Sprague-Dawley rats display metabolism-mediated sex differences in the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy).
Julien Fonsart, Marie-Claude Menet, Xavier Declèves, Hervé Galons, Dominique Crété, Marcel Debray, Jean-Michel Scherrmann, Florence Noble
Toxicology and Applied Pharmacology July 1, 2008 DOI: 10.1016/j.taap.2008.02.004 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational animal study Peer reviewed |
|---|---|
| Population | Male and female Sprague-Dawley rats |
| Interventions | MDMA MDA |
| Dose | MDMA 5 mg.kg(-1) sc |
| Duration | 3 h after dosing |
| Topics | MDMA |
| Key findings | Male Sprague-Dawley rats were more sensitive to acute MDMA toxicity than females, with a 2.4-times lower LD50 and greater hyperthermia (0.9 degrees C). The authors suggest this is probably because males have more active CYP1A2, leading to higher N-demethylation and plasma MDA concentrations, and that amphetamine-related drug toxicity largely depends on metabolic differences. |
Abstract
The use of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been associated with unexplained deaths. Male humans and rodents are more sensitive to acute toxicity than are females, including a potentially lethal hyperthermia. MDMA is highly metabolized to five main metabolites, by the enzymes CYP1A2 and CYP2D. The major metabolite in rats, 3,4-methylenedioxyamphetamine (MDA), also causes hyperthermia. We postulated that the reported sex difference in rats is due to a sexual dimorphism(s). We therefore determined (1) the LD50 of MDMA and MDA, (2) their hyperthermic effects, (3) the activities of liver CYP1A2 and CYP2D, (4) the liver microsomal metabolism of MDMA and MDA, (5) and the plasma concentrations of MDMA and its metabolites 3 h after giving male and female Sprague-Dawley (SD) rats MDMA (5 mg.kg(-1) sc). The LD50 of MDMA was 2.4-times lower in males than in females. MDMA induced greater hyperthermia (0.9 degrees C) in males. The plasma MDA concentration was 1.3-fold higher in males, as were CYP1A2 activity (twice) and N-demethylation to MDA (3.3-fold), but the plasma MDMA concentration (1.4-fold) and CYP2D activity (1.3-fold) were higher in females. These results suggest that male SD rats are more sensitive to MDMA acute toxicity than are females, probably because their CYP1A2 is more active, leading to higher N-demethylation and plasma MDA concentration. This metabolic pathway could be responsible for the lethality of MDMA, as the LD50 of MDA is the same in both sexes. These data strongly suggest that the toxicity of amphetamine-related drugs largely depends on metabolic differences.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
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- Longitudinal Examination of Learning and Memory in Rats Following Adolescent Exposure to 3,4-Methylenedioxymethamphetamine or 5-Methoxy-N,N-Diisopropyltryptamine Journal of Behavioral and Brain Science 2017
- Adolescent MDMA exposure diminishes the physiological and neurotoxic consequences of an MDMA binge in female rats Developmental Psychobiology July 1, 2014
- MDMA impairs response to water intake in healthy volunteers bioRxiv (Cold Spring Harbor Laboratory)
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