Key takeaways:
~ The COMT enzyme can be slow or fast, depending on your genes.
~ Some people with slow COMT enzyme function have negative reactions to certain supplements.
~ Understanding your COMT SNPs can help you with deciding which supplements may work best for you.
Members will also see their genotype report below, plus additional solutions in the Lifehacks section. Join today.
COMT Gene Polymorphisms, Neurotransmitters, and Supplements:
Have you ever taken a supplement, such as methylfolate or methylB12, and noticed an immediate improvement in your mood? Only to have that rebound on you to the point that you are angry and irritable with everyone around you…
In this article, I’ll explain how some supplements can interact with COMT variants.
The COMT gene encodes an enzyme called catechol-O-methyltransferase, which breaks down catechols.
What are catechols — and why do we need to break them down?
Catechols include neurotransmitters such as dopamine, epinephrine, and norepinephrine. Other catechols include estrogen metabolites as well as drugs and natural substances with a catechol structure.
The COMT enzyme plays an essential role in maintaining neurotransmitter levels at the right amount.
Without the COMT-controlled methylation reaction, catecholamines can accumulate and generate free radicals, which can damage DNA. Thus, COMT is essential in protecting cells, including brain cells, from oxidative stress.[ref]
The methyl in catechol-O-methyltransferase (COMT) is because COMT uses a methyl group in the process of metabolizing catechols. Methyl groups are used in hundreds of reactions in the body, and adding a methyl group can change one substance to another. For example, serotonin is converted into melatonin through a process that involves adding a methyl group.
More on this in a minute…
Before we go any further, check your genotype below to find out whether you have a slow or fast COMT gene (using your 23 and Me, AncestryDNA, or other genetic raw data).
COMT Genotype Report:
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the members’ only information in the Lifehacks sections.
COMT rs4680, Val158Met variant: One of the most studied variants of the COMT gene is rs4680, often referred to as Val158Met.
How common are COMT polymorphisms?
The frequency of the slow or fast variants varies a little, depending on the population group. The G/G (fast) genotype is found in about 29% of Caucasians and about 52% of Chinese Han population groups. The A/A (slow) genotype is found in about 25% of Caucasians and about 10% of Chinese population groups.
Some websites label these variants with a +/+ or -/-. And some sites go so far as to give smiley faces or frowny faces. This can be really confusing, though. Whether slow COMT is ‘good’ or ‘bad’ depends on the context and many other variables.
Related article: Deep dive into COMT and studies on mood, cognitive function, and more.
Symptoms of supplement interactions with COMT:
Now that you know your COMT genotype, let’s get into how this may affect your reaction to different supplements, combinations of supplements, and other medications.
Take all of this information as a ‘heads-up‘ to look for interactions or side effects. This is NOT a “never take this supplement” list, but instead is an explanation of the circumstances that may cause interactions.
Supplements that inhibit COMT:
Some natural flavonoids use COMT for metabolism and can inhibit or slow COMT function for breaking down catecholamines. Natural flavonoids that contain a catechol structure include:[ref][ref][ref]
The COMT enzyme is also used in the metabolism of EGCG. While animal and cell studies show EGCG to be an inhibitor of COMT, studies in humans aren’t as clear. Research does show that people with slow COMT break down EGCG more slowly than people with fast COMT.[ref][ref][ref]
While the word ‘inhibit’ may sound bad, this isn’t always a bad thing… stick with me here for different scenarios in which COMT inhibitors are good or bad.
Scenario #1) Supplements that inhibit COMT function may hang around a bit longer in your system and have more beneficial effects. For example, if you are looking to enhance the beneficial effects of EGCG, research shows that quercetin or fisetin supplements along with EGCG (green tea) increased the bioactive form of EGCG in cells.[ref][ref][ref] This may be most beneficial in people with fast COMT enzyme function.
Scenario #2) In Parkinson’s disease, there is not enough dopamine in certain regions of the brain. COMT inhibitors are used to increase dopamine levels in people who are taking levodopa.[ref] EGCG and quercetin have been tested for this in animal models of Parkinson’s.[ref]
Scenario #3) On the other hand, if you have slow COMT and need to get rid of estrogen in ways that limit cancer risk, then the COMT-inhibiting flavonoids may have negative consequences.[ref][ref]
At what amounts do you need to think about these interactions? Should you stop drinking tea? or eating apples?
Research shows that at levels found in drinking green tea, EGCG doesn’t have much of an effect on COMT.[ref] While apples are high in quercetin, it would take a ton of apples to reach the levels of quercetin that are used in studies to inhibit COMT.
Essentially, high levels found in supplements are needed for COMT interactions to really matter.
Alternative supplement for slow COMT:
It may seem like everything you read suggests taking quercetin, but you decide not to go overboard there with a slow COMT enzyme. Here are some alternatives that are natural anti-inflammatories that don’t interact with COMT.
If you have low COMT function and are looking for natural anti-inflammatory supplements that don’t interact with COMT, consider:
- Berberine
- Resveratrol
- Melatonin
- Hesperidin
Methyl-donor supplements (revving up COMT reactions):
The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.
Member Content:
An active subscription is required to access this content.
Join Here for full access to this article, genotype reports, and much more!
Already a member? Log in below.
Related Articles and Topics:
Lithium Orotate + B12: Boosting mood and decreasing anxiety, for some people…
For some people, low-dose, supplemental lithium orotate is a game-changer for mood issues when combined with vitamin B12. But other people may have little to no response. The difference may be in your genes.
Is inflammation causing your depression or anxiety?
Research over the past two decades clearly shows a causal link between increased inflammatory markers and depression. Genetic variants in the inflammatory-related genes can increase the risk of depression and anxiety.
Histamine Intolerance
Chronic headaches, sinus drainage, itchy hives, problems staying asleep, and heartburn — all of these symptoms can be caused by the body not breaking down histamine very well. Your genetic variants could be causing you to be more sensitive to foods high in histamine. Check your genetic data to see if this could be at the root of your symptoms.
References:
Bodenmann, S., Xu, S., Luhmann, U. F. O., Arand, M., Berger, W., Jung, H. H., & Landolt, H. P. (2009). Pharmacogenetics of modafinil after sleep loss: Catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep. Clinical Pharmacology and Therapeutics, 85(3), 296–304. https://doi.org/10.1038/clpt.2008.222
Branched chain amino acids selectively promote cardiac growth at the end of the awake period. (2021). Journal of Molecular and Cellular Cardiology, 157, 31–44. https://doi.org/10.1016/j.yjmcc.2021.04.005
Chen, J., Lipska, B. K., Halim, N., Ma, Q. D., Matsumoto, M., Melhem, S., Kolachana, B. S., Hyde, T. M., Herman, M. M., Apud, J., Egan, M. F., Kleinman, J. E., & Weinberger, D. R. (2004). Functional analysis of genetic variation in catechol-O-methyltransferase (Comt): Effects on mRNA, protein, and enzyme activity in postmortem human brain. American Journal of Human Genetics, 75(5), 807–821. https://doi.org/10.1086/425589
Chung, J.-O., Lee, S.-B., Jeong, K.-H., Song, J.-H., Kim, S.-K., Joo, K.-M., Jeong, H.-W., Choi, J.-K., Kim, J.-K., Kim, W.-G., Shin, S.-S., & Shim, S.-M. (2018). Quercetin and fisetin enhanced the small intestine cellular uptake and plasma levels of epi-catechins in in vitro and in vivo models. Food & Function, 9(1), 234–242. https://doi.org/10.1039/c7fo01576c
Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats. (2010). Toxicology and Applied Pharmacology, 247(2), 83–90. https://doi.org/10.1016/j.taap.2010.06.011
Hall, K. T., Buring, J. E., Mukamal, K. J., Vinayaga Moorthy, M., Wayne, P. M., Kaptchuk, T. J., Battinelli, E. M., Ridker, P. M., Sesso, H. D., Weinstein, S. J., Albanes, D., Cook, N. R., & Chasman, D. I. (2019). Comt and alpha-tocopherol effects in cancer prevention: Gene-supplement interactions in two randomized clinical trials. JNCI: Journal of the National Cancer Institute, 111(7), 684–694. https://doi.org/10.1093/jnci/djy204
Hall, K. T., Loscalzo, J., & Kaptchuk, T. J. (n.d.-a). Systems pharmacogenomics – gene, disease, drug and placebo interactions: A case study in COMT. Pharmacogenomics, 20(7), 529–551. https://doi.org/10.2217/pgs-2019-0001
Hall, K. T., Loscalzo, J., & Kaptchuk, T. J. (n.d.-b). Systems pharmacogenomics – gene, disease, drug and placebo interactions: A case study in COMT. Pharmacogenomics, 20(7), 529–551. https://doi.org/10.2217/pgs-2019-0001
Hall, K. T., Nelson, C. P., Davis, R. B., Buring, J. E., Kirsch, I., Mittleman, M. A., Loscalzo, J., Samani, N. J., Ridker, P. M., Kaptchuk, T. J., & Chasman, D. I. (2014). Polymorphisms in catechol-o-methyltransferase modify treatment effects of aspirin on risk of cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 34(9), 2160–2167. https://doi.org/10.1161/ATVBAHA.114.303845
Kang, K. S., Yamabe, N., Wen, Y., Fukui, M., & Zhu, B. T. (2013). Beneficial effects of natural phenolics on levodopa methylation and oxidative neurodegeneration. Brain Research, 1497, 1–14. https://doi.org/10.1016/j.brainres.2012.11.043
Miller, R. J., Jackson, K. G., Dadd, T., Nicol, B., Dick, J. L., Mayes, A. E., Brown, A. L., & Minihane, A. M. (2012). A preliminary investigation of the impact of catechol-O-methyltransferase genotype on the absorption and metabolism of green tea catechins. European Journal of Nutrition, 51(1), 47–55. https://doi.org/10.1007/s00394-011-0189-0
Sak, K. (2017a). The Val158Met polymorphism in COMT gene and cancer risk: Role of endogenous and exogenous catechols. Drug Metabolism Reviews, 49(1), 56–83. https://doi.org/10.1080/03602532.2016.1258075
Sak, K. (2017b). The Val158Met polymorphism in COMT gene and cancer risk: Role of endogenous and exogenous catechols. Drug Metabolism Reviews, 49(1), 56–83. https://doi.org/10.1080/03602532.2016.1258075
Sak, K. (2017c). The Val158Met polymorphism in COMT gene and cancer risk: Role of endogenous and exogenous catechols. Drug Metabolism Reviews, 49(1), 56–83. https://doi.org/10.1080/03602532.2016.1258075
Scoditti, E. (2020). Neuroinflammation and neurodegeneration: The promising protective role of the citrus flavanone hesperetin. Nutrients, 12(8). https://doi.org/10.3390/nu12082336
The extra virgin olive oil phenolic oleacein is a dual substrate-inhibitor of catechol-O-methyltransferase. (2019). Food and Chemical Toxicology, 128, 35–45. https://doi.org/10.1016/j.fct.2019.03.049
Wang, L.-J., Lee, S.-Y., Chen, S.-L., Chang, Y.-H., Chen, P. S., Huang, S.-Y., Tzeng, N.-S., Chen, K. C., Lee, I. H., Wang, T.-Y., Yang, Y. K., & Lu, R.-B. (2015). A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with bipolar II disorder. Scientific Reports, 5, 8813. https://doi.org/10.1038/srep08813
Wang, P., Heber, D., & Henning, S. M. (2012). Quercetin increased the antiproliferative activity of green tea polyphenol (−)-epigallocatechin gallate in prostate cancer cells. Nutrition and Cancer, 64(4), 580–587. https://doi.org/10.1080/01635581.2012.661514