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 alpha(2A)-adrenoceptors and peripheral alpha(1)-adrenoceptors to produce cutaneous vasoconstriction to restrict heat loss, and beta(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.