Have you ever taken a supplement, such as methyl folate 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. Members will also see their genotype report below, plus additional solutions in the Lifehacks section. Join today.
COMT gene, neurotransmitters, and supplements:
The COMT gene encodes an enzyme called catechol-O-methyltransferase which breaks down catechols.
So, 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, the 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.
More on this in a minute…
COMT Genotype Report
Before we go any further, let’s make this information more specific to your genes….
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.
Check your genetic data to see if you carry the fast, intermediate, or slow COMT variant:
COMT rs4680, Val158Met variant: One of the most studied variants of the COMT gene is rs4680, often referred to as Val158Met.
How common are the COMT variants?
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.
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:
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]
At what amounts do you need to think about these interactions? Should you stop drinking tea?
Research shows that at levels found in drinking green tea, EGCG doesn’t have much of an effect on COMT.[ref] Apples are high in quercetin, but it would take a whole lot 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 the COMT interactions to really matter.
Alternative supplement for slow COMT:
It may seem like everything you read suggests taking quercetin, but you may not want 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:
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.
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.
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.
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
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.