A dual-receptor model of serotonergic psychedelics: therapeutic insights from simulated cortical dynamics
The authors present an energy-based predictive-processing model that simulates dual 5‑HT2A and 5‑HT1A receptor effects on cortical dynamics, showing how receptor-specific neuromodulation relaxes high-level belief precision and reproduces known cognitive and affective effects of serotonergic psychedelics. From these simulations they argue that combined 5‑HT2A/5‑HT1A dynamics underpin the clinical efficacy of LSD, psilocybin and DMT and highlight biased 5‑HT1A agonists (e.g. 5‑MeO‑DMT) as a promising route to more effective, tolerable therapies.
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.
Research Summary of 'A dual-receptor model of serotonergic psychedelics: therapeutic insights from simulated cortical dynamics'
Introduction
Juliani and colleagues situate their work within ongoing theoretical debates about how serotonergic psychedelics produce therapeutic effects. Earlier research has identified 5-HT2a agonism and downstream neurotrophic processes as important, and frameworks such as REBUS (Relaxed Beliefs Under Psychedelics) propose that psychedelics relax the precision of high-level beliefs, increasing cortical entropy and enabling belief revision. However, alternative perspectives (for example ALBUS) and empirical phenomena such as intense ‘‘insight’’ experiences and DMT entity encounters suggest that acute effects may sometimes transiently strengthen beliefs rather than simply relax them. The authors emphasise that many classic psychedelics also have appreciable 5-HT1a affinity, and argue that prior models under-specify the role of 5-HT1a in shaping acute phenomenology and therapeutic outcomes.
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Juliani, A., Chelu, V., Graesser, L., & Safron, A. (2024). A dual-receptor model of serotonergic psychedelics: therapeutic insights from simulated cortical dynamics. https://doi.org/10.1101/2024.04.12.589282
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