What is the COMT gene mutation?

Catechol-O-methyltransferase (COMT) is an enzyme that helps deactivate catecholamine neurotransmitters, which include dopamine, epinephrine, and norepinephrine. These neurotransmitters are involved in mood, focus, and stress responses. COMT adds a small chemical group (called a methyl group) to them, which assists in clearing them from the body.

This process is necessary for maintaining appropriate levels of these neurotransmitters in the brain, particularly in the prefrontal cortex, which is responsible for organizing and coordinating information.

The COMT enzyme also helps the body process some medications used to treat conditions like high blood pressure, asthma, and Parkinson’s disease.

There are two types of COMT enzymes in the body: one that floats freely inside cells (soluble COMT) and one that is attached to cell membranes (membrane-bound COMT). These two types are slightly different because they are made in different ways from the same gene.

A mutation on the COMT gene can affect the production and function of the COMT enzyme. People with a COMT mutation may have higher or lower levels of certain neurotransmitters and hormones, depending on the location (amino acid 158) on the COMT gene where the Valine (Val) can be swapped for Methionine (Met). Either variant (known as an allele) can potentially increase the risk of various health issues. Most studies to date have focused on common SNPs, such as rs4680 (also known as Val158Met), rs4633, rs4818, and rs6269, which have been shown to influence COMT enzyme activity and are associated with certain traits, including pain sensitivity and risk of certain health conditions.¹

Common COMT V158M (rs4680) genotypes and what they mean:²

GG genotype (Val/Val)

• High COMT enzyme activity
• Faster breakdown of dopamine (especially in the prefrontal cortex)
• Lower baseline dopamine levels
• Often linked to slightly poorer working memory and potentially higher stress resilience in some situations

AG genotype (Val/Met)

• Intermediate COMT activity
• Moderate dopamine breakdown and levels
  
  

AA genotype (Met/Met)

• Low COMT activity
• Slower breakdown of dopamine = higher baseline dopamine levels
• Sometimes linked to better working memory, but also higher anxiety or stress sensitivity in some studies

Note: Many genetics test results use:

+/+ to mean homozygous for the variant allele (AA, Met/Met)

 –/– to mean homozygous for the reference allele (GG, Val/Val)

+/– to mean heterozygous (AG, Val/Met)

The variant allele (often referred to as the mutation) in this SNP is A (Met), and the reference allele (sometimes called wild type or normal) is G (Val).

Example:

People with the Met form have three to four times less COMT activity than those with the Val version.³ Less COMT activity means that dopamine and norepinephrine remain in the brain for longer, which can increase sensitivity to pain and also the tendency for substance abuse. This COMT gene variant (also referred to as Met/Met, AA, or +/+) is also associated with HPA axis dysfunction and higher levels of cortisol, which can increase susceptibility to stress.⁴

Genetic testing for a COMT mutation can be done through a lab or with a home testing kit. 

A home kit usually involves providing a sample of bodily fluids from a cheek swab or saliva and sending it to be processed. A lab may require a blood test.

The sample will then be analyzed for variations in the COMT gene. Your results will usually be available online and may also include some information for interpreting the findings. Professional guidance is recommended.

Sex differences

COMT enzyme activity differs between men and women. COMT is involved in dopamine regulation and is implicated in cognitive function and psychiatric conditions.

Women with the Met allele may have increased sensitivity to catecholamines, which may influence mood regulation and increase risk of developing anxiety or depression, particularly during perimenopause, when significant hormonal fluctuations occur.⁵

Mood disorders

COMT helps to regulate catecholamine levels in the brain, and the Val/Val variant has been linked to mood disorders such as depression and anxiety in both adolescents and adults.⁶

One study found that COMT Val/Val was linked to symptoms of depression in young children but not with ADHD.⁷

The Val/Val genotype has also been linked to higher risk of schizophrenia.⁸ People with this variant may also respond less effectively to antipsychotic treatment.⁹

Pain sensitivity

People with Met/Met (AA) have lower COMT activity, which means they may have higher dopamine/norepinephrine levels and are more sensitive to pain. It also means they may be more responsive to pain modulation, such as treatment with morphine. People with Val/Val have lower pain sensitivity, but are less responsive to morphine because their lower dopamine/norepinephrine levels result in weaker engagement of certain pain control pathways.
One study found that cancer patients with Met/Met were most pain sensitive but responded to lower morphine doses, while patients who were Val/Val were least pain sensitive yet needed more morphine to achieve pain relief.¹⁰

Addiction

Some studies suggest certain COMT variants may influence how likely someone is to use or depend on substances like cannabis or alcohol. The dopamine system plays a role in substance use, which often begins in adolescence. Young people with the Val/Val or Val/Met genotype were found to be more likely to use substances.¹¹
Another study found that the Val/Met variant was significantly associated with nicotine dependence more so than the other variants.¹²

Estrogen-related health issues

COMT is required for inactivating catechol estrogen that can be harmful to the body. Women with a more active version of CYP1B1 (which makes more 4-OH estrogens) and a less active version of COMT (which clears estrogens more slowly) could be at higher risk of developing breast cancer, especially when other risk factors like age or hormone levels are also involved.¹³

A study based in Asia concluded that women with the Met/Met genotype have reduced COMT enzyme activity and a higher risk of breast cancer.¹⁴

Treating a COMT variant depends on your genotype. Reduced COMT activity means neurotransmitters aren’t efficiently broken down, so treatment with antidepressants, folate, and/or methylated nutrients may lead to excessive neurotransmitter levels, potentially causing adverse effects such as anxiety, agitation, insomnia, or depression.¹⁵

One study found that people with decreased COMT function who received L-methylfolate supplementation experienced decreased neurotransmitter catabolism, which could have negative effects.¹⁶ Ultimately, MTHFR status may not be sufficient to determine appropriate treatment. Treatment should always be individualized and supervised

SAM-e

S-Adenosyl-Methionine (SAM-e) functions as a major methyl group donor for several metabolic processes. SAM-e can increase COMT enzyme activity, which may be beneficial for those with low-functioning COMT variants. One small study found that SAM-e supplementation in people with chronic schizophrenia and low COMT function resulted in reduced aggression and improved quality of life.¹⁷

Methyl donors

L-methylfolate, methylcobalamin, and SAM-e can potentially increase catecholamine levels by enhancing neurotransmitter synthesis. This may be beneficial for people with low neurotransmitter activity due to high COMT function. However, those with low COMT function may experience overstimulation due to excess methyl donors, potentially causing anxiety, irritability, and insomnia.

Understanding your COMT SNPs can help you decide which supplements may work best for you.

• MTHFR is an enzyme involved in folate metabolism. It catalyzes the conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, the biologically active form of folate. This is required for converting homocysteine into methionine, which is then used to generate S-adenosylmethionine (SAM)—a universal methyl group donor critical for DNA methylation, neurotransmitter synthesis, and other biochemical reactions.
  Common variants C677T and A1298C can reduce MTHFR activity, which may result in elevated homocysteine levels and disrupted methylation processes.
• COMT is an enzyme that breaks down catechol-containing compounds such as dopamine, norepinephrine, and epinephrine. It does this by transferring a methyl group (from SAM) to these neurotransmitters via the methylation process. This is required to regulate levels of key neurotransmitters that influence cognition, mood, and stress response.
  The most studied COMT variant is Val158Met (rs4680). The Met form leads to a slower enzyme, resulting in higher dopamine levels; the Val form is faster, leading to lower dopamine.

In short:

MTHFR is an ‘upstream’ process. It produces methyl groups required for numerous biochemical processes, including the synthesis of neurotransmitters such as dopamine, norepinephrine, and serotonin. Variants that reduce MTHFR activity can lower the availability of methyl groups required for neurotransmitter production, homocysteine metabolism, and many other processes.

COMT is a ‘downstream’ process. It involves using methyl groups to inactivate and break down neurotransmitters - mainly dopamine, norepinephrine, and epinephrine. COMT activity varies by genotype: fast COMT (Val/Val) breaks down dopamine more rapidly when methyl groups are adequate, which can lead to lower levels of dopamine. Slow COMT (Met/Met) breaks dopamine more slowly, which can lead to higher levels.

When fewer methyl groups are available due to a MTHFR mutation, COMT’s ability to process neurotransmitters is also reduced. 

A combination of significantly reduced MTHFR enzyme activity with slow COMT can lead to consistently high dopamine levels, while significantly reduced MTHFR with fast COMT may still lower dopamine but also impair efficient neurotransmitter clearance. Both of these situations can affect mood, cognitive function, the stress response, and pain sensitivity.