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COMT Gene: Neurotransmitter levels and estrogen metabolism.

Having trouble with supplements containing methyl groups? Wondering why your neurotransmitters are out of balance? It could be due to your COMT genetic variants. COMT is an important enzyme tasked with breaking down neurotransmitters, such as dopamine.

This article explains the COMT enzyme and how to check your genetic data for COMT fast and slow polymorphisms on 23 and Me, AncestryDNA, or similar data.

What does the COMT gene do?

The COMT gene encodes the catechol-O-methyltransferase enzyme, which breaks down (metabolizes) the neurotransmitters dopamine, epinephrine, and norepinephrine. It controls the amount of neurotransmitters available. It is also involved in the metabolism of estrogen metabolites, as well as certain supplements.

Diggin deeper: 
COMT adds a methyl group from SAMe to the dopamine, epinephrine, or norepinephrine molecules. This additional methyl group changes the original molecule into a different substance, which can be eliminated or recycled in the cells.

image showing comt enzyme function converting catecholamines into inactive metabolites

Drug and supplement metabolism:
COMT also breaks down some drugs used for asthma, Parkinson’s, and high blood pressure. It is also involved in metabolizing natural supplements like curcumin and quercetin.

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

Two types of COMT:

There is both a soluble form of the COMT enzyme that is found in cells, and there is a membrane-bound form of COMT that is mainly expressed in the brain.[ref]

COMT Mutation and Altered Neurotransmitter levels

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

Terminology Explainer: The common variants that everyone looks at for COMT are technically polymorphisms (common changes in a gene) instead of mutations (rare changes). You’ll also see it referred to as a SNP, which stands for single nucleotide polymorphism.

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.

Synaptic cleft showing neurotransmitters

Psychiatric or mood disorders and COMT SNPs:

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

  • schizophrenia[ref][ref]
  • depression[ref]
  • anxiety (in some groups)
  • bipolar disorder 

The COMT variants do not cause these disorders alone. They simply add to the susceptibility.

Estrogen dominance and COMT:

COMT is also important outside of the realm of neurotransmitters. Since it also breaks down estrogens, there are differences in the amount of COMT available in the prefrontal cortex between males and females after puberty.[ref][ref]

For example, higher levels of estrogen can decrease COMT, leading to an increase in dopamine in female brains.[ref]

Is the Val158Met SNP “bad”?

One of the well-studied COMT genetic variants is known as Val1158Met or rs4680. This variant affects the speed 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 online about COMT – from Facebook groups to healthcare gurus selling supplements.

Often the information leads you to believe that carrying one of the other COMT rs4860 alleles is really bad! This simply isn’t true. Research shows there are both positive and negative effects of the variant.

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. 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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Methyl Donor Supplements:

Clinicians often suggest that those with the rs4680 A/A genotype (slow COMT) avoid going overboard with foods and supplements 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 specific to this topic: Supplement Interactions and COMT

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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 from Colorado School of Mines 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.