Philos Trans R Soc Lond B Biol Sci. 2026 Nov 10;381(1962):20250168. doi: 10.1098/rstb.2025.0168.
ABSTRACT
Psychedelic-assisted therapy, particularly with psilocybin, is increasingly proposed as a treatment for major depressive disorder, yet the neural and psychological mechanisms underlying its effects remain under investigation. In a randomized, double-blind, placebo-controlled clinical trial, individuals diagnosed with major depressive disorder received a single, moderate dose of psilocybin (0.215 mg kg-1) or placebo, with the same psychological support. We analysed N = 37 individuals with major depressive disorder undergoing assessments of depressive symptoms (Beck’s depression inventory and Montgomery-Åsberg depression rating scale), self-concept (Frankfurt self-concept scale) and neural markers of self-referential processing using an fMRI-based task. Compared with placebo, the psilocybin group exhibited significant reductions in depressive symptoms and a significant increase in positive self-concept two weeks after substance administration. Changes in self-concept were significantly correlated with decreased depressive scores. Neuroimaging revealed psilocybin-associated modulation of caudate activation during externally oriented attention after two weeks, contrasting with placebo-induced caudate changes during self-referential processing. These findings extend prior evidence linking psychedelics to changes in self-referential processing and self-concept and demonstrate that such changes occur concurrently with reductions in depressive symptoms. Future research should aim to replicate and extend these results and refine therapy protocols targeting self-processing and self-concept in psychedelic-assisted therapy in major depressive disorder. This article is part of the discussion meeting issue ‘From being to identity: analysis and synthesis of the self’.
PMID:43007824 | DOI:10.1098/rstb.2025.0168
