The metabolism of amphetamine-like psychostimulants is regulated by the polymorphic enzyme CYP2D6. Methamphetamine acts as a weak substrate and competitive inhibitor of CYP2D6, while MDMA is a high-affinity substrate and potent mechanism-based inhibitor, causing all users to phenocopy the poor metabolizer phenotype regardless of genotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than in vitro studies suggest, with other cytochrome P450 isoenzymes and renal excretion contributing significantly. Overall, the clinical relevance of CYP2D6 polymorphism is lower than predicted by in vitro findings.
Levo-tetrahydropalmatine (l-THP), an alkaloid from Chinese medicinal plants, reduces the rewarding effect of ketamine in rats, as measured by conditioned place preference. The compound activates the BDNF/TrkB signaling pathway and reverses increased expression of miR-27a-3p in ketamine-exposed rats and PC12 cells. Inhibiting miR-27a-3p in PC12 cells increases MAP2K4 expression, suggesting MAP2K4 is a functional target of this microRNA. These findings indicate that l-THP attenuates ketamine reward through modulation of the BDNF/TrkB pathway and the miR-27a-3p/MAP2K4 axis, which may offer targets for intervention.