The COMT gene encodes the enzyme catechol-O-methyltransferase which is involved in breaking down the neurotransmitters dopamine, epinephrine, and norepinephrine. This enzyme adds a methyl group (from SAMe) to the dopamine, epinephrine, or norepinephrine molecules, thus changing them into a different substance. COMT is also involved in the metabolism of some drugs used for asthma, Parkinson’s, and high blood pressure.

There are several well-studied polymorphisms of COMT.  Some of the psychiatric disorder with increased risk associated with COMT polymorphisms include schizophrenia, depression, anxiety, and bipolar disorder.  Outside of the brain, COMT is also involved in the methylation of catechol estrogens.[ref][ref]

There are several blogs and clinicians online that write about the effects of using supplements that are ‘methyl donors’ on people who have lower COMT activity. [ref][ref] The logic is that the slower COMT variant uses fewer methyl groups, and pushing it with a quick influx of methyl groups can dopamine levels to build up and then fall, causing mood swings.  I’m not finding any studies that back this up (doesn’t mean there aren’t any, just that I haven’t read them), but there seems to be a lot of anecdotal reports on the web that indicate that people who have the low activity variant (listed below) may want to be careful when supplementing with methyl donors such as theanine, SAMe, methyl B12, curcumin, TMG and more.

COMT rs4680, Val158Met
One of the most studied variants of the COMT gene is rs4680, often referred to as Val158Met.  In looking at research studies, the G is “Val” and the A allele is usually noted as “Met”.

The G allele has higher COMT enzymatic activity, causing a more rapid breakdown of the neurotransmitters and thus lower levels of dopamine. In most populations, the G allele is the most common.[ref]

The A allele has lower COMT enzyme activity and thus higher levels of dopamine.

Check your 23andMe results for rs4680 (v.4 and v.5):

  • GG: higher COMT activity, lower dopamine & norepinephrine, higher pain tolerance (Val)
  • AG: intermediate COMT activity
  • AA: lower COMT activity, higher dopamine & norepinephrine, lower pain tolerance (Met)

Here are the findings from a few recent studies on this COMT variant:

  • A 2015 study of cognitively normal adults found that those with GG genotype had lower Neuroticism scores and higher Agreeableness and Conscientiousness scores than those with AG or AA.[ref]
  • A 2015 study of self-administered morphine in 973 patients following surgery found that the minor (A) allele was associated with more morphine use.  This result backs up the many other studies showing that those with rs4680 AA often have a lower pain tolerance than those with rs4680 GG.[ref]
  • A 2015 study of approximately 800 young adults looked at the combined effects of gender and COMT polymorphisms on schizophrenia and psychosis proneness traits.  Males carrying the G allele scored higher on the negative symptoms and traits of schizophrenia and psychosis. [ref]
  • A small 2014 study looked at the differences in fat oxidation and energy expenditure with green tea based on COMT genotype.  Those with the rs4680 GG genotype had significantly increased energy expenditure and fat oxidation with green tea, while those with the AA genotype had no increase. [ref]
  • Lots of other studies are listed on SNPedia including several that look at the response to antidepressants.  There are hundreds of studies in PubMed on this COMT polymorphism.
  • Dr. Amy Yasko looks at COMT in reference to which type of B-12 works best for an individual. In general, she suggests that methylcobalamin (B12) usually works well for those with the GG genotype, and those with the AA genotype may find that hydroxycobalamin or adenosylcobalamin work better.

COMT rs4633
This common variant is also involved in the activity level of COMT. T is the less common version with lower COMT enzyme activity; C is the more common version with higher activity. It correlates with the rs4680 polymorphism, and thus most people will have the same activity levels on both.

Check your 23andMe results for rs4633:

  • CC: higher COMT activity, lower dopamine, norepinephrine
  • CT:  medium COMT activity
  • TT: lower COMT activity, higher dopamine, norepinephrine

Recent studies on this variant have found:

  • A small 2015 study showed that rs4633 was associated with disc degeneration and lower back pain.  Other studies have also found this result. [ref] [ref]
  • A 2014 study looked at the effects of mercury exposure on boys and girls in relation to COMT status.  Boys with the T polymorphism had impaired test performance in response to increasing acute mercury exposure.  This was in contrast to girls with the polymorphism who showed fewer effects from acute mercury exposure.  [ref]
  • A 2012 study of atherosclerosis in elderly Japanese found that the CC genotype was associated with atherosclerosis, especially in women.  [ref]
  • A study found that those with TT had a higher risk of endometrial cancer.  [ref]

Other COMT Polymorphisms:
There are a couple of other COMT variants that may add to (or subtract from) the effect of the main COMT variants listed above.

Check your 23andMe results for rs6267 (v.4 and v.5):

  • GG: normal
  • GT: risk of higher pain sensitivity, somewhat lower COMT activity [ref]
  • TT: risk of higher pain sensitivity, somewhat lower COMT activity [ref]

Check your 23andMe results for rs165599 (v.4 and v.5):

  • AA: increased risk of anxiety, schizophrenia[ref] [ref][ref]
  • AG: increased risk of anxiety, schizophrenia[ref] [ref][ref]
  • GG: normal


A study in mice found that COMT deficiency led to glucose intolerance on a high-fat diet.  Keeping in mind that this is just a mouse study, if you have blood sugar regulation issues and have COMT rs4680 AA, you may want to look at the amount of fat in your diet.  Again, mouse study caveat… but it is interesting to see the link.

It is often suggested by clinicians (and online anecdotes) that those with rs4680 AA (lower COMT levels) should avoid going overboard with foods and supplements that are considered methyl donors.

Magnesium is a cofactor for the COMT enzyme. A study found positive effects for liver COMT levels and heart health from supplementing with magnesium. A good quality magnesium supplement, such as Jigsaw MagPure, may be worth trying if you aren’t getting enough magnesium from food sources.

More to read about COMT and the methylation cycle:
There are quite a few websites that give suggestions for actions to take if you are having problems balancing out your dopamine and other neurotransmitter levels. Knowing if you are genetically predisposed to breaking down dopamine either quickly or slowly may help you and your doctor to understand which route to take to help balance out your neurotransmitters.


Updated 10/2017

1 Comment

Laura · January 5, 2019 at 10:42 am

Another great post!
Could you link me to more information regarding rs4680 AA and methyl donor interaction?
Polymorphisms in rs1805087 and rs1801394 would recommend following a diet high in folate… So what’s the best approach?

Thanks again :)

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