RESEARCH ON ECSTASY IS CLOUDED BY ERRORS

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 said Dr. 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 aEUR" invented in Germany in 1912 by Merck Pharmaceuticals in
its search for an anti-bleeding drug aEUR" 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 aEUR" PET scans of the brains of Ecstasy users
aEUR" 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."