PROJECT SUMMARY/ABSTRACT PROJECT 3: OLDER ADULT STUDY Recent epidemiological data indicates a 10-fold increase in cannabis use among older adults (65+ years). Given this rise in use, an important public health question is how cannabis use might impact physical and cognitive health in older individuals, especially since they are at increased risk of mild cognitive impairment (MCI) and Alzheimer’s dementia (AD). This is additionally important with the rapidly aging population in the U.S., the prevalence of MCI and AD, and the enormous mortality, morbidity, and socioeconomic costs of associated with age-related cognitive decline. There is compelling evidence that older adults use cannabis to treat chronic pain, sleep problems, and anxiety, and it is possible that cannabis use may decrease the “polypharmacy” effect often associated with aging. In addition, animal studies suggest that cannabidiol (CBD) and low doses of ∆9-tetrahydrocannabinol (THC) may be neuroprotective, reverse cognitive decline, and be associated with lower levels of neurodegeneration in subcortical areas. Conversely, high doses of THC may be harmful, with acute deleterious effects on cognition and motor control (e.g., risk of falling). Key biological mechanisms that may help explain how cannabinoids differentially affect outcomes are age- associated changes in inflammation and in the endocannabinoid system (ECS). Research shows that cannabis (specifically CBD) has anti-inflammatory properties, and inflammation is in turn positively associated with sleep problems, anxiety, and pain. Similarly, there are links between CBD and THC and particular endocannabinoids (i.e., arachidonoyl ethanolamide [anandamide, AEA] and 2-arachidonoylglycerol [2-AG]), which are differentially related to sleep, anxiety and pain. A mechanistic exploration of inflammatory biomarkers and endocannabinoids could help elucidate the mechanisms of action of THC and CBD in older adults and potentially more broadly. The main goal of this project is to investigate these mechanisms and outcomes by randomly assigning older adults interested in cannabis use to either hemp-derived CBD/+THC, CBD/-THC, or placebo in an 8 week randomized controlled trial. This design will determine 1) impacts of THC and CBD on inflammatory and endocannabinoid biomarkers and 2) if these mechanistic changes are associated with the impact of cannabis on anxiety, sleep, and pain, and 3) the harm to benefit ratio in terms of acute (impaired balance, impaired cognition) and longer term (polypharmacy, sleep, pain) outcomes.