Epidemiological evidence demonstrates an association between the use of cannabis and increased risk of psychosis.1 Cannabis users are more likely to report psychosis-like experiences than non-users; daily use of cannabis is associated with a 3-fold increase in the risk for psychotic disorders.1 At SIRS 2023, a panel of neuroscientists and clinicians discussed the link between genetics, cannabis use and psychosis.
UK Biobank Analysis
Prof. Michael Wainberg (Centre for Addiction and Mental Health, Canada) explained that there are four types of psychotic experiences: auditory hallucinations, visual hallucinations, delusions of persecution, and delusions of reference.2 Delusions of reference refers to an individual’s belief that “a strange force” is trying to communicate directly with them through special signs or signals that no one else could understand.2
There are four types of psychotic experiences: auditory hallucinations, visual hallucinations, delusions of persecution, and delusions of reference
Prof. Wainberg and his team performed a cross-sectional study of 109,308 UK Biobank participants to explore whether cannabis use disproportionately increased the risk of specific types of psychotic experiences, and if there seems to be a genetic link between cannabis use and psychotic experiences.2,3 They found that frequent cannabis use was associated with all four types of psychotic experiences, especially persecutory delusions.2 Cannabis ever-users reported earlier-onset and more distressing psychotic experiences than those who had never used cannabis.2 Dr. Wainberg and his team also found that individuals who had high schizophrenia polygenic risk scores (PRS) also had stronger associations between cannabis use and auditory hallucinations, visual hallucinations, and delusions of reference, as well as psychotic experiences overall.3 Dr. Wainberg hypothesized that cannabis harm reduction efforts may show maximal public health benefit if they target individuals with psychosis risk factors.2
Frequent cannabis use was associated with all four types of psychotic experiences, especially persecutory delusions
The Genetic Relationship between Cannabis Use and Psychosis
Prof. Isabelle Austin-Zimmerman (King’s College, UK) explained that previous genome-wide association studies (GWAS) have elucidated multiple genetic risk variants for both psychosis and cannabis use; furthermore, there is evidence of shared genetic liability for these traits.4 However, the causal relationship between these traits is unclear. While schizophrenia PRS does not predict cannabis use, it improves the prediction of psychosis status by cannabis use.4
There is evidence of shared genetic liability for psychosis and cannabis use
Prof. Austin-Zimmerman and her team built on previous GWAS work by using LAVA, an integrated framework for local genetic correlation analysis, to map the specific regions that contribute to the overall genetic correlation.4 Multi-marker analysis of genomic annotation (MAGMA) of these regions revealed enrichment of gene sets in the brain, including the frontal cortex, basal ganglia, hippocampus and pituitary gland.4 These analyses contribute to the understanding of the differing genetic architecture underlying cannabis-related psychotic disorders, as well as psychosis in the absence of cannabis use.4
Prof. Austin-Zimmerman also brought attention to a research study that she is currently involved in, called “Cannabis & Me,” an independent study which aims to explore the environmental and biological factors that explain the different effects people experience when using cannabis. Led by Prof. di Forti, the study will use a combination of DNA genetic and epigenetics testing, psychological and cognitive analysis, and virtual reality to understand the link between a user’s biological makeup and the effect cannabis has on them. In particular, the study will aim to identify the environmental (e.g. history of trauma), genetic and epigenetic markers that are most likely to cause mental health and social problems in users.5
Genetic Overlap Between Cannabis Use Disorder and Schizophrenia
Prof. Emma Johnson (Washington University School of Medicine, USA) presented results of a cross-disorder analysis (ASSET) which aimed to identify genome-wide significant loci that are pleiotropic for cannabis use disorder (CUD) and schizophrenia.6 They were able to identify over 100 such loci, 54 of which showed convergent effects (i.e., same direction of effect on both disorders), and 51 of which showed divergent effects (i.e., risk-increasing for one disorder, and protective for the other).6 Two showed significantly partial genetic correlation between CUD and schizophrenia. They conclude that genetic liability of CUD is uniquely and positively correlated with risk of schizophrenia.6
Over 100 genetic variants exert an effect on both cannabis use disorder and schizophrenia
Future work will update these analyses with a larger GWAS of CUD that is forthcoming, as well as extending the analyses to include individuals of non-European ancestries.6
Bidirectional Association Between Psychosis and Cannabis Use
Prof. Sinan Goloksuz (Maastricht University, Netherlands) shared the results of his group’s research findings which explored the temporal relationship between cannabis use, anxiety/depressive symptoms and psychotic experiences. Performing mediation analysis on data from the second longitudinal Netherlands Mental Health Survey and Incidence Study (NEMESIS-2), they discovered that there is a bidirectional relationship between cannabis use, anxiety/depressive symptoms and psychotic experiences.7 That is, anxiety/depression symptoms mediate the link between cannabis use and psychosis, while cannabis use also mediates anxiety/depression symptoms and psychosis. Anxiety/depression symptoms proved to be a greater mediator of psychosis than cannabis use.7
The link between cannabis use, anxiety and depressive symptoms and psychosis is bidirectional
Prof. Goloksuz also shared the results of another study which explored nongenetic factors associated with psychotic experiences among UK Biobank participants.7 The top three exposures with the highest odds ratio of being associated with a psychotic experience were an individual’s ever having had a period of mania/excitability, ever having self-harmed or contemplated self-harm. When considering cannabis use exposure, analysis again revealed a bidirectional link between it and psychotic experiences.7 Prof. Goloksuz’ team concluded that cannabis use results in increased affective dysregulation, supporting the theory of an ‘affective pathway’ to psychosis.7
Prof. Goloksuz closed by sharing the goals of one of his upcoming collaborations, the Youth-GEMs project. This project aims to integrate data from molecular, genetic, epigenetic, epidemiological and clinical studies to establish links between dynamic, environmentally-shaped biological processes taking place during key periods of neurodevelopment and expression of mental ill-health.8
UK: United Kingdom
PRS: Polygenic risk score
GWAS: Genome wide association study
LAVA: Local analysis of (co)variant annotation
MAGMA: Multi-marker analysis of genomic annotation
DNA: Deoxyribonucleic acid
ASSET: Association analysis based on subsets
CUD: Cannabis use disorder
NEMESIS-2: The Netherlands mental health survey and incidence study-2
Youth-GEMS: Gene environment interactions in mental health trajectories of Youth
BE-NOTPR-0347
Approval date: 08-2023
