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.
Psilocybin and MDMA are both psychedelic drugs but produce different behavioral effects. MDMA, but not psilocybin, raises both serotonin and norepinephrine in the medial prefrontal cortex. Blocking norepinephrine release reveals head-twitch responses (a rodent correlate of psychedelic effects) from MDMA, suggesting that noradrenergic signaling opposes serotonin 2A receptor effects. Artificially raising norepinephrine also reduces psilocybin-induced head-twitch responses. Activating the noradrenergic alpha-2 receptor alone suppresses these responses, even in mice lacking the locus coeruleus, indicating action via heteroreceptors. Importantly, alpha-2 receptor activation does not block psilocybin's antidepressant-like effects in the forced swim test. This suggests that side effects of serotonin 2A activation can be reduced without losing therapeutic benefits.
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.