COMT: Slow vs. Fast, Interactions with Supplements

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.Β 

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:

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COMT rs4680, Val158Met variant:Β One of the most 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 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:

Methyl-donor supplements (revving up COMT reactions):

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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.



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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 and also 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.

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