The role of psilocybin as an adjuvant treatment for resistant major depressive disorder: An integrative literature review

Abstract

Introduction: Treatment-resistant Major Depressive Disorder (TR-MDD) represents a significant clinical challenge, affecting patients who do not respond adequately to multiple conventional therapeutic approaches. In recent years, psychedelic substances such as psilocybin have emerged as promising alternatives in the adjunctive management of resistant depression, generating increasing scientific interest. Objective: To critically analyze the current evidence on the efficacy and safety of psilocybin as an adjunctive treatment for treatment-resistant major depressive disorder. Materials and Methods: The research methodology used was an integrative literature review. The PICO strategy was applied to formulate the guiding research question. In addition, a cross-search of the descriptors “Treatment-Resistant Depressive Disorder”; “Adjunctive Pharmacological Therapy”; “Psilocybin” was performed in the following databases: National Library of Medicine (PubMed MEDLINE), Scientific Electronic Library Online (SCIELO), Ebscohost, Google Scholar, and the Virtual Health Library (VHL). Results and Discussion: Recent clinical studies show that psilocybin, when administered in a controlled setting and accompanied by psychotherapeutic support, promotes rapid and sustained antidepressant responses in patients with TR-MDD. Its effects appear to be related to the modulation of brain connectivity and the induction of intense subjective experiences, which favor cognitive-affective restructuring. Reported adverse events are generally mild to moderate and self-limited, underscoring the importance of qualified professional supervision. Conclusion: Psilocybin represents an innovative and promising approach as an adjunctive therapy for TR-MDD. Despite encouraging results, further studies are necessary to consolidate its safety, standardize protocols, and expand its responsible clinical use.