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November 4, 2020

Use of Genetically Informed Methods to Clarify the Nature of the Association Between Cannabis Use and Risk for Schizophrenia

Author Affiliations
  • 1Virginia Institute for Psychiatric and Behavior Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond
  • 2QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
JAMA Psychiatry. 2021;78(5):467-468. doi:10.1001/jamapsychiatry.2020.3564

Cohort studies and meta-analyses have documented a robust association between cannabis use, heavy use, and misuse with future risk of schizophrenia.1-3 Despite adjusting for covariates, including current psychotic symptoms, other psychopathology, and social integration,1 the ability of these models to determine the degree to which cannabis causes schizophrenia is limited and dependent on their ability to capture all relevant confounders. When evaluating efforts to reduce cannabis use as a means of preventing schizophrenia, the proportion of this association that is causal is critical.

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    3 Comments for this article
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    Confounding Factors in Schizophrenia and Cannabis Association
    Marcelo Cetkovich, MD. Psychiatrist | Institute of Cognitive Neurology, Buenos Aires. Argentina.
    Dear Sires
    It seems to me that the main confounding factor that has to be taken into account is the fact that, as in this excellent paper, we do not abandon the confusion between Psychosis and Schizophrenia.
    Research has to split the sample between all those subjects with a confirmed cannabis-related onset, from those where the relationship is not present.
    Relationship between cannabis and psychosis more clearly established.
    Thanks a lot
    CONFLICT OF INTEREST: None Reported
    A potentially important epigenetic confounder should also be addressed
    George Henderson | Auckland University of Technology
    Dear editor,

    applying genetic methods to environmental associations is an important check on their causal validity, but similar confounding is also likely to arise from epigenetic factors.
    Maternal meat avoidance was found to increase the odds of early cannabis use in offspring, OR = 2.70, 95% CI = (1.89, 4.00), p < 0.001. Similar but slightly smaller effects were found for alcohol and tobacco, indicating that the cannabis association is not solely a cultural one. Stratification for genetic causes of vitamin B12 deficiency confirmed the likely causality; the association was only significant in those people with the normal, functional
    B12 transport protein allele.[1]

    Meat avoidance is also associated with significantly increased rates of anxiety, depression and self harm - the evidence is heterogenous, but the associations in the most robust studies are large.[2] Data including schizophrenia is lacking, as it is a relatively rare condition and sufferers may by less likely to take part in dietary surveys, but about 25% of people diagnosed with schizophrenia meet the criteria for depression.[3]

    If we are trying to attribute causality between cannabis use and mental disorders, we need to rule out those dietary factors associated with both cannabis use and mental disorders as causal factors. Everyone admitted to a hospital these days is asked their dietary preference. It should be possible to aggregate this data to improve our knowledge in this area. The role of in utero exposure to suboptimal nutrition is more challenging to determine on the scale required to detect the incidence of a rare condition.


    [1] Hibbeln, J.R., SanGiovanni, J.P., Golding, J., Emmett, P.M., Northstone, K., Davis, J.M., Schuckit, M. and Heron, J. (2017), Meat Consumption During Pregnancy and Substance Misuse Among Adolescent Offspring: Stratification of TCN2 Genetic Variants. Alcohol Clin Exp Res, 41: 1928-1937. doi:10.1111/acer.13494


    [2] Urska Dobersek, Gabrielle Wy, Joshua Adkins, Sydney Altmeyer, Kaitlin Krout, Carl J. Lavie & Edward Archer (2020) Meat and mental health: a systematic review of meat abstention and depression, anxiety, and related phenomena, Critical Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2020.1741505

    [3] Siris SG. Depression in schizophrenia: perspective in the era of “atypical” antipsychotic agents. American Journal of Psychiatry 2000; 157: 1379-1389.
    CONFLICT OF INTEREST: I do smoke cannabis from time to time
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    Use of Genetically Informed Methods to Clarify the Nature of the Association Between Cannabis Use and Risk for Schizophrenia
    Nathan Gillespie, PhD | Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University
    Our original version is substantively correct, but technically our discussion may be considered too simplified. Measures demonstrating genetic associations based on linkage disequilibrium score regression (LDSR) and polygenic risk score (PRS) suggest a very nuanced association. For instance, two LDSR studies [1,2] have reported significant but modest genome-wide genetic correlations between lifetime cannabis use/abuse and schizophrenia (rg=+0.25 to +0.31). This is consistent with hypotheses II and III in the presence of non-causal mechanisms such as horizontal pleiotropy, defined as genetic causes directly influencing multiple traits. However, if vertical pleiotropy exists, whereby the impact of CAN genes on SZ is mediated by exposure to cannabis, this will generate an LDSR rg > 0 consistent with hypothesis I. We note however, that MR studies, which rely on vertical pleiotropy, have found little evidence to support this mediated pathway. Thus, in Table 1, correlations greater than zero can indicate causal and non-causal mechanisms consistent with hypotheses 1-3, and must be interpreted in the context of the plausibility of horizontal or vertical pleiotropy.

    1. Pasman JA, Verweij KJH, Gerring Z, et al. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nat Neurosci. 2018;21(9):1161-1170.
    2. Johnson EC, Demontis D, Thorgeirsson TE, et al. A large-scale genome-wide association study meta-analysis of cannabis use disorder. Lancet Psychiatry. 2020;7(12):1032-1045.
    CONFLICT OF INTEREST: None Reported
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