Having trouble with supplements containing methyl groups? Wondering why your neurotransmitters are out of balance? It could be due to your COMT genetic variants. This important enzyme is tasked with breaking down neurotransmitters, such as dopamine.
The COMT gene codes for the enzyme catechol-O-methyltransferase which breaks down (metabolizes) the neurotransmitters dopamine, epinephrine, and norepinephrine. To do this, the enzyme adds a methyl group from SAMe to the dopamine, epinephrine, or norepinephrine molecules, thus changing them into a different substance so that the body can then get rid of it.
COMT also breaks down some drugs used for asthma, Parkinson’s, and high blood pressure. Additionally, COMT is important in the phase II metabolism of estrogens.
There are several common genetic variants that alter how the enzyme functions. Researchers link COMT genetic variants to quite a variety of different diseases from mood disorders to heart disease, possibly due to the COMT variants metabolizing neurotransmitters at different rates.
The COMT enzyme is active in the prefrontal cortex.
Some of the psychiatric disorder with increased risk associated with COMT variants include schizophrenia[ref][ref], depression [ref], anxiety, and bipolar disorder. Keep in mind, though, that the COMT variant doesn’t cause these disorders – it just adds to the susceptibility.
Estrogens can inhibit COMT, leading to an increase in dopamine in female brains. [ref]
One of the most studied COMT genetic variants is known as Val1158Met or rs4680. This variant affects 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. [ref]
There is a lot written on the internet about COMT – from Facebook groups to clinicians making videos on the topic. Often the information leads you to believe that carrying one of the other of the COMT rs4860 alleles is really bad… Instead, the research shows that there are both positive and negative effects from the variant. So instead of one allele being bad and one being good, studies show that these common variants just add to our uniqueness.
Instead of focusing on bad vs good, I suggest looking at the various interactions between your genotype and supplements or lifestyle factors. Use the genetic information to optimize your health – mental and physical.
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; AncestryDNA):
Here are the findings from some studies on this COMT variant:
This common variant also changes the activity level of COMT. The T allele 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; AncestryDNA):
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; AncestryDNA):
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 — causing mood swings, anger, or anxiety.
Instead of supplementing with methyl-B12, people with rs4680 A/A genotype may want to try hydroxocobalamin or adenosylcobalamin. These types of B12 don’t contain a methyl group and are thus less likely to cause problems for people sensitive to methyl donor supplements.
Stacking supplement: 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 together at the same time that are metabolized using the COMT enzyme.
A study in mice found that COMT deficiency led to glucose intolerance on a high-fat diet.[ref] 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. Test your blood glucose levels and keep track of whether dietary fat impacts your levels.
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.
Originally published 7/2015. Updated 1/2020.