Neuron
July 15, 2025
Manish K. Jain, Ryan H. Gumpper, Samuel T. Slocum et al.
42 citations
Classical psychedelics like LSD, psilocybin, and mescaline produce their mind-altering effects by activating the 5-HT2A serotonin receptor. Recent clinical studies indicate they may also help treat depression, anxiety, migraines, cluster headaches, drug abuse, and PTSD. This work examined 41 psychedelics from three chemical classes, testing them against 318 human G-protein-coupled receptors and, for LSD, over 450 human kinases. The compounds potently activated nearly every serotonin, dopamine, and adrenergic receptor. They also stimulated multiple signaling pathways through the 5-HT2A receptor, each linked to psychedelic-like effects in animals. The findings suggest that many molecular targets contribute to the overall actions of psychedelics.
bioRxiv (Cold Spring Harbor Laboratory)
September 26, 2023
Yi-Ting Chiu, Wei Wang, Pierre Llorach et al.
15 citations
preprint
Psychedelic drugs such as LSD and psilocybin show promise as treatments for depression, anxiety, PTSD, migraine, and cluster headaches by activating the 5-HT2A receptor (HTR2A). Researchers engineered several new mouse lines to study the role of HTR2A and the neurons that express it. One line allows visualization of the receptor and identification of HTR2A-containing cells, providing a detailed anatomical map. Another line has a humanized version of the receptor, and a third enables targeted genetic manipulation. The mice exhibited expected behavioral responses to psychedelics, confirming their usefulness. Electrophysiology showed that serotonin increases firing of specific pyramidal neurons through HTR2A, consistent with the receptor's location on the cell surface. These tools will help clarify how psychedelics work at molecular, cellular, and behavioral levels.
bioRxiv (Cold Spring Harbor Laboratory)
November 15, 2022
Gavin P. Schmitz, Yi-Ting Chiu, Gabriele M. König et al.
15 citations
preprint
Psilocin, the active compound in psilocybin mushrooms, activates serotonin 2A receptors (5-HT2ARs) in the prefrontal cortex (PFC), but its specific effects on PFC neurons were unclear. Using slice electrophysiology in mice, researchers found that psilocin application onto layer 5 pyramidal neurons in the prelimbic PFC produced variable firing changes (increase, decrease, or no change) in unspecific neurons. However, in neurons identified as expressing 5-HT2ARs, psilocin consistently increased firing without altering synaptic transmission. The results demonstrate that psilocin evokes strong, 5-HT2AR- and Gαq-dependent firing changes in the PFC, offering insights into how psychedelics affect a brain region key to their therapeutic actions.
Translational Psychiatry
October 6, 2025
Gavin P. Schmitz, Yi-Ting Chiu, Mia L. Foglesong et al.
13 citations
Psilocybin's active metabolite psilocin increases activity in the medial prefrontal cortex (mPFC), a brain region rich in 5-HT2A receptors. A specific population of neurons in the prelimbic/anterior cingulate mPFC that express these receptors becomes more excitable and fires more in response to psilocin and a selective 5-HT2A receptor compound, effects dependent on both the receptor and Gα q signaling. A novel non-hallucinogenic psychedelic compound produced similar effects. These results point to membrane-bound 5-HT2A receptors and intracellular Gα q signaling as potential therapeutic targets for psychedelic-associated plasticity.
UNC Libraries
May 21, 2026
Gavin P. Schmitz
Psychedelics are being investigated as therapeutic tools, but their brain-region-specific effects and signaling mechanisms are not fully understood. A comprehensive study of about 40 diverse psychedelic substances from the tryptamine, phenethylamine, and lysergamide classes found that all tested compounds activate the 5-HT2A serotonin receptor, while also showing serotonergic, dopaminergic, and adrenergic activity. The 5-HT2A receptor is enriched in layer V pyramidal neurons in rodent and human cortices. Electrophysiological studies identified a population of 5-HT2A receptor neurons in the prelimbic and anterior cingulate regions of the prefrontal cortex. Psilocin and a 5-HT2A-preferring compound increased firing in these neurons via a 5-HT2A- and Gαq-dependent mechanism, whereas the non-hallucinogenic LSD analog 2-bromo-LSD reduced firing in both 5-HT2A and non-5-HT2A neurons through a different mechanism.
bioRxiv Preprint Server
December 9, 2021
Gavin P. Schmitz, Manish K. Jain, Samuel T. Slocum et al.
preprint
Random genetic variations in the serotonin 2A receptor can modestly alter how four commonly used psychedelic drugs activate this receptor, with effects that differ depending on the specific drug. Seven naturally occurring receptor variants were tested in the lab; each showed small but statistically significant changes in drug potency and efficacy. These findings suggest that individual genetic differences may influence responses to psychedelic medications.