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Reneman L, Booij J, de Bruin K, Reitsma JB, de Wolff FA, Gunning WB, den Heeten GJ, van den Brink W. 
“Effects of dose, sex and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons”. 
Lancet,. 2001;358(9296):1864-1869.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to damage brain serotonin neurons in high doses. However, effects of moderate MDMA use on serotonin neurons have not been studied, and sex differences and the long-term effects of MDMA use on serotonin neurons have not been identified. We investigated the effects of moderate and heavy MDMA use, sex differences, and long-term effects of MDMA use on serotonin neurons in different brain regions.

METHODS: By means of flyers posted in 'rave' venues in Amsterdam, the Netherlands, we recruited 15 moderate MDMA users, 23 heavy MDMA users, 16 ex-MDMA users who had stopped using MDMA for more than 1 year, and 15 controls who claimed never to have used MDMA. We studied the effects of MDMA on brain serotonin neurons using 123iodine-2-carbomethoxy-3-(4-iodophenyl) tropane ([123I]-CIT)--a radioligand that binds with high affinity to serotonin transporters. Density of binding (expressed as a ratio of region-of-interest binding over binding in the cerebellum) was calculated by single-photon-emission computed tomography (SPECT).

FINDINGS: We saw significant effects of group and group by sex (p=0041 and p=0022, respectively) on overall [123I]-CIT binding ratios. In heavy MDMA users, significant decreases in overall binding ratios were seen in women (p< 001) but not men (p=0587). In female ex-MDMA users, overall densities of serotonin transporters were significantly higher than in heavy MDMA users (p=0004), but not higher than in controls (p=0524).

INTERPRETATION: Our results indicate that heavy use of MDMA is associated with neurotoxic effects on serotonin neurons, that women might be more susceptible than men, and that MDMA-induced neurotoxic changes in several brain regions of female ex-MDMA users are reversible.
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