The Nature of 3, 4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonergic Dysfunction: Evidence for and Against the Neurodegeneration Hypothesis

High doses of MDMA (Ecstasy) reduce the expression of serotonergic markers in the forebrains of rats and nonhuman primates, and neuroimaging suggests similar reductions in the serotonin transporter (SERT) in heavy human users. These effects have often been interpreted as a loss of serotonergic fibers and terminals. However, this view is challenged because MDMA usually does not trigger glial cell reactions typical of central nervous system damage. This review addresses both sides of the MDMA-neurotoxicity controversy, including recent data from a rat binge model. The findings implicate neuroregulatory mechanisms underlying MDMA-induced serotonergic dysfunction and question the need to invoke degeneration.

Study at a glance

Abstract

High doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") have been well-documented to reduce the expression of serotonergic markers in several forebrain regions of rats and nonhuman primates. Neuroimaging studies further suggest that at least one of these markers, the plasma membrane serotonin transporter (SERT), may also be reduced in heavy Ecstasy users. Such effects, particularly when observed in experimental animal models, have generally been interpreted as reflecting a loss of serotonergic fibers and terminals following MDMA exposure. This view has been challenged, however, based on the finding that MDMA usually does not elicit glial cell reactions known to occur in response to central nervous system (CNS) damage. The aim of this review is to address both sides of the MDMA-neurotoxicity controversy, including recent findings from our laboratory regarding the potential of MDMA to induce serotonergic damage in a rat binge model. Our data add to the growing literature implicating neuroregulatory mechanisms underlying MDMA-induced serotonergic dysfunction and questioning the need to invoke a degenerative response to explain such dysfunction.