MAPS Response to Ricaurte’s Retraction of Ricaurte et al. 2002
Ricaurte and colleagues have issued a retraction of a report appearing in Science (Ricaurte et al. 2003). The retraction refers to study findings of reduced dopamine transporter and signs of damage to dopamine axons after three repeated injections of 2 mg/kg MDMA in squirrel monkeys and baboons (Ricaurte et al. 2002). On the basis of these findings, the authors speculated that Ecstasy users might face greater risk of developing Parkinson’s disease, despite there being no support for reduced dopamine function in Ecstasy users (Kish et al. 2000; Reneman et al. 2002; Semple et al. 1999). Scientists criticized the study on methodological grounds prior to the retraction (http://www.maps.org/research/mdma/studyresponse.html), including a letter written by Mithoefer et al, published in Science in June, 2003 (Mithoefer et al. 2003). At issue was the unusually high mortality rate after drug treatment, choice of dose regimen, route of administration, lack of supportive evidence for dopamine neurotoxicity in humans, and ambiguous and potentially misleading reporting the number of research subjects studied. (The same research team has since retracted another paper (Boot et al. 2002) comparing the effects MDMA with the serotonin synthesis inhibitor p-CA on rat brain serotonin, published in the European Journal of Pharmacology (Walgate 2003A)).
Nearly a year after the original publication, and six months after defending their study findings in Science (Ricaurte et al. 2003A) [PDF}, Ricaurte et al. now report that they administered methamphetamine, and not MDMA, to all but one animal, reportedly because the two drugs were misidentified. Analyses of the bottle labeled "(+)-methamphetamine HCl" found only MDMA, and no traces of methamphetamine therein, and analyses of brain slices from two animals that had died shortly after drug treatment detected only d-methamphetamine, and not MDMA. Hence these findings have no import on the effects of MDMA. Despite this mishap and the continued failure to find dopamine toxicity in non-human primates, the authors continue to hypothesize that an unspecified dose regimen of MDMA could be neurotoxic to dopaminergic cells.
Information contained within the retraction raises yet more questions concerning both the research itself and the chronology of research discovery as it relates to continued defense of the original findings. These issues relate to the reporting of the events in the retraction, failure to acknowledge research findings relevant to study critique, and the nature of evidence used to support hypothesized MDMA-induced dopamine toxicity in humans.
Ricaurte et al state that "subsequent to the publication of these findings, we were unable to extend the dopamine toxicity to orally administered doses." Yet in response to criticisms relating to the choice of route of administration offered by Mithoefer and colleagues, Ricaurte et al asserted that route of administration offers no protection from neurotoxicity (Ricaurte et al. 2003B), referring only to studies of serotonin neurotoxicity, and failing to give any indication that they had already failed to replicate their original findings with orally administered MDMA.
In their retraction, Ricaurte et al. also state that "multiple subsequent attempts to reproduce the original findings, with systematically administered doses of MDMA identical to those used in the original study were also unsuccessful, under a variety of laboratory conditions." They provide no information on the nature of these conditions, though at a conference presentation given on September 8, 2003 at Basel, Switzerland, Ricaurte stated that increased ambient temperature was one such condition (Gamma 2003, personal communication, http://www.maps.org/mdma/retraction/gamma090803.html).
In describing the method used to detect the error, the Authors state that the 10 g of "MDMA" used in the original study was depleted and that "the empty bottle labeled MDMA had been discarded." However, in reference to the implications of the misidentified drugs, Ricaurte et al said "this apparent labeling error does not call into question the results of multiple previous studies" reporting serotonin neurotoxicity in "various animals." However, on the basis of average weights of squirrel monkeys (750 g-1.1 kg) and baboons (14-45 kg), the estimated amount of mislabeled drug used in the retracted study would be approximately 1.5 g, or only a little over a tenth of the bottle. This strongly suggests that the mislabeled d-methamphetamine was used in other studies, published or unpublished, and that other retractions may in fact be necessary. A recent report indicates that this is the case, though the study has no bearing on findings of dopamine neurotoxicity (Walgate 2003B). As well, Ricaurte and colleagues fail to provide any information on whether mislabeled "methamphetamine" was used in studies. After calculating the amount used in this study and the more recently retracted study, much of the mislabeled drug remains unaccounted for. The retraction as written is incomplete as it fails to acknowledge the scope of the error, once discovered. MAPS has submitted a letter to Dr. Nora Volkow, current director of NIDA, requesting this information (MAPS Letter to NIDA Director Nora Volkow, 2003: http://www.maps.org/mdma/retraction/volkowletter091803.html.
Still clinging to the possibility of MDMA-induced dopamine neurotoxicity, Ricaurte et al speculate that "Regarding the dopamine neurotoxic potential of MDMA in nonhuman primates, it remains possible that dose regimens in the range of those used by some humans, but different from those thus far tested, produce dopamine neurotoxicity in primates, as they do in rodents." The statement is irrefutable, as it is always "possible" that future research will uncover such a dose regimen. This statement also raises a number of issues concerning the meaning of such a finding. If such an MDMA dose regimen did exist, could it be claimed to be one "commonly used" by humans? On what basis will Ricaurte assert the common usage of a specific dose regimen? If so, Ricaurte should be sure to cite his sources. And if the pattern of use is not a common one, then can further research in non-human primates to establish this dose regimen be justified? It should also be pointed out that to date, only mice exhibit dopamine neurotoxicity after MDMA, whereas this effect is not seen in rats. Furthermore, research comparing MDMA neurotoxicity in mice and rats presents a coherent explanation for the difference between mice and rats (Colado et al. 2001). Ricaurte and colleagues give no indication that they will measure MDMA metabolism or response to oxidative stress in test animals, a step that would allow them to assess whether dopamine neurotoxicity might be likely. It seems odd that a pattern seen only in one rodent species, and not verified in humans, should still be sought in non-human primates.
Ricaurte and colleagues seek to bolster support for hypothesized MDMA dopamine neurotoxicity by referring to a study of neuroendocrine response to challenge with the dopaminergic drug bromocryptine in 12 male Ecstasy users (Gerra et al. 2002), and cases of Parkinsonism and Parkinson’s disease after Ecstasy use. However, when compared with imaging studies, evidence from neuroendocrine studies is less direct and may be multiply determined. For instance, it is notable that Ecstasy users in this study had a higher rate of personality disorders than did non-drug-using controls. It is also possible that changes in serotonin function, such as changes in serotonin receptor density, could affect neuroendocrine response to a dopaminergic drug (Reneman et al. 2002B). Hence study findings by Gerra et al. do not offer strong support for dopamine neurotoxicity, particularly when neuroimaging studies of Ecstasy users failed to find reduced dopamine transporter levels in Ecstasy users.
That there have been only two reports of Parkinsonism or Parkinson’s disease after over thirty years of recorded non-medical use (Mintzer et al. 1999; Kuniyoshi and Jankovic 2003) suggests the relative rarity of this occurrence rather than its likelihood. Ecstasy use in both cases was low ((1-2 tablets on 10 occasions in the first case, 1 tablet on 12 occasions in the second case). Ecstasy use in these cases was so low that both subjects would have been barred from participating in most studies of long-term effects of Ecstasy use, including the imaging studies that failed to find reduced dopamine transporter. Reported dose per occasion in each case (estimated to be no more than 2 mg/kg per occasion) was significantly lower than oral or systemic doses of MDMA given to monkeys in the failures to replicate findings reported in the retraction (2 mg/kg every 3 hours for a duration of 6 hours). Since these individuals’ Ecstasy use is at the low end of that typically reported in other comparisons of Ecstasy users (see for example, Reneman et al. 2002; Thomasius et al. 2003), the relationship between MDMA and Parkinson’s disease is neither direct nor readily demonstrated by these case reports. It appears that Ricaurte and colleagues are holding out hope for a hypothesis that is largely unsupported in the literature, even after issuing a retraction of the study. In the words of British scientist Leslie Iversen, quoted in The Scientist, "Even in the retraction statement published recently, the authors continue to maintain that they will in future show that they were right after all, and ecstasy does cause Parkinson's disease!" (Walgate 2003A).
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