MDMA as a clinical tool: a note of caution. A response to Sessa and Nutt

We were interested in the recent editorial by Sessa and Nutt (2007), which discusses the potential medical uses of 3,4methylenedioxymethylamphetamine (MDMA) and would not argue with much of the article. Indeed, one of us commented on the probable low adverse event profile of MDMA and the problems of accurate media coverage some time ago (Green, 2004). However, their comment that “heavy recreational ecstasy” (and what does that mean in terms of animal experiments? ) may be linked to “transient and reversible neurotoxicity” is a gross inaccuracy and must be challenged. There is not room to review all the work done in this area, but a recent study in rats detected damage in both cortex and hippocampus at 32 weeks (O’Shea, et al., 2006). Other studies have reported loss of serotonergic markers for up to an year in some regions of rat brain (Sabol, et al., 1996; Lew, et al., 1996), a time that could scarcely be called transient in the lifetime of a rat. These findings and others are reviewed in detail elsewhere (Green et al., 2003). Furthermore, in primates, the serotonergic toxicity in brain has been reported up to seven years after MDMA (Hatzidimitrou, et al., 1999). In some studies, there is also evidence for hyperinnervation, which can complicate evidence of “recovery” when amine levels are being measured (Lew, et al., 1996; Sabol, et al., 1996). Again, this is reviewed in detail elsewhere (Green, et al., 2003). However, we support the general point made by Sessa and Nutt (2007) that clinically there is a low likelihood of long-term adverse events when low doses of MDMA are given intermittently and can cite a preclinical study to support that contention. A modest dose of MDMA (4 mg/kg) given to rats twice weekly for eight weeks or even once daily for four days produced no loss in serotonin content, whereas the same dose given twice daily for four days did produce a greater than 50% depletion in serotonin concentration (O’Shea, et al. 1998). This suggests that low doses given infrequently are unlikely to result in long-term neurotoxicity. However, such data give no hint as to translation into what constitutes a non-neurotoxic dose in humans, merely that undertaking intermittent dosing may be feasible. It is also clear from preclinical studies that short treatments with sub-neurotoxic doses of MDMA can produce long-lasting changes in emotional responses to conspecifics or aversive contexts, as in the social interaction or elevated plus maze paradigms (Bull, et al., 2004; McGregor, et al., 2003), which may equate with changes in mood seen in humans. Acute adverse events are also unlikely at low dose, and this view is strengthened by the fact that if used in psychotherapy, MDMA would be given in a quiet, cool, uncrowded environment. It is well established in experimental animals that aggregation (grouping), loud noise, and high ambient temperatures all enhance toxicity induced by amphetamine (Gunn and Gurd, 1940; Chance, 1946; 1947). This finding was extended by confirming that in rats MDMA-induced acute toxicity is potentiated by high ambient temperature (Malberg and Seiden, 1998) and that high ambient temperature and crowding also potentiated MDMA-induced toxicity in mice (Fantegrossi, et al., 2003). Therefore, it is reasonable to suggest that many of the acute toxicity problems reported in recreational drug users are related to ingestion of MDMA while present in hot, crowded, noisy environments. The discussion of the possible value of MDMA as a psychotherapeutic drug was interesting but suffered from an incomplete discussion of the available information about the effect of MDMA on monoamine neurotransmission. Specifically, it stated that MDMA releases serotonin (5-hydroxytryptamine or 5-HT) “and probably also, although to a lesser extent, dopamine and noradrenaline” and went on to link the 5-HT release with the elevation of mood and strong feelings of well-being. Although it is true that MDMA is more effective in releasing 5-HT than dopamine in studies using in-vitro brain slice or four synaptosomal preparations, this does not hold true when in-vivo techniques are used; probably because MDMA-induced dopamine efflux is regulated by 5-HT receptors (Koch and Galloway, 1997). Therefore, we will ignore the many in-vitro papers on MDMA-induced dopamine efflux as they are Letter to the Editors