Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential PMID: 38102107

ADC Targets in Oncology

2026-04-10

Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential

Nat Commun. 2023 Dec 15;14(1):8221. doi: 10.1038/s41467-023-44016-1.

Jason Wallach ¹ , Andrew B Cao ² , Maggie M Calkins ² , Andrew J Heim ³ ⁴ , Janelle K Lanham ² , Emma M Bonniwell ² , Joseph J Hennessey ² , Hailey A Bock ² , Emilie I Anderson ² , Alexander M Sherwood ⁵ , Hamilton Morris ⁶ , Robbin de Klein ⁷ , Adam K Klein ⁸ ⁹ , Bruna Cuccurazzu ⁸ , James Gamrat ⁶ , Tilka Fannana ⁶ , Randy Zauhar ³ ¹⁰ , Adam L Halberstadt ¹¹ ¹² ¹³ , John D McCorvy ¹⁴ ¹⁵ ¹⁶

Affiliations

1. Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA. [email protected].
2. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
3. Department of Chemistry, Saint Joseph's University, Philadelphia, PA, 19104, USA.
4. Chemical Computing Group ULC, 910-1010 Sherbrooke W, Montréal, QC, H3A 2R7, Canada.
5. Usona Institute, Madison, WI, 53711, USA.
6. Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA.
7. Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA.
8. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA.
9. Gilgamesh Pharmaceuticals, New York, NY, 10003, USA.
10. Artemis Discovery, LLC, Suite 300, 709 N 2nd Street, Philadelphia, PA, 19123, USA.
11. Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA. [email protected].
12. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA. [email protected].
13. Center for Psychedelic Research, University of California San Diego, La Jolla, CA, 92093, USA. [email protected].
14. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. [email protected].
15. Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. [email protected].
16. Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. [email protected].

Abstract

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT_2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT_2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT_2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT_2A-Gq but not 5-HT_2A-β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT_2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT_2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT_2A agonists. We also demonstrate that β-arrestin-biased 5-HT_2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT_2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.