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):

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, and increasing methyl donors through high dose supplements can increase COMT reactions.

BUT… Some clinicians recommend against taking any methyl donor supplements for slow COMT (rs4680 A/A).

The reasoning for this is that suddenly adding a bunch of methyl donors may 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.  Anecdotal for sure, but it is worth watching out for these types of reactions if you have the slow COMT variant.

Methyl-donor supplements include:

  • SAMe (s-adenosylmethionine)
  • methylfolate
  • methylcobalamin (methylB12)
  • TMG / betaine

Without good clinical trials on this interaction with methyl donors, the need to limit this 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 plan to take supplemental vitamin B12, instead of methylB12, look for

  • adenosylB12 (adenosylcobalamin)
  • hydroxyB12 (hydroxocobalamin)
  • combination of adenosyl and hydroxyB12

Instead of a high-dose methyl folate supplement,  try this:

  • Consume more folate  in your diet (RDA 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.
  • Increase the amount of choline-rich foods to ensure that you meet your daily choline needs.

What if you have a fast COMT enzyme function?

Methyl donors may be used up more quickly in people with fast COMT. Depending on your situation, adding in methyl donors may be a good thing.

  • 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]
  • MethylB12 is a good source if you are planning to supplement with vitamin B12.

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 (A/A – slow) who took vitamin E (alpha-tocopherol) had about a 12% reduction in overall cancer rates. On the other hand, people with rs4680 (G/G – fast) 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:

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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