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

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 a2A-adrenoceptors and peripheral a1-adrenoceptors to produce cutaneous vasoconstriction to restrict heat loss, and b3-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.

Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA)

“…3). Conversely, the 5-HT 2A receptor blocker ketanserin blunted the hyperthermic effects of MDMA both in TA 1 -KO and WT mice (Liechti et al, 2000;Docherty and Green, 2010), consistent with clinical studies of the hyperthermia provoked by MDMA in humans (Vollenweider et al, 2002;Docherty and Green, 2010).…”

Caffeine alters the behavioural and body temperature responses to mephedrone without causing long-term neurotoxicity in rats

“…There is substantial evidence that dopaminergic mechanisms are involved in MDMA-induced temperature changes, both hypothermia and hyperthermia (Docherty and Green, 2010). In contrast, evidence suggests that serotonergic mechanisms are key to the hypothermic effect of mephedrone (Shortall et al, 2015).…”

“…When caffeine is administered together with MDMA it results in a further enhancement of the hyperthermic response which can prove fatal (Green et al, 2003;McNamara et al, 2006;Vanattou-Saifoudine et al, 2012). However, when MDMA is given to individually housed rats it generally results in hypothermia (Bull et al, 2004;Docherty and Green, 2010). Mephedrone administration also induces hypothermia even when the rats are grouped or exposed to a high ambient temperature .…”

Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone

“…Considerable evidence shows that 5-HT plays a major role in thermoregulation, particularly when body temperature is perturbed by amphetamine-like drugs (Docherty and Green, 2010).…”

“…Most studies show the acute effect of a single injection, or self-administration of mephedrone in the rat is hypothermia (Aarde et al, 2013;Miller et al, 2013;Shortall et al, 2013a), but hyperthermia has also been reported following rapid repeated dosing (Baumann et al, 2012;Hadlock et al, 2011). Given the established association of hyperthermia with life-threatening adverse effects of MDMA (Docherty and Green, 2010), it is essential to see if there might be a similar adverse risk with repeated mephedrone. The current study therefore examined the temporal profile of the temperature and locomotor response to short-term repeated mephedrone and established the involvement of serotonergic and dopaminergic neurons in these changes because of their known role in the effects of MDMA.…”