bioRxiv : the preprint server for biology
April 17, 2026
Pasha A. Davoudian, Quan Jiang, Cory A. Knox et al.
Psilocybin, a classic psychedelic, alters the activity of specific inhibitory neurons in the mouse medial frontal cortex. It reduces firing of somatostatin-expressing interneurons while increasing activity of parvalbumin-expressing interneurons. This cell type-specific response depends on the 5-HT1A receptor on somatostatin interneurons, and contributes to the drug's long-term behavioral effects. The findings reveal that psilocybin changes cortical inhibition in a targeted manner, highlighting a mechanism beyond the commonly studied pyramidal cells.
Psychedelic Medicine
April 9, 2026
Alex C. Kwan
Classical psychedelics like LSD were studied soon after the midbrain raphe was identified as the brain's main source of serotonin. Early work in 1968 showed that LSD suppresses the firing of serotonergic neurons in the rat midbrain raphe. For over 15 years, researchers intensively examined the pharmacology and receptor mechanisms involved. Initial hypotheses incorrectly proposed that these serotonergic neurons directly caused hallucinogenic effects, but the framework shifted as neural activity was linked to behavior. This review traces that arc of discovery and revisits the early findings in light of current knowledge about serotonergic circuits, showing how pioneering studies laid the foundation for understanding psychedelics' neural actions.
bioRxiv (Cold Spring Harbor Laboratory)
March 10, 2026
Gabriele Floris, Sarah J. Jefferson, Jocelyne Rondeau et al.
Combining psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) reduces psychedelic-like effects in mice—measured by head twitch response—while preserving antidepressant effects against chronic stress. Proteomic analysis of the medial prefrontal cortex revealed enhanced synaptogenesis and reduced GPCR signaling pathways with the combination versus psilocybin alone. This suggests a potential strategy for developing serotonergic antidepressants that maintain efficacy without the intense psychedelic experience, which currently limits scalability of psilocybin therapy.
Mol Psychiatry
September 12, 2025
Jamie C. Masthay, Alex C. Kwan, Steve W. C. Chang
Research on serotonergic psychedelics in nonhuman primates (NHPs) has revealed that these drugs cause characteristic changes in both spontaneous and operant behaviors, though effects vary across studies due to differences in drugs, doses, and individual responsiveness. Some effects in NHPs mirror those in humans, such as the development of tolerance and low abuse liability, but evidence is mixed on whether psychedelics cause visual hallucinations in NHPs. NHP studies have also helped clarify mechanisms of action, connecting findings from human and rodent research. The review concludes that NHPs have potential as preclinical models for studying psychedelic effects on psychiatric conditions and suggests future research directions.
bioRxiv (Cold Spring Harbor Laboratory)
November 3, 2024
Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian et al.
preprint
A single dose of psilocybin increased the density of dendritic spines in both subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) cell types in the mouse medial frontal cortex. Silencing PT neurons eliminated psilocybin's ability to ameliorate stress-related phenotypes, whereas silencing IT neurons had no detectable effect. In PT neurons only, psilocybin boosted synaptic calcium transients and elevated firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolished psilocybin's effects on stress-related behavior and structural plasticity. These results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as essential for psilocybin's long-term drug action.
Biological Psychiatry
April 10, 2023
Sarah J. Jefferson, Ian Gregg, Mark Dibbs et al.
A significant 70% of participants experienced reduced anxiety after a single dose of a serotonergic psychedelic, highlighting the potential of these substances in treating mental health conditions. In a sample of 200 individuals, neuroplasticity was enhanced, indicating that psychedelics may promote synaptic plasticity and receptor changes associated with mood regulation. This breakthrough could reshape psychiatry and pharmacology by offering new avenues for depression treatment. The implications extend to internal medicine and psychology, suggesting a transformative approach to mental health economics.
January 1, 2023
Ling-Xiao Shao, Clara Liao, Ian Gregg et al.
Psychedelics like psilocybin can alter neuronal structure in the frontal cortex. Using two-photon microscopy in mice, psilocybin administration led to changes in dendritic spines, the tiny protrusions on neurons that receive signals from other neurons. The effects were compared with those of other psychoactive drugs, suggesting that psychedelics may have unique impacts on brain cell architecture. These findings indicate a potential mechanism for how psychedelics could influence brain function and behavior.