A dual-receptor model of serotonergic psychedelics
bioRxiv (Cold Spring Harbor Laboratory) April 15, 2024 Arthur Juliani, Veronica Chelu, Laura Graesser et al. 4 citations preprint
Serotonergic psychedelics show promise for treating mood and anxiety disorders, but their therapeutic mechanism remains debated. A popular theory holds that strong 5-HT2a receptor activation disrupts cortical dynamics, loosening rigid, maladaptive beliefs and making them open to revision. This work extends that perspective by developing a simple energy-based model of cortical dynamics rooted in predictive processing and neuromodulation. The model simulates hypothetical computational mechanisms for both 5-HT2a and 5-HT1a agonism, and its results account for several existing empirical observations about psychedelics' effects on cognition and affect. The model provides a theoretically grounded hypothesis for the clinical success of LSD, psilocybin, and DMT, and identifies biased 5-HT1a agonist psychedelics like 5-MeO-DMT as potentially fruitful for developing more effective and tolerable psychotherapeutic agents.