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Catechol-O-Methyltransferase (COMT) is one of several enzymes that degrade dopamine, epinephrine, and norepinephrine.

COMT breaks down dopamine mostly in the part of the brain responsible for higher cognitive or executive function (prefrontal cortex). (R)

COMT and Methylation

Catechol- O -Methyltransferase is an enzyme that transfers methyl groups (hence the name methyltransferase).

COMT introduces a methyl group to the catecholamine (dopamine, epinephrine, and norepinephrine), which is donated by S-adenosyl methionine (SAM) (R).  Therefore you need adequate SAM for COMT to work.

Having too little SAM (s-adenosylmethionine) and too much SAH (s-adenosylhomocysteine) from undermethylation results in COMT inhibition as well (R).

For this reason, having MTHFR SNPs that cause undermethylation and COMT SNPs that result in lower COMT are a bad combination.

COMT helps with methylation, including in the gut (R).

COMT gene production is itself influenced by methylation (R).  Usually, methylation shuts down gene production.

Reactions By COMT

Specific reactions catalyzed by COMT include:

  • Dopamine → 3-Methoxytyramine
  • DOPAC → HVA (homovanillic acid)
  • Norepinephrine → Normetanephrine
  • Epinephrine → Metanephrine
  • Dihydroxyphenylethylene glycol (DOPEG) → Methoxyhydroxyphenylglycol (MOPEG)
  • 3,4-Dihydroxymandelic acid (DOMA) → Vanillylmandelic acid (VMA)

Catechol Estrogens, Cancer and Autoimmunity


Catechol estrogens form from CYP enzymes breaking down Estradiol and Estrones.

Catechol estrogens can break DNA and cause cancer and autoimmune conditions.

COMT methylates (using SAM) and inactivates these catechol estrogens (2- and 4-hydroxycatechols).

The products of COMT methylation are 2- and 4-o-methyl ethers, which are less harmful and excreted in the urine (they have anti-estrogen properties).

However, if COMT is inhibited too much either because of genetics or dietary inhibition, it should result in higher levels of catechol estrogens, especially if glucuronidation and sulphation pathways are not working.

4-Hydroxyestrone/estradiol was found to be carcinogenic in the male Syrian golden hamster kidney tumor model, whereas 2-hydroxylated metabolites were without activity.

4-Hydroxyestrogen can be oxidized to quinone intermediates that react with purine base of DNA, resulting in depurinating adduct that generates cancerous mutations. Quinones derived from 2-hydroxyestrogens are less toxic to our DNA (R).

Estrone and estradiol are oxidized to a lesser amount to 2-hydroxycatechols by CYP3A4 in the liver and by CYP1A in extrahepatic tissues or to 4-hydroxycatechols by CYP1B1 in extrahepatic sites, with the 2-hydroxycatechol being formed to a larger extent (R).

It has been observed that tissue concentrations of 4-hydroxyestradiol are highest in malignant cancer tissue, out of all the estrogens (R).

The concentration of these Catechol Estrogens in the hypothalamus and pituitary are at least ten times higher than parent estrogens (R).

Catechol Estrogens have potent endocrine effects and play an important role in hormonal regulation (those produced by hypothalamus and pituitary) (R).

Increased availability of estrogen and estradiol for binding and hypothalamic sites would facilitate the formation of Catechol Estrogens. These estrogens affect Luteinizing Hormone (LH) and maybe follicle stimulating hormone (FSH) and prolactin (R).

Catecholestradiol competes with estradiol for estrogen binding sites in the anterior pituitary gland and hypothalamus and dopamine binding sites on anterior pituitary membranes (R).

Other possible mechanisms of inactivation of these catechol estrogens include conjugation by glucuronidation and sulphation (R).

High concentration of 4-hydroxylated metabolites caused insufficient production of methyl, glucuronide or sulfate conjugate which in turn results in catechol estrogen toxicity in cells and oxidation to semiquinone and quinone, which may reduce glutathione (GSH). These oxidation products could lead to DNA mutations (R).

The quinone/semiquinone redox system produces superoxide ions (O2¯ ) which can react with NO to form peroxynitrite, which could cause DNA damage (R).

In summary, CEs lead to the production of potent ROS, capable of causing DNA damage, thus playing an important role not only in causing cancer but also in systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (R).

The abilities of the estrogens to induce DNA mutations were ranked as follows:

4-hydroxyestrone (most damaging) > 2-hydroxyestrone > 4-hydroxyestradiol >2-hydroxyestradiol > > Estradiol, Estrone (R).

Supplements and COMT

Any compound having a catechol structure, like catechol estrogens and catechol-containing flavonoids, are targets of COMT (R) and are also capable of inhibiting enzyme function (either directly or through competition) (R).

Such flavanoids that are modified by COMT and also inhibit/compete with COMT include Quercetin (R, R), Rutin, Luteolin (R), EGCG (R), Catechins, Epicatechins, Fisetin (R), Ferulic acid, and Hydroxytyrosol (R, R2).

L-dopa also is modified and competes for COMT (R).

The following flavanoids don’t have the catechol structure: apigenin (R), genistein, chrysin, myricetin (R), and flavones (includes apigenin, tangeritin, chrysinbaicalein, scutellarein, wogonin) (R).

Intro to COMT V158M (rs4680)

This is one of the most researched SNPs because it plays an important role in intelligence, personality and disease risk.

The A allele results in 3 to 4-fold decrease in COMT enzyme activity (R, R2).

This gene variant has been found to affect executive functions such as cognitive flexibility, impulse control, abstract thought, and being able to follow rules or task structure. (R)

If you have AA then you will have the highest dopamine, while GG results in the lowest dopamine.  AG is somewhere in the middle.

Either too little or too much Dopamine can decrease cognitive performance (R).

Under stress, dopamine increases.  High dopamine producers (AA) will perform worse under stress because they will have too much dopamine.  Low dopamine producers (GG) will perform better because now they’ll have an optimal level.

Most of the research involves AA and GG because you can find more statistically significant differences between these.

People with AG have COMT levels that are midway between that of AA and GG (R).

References: COMT and executive function.

COMT and Gender Effects

COMT is decreased by estrogen (R), such that overall COMT activity in prefrontal cortex and other tissues is about 30% lower in females than in males (R). This diminished COMT activity translates to about 30% higher baseline Dopamine levels in females than males (R).

Females have near optimal levels of baseline dopamine levels, but males having somewhat too low baseline dopamine, such that male performance improves when dopamine levels are slightly increased, whereas female performance does not.

Therefore, having SNPs that result in lower COMT (such as the A allele for rs4680) will be more helpful for males, but not females.  Indeed, males with lower COMT do, in fact, demonstrate improved performance on tasks dependent on the prefrontal cortex, whereas females do not (R).

COMT and Cognitive Function

Here’s a summary of cognitive scores on tests taken by AA/AG/GG.

  • Met/Met=AA; High dopamine in prefrontal cortex.
  • Val/Met=AG; Higher dopamine in prefrontal cortex (not as high as AA).
  • Val/Val= GG; Lower dopamine in prefrontal cortex.
  • PIQ= Performance IQ
  • VIQ= Verbal IQ

Interestingly, the AG group tended to have the best IQ (both verbal and performance IQ) and best scores overall, though most weren’t statistically significant.

AA and AG had superior performance relative to GG on reading-related skills (PA, Spelling), and marginally better performance for Decoding but not on more general language skills (Oral Language, Comprehension) or IQ. (R)  Various groups showed more activation in different regions of the brain.  The AA group showed the most activation in areas responsible for reading comprehension (frontal lobe) and these were the best readers, overall.

Screenshot 2014-12-25 09.31.41(R)

Performance IQ (PIQ)+Verbal IQ (VIQ)= Total IQ

Screenshot 2014-12-25 09.41.34

COMT and Personality

The lower dopamine producers (GG) were more extroverted and less neurotic.

  • Met/Met=AA; High dopamine in prefrontal cortex.
  • Val/Val= GG; Lower dopamine in prefrontal cortex.

Screenshot 2014-12-25 10.31.05

The Worrier (A)…Lower COMT, Higher Dopamine.  (Met)

AA is considered the ‘risk’ or ‘bad’ allele in part because people don’t do well with stress and because lower COMT can create issues with methylation and not breaking down estrogen byproducts (catechol estrogens).

AA’s get more pleasure out of life but also more misery (bigger high’s and low’s).

The Good

  • Gets more pleasure out of life –  AA’s had twice the positive emotion towards a pleasant event than GG’s.  GG people subjectively viewed a very pleasurable event on the same level that AA would view a slightly pleasurable event.  AG had a mid-level effect for this was “quite large”. (R)
  • More Creative (divergent thinking fluency – more of an effect with other genes).  Dopamine in the Prefrontal cortex promotes cognitive stability by being more resistant to distractions. (R)
  • Higher IQ (tested in people with schizophrenia). (R)
  • Better working memory. (R, R2) –  during an N-back task and a go-no-go task, there was increased activation in the right posterior cingulate cortex for healthy adults with AG and AA compared to GG. (R) Also, better verbal working memory(letter-number sequencing) in AA and AG compared to GG. (R)
  • Better reading comprehension (R)
  • More plasticity in older age – better responses to N-back brain training. (R)
  • Better cognitive function when not under stress: Better attention and processing of information (executive function). (R) However, realize that this one gene only accounts for 4% of the difference in executive function.  The FAB exam tests executive function.  GG scored an average of 16.0, GA 15.7 and AA 15.3.  These scores are statistically significant, but not large.
  • More Exploratory (R)
  • Have a better response to placebos. (R) – Dopamine is thought to link to reward and ‘confirmation bias’ which enhance the sense that the treatment is working. More prominent in studies with subjective conditions such as pain and fatigue rather than objective physiological measurements. The response of patients with AG fell in the middle.
  • Higher cognitive stability? but comparatively low
    cognitive flexibility. (R)
  • Increased verbal fluency for males (but decreased it for females). (R)
  • Better fine motor skills(AA vs GG) (control of small muscles in the fingers for grasping and manipulation). (R)
  • Better ability to Aim. (R)
  • AA’s focus more when they realize they have made an error.
  • Better absorption of tea polyphenols/EGCG. (R)
  • AA’s had a lower risk for alcoholism. (R)
  • AA’s had a better response to Paxil/paroxetine. (R)

The Bad

  • Worse handling of stress or pain.  Researchers found when viewing unpleasant pictures, the startle response of women with AA was about six times stronger compared to those with only one A or none at all. (R)
  • Anxiety: Studies have correlated AA allele with OCD, panic disorder, phobic anxiety. (R, R2)
  • Lower emotional resilience/more negative emotions/less able to handle negative events well.
  • More impulsive (AA vs GG). (R) More significant in people who had AA for this gene AND TT for rs6313. (R)
  • More depression – but the relationship is complex. (R)
  • Less Cooperative, Helpful and Empathic (AA, in females) (R)
  • Less Extroverted (R)
  • More neurotic (trended). (R)
  • Higher Homocysteine – 10.4% in AA. [R]
  • Higher risk of ADHD and ADHD severity (R)
  • Higher sensitivity to mercury – boys (but not girls) with AA had impaired cognitive performance when exposed to mercury. (R)
  • Fibromyalgia people with AA showed higher sensitivity to heat and pressure pain stimuli (R)
  • It has also been linked with breast cancer risk — Asian-American women who have an AA or one A who also drink black or green tea appear to have a decreased chance of developing the disease. (R)
  • 44% Increased risk for cocaine dependence. [R]
  • boys with TT had worse cognitive performance when acutely exposed to mercury. (R)

The Warrior (G)…Higher COMT, Lower Dopamine (Val)

The Good

  • Better handling of stress and pain. [R]
  • Better at learning languages. (R)
  • More Cooperative, Helpful and Empathic (GG, in females) (R)
  • Higher emotional resilience/able to handle negative events well. [R]
  • Increased verbal fluency for females (also decreased for males). (R)
  • Better working memory and higher hippocampal volume – in healthy Chinese. (R) As you can see AA is not always smarter than GG and it depends on other factors.
  • GG deprived of sleep responded well to modafinil in terms of improved vigor, well-being, and maintained baseline performance with respect to executive functioning.  AA  individuals barely responded to the drug at all. [R]
  • Can more easily get into hypnosis. [R]
  • GG results in more methylation in the gut (R).

The Bad

  • Less pleasure out of life – AA’s had twice the positive emotion towards an event than GG’s.  GG people subjectively viewed a very pleasurable event on the same level that AA would view a slightly pleasurable event.
  • Lower IQ (tested in people with schizophrenia) (R)
  • Worse executive function/processing information, but better under stress. However, realize that this one gene only accounts for not more than 4% of the difference in executive function.  The FAB exam tests executive function.  GG scored an average of 16.0, GA 15.7 and AA 15.3.  These scores are statistically significant, but not large. [R]
  • Worse fine motor skills (AA vs GG) (control of small muscles in the fingers for grasping and manipulation). (R)
  • Less Exploratory (R)
  • More childhood depressive symptoms for GG. (R)
  • 2X increased risk for breast cancer. (R)
  • GG has 11X Higher risk of getting schizophreniform disorder from smoking pot as a teenager.  AG has a 2.5X likelihood.  However, a later study did not find this. (R)
  • Increased risk for endometrial cancer.

Drug Interactions

G alleles had a worse response to Paxil/paroxetine.

Parkinson’s patients may respond to lower doses of levodopa and benefit from vitamin B6.

Continental Differences

G allele frequencies: East Asians have 71% G’s, Africans 69% G’s Americans 61% G’s, Europeans 48% G’s (R).  So East Asians are going to be more likely to have GG vs Europeans.

Other COMT Genes

Rs4633– boys with TT had worse cognitive performance when acutely exposed to mercury. (R)

Rs6269– boys with AA had worse cognitive performance when acutely exposed to mercury. (R)

Rs165599 – The G allele is associated with Bipolar 1 and GG is associated with poorer performance on verbal memory and learning test in healthy people compared to AA/AG (lower dopamine in the prefrontal cortex).  It’s assumed that the worse verbal memory performance contributes to Bipolar. (R)

Rs737865Haplotype associated with panic and anxiety disorder: rs737865 (T), rs4680 (G) and rs165599 (G) (R).

Fixes For Low COMT

If you have lower levels of COMT, you should take/do the following:

  • SAM-e  – however, this can increase dopamine levels in people who already have high dopamine.
  • Adequate B6, B12, folate, and betaine to support formation of S-adenosylmethionine and prevent elevated homocysteine; S-adenosylhomocysteine inhibits COMT activity (R).
  • DIM if you have high estrogens because estrogens inhibit COMT (R) and also because these estrogens can cause cancer – especially breast cancer.
  • Ensure adequate anti-oxidants to prevent oxidation of dopamine and pro-carcinogenic 4-hydroxyestrogens,
  • Magnesium (magnesium is a cofactor)
  • Be careful of the following supplements that are the targets of COMT: quercetin, rutin, luteolin, EGCG, catechins, Epicatechins, Fisetin, Ferulic acid, Hydroxytyrosol
  • Avoid excessive alcohol consumption.  Since alcohol-induced euphoria is associated with the rapid release of dopamine in limbic areas, low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of alcohol dependence (R).
  • Avoid stimulants, especially amphetamines.  Amphetamines may do worse with people who are AA, but later studies did not replicate this.  It could be differences in study design (R).
  • Avoid chronic stress (stress hormones require COMT for degradation and compete with estrogens),

Stay away from COMT inhibitors, which include:

Quercetin (R), Rutin, Luteolin (R), EGCG (R), Catechins, Epicatechins, Fisetin, Ferulic acid, Hydroxytyrosol, (R, R2).

Mercury is also a COMT inhibitor (R), so make sure you reduce your load or take supplements that bind to mercury.

Fixes For Higher COMT

If you have higher COMT levels:

Advanced Fixes For High COMT

These are not recommended without serious thought and a doctor’s guidance:

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.


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  • Sayef Hossain

    Lol same

  • Lori Gazaille

    What test on 23andme would I get for COMT like you suggest? I don’t see it listed anywhere in 2018.

  • Jill Peterson

    I am also an AG, and Modafinil had a marginal effect on my ability to sleep. As well, caffeine has either no effect or the opposite intended effect – have actually had it cause me to fall asleep faster than something like Ambien.

    1. Rik

      I’ve found coffee made me drowsey, but usualy when it’s warm. Coffee itself can be a relaxant and stress/tension releaser.

  • Jen

    My genetics test list COMT VAL158Met A/G
    Intermediate COMT Activity. Can anyone explain what this means??

  • Juan

    Surely he was already psychotic just that the drug precipitated a crisis.

  • ROB

    Now I’m confused about estrogen.

    Six-month old male but not female ArKO mice develop compulsive behaviors such as excessive barbering, grooming and wheel-running. Excessive activities were reversed by 3 weeks of 17beta-estradiol replacement. Interestingly, the presentation of compulsive behaviors is accompanied by concomitant decreases (p < .05) in hypothalamic COMT protein levels in male ArKO mice. These values returned to normal upon 17beta-estradiol treatment. In contrast, hepatic and frontal cortex COMT levels were not affected by the estrogen status, indicating region- and tissue-specific regulation of COMT levels by estrogen. No differences in COMT levels were detectable between female animals of both genotypes.

    This study describes the novel observation of a possible link between estrogen, COMT and development of compulsive behaviors in male animals which may have therapeutic implications in obsessive compulsive disorder (OCD) patients.

  • Anne

    Thanks a lot for this great summary!
    I heard that it is very important to avoid hypoglycemia if you have a AA variant of the COMT. Can you tell me why? I tried to keep my blood sugar as stable as possible by eating starches with lots of fat and fibre. Is that correct? I have the feeling that I still get hypoglycemic when I have to concentrate very hard. You think eating fruits or MCT oil is a good idea in times of ‘extensive thinking? I am afraid that I could crash afterwards. Thanks a lot and best regards

  • Nicole

    I have rs4680 AA, rs4633 TT. Do you need to avoid sulfur? I saw some comments on this but no answer. Thank you!

  • Rob

    Does the supplement Pterostilbene have any effect on COMT?

    1. Helen

      Hi Rob, there is no available evidence that pterostilbene has any effect on COMT.

  • J Pettersen

    Hi, This is purely anecdotal but I gave my husband 50 mg of Niacin on the theory it would help lower cholesterol (that NIH campaign about cholesterol almost ended up killing him). In just one or two days, he dove into a deep depression. This seemed odd as I had read many women on a forum that said Niacin was hugely helpful for depression and found other citations as well. I looked and looked and found a small discussion of some men that had a strong depressive reaction to Niacin. This is when I started reading about methylation and it made sense as he had already had a positive reaction to SAMe but dropped it for other possible side effects. Anyway we started him on B vitamin and TMG methylation supplementation and he has had no noticeable depression since we started on the methylation protocol. So I do believe that SAMe and Niacin are powerful supplements that have an opposite reaction if you are one end of the spectrum or the other. I am in the middle as I don’t notice a particular swing either way if I take SAMe or Niacin. But I always take SAMe when I am going to the pub to help avoid a hangover.

  • J Pettersen

    Hi Heather, Not sure if you will see this a year later but I really feel for you.. from the position of a spouse who had to deal with my husband’s severe insomnia. First, the insomnia is not necessarily related to be AA on COMT 158V. I am AA and am the opposite I have hypersomnia.
    Things that helped my husband
    1) Neurontin ~1800 mg. This was prescribed off label for nerve pain for a genetic condition that is very painful but it helped tremendously with sleep. As you point out it works on the GABA receptors.
    2) Methylation protocol – B12, P-5-P (methylated form of B-6), Tri-methylglycine, Magnesium and zinc. Not currently taking any folate for fear it will drive his glutamate sensitivity. Do you react to MSG?

    The two of those together have made a huge difference. If he still can’t relax, the magic solution to drive at least a 20 minute nap is foot rubbies.

    If cortisol is involved you may want to try something that counterbalances cortisol, theanine and phospatidylyserine come to mind but I am not sure if I am getting those right.

    If you have 23andme results you may already be further along in your research as there are all sorts of sites now that will help tease out the rest of your methylation and psych related gene influences.

    I am the calmest least insomniac person and as I mentioned I am AA for COMT 158V so it is rarely one gene in isolation but a pattern of genes that drives your symptoms strongly in one direction. By the way, would you be considered ADHD?

  • Laurie DePauw

    Does anyone know what an “intermediate result” means on a COMT blood test? Any help would be much appreciated!

  • Jyan

    Hi. Good article. What are good nootropics for the worrier genes?

  • Craig

    read your post about insomnia.. I had it for years when I turned 40 in 1995. It went away gradually but other things crop up. Insomnia isnt so bad- All it means is that youve got alot going on that your brain wants to take care of. Most all of that is just the thoughts you are generating. Insomnia is not a bad thing- embrace it, and show it some love and it will go away. I know what that sounds like. There is something much worse than insomnia- and that is no energy. Youve got too much energy- believe me, when compared to the opposite, of no energy, insomnia wins hands down..

  • Mr. Sick

    are there studies though? A study which was measuring dopamine and norepinephrine after adminstering niacin, that found that in the end there was less of the neurotransmitters?

  • andreia

    Hi. I am not sure if I have a COMT polyphormism, as I live in a country where the government prohibits importation of tests like the 23andMe. Anyway, I do have an issue with quercetin, rutin, luteolin and also resveratrol. Whenever I take any of those supplements, even in small doses, I get a lot of pain in my breasts (like when I am pregnant) and my period comes before it is supposed to. My hair also fall a lot when I am on quercetin. I thought it was because they are aromatase inhibitors and rose testosterone levels (causing the hair loss) and, in a second stage, because the pituitary made my body produce more aromatase and estrogen to maintain hormonal equilibrium. But then I found this page and I began to wonder if it is because my catechol estrogens aren’t being broken down properly.

  • Natasha

    I find this article very helpful. I do have a question though about when you talk about avoiding certain foods, Stay away from COMT inhibitors, which include:

    Quercetin (R), Rutin, Luteolin (R), EGCG (R), Catechins, Epicatechins, Fisetin , Ferulic acid, Hydroxytyrosol, (R, R2).

    Mercury is also a COMT inhibitor (R), so make sure you reduce your load or take supplements that bind to mercury.

    Do these include the foods or are you meaning only the supplement versions?

    1. Mel

      I would love to know this also. I have decreased COMT. Just new to this.
      So should we avoid things like green tea, broccoli. Or the supplement versions.

  • Taube Becker

    I meant to add this is a phenomenal article. Love your articles Joe !

  • Taube Becker

    Hi Joe Why didn’t you mention niacin helps with slow COMT ? It’s a huge help for us with slow clearance of dopamine / adrenaline ?

  • Omar


    I have read about the Met/Met. In one part you said they are lower risk of alcoholism, and in the other you said they have a higher risk on Alcoholism as the lower COMT, so which one is it ?

    I carry the AA Met/Met and would like to know more.

    1. Nattha Wannissorn

      Search for this on SelfDecode.

  • Ted Hu

    Lithium can also increase comt activity.

    1. H E

      Yes, surprised to not see this here

  • Heather

    Hello. I have COMT V158M rs4680 AA +/+ type and horrible insomnia. I have tried EVERY type of sleep medication possible (both on and off label). The Z-type and benzos work the best for me, but I am immune from them, Canymore. It seems that medications that work on Gaba A work best.

    I am an ultrarapid metabolizer of the CYP2C19 and a Non-expressor (poor metabolizer) of CYP3A5 (which, I guess is common).

    I have been taking the Methyl Guard Plus, as you suggested, for one week now.

    I am at a loss as to what may help my insomnia. As most of us with this type of genotype may be experiencing, this is a near life-long issue for me. I have supplemented with tryptophan, Valerian root, GABA, iron, mag citrate, etc. I have been prescribed anti-depressants, such as Remeron, Trazodone, Seroquel, Amitriptiline, etc…all with HORRIBLE side effects (which I think has something to do with my metabolizm of these type of antidepressants). Ambien worked great for years but now, I have to take at least 50mg to get a few hours of sleep; Lorazepam takes at least 6-8 mg. These are obviously very dangerous dosages. Maybe I can handle more of these doses, again, because of my metabolism…but I don’t want to have to take these types of medications anymore if something else will work.

    I also have an issue with absorption and I have already done a candida cleanse and have been replacing pre and probiotics, and have been on a raw, gluten/dairy free diet. I STILL cannot sleep. I have already had a sleep study done which shows that I get 0 REM sleep at times, because of RLS. I think the lack of REM is because I cannot shut my mind off–not the RLS.

    ANY SUGGESTIONS, given my genotypes??? I am desperate!!! I cannot even work because of this!

    Thank you!!!!

    1. Nattha Wannissorn

      Sorry to hear this. I have a lot of trouble with sleep, too, but I don’t know everything about you so it’s hard to say. Inflammation could do it. High histamine could do it. EMF and WiFi could do it. Also, you having been on medications means that your neurotransmitter levels and brain could be a bit different (neither good nor bad).

      Consider testing for EMF and WiFi where you sleep. Also, try things like PEMF to induce sleep. I’ve tried acupuncture which often works, but it won’t if I am very inflamed from eating something wrong. Since I killed off blasto, I am also sleeping better. ~Nattha @ Team SelfHacked

      1. Heather

        Hi, Nattha, thank you so much for your reply. Are you referring to blastomycosis? Or is that just a term that you are using for candida?

        I removed the wifi from my room, but I may shut it off completely, in my home at night. As far as others around me, I may have to look into something to block that. I have often wondered if it wasn’t the wifi, though, I have insomnia ANYWHERE AND EVERYWHERE I go–even if I were in the middle of the woods with no signal. I do have a card that I have put under my mattress that is supposed to block EMF (long story), but I don’t know how effective it is.

        On the subject of histamine, I have a real sensitivity to antihistamine medication (especially diphenhydramine and drugs like Reglan and Promethazine). I wonder if my histamine may be too low, instead of too high???

        I tested a high positive for MCTD (positive ANA and high RNP), which should mean quite a bit of inflammation, but on a retest I was negative….then, on another retest, I had a positive ANA but negative RNP. My sed rate and other levels varied (almost conflicting the pos and neg results). My rheumy determined that I did not have inflammation going on, but I am positive there is. Every other doc I see agrees, especially my GI, as I have also been diagnosed with Pelvic Floor Dysfunction. My neurologist has diagnosed me with FM.

        I have bone spurs impinging my spinal canal in my T4 and T5 and sometimes I wonder if I have issues with my vagus nerve, because of all of my back issues and muscle spasms. I have horrible spasms on the sides of my neck. I have brought this up to a few specialists (even pain mgmt.) and they don’t think any of my issues have to do with it, but I beg to differ, knowing how it affects all the organs (I was born with Medullary Sponge Kidney, and I have gastritis and gastroperesis, severe nausea, migraines, sciatica, and neropathy). I had a very rough pregnancy with horrible swelling and preeclampsia, and I think a lot of my neuropathy may have been caused by the swelling. I use a TENS machine for many of these issues.

        I am very interested in PEMF. Do you have a suggestion on a specific brand/model? I have an apt coming up soon with my sleep doc. I will ask him about it (funny, he never suggested it).

        Maybe this gives you a little more info about me. I hope you reply again, as I look forward to it.

        Thanks so much!


        1. Nattha Wannissorn

          Hi Heather,
          If you feel pain, you have some inflammation. If you have been diagnosed with anything that ends with -itis, then that’s inflammation. Blood tests like ESR and ANA can detect inflammation, but values below cutoffs don’t mean that you don’t have any. Lab tests have to be correlated in the context of your history, and signs and symptoms, so labs on their own don’t mean much.

          Look at the symptoms list here to see if you have histamine intolerance:

          I personally don’t find medical doctors very helpful. Sometimes I go to them to get diagnoses, but very often I refuse conventional treatments if I disagree with how they work. The model with trying to diagnose and treat the conditions only go so far because when you really understand the biology, everything is connected, and a lot of times the root causes seem to have nothing to do with the symptoms.

          For PEMF – here’s a suggestion: It’s a bit steep but with the money back guarantee it’s a good one to try.

  • An-Marie

    An estrogen urine test made clear that my methylation ratio (0,04) is too low (should be > 0,15) so COMT isn’t working properly. In line with this are very low bloodtest results of Q10 and cholesterol.
    However bloodtest results of vitamins B6, B12, folate acid were very good and homocysteine acid (7 uMol/L) was acceptable. And that seems strange to me, because if COMT is too low, these vitamins should be low too and the homocysteine should be high.
    So what is left to get the methylation working again?

  • Vicki Muldrow

    Hi Joe! I have read mostly your articles about my DNA and I could really use some help. I have confusing info. So, here’s my mix
    DRD2 TAQ1A AA report says low dopamine receptors
    VAL158MET AA report says low COMT
    CYP2C9 Intermittent metabolizer
    CYP3A5 “”””
    MTHFR BOTH 1298A C AA You mentioned Val158met as a bad mix
    AND 677C. T TT

    From a psychiatric standpoint do I need to increase or decrease dopamine? Is there a homeopathic solution to these genotype problems? Am I a movie title or curable?

    I would really appreciate some input, as when I put the articles together, they don’t work. There doesn’t seem to be a low Comt and Low Dopamine option. Anywhere. I feel low dopamine but the met is AA, that means high right?

    Anyways, I know this is messy but if you could try to help me out?


  • Gianluca

    What about people who are heterogeneous? Are they more similar to AA or GG? From what I looked up, all AG does it maybe give you schizophrenia and have good reading skills. I do believe I have good reading skills, is there anything else on AG? How rare/common is AG?

  • Ryan

    There’s a lot out there on marijuana use and mental illness. Just curious, have you found anything out there that proves a link, or is it still largely unknown? I ask because my brother developed a schizophreniform disorder shortly after a semester of heavy cannabis use….

  • N. M.

    I am confused as to why the title of this post is “Worrier or Warrior” —

    While I can see why having AA on COMT v158m could be described as predisposing people to be Worriers: feeling stress and having anxiety, plus being more introverted and neurotic,

    The description of people who have GG on this SNP does not seem to describe a Warrior type of person at all: more extraverted, better handling of stress, better at languages, higher emotional resilience, more cooperative, more easily hypnotized, better gut methylation, less exploratory.

    I then saw another of your posts that had “Warrior” in the title and I thought it might be a continuation of the COMT subject, but then I noticed that that post was about the MAO-A gene, and I realized that in my limited past reading on this subject, the “Warrior” label had been applied by other commentators to MAO-A and not to COMT. You wrote in that post about MAO-A that “It’s known as the “Warrior Gene” because 2R and 3R are associated with increased violence and agressiveness”, so it makes more sense to call it a “Warrior” mutation.

    On the other hand, the COMT GG version does not seem to lead to increased violence and aggressiveness, but rather to being more calm, more sociable, more able to interact with people via languages, more cooperative, more satisfied with the status quo without a need to constantly explore.

    Maybe COMT AA and GG are more like anxious high-achieving nerd vs. socially-comfortable happily-average person, or such.

    I was fascinated to learn from your post that Asian peoples have a higher incidence of G, and in contrast to the greater incidence of A in Europeans/European-descended Americans, that fits in with the stereotypical Asian focus on social cooperation, valuing of group harmony versus individual rights, generally calmer demeanors and greater concern for social politeness, living within a hierarchy, respect, rule-following, and so forth.

  • Matt

    I have COMT V158M rs4680 AA +/+

    I am taking the suppliment SAMe to assist COMT production.

    I have MTHFR A1298C rs1801131 GG +/+

    I am taking 5-MTHF to improve methylation.

    So far I feel great, my head feels clear and “normal” my anxiety is gone. I believe I am really onto something with this.

  • Ike

    I have rs4680 GG and I’ve been a worrier and suffered anxiety all my life.

  • JD

    Interesting article, Joseph…….do you know where I can find dietary guidelines for low COMT?
    For example, foods with flavanoids that don’t have the catechol structure often also shares the avoiding compounds with a catechol structure. Most of the time fruits have both in them.

    1. Matt

      Hey JD.

      I am experimenting with diet myself. I have a COMT issue. I was eating a lot of fruit, vegetables, red berries, and love red wine so that was all a problem. I’m now eating a diet mostly or starches, oats, potatoes, and rice. I throw it garlic, tumerec, ginger, and mushrooms. I stay away from red foods or foods containing tyrosine.

      If I do all this I immediately afterwards feel a sense of general wellbeing and my thoughts are less scattered. Pressing on trying to make my meals interesting.

      All the best to you.

  • Matt

    Anyone have specific diet advice to increase COMT? One caveat is that I am a vegan, I do not eat animal products and I also eat a lot of fruit. I’ve started taking large doses of B12 Methylcobalamin to boost my COMT. A concern I have is that it seems my high antioxidant intake from colorful fruits and vegetables seem to be a COMT inhibitor! Problem is this is a large part of my diet. Any suggestions?

  • Joyce

    LOL, any single trait is definitely decided by quite a lot of genes and it will take a while to unravel the complexity. It is not conclusive at all if the mean difference is smaller than SD. People start to take meds for this? LOL.

  • Eelia

    Hi Joseph, I have a triple variant and was wondering about this it seems to me in my personal life I see all the traits of both and am curious about what you think on the triple variant if anything, Also because they are opposite or sort of I was thinking that it could be a huge factor in my methylation health Thanks

  • Matt

    I have rs4680 AA.

    I’m an alcoholic and I’m currently on 125 mg of Sertraline (Zoloft) per day.

    I found the description of “The Worrier” hauntingly familiar. I have experienced obsessive compulsive disorder, agoraphobia, and some bouts of manic depression. I would be described as an “early adopter” and have an IQ from 126 to 136. In my life I have been plagued with worry and anxiety from a young age. The information here is very useful and should assist in moving forward and managing my stress and anxiety. Very helpful thanks!

  • Lyssah Van Baalen

    There is a lot of truth in here, and a lot of reliability.
    I’m homozygous on most of the critical COMT SNPs: rs4633, rs4646312, rs4680, and rs5993882. I’m also homozygous on MTHFR. I’m always wired even though I look relaxed. My boyfriend loves to scare me, because no matter how many times he’s done it, I shoot off like a rocket. I have zero cognitive abilities under stress even though I’m a successful engineer when not stressed. I have a low pain tolerance, and I consistently overreact under stressful emotional situations. I work daily to keep my environment stressfree and peaceful because I simply can’t handle it otherwise. I can’t take stimulants of any kind except coffee because they make me nuts and my body goes haywire. I am now 35 and experiencing signs of estrogen dominance because of what you mentioned in the article and trying to deal with it. The good is that I have an incredible memory, I’m creative and great with words and mind puzzles. I also have intense focus.

  • Judd Crane

    Could you explain a bit more about the Advanced Fixes For Low COMT? They seem to contradict the first recommendation of staying away from COMT inhibitors.

    Thanks for the article, by the way.

  • Alice

    Hi Joe, I recently got the following results from 23andme:

    COMT V158M rs4680 AA +/+
    COMT H62H rs4633 TT +/+
    COMT P199P rs769224 GG -/-

    How does that translate in which category my genetic mapping falls? Thanks in advance!

    1. Donna

      Did you get an answer? My COMT numbers are precisely the same ad yours…

      1. Lora Treadway

        Hello Donna! I got the exact comt numbers also. What are you doing for this? This is all new to me. Would love some info. Thanks!!

  • Nolan

    Found an interesting study that implies the opioidergic system in Met carriers, with MOR and met-enkephalin in particular. This could contribute in part to the understanding of the increased neuroticism observed in Met carriers.

    1. Joseph M. Cohen


      “We have recently shown by post-mortem receptor autoradiography that the number of mu-opioid (MOP) receptor binding sites depends on the number of COMT Met108/158 alleles in distinct human brain regions…..MOP receptor protein levels paralleled previous ligand binding results with a significantly higher MOP receptor expression in the mediodorsal nucleus of the thalamus of COMT Met108/158 allele carriers.”

  • Luis

    I’m A/G on V158M so would it be something in between? Trying to understand if I have low levels of COMT and hence take the supplements you recommend.


    1. Joseph M. Cohen


  • brenda de wet

    What are the implications if I do not have this gene ?

  • fearlessnomore

    Yes, but what if you have a COMT SNP? Is there anything you can take to help? Seems like the death sentence of genetic mutation.

  • Guin

    Hi Joe,

    As you are aware, Rs4680 is associated with a 40% decrease in COMT activity, but that is only part of the story. I’ve been digging through my 23andme report and I found several SNPs associated with COMT activity AND expression. Given that one can have several SNPs either on the gene itself or on promoter regions or exons, I found that it is likely the complex interaction btw SNPs that dictates COMT activity and expression. This paper is a good place to start:

    Here is a passage from the intro:
    “The increased cortical efficiency associated with Met carriers in neuroimaging experiments only indirectly and less distinctly translates to improved cognitive performance. For example, a recent meta-analysis (17) observed no significant effect of the Val 158 Met SNP on frontal cognitive tasks. Possible reasons for this include heterogeneities in task and sample across studies. An alternative explanation is that the cognitive action of Val 158 Met is confounded by effects of other polymorphisms within COMT, which affect the level of gene expression and are in partial, but not complete, linkage disequilibrium with Val 158 Met. The importance of several such noncoding SNPs has been convincingly demonstrated by functional studies. In the most comprehensive account of COMT function, Nackley et al. (18) described a haplotype block defined by Val 158 Met, SNP rs6269 in the P1 promoter, and two synonymous SNPs, rs4633 in exon 3 and rs4818 in exon 4. The greatest differences in COMT expression were reported between haplotypes divergent in the two synonymous SNPs, which together accounted for 9% of variance in a pain sensitivity phenotype. COMT enzymatic activity in transfected rat adrenal cells showed 18- to 25-fold differences across haplotypes, which were ascribed to differences in the stability of mRNA secondary structure (18) . ”

    So, I have a theory about COMT. We know that scores on cognitive tasks follow an inverted U-shape with respect to dopamine concentration; there is an optimal dopamine level that keeps us on task–too much or too little is bad. One possible explanation is that enzyme activity and gene expression can both dictate 1) the dopamine level associated with the optimal position on the inverted U-shape, 2) the shape of the U (i.e., wide and flat or narrow and sharp), and 3) the magnitude of the U shape (maximum cognitive ability irrespective of U-shape). For example, based on a cursory look at my COMT SNPs, it looks like I have decent enzyme activity, but crappy gene expression. My U-shape could be shifted toward higher (?) dopamine levels, but have a narrow shape (?). This would make it difficult maintain an optimal dopamine level. Other factors can influence the U-shape, for example, hypomethylation (I am compound heterozygous for the two main MTHFR SNPs). Another thing–enzymes follow Michaelis–Menten kinetics, so enzyme activity is dictated by dopamine concentration in a linear fashion at low dopamine levels and a non linear fashion at medium levels; saturation (no change with respect to concentration) occurs when maximum velocity is reached. I believe that this explains the front end of the U-shape.

    What do you think?


  • Duder

    I find it quite ironic that East Asians have a higher probability of being GG when in the West they are touted and stereotyped to being very good students and overachievers….
    …could it be that true success is tied to those with low IQs ( those whom are less likely to process boredom and the tediousness of the repetitive habits that lead to success)?


    1. Joseph M. Cohen

      “Success” is a lot more than just IQ…Hard work is more important. But success does correlate with IQ.

      1. Duder

        Haha; thank you for the hasty response! I was just reading a thread at regarding the extraordinary work ethic of East Asians and I then decided to research their COMT genes only to stumble onto your website. Initially I expected the East Asians to have a higher propensity to develop AA mutations (high IQ) only to my surprise that they are more likely to have the opposite (GG). I’ve read that EQ, and not IQ, is the key determining factor to success and now it seems as if the best students and professionals are the ones whom are average or slightly above average in IQ but they do possess the ability to persist. I speculate that people with very high IQs are average workers because they process boredom too easily and thus stop persisting and are less likely to attain the highest orders of society. True or false?

        1. Joseph M. Cohen

          There’s something to that idea…but overall false, IMO

  • Kyle

    What are good supplements for Warrior A?

  • Jack

    “Interestingly, the AG group tended to have the best IQ (both verbal and performance IQ) and best scores overall”

    As a fellow AG that’s good to know!

    On As: “This type doesn’t do well with Modafinil”

    Can you clarify that statement? What do you mean by “doesn’t do well”? I have taken Modafinil but ultimately thought it was 80% placebo as it had almost no effect on me.

  • Johnny G

    Not sure if anyone will see this, but what can I do if I’m AG for COMT V158M?

    Obviously there are advantages, but I have a really bad reaction to stress. I cannot even think properly when a certain level of stress is in my daily life. Any supplements that could help me? I’ve tried basically every psychiatric medication that had a chance at helping me, and nothing helped without causing other problems.

  • Gabriel

    From the abstract i don’t see paroxetine compared to other SSRI. What does this study mean? That rs4680 polymorphism is a predictor to a good response to any SSRI?

  • bawsh

    Those results regarding risk of schizophrenia have been refuted in better designed studies, twice.

    1. Joseph M. Cohen

      The schizo ones have but not the schizo from marijuana. If that was included in the refutation, post a link to the study where it says that I will take it off.

    2. Joseph M. Cohen
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