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. 2012 Apr;69(4):399-409.
doi: 10.1001/archgenpsychiatry.2011.156. Epub 2011 Dec 5.

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

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

Christina R Di Iorio et al. Arch Gen Psychiatry. 2012 Apr.

Abstract

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(2A)BP(ND)).

Results: MDMA users had increased serotonin(2A)BP(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(2A)BP(ND) in 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(2A)BP(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.

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Figures

Figure 1
Figure 1
Panels a. and b. depict right hemisphere and bilateral superior regions, respectively, in which 5-HT2ABPND was greater in ecstasy (MDMA) users than in controls (Table 2). Panels c.-f. show representative clusters from a. and b. with Brodmann Area labels on brain sections having increased 5-HT2ABPND in MDMA users (after adjusting for age, birth control, and estrogen). Color scale indicates t-score for significant voxels (voxel level p=0.05, cluster volume 910 voxels, family wise error [FWE] corrected p=0.05).
Figure 2
Figure 2
Panels a. and b. depict right hemisphere and bilateral superior regions, respectively, in which lifetime ecstasy use correlates positively with 5-HT2ABPND in the ecstasy (MDMA) user group after adjusting for birth control, estrogen, and age (Table 4). Panels c.-f. show representative clusters from a. and b. with Brodmann Area labels on brain sections (left) and scatterplots (right) showing correlation of lifetime MDMA use (as mg ecstasy) with 5-HT2ABPND. Color scale indicates t-score for significant voxels in the regression analysis (voxel level p=0.05, cluster volume 910 voxels, family wise error (FWE) corrected p=0.05). Scatterplots are rank data to account for non-parametric distribution of lifetime ecstasy use (Max/Min use in mg: 250–112,500) and adjusted predicted rank data for 5-HT2ABPND (adjusted for age, birth control, and estrogen). Rank of lifetime use was calculated as the product of the average use per episode and the number of use episodes. Ranks were determined within SPSS using the “rank” function.

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