Neurocomputational evidence of sustained Self-Other mergence after psychedelics

Abstract Mental illness is often characterised by a maladaptive sense of self. The neurobiological basis of Self-Other distinction may provide targets for therapeutic interventions. Psychedelics alter the experience of selfhood, but the neurocomputational mechanism is unclear. We used a computationally-informed behavioural assay to investigate whether psychedelics disrupt Self-Other boundaries in belief formation. In a double-blind, crossover design, 22 participants received placebo, psilocybin or 2C-B (2,5-dimethoxy-4-bromophenethylamine). The next day, we fitted reinforcement learning models to probabilistic false-belief task behaviour, yielding objective Self-Other distinction measures. Compared to placebo, psychedelics induced a state of Self-Other mergence, associated with a multivariate signal of sustained psychosocial wellbeing. Effective-connectivity estimates from resting-state fMRI showed that Self-Other boundary disruption was associated with reduced inhibitory tone from right temporoparietal junction to dorsomedial prefrontal cortex. We show that psychedelics quantifiably act on the neural basis of Self-Other distinction, offering potential routes to precision therapeutics in psychedelic psychiatry.