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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper |
|---|---|
| Topics | Serotonin |
| Keywords | Dual grammatical number Dynamics music Receptor |
| Citations | 4 |
| Key points | Proposes that a computational model of cortical dynamics incorporating 5-HT2a and 5-HT1a agonism can account for empirical observations of psychedelic effects and identifies 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.
Comparable studies
Other theoretical and historical papers on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics as Medicines: An Emerging New Paradigm General population | 2016 | Theoretical or philosophical paper | |
| Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate | 2018 | Theoretical or philosophical paper | |
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Dreams, Hallucinogenic Drug States, and Schizophrenia: A Psychological and Biological Comparison | 1983 | Theoretical or philosophical paper | |
| Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract. | 2022 | Theoretical or philosophical paper |
Citations in the library
Cited by 3
- Network control energy reductions under DMT relate to serotonin receptors, signal diversity, and subjective experience. Communications Biology April 18, 2025
- Spatiotemporal mapping of brain organisation following the administration of 2C-B and psilocybin Molecular Psychiatry February 3, 2026
- Die integrierte Wirkung von Serotonin: Eine neurobiologische Synthese psychopraxis neuropraxis August 11, 2025
Cites 66
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology December 1, 2011
and 61 more in the library