Elizabeth Battey

Introduction. Psychosis is one of the top 15 major causes of disability and is characterized by hallucinations and delusions (positive symptoms), disorganized behavior, and cognitive dysfunction^1,2. While it has been known that psychosis is hereditary, interactions between genes and environment are still being examined². Cannabis is the most used illicit drug in the world, with 51% of American adults having tried marijuana at least once³. The connection between cannabis in psychosis is controversial, but with the legalization of marijuana in some states and growing numbers of people using marijuana, it’s worth discussing potential risks³. It has been found that increases in dopaminergic activity in the mesolimbic pathway are associated with positive symptoms of psychosis, and decreases in dopamine release in the cortex and other extrastriatal regions are associated with deficits in working memory and cognition^4,5. Catechol-O-Methyl-Transferase (COMT) has a functional polymorphism where individuals with the Val/Val genotype have higher COMT activity and therefore lower dopamine levels than those with other genotypes⁶. Also, AKT1 encodes a serine/threonine kinase that is involved in the dopamine receptor cascade in the striatum, and has a functional polymorphism where individuals with the C/C genotype have decreased functioning of AKT1 and higher striatal dopamine release⁸. The purpose of this study was to investigate whether people with certain genotypes have higher risk of developing psychosis. Methods. Participants were genotyped using their blood or saliva using Taqman assays or phenol-chloroform methods^6-8.The Comprehensive Assessment of At-Risk Mental States (CAARMS)⁶ and Psychotomimetic States Inventory⁷ were administered to assess symptoms of psychosis. Results. Researchers found that individuals who use cannabis weekly reported more severe positive symptoms of psychosis than people who do not use cannabis, and this effect was greater in those with the COMT polymorphism Val/Val genotype^6,7. Another study found that individuals with the AKT1 C/C genotype showed more positive symptoms of psychosis than those with the T/T genotype, and that daily cannabis users who have the C/C genotype were seven times more likely to develop psychosis than daily cannabis users with the T/T genotype⁸. Conclusions. These studies offer evidence that some cannabis users with certain genotypes may have increased risk of developing psychosis. A better understanding of the mechanisms involved may lead to novel therapeutic targets and more effective prevention, diagnosis, and treatment for psychosis.

1. Moreno-Ku¨stner B, Martı´n C, Pastor L (2018) Prevalence of psychotic disorders and its association with methodological issues. A systematic review and meta-analyses. PLoS ONE 13(4): e0195687. https://doi.org/10.1371/journal. Pone.0195687
2. Zwicker A, Denovan-Wright EM, Uher R (2018). Gene–environment interplay in the etiology of psychosis. Psychological Medicine 48, 1925–1936. https:// doi.org/10.1017/S003329171700383X
3.  Ortiz-Medina, M. B., Perea, M., Torales, J., Ventriglio, A., Vitrani, G., Aguilar, L., & Roncero, C. (2018). Cannabis consumption and psychosis or schizophrenia development. International Journal of Social Psychiatry, 64(7), 690–704. https://doi.org/10.1177/0020764018801690
4. 4) Weinstein, J. J., Chohan, M. O., Slifstein, M., Kegeles, L. S., Moore, H., & Abi-Dargham, A. (2017). Pathway-Specific Dopamine Abnormalities in Schizophrenia. Biological Psychiatry, 81(1), 31–42. doi: 10.1016/j.biopsych.2016.03.2104
5. Kesby, J., Eyles, D., McGrath, J. et al. Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Transl Psychiatry 8, 30 (2018). https://doi.org/10.1038/s41398-017-0071-9
6. Nieman, D. H., Dragt, S., Duin, E. D. V., Denneman, N., Overbeek, J. M., Haan, L. D., Linszen, D. H. (2016). COMT Val 158 Met genotype and cannabis use in people with an At Risk Mental State for psychosis: Exploring Gene x Environment interactions. Schizophrenia Research 174(1-3), 24–28. doi: 10.1016/j.schres.2016.03.015
7. Verdejo-García, A., Fagundo, A. B., Cuenca, A., Rodriguez, J., Cuyás, E., Langohr, K., Torre, R. D. (2013). COMT val158met and 5-HTTLPR Genetic Polymorphisms Moderate Executive Control in Cannabis Users. Neuropsychopharmacology, 38(8), 1598-1606. doi:10.1038/npp.2013.59
8. Morgan, C. J. A., Freeman, T. P., Powell, J., & Curran, H. V. (2016). AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers. Translational Psychiatry, 6(2). doi: 10.1038/tp.2015.219