There have been no studies directly comparing the pharmacodynamics and pharmacokinetics of the methamphetamine enantiomers in mice. It is often suggested that
d-methamphetamine exerts more potent physiological and pharmacological effects than
l-methamphetamine does, and that the stimulating effects exerted by
l-methamphetamine on the central nervous system are 2–10 times less potent than those of
d-methamphetamine (Mendelson et al.
2006). The results of the present study indicated that psychostimulant effects induced by
l-methamphetamine are lower than those elicited by one-tenth the dose of
d-methamphetamine. In addition, plasma pharmacokinetic parameters and striatal concentrations of methamphetamine following administration of
l-methamphetamine at 10 mg/kg (which did not induce psychomotor activity) were approximately 11 and 16 times as high, respectively, as those following administration of 1 mg/kg
d-methamphetamine. Despite the fact that there are differentiable psycho-stimulating effects between two enantiomers, no significant difference in plasma pharmacokinetic parameters was detected at 1 mg/kg. In comparative positron emission tomography studies, the pharmacokinetics in the baboon brain was comparable for
11C-
d- and
11C-
l-methamphetamine (Fowler et al.
2007). Thus, factors other than brain or plasma pharmacokinetics, especially differences in the affinity of each enantiomer for its pharmacological targets, may account for the more potent psychomotor effects of
d-methamphetamine. For instance, the effects of
d-methamphetamine on the release and uptake of dopamine in rat caudate synaptosomes are reportedly approximately 17- and 42-fold greater, respectively, than those of
l-methamphetamine (Rothman et al.
2001). Kuzcenski et al. (
1995) demonstrated that the peak dopamine concentration in rat caudate following s.c. administration of 2 mg/kg
d-methamphetamine is approximately 2.3 times as high as that after administration of 12 mg/kg
l-methamphetamine. Comparative studies to differentiate the affinities of the enantiomers to target molecules will be required to clarify the mechanisms that give rise to the difference in psychomotor efficacies between
d- and
l-methamphetamine.
Selegiline is sometimes regarded as an inducer of psychoactive effects through its metabolites having a component of
N,α-dimethyl-
N-2-propynyl phenethylamine. Previous clinical studies have reported that the
C
max of
l-methamphetamine following administration of conventional selegiline tablets 10 mg (Clarke et al.
2003) was fivefold lower than the
C
max observed in methamphetamine abusers who had received intravenous
l-methamphetamine at a dose of 0.25 mg/kg, which does not exert psychoactive effects (Mendelson et al.
2006). Thus, the results of these previous reports suggest that the
l-methamphetamine available as a metabolite after selegiline administration at clinical doses may have little potential to induce psychoactive effects.
Taken together, our results indicated that the psychostimulant effects elicited by d-methamphetamine are at least 10 times stronger than those induced by l-methamphetamine based on their doses for inducing psychomotor activities. Furthermore, the distinct psychoactive efficacies of the enantiomers are not due to differences in plasma pharmacokinetics or brain concentrations of methamphetamine/amphetamine following administration of the respective enantiomers.