ABSTRACT This proposal aims to characterize the unique effect of recreational cannabis use on sleep in women. Sleep was once believed to be a quiescent state, where self-reported measures might be sufficient; however, biomedical technology advances now demonstrate that remarkable, essential biological processing occurs in the brain and body throughout the night, including characteristic patterning of brain (EEG) and peripheral (autonomic nervous system, HPA Axis) activity. Yet, the current void of scientific evidence on cannabis has led to unsubstantiated marketing claims and public endorsement of cannabis as a sleep aid based nearly exclusively on perceptions of improved sleep. Such claims carry specific health harms for women, whose cannabis use may interact with a changing physiological context due to increases and decreases in reproductive hormones. This application, submitted by an interdisciplinary sleep and addiction team, proposes a 60-day prospective study with a within-subject design of 100 cannabis using, naturally cycling biological females. It pairs sleep behavior with nocturnal physiology of brain and body systems to deconstruct the proximal sleep effects of acute cannabis exposure at different phases of the menstrual cycle. Using multigroup multilevel moderated mediation path analysis, stress-reactivity systems will be characterized as potential mediators of the cannabis-sleep relationship. Framed through the lens of allostatic theory, this study views repeated exposure to acute cannabis use episodes as stressors that can ‘pile up’ over time by increasing multi- organ physiological load. Thus, apparent short-term improvements in sleep from cannabis use come at a cost of wear and tear on multiple brain/body systems, potentially explaining the persistence of poor sleep outcomes in individuals seeking treatment for or in recovery from addiction. The three study aims focus on comparing sleep (self-report, actigraphy and EEG, Aim 1), HPA axis activity (cortisol, Aim 2) and autonomic nervous system function (ECG, skin conductance, Aim 3) on nights following cannabis use to nights following no cannabis use. To balance internal and external validity, recreational, non-daily cannabis users will self- administer cannabis as usual with the exception that they self-purchase cannabis strains within a potency range from legal state dispensaries and consume it with a cannabis flower vaporizer. Sleep and stress- reactivity system data will be collected at home using FDA-approved wearable devices and saliva sampling. Estradiol and progesterone will be assayed and used to distribute testing nights across the menstrual cycle; menstrual phase will be tested as a moderator in Aims 1-3. This study addresses critical, and currently lacking, information about women, a population that experiences more negative consequences from cannabis use and a higher rate of sleep disturbances and disorders, yet has been largely overlooked in biological research due to the complexity of the menstrual cycle.

Narrative Using cannabis as a sleep aid may carry specific health harms for women. Cannabis use can affect biological sleep directly or through altering stress-reactivity systems, and such relationships may be influenced by fluctuating reproductive hormones. The goal of this application is to study women across the menstrual cycle and compare sleep, cortisol, and autonomic nervous system functioning on nights of cannabis use versus nights of no use.