Spotlight: Endocannabinoids, depression, and treatment resistance: Perspectives on effective therapeutic interventions (Rosa, et al, 2025)
"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.