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

Floris, G.; Jefferson, S. J.; Rondeau, J.; Menniti, F. S.; Kwan, A. C.; De Aquino, J. P.; Krystal, J. H.; Pittenger, C.; Kaye, A. P.

doi:10.64898/2026.03.06.710108

bioRxiv · 10.64898/2026.03.06.710108

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

Floris, G.·Jefferson, S. J.·Rondeau, J.·Menniti, F. S.·Kwan, A. C.·De Aquino, J. P.·Krystal, J. H.·Pittenger, C.·Kaye, A. P.

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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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Floris, G., Jefferson, S. J., Rondeau, J., Menniti, F. S., Kwan, A. C., De Aquino, J. P., Krystal, J. H., Pittenger, C., Kaye, A. P.. 2026-03-10. Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response. https://doi.org/10.64898/2026.03.06.710108

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