Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA

MDMA primarily works by releasing serotonin in the primate brain, with additional contributions from dopamine release and stimulation of dopamine D2 and serotonin 5-HT2A receptors. The role of serotonin 5-HT1A receptors in MDMA's effects in humans was unclear. In a double-blind, placebo-controlled study, 15 healthy men received placebo, the 5-HT1A antagonist pindolol, MDMA alone, or MDMA after pindolol. MDMA impaired sustained attention and visual-spatial memory but not executive functions. Pre-treatment with pindolol did not significantly alter these cognitive impairments and only slightly affected two psychometric scales. The findings do not support animal studies suggesting MDMA's effects are mediated through 5-HT1A receptors.

Study at a glance

Abstract

Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT 2A receptors also contributes to the overall action of MDMA. The role of 5-HT 1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT 1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT 1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment (‘positive derealization’ and ‘dreaminess’). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT 1A receptor system.