COMT – A gene that affects your neurotransmitter levels

Having trouble with supplements containing methyl groups? Wondering why your neurotransmitters are out of balance? It could be due to your COMT genetic variants.

What does the COMT gene do?

The COMT gene codes for the enzyme catechol-O-methyltransferase which breaks down (metabolizes) the neurotransmitters dopamine, epinephrine, and norepinephrine. This enzyme adds a methyl group from SAMe to the dopamine, epinephrine, or norepinephrine molecules, thus changing them into a different substance.

COMT also breaks down some drugs used for asthma, Parkinson’s, and high blood pressure.

Researchers link COMT genetic variants to quite a variety of different diseases from mood disorders to heart disease. This variety is due to the COMT variants metabolizing neurotransmitters at different rates.

Some of the psychiatric disorder with increased risk associated with COMT variants include:

  • schizophrenia,
  • depression,
  • anxiety,
  • bipolar disorder

Outside of the brain, COMT also breaks down estrogens.[ref][ref]  This leads to differences in the amount of the COMT available in the prefrontal cortex between males and females after puberty.

Estrogens can inhibit COMT, leading to an increase in dopamine in female brains. [ref]

What is the Val158Met polymorphism?

One of the most well studied genetic variants, the COMT Val1158Met polymorphism controls the rate at which the enzyme function. Also know as COMT rs4680, the A/A or Met/Met variant is found in almost 20% of the population. The slightly more common G/G or Val/Val variant is found in 35-40% of the population.

There are various health websites and Facebook groups dedicated to the negative effects of being ++ or — for this variant.  In general being ++ indicates having the slower Met/Met version, but double check with whatever report format you are looking at to make sure that is the case.

Instead of focusing on any perceived negative effects, I suggest looking at the various interactions between your genotype and diet/supplements/environment and using the information to optimize for your genes. There are positive and negative aspects to most genetic variants, and COMT is no exception.

COMT Genetic Variants:

COMT rs4680, Val158Met

One of the most studied variants of the COMT gene is rs4680, often referred to as Val158Met.  In looking at research studies, the G is “Val” and the A allele is usually noted as “Met”.

  • The G allele (Val) has higher COMT enzymatic activity, causing a more rapid breakdown of the neurotransmitters and thus lower levels of dopamine. In most populations, the G allele is the most common.[ref]
  • The A allele (Met) has lower COMT enzyme activity and thus higher levels of dopamine.  This variant of the COMT enzyme is said to have lower activity because it breaks down faster at normal body temperature.[ref]

Check your genetic data for rs4680 (23andMe v.4 and v.5):

  • G/G: higher COMT activity, lower dopamine & norepinephrine, higher pain tolerance (Val)
  • A/G: intermediate COMT activity
  • A/A: 40% lower COMT activity, higher dopamine & norepinephrine, lower pain tolerance (Met)
Here are the findings from a few recent studies on this COMT variant:
  • A 2015 study of cognitively normal adults found that those with G/G genotype had lower Neuroticism scores and higher Agreeableness and Conscientiousness scores than those with A/G or A/A.[ref]
  • A 2015 study of self-administered morphine in 973 patients following surgery found that the minor (A) allele was associated with more morphine use.  This result backs up the many other studies showing that those with rs4680 A/A often have a lower pain tolerance than those with rs4680 G/G.[ref]
  • A study of adolescent cannabis users found that those with the G/G genotype (Val) were more likely to develop schizophrenia than those with the A/A genotype. (The risk is still small.)[ref]
  • A 2015 study of approximately 800 young adults looked at the combined effects of gender and COMT polymorphisms on schizophrenia and psychosis proneness traits.  Males carrying the G allele scored higher on the negative symptoms and traits of schizophrenia and psychosis. [ref]
  • A small 2014 study looked at the differences in fat oxidation and energy expenditure with green tea based on COMT genotype.  Those with the rs4680 G/G genotype had significantly increased energy expenditure and fat oxidation with green tea, while those with the A/A genotype had no increase. [ref]
  • Lots of other studies are listed on SNPedia including several that look at the response to antidepressants.  There are hundreds of studies in PubMed on this COMT polymorphism.

COMT rs4633

This common variant also changes the activity level of COMT. T is the less common version with lower COMT enzyme activity; C is the more common version with higher activity.

Check your genetic data for rs4633 (23andMe v4, v5):

  • C/C: higher COMT activity, lower dopamine, norepinephrine
  • C/T:  medium COMT activity
  • T/T: lower COMT activity, higher dopamine, norepinephrine

Recent studies on this variant have found:

  • Rs4633 T/T is associated with less back pain with lower back disc degeneration [ref] [ref]
  • A study of mercury exposure in children found that boys with the T/T genotype had impaired test performance in response to increasing acute mercury exposure.  This was in contrast to girls with the variant who showed fewer effects from acute mercury exposure. [ref]
  • A study of atherosclerosis in an elderly Japanese population found that the C/C genotype was associated with atherosclerosis, especially in women.  [ref]
  • A study found that those with T/T had a higher risk of endometrial cancer.  [ref]

Other COMT Polymorphisms:

A couple of COMT variants add to the effect of the main variants listed above.

Check your genetic data for rs6267 (23andMe v.4 and v.5):

  • G/G: normal
  • G/T: risk of higher pain sensitivity [ref] and more pain in Parkinson’s[ref]
  • T/T: risk of higher pain sensitivity[ref] and more pain in Parkinson’s[ref]

Check your genetic data for rs165599 (23andMe v.4 and v.5):

  • A/A: increased risk of anxiety, schizophrenia, especially in females and  in combination with rs4680 A/A[ref] [ref][ref]
  • A/G: increased risk of anxiety, schizophrenia[ref] [ref][ref]
  • G/G: normal


Clinicians often suggest that those with the rs4680 A/A genotype (lower COMT levels) avoid going overboard with foods and supplements that are considered methyl donors. Methyl donors include methylcobalamin (methyl-B12), curcumin, TMG, SAMe, theanine, and choline. [ref]  The logic behind this suggestion is that overwhelming the pathway with too many methyl groups can lead to a sudden rise and then subsequent fall in dopamine levels — aka mood swings, anger, or anxiety.

Which type of B12?
Instead of supplementing with methyl-B12, people with rs4680 A/A genotype may want to try hydroxocobalamin or adenosylcobalamin.

Diet and Supplements:
The COMT enzyme breaks down supplements that have a catechol structure. This includes quercetin, EGCG, and luteolin [ref][ref]. If you have lower COMT enzyme activity, you may want to be careful of stacking too many supplements metabolized by COMT together at the same time.

A study in mice found that COMT deficiency led to glucose intolerance on a high-fat diet. Keeping in mind that this is just a mouse study, if you have blood sugar regulation issues and have COMT rs4680 A/A, you may want to look at the amount of fat in your diet.

Magnesium is a cofactor for the COMT enzyme. A study found positive effects for liver COMT levels along with better heart health from supplementing with magnesium. A good quality magnesium supplement may be worth trying if you aren’t getting enough magnesium from food sources.

More to read:

Updated 7/2019


Enjoying Genetic Lifehacks? Thank a patron!
These articles are supported by patrons on Patreon. Please consider joining as a patron

Wishing that you had an easy way to know which Genetic Lifehacks articles apply to you? Get a Genetic Lifehacks Ultimate Cheat Sheet that matches your data to all of the articles available.

Genetic Lifehacks Weekly Update

* indicates required

10 Comments on “COMT – A gene that affects your neurotransmitter levels

  1. Another great post!
    Could you link me to more information regarding rs4680 AA and methyl donor interaction?
    Polymorphisms in rs1805087 and rs1801394 would recommend following a diet high in folate… So what’s the best approach?

    Thanks again :)

  2. I have homo MTHFR A1298c mutation which I read says I should take methylfolate and methylb12, however since I also have MTRR, CBS, and COMT rs4680 AA mutations, this article says I should should take hydroxocobalamin or adenosylcobalamin to avoid overwhelming the COMT pathway but Is that recommended for someone with a MTHFR mutation? if so, great! What options do I have in place of methylfolate? I currently have low gluthione, methionine, tyrosine, melatonin and high uric acid /purines/homocysteine. Trying to wrap my head around what I should take :) Thanks for the help! Great site btw!

    • Hi Heather,
      I’m not a doctor and don’t feel that I should tell you which supplement to take. Instead, let me explain my experience (myself and others): people with the COMT rs4680 AA variant often get mood swings – irritable, angry, anxious – when stacking methylfolate with methylcobalamin. Both methylfolate and cobalamin are needed in the methylation cycle, but you can get the cobalamin from hydroxy- or adenosylcobalamin. For people without the rs4680 AA variant, methylcobalamin is usually the starting point because it is less expensive, easier to find, and works well.

      Let me throw a couple of other ideas at your list of things to investigate:
      – There are several studies that show vitamin B6 is important along with folate and B12 to lower homocysteine.
      – Choline is another way to support the methylation cycle without adding methyl donors.
      – Wearing blue blocking glasses for two hours before bed can raise melatonin levels by 50% after one week.

      Hope this helps. Thanks for reading!

  3. Due to my borderline low B12 level, I’m being prescribed B12 injections by the Naturopath. I am also have muscle/nerve type issues that might be a result of my level (still uncertain). I hope this won’t be bad for me, as I don’t think injections come in anything but methylcobalamin?

    • Hi Amy,
      I think hydroxycobalamin is available most places as an injectable form of B12. If you react poorly to the methylcobalamin, it would definitely be something to check into.
      Thanks for reading and commenting.

  4. This article talks about rs4680 but i dont see any specific SNPs in my 23andme data with just that short identifier, but there are about 80 of them with an additional 3 numbers on the end. (i.e. rs4680123) I’m wondering which specific one i’m supposed to be looking for here with this, or if i’ve missed something.

    • Hi Matt,
      It really should be in your 23andMe data.
      If you log into 23andMe and go to the “Browse Raw Data” section under your profile, you can put the rs id number in there.
      If you are just doing a ‘find’ on the .txt file, I’m not sure how to discriminate between the 80 different SNPs that start with rs4680… But if you import the .txt file into Excel and then go to Edit, Find> you should have the option to “find whole cell only”. Checking that will bring up just rs4680 and not all of the rest.

  5. Is there any additional information on the A/G variant and supplementation? I’m not sure what I need. Thanks for a great article!

    • Hi Broc,
      For rs4680, the A/G variant is the intermediate enzyme activity — not too fast and not too slow. It is actually the most common genotype for most population groups.
      I don’t think it should affect you much when it comes to supplements that contain methyl groups. Everyone is unique, of course, but for most with the intermediate enzyme activity, supplementing with a normal amount of methyl groups isn’t going to have much of an effect. (Does that answer your question? )

  6. I have 2 COMT genes that cause lower dopamine and norepinephrine. I wonder if they can be one of the genes that can also cause Inattentive ADD? I also have a gene from your site that’s relevant to girls with ADHD and lower asthma risk.

    rs4633 CC
    rs4680 GG

Leave a Reply

Your email address will not be published. Required fields are marked *