Endocannabinoid Metabolism in Cannabis Users: PET Studies with the Novel Probe [1

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DESCRIPTION (provided by applicant): Cannabis is the most prevalent illicit drug consumed by Americans and its abuse is associated with significant consequences to social and personal health, including addiction. In this regard, a third of individuals experimenting with cannabis progress to develop abuse, and of those who try to quit, 70% fail. There are currently no approved pharmacotherapies for cannabis use disorder (CUD). Evidence from preclinical and human genetic studies suggests the involvement of Fatty Acid Amide Hydrolase (FAAH), the enzyme metabolizing the major endocannabinoid anandamide in CUD. In particular, studies of FAAH functional polymorphisms suggest that higher enzyme activity is linked to greater risk for CUD as well as increased severity of withdrawal, cannabis-induced euphoria, and cue- induced neural response. As well, pharmacological studies in rodent models of CUD suggest that FAAH inhibitors alleviate cannabis withdrawal. Together these findings suggest that FAAH inhibitors, which have been avidly developed by pharmaceutical companies and are currently being tested in CUD, might offer a possible therapeutic avenue for the treatment of this disorder. Despite evidence suggesting the involvement of FAAH in CUD and the investment in developing FAAH-targeting drugs, there are no direct data on this enzyme in CUD. We are the only group world-wide to have developed a (PET) radioligand, [11C]-CURB, which allows direct measurement of FAAH. We are uniquely suited to investigate the role of FAAH in CUD as we have the clinical and scientific expertise in the field of CUD (Huestis, Le Foll, George) and imaging (Boileau) and have the only available neuroimaging tool (Wilson, Houle) to investigate this question. There is an urgent need to accelerate the translation, into clinic, of pharmacotherapies already in development for CUD, by providing neuroimaging information which could advance our understanding of endocannabinoid metabolism in CUD. Following upon our development of [11C]-CURB, our major specific aim and hypothesis is to establish by PET imaging whether FAAH activity is elevated in CUD and whether differences are related to addiction severity. Confirmation of this hypothesis, in a 2 year proof-of-concept study, can help identify a drug target to treat (perhaps prevent) CUD and can guide clinical application of treatment approaches (using FAAH inhibitors) already in development. The potential impact of this project is immense, as it provides the first imaging investigation of endocannabinoid metabolism in CUD. The knowledge generated by this project will provide the basis for the further development of evidence-based therapeutic approaches targeting FAAH. The availability of compounds targeting FAAH that are in development by major pharmaceutical companies allows for a quick translation of our human brain findings into the clinic.