Reevaluation of the Risks of MDMA after the Ricaurte/McCann Retraction

Exaggerating MDMA’s Risks to Justify A Prohibitionist Policy
by Rick Doblin, Ph.D.
January 16, 2004

The Ricaurte et al. retraction of their article claiming that MDMA causes Parkinson’s, originally published in Science in September 2002 and retracted in September 2003, has created a unique opportunity for an interwoven series of challenges to the perception that any use of MDMA (Ecstasy) is exceptionally risky and dangerous. This perception has been created in the minds of the general public, regulators and lawmakers by NIDA/ONDCP/DEA/ Partnership for a Drug-Free America. According to this dominant but misleading view, even a single or a few uses can cause significant long-term brain damage with important deleterious functional consequences. From a scientific perspective, however, claims about the negative effects of MDMA on dopamine, serotonin and cerebral blood flow, by Drs. Ricaurte, McCann and Dr. Alan Leshner, ex- Director of the National Institute on Drug Abuse, respectively, have either been retracted, shown to contain major methodological flaws, or are clearly misleading.

The controversy surrounding the retraction provides some relatively easy ways to explain how scientific information has been misleadingly presented by grant- addicted scientists and prohibitionists and has facilitated the ramping up of the penalties against the non-medical use of MDMA, the efforts to shut down the rave movement, and the pressure to prevent research into the therapeutic uses of MDMA-assisted psychotherapy. Fortunately, the new NIDA Director Dr. Nora Volkow seems likely to live up to a statement she made in an August 19, 2003, New York Times interview, in which she said “If you want to be a scientist, you cannot allow politics to get in the way of your objectivity.”

1. MDMA and Dopamine

Ricaurte/McCann now acknowledge that their evidence about MDMA damaging dopamine neurons was erroneous (Ricaurte et al. 2003) and was based on the mistaken administration to their primates of methamphetamine instead of MDMA, supposedly due to mislabeled 10 gram bottles of MDMA and methamphetamine which arrived from the same provider in the same package. A September 18, 2003 editorial in Nature asked NIDA Director Nora Volkow to conduct a “thorough public review of the circumstances and participant’s roles in one of the more bizarre episodes in the history of drug research. The Nature editorial also accused former NIDA Director Leshner, now Executive Director of the American Association for the Advancement of Science (AAAS), which publishes Science, of “pander [ing] to the Bush administration’s jihad against recreational drug use. ” The accusation was based in part on his hyperbolic statements in the press release that Science issued to draw attention to the original article, in which he said, “Using Ecstasy is like playing Russian roulette with your brain function.” A September 18, 2003 news report in The Scientist mentions that Ricaurte/McCann have retracted a second paper and reports that two senior British scientists have demanded that Science investigate its review of the original article and release the comments of the peer reviewers.

An October 14, 2003 article in Lancet Neurology reports that MAPS has filed a FOIA request with NIDA seeking more data on Ricaurte/McCann’s other recent NIDA-funded research in order to determine whether additional studies need to be retracted. To date, Ricaurte et al. have accounted for less than 2 1/4 grams of the 10 grams of methamphetamine that was contained in the original bottle mislabeled MDMA, all of which was used in research before the mislabeling was discovered. No accounting has yet been made of which studies used the MDMA from the bottle mislabeled methamphetamine.

Since MAPS is seeking to conduct FDA-approved research in which MDMA is administered to human subjects, our FOIA request also seeks the release of more details about the design and results of Dr. Ricaurte and McCann’s subsequent studies that they mention in their retraction, in which they administered genuine MDMA to primates, both orally and by injection, and found no evidence of dopaminergic neurotoxicity. These studies can provide data that bears directly on the estimation of the risk of dopaminergic neurotoxicity to subjects in the human research that MAPS is seeking to conduct.

Ricaurte/McCann’s anti-Ecstasy bias is now more clearly visible. In their original Science paper (Ricaurte et al. 2002) with its surprising results, the authors ignored three published human studies showing no effect of MDMA on dopamine (Kish 2000; Reneman et al. 2002; Semple et al. 1999), claimed that they administered the equivalent of a “common recreational dose regime” despite a reported 20% mortality rate in their primates (later modified to a 13.3% death rate when Ricaurte et al. admitted that they actually used 5 more animals than they reported to gather the data for their original Science article), and ignored their own research showing that oral administration of MDMA is less neurotoxic than the injection of MDMA (Ricaurte et al. 1988). These and other criticisms of the original study were published in Science in a letter written by the MAPS MDMA/PTSD research team (Mithoefer et al. 2003).

Ricaurte et al.’s retraction letter itself provides further evidence of their anti- Ecstasy bias. In the retraction letter, Drs. Ricaurte and McCann still claim that doses of MDMA used by some humans could cause dopaminergic neurotoxicity and Parkinson’s, based on exceedingly flimsy evidence.

Ironically, recent animal research has been published showing that MDMA, when administered in combination with L-Dopa, actually helps reduce dyskinesias, painful symptoms of Parkinson’s (Iravani et al. 2003).

2. MDMA and Serotonin

McCann et al.’s evidence from their PET studies in Ecstasy users on which they based their claims that MDMA causes massive reductions in serotonin, published in the Lancet (McCann et al. 1998), are now generally considered to be based on methodologically flawed data. Basically, the values for the serotonin transporter levels in McCann’s control group are so spread out, with some control subjects having 35 times more serotonin transporters than others, as to be biologically implausible. To deal with this variation, McCann et al. log transformed their data, something no other PET researchers have needed to do (Kish 2002). Subsequent studies by other researchers using the same PET technique generated control values similar to McCann’s Ecstasy users. A much larger and better controlled study, published in the Journal of Nuclear Medicine (Buchert et al. 2003), with 117 subjects as compared to McCann’s 29, found that former users of Ecstasy, who had consumed an average of 799 doses and had abstained for about 18 months, had serotonin levels identical to that of the control subjects. Buchert et al. found that current users of Ecstasy, with an average exposure of 827 doses, showed no reductions in some brain regions and only minimal reductions (4-6%) in two other brain regions, unlikely to be of even temporary clinical significance.

The data from McCann et al.’s Lancet paper formed the basis of NIDA’s major anti-Ecstasy educational campaign, the Plain Brain/Brain After Ecstasy image. NIDA had this image printed on hundreds of thousands of cards distributed in bars and restaurants across the United States, used the image in NIDA publications and websites, and encouraged its use in media reports, all part of its now abandoned $42 million “club drugs” campaign. This image wasn’t even an accurate representation of the data in the Lancet article if that data had actually been valid. NIDA used images chosen for dramatic effect comparing subjects from the extremes of the MDMA and control groups rather than from the subjects scoring closest to the median, using some normal individual variability to exaggerate the evidence of MDMA neurotoxicity. NIDA has now withdrawn this educational campaign and even told the Peter Jennings’ Ecstasy documentary team that it couldn’t locate a copy of the image!

From another perspective, NIDA’s anti-Ecstasy educational campaign, and Dr. Leshner’s other efforts to pander to the Bush and Clinton administration’s jihad against recreational drug use, have been wildly successful. A simple chart showing the annual increases provided by Congress to NIDA’s budget during the tenure of Dr. Leshner reveals the short-term dividends of exaggerating the risks of MDMA and other illicit drugs in support of prohibitionist policies.

3. MDMA and Cerebral Blood Flow

Testimony that then-NIDA Director Alan Leshner gave on July 30, 2001 to the Senate Subcommittee on Government Affairs, illustrated with a large poster purporting to show that MDMA negatively affects (reduces) cerebral blood flow, was clearly misleading. The poster showed a healthy-looking brain with what was represented as normal cerebral blood flow, with this image labeled “Baseline.” For comparison purposes, the poster also contained a second brain scan image of the same subject with reduced cerebral blood flow. This image was labeled “Two weeks post-MDMA.” What Leshner didn’t tell the Senators is that the scans were drawn from a study that showed no difference between Ecstasy users (N=3D21) and controls (N=3D21) in cerebral blood flow (Chang et al. 2000).

The images Leshner used in his Senate testimony came from one of the subset (N=3D10) of the Ecstasy users in the larger study who participated in Dr. Grob’s Phase I MDMA safety study. These 10 subjects were scanned at baseline, like the other 11 Ecstasy-using subjects in Dr. Chang’s research. They were then scanned again after receiving two doses of MDMA administered in the context of Dr. Grob’s study, at time points ranging from two weeks to 2-3 months after the last dose of MDMA. Subjects scanned two weeks after MDMA showed a temporary reduction in cerebral blood flow while subjects scanned from 2-3 months after MDMA showed a return to baseline. The impression Leshner left the Senators was that MDMA caused permanent changes in cerebral blood flow when the changes were both temporary and of no clinical consequence.

Ironically, Leshner didn’t realize that in order to participate in the Phase 1 study and receive MDMA, FDA required subjects to have already had substantial exposure to MDMA. On average, the subjects in Dr. Chang’s study had an exposure to MDMA of 211 times. Thus, the healthy -looking brain that Leshner showed to the Senators to contrast with the image of the same brain two weeks post-MDMA was actually the brain of a heavy MDMA user at baseline! If he had fully understood the science underlying the images he showed to the Senator, Leshner should have reported that the baseline image dramatically illustrated that MDMA caused no persisting long-term differences in cerebral blood flow as compared to the non-MDMA using controls. Instead, he used the image to convey an impression of the dangers of MDMA at odds with what the study actually demonstrated.

Frightening and disturbing images of the brain of an MDMA user that showed explicit holes in the brain that were claimed to have been caused by MDMA have been shown on an MTV special documentary about Ecstasy, as well as on an Oprah Winfrey show. These images were graphically manipulated to represent areas of lower cerebral blood flow as holes and are completely fraudulent. According to a March 2001 educational program about drugs aimed at young people that NIDA helped create, Alan Leshner stated, “We’ve heard people talk about Ecstasy causing holes in the brain and of course that’s a bit of an exaggeration, but there is a core truth to it.” (PBS, In the Mix) We should be appalled, but not surprised, at the fact that the young woman whose brain scan image was manipulated has been working for several years at the Partnership for a Drug-Free America, miseducating other young people about the dangers of MDMA (her choice of employment, perhaps, reflecting the only genuine signs of brain damage).

4. MDMA and Research into Therapeutic Uses

Ever since MDMA was criminalized in the United States in 1985, exaggerated risk estimates have played an essential role in preventing research into the therapeutic uses of MDMA. In 1985, the FDA even refused to permit researchers to administer MDMA-assisted psychotherapy to a dying cancer patient who had experienced no significant side effects and had obtained relief from pain, both physical and emotional, through the use of such therapy that he had received prior to MDMA being made illegal. An FDA official wrote that even dying subjects deserved to be protected by US law from the potential damaging effects of MDMA neurotoxicity. In this case, it didn’t matter that the damage was hypothetical, the benefits were real, and the patient was willing to accept the consequences of participating in the research.

In 1999, after human research with MDMA had begun in Switzerland, a group of Dutch researchers tried to stop Swiss researcher Dr. Franz Vollenweider from conducting basic safety studies by claiming in a letter to the journal Neuropsychopharmacology (Gijsman et al. 1999) that Dr. Vollenweider was engaging in unethical research. Their rationale was that Dr. Vollenweider was administering MDMA to MDMA-naive subjects, a design that Dr. Vollenweider considered useful to obtain the clearest evidence of the effects of MDMA but that Gijsman considered too risky due to the dangers of MDMA neurotoxicity. A debate took place in a series of letters published in Neuropsychopharmacology. Dr. Vollenweider defended his research and risk estimates (Vollenweider et al. 1999). Courageously, the editors disagreed with Gijsman and supported Dr. Vollenweider’s research (Lieberman and Aghajanian 1999). Two years later, Drs. McCann and Ricaurte entered the discussion to raise the issue of the dangers of MDMA neurotoxicity from even a single dose (McCann et al. 2001) but were rebutted by Dr. Vollenweider (Vollenweider et al. 2001) and again by the editors (Aghajanian and Liberman 2001).

Sadly, the world’s only fully-approved MDMA psychotherapy study was successfully halted for political reasons, with efforts to restart the study complicated by Dr. Ricaurte. In 2000, in Madrid, Spain, Jose Carlos Bouso (Ph.D. candidate), with the support of MAPS, was able to obtain all the necessary federal and local permissions to start the world’s first legally-approved controlled study into any therapeutic use of MDMA. The study was designed as a double-blind, placebo-controlled, dose-response pilot study into the use of MDMA-assisted psychotherapy in the treatment of women survivors of sexual assault with chronic, treatment-resistant posttraumatic stress disorder (PTSD). By April 2002, six subjects had been enrolled in the study without any complications. On May 6, 2002, favorable media coverage of the study appeared in prominent Spanish media. On May 13, 2002, as a result of pressure from the Madrid Anti-Drug Authority, the Manager of the Hospital Psiquiatrico de Madrid sent a letter saying that he wouldn’t let the experimenters use the facilities of the Hospital anymore. In October 2002, just one week after Ricaurte’s paper in Science came out, the research team’s struggles to resume the study were significantly complicated by the appearance in Madrid of Dr. Ricaurte, who give a highly-publicized talk about his MDMA/Parkinson’s findings at the invitation of the Spanish Anti-Drug Agency. Additional talks by Dr. Ricaurte in Spain in April, June and July 2003, further reinforced both the scientific and popular perception in Spain of the dangerousness of even a few doses of MDMA.

MAPS has now worked for 17 years, since it was founded in 1986, to sponsor FDA-approved research investigating the therapeutic uses of MDMA. From 1986 to 1992, concerns over the risks of MDMA neurotoxicity were used to justify FDA refusals to approve any research in which MDMA was to be administered to human subjects. Starting in 1992, after a change in personnel and policy, FDA approved three basic safety studies with MDMA. The evidence from these studies, as well as from research conducted abroad, eventually persuaded the FDA that the risk/benefit ratio of MDMA was favorable in certain patient populations. As a result, in November 2001, the FDA approved a MAPS – sponsored pilot study into the use of MDMA-assisted psychotherapy in treatment-resistant PTSD subjects.

The controversy over the neurotoxic risks of MDMA, and over its widespread recreational use, made it exceptionally difficult for MAPS to obtain Institutional Review Board (IRB) approval for our study of the use of MDMA-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder (PTSD). One IRB approved the study, then two months later revoked approval after an IRB official who wasn’t comfortable with the approval of MDMA psychotherapy research spoke to Dr. Una McCann and two other researchers. The other two researchers actually supported the study (one initially and the other after MAPS agreed to add some language to the informed consent form), but Dr. McCann and Dr. Ricaurte refrained from doing so. The IRB refused to review the scientific evidence and made a policy decision to return the fee that MAPS’ paid for the review. Five other IRBs refused to even accept the protocol for review and one that did accept it finally tabled the review, after spending months formally reviewing the study before making it clear, through unreasonable demands, that the committee did not feel comfortable approving it. After diligent and persistent work, MAPS managed to obtain IRB approval in September 2003.

However, the study is still not fully approved. Research can start only after the principal investigator, Dr. Michael Mithoefer, receives a Schedule I license from the DEA so that he can legally possess and administer the total of 3 grams of MDMA that will be given to the subjects in the study (each MDMA subject in the MDMA group will receive two oral doses of 125 mgs each, three to five weeks apart). Dr. Mithoefer submitted his application to DEA for a Schedule I license over 17 months ago, with a decision from DEA still pending. On October 28. 2003 South Carolina DEA agents and officials from the South Carolina Department of Health and Environmental Control (DHEC) finally inspected Dr. Mithoefer’s facility. They examined the DEA-required safe bolted to the concrete floor, the alarm system and the MDMA tracking procedures, in order to ensure that the 3. 5 grams of MDAM will be protected from diversion to non- research uses. On November 12, 2003, Dr. Mithoefer received his Schedule I research registration (R1) from the DHEC. We expect that sometime soon DEA will issue Dr. Mithoefer his Schedule I license so that we can start MDMA psychotherapy research after more than 18 years of struggle. (MDMA was criminalized in 1985 on an emergency basis, justified in part based on Dr. Ricaurte’s research in rats showing that MDA, a drug related to MDMA, caused reductions in serotonin at some doses.)

The above review isn’t meant to build a case that MDMA is harmless, or completely benign. MDMA has its risks, some of which can be fatal, like hyperthermia, a very rare occurrence that results from overheating, most often due to prolonged exercise and inadequate fluid replacement. The effects of heavy Ecstasy use on neurocognitive functioning is still being researched, with some well-designed studies showing that heavy MDMA users perform worse on some neurocognitive tests. Whether this is due to MDMA remains to be determined. What the above review is trying to communicate is that the risks of MDMA-related brain damage have been exaggerated, in yet another historical example of science being twisted to suit political ends. The risks that MDMA does present can be mitigated to a large extent by the wise use of harm reduction efforts. Unfortunately, the anti-rave legislation that Congress passed under the false assumption that MDMA caused unusually powerful brain damage after only a few doses perversely empowers police and prosecutors to use harm reduction efforts as a legal weapon against promoters and venue owners.

For almost two decades, MDMA research has been primarily focused on neurotoxicity research into the risks of MDMA, with MDMA psychotherapy research essentially forbidden. Perhaps the tide is turning and the next two decades will see a more balanced focus on research into both the potential risks and benefits of MDMA, with a variety of social, legal structures eventually to be created that will minimize the potential harms of MDMA and maximize its benefits. If we will it, it need not remain a dream.

  • Aghajanian GK, Liebermann JA (2001)
    Caveat Emptor: Editors Beware
    Neuropsychopharmacology. 24,3:335-6.
  • Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M. (2003)
    Long-term effects of “ecstasy” use on serotonin transporters of the brain investigated by PET.
    J Nucl Med. Mar;44(3):375-84.
  • Chang L, Grob CS, Ernst T, Itti L, Mishkin FS, Jose-Melchor R, Poland RE. (2000)
    Effect of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] on cerebral blood flow: a co-registered SPECT and MRI study.
    Psychiatry Res. Feb 28;98(1):15-28.
  • Gijsman HJ, Verkes RJ, van Gerven JM, Cohen AF. (1999)
    MDMA study.
    Neuropsychopharmacology. Oct;21(4):597.
  • Iravani MM, Jackson MJ, Kuoppamaki M, Smith LA, Jenner P. (2003)
    3,4-methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- treated primates.
    J Neurosci. Oct 8;23(27):9107-15.
  • Kish S.J. et al. (2000)
    Striatal serotonin is depleted in brain of a human MDMA (Ecstasy) user.
    Neurology 55: 294-296.
  • Kish S. (2002)
    How strong is the evidence that brain serotonin neurons are damaged in human users of ecstasy?
    Pharmacol Biochem Behav. Apr;71(4):845-55. Review.
  • Lieberman J and Aghajanian G. (1999)
    Editorial=D1Caveat Emptor: Researcher Beware.
    Neuropsychopharmacology 21 4:471-473.
  • McCann UD, Ricaurte G (2001)
    Caveat Emptor: Editors Beware.
    Neuropsychopharmacology 24: 333-334.
  • McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA (1998)
    Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings.
    Lancet 352: 1433-7.
  • Mithoefer M, Jerome L, Doblin R (2003)
    MDMA (“Ecstasy”) and Neurotoxicity.
    Science, 300: 1504.
  • Reneman L. et al. (2002A)
    Use of amphetamine by recreational users of ecstasy (MDMA) is associated with reduced striatal dopamine transporter densities: a [123I]beta-CIT SPECT study– preliminary report.
    Psychopharmacology (Berl) 159: 335-340.
  • Ricaurte GA, DeLanney LE, Irwin I, Langston JW (1988)
    Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration.
    Brain Res 446: 165-168.
  • Ricaurte GA, Yuan J, Hatzidimitriou G, Cord BJ, McCann UD (2002)
    Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (“Ecstasy”).
    Science 297: 2260-3.
  • Ricaurte GA, Yuan J, Hatzidimitriou G, Cord BJ, McCann UD (2003B)
    Science 301: 1429.
  • Semple D.M. et al. (1999)
    Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (‘ecstasy’) users.
    Br J Psychiatry 175: 63-69.
  • Vollenweider F, Gamma A, Liechti M, Huber T. (1999)
    Is A Single Dose of MDMA Harmless?
    Neuropsychopharmacology 21 (October) 4: 598-600.
  • Vollenweider FX, Jones RT, Baggott MJ. (2001)
    Caveat emptor: editors beware.
    Neuropsychopharmacology. Apr;24(4):461-3.