Bridging reward and resilience: the endocannabinoid system as a unifying mechanism in exercise-induced protection against major depressive disorder.

Major depressive disorder (MDD) refers to a complex mental disorder defined by hindered reward system and hindered stress resilience. The limitations of traditional monoamine antidepressants have prompted the academic community to study new pathological processes and intervention strategies. Major depressive disorder arises from a complex interplay of psychological, social, and biological factors. Among the latter, dysfunction of the endocannabinoid system (ECS) has emerged as a critical pathological mechanism contributing to the core symptoms. This review demonstrates the key idea that exercise as a powerful non-pharmacological intervention can increase stress resilience and exert antidepressant effects by positively activating the ECS. Exercise, especially moderate intensity aerobic exercise, can significantly increase the levels of major endogenous cannabinoids AEA and 2-AG, and exert effects at multiple levels by activating CB1 receptors: at the acute level, it can immediately promote mood, generate analgesic effects and improve the termination of the stress response; At the long-term level, it can drive synaptic plasticity, facilitate hippocampal neurogenesis, and regulate neuroimmunity, thereby obtaining lasting structural improvement of emotional and stress neural circuits. These processes work together to reshape the brain's reward function and establish internal resilience against stress. In comparison to drug therapy, ECS-regulated exercise interventions have the unique benefits of high safety, systemic advantages, and endogenous reward reinforcement. Thus, individualized exercise therapy for ECS represents a promising mechanism-induced non-pharmacological intervention approach offering a new aspect and perspective for the prevention and rehabilitation of depression.