Project Summary Approximately 70% of people with multiple sclerosis (PwMS) self-medicate their symptoms with cannabis. Δ-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most abundant cannabis components. THC exhibits psychoactive effects, may induce acute psychosis, and impacts executive function. CBD is not psychoactive like THC and has been shown to be emotionally beneficial (i.e., anxiolytic), anti-inflammatory, and neuroprotective. Critically, there is a vast diversity in the amounts (i.e., ratios) of THC and CBD commercially available. Therefore, the ratio of THC: CBD of various strains of cannabis may have a pivotal impact on executive function and emotional processing (i.e., fear, anxiety) in PwMS. Currently, there is a gap of understanding surrounding the effects of different ratios of THC:CBD on brain activity, executive function, and emotional processing in PwMS. The goal of this application is to conduct a unique observational, cross-sectional study that employs real-world cannabis products of varying THC:CBD ratios currently available to Iowa residents. We will investigate differences in executive function, emotional processing, and brain activity in PwMS who have been using different THC:CBD ratios of cannabis for at least 6 months [High CBD group (CBD >THC); 1:1 group (THC = CBD); High THC group (THC > CBD); Non-Users group (no cannabis)]. Executive function and emotional processing will be assessed with valid psychiatric and neuropsychological measures. Positron Emission Tomography (PET) with [18F]-Fluorodeoxyglucose (FDG) will be used as a measure of brain activity. Our central hypothesis is that the High THC group will have worse executive function and emotional processing compared to the High CBD, 1:1, and Non-Users groups, and that the High CBD group will have better emotional processing compared to the High THC, 1:1, and Non-Users groups. These hypotheses were formulated based on previous studies and our own preliminary data. This research on PwMS who are currently using cannabis is well-positioned to critically inform our understanding of the effects of different THC:CBD ratios and highlight avenues for future longitudinal studies (R01).