COMT — a single nucleotide polymorphism

Review Article – COMT — a single nucleotide polymorphism

Author – Spectrumceuticals Education, Research and Development

©Spectrumceuticals 2017 – This article, or parts thereof, may not be reproduced in any form without permission, except in the case of brief quotations embodied in critical articles and reviews.


There is growing awareness of the COMT SNP (a single nucleotide polymorphism) among integrative practitioners. The reason for this is that patients with this genetic variant have a particular clinical profile which involves adverse reactions to particular supplements. Patients who have reacted to previous treatments — often those which contain methyl groups — will tend to gravitate towards experienced practitioners due to their symptoms being less straightforward to treat. It is for this reason that patients with the catechol-O-methyltransferase enzyme (COMT) SNP can comprise a significant proportion of a practitioner’s caseload.

Mechanism of action

COMT is the name of the gene which codes instructions for making an enzyme called catechol-O-methyltransferase. Catechol- O-methyltransferase is involved in the inactivation of catecholamine neurotransmitters (dopamine, noradrenalin and adrenalin), as well as any compound having a catechol structure, such as catechol oestrogens and catechol-containing flavonoids.[1] In the process of degradation of the catecholamines, the enzyme uses a methyl group in the form of SAMe.

The theory behind why patients react to methyl groups is because the COMT enzyme uses SAMe — the body’s main methyl donor — to catalyse the breakdown of catecholamines. If a person is homozygous to the COMT SNP, the enzyme is only functioning at 25% of the normal level. Hence it is using up less SAMe, which can lead to an accumulation of SAMe and this leads to symptoms of overmethylation.


Severe variation in the COMT enzyme, among others, is implicated in gene deletion in the 22q11 region (DiGeorge syndrome/ velocardiofacial syndrome). It has been postulated that this COMT variation has an impact on the psychiatric behaviour observed in velocardiofacial syndrome. [2] This gene variation is also associated with a wide range of physical and mental conditions including schizophrenia, bipolar disorder, depression and anxiety.[3]


The COMT gene that codes the COMT protein has allelic variants associated with it. The best studied is Val158Met (valine and methionine). This polymorphism is called Val158Met in the long form of the enzyme and affects the brain (called COMT V158M rs4680), and Val108Met in the short form. This pair of polymorphisms is often abbreviated to Val108/158Met.

The three COMT gene variants are:

1. COMT V158M (-/-): These individuals have a quicker COMT system and therefore have lower levels of dopamine at a steady, resting state. They can handle multiple stressors at a single time better than the other genotypes.

2. COMT V158M (+/-): These individuals live in the middle between a fast and slow COMT. Compared to the -/- group, they have a slowed COMT system and therefore have slightly higher levels of dopamine at a steady, resting state. They can handle less stress than the COMT -/- group but more than COMT +/+.

3. COMT V158M (+/+): These individuals have the slowest COMT system and therefore have the highest levels of dopamine at a steady, resting state. They are going to have higher performance and more brain function in low stress states, but will lose brain function as the number of stressors increases.

The single nucleotide polymorphism Val158Met (Val/Met) reduces the activity of the enzyme to 40% of the normal enzyme.

The Val/Met variant catabolises dopamine up to four times the rate of its methionine counterpart.[2] Met/Met catechol-Omethyltransferase will be only 25% as effective as a person with the Val/Val genotype.

COMT gene polymorphisms are common. It is estimated that around 80% of the population has a SNP in the COMT V158M gene. Other SNPs with possible effects are COMT H62H rs4633 and COMT P199P rs769224. Several factors affect the expression of the COMT gene:

• The bioflavonoid quercetin inhibits COMT production.
• Tea catechins (flavanols) also inhibit COMT expression.
• Catechol oestrogens have been found to down-regulate COMT gene expression.

Clinical features

• Reactive to methyl groups with patients often describing they feel ‘weird’.
• Reactive to selective serotonin reuptake inhibitor (SSRI) medications.
• More pain sensitive.
• Alteration in the feeling of wellbeing; COMT-positive patients experience high reward. [4]
• Responsive to GABA.
• Higher incidence of temporomandibular joint dysfunction (TMJ). [5]
• May increase susceptibility to developing schizophrenia. [6]
• More common in attention deficit and hyperactivity disorder (ADHD). [7]


Although patients with the COMT SNP are often more challenging to treat, there are some strategies to use when navigating their potential problems:
• Avoid methyl groups.
• Avoid SSRI medications.
• Trial the use of folinic acid, hydroxy B12, niacinamide (vitamin B3) and GABA (gamma-Aminobutyric acid) for anxiety.


1.Grossman MH, Emanuel BS, Budarf ML. ‘Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1—q11.2’. Genomics, 1992, 12(4): 822–5. doi:10.1016/0888-7543(92)90316-K. PMID 1572656.
2.Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faedda G, Goldberg R, Kucherlapati R, Papolos DF. ‘Association of codon 108/158 catechol- O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome’. American Journal of Medical Genetics, 1996, 67(5): 468–72. doi:10.1002/(SICI)1096-8628(19960920)67:5<468::AID-AJMG5>3.0.CO;2-G. PMID 8886163.
3.Hosák L. ‘Role of the COMT gene Val158Met polymorphism in mental disorders: A review’. Eur Psychiatry, 2007, 22(5): 276–81. Epub 2007 Apr 6.
4.Wichers M, Aguilera M, Kenis G, Krabbendam L, Myin-Germeys I, Jacobs N, Peeters F, Derom C, Vlietinck R, Mengelers R, Delespaul P, van Os J. ‘The catechol-O-methyl transferase Val158Met polymorphism and experience of reward in the flow of daily life’. Neuropsychopharmacology, 2008, 33(13): 3030–6.
5. Cairns BE. ‘Pathophysiology of TMD pain—basic mechanisms and their implications for pharmacotherapy’. Journal of Oral Rehabilitation, 2010, 37(6):
391–410. doi:10.1111/j.1365-2842.2010.02074.x. PMID 20337865.
6. Diaz-Asper CM, Weinberger DR, Goldberg TE. ‘Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics’. NeuroRx, 2006, 3(1): 97–105. doi:10.1016/j.nurx.2005.12.010. PMC 3593358. PMID 16490416.
7. Qian, Q. et al. (2003). ‘Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism’. American Journal of Medical Genetics, 2003, 1:118B(1): 103–9.


©Spectrumceuticals 2017 – This article, or parts thereof, may not be reproduced in any form without permission, except in the case of brief quotations embodied in critical articles and reviews.