Enhanced neurotoxic effects following co-administration of methamphetamine and ethanol in rats: Insights from integrated analysis of behavior, pharmacokinetics, and metabolomics

Methamphetamine (MA) is a psychostimulant with high potential for abuse and neurotoxicity, and overdose or concurrent use with ethanol (EtOH) has been associated with increased hospitalizations and mortality. This study investigated the pharmacokinetic and metabolic interactions resulting from concomitant exposure to MA (1, 4, and 10 mg/kg, intraperitoneal [i.p.]) and EtOH (2 g/kg, 30 % v/v, i.p.) in a rat model by assessing dose-dependent behavioral responses and EtOH-induced potentiation of MA-mediated neurotoxicity. Pharmacokinetic analysis revealed that EtOH co-administration increased the maximum plasma concentration, half-life, and area under the plasma concentration-time curve of MA while decreasing its volume of distribution and total clearance. Notably, EtOH co-administration reduced the hydroxylation of MA and enhanced its demethylation, potentially contributing to elevated toxicity and addictive potential. Time-course metabolic profiling of amino acids and polyamines showed that EtOH-induced potentiation of stereotypic behaviors correlated with a significant increase in plasma spermidine and spermine levels, suggesting a temporal association between behavioral and metabolomic alterations. At the time of peak behavioral abnormalities, extensive metabolic perturbations were observed following MA and EtOH co-administration. Receiver operating characteristic curve and network analyses identified two polyamines (spermidine and spermine) and two bile acids (glycocholic acid and taurocholic acid) as key metabolites associated with the MA-EtOH interaction, implicationg their roles in MA-EtOH intoxication. These findings reveal previously uncharacterized pharmacometabolic pathways and behavioral manifestations resulting from MA and EtOH co-exposure, providing novel mechanistic insights into the pathophysiology of MA-EtOH co-intoxication.