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 work… 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."