The role of monoamines in the changes in body temperature induced by 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) and its derivatives

Hyperthermia is a well-known acute adverse effect of MDMA (ecstasy) use, but the drug's influence on body temperature is complex, involving actions on serotonin, dopamine, and noradrenaline systems. In laboratory animals, MDMA can cause either hyperthermia or hypothermia depending on ambient temperature, through central thermoregulation and peripheral changes in blood flow and heat generation. Serotonin receptors modulate the hyperthermic response, while dopamine and noradrenaline systems also contribute—noradrenaline activates receptors that constrict skin blood vessels and increase heat production in brown fat. Hyperthermia in recreational users can be fatal, and no single drug is likely to reverse it; careful body cooling remains the main treatment. Educating users about ambient temperature control is key to prevention.

Study at a glance

Abstract

Hyperthermia is probably the most widely known acute adverse event that can follow ingestion of 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) by recreational users. The effect of MDMA on body temperature is complex because the drug has actions on all three major monoamine neurotransmitters [5‐hydroxytryptamine (5‐HT), dopamine and noradrenaline], both by amine release and by direct receptor activation. Hyperthermia and hypothermia can be induced in laboratory animals by MDMA, depending on the ambient temperature, and involve both central thermoregulation and peripheral changes in blood flow and thermogenesis. Acute 5‐HT release is not directly responsible for hyperthermia, but 5‐HT receptors are involved in modulating the hyperthermic response. Impairing 5‐HT function with a neurotoxic dose of MDMA or p ‐chlorophenylalanine alters the subsequent MDMA‐induced hyperthermic response. MDMA also releases dopamine, and evidence suggests that this transmitter is involved in both the hyperthermic and hypothermic effects of MDMA in rats. The noradrenergic system is also involved in the hyperthermic response to MDMA. MDMA activates central α 2A ‐adrenoceptors and peripheral α 1 ‐adrenoceptors to produce cutaneous vasoconstriction to restrict heat loss, and β 3 ‐adrenoceptors in brown adipose tissue to increase heat generation. The hyperthermia occurring in recreational users of MDMA can be fatal, but data reviewed here indicate that it is unlikely that any single pharmaceutical agent will be effective in reversing the hyperthermia, so careful body cooling remains the principal clinical approach. Crucially, educating recreational users about the potential dangers of hyperthermia and the control of ambient temperature should remain key approaches to prevent this potentially fatal problem.