Metabolomic insights into amphetamine-type stimulant misuse: unraveling biochemical pathways and biomarkers

Amphetamine-type stimulants (ATS), such as methamphetamine, amphetamine, and MDMA, are highly risky substances linked to neurochemical disruptions, metabolic disturbances, and systemic toxicity. Despite substantial research on their neurotoxic effects, the metabolic pathways involved in ATS dependence remain poorly understood. This study aimed to characterize the metabolic signatures associated with ATS dependence using NMR-based metabolomics to identify systemic metabolic disruptions related to chronic ATS use. A cross-sectional study was conducted involving 583 participants, comprising ATS-dependent individuals from Malaysian drug detention centers and healthy controls. Plasma samples were analyzed using 1H-NMR, CPMG, and HSQC spectroscopy to obtain comprehensive metabolomic profiles. Multivariate analyses, including PCA-X, OPLS-DA, and logistic regression, were employed to identify metabolites that differentiated ATS patients from controls. Metabolites were cross-referenced with BMRB and HMDB databases for validation. ATS-dependent individuals showed significant alterations in metabolic pathways, with reductions in cholic acid, L-valine, L-alanine, lactic acid, creatinine, histidine, taurine, and homovanillic acid (all <i>p</i> < .005), indicating disruptions in energy metabolism, neurotransmitter biosynthesis, and oxidative stress defenses. Elevated L-arginine levels (<i>p</i> < .001) suggested nitrogen metabolism dysregulation. OPLS-DA analysis demonstrated robust group separation (R²Y = 0.762, Q²Y = 0.756, AUROC = 0.987), with sensitivity, specificity, and classification accuracy of 86.9%, 97.4%, and 91.5%, respectively. This study presents the first NMR-based metabolomic profile of ATS misuse in Malaysia, identifying critical metabolic disruptions linked to chronic ATS use. Key biomarkers, including cholic acid, L-valine, and homovanillic acid, highlight potential targets for biomarker development and precision medicine strategies to improve the diagnosis, treatment, and understanding of ATS use disorder.