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

Summary

MDMA, commonly known as ecstasy, significantly impairs sustained attention and visual-spatial memory in healthy males. In a study involving 15 participants, those administered MDMA (1.6 mg/kg) showed cognitive deficits compared to a placebo group. Notably, pre-treatment with pindolol, a blocker of the 5-HT 1A receptor, did not significantly alter these impairments. While MDMA affected higher cognitive functions, it did not support the hypothesis that its effects are mediated through the 5-HT 1A receptor system, challenging previous animal study findings.

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.

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