Exercise-Induced Metaplasticity: Breaking the Addiction Cycle in Methamphetamine Use Disorder.

The high relapse rate in methamphetamine (MA) use disorder (MUD) highlights limitations in current treatment approaches. MA disrupts neural circuits underlying reward processing and executive control, inducing maladaptive neuroplastic changes that reinforce compulsive drug-seeking behaviors. We propose a core pathology of MUD that lies in the dysregulation of metaplasticity, pathological alterations in the rules that govern synaptic plasticity. This dysregulation lowers the threshold for strengthening drug-related cues while simultaneously blunting plastic responses to adaptive, non-drug stimuli. This review posits that exercise may interrupt the MA addiction cycle through three interrelated metaplasticity-regulating mechanisms: a threshold recalibration mechanism whereby exercise synergistically lowers the threshold for adaptive learning across molecular (e.g., brain-derived neurotrophic factor-N-methyl-D-aspartic acid receptor signaling), neural circuit (prefrontal-striatal pathways), and large-scale brain network levels (default mode network-central executive network interactions). A competitive resource reallocation mechanism, in which exercise, acting as a natural reward, competes with drug cues for plasticity-related neural resources (e.g., dopamine D2 receptor availability), thereby weakening the dominance of drug-associated representations. This is a self-reinforcing mechanism, through which exercise enhances neural sensitivity to subsequent therapeutic interventions. The metaplasticity dysregulation framework integrates evidence spanning molecular and cellular processes, neural circuits and brain networks, and peripheral-central regulatory pathways (including the gut-brain axis). The framework suggests that exercise shifts the rules of neural plasticity away from pathological drug cue dominance toward adaptive processing of natural rewards, providing a strong neurobiological rationale for incorporating exercise into comprehensive MUD treatment strategies.