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 (TPH1 [tryptophan 5-hydroxylase
1] rs1800532 and rs1799913, TPH2 [tryptophan 5-hydroxylase
2] rs7305115, HTR1A [5-HT1A receptor]
rs6295, HTR1B [5-HT1B receptor] rs6296, HTR2A [5-HT2A receptor] rs6313, and SLC6A4 [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. TPH2 rs7305115, HTR2A rs6313, and SLC6A4 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.

甲基苯丙胺（MDMA；俗称摇头丸）作为一种娱乐性药物，亦被探究作为心理治疗辅助药物之用。MDMA的多数急性作用可归因于血清素（5-羟色胺[5-HT]）系统的激活。遗传变异，诸如5-HT系统基因中的单核苷酸多态性（SNPs）和多态性区域，可能对MDMA急性作用中个体间差异产生贡献。本研究对编码5-HT系统的选定基因中常见的遗传变异（TPH1[色氨酸5-羟化酶1] rs1800532和rs1799913、TPH2[色氨酸5-羟化酶2] rs7305115、HTR1A[5-HT1A受体] rs6295、HTR1B[5-HT1B受体] rs6296、HTR2A[5-HT2A受体] rs6313以及SLC6A4[血清素转运蛋白] 5-HTTLPR和rs25531）对125毫克MDMA与安慰剂在124名健康受试者生理和主观反应中的影响进行了描述。数据整合自八项在同一实验室进行的随机、双盲、安慰剂对照研究。TPH2 rs7305115、HTR2A rs6313和SLC6A4 5-HTTLPR多态性倾向于适度改变MDMA的一些作用。然而，在调整多重比较后，所测试的遗传多态性无一显著影响MDMA的反应。编码5-HT系统关键靶点的基因变异并未显著影响健康受试者对MDMA的反应。因此，在MDMA作为娱乐或治疗用途时，5-HT系统中个体间差异可能仅起着边缘作用。