Nat Commun
December 15, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
153 citations
Serotonergic psychedelics show therapeutic potential, but the specific roles of 5-HT2A receptor signaling pathways are unclear. Researchers developed selective ligands with varying Gq efficacies, including β-arrestin-biased ones. In male mice, 5-HT2A-Gq recruitment efficacy, not β-arrestin2 recruitment, predicted psychedelic potential measured by head-twitch response magnitude. Disrupting Gq-PLC signaling reduced this response, and a threshold Gq activation level was needed for psychedelic-like effects, explaining why partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists blocked psychedelic effects and caused receptor downregulation and tachyphylaxis. Fine-tuning 5-HT2A Gq-signaling enables development of non-psychedelic 5-HT2A agonists.
Cell Reports
March 28, 2023
Vern Lewis, Emma M. Bonniwell, Janelle K. Lanham et al.
129 citations
The non-hallucinogenic LSD analog 2-Br-LSD acts as a partial agonist at several aminergic G protein-coupled receptors, including 5-HT2A, but does not induce the head-twitch response in mice, indicating it lacks hallucinogenic effects. Unlike LSD, 2-Br-LSD does not activate 5-HT2B, avoiding a risk of cardiac valvulopathy. It produces weak 5-HT2A β-arrestin recruitment and internalization in vitro and does not cause tolerance after repeated dosing. In cultured rat cortical neurons, 2-Br-LSD promotes dendritogenesis and spinogenesis, and in mice it increases active coping behavior—an effect blocked by a 5-HT2A antagonist—and reverses behavioral effects of chronic stress. These findings suggest 2-Br-LSD has an improved pharmacological profile over LSD and potential therapeutic value for mood disorders.
The Journal of neuroscience : the official journal of the Society for Neuroscience
November 8, 2023
Lindsay P. Cameron, Joseph Benetatos, Vern Lewis et al.
88 citations
Serotonergic psychedelics like psilocybin and LSD activate serotonin 5-HT2A receptors in cortical brain regions, altering perception, cognition, and emotions. Their ability to promote neuroplasticity—forming new neural connections and rewiring networks—is thought to underlie therapeutic potential for depression, anxiety, and substance use disorders. These compounds also interact with other serotonin receptor subtypes (5-HT1A, 5-HT2C) and neurotrophin receptors, adding complexity to their effects. Research is exploring nonhallucinogenic derivatives that retain therapeutic benefits without intense psychedelic experiences, potentially reducing adverse reactions. The review also discusses psychedelics as substrates for post-translational protein modification as part of their mechanism.
ACS Chemical Neuroscience
December 15, 2022
Michael J. Cunningham, Hailey A. Bock, Inis C. Serrano et al.
65 citations
Ariadne, a non-hallucinogenic analog of the hallucinogen DOM, demonstrates significant therapeutic potential in treating various conditions. In clinical trials, Ariadne led to rapid remission of psychotic symptoms in schizophrenia and improved cognition in elderly patients. It acts as a 5-HT<sub>2A</sub> receptor agonist with modest selectivity for 5-HT<sub>1</sub>, exhibiting lower signaling potency than DOM. Notably, in a Parkinson’s disease model, Ariadne alleviated severe motor deficits comparable to l-DOPA, positioning it as a promising candidate for future psychiatric and neurological therapies.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 1, 2024
Thomas J. Kelly, Emma M. Bonniwell, Lianwei Mu et al.
26 citations
4-OH-DiPT, a fast-acting and shorter-lasting derivative of psilocybin, reduces learned fear responses in mice by enhancing inhibitory signaling in the brain. It activates 5-HT2A receptors on interneurons in the basolateral amygdala, increasing GABAergic inhibition of principal neurons. In female mice, 4-OH-DiPT before extinction training reduced freezing to conditioned cues and later decreased avoidance behaviors in several tests, while male mice showed no significant differences. The compound acts as a near full agonist at 5-HT2A receptors and has comparable activity at mouse and human 5-HT2A/2B/2C receptors. These findings suggest a potential mechanism for suppressing learned fear.
bioRxiv (Cold Spring Harbor Laboratory)
July 31, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
11 citations
preprint
Serotonergic psychedelics show therapeutic promise, but the specific signaling pathways responsible for their effects have been unclear. Researchers developed a series of 5-HT2A receptor ligands with varying Gq efficacies, including β-arrestin-biased ligands. They found that 5-HT2A-Gq efficacy, not β-arrestin2 efficacy, predicts psychedelic potential, measured by head-twitch response in male mice. Disrupting Gq-PLC signaling reduced this response, and a threshold of Gq activation is needed for psychedelic-like effects, explaining why some partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists caused receptor downregulation and tachyphylaxis, and showed an anti-psychotic-like profile. This fine-tuning of 5-HT2A signaling can generate ligands distinct from classical psychedelics.
ACS Chem Neurosci
September 13, 2025
Emma M. Bonniwell, Rana Alabdali, Joseph J. Hennessey et al.
3 citations
The serotonin 2C receptor (5-HT 2C ) is involved in processes like mood and appetite and is a target for drugs treating obesity, addiction, and depression, including psychedelics. This analysis of 5-HT 2C signaling confirms that the receptor activates multiple G protein pathways—Gi/o/z and G12/13 in addition to its main Gq/11 pathway—and preferentially recruits β-arrestin2 over β-arrestin1. Increased RNA editing of the receptor reduces signaling across all G protein pathways, especially G12/13, while preserving β-arrestin recruitment. Profiling of ligands shows that psychedelics like LSD and psilocin produce a strong Gq/11 bias by minimally activating other G proteins. These findings provide a foundation for considering broader signaling modalities in 5-HT 2C drug development.
Journal of Medicinal Chemistry
September 25, 2025
Tyler G. Fenske, J. M. T. Mckee, Natalie G. Cavalco et al.
Selectivity for the 5-HT2A receptor over the closely related 5-HT2C receptor can be achieved by targeting residue L1232.53 in transmembrane 2 of the extended binding pocket through increasing steric aliphatic bulk on the α-methylene group of the N-benzyl chemical scaffold. This selectivity was confirmed across 5-HT2C RNA editing isoforms, TM2 reciprocal mutants, and mouse orthologs, producing the most highly selective 5-HT2A agonists to date. Using structure–activity relationships, molecular docking, and mouse head-twitch response assays, the work demonstrates that such agonists can be rationally designed to improve target engagement, advancing the study of the neurobiological mechanisms of psychedelic effects.