Cannabis use disorder showed a genetic link to schizophrenia even after accounting for tobacco | Research

The takeaway

Genetic liability to cannabis use disorder was significantly associated with schizophrenia risk even when controlling for tobacco smoking, cannabis ever-use, and nicotine dependence, with mixed evidence for a causal relationship.

Psychiatric genetics researchers and clinicians communicating cannabis risk to patients.

CUD genetically predicted schizophrenia even after controlling for tobacco and cannabis ever-use

What the researchers found

Genetic liability to CUD predicted schizophrenia (beta=0.29, p=0.001) even after accounting for cannabis ever-use, tobacco smoking, and nicotine dependence. Mendelian randomization found a small but significant causal effect of CUD on schizophrenia (beta=0.10, p=0.02), but latent causal variable analysis did not support causation. The key distinction was between CUD (disordered use) and ever-use (trying cannabis), with only CUD showing the association.

Why it matters

This study separates CUD from merely trying cannabis, finding that only disordered use genetically predicts schizophrenia. It also controls for tobacco (a major confounder), strengthening the CUD-specific signal. The mixed causal evidence keeps the question open but points toward CUD as more concerning than casual use.

The numbers in context

Sample sizes: 161,405-357,806. CUD-schizophrenia genetic association: beta=0.29 (95% CI: 0.11-0.46, p=0.001). Multivariable MR causal estimate: beta=0.10 (95% CI: 0.02-0.18, p=0.02). Latent causal variable: no significant causality (GCP=-0.08, p=0.87).

How the study worked

Used GWAS summary statistics (sample sizes 161,405-357,806 Europeans) for genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization. Examined genetic relationships between CUD, cannabis ever-use, tobacco smoking, nicotine dependence, and schizophrenia.

What this study cannot tell us

European ancestry GWAS limits generalizability. Two causal methods gave conflicting results. GWAS summary statistics may not capture all genetic variation. Cannot determine which aspects of CUD (frequency, potency, age of onset) drive the association.

How to read the evidence

Very large GWAS samples with sophisticated analytical methods. Strong genetic association with mixed causal evidence.

When this study was published

2021 genetic study using international consortium GWAS data.

The bigger picture

The distinction between CUD and ever-use is critical. Most people who try cannabis do not develop schizophrenia, and this study genetically confirms that ever-use does not carry the same risk signal as disordered use. This nuance is often lost in public debate.

Questions still open

Why do the two causal methods give different answers? Is there a threshold of cannabis use intensity where genetic risk translates to schizophrenia? Would these findings replicate in non-European populations?

Common questions

Is any cannabis use genetically linked to schizophrenia?

No. This study found that cannabis use disorder (problematic, heavy use) was genetically linked to schizophrenia, but simply having tried cannabis (ever-use) was not, when both were tested simultaneously.

Does the link survive controlling for tobacco?

Yes. The CUD-schizophrenia genetic association remained significant after simultaneously accounting for tobacco smoking and nicotine dependence, ruling out tobacco as the driver.

Read the original research

The relationship between cannabis and schizophrenia: a genetically informed perspective.

Addiction (Abingdon, England), 116(11), 3227-3234

View on PubMed ↗Publisher’s paper ↗

Citation

Johnson, Emma C; Hatoum, Alexander S; Deak, Joseph D; Polimanti, Renato; Murray, Robin M; Edenberg, Howard J; Gelernter, Joel; Di Forti, Marta; Agrawal, Arpana. (2021). The relationship between cannabis and schizophrenia: a genetically informed perspective.. Addiction (Abingdon, England), 116(11), 3227-3234. https://doi.org/10.1111/add.15534