Abstract
Cannabis is known to produce acute, transient psychotic-like experiences. However, it is unclear whether cannabis disproportionately increases the risk of specific types of psychotic experiences and whether genetic predisposition influences the relationship between cannabis use and psychotic experiences. In this cross-sectional study of 109,308 UK Biobank participants, we examined how schizophrenia polygenic risk modulates the association between self-reported cannabis use and four types of self-reported psychotic experiences (auditory hallucinations, visual hallucinations, persecutory delusions, and delusions of reference). Cohort-wide, we found a strong, dose-dependent relationship between cannabis use and all four types of psychotic experiences, especially persecutory delusions. Cannabis users’ psychotic experiences tended to be earlier-onset and cause greater distress than non-users’, but were not more likely to lead to help-seeking. Participants with high schizophrenia polygenic risk scores showed stronger associations between cannabis use and auditory hallucinations, visual hallucinations, and delusions of reference, as well as psychotic experiences overall. For instance, cannabis ever-use was associated with 67% greater adjusted odds of delusions of reference among individuals in the top fifth of polygenic risk, but only 7% greater adjusted odds among the bottom fifth. Our results suggest that cannabis use is a predictive risk factor for psychotic experiences, including early-onset and distressing experiences. Individuals genetically predisposed to schizophrenia may be especially vulnerable to psychotic experiences as a result of using cannabis, supporting a long-postulated hypothesis. This study exemplifies the utility of population-scale biobanks for elucidating gene-by-environment interactions relating substance use to neuropsychiatric outcomes and points to the translational potential of using polygenic risk scores to inform personalized harm reduction interventions.
Highlights
Substantial epidemiological evidence associates cannabis use with psychosis[1] and accelerated age of onset of psychosis[2,3], the causality of these relationships have long been debated[1,4]
4.1% of cannabis never-users reported one of the four types of experiences surveyed, this rose to 7.0% among ever-users (AOR = 1.54 [1.43, 1.65]) and rose further to 8.4% among those reporting ever using cannabis at least monthly (AOR = 1.69 [1.54, 1.87]), 8.8% among ever-weekly users (AOR = 1.69 [1.51, 1.89]), and 9.6% among ever-daily users (AOR = 1.79 [1.52, 2.20])
Defining never-use as 0 “risk units”, ever-use as 1 “risk unit”, and so forth up to 4 “risk units” for daily use, we found that the odds of any of the four psychotic experiences increased by 20% per risk unit (AOR = 1.20 [1.16, 1.24])
Summary
Participants were included from the UK Biobank, a prospective cohort study with genetics and deep phenotyping on ~500,000 British individuals, aged 40–69 years at recruitment. 157,348 participants completed an online Mental Health Questionnaire[23], of which 109,308 participants (61,047 female and 48,261 male) of unrelated White British ancestry (defined using the same criteria as a previous study24) met the inclusion criteria These participants answered questions on both cannabis use and psychotic experiences, and lacked a diagnosis of any psychotic disorder (ICD-10 codes F20–F29) according to linked inpatient, primary care, or death records (e.g., according to “Source of report of F20 (schizophrenia)”, Data-Field 130875). Covariate-corrected adjusted odds ratios (AORs) and associated 95% confidence intervals were calculated, via logistic regression of each psychotic experience on cannabis ever-use (coded as binary variables) and covariates, using the glm function in R.
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