Body temperature regulation and drugs of abuse

Phenethylamine-induced hyperthermia can occur following exposure to several different types of illicit stimulants, such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine ("Molly"), synthetic cathinones ("bath salts"), and N-methoxybenyl ("NBOMe"), to name a few. Peripheral norepinephrine release mediated by these sympathomimetic agents induces a double-edged sword of heat accumulation through β-adrenoreceptor-dependent activation of uncoupling protein (UCP1 and 3)-regulated thermogenesis and loss of heat dissipation through α₁-adrenoreceptor-mediated vasoconstriction. Additionally, thyroid hormones are important determinants of the capacity of thermogenesis induced by phenethylamines through the regulation of free fatty acid release and the transcriptional activation of a host of metabolic genes, including adrenergic receptors and mitochondrial uncoupling proteins. Here, we review the central and peripheral mechanistic "triggers" of phenethylamine-induced hyperthermia and outline potential pharmacologic interventions for managing phenethylamine-induced hyperthermia based on these recently discovered hyperthermia mediators.