EFFICACY AND SAFETY OF PSILOCYBIN IN TREATMENT-RESISTANT DEPRESSION: A REVIEW

Abstract

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. A substantial proportion of patients fail to achieve remission through standard monoaminergic therapies, meeting the clinical criteria for treatment-resistant depression (TRD). TRD is associated with significant clinical morbidity and a profound economic burden on healthcare systems. This review evaluates the clinical efficacy, safety profile, and neurobiological mechanisms of psilocybin, a serotonergic psychedelic, as a targeted intervention for TRD. Current neurobiological evidence indicates that psilocybin, upon conversion to its active metabolite psilocin, acts primarily as a 5-HT2A receptor agonist. This mechanism promotes rapid structural neuroplasticity and modulates the aberrant functional connectivity characteristic of severe depression. Recent randomized clinical trials demonstrate that psilocybin, when administered in controlled settings with psychological support, produces rapid and clinically significant reductions in depressive symptoms. Comparative data indicate that its therapeutic efficacy is at least comparable to standard first-line treatments, such as SSRIs, while frequently offering a faster onset of action. Regarding safety, psilocybin is generally well-tolerated in clinical environments; adverse events are typically mild to moderate and transient. However, the strict requirement for concurrent psychological support and rigorous psychiatric screening highlights a clinical complexity distinct from traditional pharmacotherapies. Overall, current evidence indicates that psilocybin is a promising intervention for TRD with a manageable safety profile in controlled settings. Nevertheless, large-scale, long-term randomized trials are required to determine the durability of its effects and to establish standardized treatment protocols.