Understanding the neural mechanisms underlying the impact of psychedelics on social perception and cognition may be instrumental to unravel their therapeutic potential. We conducted a pharmacoimaging study to examine ayahuasca's effects on a key theory of mind region, at the core of the third visual pathway (TVP)-the posterior superior temporal sulcus (pSTS), which is involved in facial emotion recognition and social perception. Twelve healthy participants (mean age: 40 ± 6.6 years; four females) completed a crossover design with three conditions: 0.5 mg/kg N, N-dimethyltryptamine (DMT), 0.8 mg/kg DMT, and placebo, with 1-2 months washout intervals. Resting-state functional magnetic resonance imaging (fMRI) was used to assess pSTS functional and effective connectivity. The highest dose significantly increased right pSTS connectivity and directed modulation from visual (primary and extrastriate cortices) and mirror neuron regions (supplementary motor cortex; SMC). Subjectively, this enhanced social cognitive states, with a strong positive correlation between pSTS-SMC connectivity and perspective-taking experiences. Additionally, ayahuasca produced positive psychological effects, including improved perceived social relationships, at 1-week follow-up despite minimal acute effects. Our findings reveal a novel mechanism of action of psychedelics at early stages of social information processing, with enhanced integration of the TVP and mirror neuron systems. The pSTS emerged as a critical hub supported by top-down and bottom-up evidence, providing a basis for understanding ayahuasca's prosocial therapeutic effects.
Keywords: ayahuasca; mirror neuron system; pharmacoimaging; psychedelics; social cognition; third visual pathway.
© The Author(s) 2026. Published by Oxford University Press.