Evidence for chronically altered serotonin function in the cerebral cortex of female 3,4-methylenedioxymethamphetamine polydrug users

Context: MDMA (3,4-methylenedioxymethamphetamine, also popularly known as "ecstasy") is a popular recreational drug that produces loss of serotonin axons in animal models. Whether MDMA produces chronic reductions in serotonin signaling in humans remains controversial. Objective: To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin _2A receptor levels. Design: Cross-sectional case-control study comparing serotonin _2A receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin _2A receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin _2A receptor levels in the cerebral cortex were determined using serotonin _2A-specific positron emission tomography with radioligand fluorine 18-labeled setoperone as the tracer. Setting: Academic medical center research laboratory. Participants: A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness. Main Outcome Measures: Cortical serotonin _2A receptor nondisplaceable binding potential (serotonin _2ABP _ND). Results: MDMA users had increased serotonin _2ABP _ND in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal- parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin _2ABP _NDin frontoparietal (β = 0.665; P = .007), occipitotemporal (β = 0.798; P = .002), frontolimbic (β = 0.634; P = .02), and frontal (β = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin _2ABP _ND. Conclusions: The recreational use of MDMA is associated with long-lasting increases in serotonin _2A receptor density. Serotonin _2A receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.