Psilocybin has been shown to induce fast and sustained symptoms improvements across various psychiatric conditions, yet its long-term mechanisms of action are not fully understood. Initial evidence suggests that longitudinal functional and structural brain changes implicate fronto-striatal-thalamic (FST) circuitry, a broad system involved in goal-directed behavior and motivational states. Here, we performed secondary analyses and applied computational modeling to resting-state fMRI data from a within-subject longitudinal psilocybin trial in psychedelic-naïve healthy volunteers. We first showed that dynamic FST activity increased 4 weeks after a full dose of psilocybin. We then proceeded to mechanistically account for these changes by providing tentative model-based support that reductions in the structure-function coupling contribute to increased dynamic FST activity postpsilocybin. Finally, we used computational approaches to show that psilocybin induces longitudinal increases in bottom-up and reduced top-down modulation of FST circuits. We then used publicly available receptor maps to show that cortical reductions in top-down modulation are linked to regional 5-HT2A receptor availability, while increased information outflow via subcortical and limbic regions relates to local D2 receptor availability. Together, these findings suggest that increased FST flexibility weeks after a high dose of psilocybin is linked to serotonergic-mediated decreases in top-down information flow and dopaminergic-mediated increases in bottom-up information flow. This long-term functional re-organization of FST circuits may represent a common mechanism contributing to the potential clinical efficacy of psilocybin across various neuropsychiatric disorders including substance abuse, major depression, and anorexia nervosa.
