Abstract As legalization of cannabis, whether for recreational or medical use, rapidly spreads in the United States, it is acutely necessary to study it. Environmental factors play a role in the development of cannabis use disorder (CanUD), but less is known about the genetic basis of the risk for developing CanUD, its short- and long-term effects, the individual's response to cannabis derivatives such as cannabidiol (CBD), and the individual's response to new treatments for CanUD. Because people of many different ancestries use cannabis, genetic analyses must include non-European populations, including African ancestry, East Asian, and admixed American (Latino). Our group published the first genomewide association study (GWAS) of CanUD with genomewide significant results and the most powerful GWAS (Levey et al Nat Genet 2023), but more work needs to be done. The parent grant, Genetics of Cannabis Use and Cannabinoid Response in Humans, will study, among other things, the genetic interplay of CanUD and schizophrenia (SCZ), which have long been understood to be clinically correlated; preliminary genetics studies have also shown bidirectional causality between the two; and PRS of those traits with respect to THC infusion. This supplement proposes to study the genetic interplay of CanUD and major depressive disorder (MDD), which is more common than SCZ (lifetime prevalence 20% in the U.S. vs. 1-2% for SCZ) but highly morbid, with an estimated $24 billion in lost productivity per year in the U.S. Our group also conducted a well-powered GWAS of MDD. Genetic findings, however, need to be put into biological and ultimately clinical context. For this reason, this supplement proposes a translational research program built on that of the parent grant, in which results of GWAS and post- GWAS analyses are used to generate polygenic risk scores for CanUD and MDD, which then are used to predict facets of the acute response to THC, CBD, and CanUD treatments in the lab. The work will be divided between two experienced and productive research groups: Dr. Gelernter's for genetic analyses and Dr. D'Souza's for human laboratory studies (HLS) of cannabinoid pharmacology. This will result in 1) better understanding of genetic variants that influence both MDD and CanUD risk, 2) in non-European and European populations, 3) with translation to HLS of THC, CBD, and THC treatment administration, to better understand the acute response and long-term risk for addiction, and 4) the potential for a better understanding of the influence of genetic factors on response to new treatments for CanUD and neuropathic pain.