The synthetic psychostimulant 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") has a structural resemblance not only to amphetamine, but also to the hallucinogen, mescaline. These similarities, at least in part, probably account for its unique blend of psychomotor stimulation and mild psychedelic action.1 Despite the rapidly increasing recreational use of MDMA, both in the USA2 and western Europe,3 little is known about its pharmacology, although most experts suspect that, like other amphetamine derivatives, MDMA acts indirectly, primarily by stimulating the release of monoamines, such as dopamine and serotonin.4 The intriguing possibility that MDMA may have a novel mechanism of action, however, should not be overlooked.
Although much remains to be learned about the pharmacology of MDMA, a great deal is now known about its toxicology, largely because detailed studies in animals have shown that MDMA is a potent serotonin neurotoxin.4,5 There are also reports that MDMA produces serotonin neurotoxic effects in human beings.6-10 The report by Liesbeth Reneman and colleagues in this issue of The Lancet raises the interesting possibility that there may be differences between men and women in the long-term effects of MDMA on serotonin neurons, an issue that has not been explored in animals. In particular, on the basis of findings obtained with single-photon-emission computed tomographic (SPECT) imaging and the radioligand 123iodine-2ß-carbomethoxy-3ß- (4-iodophenyl)tropane ([123I]ß-CIT), which binds to serotonin and dopamine transporters, the researchers conclude that women may be more susceptible than men to MDMA-induced serotonin neural injury. This conclusion is intriguing but must be viewed with caution because if people who meet criteria for major depression are excluded from their analyses (a reasonable approach given the role of serotonin in depression) then there are only four women in two of the MDMA groups and only six women in the control group.
Reneman and colleagues also infer that MDMA-induced neurotoxicity is partly reversible in most regions of the brain. If true, these findings are important for understanding the neurotoxicology of MDMA and for public health. However, some technical issues need to be considered. First, whether SPECT imaging with [123I]ß-CIT is sensitive enough to measure the density of serotonin transporters in areas of the cerebral cortex is controversial.12,13 Second, the low signal-to-noise ratio (less than 1á5 to 1) with SPECT and [123I]ß-CIT, even in regions with high density of serotonin transporters, compounds the difficulty of ascertaining the sensitivity of this method. Third, the cerebellum was used as a reference region, but it contains serotonin-transporter-bearing axons14 that are sensitive to MDMA neurotoxicity. Therefore, estimates of regional brain densities of serotonin transporters based on the cerebellum as a reference could be highly unstable. Given these methodological uncertainties, it would be premature to conclude that the long-term effects of MDMA in human beings are "reversible".
The researchers based their conclusion on reversibility on the finding on the finding that ex-MDMA users have higher densities of serotonin transporters than do heavy users. Studies in non-human primates have shown that, over time, there is regrowth of ascending serotonin axonal projections after MDMA-induced injury but that a normal innervation pattern is not restored.14 In some regions of the basal forebrain, such as the lateral hypothalamus, density of serotonin axons becomes greater than normal,14yet in other regions, such as the dorsal neocortex, density of serotonin axons remains significantly reduced for up to 7 years after MDMA exposure.15 Thus, use of the term "reversibility" could easily be misinterpreted since serotonin innervation in the brain may have been changed irreversibly.
Although the study is timely and potentially important, the small sample size and methodological questions limit confidence in the conclusions about differences between sexes or possibility of reversibility of the effects of MDMA in human beings. Studies in larger cohorts of both sexes, free of psychiatric illnesses in which serotonin is implicated, are needed.
*George A Ricaurte, Una D McCann
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