ECSTASY AGONISTES

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

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."

[sidebar]

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.