PROJECT SUMMARY AND ABSTRACT Background: Cannabis is the most commonly used illicit drug by young people. The potency of cannabis has increased and so has the use of highly potent synthetic cannabinoids (`Spice'). Furthermore, the “medical” and recreational use of cannabis is increasingly being legalized across the U.S. Perceptions of the risks of cannabis use amongst teenagers has 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 both rodents has been shown to lower synaptic density, but this has yet to be studies in humans. We recently developed [11C]-UCB-J, a tracer for imaging of the synaptic vesicle protein SV2A in vivo. The purpose of this exploratory study is to compare synaptic density in cannabis dependent subjects (CDs) and healthy controls (HCs) and to relate changes in synaptic density to proximal and distal measures of brain activity, namely evoked ɣ oscillations in the EEG and verbal memory. Furthermore, the relationship between [11C]-UCB-J binding, evoked ɣ oscillations, verbal memory, and measures of cannabis exposure (age of first use and lifetime exposure) will be explored. Hypotheses: Compared to HCs, CDs will show 1) ↓ [11C]-UCB-J binding, 2) ↑ deficits in measures of evoked ɣ oscillations, and 3) ↑ deficits in verbal memory. In CD subjects, lower [11C]UCB-J binding will be positively correlated with earlier age of initiation of cannabis use, lifetime cannabis exposure, worse verbal memory and greater deficits in ɣ oscillations. Methods: We will compare synaptic density in CDs (n=12) vs. HCs (n=12) using [11C]- UCB-J and the High Resolution Research Tomograph. CDs and HCs will also be compared on measures of evoked ɣ oscillations (auditory steady state response: ASSR) and verbal memory (Rey Auditory Verbal Learning Task: RAVLT). The relationship between [11C]- UCB-J binding, evoked ɣ oscillations, verbal memory, and measures of cannabis exposure (age of initiation of use and lifetime exposure) will be explored. Pilot data: To demonstrate feasibility, CDs (n=2) and HC (n=6) have been studied; CDs showed reduced SV2A binding of 10% or more (i.e., greater than the margin of test-retest variability) in several brain regions.

PROJECT NARRATIVE The brain continues to develop until around 25 years of age. Animal studies suggest that exposure to cannabis may affect brain microstructure, but this has yet to be shown in humans. This grant application proposes to use brain imaging to study the changes in brain microstructure (synaptic density) and function (cognition and electrophysiology) in young cannabis dependent people.