Studies of MDMA-Induced Neurotoxicity in Nonhuman Primates: A Basis for Evaluating Long-Term Effects in Humans

MDMA's neurotoxic effects extend to primates, with monkeys far more sensitive than rats to serotonin depletion and exhibiting a steeper dose-response curve. In monkeys, damage involves both serotonergic nerve fibers and cell bodies, whereas in rats only fibers are affected. The toxic dose in monkeys (5 mg/kg) closely approaches typical human doses (1.7–2.7 mg/kg), raising concern for human neurotoxicity, especially given the narrow margin of safety suggested by the steep primate dose-response curve. Cerebrospinal fluid 5-HIAA can detect MDMA-induced serotonergic damage in primates, and ongoing studies in humans aim to clarify long-term effects on serotonergic neurons.

Study at a glance

Abstract

The results of the studies reviewed here show that the neurotoxic effects of MDMA generalize to the primate. Further, they indicate that monkeys are considerably more sensitive than rats to the serotonin-depleting effects of MDMA, and that the dose-response curve of MDMA in the monkey is much steeper than in the rat. Perhaps as a consequence of this, the toxic effects of MDMA in the monkey involve serotonergic nerve fibers as well as cell bodies, whereas in the rat, only nerve fibers are affected. The present studies also show that the toxic dose of MDMA in the monkey (5 mg/kg) closely approaches the dose typically used by humans (1.7 to 2.7 mg/kg). This finding heightens concern that MDMA may be neurotoxic in humans, particularly since the steepness of the dose-response curve of MDMA in the primate suggests a narrow margin of safety. Finally, preclinical studies in monkeys have shown that CSF 5-HIAA can be used to detect MDMA-induced serotonergic damage in the primate CNS. Studies now underway in MDMA-exposed humans should help determine if MDMA exerts long-term toxic effects on serotonergic neurons in the human brain.