A specific gene variant made cannabis users 10 times more likely to experience a first psychotic episode | Research

The takeaway

Cannabis users who carried two copies of the T allele of the FAAH gene variant rs2295633 had tenfold higher odds of experiencing a first psychotic episode compared to cannabis users without this genotype, revealing a specific gene-environment interaction.

Psychiatrists, geneticists, cannabis users concerned about psychosis risk, and personalized medicine researchers.

10x higher psychosis risk

What the researchers found

The FAAH rs2295633 genetic polymorphism interacted with cannabis use to dramatically increase psychosis risk. Cannabis users homozygous for the T allele had OR 10.69 for first-episode psychosis compared to cannabis users without this genotype. The effect was absent in non-cannabis users, confirming a true gene-environment interaction. TT carriers with cannabis use were also more likely to need high-potency antipsychotics.

Why it matters

This identifies a specific genetic vulnerability that could explain why some cannabis users develop psychosis while most do not. If replicated, it could enable genetic screening to identify individuals at highest risk from cannabis use.

The numbers in context

321 FEP patients, 241 healthy controls. FAAH rs2295633 TT genotype + cannabis use: OR 10.69 for FEP. 15 ECS-related SNPs tested. TT carriers with cannabis use more often required high-potency antipsychotics.

How the study worked

Case-control study of 321 first-episode psychosis patients and 241 matched healthy controls in Spain. Examined gene-environment interactions between 15 endocannabinoid system SNPs and cannabis use history.

What this study cannot tell us

This is a single study requiring replication in independent samples. The specific FAAH variant has not been widely studied. The mechanism linking this polymorphism to psychosis risk is not established. Self-reported cannabis use history may be inaccurate.

How to read the evidence

Rated moderate because this is a well-designed case-control study with a large combined sample, though replication is needed and the effect size is very large for a genetic finding.

When this study was published

Published in 2019. The authors explicitly noted this preliminary finding needs replication.

The bigger picture

The cannabis-psychosis link has been debated for decades because most users never develop psychosis. Gene-environment interaction studies like this begin to explain this selectivity: specific genetic backgrounds may create vulnerability that cannabis use activates.

Questions still open

Will this gene-environment interaction replicate in other populations? Could FAAH genotyping become a clinical screening tool? What is the biological mechanism linking FAAH rs2295633 to psychosis vulnerability?

Common questions

Why do some cannabis users develop psychosis but not others?

This study identified a specific genetic variant (FAAH rs2295633) that, when present in two copies, increased psychosis risk tenfold among cannabis users. The same variant had no effect in non-users, suggesting cannabis activates a pre-existing genetic vulnerability.

What is FAAH?

FAAH (fatty acid amide hydrolase) is an enzyme that breaks down the natural endocannabinoid anandamide. Genetic variations in FAAH could alter how the brain processes both natural and plant-derived cannabinoids.

Can you get tested for this gene?

While the genetic variant can be identified through genotyping, this finding needs replication before clinical screening would be appropriate. It is preliminary evidence of a potential risk factor, not yet a validated screening tool.

Read the original research

Gene-environment interaction between an endocannabinoid system genetic polymorphism and cannabis use in first episode of psychosis.

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29(6), 786-794

View on PubMed ↗Publisher’s paper ↗

Citation

Bioque, Miquel; Mas, Sergi; Costanzo, Maria Cristina; Cabrera, Bibiana; Lobo, Antonio; González-Pinto, Ana; Rodriguez-Toscano, Elisa; Corripio, Iluminada; Vieta, Eduard; Baeza, Immaculada; Ibáñez, Ángela; Fraile, Miguel Gutiérrez; Cuesta, Manuel J; Mezquida, Gisela; Lafuente, Amalia; Bernardo, Miguel. (2019). Gene-environment interaction between an endocannabinoid system genetic polymorphism and cannabis use in first episode of psychosis.. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29(6), 786-794. https://doi.org/10.1016/j.euroneuro.2019.04.005