Ovarian Steroid Mechanisms of Female Cannabis Use: Longitudinal and Experimental Models - As cannabis use patterns rapidly evolve due to changes in legality and societal norms across the United States, it is crucial to identify risk factors of problem use in vulnerable populations. Recent widespread legalization of recreational cannabis has coincided with an increased prevalence of problem use and cannabis use disorder (CUD), with females and those with a psychiatric diagnosis displaying unique risk factors. Females exhibit stronger cannabis withdrawal symptoms and a faster transition from first use to CUD than males, suggesting hormonal risk factors for problem cannabis use. The reproductive-aged window is especially imperative to examine for risks of problem use, given the potential for childbearing and established risks to the offspring of pregnant cannabis users. Cyclical changes in progesterone (P4) and estradiol (E2), such as across the menstrual cycle, could contribute to problematic cannabis use in some individuals. Observational evidence suggests that periods of rising E2 (periovulatory phase), as well as periods of declining P4 and E2 (perimenstrual phase), could be windows of acute risk of problem cannabis use. However, there is a complete lack of experimental research testing a causal relationship between acute menstrual cycle hormone changes and cannabis use. In alignment with the 2022-2026 NIDA Strategic Plan to expand our understanding of the biological mechanisms underlying drug use (Goal 1.1), the proposed project seeks to examine what ovarian hormone mechanisms may give rise to windows of acute risk for problem substance use. Specifically, we plan to use a novel computational modeling approach that leverages generalized additive mixed models and group iterative multiple model estimations to model drug use across the menstrual cycle. These techniques consider both individual and group-level effects. The proposed study will utilize archival data from two of the primary mentor’s recently completed RCTs to evaluate the effects of the menstrual cycle on acute cannabis use risk in a transdiagnostic sample of naturally cycling psychiatric outpatients. Further, the primary mentor’s experimental work indicates that ovarian hormone-driven changes in acute mood and cognitive deficits can be prevented by administering stabilizing doses of E2 and P4 perimenstrually. The proposed study will build upon these findings and be the first of its kind to experimentally examine the perimenstrual drop in E2 and P4 as a potential mechanism of female-specific acute cannabis use risk. Identifying windows of immediate vulnerability to problem drug use will benefit the scientific and clinical communities from both diagnostic and intervention standpoints. Providers will gain additional context to deliver precise, accurate diagnoses and subsequently be able to deliver personalized, temporally-specific treatment interventions. The proposed project and training plan will provide the candidate with comprehensive mentorship from a team of experts, equipping the candidate with the analytic skills and scientific knowledge required to become an independent investigator.
