RETRACTED ECSTASY PAPER "AN OUTRAGEOUS SCANDAL"

Prominent scientists who raised concerns about paper now say Science
should publish referees' reports

The retraction last week of a highly controversial paper published in
Science September 2002, which purported to show that the recreational
drug Ecstasy (methylenedioxymethamphetamine, or MDMA) caused severe
damage to dopaminergic neurons, predisposing takers to Parkinson
disease, has prompted two leading British scientists to call for the
journal to publish the referees' reports.

Colin Blakemore-professor of physiology at Oxford University and
chairman of the British Association for the Advancement of Science,
who will shortly take up the position of chief executive of the UK
Medical Research Council-and Leslie Iversen-a prominent pharmacologist
who holds professorships at King's College London and Oxford
University and reviewed the effects of cannabis for a House of Lords
select committee report-both made the recommendation in interviews
with The Scientist last week.

Even before the retraction, Blakemore and Iversen had been involved in
a lengthy e-mail exchange about the original paper with Donald
Kennedy, the editor-in-chief of Science, last year. Neither believed
the paper should have been published, because of several glaring
discrepancies.

The retraction came about because George Ricaurte of Johns Hopkins
University, lead author of the paper in question, discovered that
certain reagents had been mislabeled after further experiments had
failed to reproduce the results. It turned out that the monkeys and
baboons in the experiment had received methamphetamine ("speed"), a
more dangerous drug that has a known effect on the dopamine system,
not MDMA, which mainly affects serotonin. The reagents had been
obtained through the National Institute on Drug Abuse (NIDA).

Science argued the retraction itself was good news for research. In a
public statement accompanying the retraction, Katrina Kelner, deputy
managing editor for Life Sciences, wrote, "The problem, in this case,
was something that would have been almost impossible to pick up with
peer review. The authors are to be commended for so thoroughly
investigating the conflicting data that they had received in their
laboratory, and for tracking down the source of the inconsistencies.
This is an excellent example of how science is self correcting-in this
case, even within the same lab."

But Blakemore and Iversen had concerns about the work even before the
mislabeling came to light. The paper claimed to demonstrate that
dopaminergic neurons were damaged after MDMA doses equivalent to those
typically taken recreationally by humans. In the original Science
press package distributed to journalists, "damaged" was altered to
"destroyed." According to Blakemore, Kennedy told him in an e-mail
exchange that this was done "after consultation with the authors."
Understandably, media reports found the release sensational and
claimed a night's clubbing could give you Parkinson disease.

Ricaurte later told a journalist that the press release "was never
meant to imply that cell bodies had degenerated." Kennedy was
unavailable to comment to The Scientist, but Ginger Pinholster,
director of the Office of Public Programs at the American Association
for the Advancement of Science (AAAS), which publishes Science,
pointed out that only one paragraph of the press release said
"destroyed," whereas all the other paragraphs said "damaged."

"That's true," Blakemore told The Scientist, "but the crucial
paragraph, and the one that got reproduced in press reports around the
world, said 'destroyed.' And it's quite clear that the authors
intended that, as they point out that Parkinsonian symptoms arise when
60 to 80% of dopaminergic cells are destroyed, and say that we can
therefore expect an epidemic of Parkinson's disease."

There were obvious weaknesses in the paper, claimed Blakemore. First,
40% of the animals given supposed MDMA at a "common recreational dose"
were found to be dead or dying. "But police [in the UK] estimate that
one million young people take Ecstasy each weekend, yet there are only
a few deaths each year," Blakemore told Kennedy.

Second was the question of the dose. The drug was administered
subcutaneously, which would give a much larger dose to the brain than
the usual clubber's tablet, Iversen told The Scientist; but blood
plasma levels of the drug were not measured.

And third was the extreme effect on the dopamine system, which had not
before been recorded for MDMA but was known for methamphetamine (the
drug actually administered, as it later turned out).

According to Blakemore, Kennedy suggested Blakemore and Iversen submit
a "technical comment" to Science, which would have been permanently
associated with the paper. "We thought a lot about that," Blakemore
told The Scientist. "Don Kennedy had admitted there was a problem
[with the dose and plasma levels], and we thought that if anyone was
to make a correction it should be Science itself. It would have had
much less impact if two scientists sent in a carping note. It was a
point of principle."

The issue is no small spat, but of profound public importance, say
Blakemore and Iversen. "Scientific evidence is of crucial importance
in our approach to the problem of drug abuse," Blakemore wrote to
Kennedy last year, "but deliberate misrepresentation or exaggerated
presentation of risk is likely to do more harm than good."

"It's an outrageous scandal," Iversen told The Scientist. "It's
another example of a certain breed of scientist who appear to do
research on illegal drugs mainly to show what the governments want
them to show. They extract large amounts of grant money from the
government to do this sort of biased w ork. I hope the present
retraction and embarrassment to the people involved will be some sort
of lesson to them."

The paper was published and widely publicized shortly before
"anti-rave" legislation promoted by Senator Joe Biden came up for
consideration in Congress, and it may well have influenced congressmen
to support the legislation, passed earlier this year as the Illicit
Drug Anti-Proliferation Act of 2003. This act is considered to make
club and other "rave" venue owners responsible and liable for illicit
drug taking on their premises, even if it is without their knowledge,
and has met much public opposition.

Una McCann, one of the coauthors of the paper, told The Washington
Post she regretted the role the false results may have played in the
debate. "I feel personally terrible," she said. "You spend a lot of
time trying to get things right, not only for the congressional record
but for other scientists around the country who are basing new
hypotheses on your work and are writing grant proposals to study
this." Neither Ricaurte nor McCann responded to queries from The
Scientist for this article.

"This paper was submitted at the end of May and accepted in August.
But it was obvious at a glance that there was something fishy about
this paper," Blakemore told The Scientist. "We should see the reports
of the referees, without disclosure of their identity, of course."

"Science is a very high quality journal, with very rigorous reviewing
procedures, so I don't know how this paper got through the system,"
Iversen told The Scientist, "but I suppose the result was so dramatic
in the few animals that survived that it was felt to be of high
general interest. I agree with Colin Blakemore. They should publish
the referees' reports. AAAS should be embarrassed about this too."

The chief executive officer of the AAAS, Alan Leshner, was director of
NIDA until September 2001. NIDA has supported much of Ricaurte's
extensive work on MDMA neurotoxicity. But, after seeking the facts
from Leshner, Pinholster told The Scientist, "No one [in the editorial
unit of Science] had even alerted Dr. Leshner that the paper was
pending, much less asked his opinion. The peer review process is
handled strictly by Science's editorial unit."

Links for this article G.A. Ricaurte et al., "Retraction," Science,
301:1479, September 12, 2003. http://www.sciencemag.org/

G.A. Ricaurte et al., "Severe dopaminergic neurotoxicity in primates
after a common recreational dose regimen of MDMA ("ecstasy"),"
Science, 297:2260-2263, September 27, 2002. [PubMed Abstract]

P. Hagan, "New MRC head named," The Scientist, May 13, 2003.
http://www.biomedcentral.com/news/20030513/03/

Cannabis: The Scientific and Medical Evidence, House of Lords Select
Committee on Science and Technology, Ninth Report, November 4, 1998.
http://www.erowid.org/plants/cannabis/uk_lords_report/IndexOfReport.shtml

National Institute on Drug Abuse http://www.nida.nih.gov/

American Association for the Advancement of Science
http://www.aaas.org/

Illicit Drug Anti-Proliferation Act of 2003
http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=108_cong_bills&docid=f:s226is.txt.pdf