Dear Science Editors,

Ricaurte and colleagues report dopamine neurotoxicity in primates injected repeatedly with MDMA (1). Since human MDMA users very rarely die from MDMA use (2, 3), the high mortality in Ricaurte's primates suggests they failed to administer a "common recreational dose regimen," further calling into question their interspecies scaling model (4, 5, 6). Ricaurte previously reported subcutaneous injection in squirrel monkeys was twice as neurotoxic as oral administration (7), yet now claims oral administration offers "little or no" neuroprotection. Ricaurte and colleagues nonetheless suggest that even one night's recreational use of MDMA may result in dopamine toxicity and increased risk of Parkinson's Disease. Curiously, they fail to cite studies finding normal dopamine (but reduced serotonin) levels, in heavy MDMA users. Two reports used in vivo imaging to estimate brain dopamine transporter levels (8, 9); another conducted postmortem analysis of an individual (10).

Furthermore, previous studies in heavy MDMA users conducted by Drs. Ricaurte and McCann failed to find reduced dopamine metabolites in cerebrospinal fluid (11, 12, 13). The dopamine changes produced by MDMA in this study have long been known as potential effects of d-amphetamine and d-methamphetamine, two prescription drugs that have been available for over eighty years (14). There is no credible evidence linking these drugs or the monoaminergic changes they can produce in animals (and, perhaps, humans) to Parkinson's Disease, nor is there any evidence of increased incidence of early-onset Parkinson's (15).

We hope the theoretical risks suggested by this study are not inappropriately generalized to clinical MDMA research, which has been conducted without evidence of toxicity (including no detectable changes in serotonin transporter or memory) (4, 16, 17).

Michael Mithoefer MD
Lisa Jerome PhD
Richard Doblin PhD

References

1. Ricaurte GA, Yuan J, Hatzidimitriou G, Cord BJ, McCann UD (2002) Severe dopaminergic neurotoxicity in primates after common recreational dose regimen of MDMA ("Ecstasy.") Science, 297: 2260-2263 (Sept 27, 2002)

2. Gore SM (1999) Fatal uncertainty: death-rate from use of ecstasy or heroin. Lancet 354: 1265-1266

3. Henry JA and Rella JG (2001). Medical risks associated with MDMA use. In Holland J (Ed). Ecstasy; the complete guide. Rochester, VT: Inner Traditions

4. Vollenweider FX, Jones RT, Baggott MJ (2001) Caveat emptor; Editors Beware. Neuropsychopharmacology, 24; 461-462

5. Mahmood I and Balian JD (1996). Interspecies scaling: A comparative study for the prediction of clearance and volume using two or more than two species. Life Sci, 59: 579-585.

6. Grob C. (2000) Deconstructing Ecstasy: The Politics of MDMA Research. Addiction Research 8:549-588.

7. 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

8. Reneman L, Booij J, Lavalaye J, de Bruin K, Reitsma JB, Gunning B, den Heeten GJ, van Den Brink W (2002) 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

9. Semple DM, Ebmeier KP, Glabus MF, O'Carroll RE, Johnstone EC (1999) Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA ("ecstasy") users. Brit J Psychi, 175; 63-69

10. Kish SJ, Furukawa Y, Ang L, Vorce SP, Kalasinsky KS (2000) Striatal serotonin is depleted in brain of a human MDMA (Ecstasy) user. Neurology 55: 294-296

11. McCann UD, Mertl M, Eligulashvili V, Ricaurte GA (1999) Cognitive performance in (+/-) 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") users: a controlled study. Psychopharmacology (Berl) 143: 417-425

12. McCann UD, Ridenour A, Shaham Y, Ricaurte GA (1994) Serotonin neurotoxicity after (+/-)3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy"): a controlled study in humans. Neuropsychopharmacology 10: 129-38

13. Ricaurte GA, Finnegan KT, Irwin I, Langston JW (1990) Aminergic metabolites in cerebrospinal fluid of humans previously exposed to MDMA: preliminary observations. Ann N Y Acad Sci 600: 699-708; discussion 708-710

14. Ernst T, Chang L, Leonido-Yee M, Speck O (2000) Evidence for long-term neurotoxicity associated with methamphetamine abuse: A 1H MRS study. Neurology 54: 1344-1349

15. Concar D (2002) Ecstasy users 'risk Parkinson's disease'. New Scientist 297: 2260

16. Grob CS, Poland RE, Chang L, Ernst T (1996) Psychobiologic effects of 3,4-methylenedioxymethamphetamine in humans: methodological considerations and preliminary observations. Behav Brain Res 73: 103-107

17. Vollenweider, FX, Gucker, P., Schonbachler, R, Kamber, E, Vollenweider-Scherpenhuyzen, MFI, Schubiger, G, & Hell, D (2000). Effects of MDMA on 5-HT uptake sites using PET and [11C]-McN5652 in humans. Data presented at 2000 conference of the German Society for Psychiatry, Psychotherapy and Neuromedicine [Deutsche Gesellschaft fur psychiatrie, Psychotherapie und Nervenheilkunde]