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COMT: How to Optimize Your Supplements for Your COMT Genotype

Key takeaways:
~ The COMT enzyme can be slow or fast, depending on your genes.
~ Some people with slow COMT enzyme function have side effects from methylated vitamins (methylfolate, methylB12), methyl donor supplements, and COMT inhibitor 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 Genetics: SNPs, 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 (COMT slow and fast SNPs).

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]

COMT also is important in converting estrogen metabolites into forms that can easily be excreted by the body. [ref]

How does COMT relate to methylation?

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.

Side effects of methylated vitamins with slow COMT:

Everyone is unique, and genetics can play a big role in your response to natural supplements or dietary changes.

People with slow COMT enzyme variants may find that supplements that affect the methylation cycle can affect their neurotransmitter levels.

For example, a sudden influx of methyl groups from high doses of methyl donor supplements may increase and then decrease the pool of methyl groups available for COMT to use in neurotransmitter reactions.

A quick cycling of neurotransmitter levels may make someone irritable, angry, or anxious.

For example, some people with slow COMT function initially feel great when taking supplemental methylfolate, but then they may notice later in the day that they are more irritable and anxious than normal. Or, their friends and family may notice their irritability and mood swings.

COMT also interacts with the perception of pain through neurotransmitter levels. Research shows that there can be interactions between slow COMT and medications in pain management.[ref] Adding methyl donor supplements to the stack may cause fluctuations in how well pain medications work.

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:

Members: Log in to see your data below.
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.

 

🖨 Printable Overview (Members)

COMT rs4680, Val158Met variant: One of the most well-studied variants of the COMT gene is rs4680, often referred to as Val158Met.

Check your genetic data for rs4680 Val158Met (23andMe v4, v5; AncestryDNA):

  • G/G: Val/Val – fast (higher) COMT activity[ref]
  • A/G: Val/Met – intermediate COMT activity (most common genotype in Caucasians)
  • A/A: Met/Met – slow (40% lower COMT activity) [ref]

Members: Your genotype for rs4680 is .

 

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 use smiley faces, which is really confusing. Whether slower COMT is ‘good’ or ‘bad’ depends on the context. There are benefits and drawbacks to both slow and fast COMT enzyme function.

Related article: Deep dive into COMT and studies on mood, cognitive function, and more.


COMT and supplement sensitivity: Methylated vitamin side effects

Now that you know your COMT genotype, let’s go 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:

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Related Articles and Topics:

COMT in Pain Disorders

 

Lithium Orotate and Vitamin B12: Benefits for Mood and Cognitive Support

 


 

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

 


About the Author:
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 from Colorado School of Mines 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.