A single 1 mg/kg dose of psilocybin did not alter decision-making in probability or delay discounting tasks and did not reduce motivation in a progressive ratio task in healthy male and female rats. Psilocybin did produce the expected increase in head twitch responses, confirming the drug was pharmacologically active. These results suggest psilocybin may not impair or improve reward-based decision-making or motivation, indicating that its therapeutic effects in mental health disorders may not involve changes to brain systems underlying reward and decision-making. The findings also imply that widespread cognitive impairments may not occur even with chronic psilocybin treatment.
A single dose of the psychedelic psilocybin reduces conditioned behavior and withdrawal caused by the opioid oxycodone in male mice but not in females. This sex-specific effect is mediated by the 5-HT2A receptor in frontal cortex pyramidal neurons that project to the nucleus accumbens. Psilocybin also alters epigenomic regulation after repeated oxycodone exposure and induces sex-specific structural plasticity in the nucleus accumbens independently of the 5-HT2A receptor. Female frontal cortex and nucleus accumbens show fewer changes at gene enhancer regions in response to psilocybin, repeated oxycodone, or their combination compared to males, with the frontal cortex displaying more pronounced sex differences at the epigenomic level.