Psychedelics in treatment-resistant depression: a comprehensive review of mechanisms, clinical evidence, and recommendations.
Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater June 30, 2026 Cielo A Estela-Fernandez, Reem Mohamed Yousif Elsheikh, Dal Bianco Beatrice et al.
Psychedelics show significant potential for treatment-resistant depression (TRD) by promoting neuroplasticity, corticolimbic function, and epigenetic changes beyond serotonergic agonism. Psilocybin-assisted therapy induces short-term symptom improvement lasting weeks to months. Ketamine, in intravenous, subcutaneous, and oral forms, produces rapid and robust reductions in depressive symptoms and relapses without impairing cognitive function. Esketamine yields early, clinically meaningful improvements in function and productivity. Ayahuasca demonstrates fast and sustained effects with higher remission rates and good safety. Despite encouraging findings, large, well-designed studies are needed before psychedelics become standard recommendations for TRD.