Role of serotonin transporter and receptor gene variations in the acute effects of MDMA in healthy subjects

Introduction

Vizeli and colleagues situate their study in the context of growing interest in MDMA (ecstasy, molly) both as a recreational drug and as an adjunct to psychotherapy, particularly for PTSD. MDMA's typical acute effects are largely mediated by the serotonin (5-HT) system through actions on tryptophan hydroxylase (TPH), the serotonin transporter (SERT, encoded by SLC6A4), and 5-HT receptor subtypes (5-HT1A, 5-HT1B, 5-HT2A). Previous pharmacological manipulations of these targets altered MDMA effects, and genetic variants in metabolising enzymes (notably CYP2D6) have been shown to affect MDMA pharmacokinetics and some pharmacodynamics. However, whether common genetic polymorphisms in genes encoding core 5-HT system components modify the acute subjective, empathic, physiological, or adverse responses to MDMA in humans remained uncertain, with only small or inconsistent findings reported in earlier studies. This pooled analysis tested whether common variants in selected serotonergic genes influence the acute response to a single oral 125 mg dose of MDMA in healthy subjects. Specifically, the investigators evaluated TPH1 (rs1800532, rs1799913), TPH2 (rs7305115), HTR1A (rs6295), HTR1B (rs6296), HTR2A (rs6313), and SLC6A4 5-HTTLPR together with an associated SNP (text refers to rs25531 and also to rs25331 in one place; the extraction does not clearly resolve this discrepancy). The primary aim was to determine whether these polymorphisms modulate MDMA-induced subjective, emotional, empathic, cardiovascular, thermogenic, and adverse effects, and to attempt replication of findings reported in smaller earlier studies.