Development of a Physiologically Based Pharmacokinetic/Pharmacodynamic Model of Psilocybin/Psilocin from Psilocybe cubensis (Magic Mushroom) in Treatment-Resistant Depression.

BACKGROUND: Psilocybin, a prodrug that converts to psilocin, exerts psychedelic and antidepressant effects primarily through serotonin 2A (5-HT2A) receptor agonism. Although psilocybin has demonstrated rapid and sustained antidepressant effects in treatment-resistant depression, the optimal dose selection that balances therapeutic benefit and safety remains unclear. OBJECTIVE: This study aims to develop a physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model to predict psilocin exposure, 5-HT2A receptor occupancy, and antidepressant response following a single oral dose of psilocybin. METHODS: A previously developed PBPK model that simulates psilocin plasma concentrations was coupled to two pharmacodynamic models. A maximum effect model was used to predict 5-HT2A receptor occupancy. A second model combined a turnover model for acute effects and a log-linear function for sustained effects to predict changes in Montgomery-Åsberg Depression Rating Scale (MADRS) scores. This model was applied to simulate MADRS scores at 24 h and 12 weeks after psilocybin doses ranging from 10-30 mg in virtual subjects with moderate to severe depression. RESULTS: The model adequately predicted 5-HT2A receptor occupancy for psilocybin doses ranging from 3-30 mg and reproduced the observed reduction in MADRS scores for the 10- and 25-mg psilocybin doses. Although the model overpredicted MADRS changes in the 1-mg control group and underpredicted changes in the 15-mg dose group from another study, the predicted scores remained within the same depression severity category as the observed data. Simulation analyses illustrate how the model can predict a range of MADRS reductions for psilocybin doses between 10 and 30 mg, with varying baseline depression severities. This approach could potentially guide individualized dose adjustment. CONCLUSION: This PBPK/PD framework links psilocin exposure to receptor engagement and clinical antidepressant response following psilocybin administration. The model may support dose selection and hypothesis generation for future clinical studies while also highlighting the need for more mechanistic models that integrate neuroplasticity and network-level processes.