Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response

Gabriele Floris; Sarah J. Jefferson; Jocelyne A. Rondeau; Abigail L. Yu; Frank S. Menniti; Alex C. Kwan; João Paulo De Aquino; John H. Krystal; Christopher Pittenger; Alfred P. Kaye

doi:10.64898/2026.03.06.710108

NeurosciencebioRxivApr 16, 2026

Preprint

Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response

Gabriele Floris iD, Sarah J. Jefferson iD, Jocelyne A. Rondeau, Abigail L. Yu iD, Frank S. Menniti iD, Alex C. Kwan iD, João Paulo De Aquino iD, John H. Krystal, Christopher Pittenger iD, Alfred P. Kaye iD

Abstract

Psilocybin has antidepressant effects, but its 5-HT2AR-mediated perceptual effects limit tolerability. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) and observed suppression of head-twitch response, but maintenance of antidepressant-like behavior. Proteomics showed that PDE9i-psilocybin reduced 5-HT2AR-mediated pathways while enhancing synaptogenesis. These results suggest that PDE9i-psilocybin represents a promising therapeutic strategy.

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