Pharmacogenomics (PGx) and Cannabis:
An Overview

Written by Austin Eastmure; Edited and Reviewed by Rachel Baer, MSc, and Andrew McCarty, MS, LCGC

 
 

Disclaimer: This article is not intended to provide any medical advice, treatments, recommendations, or otherwise. This information is not endorsing the use of recreational or medical cannabis, but is meant to provide an idea of the genetic influences on drug metabolism with cannabis as an example.

Introduction

Drug metabolism is a complex topic that is gaining more and more research each day. Federal law makes consumption of cannabis in the United States illegal. However, with varying state legislation, the use of medical or recreational cannabis products may be legal within specific states. Current state laws can be viewed here. There is ongoing research on the possible medical benefits of cannabis. This page is meant to give a broader understanding of what role genetics play in an individual’s response to cannabis.

Cannabis

Scientific Name: Cannabis indica and Cannabis sativa

Also Called: marijuana*, weed, grass, bud, flower, hash
*the term marijuana is controversial due to its ties with anti-immigrant racism, but many feel differently. We use the term cannabis throughout this article.

Includes: hemp (non-psychoactive), THC (psychoactive), CBD, terpenes, and other molecules

 

To learn about the current practical uses of Pharmacogenomics (PGx Testing) click here.

 

Historical Uses of Cannabis

Cannabis has been historically used across cultures around the world for religious, medicinal, and numerous other purposes. Around the 2nd century BCE, Emperor Shen Nung of China wrote descriptions of cannabis being used for treating human diseases. Documents recorded on Egyptian papyri and Sumerian tablets also reference cannabis use for conditions including nocturnal convulsions and infections (2, 8). Today in the United States, differing state laws surrounding cannabis have led to a lasting debate over how cannabis should be treated by the law. Some states have legalized cannabis recreationally, medicinally, or in both capacities (1). As of January 2024, 38 states, have medicinal cannabis laws while 24 states have recreational cannabis laws, with Washington D.C., and three territories having both recreational and medicinal laws (16). This does not include federal, tribal, or local laws. Moreover, Native American (Indigenous) Reservations have faced disputes with state and federal governments regarding the use and sale of cannabis on Tribal Lands (11). In 2021, over 69,000 people in the United States ages 12 and older were surveyed asking if they had used cannabis in the preceding year and about 18% indicated they had (14, 15). With the legalization of both medicinal and recreational cannabis spreading, concerns have grown regarding possible risks of cannabis use (5).

What does this have to do with genetics?

Genes are the instructions that every living being’s cells use to create proteins, some of which are called enzymes.

These enzymes are responsible for a number of things in the body, one of which is breaking down, or digesting, drugs and chemicals.

The process of breaking down drugs or chemicals is called metabolism and each individual has different rates of metabolism for each drug based on their genetics.

CYP genes are a group of genes that produce these enzymes, which collectively are called the Cytochrome P450 Superfamily (4). 

Pharmacogenomics (PGx) is the study of genetic variations between people resulting in differences in the way their respective enzymes metabolize drugs. This includes the molecules that are metabolized during cannabis use.

 

Genetics and Cannabis Metabolism

There are a handful of genes known to produce the enzymes that metabolize the various molecules of cannabis. CYP2C9 and CYP3A4 each metabolize both THC and CBD, but CBD is also metabolized by CYP2C19 (12). These enzymes not only metabolize cannabis, but are vital for human health and are responsible for about 75% of all drug metabolism in humans. However, it is important to note that external factors, like diet or drug use, can alter the efficiency of CYP enzymes and their expression (6).

When THC is first metabolized, it is converted to 11-Hydroxy-THC or, OH-THC, by the enzyme CYP2C9. OH-THC is the molecule that induces the psychoactive properties, or the “high,” typically associated with cannabis. After this conversion, OH-THC is further broken down by the CYP2C9 enzyme to an inactive molecule called 11-Nor-9-Carboxy-THC, or COOH-THC (5). 

Some individuals have genetic variations on their CYP2C9 genes, which can result in individual differences in the way people process THC. The CYP2C9*3 gene variant, codes for a version of the CYP2C9 enzyme that metabolizes molecules slower than its standard form (3). When an individual’s genes instruct for the production of this version of the CYP2C9 enzyme, the conversion of OH-THC to COOH-THC takes longer. This causes OH-THC molecules to accumulate, which can increase the psychoactive effects beyond a typical individual’s response when using cannabis. Overall, this can increase the likelihood of negative effects, such as paranoia or anxiety, when using cannabis. 

 

Image created by Aishwarya Satheesh-Kumar

The probability of negative effects is further increased when taking into account the variability of products that cannabis users may encounter. Trial-and-error is often used when selecting products to achieve the desired effect, and further, those consuming unregulated cannabis products may not have any information to control the dosage. Additionally, due to variations in an individual's genetics, each cannabis user will experience different effects (5).

These concerns have pushed some researchers to use PGx to determine additional genes associated with cannabis metabolism and to further understand how individual genetic variation impacts the effects of cannabis. Identifying these variations can indicate the speed at which an individual will break down cannabis and may provide guidance on an individual’s risk of experiencing psychological conditions, such as psychosis, during or after cannabis use. This is especially important since the rate at which THC is broken down is linked to the predisposition of psychological conditions known to be triggered by cannabis use (5).

Research on the Medical Benefits of Cannabis

Currently, there are a number of scientifically studied medical benefits associated with the use of cannabis (9). More research is needed overall, and it’s important to note that smoking cannabis as an inhalant, as a “joint” or cannabis cigarette, is never medically recommended due to the inherent respiratory inflammation associated with inhaling hot smoke, whereas oral ingestion of cannabis, like as a pill, oil, or other edible form, mitigates increased risk for lung disease that is associated with smoking any combustible materials (17).

Note: any link between lung cancer and smoking cannabis has yet to be found or established (17).

Cannabis is often associated with treating symptoms related to:

  • chronic pain management:

    • reducing opioid reliance; suggests a potential path for replacement or reduction of prescribed highly-addictive opioids for those requiring long-term pain management (9)

    • migraines,

    • physical trauma,

    • Complex Regional Pain Syndrome (CRPS),

    • fibromyalgia, and others

  • reducing neurological symptoms:

    • Multiple Sclerosis,

    • seizure disorders

  • managing nausea, vomiting, or GI symptoms:

    • Crohn’s Disease,

    • anorexia,

    • HIV/AIDS,

    • cancer, and others

Effects of Cannabis

Although cannabis research has indicated benefits for ailments such as chronic pain, anorexia, nausea, or anxiety, the use of cannabis as a medicine remains controversial due to the risk or concern for certain populations prone to negative effects.

General effects of cannabis can include:

  • euphoria,

  • relaxation or drowsiness,

  • deficits in cognitive processes,

    • can result in accidents when individuals are not in a safe environment (car accidents*, falls, injuries)

      *Never operate a vehicle while under the influence of mind-altering drugs, including cannabis, alcohol, opioids, and other substances.

  • poor memory and attention,

  • slowing of other executive brain functions,

  • possible reduction or increase in anxiety*

*Some individuals experience an increase in anxiety rather than a decrease in anxiety. This may have to do with their individual metabolism, psychological state, or other factors.

For those in a vulnerable subset of the population with particular risk factors may also be at a higher risk of having a psychotic episode or developing schizophrenia (10). These negative effects need consideration when deciding to use cannabis, but it is important to note that they are often observed in individuals with multiple risk factors rather than the general population as a whole(10).

Examples of increased risk factors for cannabis induced psychosis or schizophrenia include:

  • heavy long-term cannabis use,

  • a history of child abuse,

  • a family history of psychotic disorders,

  • or certain genetic predispositions:

    • certain variants in the genes COMT and AKT1 are linked to a predisposition to psychotic disorders (10)

 

PGx and the Future of Personalized Medicine

Using PGx to guide cannabis usage for patients could provide a potential way of reducing the risk of negative symptoms. The ability for medical providers to order tests that detect changes in CYP2C9, and other genes associated with the side effects of cannabis, such as AKT1 or COMT, could provide vital information regarding the recommendations for or against cannabis use for patients (6). However, it is still important to note that factors such as tolerance to cannabis or cannabis interacting with other drugs can impact a patient’s experience (10). Further, due to legal barriers that have been placed on cannabis, research on its physiological and psychological effects is still very much in its infancy and new guidance about cannabis consumption or recommendations should be analyzed with a healthy amount of skepticism.

PGx has the potential to serve as a tool to both reduce and understand risks and the effects of cannabis for those currently using, or planning on using the drug. The amount of research yet to be done on cannabis has been hindered by legal barriers between state and federal legislatures preventing further research, which ultimately could impact the adoption and increased utility of PGx testing related to cannabis use. Even with the limited amount of information known about cannabis, it is vital that patients have the ability to make decisions for their own health regarding using cannabis medicinally. In an ideal future, patients could meet with a genetic counselor and discuss the risks and benefits of PGx testing evaluating both standardly reviewed medications as well as being inclusive of cannabis empowering patients to discuss their results with their physician regarding medication changes. Whether or not this future is realized, PGx testing is already acting as a crucial tool in empowering patients to make their own healthcare decisions personalized to their own genetics.

 

Sources:

  1. Borodovsky, Lee, D. C., Crosier, B. S., Gabrielli, J. L., Sargent, J. D., & Budney, A. J. (2017). U.S. cannabis legalization and use of vaping and edible products among youth. Drug and Alcohol Dependence, 177, 299–306. https://doi.org/10.1016/j.drugalcdep.2017.02.017 

  2. Curran HV, Freeman TP, Mokrysz C, Lewis DA, Morgan CJ, Parsons LH. Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci. 2016 May;17(5):293-306. doi: 10.1038/nrn.2016.28. Epub 2016 Apr 7. PMID: 27052382. https://doi.org/10.1038/nrn.2016.28 

  3. Hirota T, Eguchi S, Ieiri I. Impact of genetic polymorphisms in CYP2C9 and CYP2C19 on the pharmacokinetics of clinically used drugs. Drug Metab Pharmacokinet. 2013;28(1):28-37. doi: 10.2133/dmpk.dmpk-12-rv-085. Epub 2012 Nov 20. PMID: 23165865. https://doi.org/10.2133/dmpk.DMPK-12-RV-085 

  4. Hryhorowicz S, Walczak M, Zakerska-Banaszak O, Słomski R, Skrzypczak-Zielińska M. Pharmacogenetics of Cannabinoids. Eur J Drug Metab Pharmacokinet. 2018 Feb;43(1):1-12. PMID: 28534260; PMCID: PMC5794848. https://doi.org/10.1007/s13318-017-0416-z 

  5. Nicholson WT, Formea CM, Matey ET, Wright JA, Giri J, Moyer AM. Considerations When Applying Pharmacogenomics to Your Practice. Mayo Clin Proc. 2021 Jan;96(1):218-230. Epub 2020 Dec 9. PMID: 33308868. https://doi.org/10.1016/j.mayocp.2020.03.011 

  6. Papastergiou J, Li W, Sterling C, van den Bemt B. Pharmacogenetic-guided cannabis usage in the community pharmacy: evaluation of a pilot program. J Cannabis Res. 2020 Sep 1;2(1):24. PMID: 33526106; PMCID: PMC7819344. https://doi.org/10.1186/s42238-020-00033-1 

  7. Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X, Huai C, Shen L, Zhang N, He L, Qin S. Cytochrome P450 Enzymes and Drug Metabolism in Humans. Int J Mol Sci. 2021 Nov 26;22(23):12808. PMID: 34884615; PMCID: PMC8657965 https://doi.org/10.3390/ijms222312808 

  8. Friedman, Daniel, and Joseph I. Sirven. Historical Perspective on the Medical Use of Cannabis for Epilepsy: Ancient Times to the 1980s. Epilepsy & Behavior, vol. 70, no. Pt B, 2017, pp. 298–301, https://doi.org/10.1016/j.yebeh.2016.11.033.

  9. Baron, Eric P. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. Headache, vol. 58, no. 7, 2018, pp. 1139–86, https://doi.org/10.1111/head.13345 

  10. Radhakrishnan, Rajiv, et al. Gone to Pot- A Review of the Association Between Cannabis and Psychosis. Frontiers in Psychiatry, vol. 5, 2014, pp. 54–54, https://doi.org/10.3389/fpsyt.2014.00054 

  11. Centers for Disease Control and Prevention. (2023, March 6). CDC - marijuana legalization in Indian country - publications by topic - public health law. Centers for Disease Control and Prevention. Retrieved April 29, 2023, from https://www.cdc.gov/phlp/publications/topic/resources/resources-marijuana.html

  12. Babayeva M, Loewy ZG. Cannabis Pharmacogenomics: A Path to Personalized Medicine. Curr Issues Mol Biol. 2023 Apr 17;45(4):3479–514. doi: 10.3390/cimb45040228. PMCID: PMC10137111. www.ncbi.nlm.nih.gov/pmc/articles/PMC10137111/#:~:text=CYP2C9.,3%20%5B180%2C181%5D. 

  13. Sharma P, Murthy P, Bharath MM. Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry. 2012 Fall;7(4):149-56. PMID: 23408483; PMCID: PMC3570572 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570572/#:~:text=Most%20of%20the%20cannabis%20

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  15. Substance Abuse and Mental Health Services Administration. (2022). Key substance use and mental health indicators in the United States: Results from the 2021 National Survey on Drug Use and Health (HHS Publication No. PEP22-07-01-005, NSDUH Series H-57). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report

  16. National Conference of State Legislatures. (2023). State Medical Cannabis Laws. https://www.ncsl.org/health/state-medical-cannabis-laws

  17. Kaplan AG. Cannabis and Lung Health: Does the Bad Outweigh the Good? Pulm Ther. 2021 Dec;7(2):395-408. doi: 10.1007/s41030-021-00171-8. Epub 2021 Oct 25. PMID: 34697771; PMCID: PMC8589923. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589923/

 

About the Author:

Austin Eastmure is a class of 2025 genetic counseling student at Columbia University. During his time at Clover Genetics, he specialized in researching and creating resources regarding pharmacogenomics and its relation to drugs such as cannabis. In the future, he hopes to develop novel counseling techniques that can be utilized with pharmacogenomics to help those with addiction issues.