03/12/2026
Struggle with anxiety, mood changes… this could be one reason it’s not getting better.
Have you done genetic testing? If you have done ancestry or 23 and me, we can take a look.
COMT, catechol O methyltransferase, is the enzyme responsible for methylating and clearing catecholamines such as dopamine, epinephrine, and norepinephrine. It also participates in estrogen metabolism and the breakdown of catechol containing compounds from foods, supplements, and medications. The speed of this enzyme changes how long stimulation signals remain active in the nervous system.
When I analyze someone’s DNA, I do not rely on a single marker. I look at a cluster of COMT variants that influence enzyme activity. The most well known is rs4680, often called Val158Met. The Val form increases enzyme speed and clears dopamine faster. The Met form slows the enzyme and allows dopamine to remain active longer.
But rs4680 alone does not tell the whole story. I also examine supporting COMT variants such as rs4633 and rs6269. These variants influence how much COMT enzyme is produced and how stable the enzyme structure is. When certain combinations appear together, they consistently predict whether the nervous system will clear catecholamines quickly or slowly.
Once those variants are reviewed together, the pattern becomes clear.
Slower COMT activity means dopamine, epinephrine, and norepinephrine remain active longer. These individuals often show deep cognitive focus, emotional intensity, sensitivity to caffeine or stimulants, and difficulty shutting down mental activity at night. Stress signals linger longer because the enzyme clears them slowly.
Faster COMT activity means catecholamines are broken down rapidly. Dopamine drops more quickly after it is released. These individuals often tolerate caffeine well, seek stimulation, feel motivated by novelty, and may experience dips in focus or drive when dopamine levels fall.
In practice, I can often predict the COMT pattern before I even open the genetic data. People describe their stress tolerance, caffeine response, sleep patterns, and reactions to supplements. When I then look at rs4680, rs4633, and rs6269 together, the genetics usually confirm what their physiology has already been showing.
This is why genetic context matters. COMT influences neurotransmitter turnover, stress physiology, estrogen metabolism, and methylation demand. When the enzyme speed is known, nutrient support can be aligned with the nervous system instead of guessing how someone will respond.
Below is the exact cluster of COMT variants I review when determining whether someone is fast or slow COMT.
