Gender and Sex Hormone Influences on Cannabis Use Disorder Remission

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PROJECT SUMMARY/ABSTRACT Cannabis use disorder (CUD) is prevalent and associated with significant clinical sequelae. Effective treatment for CUD may be complicated by gender and sex differences in the behavioral, biological, and clinical correlates of CUD. Women demonstrate more severe withdrawal, more rapid progression from first use to CUD, and greater likelihood of comorbid psychiatric disorder, while men tend to initiate use earlier and have higher lifetime prevalence rates of CUD. In other addictive disorders, such as alcohol use disorder, clinical trial endpoints are sex/gender specific. However, to date, no work has focused on whether different clinically relevant endpoints may be needed for men and women with CUD. An expert workgroup recently concluded that reduced cannabis use is a viable alternative endpoint to abstinence in CUD trials, particularly in the context of changing patient preferences and growing cannabis legalization. However, the amount of reduction necessary for remission from CUD is unknown and may differ for men and women. An emerging literature suggests that ovarian hormones play a key role in drug use. Preclinical and clinical research suggests that endogenous progesterone attenuates drug sensitivity and behavior. Recent clinical studies investigating exogenous progesterone as a potential pharmacotherapy have shown that it attenuates the subjective and physiological effects of cocaine and tobacco in drug-dependent individuals. Presently, little is known regarding the interface of progesterone and CUD, and if fluctuations in progesterone levels may impact ability to reduce cannabis use. This proposal addresses a key gap in CUD treatment research by empirically-deriving the threshold of cannabis quantity and frequency of use below which most individuals in CUD treatment can achieve CUD remission. Importantly, the roles of gender and ovarian hormones in CUD outcomes are considered and gender-specific endpoints will be derived. Treatment-seeking adults who meet criteria for CUD (N=224, ages 18+, 50% female) will receive 8 weeks of a psychosocial intervention, including computerized CBT4CBT. CUD symptoms and detailed information on cannabis use will be collected from participants during the 8-week treatment period and during a three month follow-up (1, 2, and 3 month follow-up visits). Participants will complete daily electronic diaries to enhance assessment of self-reported cannabis quantity and frequency of use, corroborated by weekly assessment of a urinary cannabis metabolite, 11-nor-9-carboxy- Δ⁹-tetrahydrocannabinol. Daily saliva samples will be collected for assessment of progesterone. Analyses will examine whether the threshold for cannabis reduction necessary to achieve remission from CUD differs by gender and the effect of variation in progesterone on successful cannabis reduction. The establishment of gender-specific reduction endpoints will have both real-world clinical treatment implications as well as enable future studies to rigorously test promising candidate treatments for CUD.