A rodent study found that a PDE9 inhibitor reduced psilocybin-induced head-twitch behaviour and 5-HT2A-related signalling while preserving antidepressant-like responses.

The Neuropsychopharmacology study tested whether boosting cGMP signalling with a phosphodiesterase-9 inhibitor could reduce psilocybin’s perceptual side effects in rodents. The combination also reshaped the synaptic proteome towards synaptogenesis signalling while maintaining antidepressant-like effects.