Move Over, MTHFR: Time to Look at COMT

 In Anxiety/Depression/Mental Health, Pediatrics

Jared M. Skowron, ND

After giving methylfolate to hundreds of patients, I noticed some of them responded with aggression, anxiety, anger, and irritability. When they stopped their supplementation, the side effects resolved. While many practitioners adjust dose, add methylcobalamin, or various amino acids, I wanted to go deeper into the genetic pathology. Treat the cause, right? Thank you, Dr Ben Lynch. You’ve helped change the face of functional medicine. While he didn’t discover the gene or formulate L-methylfolate, there’s no doubt that he (and other naturopathic physicians and functional medicine folks) have helped expand the role of genetic testing and methylfolate treatment in the United States. I know that my practice has changed since I learned about methylenetetrahydrofolate reductase (MTHFR) testing and treatment. I’m sure many of your practices have incorporated MTHFR testing as a daily activity. (If you haven’t, get on board quickly before the conventional folks figure it out in 10 years.)

What are MTHFR and COMT?

MTHFR activates 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF). While MTHFR is a key enzyme involved in serotonin, dopamine, and catecholamine production, catechol-O-methyltransferase (COMT) is the enzyme responsible for degradation of catecholamines. Focusing primarily on epinephrine as our major example, if COMT is not metabolizing effectively (the result of carrying a polymorphism in the gene), epinephrine will build up, potentially leading to aggression, anxiety, anger, etc. The metaphor always comes down to plumbing: if we open the flood gates of neurotransmitter production with methylfolate supplementation, but the exit pipe is small, it’s like putting a thumb over a rushing garden hose…. Explosion!

Sorting It Out in Your Patients

So, how do you know if your patients have a COMT enzyme malfunction? And, if they do, what do you do about it? First, if your patient gets better but then soon worsens on 5-MTHF treatment, a COMT malfunction may be present. Genetic testing can also identify a COMT polymorphism. However, we always need to keep epigenetic expression in mind. Even a perfect gene can have its expression hindered by toxins. Testing of catecholamines, metanephrines, and vanillylmandelic acid (VMA) can be helpful. COMT is the enzyme that methylates norepinephrine to normetanephrine, and epinephrine to metanephrine. Monoamine oxidase (MAO) converts both metanephrines to VMA. So, the bottom line is to look for a pattern of elevated catecholamines and low metanephrines, as that usually reflects slow COMT activity.

Genetically, this is known as the Val158Met polymorphism. The variant results from a methionine molecule replacing a valine molecule at this position on the gene. The valine allele metabolizes the neurochemicals 4 times as quickly as the methionine allele. A heterozygous genotype (Val/Met) is associated with a normal balance of catecholamines, whereas a homozygous genotype of either valine or methionine can result in symptoms of elevated (Met/Met) or depressed (Val/Val) catecholamine levels, respectively.

Clinical Correlations

Copious research has been conducted demonstrating associations of COMT variants with different conditions. COMT mutations have been associated with both ADHD1 and autism.2 Children carrying the methionine allele (associated with higher dopamine) show better performance in numerical tasks such as magnitude assessment, while children who are homozygous for the COMT valine allele (associated with lower dopamine) have slower processing in this area.3 The methionine allele has been associated with impulsiveness and poor decision-making.4 Individuals carrying
2 valine alleles show more cognitive flexibility5 and less anxiety compared to individuals carrying 2 methionine alleles.6 Epinephrine and other catecholamines are a bit tricky. Having a lot can create anxiety, but a certain amount is necessary for focus, concentration, and motivation.

Be forewarned: symptoms that you might associate with MTHFR malfunction may actually be due to COMT malfunction. The COMT valine polymorphism (associated with lower dopamine and lower cognitive function) has been associated with apathy and depression.7 In this case, the lower dopamine is caused by high metabolism, not low production. A higher risk of violence has been found in schizophrenics carrying the methionine allele (associated with high epinephrine).8 Both homozygous genotypes have been associated with PTSD, in contrast with the heterozygous genotype.9

Genetic inheritance should be only the first part of our analysis. Epigenetics (environmental effects on gene expression) plays a role in everything. In vitro research has shown that estrogenic plasticizers, such as bisphenol A (BPA), benzyl butyl phthalate (BBP), and di-n-butyl phthalate (DBP) inhibit COMT activity, which leads to higher catecholamine levels.10 Mercury toxicity also inhibits COMT activity through inhibition of S-adenosylmethionine (SAM), a coenzyme for COMT.11

What Can You Do About It?

The ultimate question is how can we change the function of the COMT enzyme to help our patients feel happier. The effects of the valine allele (faster metabolism, lower catecholamines) are easier to change than those of the methionine allele. A multitude of treatments, from pharmaceutical COMT inhibitors (tolcapone, entacapone), to green tea and epigallocatechin gallate (ECGC), can inhibit COMT activity, thereby elevating catecholamines. Theoretically, treatment with methylfolate would have the same effect. More difficult is finding a COMT activator. Surprisingly, with the amount of violence and anxiety in the world, exacerbated by slower COMT activity, one would think this treatment would be welcomed. Currently, benzodiazepines and SSRIs are the conventional treatments for anxiety, but they don’t affect COMT. Our natural alternative is magnesium, well-known for its calming activity. Magnesium is necessary for COMT function, while COMT activity is inhibited by calcium and iron.12 While an effective potential treatment, others need to be discovered.

I always remember the scene from “I Love Lucy,” when Lucille Ball is working at the chocolate factory machine. (Consider the chocolates as our neurotransmitters.) When things are slow, she’s bored, and when the pace picks up a bit, she’s engaged and can handle things. However, there’s a point at which she can’t get rid of the chocolates as fast as they’re being made. This is like COMT degradation. Can you handle it, or do you get angry and anxious when things get too fast? It’s all in the balance.

Dr Jared M Skowron, NDJared M. Skowron, ND, is the Amazon best-selling author of the books, 100 Natural Remedies For Your Child and Fundamentals of Naturopathic Pediatrics. Vice-president of the Pediatric Association of Naturopathic Physicians (PedANP), and a graduate of NCNM, his practice specializes in treating neuropsychiatric disorders of children.



  1. Ghosh P, Sarkar K, Bhaduri N, et al. Catecholaminergic gene variants: contribution in ADHD and associated comorbid attributes in the eastern Indian probands. Biomed Res Int. 2013;2013:918410.
  2. Yoo HJ, Cho IH, Park M, et al. Association of the catechol-o-methyltransferase gene polymorphisms with Korean autism spectrum disorders. J Korean Med Sci. 2013;28(9):1403-1406.
  3. Júlio-Costa A, Antunes AM, Lopes-Silva JB, et al. Count on dopamine: influences of COMT polymorphisms on numerical cognition. Front Psychol. 2013;4:531.
  4. Malloy-Diniz LF, Lage GM, Campos SB, et al. Association between the Catechol O-methyltransferase (COMT) Val158met polymorphism and different dimensions of impulsivity. PLoS One. 2013;8(9):e73509.
  5. Colzato LS, van den Wildenberg WP, Hommel B. Cognitive control and the COMT Val158Met polymorphism: genetic modulation of videogame training and transfer to task-switching efficiency. Psychol Res. 2013 Sep 13. [Epub ahead of print]
  6. Baumann C, Klauke B, Weber H, et al. The interaction of early life experiences with COMT val158met affects anxiety sensitivity Genes Brain Behav. 2013;12(8):821-829.
  7. Mitaki S, Isomura M, Maniwa K, et al. Apathy is associated with a single-nucleotide polymorphism in a dopamine-related gene. Neurosci Lett. 2013;549:87-91.
  8. Singh JP, Volavka J, Czobor P, et al. A meta-analysis of the Val158Met COMT polymorphism and violent behavior in schizophrenia. PLoS One. 2012;7(8):e43423.
  9. Clark R, Deyoung CG, Sponheim SR, et al. Predicting post-traumatic stress disorder in veterans: Interaction of traumatic load with COMT gene variation. J Psychiatr Res. 2013;47(12):1849-1856.
  10. Ho PW, Tse ZH, Liu HF, et al. Assessment of Cellular Estrogenic Activity Based on Estrogen Receptor-Mediated Reduction of Soluble-Form Catechol-O-Methyltransferase (COMT) Expression in an ELISA-Based System. PLoS One. 2013;8(9):e74065.
  11. Yeter D, Deth R, Kuo HC. Mercury Promotes Catecholamines Which Potentiate Mercurial Autoimmunity and Vasodilation: Implications for Inositol 1,4,5-Triphosphate 3-Kinase C Susceptibility in Kawasaki Syndrome. Korean Circ J. 2013;43(9):581-591.
  12. Sparta M, Alexandrova AN. How metal substitution affects the enzymatic activity of catechol-o-methyltransferase. PLoS One. 2012;7(10):e47172.


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