The COMT polymorphism

This is a thoroughly researched gene.

One polymorphism, in particular, has been extensively researched in association with various mental and emotional conditions.

This article explains the basics and summarises the research.

Which polymorphisms are we talking about?

Genetic Genie reports on the following polymorphisms:

COMT V158M   rs4680  (also called Val/Met and Met/Met) 

COMT H62H  rs4633

COMT P199P  rs769224

There are some other variants too. There is a severe variation in this gene (and other genes) called 22q11.2 deletion syndrome, which is associated with a wide range of physical and mental conditions including schizophrenia, bipolar disorder, depression and anxiety. This well-documented genetic disease is not covered in this article.

Definition

COMT is the name of the gene which codes instructions for making an enzyme called catechol-O-methyltransferase.

The COMT gene in brain cells makes a long version of this enzyme, called membrane-bound catechol-O-methyltransferase (MB-COMT), which helps break down neurotransmitters. Neurotransmitters are chemicals that conduct signals from one nerve cell to the next. Everything your brain does is controlled by these.

The COMT gene in the cells of your liver, kidneys, blood and some other organs produces a short form of the enzyme, called soluble catechol-O-methyltransferase (S-COMT). This regulates the levels of certain hormones around your body, most notably estrogens.

This is an actual cartoon type picture of catechol O methyltransferase, from Wikipedia.

 

What does this do normally?

Catechol-o-methyltransferase breaks down certain neurotransmitters and catecholamines, including dopamine, epinephrine (=adrenaline) and norepinephrine (=noradrenaline).

Yeah, ANGRY!

The work of Catechol-o-methyltransferase is particularly important in the prefrontal cortex. This part of the brain co-ordinates and decides what to do with information from all the other parts of the brain, and makes particularly heavy use of neurotransmitters. This is where you make plans, process your emotions, and decide what to do, and what NOT to do. It is where you hold information – like the information you are reading right now – in your short term memory, so you can analyse it, assess how it relates to you, and decide how to use it. You could say this part of the brain is where your personality resides. For it to work as it should, it needs exactly the right level of each neurotransmitter.

Normally these neurotransmitters are balanced.

1. Adrenaline causes a rush of excitement and stimulation to deal with a crisis, known as the “fight or flight” response. At normal levels, it maintains correct breathing and mental alertness.
   Low adrenaline levels may be a cause of brain fog.
   This is made in your adrenal glands, mainly out of the amino acid tyrosine. Adrenaline causes your lungs to dilate.
2. Noradrenaline speeds up your heart beat and keeps you vigilantly alert, which means you are more likely to notice all the little details of what is going on around you. It makes you better at making snappy, quick decisions. Most of the symptoms we are describing when we talk about an “adrenaline rush” are actually caused by noradrenaline. At normal levels, noradrenaline plays a part in keeping blood pressure high enough and maintains a normal level of mental alertness and brain activity.
   Low noradrenaline levels may be a cause of brain fog.
   This is made in your adrenal glands, mainly out of the amino acid tyrosine. Noradrenaline takes glucose out of storage to give you an energy boost and, by increasing blood flow, it carries extra oxygen to your brain. People with too much adrenaline and not enough noradrenalie to work with it are at high risk of heart attack. Giving yourself a sugar rush can significantly increase your noradrenaline levels but non-carbohydrate foods cannot. Absolute fasting, for up to 4 days, will also cause you to have somewhat higher levels or noradrenaline.
3. Dopamine, on the other hand, brings about the relaxed, warm fussy feeling people enjoy after a good, hard session of exercise: the word “dopamine” is derived from the same linguistic root as “dopey”. Dopamine motivates you to put an effort into activities which will bring about a reward, as the reward triggers the production of dopamine.
   Your body makes dopamine out of adrenaline and noradrenaline. Dopamine has to be made inside the brain for it to work there – it cannot enter the brain from the blood stream.

 

Adrenaline now… the dopamine comes afterwards!

Dopamine plays important roles around the body, though still a lot is unknown.

• It controls the dilation and contraction of blood vessels and hence blood pressure. It regulates the immune system, especially deactivating white blood cells called lymphocytes, and it may be associated with certain autoimmune diseases.
• When dopamine receptors in a certain part of the brain are heavily stimulated, the result is nausea. People with constantly high dopamine are likely to experience frequent nausea.
• The kidneys are full of dopamine receptors and dopamine stimulates the excretion of sodium in the urine: people with abnormally high dopamine levels may need extra salt to keep their blood pressure high enough.
• Dopamine maintains the right amount of fluid in the cells throughout the body by regulating the balance between potassium and sodium. This is essential for muscular strength and physical energy. If your fingertips looks wrinkled when you have not been soaking in the bath, your potassium-sodium balance is probably wrong.
• The pancreas produces dopamine which, it is believed, ends up on the intestine, It is thought that it slows the speed at which food moves through the intestine. It may also protect the intestinal lining. It is also thought that dopamine reduces the amount of insulin that is produced – there is some kind of balancing relationship between the two substances.
• Dopamine plays a role in controlling physical movement as well as emotions. Parkinsons Disease is associated with a loss of dopamine production in the brain.
• Hyperactivity and restless leg syndrome are associated with low dopamine production.
• Schizophrenia is associated with excessively high dopamine production.
• The membrane which wraps up the intestine makes an enzyme called Sulfotransferase 1A3/1A4 which sulfates dopamine in the intestine. It is then excreted in the urine.

The full list of substances that catechol-o-methyltransferase works upon is:

• catechol estrogens (e.g., carcinogenic 4-hydroxyestradiol),
• indolic intermediates in melanin metabolism,
• xenobiotic catechols (e.g., carcinogenic flavonoids),
• catechol neurotransmitters (e.g., dopamine and noradrenaline), and
• drugs (e.g., levodopa)

COMT is believed to play an important role in the development of human disorders including estrogen-induced cancers, Parkinson’s disease, depression, and high blood pressure.

What do these polymorphisms cause?

People with the COMT polymorphisms listed above may be slower than average at breaking down the neurotransmitters dopamine, adrenalie and noradrenaline.

Imagine a child at school with a COMT polymorphism which makes him slow at clearing these substances out. He is full of dopamine, so he has immense difficulty concentrating and he appears to be making no effort. His teacher tells him off, frightening him and provoking a major adrenaline rush. Now the child is full of both adrenaline and noradrenaline, yet still full of dopamine too. He feels tired but wired, both at once. Having high levels of these catecholamines can cause tachcardia and high blood pressure.

The commonest symptom of both children and adults with this problem is mood swings and extreme irritability, according to Amy Yasko and James Roberts (more below).

Research

Researchers have looked extensively at the potential connection between changes in the COMT gene and the risk of developing schizophrenia, depression, hyperactivity and other mental conditions.

COMT V158M

Most research has focused on a single polymorphism in COMT V158M.

This polymorphism is called Val158Met in the long form of the enzyme which affects the brain (called COMT V158M by Genetic Genie); and Val108Met in the short form. This pair of polymorphisms is often abbreviated to Val108/158Met or just Val/Met. (That’s short for Valine and Methionine).

You can have three versions of this gene.

• In the ideal version, you use the amino acid valine in your catechol-o-methyltransferase; this genotype is called Val/Val and it produces the most active version of the enzyme. Genetic Genie will report this as GG.
• A heterozygous polymorphism makes you use valine and methionine, and this genotype of called Val/Met. On Genetic Genie results this will be reported as AG.
• A homozygous polymorphism means you will use two methionine molecules and this is known as Met/Met. Genetic Genie reports this as AA. If you have this version, your catechol-o-methyl transferase will be only one quarter as effective as a person with the Val/Val genotype.

The Met/Met version of the COMT gene is not only less active, but also unstable at 37 degrees centigrade or any temperature above that. This means that, if you have this version, you will end up with even lower levels than normal every time you get a fever.

No, not that kind of fever

It is believed that people with the Val/Met version of the COMT gene, and particularly the Met/Met version, accumulate high levels of dopamine and that, as a result, the brain starts to ignore dopamine.

Results have been mixed and contradictory, but it seems that people with the Val108/158Met polymorphism may have problems with working memory, attention and self control. These changes in mental processes have been associated with schizophrenia, bipolar disorder, panic disorder, anxiety, obsessive-compulsive disorder (OCD), eating disorders, and attention deficit hyperactivity disorder (ADHD). A direct link between these conditions and COMT polymorphisms has NOT been established. These conditions appear to be multi-factorial and COMT polymorphisms may be just one factor involved.

COMT H62H

Research into the COMT H62H version of the gene has been widely varied, but particularly looking at cancer and pain. This is logical since dopamine reduces pain sensations, and COMT also breaks down some cancer-causing versions of estrogen.

This polymorphism results in an alteration in the COMT enzyme in a different spot, and does not result in replacing valine with methionine in catechol-o-methionine, which means the usage of methyl donors in people with the polymorphism will be the same as in people without it. It does, however, result in the production of a less active version of the enzyme. People with both the V158M polymorphisms and the H62H polymorphism are likely to have a significant reduction in enzyme efficiency.

One research project found that people with the V158M polymorphism described above AND this H62H version were much more likely to be hyperactive and impulsive, whilst people with only the V158M polymorphism were not.

COMT P199P

Very little research has been published on the COMT P199P polymorphism. Indeed, SNPedia has found only 4 articles on the Internet which refer to this gene variant.

One article from Japan has found that mercury suppresses levels of SAMe, which in turn reduces the level of catechol-o-methyltransferase and leads to increased levels of catecholamines. This in turn has been associated with autoimmunity and Kawasaki disease, particularly in children with the COMT P199P polymorphism.

All the above is a summary of published, peer-reviewed medical research. The following section is not.

Treatment

People with the Met/Met version of the COMT gene (“COMT positive”) will use up extra methionine to produce catechol-o-methyltransferase. They take this from S-adenosyl Methionine, or SAMe. (In medical research this is usually called AdoMet).

Since their version of catechol-o-methyltransferase is a quarter as effective as Val/Val types, the more they can make of it, the better. Therefore SAMe supplementation should definitely be helpful, provided it is not contra-indicated by other relevant polymorphisms.

Amy Yasko

Amy Yasko’s online therapy programme claims that the COMT polymorphisms result in slower breakdown of dopamine and hence higher dopamine levels, and then says: “As a result, these higher levels then feed back and inhibit additional dopamine synthesis. For this reason, individuals who are COMT +/+ seem to have a reduced tolerance for methyl donors.”

The research I have read says that the feedback loop results in decreased reaction to dopamine by the brain’s dopamine receptors, NOT decreased dopamine production. I am not aware of any published medical literature supporting Amy Yasko’s interpretation of this and, as usual, does not cite any. If her take on this were true, then the COMT polymorphism would be no problem because this corrective feedback loop would automatically correct any imbalance in the dopamine level.

Yasko recommends avoiding methylcobalamin in individuals with COMT polymorphisms, and suggests that to correct their methylation issues they should take hydroxocobalamin or cyanocobalamin instead. She does not comment on whether or not she recommends SAMe for “COMT positive” individuals.

 James Roberts

The Heartfixer website says that COMT positive individuals are sensitive to methyl groups because they are not using them up to break down dopamine.

Roberts says: “The downside of being COMT (+) is that you will have a lot of free methyl groups floating around, as you are not using them up breaking down dopamine.” He goes on to say that taking methyl B12 may result in “overdosing on methylcobalamin.”

My own view

I find this confusing since there is no known medical level of toxicity for methylcobalamin, hence technically, it is impossible to overdose on it.

I wish either one of them would explain how vitamin B12 affects COMT in any way since, in peer-reviewed medical literature, COMT and vitamin B12 have no connection.

Anecdotally, I can say that I have a heterozygous COMT V158M polymorphism and a heterozygous COMT H62H polymorphism. I take 10,000mg of methylcobalamin daily and it makes me feel noticeably better than I do without it.

I believe it has no relevance to COMT polymorphisms.

Factors affecting gene expression

This section is based on peer-reviewed medical research and the hyperlinks take you to sources.

The bioflavonoid quercetin inhibits COMT production. This substance is regarded as a nutrient since it aids vitamin C in some of its antioxidant activities, and it is often added to vitamin C supplements. It is found at high levels in capers, onions and dark red fruits, apples, cauliflower, grapes and wine, nectarines, spinach, tea and tomatoes. There is actually a website all about Quercetin!

Tea catechins also inhibit COMT expression. Catechins are another type of bioflavonoid known as flavanols. (These are a type of phenol.)

My favourite tipple

Catechol estrogens have been found to down-regulate COMT gene expression, in other words, to inhibit production of catechol-o-methyltransferase.  COMT breaks down cancerous estrogens, on the other hand, and low COMT activity has been associated with breast cancer. So, essentially, these two substances work against each other and must remain in balance.

Catechol estrogens are produced by the estrogen found in the contraceptive pill. I have the Val/Met version of COMT 158 and another heterozygous COMT polymorphism. When I have taken the contraceptive pill the effect was shocking; tears, hysteria, uncontrollable anger, and effects on my emotions which made me afraid I was losing my mind. Since both my sisters and all my female cousins are unable to use the contraceptive pill for the same reason, I do wonder if this is because it compounds the effect of an already under-active form of catechol-o-methyltransferase.

 The following drugs directly inhibit production of COMT:

• Entacapone
• Tolcapone
• Nitecapone

These drugs are used to treat Parkinsons disease and are used specifically for their ability to inhibit COMT activity.

The following drugs, or drug metabolites, are broken down by COMT. If taking these, the overall amount of COMT available to also break down dopamine will be reduced.

• Alpha-methyl DOPA
• Apomorphine
• Benserazide
• Bitolterol
• Dihydroxyphenylserine
• Dobutamine
• Dopamine
• Epinephrine
• 2-Hydroxyestrogens
• 4-Hydroxyestogens
• Isoetherine
• Isoprenaline
• Isoproterenal
• Norepinephrine
• Rimiterol
• Albuterol
• Metaproterenol
• Methoxamine
• Phenylephrine
• Perbuterol
• Terbutaline

Please note, I am not a medical professional and this is not medical advice. I am a researcher and this is a summary of peer-reviewed medical research that I have read online. My sources are listed and linked so you can double check them.

Sources and further reading

Genetics Home reference
http://ghr.nlm.nih.gov/gene/COMT

An excellent article on all aspects of the COMT gene
http://pharmrev.aspetjournals.org/content/51/4/593.full#title6

A collection of research on the COMT gene, including a lot of research associating COMT activity with cancer and evaluating COMT inhibitors as cancer treatments.
https://www.wikigenes.org/e/gene/e/1312.html

General information on the COMT gene
http://flipper.diff.org/app/pathways/info/7006

Information about COMT genetic testing at the Mayo Clinic
http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/83301

Wikigenes: a very comprehensive list of medical research into the COMT polymorphisms.
https://www.wikigenes.org/e/gene/e/1312.html

A very detailed analysis of the effects of medicinal COMT inhibition in the treatment of Parkinsons disease, which is treated with large doses of dopamine. 
http://pharmrev.aspetjournals.org/content/51/4/593.full#title25