Psilocybin robustly enhances fear extinction in male and female mice when given acutely before testing, across all doses tested. It also produces long-term improvements in extinction retention and reduces fear renewal in a novel context, though these effects depend on dose. Females may respond to a narrower dose range than males. Administration before fear learning or immediately after extinction does not alter behavior, showing that concurrent extinction experience is necessary. Blocking the 5-HT2A receptor eliminates psilocybin's effects on extinction, retention, and renewal, while blocking the 5-HT1A receptor only attenuates the effect on fear renewal. These findings highlight dose, context, and serotonin receptors as key factors in psilocybin's facilitation of fear extinction.
Psilocybin robustly enhances fear extinction in male and female mice when given acutely before testing, with effects observed at all doses tested. It also produces long-term improvements in extinction retention and suppression of fear renewal in a novel context, though these effects depend on dose. Administration before fear learning or immediately after extinction does not alter behavior, showing that concurrent extinction experience is required. Blocking the 5-HT2A receptor eliminates psilocybin's effects on extinction, extinction retention, and fear renewal, while blocking the 5-HT1A receptor only reduces the effect on fear renewal. These results indicate dose, timing, context, and serotonin receptors are critical for psilocybin's facilitation of fear extinction, supporting its potential as an adjunct to extinction-based therapy for PTSD.