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Clarifying the link between cannabis use and risk for psychosis

As ever greater numbers of people throughout world have access to cannabis for recreational or medical purposes, assessing the risks of its use, especially for young people, assumes paramount importance. Among the best-documented harms of cannabis use are those related to development of mental disorders, including psychosis and substance use disorders. The article by Carney et al. (this issue) adds to our knowledge of the links between cannabis use and psychosis by focusing on the effects of heavy use (or use disorders) among young people without a prior psychotic episode but with ultrahigh risk (UHR) for developing the disorder. The designation of UHR was based on the presence of mild or brief psychotic symptoms, or of genetic risk and recent decline in functioning. The authors’ metaanalysis of 30 studies reporting cannabis use in UHR individuals indicated that these individuals were more than twice as likely as healthy controls to report ever using cannabis and were five times as likely to have a cannabis use disorder. Cannabis users in the UHR group, compared to non-users, also showed increased unusual thought content and suspiciousness. Previous research has also shown increased substance use (including smoking and alcohol use) as well as other health risk factors such as low physical activity among this high-risk population, pointing to the need for both targeted prevention and for further research to clarify causal relationships. All existing epidemiological studies involving cannabis use and health outcomes, including psychosis, suffer from multiple limitations. Among them are inconsistent measures and methodologies across studies, inability to disentangle the effect of multiple substances used or involvement of other risk behaviours, subject recall bias, and changing products and routes of administration over time. The latter is especially problematic for illicit products, for which dosages and content may be highly variable. The Carney et al. meta-analysis could not take into account alcohol or tobacco use, which may be important confounding variables, or the varying potencies and frequencies of cannabis used by individuals in different studies. Highpotency products (containing high concentrations of THC) and potent synthetic cannabinoids have been particularly associated with both acute psychotic symptoms and onset of psychotic disorders. These limitations constrain the conclusions that can be drawn from meta-analyses of observational studies. Despite these limitations, it likely attests to the strength of an association between cannabis use and psychosis that findings are so consistent. Cannabis use is associated with psychosis-related variables including age of onset, symptomatology, and course of illness, and studies consistently find high rates of comorbidity between cannabis use and psychotic disorders. Biological plausibility for such a link is provided by evidence showing abnormalities in the endocannabinoid system in individuals with schizophrenia. Such individuals show increased CB1 receptor binding density in corticolimbic circuits and higher levels of anandamide in cerebrospinal fluid. A recent study by D’Addario et al. found alterations in DNA methylation at the CNR1 promoter in individuals with schizophrenia (but not major depressive disorder or bipolar disorder). The mounting evidence for links between cannabis use and psychosis points to the need for addressing comorbidities, and for improved integration of prevention and treatment for substance use and other psychiatric disorders. Psychiatric disorders, including psychosis and substance use disorders, share many risk factors, and improvement in one mental disorder is consistently and prospectively associated with improvement in others. Furthermore, comorbidity of substance use and mental illness is complex and costly to treat; providing personalized and precise interventions for high-risk individuals before they develop a psychotic disorder could greatly benefit the individual’s life and health and reduce unnecessary healthcare costs. Carney et al. add to growing evidence that cannabis use is associated not only with psychosis but also with a broader spectrum of at-risk individuals, such as those with ultrahigh risk and with