MDMA reduced the arousal normally elicited by negative sounds, and this effect was blocked by pre-treatment with ketanserin, a 5-HT2 receptor antagonist, indicating the involvement of the serotonin 2A receptor. The drug did not produce a bias toward emotional or social stimuli in the tasks used. MDMA increased both positive and negative mood ratings and elevated oxytocin plasma concentrations. The reduction in arousal to negative sounds was unrelated to subjective arousal levels. This decrease in defensive arousal may contribute to MDMA's therapeutic effects.
MDMA's mood effects depend partly on a genetic variation in the serotonin transporter gene (5-HTTLPR). People with the short variant of this gene typically show more anxiety and negative mood, while those with two long alleles (l-group) tend to be less anxious. In a pooled analysis of four placebo-controlled studies with 63 polydrug ecstasy users, MDMA (75 mg) generally improved mood but also increased anxiety and confusion. Unexpectedly, the l-group reported higher anxiety regardless of MDMA or placebo. MDMA reduced depressive feelings only in females from the l-group, suggesting a sex- and genotype-dependent effect.