Exercise-induced Biomarkers in Methamphetamine Addiction: Molecular Mechanisms and Clinical Implications

Methamphetamine (METH) addiction is a severe and increasingly prevalent neuropsychiatric disorder for which current diagnostic and therapeutic approaches remain limited and predominantly symptom-oriented. Exercise, as a safe, accessible and cost-effective non-pharmacological intervention, has emerged as a promising strategy to ameliorate METH-induced neurotoxicity and addiction-related behaviors. Growing evidence indicates that these benefits are closely linked to the regulation of exercise-induced biomarkers, defined as molecular indicators whose expression or activity is dynamically altered during or after physical activity. This review focuses on the core regulatory role of exercise-induced biomarkers in METH addiction and systematically summarizes their involvement in key neurobiological pathways, outlining molecular pathological mechanisms such as dysregulation of dopamine, glutamate and GABA neurotransmitter systems, neuroinflammation and oxidative stress, and epigenetic remodeling, and emphasizing how these processes converge on changes in candidate biomarkers in the brain and periphery. On this basis, the review describes how exercise modulates neural plasticity, neurotransmitter systems, inflammation and oxidative stress through biomarkers such as brain-derived neurotrophic factor (BDNF), exerkines, inflammatory cytokines, metabolites and non-coding RNAs, with particular attention to neurotrophic and immune-related markers, microRNAs and other epigenetic regulators that can reverse METH-induced synaptic and structural abnormalities and promote recovery of cognitive and emotional functions. Advances in high-throughput omics technologies, including transcriptomics, metabolomics and multi-omics integration, are summarized to illustrate the screening and identification of key exercise-responsive biomarkers. Studies in METH-addicted animal models have revealed differentially expressed genes, signaling pathways (e.g., PI3K-Akt, mTOR, Wnt) and core nodes such as NFKBIA and CXCL12 that may mediate the protective effects of exercise. The review further discusses the potential of exercise-mediated biomarkers as objective indicators for diagnosis, dynamic monitoring of therapeutic efficacy and patient stratification. Multi-gene diagnostic models based on peripheral samples (e.g., hair follicles, blood) demonstrate how biomarker panels can distinguish non-recovered, almost-recovered and healthy individuals, providing a molecular basis for staging METH use disorder and evaluating the impact of exercise interventions. The temporal dynamics of biomarker changes before and after exercise are highlighted, underscoring the value of longitudinal monitoring of factors such as BDNF, immune-related genes and circulating microRNAs to capture treatment-relevant windows of plasticity. In addition, the underlying molecular basis of exercise as an adjunct therapy and gene-targeted exercise strategies that leverage individual biomarker and gene expression profiles to optimize exercise prescriptions are summarized. Current conceptual and technical challenges are outlined, including heterogeneity of biomarker responses, individual variability, assay sensitivity and specificity, and gaps between preclinical findings and clinical application, together with future directions for integrating exercise with multi-omics, artificial intelligence-assisted biomarker discovery and, prospectively, gene-editing-based interventions. Particular emphasis is placed on the need to standardize exercise protocols, incorporate stage-specific and sex-sensitive designs, and combine exercise with pharmacotherapy and psychosocial rehabilitation in real-world clinical settings across diverse healthcare systems. Overall, this review aims to provide a comprehensive and integrated mechanistic framework and updated theoretical support for the application of exercise-mediated biomarkers in the diagnosis, therapeutic effect monitoring and personalized intervention of METH addiction, and to offer new and clinically relevant insights into the development of precision medicine strategies for substance use disorders.