PROJECT SUMMARY AND ABSTRACT Background: Cannabis is amongst the most commonly used drugs globally. The potency of cannabis has increased, and the “medical” and recreational use of cannabis is increasingly being legalized across the U.S. Perceptions of the risks of cannabis use amongst teenagers have declined over the past decade. The initiation of cannabis use typically occurs during adolescence and young adulthood, when the brain is still developing and is most vulnerable to insults, particularly drugs. Therefore, it is important to understand the consequences of chronic cannabinoid exposure on the structure and function of the brain. Repeated administration of cannabinoids to rodents has been shown to result in lower synaptic density. Consistently, we recently showed lower synaptic vesicle density in the hippocampus in cannabis use disorder (CUD) participants as measured using [11C]UCB-J, a positron emission tomography (PET) tracer for imaging of the synaptic vesicle protein SV2A in vivo. CUD participants performed worse on a hippocampal verbal memory task, and verbal memory performance correlated with hippocampal [11C]UCB-J binding. However, whether the lower hippocampal synaptic density and deficits in memory performance normalize with abstinence from cannabis use is not known. The purpose of this study is to compare synaptic vesicle density in CUDs before and after 4 weeks of abstinence from cannabis use, and to relate changes in synaptic density to hippocampal function (verbal memory). Furthermore, the relationship between hippocampal [11C]UCB-J binding, verbal memory, and measures of cannabis exposure (age of first use and lifetime exposure) will be explored. Hypotheses: CUDs will show an increase in both hippocampal [11C]UCB-J binding, and verbal memory performance following 4 weeks of confirmed abstinence. In CUD participants, earlier age of cannabis use and cumulative exposure to cannabis will be correlated to hippocampal [11C]UCB-J binding. Methods: We will compare synaptic vesicle density in CUDs before and after 4 weeks of abstinence using [11C]UCB-J PET and the High Resolution Research Tomograph. Age-, gender matched healthy controls (HCs) will also be scanned at baseline and at 4 weeks in order to verify longer-term test-retest stability. The relationship between hippocampal [11C]UCB-J binding, verbal memory, and measures of cannabis exposure (age of initiation of use and lifetime exposure) will be explored in CUDs. Pilot data: CUDs (n=12) show lower hippocampal SV2A and verbal memory, which are correlated. CUDs (n=2) show an increase in [11C]UCB-J binding with confirmed abstinence from cannabis for ~4 weeks.