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Review
. 2012 Jul;166(5):1523-36.
doi: 10.1111/j.1476-5381.2011.01819.x.

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

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Review

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

A R Green et al. Br J Pharmacol. .
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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.

Figures

Figure 1
Figure 1
Plot of mean values of peak plasma MDMA concentration versus dose of MDMA administered taken from publications examining these parameters in rats and humans. Data in rats shown as mean value ± SEM of values from each study at that dose. Data in humans shows each separate study value obtained. Variance in these studies can be ascertained from the original papers. Insert figure shows human data in an expanded graph for clarity. Reproduced from Green et al. (2009) with permission of Springer-Verlag.
Figure 2
Figure 2
Proposed pathway for MDMA metabolism to neurotoxic metabolites. MDMA can undergo N-demethylation to MDA. Cytochrome P450 (CYP) enzymes also mediate demethylenation of MDMA and MDA to N-Me-α-MeDA and α-MeDA respectively. The catechols are readily oxidized to the corresponding o-quinones, which can enter redox cycles with their semiquinone radicals, leading to formation of ROS and RNS. On cyclization, o-quinones give rise to the formation of aminochromes and related compounds, such as 5,6-dihydroxyindoles, which can undergo further oxidation and polymerization to form brown or black insoluble pigments of melanin type. Alternatively, o-quinones can react readily with GSH to form the corresponding GSH conjugates like 5-GSH-α-MeDA. Reproduced from Capela et al. (2006) with permission of the American Society for Pharmacology and Experimental Therapeutics.

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