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Cannabis and Schizophrenia

Cannabis and Schizophrenia. Erik Messamore, MD, PhD Associate Professor of Psychiatry, Northeast Ohio Medical University Medical Director, Best Practices for Schizophrenia Treatment (BeST) Center. Overview. Cannabis association with acute psychosis is well-known

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Cannabis and Schizophrenia

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  1. Cannabis and Schizophrenia Erik Messamore, MD, PhD Associate Professor of Psychiatry, Northeast Ohio Medical University Medical Director, Best Practices for Schizophrenia Treatment (BeST) Center

  2. Overview Cannabis association with acute psychosis is well-known Cannabis use is more frequent among those with schizophrenia than those without schizophrenia Epidemiological studies show clear association between earlier-life cannabis use and later-life schizophrenia However…

  3. Confounds and Bias But, epidemiological association weaknesses include: Confounding Variables maybe some cannabis use is irrelevant, simply associated some other actually-causative variable e.g., cannabis users have greater life stress, and life stress is reason for increased schizophrenia risk Reverse Causation Bias people destined to develop schizophrenia may preferentially choose to use marijuana, possibly to ‘self-medicate’ very early, subclinical distress, or because they derive greater enjoyment from it than neurotypical people

  4. A Difficult Dilemma • We obviously can’t perform a direct test of the hypothesis that long-term marijuana use causes schizophrenia

  5. Criteria to Meet if Cannabis were Causal • Plausible mechanism whereby cannabis exposure could cause schizophrenia • Evidence of a dose-response relationship

  6. Putative Mechanisms of Causation • Cannabis use causes excessive dopamine release Voruganti, L.N., Slomka, P., Zabel, P., Mattar, A., and Awad, A.G. (2001). Cannabis induced dopamine release: an in-vivo SPECT study. Psychiatry Res 107, 173–177. • Cannabinoid receptors affect glutamate signaling at the NMDA receptor Sánchez-Blázquez, P., Rodríguez-Muñoz, M., and Garzón, J. (2014). The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Front Pharmacol 4, 169. • Cerebral cannabinoid receptors are modified by cannabis use Dean, B., Sundram, S., Bradbury, R., Scarr, E., and Copolov, D. (2001). Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103, 9–15. • Cortical maturation is altered by cannabis use in adolescents French, L., Gray, C., Leonard, G., Perron, M., Pike, G.B., Richer, L., Séguin, J.R., Veillette, S., Evans, C.J., Artiges, E., et al. (2015). Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence. JAMA Psychiatry 72, 1002–1011.

  7. Dunedin Multidisciplinary Health and Development Study N=803 26% of study members were classified as adolescent-onset cannabis users if they had used cannabis before age 15 or if they were at least monthly cannabis users by age 18 Strongly increased prevalence of schizophreniform diagnoses by age 26 among cannabis users with Val/Val genotype Caspi, A., et al. (2005). Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol. Psychiatry 57, 1117–1127. COMT variant mediates cannabis-associated psychosis

  8. Earlier Age of Onset of Schizophrenia Among Cannabis Users 1.8 year earlier age of onset in cannabis users vs non-users Dekker, N., Meijer, J., Koeter, M., van den Brink, W., van Beveren, N., Kahn, R.S., Linszen, D.H., van Os, J., Wiersma, D., Bruggeman, R., et al. (2012). Age at onset of non-affective psychosis in relation to cannabis use, other drug use and gender. Psychol Med 42, 1903–1911. 3 year earlier onset of schizophrenia-spectrum disorder among cannabis users Helle, S., Ringen, P.A., Melle, I., Larsen, T.-K., Gjestad, R., Johnsen, E., Lagerberg, T.V., Andreassen, O.A., Kroken, R.A., Joa, I., et al. (2016). Cannabis use is associated with 3years earlier onset of schizophrenia spectrum disorder in a naturalistic, multi-site sample (N=1119). Schizophr. Res. 170, 217–221. 3.2 year earlier age of onset for cannabis users vs non-users, and 6.2 year earlier age of onset for daily users of high-potency cannabis Di Forti, M., Sallis, H., Allegri, F., Trotta, A., Ferraro, L., Stilo, S.A., Marconi, A., La Cascia, C., Reis Marques, T., Pariante, C., et al. (2014). Daily Use, Especially of High-Potency Cannabis, Drives the Earlier Onset of Psychosis in Cannabis Users. Schizophr Bull 40, 1509–1517.

  9. Meta-analysis reveals a dose-response relationship between the level of cannabis use and the risk for psychosis. Marconi, A., Di Forti, M., Lewis, C.M., Murray, R.M., and Vassos, E. (2016). Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis. Schizophr Bull 42, 1262–1269. Dose-Response Relationship

  10. Cannabis use is associated with worse outcomes in first-episode psychosis • 2,206 individuals with first-episode psychosis • Cannabis users (46% of sample) had: • Higher rates of hospitalization • Higer rates of involuntary treatment • Higher rates of medication switching • Higher rates of polypharmacy Indicators of treatment-resistance Patel, R., Wilson, R., Jackson, R., Ball, M., Shetty, H., Broadbent, M., Stewart, R., McGuire, P., and Bhattacharyya, S. (2016). Association of cannabis use with hospital admission and antipsychotic treatment failure in first episode psychosis: an observational study. BMJ Open 6, e009888.

  11. Mendelian Randomization If cannabis use is irrelevant to schizophrenia, then… Frequency of cannabis use-associated genes in large samples of patients with schizophrenia Frequency of cannabis use-associated genes in large samples of patients without schizophrenia = This approach eliminates environmental confounds

  12. Vaucher, J., Keating, B.J., Lasserre, A.M., Gan, W., Lyall, D.M., Ward, J., Smith, D.J., Pell, J.P., Sattar, N., Paré, G., et al. (2017). Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol. Psychiatry. Mendelian Randomization Suggests Causal Relationship Between Cannabis Use and Schizophrenia

  13. Summary There is little doubt that long-term cannabis use is a causal risk factor for schizophrenia. These findings have important public health policy implications.

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