Genetics of Cannabis Use Disorder and Cannabinoid Response In Humans Cannabis is widely used worldwide and is associated with negative outcomes including cannabis use disorder (CanUD), psychosis, and cognitive impairment amongst others. Given the legalization of “recreational” and “medical” cannabis globally, the increasing availability of cannabis, the higher potency of cannabis, the availability of highly potent cannabinoid products, the commercialization of cannabis, and the rising rates of cannabis use, it is critical to understand how genetic factors influence 1) an individual's vulnerability for addiction and psychosis, 2) the response to cannabinoids, 3) the response to novel treatments for CanUD.CUD is strongly genetically influenced; we published the first CUD genomewide association study (GWAS) with genomewide-significant results; however, the precise nature of the contribution of genetic factors in the development of CUD is still not clear. Cannabis exposure has also been linked to a number of psychosis outcomes including schizophrenia (SCZ). SCZ is highly heritable and population-based and genetics studies both support a bidirectional genetic relationship between SCZ and CanUD. However, the precise contribution of genetic factors in the development of psychosis outcomes related to cannabis are not clear. We propose a translational research program bringing together two highly productive and complementary research groups (genetics [Gelernter] and cannabinoid pharmacology [D'Souza]). 1) We will conduct a genomewide association analyses and meta-analyses of CanUD to compute PRS for CanUD (CanUD-PRS) based on best- and largest-available datasets. that includes existing and new data releases of MVP, AllofUs; FinnGen and other relevant data that becomes available over the course of the project. We will study genetic overlap and causality of CanUD with other complex traits in EA, AA, and other ancestry groups. 2) We will also determine the extent to which CanUD-PRS and SCZ-PRS influence the acute effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis in a Human Lab Study (HLS). Lastlywe will explore the extent to which 3a) CanUD-PRS predicts response to FAAH-Inhibitor treatment and also severity of CanUD pretreatment in a completed NIDA funded trial, and 3b) CanUD-PRS and SCZ-PRS, respectively influence the efficacy and safety of cannabis derivatives in a prospective large VA-funded multicenter trial with cannabinoids. Successful completion of this study is expected to 1) identify many more genetic risk loci for CUD, 2) in European and non-European populations, 3) with post-GWAS statistical analysis to understand the biologyof CUD, 4)translation via human experimental studies to increase our understanding of the response to THC infusion, and its implications for the development of cannabis use disorder and psychosis, and 5) the genetic influence on response to novel treatments for cannabis use disorder and cannabinoid treatments for neuropathic pain.

Genetic Basis of the Risk and Consequences of Cannabis Exposure in Humans Cannabis use is associated with negative outcomes including cannabis use disorder (CanUD), psychosis, and cognitive impairment. We propose a translational research program to 1) understand the genetics of CanUD, and 2) study the influence of genetic risk for CanUD and SCZ on the effects of cannabinoids administered in human laboratory studies and clinical trials.