Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter

Introduction

MDMA acts primarily on the central serotonin (5-HT) system, with the serotonin transporter (SERT, encoded by SLC6A4) being a major target. Acute MDMA causes reverse transport of the reuptake transporter, elevating synaptic 5-HT, and reliably produces increases in positive affect (for example vigour, elation) as well as increases in some negative affective states (notably anxiety and confusion). A common functional polymorphism in the SERT promoter region (5-HTTLPR) exists as long (l) and short (s) alleles; the l-allele is associated with higher transporter expression and greater 5-HT uptake capacity than the s-allele. Previous literature has associated the s-allele with higher anxiety and negative mood and altered amygdala structure/function, but findings are not fully consistent and other factors such as methylation may modify effects. Kuypers and colleagues set out to test whether acute MDMA-induced mood effects differ by 5-HTTLPR genotype and by sex. Because individual placebo-controlled MDMA studies are typically underpowered for genotype comparisons, the investigators pooled data from four within-subject, placebo-controlled trials to examine whether carriers of the slow-working SERT variants (s-allele carriers) show different acute mood responses to MDMA (75 mg) than homozygous l-allele individuals, and whether any mood effects correlate with MDMA blood concentrations. The primary clinical question was whether genotype and sex moderate MDMA's acute effects on positive and negative mood states.