing no effect on dopamine and noted in the article that in previous research Ecstasy had been shown to affect only serotonin neurons.

He says it was not necessary to cite the other research because the dosing regime-the frequency with which the primates were injected with Ecstasy -- had not been attempted in this way before, under these conditions. It was possible, Dr. Ricaurte says, that this dosing regime could account for the unusual results.

And yet, long before he acknowledged there had been a mistake, others in the field voiced skepticism. In fact, four months before the retraction, Rick Doblin, president of the Multidisciplinary Association for Psychedelic Studies, which supports research on the benefits of drugs like Ecstasy and marijuana, had a letter published in Science questioning Dr. Ricaurte's results. Dr. Ricaurte responded in the same issue, dismissing Mr. Doblin's concerns.

When that letter was published, Dr. Ricaurte says, he was trying to determine why he had been unable to replicate the results of his earlier experiments. The following month, he wrote to his backers at NIDA, telling them that the primates had been injected with methamphetamine, not MDMA. He blamed the error on "mislabeled drug bottles" from the supplier of the drug, RTI International. In the report to NIDA, he wrote that tests showed that bottles from the company labeled MDMA had contained methamphetamine, and vice versa. (A spokesman for RTI denies that the company mixed up the drugs, but offers no additional details.)

Dr. Grob, who has battled Dr. Ricaurte in public for years, has trouble believing that explanation. "How the hell could he have mixed up drugs?" says Dr. Grob. "It's unheard of. Where's the precedent for people doing this level research, of this supposed caliber, where they are mixing up drugs?" He goes on to call the retraction "one of the more bizarre episodes in the history of science."

The Straight Dope

So what do we know for sure about Ecstasy?

After it was created -- apparently by accident -- in 1912, MDMA mostly disappeared from view for the next 65 years.

It re-emerged in the 1970s when psychotherapists found that it helped patients relax and be more open.

In the early 1980s, MDMA moved out of the therapist's office and into the streets, acquiring the sexier name of Ecstasy. It became available for sale legally in some bars. At one point, tablets could even be ordered by telephone from a company in Texas.

That all changed in 1985 when Ecstasy was made illegal even for psychotherapy. That decision remains controversial, and Ecstasy advocates argue that it was banned before there was any evidence that the drug was dangerous.

Indeed, the first studies definitively linking MDMA to the damage of serotonin neurons came only after the drug was declared illegal.

One of those pioneering studies was the work of a young researcher named George Ricaurte.

In those early years, Dr. Ricaurte had a close working relationship with Mr. Doblin, a believer in the therapeutic uses of Ecstasy who nevertheless helped arrange financing and volunteers for Dr. Ricaurte's research. "I felt that those of us who were looking into the benefits should also be at the forefront of looking into the risks," says Mr. Doblin.

That working relationship broke down eventually as, in Mr. Doblin's view, his colleague began reporting his results selectively-trumpeting Ecstasy's harmful effects, and leaving out contradictory data.

That Ecstasy can damage serotonin neurons in animals is beyond question.

What is debatable is at what dose that damage occurs, whether the damage is permanent, and if the damage occurs in humans.

There is evidence suggesting that, at low enough doses, Ecstasy does not cause damage to the brain, according to Mr. Doblin. He says Dr. Ricaurte has consistently ignored and suppressed evidence of this "no-effect level."

That isn't so, according to Dr. Ricaurte. He says a study in squirrel monkeys did produce such results, but that there were good reasons not to publish them. "I discussed these data with Rick Doblin on numerous occasions and explained that until these negative data were fleshed out by conducting full dose-ranging studies, they would never be accepted by a peer-reviewed journal," he wrote in an e-mail message.

Besides, Dr. Ricaurte argues, the doses were much lower than what people normally take. "I think it's fair to say that if there is a margin of safety, it appears to be a narrow one," he says. As for the potential therapeutic benefits of the drug, Dr. Ricaurte says they are not his concern. "I'm a neurologist," he says. "What I can speak to are the risks. Period."

Collateral Damage

The effect of the retraction on Dr. Ricaurte's career is still unclear.

A spokesman for Johns Hopkins says the university has taken no action against him because it was determined that the drug mix-up was not his fault.

He continues to receive grants from NIDA, but some researchers, including Dr. Grob, doubt that his professional reputation can ever recover.

"I don't think he shot himself in the foot. I think he shot his whole foot off," says Dr. Grob. Dr. Ricaurte argues that the retraction should bolster his credibility. "Anybody who looks at this current situation would see that here is a scientist who recognized an error and immediately did everything in his power to correct the scientific record as quickly as possible," he says. Dr. Ricaurte continues to research the possibility that MDMA harms the dopamine system.

Larger questions about the future of Ecstasy research-and its public reception-remain open. Martha Rosenbaum, who has also received NIDA grants to study Ecstasy, says Dr. Ricaurte's studies have contributed to a steady stream of misinformation about the drug that has led to fear-driven legislation. For instance, a bill recently passed by Congress allows the government to prosecute the owners of establishments where drugs like Ecstasy are used.

"I'm now convinced that any information coming out of the government is suspect," says Ms. Rosenbaum, who is a staff member at the Drug Policy Alliance, which opposes current drug policy.

The controversy comes at a time when researchers like Marc Laruelle at Columbia believe that they are on the brink of understanding how Ecstasy affects the brain.

A new, more accurate radioactive marker is being used that scientists say will produce much more reliable brain scans. "I think it's very important that scientists behave in a way that's going to increase the trust of the public," says Dr. Laruelle.

Last month a study into the therapeutic possibilities of Ecstasy sponsored by Mr. Doblin's organization was given final government approval. His goal is to make MDMA into a prescription medicine for the treatment of post-traumatic stress disorder.

"We've got megamillions going into the demonization of Ecstasy," Mr. Doblin says, "and all we need is $5-million to do the clinical trials that will be necessary to provide the data to decide if this drug will be a helpful medicine to many, many people."

The new director of NIDA, Nora D. Volkow, worries that the retraction has sent the message that Ecstasy has been proved harmless, which is not true. She says she is committed to making sure that the information the agency disseminates is as accurate as possible. "The question that comes to light is, why has this attracted so much attention?" she says. "And I think perhaps it's because some people are exaggerating the adverse effects of drugs."

KEY MOMENTS IN ECSTASY RESEARCH

1912: Methylenedioxymethamphetamine, or MDMA, is accidentally discovered by the German pharmaceutical company Merck.

Late 1970s: Some psychotherapists begin administering the drug to help their patients relax and communicate more freely.

1985: At the urging of the U.S. Drug Enforcement Administration, the drug, which is being used recreationally and is now called Ecstasy, is banned.

1988: George A. Ricaurte, a researcher at the Johns Hopkins University, publishes one of the first studies linking Ecstasy to damage of serotonin neurons, which help regulate mood.

1998: Dr. Ricaurte publishes another study of the effects of Ecstasy on the brain.

2000: The National Institute on Drug Abuse uses Dr. Ricaurte's 1998 study as the centerpiece of a campaign against the drug, distributing 740,000 postcards advertising its ill effects.

September 2002: Dr. Ricaurte publishes his paper "Severe dopaminergic neurotoxicity in primates after a common recreational dose of MDMA" in Science, saying that Ecstasy causes severe damage to the dopamine systems of primates.

March 2003: A German study is published that challenges Dr. Ricaurte's 1998 findings.

June 2003: In response to a letter published in Science questioning his results, Dr. Ricaurte defends his study.

July 2003: Dr. Ricaurte writes to his backers at NIDA informing them of his inability to replicate the results and his suspicions that bottles labeled MDMA actually contained methamphetamine.

September 2003: Nearly a year after its publication, Dr. Ricaurte retracts his 2002 paper.