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.
Psychedelic substances produce unusual changes in conscious experience, leading some to propose they offer unique insights into consciousness. However, psychedelics are unlikely to provide information relevant to the "hard problem of consciousness," which involves explaining how first-person experience emerges. Instead, they bear on multiple "easy problems of consciousness," involving relations between subjectivity, brain function, and behavior. This review discusses common meanings of "consciousness" regarding psychedelics and considers models of their effects on the brain linked to explanatory claims about consciousness. It calls for epistemic humility about psychedelic research's potential to explain the hard problem while noting ways psychedelics may advance study of specific aspects of consciousness.
Serotonin activates 5-HT1B receptors on anterior cingulate cortex inputs to the claustrum, suppressing signaling to parietal association cortex-projecting claustrum neurons. Psilocybin, metabolized to the serotonin receptor agonist psilocin, similarly activates these presynaptic 5-HT1B receptors, reducing cortical signaling through the claustrum. This gain-control mechanism may be directly targeted by psilocybin to modulate downstream cortical network states, offering insight into how the classic psychedelic disrupts widespread brain activity.