Impact of genetic variability in the serotonin transporter, Tryptophan Hydroxylase-2, and Serotonin 2A Receptors on MDMA Use and Impulsivity

Ecstasy [MDMA; (±)-3,4-methylenedioxymethamphetamine] is popular for positive effects including enhanced mood and empathy, despite potential deleterious physical and psychological consequences. The serotonin (5-HT) system plays a prominent role in the neurochemical and behavioral effects of MDMA, and preferentially targets 5-HT neurons in humans, although this substituted amphetamine does have significant actions on other monoamine systems. Some negative effects of MDMA use, including mood and cognitive dysfunction, may involve the 5-HT system, and are often treated with 5-HTergic antidepressants. The involvement of specific 5-HT genes, including tryptophan hydroxylase-2 (TPH-2), 5-HT transporter (5-HTT), and 5-HT2A receptor (5-HT2AR) in the effects of MDMA is incompletely understood. Our initial study compared the prevalence of polymorphisms leading to reduced gene expression in those genes among MDMA users versus controls, and assessed the relationship between these polymorphisms and impulsivity. As compared to control groups, MDMA users were less likely to carry 5-HTT SS or 5-HT2AR A1438G GG/T102C CC genotypes thought to lead to decreased gene expression. No relationship was found between genotype and impulsivity, however drug-naïve controls had lower impulsivity levels than either MDMA or polydrug users. The differential distribution of 5-HTT and 5-HT2AR 1438G/ T102C suggests that these genes contribute to individuals’ choices of MDMA versus other drugs. The second study examined the relationship between TPH-2, 5-HTT, and 5-HT2AR polymorphisms, and self-reported MDMA intake or impulsivity in moderate-to-heavy MDMA users. Decreased MDMA use was reported by individuals carrying genotypes associated with reduced gene expression (TPH-2 TT, 5-HTT SS, 5-HT2AR A1438G GG/T102C CC), and 5-HTT genotype-dependent changes in impulsivity were found. Our studies are the first to show a differential allelic distribution between MDMA users and controls, and demonstrate the relationship between TPH-2, 5-HTT and 5-HT2AR A1438G/T102C polymorphisms and MDMA intake. Individuals carrying TPH-2 TT, 5-HTT SS, 5-HT2AR A1438G GG/T102C CC may represent a subset of MDMA users at higher risk to develop MDMA-related adverse events, including depression. Further, this group may display poorer response to antidepressants and decreased retention in treatment given elevated impulsivity levels. Thus, our findings may have important implications for diagnosis and treatment of MDMA-dependent individuals.