The recent article by Gouzoulis-Mayfrank and colleagues (J. Neurol. Neurosurg. Psychiartry 68: 719, 2000) describes the effects of recreational use of MDMA (in combination with the regular use of cannabis) on cognitive performance, as assessed by a comprehensive neuropsychological test battery. The conclusions reached by the authors are that "typical recreational doses of ecstasy are sufficient to cause neurotoxicity in humans." This conclusion is not justified based on the data presented. The data collected are not the problem, it is the context within which they are presented that is misleading.
Gouzoulis-Mayfrank et al. have unwittingly fallen into the same trap as have many other investigators of the neurotoxic effects of substituted amphetamines (e.g. MDMA, methamphetamine and the anti-obesity drug, dexfenfluramine). As I noted in a previous commentary in the MAPS Bulletin (O'Callaghan, 1995) and in a letter to the Journal of the American Medical Association (O'Callaghan and Miller, 1997), the papers such as those cited by Gouzoulis-Mayfrank purport to describe dexfenfluramine or MDMA-induced axotomy of serotonin-containing neuronal endings (i.e. actual pathological loss of nerve axons). Nowhere, in fact, is such evidence provided in these papers. Rather, what is described already has been widely documented: administration of dexfenfluramine or MDMA (usually at high doses to experimental animals) reduces the concentration of forebrain serotonin and associated markers. Decreases in these measures, however, cannot be equated with damage to serotonin containing neurons in the absence of evidence for underlying neuropathology. Again, no such evidence has been provided for MDMA as it has for compounds known to damage serotonin containing neurons, such as 5,7-dihydroxytryptamine (O'Callaghan and Miller, 1993).
Unfortunately, once you are "set up" to believe that the compound you are studying already has been shown to cause brain damage, any effect you observe to occur during a drug-free period is likely to be thought of as "neurotoxicity." This is the conceptual framework for the Gouzoulis-Mayfrank study. Thus, this investigation suffers from the same problems as those in the past that claimed to show evidence of MDMA "neurotoxicity." Are we dealing with neuropathological (i.e. true neurotoxic) effects of the compound? Or are the observed effects just a manifestation of the short (days)- or long (weeks)- term reversible effects of MDMA, related to it's known action of this compound on the serotonin system? While their study could be considered flawed on other grounds, such as the small subject number, the small magnitude of effects, and confounds linked to educational background or MDMA-cannabis interactions, the data, nevertheless, show fairly consistent changes with a large battery of tests. It should be emphasized, however, that the "typical recreational doses" described by Gouzoulis-Mayfrank were 3.5 tablets per month for 27 months. When administered with this frequency and duration, it would not be unexpected for MDMA to have persistent effects on the serotonin system, based on data from rats or monkeys (Fischer et al., 1995; Schmidt, 1987).
Although Gouzoulis-Mayfrank dismiss the possibility of a reversible pharmacological effect of MDMA-cannabis, down-regulation of serotonin markers would be the expected pharmacological effect of even a single (high) dose of MDMA in the rat or sub-human primate at 3 weeks post dosing (e.g. see Schmidt, 1987). Indeed, increased reaction times observed by Gouzozoulis-Mayfrank et al. for the MDMA subjects are consistent with human data on drowsiness for compounds with the potential to decrease brain levels of serotonin such as dexfenfluramine (Physcians Desk Reference, 1998) or reserpine (Goodman and Gilman, 1975). Potentially, the data of Gouzoulis-Mayfrank reflect persistent pharmacological actions of MDMA on serotonin systems, as has been observed for dexfenfluramine and reserpine. The potential adverse functional consequences for such effects remain unknown but should "be considered in future longitudinal investigations," as recommended by the authors.
James P. O'Callaghan, Ph.D.
Molecular Neurotoxicology Laboratory
Centers for Disease Control and Prevention NIOSH
Morgantown, WV. 26505
Notes:
Fischer, C., Harzidimitriou, G., Wlos, J.; Katz, J. and Ricaurte, G.: Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+) 3,4-methylendioxymethamphetamine (MDMA, "ecstasy"). J. Neuroscience 15: 5476-5485.
Goodman, L.S. and Gilman, A: The Pharmacological Basis of Therapeutics, Chapter 12, pp. 168-169, 1975.
O'Callaghan, J.P. and Miller, D.B.: Quantification of reactive gliosis as an approach to neurotoxicity assessment. In: Assessing Neurotoxicity of Drugs of Abuse. Erinoff, L., Ed., National Institute on Drug Abuse Monograph 136, pp. 188-212, Washington, D.C., U.S. Government Printing Office, 1993.
O'Callaghan, J.P.: MDMA Neurotoxicity: Commentary on article by Ricaurte and colleagues. Bull. of the Multidisciplinary Assoc. for Psychedelic Studies 6: 13, 1995.
O'Callaghan, J.P. and Miller, D.B. RE: Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and
dexfenfluramine. JAMA 278: 2141, 1997.
Schmidt, C.J.: Neurotoxicity of the psychedelic amphetamine, MDMA. J.
Pharmacol. Exp. Ther. 240: 1-7, 1987.
