Depression is a prevalent neuropsychiatric disorder with complex and heterogeneous pathogenesis, involving interactions among chronic stress, immune activation, endocrine dysregulation, impaired neuroplasticity, and psychosocial factors. Although the monoamine hypothesis has long guided antidepressant development, delayed therapeutic onset and limited efficacy in some patients indicate that additional biological mechanisms and therapeutic targets should be considered. The endocannabinoid system (ECS), consisting mainly of endogenous ligands such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), cannabinoid receptors including CB1 and CB2, and metabolic enzymes such as FAAH and MAGL, is widely distributed in the central nervous system and peripheral tissues. It participates in the regulation of mood, cognition, stress responses, immune activity, and synaptic transmission, making it a promising target for understanding and treating depression. This review summarizes current evidence on ECS alterations in depressive states and discusses the mechanisms by which ECS activation may alleviate depressive symptoms. First, ECS signaling can suppress neuroinflammation by regulating microglial polarization, inhibiting NLRP3 inflammasome activation, and reducing the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. CB2 receptor activation appears particularly important in limiting excessive microglial activation and restoring immune balance. Second, ECS activity contributes to the maintenance of hypothalamic-pituitary-adrenal (HPA) axis homeostasis. Stress-induced disruption of the FAAH-AEA-CB1 receptor pathway may increase the release of adrenocorticotropic hormone and glucocorticoid, whereas enhancing endocannabinoid tone may reduce HPA-axis hyperactivity. Third, ECS signaling interacts with brain-derived neurotrophic factor (BDNF) and related pathways to improve neuroplasticity, including hippocampal neurogenesis, synaptic remodeling, and neural circuit adaptation. In addition to its role in depression pathophysiology, ECS may also mediate the effects of current and emerging therapeutic strategies. Pharmacological treatments such as ketamine may influence ECS-related targets, while non-pharmacological interventions, including repeated transcranial magnetic stimulation (rTMS) and exercise, can enhance endocannabinoid signaling and improve mood-related outcomes. Exercise, in particular, may exert antidepressant effects by increasing endocannabinoid levels, reducing neuroinflammation, promoting neurogenesis, and improving synaptic function. Nevertheless, existing findings remain inconsistent across brain regions, disease models, and detection methods, and peripheral endocannabinoid changes may not fully reflect central ECS activity. Overall, ECS does not act through a single pathway but may serve as an integrative regulatory system linking neuroimmune responses, endocrine stress regulation, and neural plasticity. Future studies should clarify brain region-, cell type-, and circuit-specific ECS mechanisms, examine interactions between ECS and other systems such as the gut microbiota, and explore ECS-based pharmacological and non-pharmacological interventions for depression.
LIU et al. (Mon,) studied this question.