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

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. Competing Interest Statement This work was supported by a research contract from Freedom Biosciences (A.P.K., C.P., G.F.). Drs. Kaye, Krystal, and Pittenger are co-inventors on a patent application related to psychedelics. Dr. Kaye previously received contracted research funding from Transcend Therapeutics. Drs. Jefferson and Pittenger previously received research funding from Freedom Biosciences. Dr. De Aquino has received research support from Jazz Pharmaceuticals and Ananda Scientific and has served as a paid consultant for Boehringer Ingelheim. In the past three years, Dr. Pittenger has consulted for Biohaven Pharmaceuticals, Freedom Biosciences, Transcend Therapeutics, UCB BioPharma, Mind Therapeutics, Ceruvia Biosciences, F-Prime Capital Partners, and Madison Avenue Partners; has received research support from Biohaven Pharmaceuticals, Freedom Biosciences, and Transcend Therapeutics; owns equity in Alco Therapeutics, Mind Therapeutics, and Lucid/Care; receives royalties from Oxford University Press and UpToDate; and holds pending patents on pathogenic antibodies in pediatric OCD and on novel mechanisms of psychedelic drugs. Dr. Menniti has served as a consultant for Freedom Biosciences and is a co-inventor on patents claiming the use of PDE9 inhibitors in combination with psychedelic drugs. Dr. Krystal has served as a consultant for Aptinyx, Inc.; Biogen, Idec, MA; Bionomics, Limited (Australia); Boehringer Ingelheim International; Clearmind Medicine, Inc.; Cybin IRL (Ireland Limited Company); Enveric Biosciences; Epiodyne, Inc.; EpiVario, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Otsuka America Pharmaceutical, Inc.; Perception Neuroscience, Inc.; Praxis Precision Medicines, Inc.; Spring Care, Inc.; Sunovion Pharmaceuticals, Inc. Dr. Krystal has served as a scientific advisory board member for: Biohaven Pharmaceuticals; BioXcel Therapeutics, Inc. (Clinical Advisory Board); Cerevel Therapeutics, LLC; Delix Therapeutics, Inc.; Eisai, Inc.; EpiVario, Inc.; Freedom Biosciences, Inc.; Jazz Pharmaceuticals, Inc.; Neumora Therapeutics, Inc.; Neurocrine Biosciences, Inc.; Novartis Pharmaceuticals Corporation; Praxis Precision Medicines, Inc.; PsychoGenics, Inc.; Tempero Bio, Inc.; Terran Biosciences, Inc. In the past 3 years, Dr. Krystal is an inventor on patents licensed by Yale University to Janssen Pharmaceuticals, Biohaven Pharmaceuticals, Spring Health, Freedom Biosciences, and Novartis Pharmaceuticals. Dr. Kwan has been a scientific advisor or consultant for Boehringer Ingelheim, Eli Lilly, Empyrean Neuroscience, Freedom Biosciences, Otsuka, and Xylo Bio. Dr. Kwan has received research support from Intra-Cellular Therapies. The remaining authors declare no conflict of interest. Footnotes ↵# These authors jointly supervised the work Authorship edit to add Abigail Yu