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; 4female) completed a crossover design with three conditions: 0.5 mg/kg DMT, 0.8 mg/kg DMT, and placebo, with 1-2 months washout intervals. Resting-state 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 one-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.
