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.