Discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and its enantiomers in mice: pharmacokinetic considerations.

3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse with mixed stimulant- and hallucinogen-like effects. The aims of the present studies were to establish discrimination of S(+)-MDMA, R(-)-MDMA, or their combination as racemic MDMA in separate groups of mice to assess cross-substitution tests among all three compounds, to determine the time courses of the training doses, to assess pharmacokinetic variables after single injections and after cumulative dosing, and to define the metabolic dispositions of MDMA enantiomers and their metabolites. All three forms of MDMA served as discriminative stimuli, and with the exception of R(-)-MDMA in mice trained to discriminate the racemate, compounds substituted for one another. The onset of interoceptive effects for S(+)-MDMA and racemic MDMA were faster than for R(-)-MDMA, and the duration of discriminative stimulus effects was shortest for R(-)-MDMA. S(+)-MDMA and its metabolites were found in higher concentrations than R(-)-MDMA and its metabolites after a bolus dose of racemic MDMA. The N-dealkylation pathway is favored in mouse plasma with MDA as the main metabolite formed. Cumulative doses of MDMA lead to higher plasma concentrations compared with an equivalent single dose. 3,4-Methylenedioxyamphetamine (MDA) concentrations are lower after the cumulative dose compared with the single dose, which, coupled with the nonlinearity observed in MDMA pharmacokinetics after increased doses of racemic MDMA, suggests autoinhibition (or saturation) of MDMA metabolism in mice. In total, these studies suggest that the discriminative stimulus effects of racemic MDMA are perhaps driven by accumulation of S(+)-MDMA and S(+)-MDA in the mouse.