The world of science is continuing to unravel the mysteries of the interactions between genetics and drug responses, particularly studies done in pharmacogenomics. Casual hemp and cannabis users have probably never heard of the gene CYP2C9; this crucial gene encodes the proteins that are responsible for metabolizing various drugs, including the infamous tetrahydrocannabinol (THC) (Daly, et al., 2017).
Understanding CYP2C9:
CYP2C9 is found predominantly in the liver and is highly polymorphic, with more than 50 known alleles (variations) that are usually reported as diplotype (one maternal and paternal allele). These alleles can then be used to predict the phenotype of the metabolizer. The “wild-type” allele with no variation is known as CYP2C9*1 and is associated with normal enzyme activity and is considered the normal metabolizer. Through the studies of pharmacogenomics, we know that there are “poor metabolizers”; variants CYP2C9*2 and CYP2C9*3 are specifically noted in relation to the metabolization of THC. In relation to the normal metabolizer CYP2C9*1, the genotypes CYP2C9*2 and CYP2C9*3 are associated with 80-90% less metabolizing power (Babayeva & Loewy, 2023). The genotype CYP2C9*2 is found more frequently in Caucasians than in any other population (10-20%), with CYP2C9*3 being extremely rare in African populations (Dean & Kane, 2020).
THC Metabolization and CYP2C9:
The variant of the CYP2C9 gene is a key determinant of how our bodies respond to cannabis. Different enzymatic activities from the variants affect the rate at which THC is processed within the body. Small studies have found that individuals who were CYP2C9*3/*3 homozygotes when administered THC orally had a greater exposure to THC (three-fold higher than those with CYP2C9*1/*1 homozygotes) with an increased risk of sedation and adverse effects including flushed face, heart palpitations, and physical weakness (Dean & Kane, 2020). Studies have shown that the inhalation of THC has no faster onset of psychoactive effects in individuals with CYP2C9*2 and CYP2C9*3, but it has shown a longer duration of effect in these genotypes (Babayeva & Loewy, 2023).
Conclusion:
While more studies need to be done, current ones suggest that individuals with CYP2C9 polymorphism dictate the response the body has towards THC, particularly when ingested or administered orally. This can go a long way in explaining why some individuals can eat THC edibles and feel no effect, while others become extremely drowsy or hyperactive. Recognizing the influence of CYP2C9 in physical reactions to THC can pave the way forward to further research on how genetics as a whole interact with and affect individual experiences with THC.
Sources:
Babayeva, M., & Loewy, Z. G. (2023). Cannabis Pharmacogenomics: A Path to Personalized Medicine. Current issues in molecular biology, 45(4), 3479–3514. https://doi.org/10.3390/cimb45040228
Daly, A. K., Rettie, A. E., Fowler, D. M., Miners, J. O. (2017). Pharmacogenomics of CYP2C9: Functional and clinical considerations. Journal of Personalized Medicine, 8(1), 1. https://doi.org/10.3390/jpm8010001
Dean, L., & Kane, M. (2020). Dronabinol therapy and CYP2C9 genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). https://www.ncbi.nlm.nih.gov/books/NBK564166/
