Combining psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) reduces psychedelic-like effects in mice—measured by head twitch response—while preserving antidepressant effects against chronic stress. Proteomic analysis of the medial prefrontal cortex revealed enhanced synaptogenesis and reduced GPCR signaling pathways with the combination versus psilocybin alone. This suggests a potential strategy for developing serotonergic antidepressants that maintain efficacy without the intense psychedelic experience, which currently limits scalability of psilocybin therapy.
Psychedelics show promise for treating chronic pain and opioid use disorder (OUD) by acting on shared brain mechanisms that underlie both conditions. Preclinical and human evidence suggests psychedelics may reverse pain- and opioid-induced neuroadaptations such as central sensitization. The review describes how psychedelics could modulate sensory, affective, and cognitive dimensions of pain alongside opioid craving and withdrawal. Despite the clinical need, controlled studies on pain management alternatives for people with OUD or on long-term opioid therapy remain scarce. The authors propose mechanistic insights and methodological considerations for future translational studies and clinical trials to accelerate development of novel therapeutics amid the opioid crisis.