COMT – Altering 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. This important enzyme is tasked with breaking down neurotransmitters, such as dopamine.

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 controls the amount of neurotransmitters available.

Getting Specific: The COMT enzyme adds a methyl group from SAMe to the dopamine, epinephrine, or norepinephrine molecules. This changes the original molecule into a different substance so that the body can then get rid of it.

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

Estrogen: Additionally, COMT is important in the phase II metabolism of estrogens. It converts estrogen metabolites into forms that can be excreted easily.

COMT and Altered Neurotransmitter levels

There are several common genetic variants in the COMT gene that alter how the enzyme functions. Some variants increase the speed at which the enzyme metabolizes neurotransmitters, and other variants can slow down the enzyme.

The COMT enzyme is active in the prefrontal cortex, which is the brain region involved in planning, complex behaviors, and personality.

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

Psychiatric disorders and COMT:

Some of the psychiatric disorders with increased risk associated with COMT variants include schizophrenia[ref][ref], depression[ref], anxiety, and bipolar disorder.  Keep in mind, though, that the COMT variant doesn’t cause these disorders – it just adds to the susceptibility.

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]

Is the Val158Met SNP “bad”?

One of the most studied COMT genetic variants is known as Val1158Met or rs4680. This variant affects the rate at which the enzyme functions.

Also, known 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 occurs in 35-40% of the population.[ref]

There is a lot written on the internet about COMT – from Facebook groups to clinicians making videos on the topic.

Often the information leads you to believe that carrying one of the other of the COMT rs4860 alleles is really bad…  This isn’t true. Research shows there are both positive and negative effects of the variant. So instead of one allele being bad and one being good (red or green, plus or minus), studies show these common variants just add to our uniqueness.

Instead of focusing on bad vs good, I suggest looking at the various interactions between your genotype and supplements or lifestyle factors. Use your genetic information to optimize your health – mental and physical.

COMT Genotype Report

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COMT rs4680, Val158Met

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

  • G/G: higher COMT activity (often called fast COMT or Val/Val)
  • A/G: intermediate COMT activity (most common genotype)
  • A/A: 40% lower COMT activity (often called slow COMT or Met/Met)

Members: Your genotype for rs4680 is .

One of the most well-studied variants of the COMT gene is rs4680, often called Val158Met.  In looking at research studies, the G is “Val” and the A allele is “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]

Here are the findings from some studies on this COMT variant:

  • People with the A/A genotype (met/met) have shown to get more pleasure out of pleasant events.[ref]
  • A study of 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 study of self-administered morphine in 973 patients following surgery found that the A allele was associated with higher 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 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 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]
  • High activity COMT (rs4680 G/G) combined with MTHFR C677T T/T genotype is linked to high homocysteine levels.[ref]

COMT rs4633

This common genetic variant also changes the activity level of COMT.  The T allele is the less common version, with lower COMT enzyme activity; C is the more common version with higher activity. It is often found together with rs4680 in Caucasians.[ref]

Check your genetic data for rs4633 H62H (23andMe v4, v5; AncestryDNA):

  • C/C: higher (fast) COMT activity
  • C/T:  medium COMT activity
  • T/T: lower (slow) COMT activity

Members: Your genotype for rs4633 is .

Recent studies on this variant have found:

  • Rs4633 T/T is associated with less back pain with lower back disk 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 older Japanese population found the C/C genotype was associated with increased risk of 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 more COMT variants can add to the effect of the main variants listed above.

Check your genetic data for rs6267 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • G/T: risk of higher pain sensitivity[ref][ref]
  • T/T: risk of higher pain sensitivity[ref][ref]

Members: Your genotype for rs6267 is .

Check your genetic data for rs165599 (23andMe v4, v5)

  • 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: typical

Members: Your genotype for rs165599 is .


Methyl-donor supplements:

Clinicians often suggest that those with the rs4680 A/A genotype (slow COMT) avoid going overboard with foods and supplements that are considered methyl donors. Methyl donors include methylcobalamin (methyl-B12), 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 subsequent fall in dopamine levels — causing mood swings, anger, or anxiety.

Related article: Supplement interactions and COMT

Which type of B12 for slow COMT?

Instead of supplementing with methyl-B12, people with rs4680 A/A genotype may want to try hydroxocobalamin or adenosylcobalamin. These types of B12 don’t contain a methyl group and are thus less likely to cause problems for people sensitive to methyl donor supplements.

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Originally published 7/2015. Updated 1/2020.


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.