Abstract
Depression is a complex and globally prevalent mental disorder, for which conventional antidepressant medications face limitations such as delayed onset and insufficient efficacy. Classic psychedelics, most notably psilocybin, have recently emerged as promising candidates for treatment of depression and demonstrated rapid, robust, and sustained antidepressant effects in controlled clinical settings. Their unique mechanisms of action and clinical prospects have become a key research focus in psychiatry and neuroscience. This review synthesizes the latest advances in the field over the past 5 years. Results from multiple randomized controlled trials indicate that a single or limited number of sessions of psychedelic-assisted psychotherapy can induce rapid and durable antidepressant effects in patients with treatment-resistant depression. At the mechanistic level, psychedelics rapidly promote the release of neurotrophic factors, enhance neuroplasticity, and facilitate brain network reorganization, thereby creating a critical "neuroplastic window" for psychotherapeutic intervention. However, the specific molecular and circuit-level mechanisms have not been fully understood with ongoing debate primarily over the 5-HT(2A) receptor-dependent hypothesis versus the TrkB neurotrophic pathway-dependent hypothesis. Despite the promising outlook, translational applications of these substances faces several key challenges, including psychedelic-related risks, incomplete mechanistic understanding, lack of standardized treatment protocols, and insufficient long-term safety data. Future research should focus on elucidating the underlying neurobiological mechanisms, developing non-hallucinogenic derivatives, establishing standardized treatment frameworks, and identifying precise biomarkers to advance this therapeutic approach toward safer, more standardized, and personalized clinical implementation.