A dual-receptor model of serotonergic psychedelics
Arthur Juliani, Veronica Chelu, Laura Graesser, Adam Safron
bioRxiv (Cold Spring Harbor Laboratory) April 15, 2024 preprint DOI: 10.1101/2024.04.12.589282 via OpenAlex
Summary
AI-generated from the abstractSerotonergic 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.
Study at a glance
| Characteristics | Theoretical or philosophical paper |
|---|---|
| Topics | Serotonin |
| Keywords | Dual grammatical number Neuroscience Psychology Dynamics music |
| Citations | 4 |
| Key finding | A computational model of cortical dynamics based on predictive processing and neuromodulation can account for empirical observations of serotonergic psychedelics' effects and provides a hypothesis for the clinical success of LSD, psilocybin, and DMT, while also identifying biased 5-HT1a agonist psychedelics as a promising design space for future therapeutics. |
Abstract
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.