CB1 Activation Reduced Fear Memories in Stressed Female Rats But May Hinder Extinction

Chronic mild stress enhanced trace fear conditioning (episodic fear memories) in adolescent female rats. The CB1 agonist ACEA reduced fear during memory recall in both stressed and non-stressed females, but it either had no effect on or impaired both short-term and long-term fear extinction. For contextual fear, ACEA had opposite effects on extinction depending on stress history.

Adolescent female Sprague-Dawley rats underwent chronic mild unpredictable stress, then were tested on hippocampal-dependent trace and contextual fear conditioning. CB1 agonist ACEA (0.1 mg/kg) was administered before memory recall or acquisition.

This has direct implications for using medical cannabis to treat PTSD in women. While CB1 activation reduced acute fear responses, it may actually impair the therapeutic process of fear extinction that underlies exposure-based PTSD treatments.

Women are diagnosed with PTSD at roughly twice the rate of men, yet most cannabis-PTSD research uses male animals. These sex-specific findings suggest the endocannabinoid system may function differently in female stress responses, which could affect treatment outcomes.

Preprint (bioRxiv), not yet peer-reviewed. Only female rats were tested (no direct male comparison in this study, but references prior male data). The synthetic CB1 agonist ACEA may not perfectly mimic THC effects.