Having trouble with supplements containing methyl groups? Wondering why your neurotransmitters are out of balance? It could be due to your COMT genetic variants.
The COMT gene codes for the enzyme catechol-O-methyltransferase which breaks down (metabolizes) 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 also breaks down some drugs used for asthma, Parkinson’s, and high blood pressure.
Researchers link COMT genetic variants to quite a variety of different diseases from mood disorders to heart disease. This variety is due to the COMT variants metabolizing neurotransmitters at different rates.
Some of the psychiatric disorder with increased risk associated with COMT variants include:
Estrogens can inhibit COMT, leading to an increase in dopamine in female brains. [ref]
One of the most well studied genetic variants, the COMT Val1158Met polymorphism controls the rate at which the enzyme function. Also know as COMT rs4680, the A/A or Met/Met variant is found in almost 20% of the population. The slightly more common G/G or Val/Val variant is found in 35-40% of the population.
There are various health websites and Facebook groups dedicated to the negative effects of being ++ or — for this variant. In general being ++ indicates having the slower Met/Met version, but double check with whatever report format you are looking at to make sure that is the case.
Instead of focusing on any perceived negative effects, I suggest looking at the various interactions between your genotype and diet/supplements/environment and using the information to optimize for your genes. There are positive and negative aspects to most genetic variants, and COMT is no exception.
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”.
Check your genetic data for rs4680 (23andMe v.4 and v.5):
This common variant also changes 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.
Check your genetic data for rs4633 (23andMe v4, v5):
Recent studies on this variant have found:
A couple of COMT variants add to the effect of the main variants listed above.
Check your genetic data for rs6267 (23andMe v.4 and v.5):
Check your genetic data for rs165599 (23andMe v.4 and v.5):
Clinicians often suggest that those with the rs4680 A/A genotype (lower COMT levels) avoid going overboard with foods and supplements that are considered methyl donors. Methyl donors include methylcobalamin (methyl-B12), curcumin, TMG, SAMe, theanine, and choline. [ref] The logic behind this suggestion is that overwhelming the pathway with too many methyl groups can lead to a sudden rise and then subsequent fall in dopamine levels — aka mood swings, anger, or anxiety.
Diet and Supplements:
The COMT enzyme breaks down supplements that have a catechol structure. This includes quercetin, EGCG, and luteolin [ref][ref]. If you have lower COMT enzyme activity, you may want to be careful of stacking too many supplements metabolized by COMT together at the same time.
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 A/A, you may want to look at the amount of fat in your diet.
Magnesium is a cofactor for the COMT enzyme. A study found positive effects for liver COMT levels along with better heart health from supplementing with magnesium. A good quality magnesium supplement may be worth trying if you aren’t getting enough magnesium from food sources.
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