Modeled Long‐Term Effects of Psilocybin on Dynamic Activity and Effective Connectivity of Fronto‐Striatal‐Thalamic Circuits

ABSTRACT

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.