COMT: Interactions with Supplements

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 to check your COMT gene and why some supplements can interact with COMT variants.

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…

Check your COMT gene:

Before we go any further, let’s make this information more specific to your genes….

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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.

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

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

Members: Your genotype for rs4680 is .


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:

Some natural flavonoids use COMT for metabolism and can inhibit COMT function.[ref] Natural flavonoids that contain a catechol structure include:[ref][ref][ref]

  • EGCG (from green tea)
  • quercetin
  • fisetin
  • luteolin
  • rutin
  • oleacein (olive oil polyphenol)

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?
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):

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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 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.