Cannabis Use Disorder and Schizophrenia Share Genetic Roots — But the Relationship Goes Both Ways | Research

The takeaway

Using genetic data from over 200,000 individuals, researchers found that genetic liability for both cannabis use disorder and schizophrenia independently predicted each condition — and the genetic overlap was strongest when both conditions co-occurred.

Read this if you want to understand the biology behind the cannabis-psychosis link — genetics shows the relationship goes both directions, not just 'cannabis causes psychosis.'

What the researchers found

The association between heavy cannabis use and schizophrenia has been documented for decades, but a fundamental question remains: does cannabis cause psychosis, does genetic vulnerability to psychosis drive cannabis use, or both? This study used polygenic scores — genetic risk calculators derived from large genome-wide association studies — to test these pathways in real individuals with data on both genetics and diagnoses.

Using the All of Us Research Program (a diverse U.S. biobank with over 200,000 genotyped participants), the researchers generated polygenic scores for both cannabis use disorder (CUD) and schizophrenia (SCZ) for each individual, then examined how these genetic scores predicted actual diagnoses.

Both CUD and SCZ polygenic scores independently predicted heavy cannabis use — but the SCZ polygenic score's effect on cannabis use was very modest. Genetic liability for cannabis problems was the stronger predictor of cannabis use, which makes intuitive sense.

For schizophrenia diagnosis, both polygenic scores were independently significant. This is the critical finding: genetic liability for cannabis use disorder predicted schizophrenia risk even after accounting for schizophrenia-specific genetic risk. This suggests that the genetic pathways leading to problematic cannabis use share biology with those leading to psychosis — they're not completely independent genetic architectures.

When the researchers examined individuals with both conditions (dual comorbidity), the polygenic signals were strongest, suggesting a shared genetic substrate that increases vulnerability to both heavy cannabis use and psychosis.

Why it matters

The cannabis-psychosis debate has been stuck on whether the link is causal or confounded. This study shows it's partly genetic: some of the same genetic variants that increase risk for problematic cannabis use also increase risk for schizophrenia. This doesn't resolve the causation question entirely (cannabis may still trigger psychosis in genetically vulnerable individuals), but it demonstrates that shared genetic liability is a significant piece of the puzzle.

The numbers in context

All of Us Research Program participants (>200,000 genotyped). Both CUD and SCZ polygenic scores independently predicted heavy cannabis use, with CUD PGS being the stronger predictor. Both CUD and SCZ PGS independently predicted schizophrenia diagnosis. Polygenic overlap was strongest in dual-comorbidity cases. SCZ PGS effect on cannabis use was modest.

How the study worked

Observational genetic study using the All of Us Research Program. Polygenic scores (PGS) for cannabis use disorder and schizophrenia were calculated for each participant using summary statistics from published genome-wide association studies. Models tested associations of both PGS with SCZ diagnosis and heavy cannabis use. Three case definitions used: relaxed (primary condition only), strict (excluding comorbidity), and dual-comorbidity. Controlled for ancestry and demographic factors.

Who was studied

Data from the All of Us Research Program, including genetic and health information.

What this study cannot tell us

Polygenic scores explain only a fraction of total genetic liability for both conditions. All of Us, while diverse, may not represent all populations equally for genetic analyses. Electronic health record-based diagnoses may misclassify some cases. Cannabis use was defined broadly (heavy use) rather than by specific measures of dose, potency, or duration. The cross-sectional design can't establish temporal ordering. Shared genetic liability doesn't preclude additional causal effects of cannabis on psychosis.

How to read the evidence

Large-scale genetic study using a well-powered biobank with both genotypic and phenotypic data. Polygenic score analyses are methodologically strong for testing genetic overlap. Limited by the cross-sectional design and electronic health record-based diagnoses.

When this study was published

Published in 2025. The All of Us Research Program continues to grow, which will enable more refined genetic analyses.

The bigger picture

This is the genetics piece that's been missing from the psychosis-cannabis cluster. The potency studies (RTHC-00071, 00106, 00115) document rising THC exposure, the epidemiological studies document the association, and this study reveals the genetic architecture underlying both. Cannabis use and schizophrenia aren't just correlated — they share genetic roots, which means some individuals are genetically primed for both conditions simultaneously.

Replication

Not stated in abstract.

Funding

Not reported in abstract.

Conflicts of interest

Not reported in abstract.

Questions still open

Could polygenic risk scores identify individuals who should be counseled against cannabis use due to high genetic vulnerability to psychosis? Does the shared genetic architecture involve specific biological pathways (dopamine, glutamate, endocannabinoid) that could be targeted therapeutically? Would the genetic overlap look different in non-European populations where most GWAS data originates? Does the shared genetic liability fully explain the cannabis-psychosis association, or does cannabis have an additional causal effect?

Read the original research

Investigating the polygenic relationship between heavy cannabis use and schizophrenia in the All of Us Research Program.

Psychological medicine, 55, e381

Psychological Medicine is a well-respected journal focusing on mental health research.

View on PubMed ↗Publisher’s paper ↗

Citation

Austin-Zimmerman, Isabelle; Thorpe, Hayley H A; Meredith, John J; Khokhar, Jibran Y; Ge, Tian; Di Forti, Marta; Agrawal, Arpana; Johnson, Emma C; Sanchez-Roige, Sandra. (2025). Investigating the polygenic relationship between heavy cannabis use and schizophrenia in the All of Us Research Program.. Psychological medicine, 55, e381. https://doi.org/10.1017/S0033291725102717