Treatment-resistant depression (TRD) remains a major clinical challenge and is typically defined as the persistence of depressive symptoms despite at least two adequate antidepressant trials. Individuals with TRD experience substantial morbidity, impaired functioning, and elevated suicide risk, highlighting the need for therapeutic strategies beyond incremental refinements of conventional monoaminergic pharmacotherapy. Psilocybin-assisted therapy has recently emerged as a mechanistically distinct intervention, combining transient 5-HT2A receptor agonism with structured psychological support delivered in supervised sessions. Early randomized trials have demonstrated rapid reductions in depressive symptoms and encouraging short-term remission rates, primarily in patients with major depressive disorder, with more limited but emerging evidence in treatment-resistant populations. However, the central clinical question is not merely whether psilocybin can produce acute improvement, but whether these effects can be sustained without cumulative harm. Current evidence remains limited by modest sample sizes, relatively short follow-up periods, challenges in maintaining blinding, and limited comparisons with established TRD interventions such as esketamine, electroconvulsive therapy, and transcranial magnetic stimulation. The durability of benefit beyond several weeks remains an open clinical question, and the implications of repeated dosing are not yet well established. In addition, implementation demands substantial therapeutic infrastructure, raising questions regarding scalability, cost, and equitable access. Future research should prioritize standardized definitions of treatment resistance, recognition of clinical heterogeneity within TRD populations, longer-term outcomes, rigorous active comparators, improved trial methodology, safety monitoring, and cost-effectiveness analyses to determine the appropriate clinical role of psilocybin-assisted therapy.
