ACS Chem Neurosci
September 13, 2025
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.
ACS Chem Neurosci
November 5, 2025
1 citation
This paper examines chemical compounds that resemble the D-ring portion of LSD, analyzing how their structures relate to potential therapeutic effects. The authors review structure-activity relationships to identify which molecular features might produce beneficial outcomes without the hallucinogenic effects of LSD. They consider these analogs as possible treatments for conditions such as depression, anxiety, and cluster headaches. The work suggests that certain D-ring modifications could retain therapeutic potential while reducing unwanted side effects, though no clinical data are presented. The analysis is based on existing research and chemical principles, aiming to guide future drug development.
ACS Chem Neurosci
March 4, 2026
correction
A correction notice clarifies that two errors in the original paper do not affect the accuracy of the results, interpretations, or conclusions. The first correction addresses a presentation issue in Table 1, confirming the data are correct. The second correction clarifies that thigmotaxis, a measure of anxiety-like behavior, was evaluated in rats given SDA or SDMA compounds. Compared to saline, only the 10 mg/kg dose of SDA significantly increased thigmotaxis, meaning the rats spent less time in the center of the arena.
ACS Chem Neurosci
January 7, 2026
Psychedelics such as psilocybin, LSD, MDMA, and ibogaine produce rapid and lasting clinical effects in psychiatric disorders by altering perception, cognition, and emotion. Preclinical and clinical work shows they modulate glutamate and GABA transmission, enhance neuroplasticity, and reorganize brain networks. A unified explanation for how these acute changes lead to enduring outcomes has been lacking. The authors propose a neurodevelopmental hypothesis: psychedelics restore excitation/inhibition balance, initially shifting E/I dynamics to create a transient state of heightened plasticity akin to developmental sensitive periods. This window allows long-term reorganization of excitatory and inhibitory circuits, with GABAergic interneurons as key mediators. The dual-phase model links initial network excitability to subsequent neuroplasticity and circuit stabilization, offering a coherent framework for psychedelics' rapid onset and sustained efficacy.