Psilocybin facilitates fear extinction: importance of dose, context, and serotonin receptors

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.

Study at a glance

Abstract

ABSTRACT A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for posttraumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin’s potential effect in fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin’s effect on fear extinction are not understood. In this study, we used an auditory delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, though these changes were sensitive to dose. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug’s effects. Co-treatment with a 5-HT 2A receptor antagonist blocked psilocybin’s effects for extinction, extinction retention and fear renewal, whereas 5-HT 1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin’s ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.