Research on Ecstasy Is Clouded by Errors
By Donald G. McNeil Jr.
In September, the journal Science issued a startling retraction.
A primate study it published in 2002, with heavy publicity, warned that the amount of the drug Ecstasy that a typical user consumes in a single night might cause permanent brain damage.
It turned out that the $1.3 million study, led by Dr. George A. Ricaurte of Johns Hopkins University, had not used Ecstasy at all. His 10 squirrel monkeys and baboons had instead been injected with overdoses of methamphetamine, and two of them had died. The labels on two vials he bought in 2000, he said, were somehow switched.
The problem corrupted four other studies in his lab, forcing him to withdraw four other papers.
It was not the first time Dr. Ricaurte's lab was accused of using flawed studies to suggest that recreational drugs are highly dangerous. In previous years he was accused of publicizing doubtful results without checking them, and was criticized for research that contributed to a government campaign suggesting that Ecstasy made "holes in the brain."
Dr. Ricaurte, a 50-year-old neurologist at Hopkins since 1988, is probably the best-known Ecstasy expert in the war on drugs. He has received $10 million from the National Institute on Drug Abuse, more than any other investigator of the amphetamine analogs known as designer drugs, club drugs or diet drugs, including MDMA, better known as Ecstasy, and its close relative MDA.
He vigorously defends his work, saying much of it has been confirmed by other researchers, and arguing that he is often unfairly attacked by scientists who minimize the dangers of designer drugs because they want to use them in research.
Johns Hopkins stands behind him. "The institution has every confidence in his ability," said Gary Stevenson, a spokesman. Of the primate study, he saidDr. Ricaurte "made an honest mistake, then discovered it and revealed it."
But other scientists, and two human research subjects of Dr. Ricaurte's who came forward after the retraction, say they see a pattern of shaky research supporting alarmist press releases.
It is hard to find impartial observers in the highly politicized debate over illegal drugs. But even three scientists whom Dr. Ricaurte cited in his own defense said that while his high media profile had made him a "whipping boy" for those favoring Ecstasy research, some of his best-known work has nonetheless been "sloppy" or "not as methodologically rigorous as you might want."
Longtime critics are harsher.
"It's hard to trust George," said Dr. Julie Holland, a professor of psychiatry at New York University who has edited a book on Ecstasy and wants to test it in psychotherapy. She accused him of "playing games with his data" to win more federal grants by making the drugs look bad.
Dr. Richard J. Wurtman, a prominent clinician at Harvard and M.I.T. who has clashed with Dr. Ricaurte, accused him of "running a cottage industry showing that everything under the sun is neurotoxic."
For 20 years, Dr. Ricaurte has produced studies saying the amphetamine analogs may cause the tremors of Parkinsonism, depression and memory and sleep problems. But the consensus among many amphetamine researchers, Dr. Ricaurte included, is that there is no proof thus far that Ecstasy causes permanent human brain damage. In animal studies, very high doses have destroyed serotonin-pathway nerves, which convey pleasure and affect memory and appetite.
Just last month Dr. Stephen J. Kish of the Center for Addiction and Mental Health in Toronto published a review of all Ecstasy research, including Dr. Ricaurte's, and concluded that there was no evidence that Ecstasy caused the tremors of Parkinsonism or any other brain damage "with the possible (but as yet unproven) exception of mild memory loss."
Some heavy users have memory problems, but no studies prove the loss is permanent, or that it is caused by Ecstasy rather than other drugs in the mix that virtually all heavy users take.
Ecstasy, invented in Germany in 1912 by Merck Pharmaceuticals in its search for an anti-bleeding drug, has been outlawed in the United States since 1985, a decision that Dr. Ricaurte has taken partial credit for. Since about 1970, when it was called Adam, some psychiatrists had tried giving low doses to trauma victims; in 1985, they stopped, fearing arrest.
Dr. Holland says it relieves anxiety-provoking memories like a sedative, but as an amphetamine, it does not induce sleep. Patients "want to talk things through."
As a potent painkiller, she said, it also may help the terminally ill.
The Food and Drug Administration recently approved a study in traumatized crime victims who have failed to respond to antidepressants. A study of rape victims is under way in Spain, and another one in the United States is proposed for depressed patients with terminal cancer.
When Dr. Ricaurte's 2002 primate study was published, his critics said he could not possibly have given "typical recreational doses" if 2 of 10 animals died and two others collapsed of heatstroke.
According to an annual federal survey, almost 10 million Americans have tried Ecstasy. Few have died. "Those dead animals should have sent up a red flag," said Dr. Charles R. Schuster, a former director of the national drug institute whom Dr. Ricaurte has called a mentor. "The better part of valor would have been to not publish until it was repeated."
Dr. Ricaurte said such arguments "do not hold water," since animal deaths are common in amphetamine research, and two is too few to compare to human death rates. Dr. Nora Volkow, the new director of the national drug institute, declined to pass judgment on his whole body of work, but called his latest error "crying wolf and losing your credibility." Because of it, she said, she spent a weekend checking the agency's Web page on the dangers of Ecstasy "to make sure it was not overstated."
The agency had already removed all current references to another well-known study from the site, one from 1998 by Dr. Ricaurte and his wife, Dr. Una McCann. Dr. Volkow described it as using "methodologies that were not optimal."
Pictures from the study 'PET scans of the brains of Ecstasy users' were used on a famous postcard from the drug agency, "Plain Brain/Brain After Ecstasy." The postcards were distributed to thousands of teenagers and implied that Ecstasy users had shrunken brains with holes in them.
The study had nothing to do with holes, but with serotonin levels, which Dr. Ricaurte found drastically depleted in 14 subjects who had taken Ecstasy 70 to 400 times.
Dr. Marc Laruelle, a Columbia University PET scan specialist, called the work so technically flawed that it was "something to put under the rug." He cited a recent German study showing that serotonin decreased only modestly and returned to normal within six weeks. The Hopkins team, he said, presented its data in logarithmically compressed graphs that seemed calculated to mask the fact that it had found impossible results: its 15 "control" subjects had serotonin levels 50 times normal.
Dr. Ricaurte defended the study, saying his recalculation technique was common when results from two groups varied widely, although he said he no longer used it.
Of the photos, Dr. Ricaurte said he had no control over what the national drug institute did with his work, but he had asked an agency official to fix their "poor quality."
In the 1990's, Dr. Ricaurte was involved in a dispute over the danger of dexfenfluramine, another amphetamine analog sold in Europe as a prescription diet drug.
In 1994, a company founded by Dr. Wurtman, director of clinical research at the Harvard-M.I.T. health science division, sought F.D.A. permission to market it in the United States.
Dr. Ricaurte released a study saying it caused brain damage; that was immediately disputed by an Environmental Protection Agency study that found it did no permanent harm.
In September 1995, Dr. Mark E. Molliver, a Hopkins colleague who frequently published with Dr. Ricaurte, presented slides to an advisory committee of the Food and Drug Administration showing Alzheimer's-like brain tangles.
Dr. Wurtman, who contacted The New York Times after the Science article retraction, said that Dr. Molliver, with Dr. Ricaurte in the audience, misled the committee by implying the damage was done by dexfenfluramine.
In an interview, Dr. Molliver called that "a blatant lie," and asserted that he had clearly said he was showing damage done by similar drugs. Dr. Ricaurte agreed.
But transcripts of a follow-up hearing in November 1995 provided by Dr. Wurtman show that several panelists and the F.D.A.'s expert were confused and believed that Dr. Molliver had been showing dexfenfluramine damage. Ultimately the drug was not approved.
For a week in 1996, Greg M. was one of Dr. Ricaurte's lab subjects.
At the time, he said, he was using large amounts of Ecstasy, marijuana, LSD, cocaine, amphetamines and heroin.
After seeing the retraction of the primate study, he contacted The Times, and persuaded a friend who had accompanied him to call, too.
The two revealed their names and occupations but declined to be fully identified for fear their former drug use would hurt their careers. Greg is a graduate student in chemistry at a leading university. His friend, who said he used to follow Grateful Dead tours selling up to 10,000 doses of LSD a month, now works at a West Coast law firm and is in line for a federal job.
Curious to see if they had damaged their brains, and enticed by a promise of $100 a day and a free East Coast trip, they enlisted.
Although the two used many drugs, the research assistant who interviewed them by phone told them what not to admit to her if they wanted to be in the study, Greg said. They were instructed to avoid all drugs for three weeks to avoid tainting the study; Greg says he had used heroin five days earlier.
They and other Ecstasy users flown in from the West Coast took memory tests while still jet-lagged, they said.
Then after lumbar punctures to check serotonin levels, neither was given the usual night's rest to prevent fierce headaches. They had to carry their backpacks across campus and be wired up for a sleep study, which Greg argued could not reflect normal sleep patterns because they were in pain.
Both had subsequent tests after shots of morphine and a drug, mCPP, that causes the same eyeball twitching and teeth-grinding as Ecstasy, but none of the euphoria. Then they had PET scans.
Dr. Ricaurte said his research protocols are approved by university committees. He acknowledged testing sedated or jet-lagged subjects, but argued that he had always noted that limitation in his published papers, and switched to testing in early mornings when jet lag was minimal. Test subjects who get lumbar punctures are warned about headaches, and given rest and painkillers, he said.
To weed out subjects who confound results by using other drugs, Dr. Ricaurte said, his staff quizzed volunteers and did blood and urine tests. His papers acknowledge that hair tests, which can show many drugs taken even months back, would have been more accurate. (Dr. Laruelle, who does PET scans of Ecstasy users, rejects subjects with hair less than an inch long.)
Told that Greg had used heroin without getting caught, Dr. Ricaurte said that was "unfortunate." But like all drug researchers, he said it was impossible to find heavy Ecstasy users who used no other drugs. His papers, he said, always warn that poor performance by heavy Ecstasy users may have been caused by other drugs.
His critics say that such fine-print disclaimers are not enough, that all mental tests on multiple-drug users are pointless and cannot be used as evidence that one particular drug damages the brain.
Greg's friend reiterated that he had been badly treated and said he felt the research was skewed to prove he was brain-damaged.
"Most of the people I used to do drugs with are pretty screwed up," he admitted. "But if Ricaurte's studies are true, Greg and I should both be dead. We ate grams a night of pharma-grade stuff."
Nonetheless, he said: "We're fairly intelligent, rational guys. We had a stretch of three or four years where we really blew ourselves out. But we're still smart and ambitious. Some of their assertions about long-term brain damage are way off."