Abstract
This systematic review explores the comparative efficacy and functional outcomes of psychedelic-assisted therapies in the management of treatment-resistant depression (TRD). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive literature search was conducted across PubMed, Scopus, and Web of Science for randomized controlled trials (RCTs) published in the last 12 months. Ten RCTs were included, evaluating agents such as ketamine, esketamine, and psilocybin. Most studies demonstrated significant reductions in depressive symptom severity, with oral and intranasal esketamine and high-dose psilocybin showing sustained antidepressant effects. Functional improvements, such as workplace productivity and cognitive stability, were reported in select trials, notably those involving esketamine. Risk of bias was low in four studies and moderate in six due to open-label or observational extensions. Overall, psychedelic therapies were well tolerated, with favorable safety profiles and minimal cognitive adverse effects. These findings support the integration of psychedelic-assisted therapies as viable alternatives or adjuncts in the treatment of TRD and highlight the importance of assessing both clinical and functional endpoints for a more holistic understanding of therapeutic benefit.