Ecstasy AgonistesA retracted study on a controversial
substance raises questions about the reliability of
government-sponsored research on drugs
From the issue dated February 27,
Colloquy Live: Join a live,
online discussion with Rick Doblin, president of the
Multidisciplinary Association for Psychedelic Studies,
about research on the drug Ecstasy and whether its
dangers have been overstated for political reasons, on
Wednesday, February 25, at 2 p.m., U.S. Eastern
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."
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
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.
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
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
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'
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.
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
The image, once featured prominently on NIDA's
Web site, has been removed.
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
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
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,
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
Such explanations have done little to satisfy
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
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
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.
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
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.
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.
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
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
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
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
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
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.
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
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
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
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.
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.
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.
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
Methylenedioxymethamphetamine, or MDMA, is accidentally discovered
by the German pharmaceutical company Merck.
1970s: Some psychotherapists begin administering the drug to
help their patients relax and communicate more
1985: At the urging of the U.S. Drug
Enforcement Administration, the drug, which is being used
recreationally and is now called Ecstasy, is
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
1998: Dr. Ricaurte publishes another study of
the effects of Ecstasy on the brain.
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.
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
June 2003: In response to a letter published
in Science questioning his results, Dr. Ricaurte defends his
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
September 2003: Nearly a year after
its publication, Dr. Ricaurte retracts his 2002 paper.
Section: Research & Publishing
50, Issue 25, Page A14