ABSTRACT Important sex differences exist in the behavioral, biologic, and clinical correlates of cannabis use disorder (CUD); these sex differences are critical to consider in CUD treatment development. In particular, stress may be an important intervention target for women using cannabis, as multiple studies have shown that women use cannabis for coping and tension reduction more than men and are more likely to crave cannabis following stress. Ovarian hormones have been identified as potential mechanisms of these stress-related disparities, and recent clinical trials have begun to examine progesterone's utility as a possible pharmacotherapeutic agent in addictive disorders. While progesterone has shown promise as a treatment for women with cocaine and tobacco use disorders, it has not yet been tested in cannabis users. We propose to evaluate the impact of progesterone on stress reactivity and cannabis use in 140 cannabis using individuals (70 men and 70 women). Participants will complete a 3-week protocol combining naturalistic and laboratory-based methodologies. During the first week, participants will be compensated to remain abstinent and will be randomly assigned to receive either daily progesterone (200 mg twice daily) or matching placebo; additionally, stress and neutral cues will be delivered to their mobile devices and they will also collect daily saliva samples for progesterone measurement. On the first day of the second study week, participants will be exposed to a standardized laboratory stressor (Trier Social Stress Task) to assess the effects of exogenous progesterone vs placebo on stress reactivity. At the completion of the laboratory procedures, participants will no longer be compensated for abstinence but they will use their mobile device to respond to stress and neutral cues, monitor stress/craving levels, and report cannabis use (three times daily) for the next fourteen days. Throughout these two weeks, ovarian hormone levels will continue to be collected daily (via saliva samples) to evaluate their impact on stress and cannabis use. The proposed study has significant synergies with Projects 2 and 3, utilizing similar assessment and pharmacologic interventions, respectively. Presently, little is known about sex differences in CUD; this study has the potential to expand that knowledge landscape. Importantly, this project will also assess the effects of exogenous and endogenous progesterone on the challenges posed by initial abstinence and/or daily stress, which could directly inform gender-specific treatment development for CUD.