# Genetic Basis of the Risk and Consequences of Cannabis Exposure in Humans

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $564,257

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10932912
- **Project number:** 5R01DA058862-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** DEEPAK Cyril D'SOUZA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $564,257
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932912

## Citation

> US National Institutes of Health, RePORTER application 10932912, Genetic Basis of the Risk and Consequences of Cannabis Exposure in Humans (5R01DA058862-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10932912. Licensed CC0.

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