Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response
Gabriele Floris, Sarah J. Jefferson, Jocelyne Rondeau, Frank S. Menitti, Alex C. Kwan, Joao P De Aquino, John H. Krystal, Christopher Pittenger, Alfred P. Kaye
bioRxiv (Cold Spring Harbor Laboratory) March 10, 2026 preprint DOI: 10.64898/2026.03.06.710108 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Topics | Depression Psilocybin Serotonin |
| Keywords | Antidepressant Pharmacology Hallucinogen Prefrontal cortex |
| Key points | Coadministration of PDE9i with psilocybin reduces psychedelic-like behavior while maintaining antidepressant effects in a mouse model of chronic stress. |
Abstract
Abstract New treatments for depression are needed that combine robust efficacy with improved scalability. Although psilocybin has demonstrated antidepressant effects in Phase 3 clinical trials, some of its psychedelic effects limit tolerability, necessitating administration in highly supervised clinical settings, and thus motivating development of serotonergic therapeutics that preserve antidepressant efficacy while reducing the acute psychedelic experience. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i), which raises cyclic GMP levels, and observed substantial reduction in the mouse head twitch response (HTR) — a proxy for 5-HT 2 A receptor-mediated psychedelic-like behavior in rodents — suggesting attenuation of acute psychedelic effects. Significantly, rescue of chronic stress-induced depressive-like behavior by psilocybin was maintained with the coadministration of PDE9i. Proteomic analysis of medial prefrontal cortex (mPFC) synaptosomes showed that the combination of PDE9i and psilocybin enhanced synaptogenesis pathways relative to psilocybin alone, while reducing pathways involved in G protein-coupled receptor (GPCR) signaling. Together, these results suggest that the combination of PDE9i and psilocybin may be a promising direction for psychedelic treatment, and point towards molecular pathways that dissociate acute psychedelic and antidepressant responses.
Comparable studies
Other preclinical and animal studies on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| 5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines. Rodents | 2023 | Experimental study | |
| Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat Flinders Sensitive Line rats and Flinders Resistant Line rats | 2019 | Experimental study | |
| Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors Male and female mice | 2024 | Experimental study | |
| Rapid-acting antidepressant drugs modulate affective bias in rats Rats | 2024 | Experimental animal study |