Endocannabinoids, depression, and treatment resistance: Perspectives on effective therapeutic interventions

Depression is a prevalent and heterogeneous disorder with significant personal and social consequences. The rise of treatment-resistant depression (TRD) challenges traditional approaches and underscores the need for a broader neurobiological perspective. When monoaminergic modulation proves insufficient, clinical guidelines increasingly turn to non-monoaminergic interventions such as neuromodulation techniques and glutamatergic agents, which operate through distinct mechanisms. Despite their heterogeneity, these treatments may act on shared final pathways that differ from those of conventional antidepressants. Among these pathways, the endocannabinoid system (ECS) has emerged as a critical mood regulator and a potential mediator of antidepressant effects. This narrative review draws from preclinical and clinical literature to explore the role of the ECS in depression and its involvement in various non-monoaminergic treatments effective in TRD. Evidence suggests that physical interventions like repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), as well as glutamatergic and serotonergic agents such as ketamine, esketamine, and psychedelics, influence ECS components. rTMS and ECT elevate levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors and other ECS targets, contributing to their rapid effects. Psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions, while LSD affects the broader endocannabinoidome in the prefrontal cortex and hippocampus. These findings suggest that ECS modulation may constitute a unifying mechanism through which diverse, non-monoaminergic interventions exert antidepressant effects in TRD, positioning the ECS as a promising target of novel treatment strategies for individuals who do not respond to conventional treatments.