Acute anxiogenic effects of psilocybin and the related tryptamine, norbaeocystin, in male and female rats

Rationale Psychedelics are considered to be promising therapeutic agents that could effectively treat several psychological disorders. However, these compounds can exert acute adverse effects that limit their practicality. Objectives Across three experiments, the present study examined the acute and delayed effects of psilocybin (PSIL) and its putatively non-hallucinogenic analog, norbaeocystin (NOR), on anxiety-like behavior and the influence of the female estrous cycle on acute response to the compounds. Methods In Experiment 1, rats were treated with PSIL or NOR (0.3-1 mg/kg) and tested on the elevated plus maze (EPM) or open field 30 min later. In Experiment 2, male and female rats were treated with 1 mg/kg PSIL or NOR and tested on the EPM 24 h later. In Experiment 3, we tracked the female estrous cycle to determine whether it was associated with the acute effects of PSIL or NOR on EPM behavior and the acoustic startle response (ASR). Results In Experiment 1, both PSIL and NOR exerted acute anxiogenic effects in males, while only the highest dose of PSIL increased anxiety-like behavior in females. In Experiment 2, neither PSIL nor NOR impacted EPM behavior the next day. In Experiment 3, PSIL, but not NOR, had acute anxiogenic effects on EPM behavior, effects that were independent of estrous stage. Females treated with PSIL during diestrus exhibited some signs of greater ASR habituation. Conclusions PSIL and NOR exerted transient dose- and sex-specific effects on anxiety-like behavior, which may inform their use as novel therapeutics.