Neurotoxicity of MDMA controversy

"Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA^[1] ("ecstasy")'" is the title of a paper by Dr. George Ricaurte which was published in the leading journal Science and was later retracted.

The retraction of the paper led to questions over its publication. It has also been asserted that this questions the peer review process. Many have also argued that the failings in the paper (use of materials other than those specified) could not have been caught by peer review; and that the scientific process did work successfully in the end, in that the article was ultimately retracted.

The paper was published in the 27 September 2002 issue of Science (volume 297, pages 2260-3). The article had been submitted to Science on 29 May 2002 and was accepted for publication on 14 August 2002. Neither the time required for peer review nor the time between acceptance for publication and actual date of publication were unusual.

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Original publication

The Ricaurte article was published in the middle of a group of 16 "reports" and not given special prominence in the "Highlights of research in this issue" section of the 27 September 2002 issue of Science. The short editorial commentary on the article was called "More Dangers from Designer Drugs" and drew the reader's attention to previously published research indicating that "ecstasy" use alters serotoninergic synaptic transmission. Science also commented that by linking "ecstasy" to dopaminergic neurotoxicity in monkeys, the Ricaurte article suggested that recreational users of "ecstasy" might be putting themselves at risk for developing neuropsychiatric disorders that are related to dopamine dysfunction.

The Science section called "News of the Week" in the 27 September 2002 issue had an article by reporter Constance Holden called, "Drug Find Could Give Ravers the Jitters" (on pages 2185-2187). This news coverage did give some special prominence to the Ricaurte article. The Holden commentary stressed that the Ricaurte article was part of an active scientific controversy about the ability of "ecstasy" to cause permanent brain damage in human recreational drug users. This news article included a section with speculation from Ricaurte trying to justify why other researchers fail to observe ecstasy-induced dopaminergic neurotoxicity. Jon Cole of the University of Liverpool explained that the results on dopaminergic neurotoxicity in the Ricaurte article were a big surprise and was quoted as saying, “The entire human literature relies on the notion that MDMA is a selective serotonergic neurotoxin.”

Press response to original publication

Alan Leshner, former director of the National Institute on Drug Abuse (NIDA) and chief executive of the American Association for the Advancement of Science, which publishes Science, agreed. This says even a single evening's use is playing Russian roulette with your own brain, he said.

—Washington Post, September 30 2002

Ricaurte's findings were widely quoted when Congress was lining up support for the Illicit Drug Anti-Proliferation Act, also known as the Rave Act, which makes it easier to prosecute club owners and event promoters for the drug use of their customers. Congress passed the Rave Act on April 10, 2003. And tax dollars pay for public service announcements declaring that one hit of Ecstasy can destroy your brain.

—E-fer Madness, Salon.com, 2003

RAVE Act

The retracted paper left the public with the impression that ecstasy is far more hazardous than it may actually turn out to be. This perception may have influenced the fate of the Reducing Americans' Vulnerability to Ecstasy Act. The act, which was appended to another bill and signed into law in April, holds club owners responsible for drug use on their premises. Critics say it is unlikely to reduce ecstasy use, but may discourage club owners from voluntary measures to protect users, such as cool-off rooms for the dangerous overheating that can occur with ecstasy, as these are tantamount to admission that drug use is going on. The legislation might have passed anyway, even if Ricaurte' s study had never been published, but the news certainly lent it urgency.

—Nature 2003

Weeks after the botched study was published, its conclusions were repeatedly invoked by witnesses at a House subcommittee hearing on the Reducing Americans' Vulnerability to Ecstasy Act (RAVE Act)

—Village Voice 2004

Published concerns about the study

The 6 June 2003 issue of Science contained a letter ("MDMA ("Ecstasy") and Neurotoxicity", volume 300, pages 1504-1505) that questioned the results of the September 2002 Ricaurte article. Ricaurte was allowed to provide a reply. Ricaurte stood by the results of the September 2002 article and further suggested that even careful clinical MDMA research ran the risk of causing brain injury.

Formal retraction

The retraction of the September 2002 Ricaurte article was published in the 12 September 2003 issue of Science (volume 301, page 1479). Ricaurte said that methamphetamine had been the cause of the previously reported dopaminergic neurotoxicity, not "ecstasy". The retraction letter seemed to suggest that the supplier of the drugs had switched the labels on two bottles (one containing "ecstasy" and one containing methamphetamine) that were shipped to the Ricaurte lab on the same day.

Aftermath of the retraction

In the 12 September 2003 issue of Science there was also another Constance Holden "News of the Week" article called "Paper on Toxic Party Drug Is Pulled Over Vial Mix-Up". Holden reported that the drug supplier, Research Triangle Institute, was conducting a thorough review of its procedures to see if it could have switched the labels on the drug bottles. Ricaurte was reported to still be interested in previous results that suggested MDMA is toxic to dopamine neurons in mice.

In a review of the year's events published in the 19 December 2003 issue of Science (volume 302, page 2033), Editor-in-Chief Donald Kennedy wrote, "It was also a vintage year for scientific fluffs. We shared in one: Some vials containing the recreational drug Ecstasy got switched with vials containing methamphetamine, and we wound up publishing a paper we wish we hadn't".

An editorial in the journal Nature called the retraction "one of the more bizarre episodes in the history of drug research" and noted that "Some observers have in the past questioned NIDA's ability to maintain its independence in the face of the immense pressures brought to bear by those who stand behind America's interminable 'war on drugs'."

Another remarkable aspect of this episode is the public endorsement of the study, at the time of its publication, by Alan Leshner, chief executive of the AAAS and former director of NIDA. It isn't clear why an officer of the AAAS should be involved at all in publicly promoting a particular result published in its journal, least of all one whose outcome was questioned at the outset by several experts. The AAAS issued the retraction late in the afternoon on Friday 5 September, resulting in low-key media coverage, which contrasts sharply with the hype surrounding the initial paper.

—Nature 2003

In an interview in The Scientist British scientists Colin Blakemore and Leslie Iversen described how they expressed concerns about the article with editors at Science. "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."

Notes and references

1. ^ 3,4-methylenedioxymethamphetamine (MDMA) is the chemical name for the psychotropic drug commonly known as "ecstasy".

See also

• Methylenedioxymethamphetamine
• Ecstasy Rising, 2004 ABC television documentary with Peter Jennings.
• RAVE Act
• National Institute on Drug Abuse (NIDA)
• American Association for the Advancement of Science (AAAS)