Science
February 16, 2023
Maxemiliano V. Vargas, Lee E. Dunlap, Chunyang Dong et al.
467 citations
Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-HT2ARs is essential for psychedelic-induced cortical plasticity, but it is unclear why some 5-HT2AR agonists promote neuroplasticity while others do not. Using molecular and genetic tools, the authors demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. This work emphasizes location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.
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.
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 Science Policy & Governance
July 2, 2026
Alaina M. Jaster, Joseph J. Hennessey, Tanner L. Anderson et al.
Research on Schedule I substances in the United States is heavily restricted by the Controlled Substances Act, creating what is termed Research Harm—the restriction or deterrence of legitimate scientific inquiry due to governmental regulatory controls and criminal prohibitions. Barriers include lengthy DEA registration timelines, inconsistent guidance, and policy confusion, limiting access to substances with therapeutic potential like psilocybin, MDMA, cannabis, and DOI. The 2025 HALT Fentanyl Act introduces procedural improvements such as expedited registration and shared institutional access but leaves key regulatory issues unresolved. Recommended reforms include revising medical utility interpretations, conducting periodic evidence reviews, and establishing a scheduling framework for easier research access.