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Lost in translation: preclinical studies on 3,4‐methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans

Ar Green, MV King, SE Shortall, KCF Fone

British Journal of Pharmacology July 1, 2012 DOI: 10.1111/j.1476-5381.2011.01819.x (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Review Peer reviewed
Intervention MDMA
Topics MDMA
Key findings The authors argue that species differences in MDMA metabolism, especially slower clearance in humans than in rats or monkeys, mean animal dosing studies may not translate well to human neurotoxicity risk. They question whether MDMA alone produces long-term 5-HT neurotoxicity in human brain, suggesting combined use with other recreational drugs may be required.

Abstract

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. LINKED ARTICLES: This article is commented on by Parrott, pp. 1518–1520 of this issue. To view this commentary visithttp://dx.doi.org/10.1111/j.1476‐5381.2012.01941.xand to view the the rebuttal by the authors (Greenet al., pp. 1521–1522 of this issue) visithttp://dx.doi.org/10.1111/j.1476‐5381.2012.01940.x

Comparable studies

Other narrative reviews on MDMA, most cited first.

Study Year Design Participants
Human Pharmacology of MDMA 2004 Review
Human psychopharmacology of Ecstasy (MDMA): a review of 15 years of empirical research 2001 Review
3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans 1994 Review
(±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals 2000 Review
Amphetamine toxicities 2010 Review

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