Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity

The ring-substituted amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) or "Ecstasy" is widely used a recreational drug. It stimulates the release and inhibits the reuptake of serotonin (5-HT) and other neurotransmitters such as dopamine to a lesser extent. The acute boost in monoamine activity can generate feelings of elation, emotional closeness, and sensory pleasure. In the hot and crowded conditions of raves/dances, mild versions of the serotonin syndrome often develop, when hyperthermia, mental confusion, and hyperkinesia predominate. Rest in a cooler environment generally reverses these problems, although they can develop into medical emergencies, which occasionally prove fatal. This acute serotonergic overactivity is exacerbated by the high ambient temperatures, overcrowding (aggregate toxicity), and use of other stimulant drugs. The on-drug experience is generally followed by negative moods, with 80--90% of weekend Ecstasy users reporting 'midweek blues', due probably to monoaminergic depletion. Single doses of MDMA can cause serotonergic nerve damage in laboratory animals, with repeated doses causing extensive loss of distal axon terminals. Huether's explanatory model for this 5-HT neurotoxicity will be briefly described. There is an increasing body of evidence for equivalent neuropsychobiological damage in humans. Abstinent regular Ecstasy users often show: reduced cerebrospinal 5-HIAA, reduced density of 5-HT transporters, blunted response to a fenfluramine challenge, memory problems, higher cognitive deficits, various psychiatric disorders, altered appetite, and loss of sexual interest. Functional deficits may remain long after drug use has ceased and are consistent with serotonergic axonal loss in higher brain regions.