Bridging ancient substances and modern psychiatry: the role of classic psychedelics in depression treatment.

Fewer than half of patients with major depressive disorder achieve remission with standard pharmacotherapy, and many cannot tolerate it. This narrative review examines classic psychedelics as an alternative treatment. These substances primarily bind to 5-HT2A receptors, increasing connectivity between sensory and motor brain networks. They generate long-term behavioral responses comparable to traditional antidepressants. Clinical and experimental studies show that classic psychedelics alleviate depressive symptoms. The mood improvement is thought to stem from effects on neuroplasticity, including neurogenesis and related signaling pathways.

Study at a glance

Abstract

Pharmacotherapy for MDD is commonly prescribed to patients, yet fewer than half achieve remission. Moreover, many patients exhibit intolerant responses to pharmacological treatment, highlighting the need to explore new forms of therapy. The present work provides a narrative review of classic psychedelics as an alternative to MDD treatment. In addition, mechanisms by which psychedelics exert antidepressant effects are discussed. A literature review of recent studies regarding psychedelics used for the treatment of depressive disorders. The main search platform for relevant indexed articles used was PubMed, using keywords such as psychedelics, MDD, depression, and treatment. Studies have shown that classic psychedelics mainly bind to 5-HT2A receptors, increasing interaction between sensory and somatomotor brain networks. These substances play a significant role in treating psychiatric disorders. Also, classic psychedelics generate long-term behavioural responses comparable to traditional treatments. Therefore, they are strongly associated with the management of these conditions. Recent studies have shown that classic psychedelics yield favourable outcomes in alleviating symptoms of depression. This has been observed in clinical and experimental investigations. The improvement in mood is thought to arise from their influence on molecular targets associated with neuroplasticity, including the promotion of neurogenesis and the behavioural responses linked to downstream and upstream signalling pathways.