COMT and supplement interactions

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…

This article is a quick article explaining how supplements can interact with COMT variants to impact the rate at which neurotransmitters are broken down.

COMT, 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…

Before we go any further, 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.

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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 these variants? 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 green +/+  OR red -/-. This can be really confusing, though. Whether slow COMT is ‘good’ or ‘bad’ depends on the context and many other variables. Read more about 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 or combinations of supplements.

Keep in mind that there are a number of interactions and variables.

Take all of this information as a ‘heads-up’ to look for interactions or side effects. This isn’t a “never take this supplement” list, but instead is an explanation of the circumstances that may cause interactions.

Supplements that inhibit COMT:

Natural flavonoids that contain a catechol structure include:[ref][ref][ref]

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

These natural flavonoids use COMT for metabolism and can inhibit COMT function.[ref] While the word ‘inhibit’ may sound bad, this isn’t always a bad thing… stick with me here for different scenarios.

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.

In Parkinson’s disease, there is not enough dopamine in certain regions of the brain. COMT inhibitors are used to increase dopamine in people who are taking levodopa.[ref] EGCG and quercetin have been tested for this in animal models of Parkinson’s.[ref]

But, if you have slow COMT and needing to get rid of estrogen in ways that limit cancer risk, then the flavonoids may have an unintended consequence.[ref][ref]

At what levels do you need to think about these interactions? Research shows that at levels found in 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 these interactions.

Alternatives: If you have low COMT function and are looking for natural anti-inflammatory supplements that don’t interact with COMT, consider berberine, resveratrol, melatonin, and hesperidin.

Methyl-donor supplements (revving up COMT reactions):

A methyl group is a carbon plus three hydrogens (CH3). This compound is used throughout the body in many ways. Attaching a methyl group to another molecule can change the way a protein functions.

The COMT enzyme needs methyl groups for its reactions. Suddenly increasing methyl donors through high dose supplements can increase COMT reactions.

Some clinicians recommend against taking any methyl donor supplements if you have the slow COMT variant (rs4680 A/A). The reasoning for this is that suddenly adding a bunch of methyl donors can affect mood in people with slow COMT. Messing with neurotransmitter breakdown rates can affect mood – increasing and then decreasing it.

Personal experience shows this to be true: Methyl donor supplements at higher doses may cause irritability, anger, or anxiety in people with slow COMT.

Methyl-donor supplements include:

  • SAMe (s-adenyslmethionine)
  • methyl folate
  • methylcobalamin (methylB12)
  • TMG / betaine

Without good clinical trials on this interaction with methyl donors, the need to limit is something that may be unique to an individual. It may also depend on your MTHFR variants or other genes. Thus, take this as a ‘heads-up’ to watch out for mood swings when increasing your consumption of methyl donor supplements.

What are the alternatives if you have slow COMT?

  • If you are taking supplemental vitamin B12, choose adenosylB12 or hydroxyB12 instead of methylB12.
  • Instead of a high-dose methyl folate supplement, consume more folate and choline in your diet. The RDA for folate is 400 mcg. If you rarely eat folate-containing foods (e.g. dark leafy greens, lentils, liver), then try a low-dose of methyl folate – such as 100 to 200 mcg. Folinic acid may be another alternative.

What if you have a fast COMT enzyme function? A study on depression found that methyl folate worked well for people with fast COMT function (and did not work well for slow COMT).[ref]

What happens if you stack methyl donors with COMT inhibitors?

That is a good question, and I can’t find research studies to definitely answer it.

Logic says that it is like driving a car with one foot on the gas and one on the brakes. You may get along okay for a while with driving that way… But, for someone with low COMT enzyme function, this could cause mood alterations due to rapid changes to neurotransmitter levels.

Magnesium and COMT:

Magnesium is a cofactor in COMT reactions.[ref] If you are low in magnesium, you may want to try a magnesium supplement to normalize COMT.

Vitamin E and COMT:

A 10-year follow-up to a trial on vitamin E (alpha-tocopherol) supplementation showed that the COMT rs4680 variants impacted the risk of cancer. The study showed that people with rs4680 met/met (A/A) who took vitamin E (alpha-tocopherol) had about a 12% reduction in overall cancer rates. On the other hand, people with rs4680 val/val (G/G) had a slight increase in cancer rates. In the middle, with no real effect on cancer rate, were the study participants with rs4680 val/met (A/G).[ref]

Aspirin and COMT:

A study of women who took aspirin or placebo for heart disease prevention found that incidents of cardiovascular disease increased in women with rs4680 val/val (G/G) who took aspirin. The opposite was true for women with the slow COMT variant, and aspirin prevented heart disease compared to placebo.[ref]


Modafinil, a prescription drug for narcolepsy, is also popularly used as a nootropic off-label. Modafinil seems to work by increasing dopaminergic neurotransmission, which depends on COMT. Research shows that those with the COMT Val/Val genotype had a much better response than those with the Met/Met genotype in terms of sustained vigilant attention.[ref]  (Read more about modafinil and COMT)

Related Articles and Topics:

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Is inflammation causing your depression or anxiety?
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Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.