A dual-receptor model of serotonergic psychedelics
bioRxiv – April 12, 2024
Source: medRxiv/bioRxiv/arXiv
Summary
Serotonergic psychedelics like LSD and psilocybin show great promise in treating mood and anxiety disorders. This study proposes a new model explaining how these substances work, suggesting that they help revise rigid thought patterns by balancing brain signals. The findings point to the potential for developing more effective therapies, including innovative psychedelics.
Abstract
Serotonergic psychedelics have been identified as promising next-generation therapeutic agents in the treatment of mood and anxiety disorders. While their efficacy has been increasingly validated, the mechanism by which they exert a therapeutic effect is still debated. A popular theoretical account is that excessive 5-HT2a agonism disrupts cortical dynamics, relaxing the precision of maladaptive high-level beliefs and making them more malleable and open to revision. We extend this perspective by developing a simple energy-based model of cortical dynamics based on predictive processing which incorporates effects of neuromodulation. Using this model, we propose and simulate hypothetical computational mechanisms for both 5-HT2a and 5-HT1a agonism. Results from our model are able to account for a number of existing empirical observations concerning serotonergic psychedelics effects on cognition and affect. Using the findings of our model, we provide a theoretically-grounded hypothesis for the clinical success of LSD, psilocybin, and DMT, as well as identify the design space of biased 5-HT1a agonist psychedelics such as 5-MeO-DMT as potentially fruitful in the development of more effective and tolerable psychotherapeutic agents in the future.