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To the Editors of "Science" Magazine:


     Regarding the research report entitled "Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy")", published in Science in September of 2002:

     The authors (Ricaurte et al) casually refer to a case report as an example of "MDMA-induced Parkinsonism." The patient in question was a young man who had reported infrequent use of the drug (a total of ten exposures) over the course of the past year.[1] He had not used "ecstasy" for approximately three months when he presented for the symptom of "slight clumsiness in upper and lower extremities." Over several months following initial presentation for treatment, his condition rapidly worsened, developing more features characteristic of Parkinson's. The patient did not respond to "the maximal tolerated doses of levodopa and pramipexole", leaving the fundamental assumption of damage to the dopaminergic system as the source of the patient's problems very much in doubt.

     The doctors who reported this case state that "we have no firm evidence of a causal relation between this patient's drug use and his parkinsonism"; their belief that it may have been caused by infrequent MDMA use seems to be born almost entirely of their inability to make an alternative diagnosis coupled with MDMA's known dopaminergic neurotoxic potential in mice.

     The pathology of this case (delayed onset relative to drug use followed by rapid progression) is inconsistent with all known research on the progression of MDMA neurotoxicity, which produces a maximization of damage shortly after exposure followed by slow partial recovery.[2]

     If Ricaurte et al have additional information about this case that was unavailable to the doctors treating the patient, they have made no mention of it. At the least, it was dishonest to characterize this case simply as an example of "MDMA-induced Parkinsonism" with no mention of the extraordinarily tenuous and speculative nature of the proposed causal link between the patient's drug use and his neurological symptoms.

     Equally intriguing is the author's claim that "oral administration offers little or no significant neuroprotection" relative to the injected route used in the experiment. Indeed, Ricaurte's own research has demonstrated that injecting MDMA can double and even triple it's neurotoxicity (depending on brain region) vs. oral dosing.[3] While I will concede that "little or no" is not a clearly defined expression, increases of whole multiples seems to strain any common definition.

     Indeed, the very title of the report is rather difficult to defend, as it describes the dose used as "a common recreational dose" of MDMA. If the dose was pharmacologically equivalent to doses routinely taken by humans, why do the authors report that 20% of their animals died on the spot, while an additional 20% may have died had they not been exempted from the full regimen after showing serious distress from only part of the total 6 mg/kg dose? While dosages of such scale do (infrequently) occur in human users, it is likely that these users have reached such dosages in response to growing drug tolerance; with such progressive elevations of dosage over time, neurotoxic potential is reduced.[4] It seems unlikely to me that a man of Ricaurte's standing within the field of MDMA neurotoxicity was unaware of this, yet no mention of this confound is made in the author's rush to claim equivalency between their experiment and human patterns of use.

     The authors report that 6 mg/kg of MDMA total (2 mg/kg every two hours for 3x) produced profound (approx. 50%) damage to the dopaminergic system in monkeys, but fail to explain why Ricaurte's own past work has found that a cumulative dose of 40 mg/kg (5 mg/kg at a time 2x for four days) failed to produce any dopaminergic toxicity in monkeys.[5] At the very least, producing a vast increase in toxicity by giving 2 mg/kg 3x instead of a single 5 mg/kg dose seems to demand some discussion; it suggests that at the least the authors have managed to come upon an atypically toxic dosing regimen. If only on the grounds of the sheer novelty of the results from this particular dosage regimen it seems presumptuous to declare equivalency to human users until some explanation can be offered for the sharp divergence of results between these two experiments.

     Also of no small concern in the author's suggestions of severe dopaminergic toxicity commonly occurring in humans is their apparent refusal to mention retrospective studies of the brains of "ecstasy" users that found no differences in their dopamine system relative to non-users.[6][7] While the latter study may not have yet been available to the authors at the time of publication, surely they should have mentioned that there was existing evidence of the absence of harm to user's dopamine systems before publishing a paper that so shamelessly encourages public panic.

     The principle author (Ricaurte) has long championed a minimalistic method of interspecies dosage scaling between non-human primates and humans. His understanding of MDMA neurotoxicity has led him to believe that less than 1.3 mg/kg of MDMA in a human user would produce neurotoxic damage (a dose he arrived at by scaling from 5 mg/kg in non-human primates, which he reports as producing neurotoxicity.)[8] If we believe Ricaurte's claims of dosage scaling between humans and non-human primates, then the 6 mg/kg dose used in his recent experiment (which killed a significant number of his animals and severely damaged the serotonergic and dopaminergic pathways in the survivors) would be equivalent to just over 1.5 mg/kg in humans. However, prospective human brain-scan experiments have failed to find even the slightest indication of neurotoxicity (or even subject distress) at 1.5 mg/kg.[9] Human users routinely exceed this dosage, mix drugs, and use under uncontrolled and adverse conditions, yet fatalities are rare. Indeed, examinations of the brains of current human "ecstasy" users with an average lifetime exposure of ~800 tablets found only minor reductions in SERT (serotonin transporter) density, and when abstinent users were examined, their regional and total SERT densities were indistinguishable from non-drug users.[10] While regrowth of serotonin axons could explain a recovery of total SERT density, the recovery seen in these heavy human users was uniform, precisely restoring normal SERT density in all regions of the brain studied, as contrasted with the patterns of serotonin axon regrowth seen in non-human primates given neurotoxic doses of MDMA (which produced hyperenervation of regions near the raphe nuclei but failed to restore enervation to less proximal regions.) Given this pattern of recovery, there is every reason to believe that the minor temporary loss of available SERT proteins observed was not due to neurotoxic damage (destruction of axons.)

     Ricaurte also fails to explain why his "common [human] recreational dose" of MDMA produced a significant and prolonged (even lethal) hyperthermic response (as much as 41.6C) when human experiments have consistently produced little or no hyperthermic response at any dose attempted.[11][12] As hyperthermic response is well-established as a critical factor in MDMA neurotoxicity[13], I must again question why Ricaurte believes the dosages he uses are pharmacologically equivalent to those used by humans when the physiological responses produced are not equivalent. It's certainly true that malignant hyperthermia appears with some frequency among human users, but such cases are usually associated with prolonged dancing at clubs. Are we to believe that Ricaurte et al. threw a 'rave party' for their animals?

     In the final analysis, I must regard this recent product of Ricaurte et al. as more of an act of propaganda than a sincere attempt to advance public understanding. There is no reason to believe that there is a coming wave of 'Ecstasy Parkinsonism' among human "ecstasy" users, or even that common patterns of use pose a risk of injury to the dopaminergic system. Shame on the authors for the incomplete, misleading and sensationalistic nature of this research report, and shame on the editors of Science for publishing it.

 



[1] Mintzer S, Hickenbottom S, Gilman S "Parkinsonism after taking ecstasy" N Engl J Med, 1999; 340(18):1443. Abstract.

[2] Scanzello CR, Hatzidimitriou G, Martello AL, Katz JL, Ricaurte GA "Serotonergic recovery after (+/-)3,4-(methylenedioxy) methamphetamine injury: observations in rats" J Pharmacol Exp Ther, 1993; 264(3):1484-91. Abstract.

[3] Ricaurte GA, DeLanney LE, Irwin I, Langston JW "Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration" Brain Res , 1988; 446(1):165-8. Abstract.

[4] Frederick DL, Ali SF, Slikker W Jr, Gillam MP, Allen RR, Paule MG "Behavioral and neurochemical effects of chronic methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys" Neurotoxicol Teratol, 1995; 17(5):531-43. Abstract.

[5] Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, Langston JW "(+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates" JAMA, 1988; 260(1):51-5. Abstract.

[6] Semple DM, Ebmeier KP, Glabus MF, O'Carroll RE, Johnstone EC "Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA ("ecstasy") users", British Journal of Psychiatry, Vol 175, 63-69 (1999). Abstract.

[7] Reneman L, Booij J, Lavalaye J, de Bruin K, Reitsma JB, Gunning B, den Heeten GJ, van Den Brink W "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), 2002; 159(3):335-340. Abstract.

[8] Ricaurte GA, Yuan J, McCann UD "(+/-)3,4-Methylenedioxymethamphetamine (`Ecstasy')-Induced Serotonin Neurotoxicity: Studies in Animals" Neuropsychobiology, 2000; 42(1):5-10. Abstract.

[9] Vollenweider FX, Gucker P, Schönbächler R, Kamber E, Vollenweider-Scherpenhuyzen MFI, Schubiger G, Hell D "Effects of MDMA on 5-HT uptake sites using PET and [11C]-McN5652 in humans" Conference of the German Society for Psychiatry, Psychotherapy and Neuromedicine, 2000. Abstract.

[10] Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M "Long-term effects of "Ecstasy" use on serotonin transporters of the brain investigated by PET." J Nucl Med 44: 375-84 (2003). Abstract.

[11] Mas M, Farre M, de la Torre R, Roset PN, Ortuno J, Segura J, Cami J "Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans" J Pharmacol Exp Ther, 1999; 290(1):136-45. Abstract.

[12] de la Torre R, Farre M, Roset PN, Hernandez Lopez C, Mas M, Ortuno J, Menoyo E, Pizarro N, Segura J, Cami J "Pharmacology of MDMA in humans" Ann N Y Acad Sci, 2000; 914:225-37. Abstract.

[13] Yuan J, Cord BJ, McCann UD, Callahan BT, Ricaurte GA "Effect of depleting vesicular and cytoplasmic dopamine on MDMA neurotoxicity", Journal of Neurochemistry, Vol 80, 960-969 (2002). Abstract.