3,4-Methylenedioxymethamphetamine (
MDMA) induces both acute adverse effects and long-term neurotoxic loss of brain
5-HT neurones in laboratory animals. However, when choosing doses, most preclinical studies have paid little attention to the pharmacokinetics of the
drug in humans or animals. The recreational use of
MDMA and current clinical investigations of the
drug for therapeutic purposes demand better translational pharmacology to allow accurate risk assessment of its ability to induce adverse events. Recent pharmacokinetic studies on
MDMA in animals and humans are reviewed and indicate that the risks following
MDMA ingestion should be re-evaluated. Acute behavioural and
body temperature changes result from rapid
MDMA-induced monoamine release, whereas long-term neurotoxicity is primarily caused by metabolites of the
drug. Therefore acute physiological changes in humans are fairly accurately mimicked in animals by appropriate dosing, although allometric dosing calculations have little value. Long-term changes require
MDMA to be metabolized in a similar manner in experimental animals and humans. However, the rate of metabolism of
MDMA and its major metabolites is slower in humans than rats or monkeys, potentially allowing endogenous neuroprotective mechanisms to function in a species specific manner. Furthermore acute
hyperthermia in humans probably limits the chance of recreational users ingesting sufficient
MDMA to produce neurotoxicity, unlike in the rat.
MDMA also inhibits the major
enzyme responsible for its metabolism in humans thereby also assisting in preventing neurotoxicity. These observations question whether
MDMA alone produces long-term
5-HT neurotoxicity in human brain, although when taken in combination with other
recreational drugs it may induce neurotoxicity.