Role of Serotonin Transporter and Receptor Gene Variations in the Acute Effects of MDMA in Healthy Subjects

Methylenedioxymethamphetamine (MDMA; ecstasy) is used recreationally and has been investigated as an adjunct to psychotherapy. Most acute effects of MDMA can be attributed to activation of the serotonin (5-hydroxytryptamine [5-HT]) system. Genetic variants, such as single-nucleotide polymorphisms (SNPs) and polymorphic regions in 5-HT system genes, may contribute to interindividual differences in the acute effects of MDMA. We characterized the effects of common genetic variants within selected genes that encode the 5-HT system (<i>TPH1</i> [tryptophan 5-hydroxylase 1] rs1800532 and rs1799913, <i>TPH2</i> [tryptophan 5-hydroxylase 2] rs7305115, <i>HTR1A</i> [5-HT<sub>1A</sub> receptor] rs6295, <i>HTR1B</i> [5-HT<sub>1B</sub> receptor] rs6296, <i>HTR2A</i> [5-HT<sub>2A</sub> receptor] rs6313, and <i>SLC6A4</i> [serotonin transporter] 5-HTTLPR and rs25531) on the physiological and subjective response to 125 mg of MDMA compared with placebo in 124 healthy subjects. Data were pooled from eight randomized, double-blind, placebo-controlled studies that were conducted in the same laboratory. <i>TPH2</i> rs7305115, <i>HTR2A</i> rs6313, and <i>SLC6A4</i> 5-HTTLPR polymorphisms tended to moderately alter some effects of MDMA. However, after correcting for multiple comparisons, none of the tested genetic polymorphisms significantly influenced the response to MDMA. Variations in genes that encode key targets in the 5-HT system did not significantly influence the effects of MDMA in healthy subjects. Interindividual differences in the 5-HT system may thus play a marginal role when MDMA is used recreationally or therapeutically.