Classic psychedelic drugs like psilocybin and LSD may help treat psychiatric disorders by altering brain circuits. Two existing models—the cortico-striatal thalamo-cortical (CSTC) model and the relaxed beliefs under psychedelics (REBUS) model—highlight different subcortical structures in mediating these effects. This paper introduces a third circuit-level model, the cortico-claustro-cortical (CCC) model, focusing on the claustrum, a thin strip of grey matter that densely expresses serotonin 2A receptors. The CCC model proposes that the claustrum entrains canonical cortical network states, and psychedelic drugs disrupt 5-HT2A-mediated coupling between claustrum and cortex, attenuating these networks. Together, the three models may explain many phenomena of the psychedelic experience.
Psilocybin, a serotonin 2A receptor partial agonist, alters claustrum function in humans. In 15 healthy participants, psilocybin decreased the amplitude of low-frequency fluctuations and variance of BOLD signal in the left and right claustrum. It also changed functional connectivity: right claustrum connectivity with auditory and default mode networks decreased, while connectivity with the fronto-parietal task control network increased; left claustrum connectivity with the fronto-parietal task control network decreased. Subjective effects predicted these neural changes. The findings provide the first empirical evidence that 5-HT2A receptor signaling significantly modulates claustrum activity, suggesting a role for the claustrum in psilocybin's subjective and therapeutic effects.