Most cannabis users will not develop psychosis in their lifetimes. However, for those users who do experience psychotic episodes, there is a growing body of evidence that their drug of choice may have had some part to play in their disorder.



Now a new study has linked a genetic variant in humans with a higher risk of first episode psychosis (FEP), but only in subjects with a history of cannabis use.

First episodes of psychosis usually occur around a person’s late teens and early twenties and are characterized by a “loss of contact with reality”, which manifest in visual hallucinations and delusional thinking. Around 100,000 adolescents and young adults in the US experience FEPs each year.

Cannabis is the most widely used drug among patients with FEP, and previous medical research has concluded that cannabis use may approximately double the overall risk of young people developing their first episode.

But while cannabis use is associated with worse psychosis outcomes, the cannabinoid cannabidiol (CBD) has also been shown by researchers at King’s College London to have anti-psychotic properties in young people experiencing distressing psychotic symptoms.



The new genetics study, published in European Neuropsychopharmacology and authored by research groups in Spain and Italy, further examined the possibility that a combination of genetics and cannabis use could lead to FEPs.

The researchers looked at the genetics-environment interaction between 15 genetic variants, known as single nucleotide polymorphisms (SNPs), in a study population containing people with FEP and matched healthy controls. The selected SNPs all came from one of three candidate gene regions, cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2) and fatty acid hydrolase (FAAH), that are known to be related to cannabis use and the endocannabinoid system.

Researchers recruited 321 study participants, each of which had experienced an FEP, who were willing to provide genetic, clinical, and toxicological data for the study. However, there was no record as to whether the participants’ cannabis use preceded their psychosis, an omission the researchers admit to limiting the conclusions of the study.

Regardless, 241 participants who had never presented psychosis and with no family history of psychosis were also sourced. They were matched by age, gender, and parental socio-economic status to form a control group.

Psychopathological and neuropsychological assessments were carried out, and cannabis use was evaluated for each participant. Genetic data were gathered via blood test with the participants' consents, and genotyped at the Spanish National Genotyping Centre. Using all these data, researchers conducted a statistical analysis to estimate the independent contribution of each SNP to overall disease susceptibility and the effect of cannabis use.

Ultimately, the researchers found a strong association between the FAAH SNP genetic polymorphism and a greater risk of presenting an FEP in people with a history of cannabis use. This association was not reflected in the data of those who did not use cannabis.

Despite the study’s limitations, the researchers confidently concluded that the study had positively identified a gene-environment interaction between a genetic polymorphism from the endocannabinoid system and cannabis use involved in the risk of presenting an FEP.

Specifically, the likelihood of presenting an FEP was ten times larger in cannabis users who carried a particular version of the SNP, compared to cannabis users without this genotype. This would support the existence of a gene-environment interaction between at least one gene related to the endocannabinoid system and cannabis use in the risk of presenting an FEP.

It was also observed that higher than average proportions of these “TT allele carriers” of the SNP with a history of cannabis use were being treated with high potency antipsychotic medication. Carriers of this genotype who used cannabis were also more likely to be recorded by clinicians as having more disruptive symptoms of psychosis, perhaps prompting clinicians to prescribe stronger medication.

“Our results highlight the importance of the pro-psychotic effects exogenous cannabis use over the ECS in certain subjects,” conclude the study authors. “These results also point the interest to use the ECS elements as biomarkers of the FEP and to explore its pharmacological modulation. Such findings warrant greater attention in future investigations.”