A single dose of psilocybin given to rats 4–24 hours before a relapse test reduced cue-induced heroin seeking, though it did not alter actual heroin taking. Blocking the serotonin 2A receptor with antagonists worsened relapse. Psilocybin regulated about twice as many genes in the prefrontal cortex at a higher dose, with ketanserin blocking over 90% of these gene changes, including the IL-17a cytokine receptor. Psilocybin also regulated four chemokine/cytokine genes, and selectively inhibiting IL-17a in the prefrontal cortex was enough to reduce heroin relapse. The findings suggest psilocybin reduces heroin relapse and point to IL-17a signaling as a possible downstream pathway.
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.