Psilocybin and Its Derivatives as a Promising Treatment for Treatment-Resistant Depression: A Review of Molecular Docking Studies and Mechanisms of Action at the Serotonin 2A Receptor

چکیده

Treatment-resistant depression (TRD) presents a significant clinical challenge, with a substantial number of individuals failing to respond to conventional antidepressant therapies. Emerging evidence has highlighted the potential of psilocybin, a classic psychedelic compound, and its derivatives as a rapid and sustained-acting therapeutic for TRD. The primary pharmacological target of psilocybin's active metabolite, psilocin, is the serotonin 2A (5-HT2A) receptor. This review synthesizes the current understanding of the mechanisms of action of psilocybin at the 5-HT2A receptor, with a particular focus on insights gained from molecular docking studies. We explore the intricate binding interactions and conformational changes within the receptor that are thought to underpin psilocybin's therapeutic effects. Furthermore, we discuss the downstream neurobiological effects, including alterations in neural circuitry and synaptic plasticity, that are associated with its antidepressant properties. Finally, we review the promising clinical evidence supporting the efficacy and safety of psilocybin-assisted therapy in individuals with TRD, while also considering the future directions and challenges in this rapidly evolving field of psychopharmacology.