Sex differences in stress responding in a randomized, placebo-controlled clinical trial of progesterone in cannabis...

Stress is a major contributor to relapse in individuals with cannabis use disorder (CUD). Stress responding in individuals with CUD differs by sex, suggesting a potential role for sex hormones in stress modulation and relapse prevention. The hormones progesterone and its precursor, pregnanolone, have been shown to attenuate the rewarding effects of cannabinoids, cocaine, and nicotine and curb stress-induced craving for cocaine, with evidence for greater effects in females.

The present randomized controlled trial was designed to examine the impact of exogenous progesterone on stress response and cannabis use in non-treatment-seeking males and females with CUD.

Participants (n = 148; 82 males, 66 females) were randomized to receive twice daily progesterone 200 mg (n = 75) or placebo (n = 73) for one week while maintaining abstinence from cannabis. At end-of-treatment, participants were exposed to a laboratory stressor (Trier Social Stress Test), followed by a two-week medication-free follow-up period.

Progesterone attenuated cannabis craving in females, but not males, and normalized relationships between subjective stress and cortisol in females and between stress and craving in both sexes. Stress-induced changes in cortisol were positively associated with time to first use during follow-up and were negatively associated with cannabis use days in the whole sample.

Results suggest a potential role for progesterone in attenuating stress-induced relapse in CUD, particularly in females.