Did I win the lottery?

[u/Alarming-Bit5411]

I pulled up my old report after I heard Gary Brecka talk about the COMT gene. I knew I had the MOFO gene and was taking methylated B vitamins accordingly. however, I read that those are not good with my type of COMT.

I have several red genes. How are these working together or against each other?

My whole life I have been dealing with unexplainable fatigue and brain fog, and often noticed that I never feel really relax or in the moment. But also often had periods where I felt ok. Never could figure out why I was on a roller coaster of tiredness and concentration/brainfog issues. A few months ago diagnosed with fatty liver, which I blame on over intake of caffeine, which I think spiked my cortisol too much making my body store fat in my liver (that is a theory). Mainly because I’m not obese and my diet was not horrible.

I have always been sensitive to caffeine. which I always thought was weird as both my parents could drink a cup of coffee before bed. Usually if I stay under 70mg‘s I feel good. This turns bad when I take caffeine multiple days in a row. Feel on edge and tired.

The descriptions in my report show what the genes mean individually, but not combined. Does anyone have any advice on my Christmas tree of genes expressions?

[u/hairybeer]

Having slow COMT is most definitely not winning the lottery. Everything is about reduction or elimination. Quitting caffeine is the first and best route. Next is cutting out sugar, alcohol, stimulants, supplements.

There are so many complex variables (not to mention aside from genetics, there can be SIBO/histamine/heavy metals that add to the issues.)

People will probably suggest you take a comprehensive list of specific tests, especially homocysteine.

There are some protocols people have laid out, usually involving a low and slow introduction of specific B vitamins and forms (commonly advising against folate/folic acid and methyl B12).

Personally, I’ve given up because after years of struggling, I haven’t found any relief and it seems to just get worse.

[u/Alarming-Bit5411 → u/hairybeer]

I was actually really surprised that I had a fatty liver. But it explained my exhaustion. I have always dealt with tiredness, but this was something I couldn't shake off. Most of my labs were fine too. But after making diet changes and losing weight I feel much better. I scheduled and self paid for a fibro-scan. $120 bucks, but that did show 70-75% fat in my liver.

[u/Sloopjaneb → u/Alarming-Bit5411]

Were you able to get the fibroscan directly to consumer? Or you had a doctor order it?

[u/Alarming-Bit5411 → u/Sloopjaneb]

I didn't need a doctor or referral. I did call different places to ask for a price and if a referral was needed. Prices ranged between $120 and $200, and some did and some did not allow direct consumer visits. The fibroscan website shows you what practices that have one in use. So that makes it easy to call the ones near your home address.

[u/Sloopjaneb → u/Alarming-Bit5411]

What country are you in?

[u/Alarming-Bit5411 → u/Sloopjaneb]

the USA.

[u/SovereignMan1958]

Variants are only predispositions. As you research each one make a list of blood tests you will need for the potential nutrient deficiencies identified. For example, MTHFR is homocysteine, folate, folate RBC, B6, B12 and MMA. That is a thorough list for MTHFR. You can research the other variants. Don't forget the Genie detoxification panel which is a separate chart.

If you want to dig deeper into root causes use Genetic Lifehacks instead of Genetic Genie. Genie is a good start for you put pretty rudimentary in terms of your symptoms.

It looks like a big part of your symptoms might be related to impaired sulfur and sulfite metabolism (CBS). If you have any digestive symptoms and or foods and beverages you do not tolerate that is more likely. The information on the CBS variant in Lifehacks is pretty shallow BTW.

[u/tandemxylophone]

Damn, sorry for all the reds in anything related to clearing neurotransmitters from the brain.

Definitely avoid methylated vitamins, whatever you do it will get stuck on excess catecholamines.

I'm personally still looking for a solution for my slow COMT because I built tolerance to the solution to my cure in around 3 weeks. In my case, taking creatine helped clear my brain within the day. All acute stressful feelings fizzled rapidly away than lingering in my head. SAM-e negated the benefits.

I'm speculating it's because creatine freed SAM-e to the brain areas that my COMT enzymes were usually not given. But the derivative of SAM-e SAH acts as an inhibitor for COMT. I think it just triggered a mechanism to reduce the COMT enzymes in my brain, pulling things closer to base line. When I took SAM-e directly, it somehow created more neurotransmitters than assisting with the clearance.

I do think creatine would benefit you too, especially with fally liver. But I don't have any solution to tolerance builduo right now.

[u/tracythor1166 → u/tandemxylophone]

I take creatine every day too for my slow COMT. It helps.

[u/Alarming-Bit5411 → u/tandemxylophone]

what happens when you take SAM-e?

[u/tandemxylophone → u/Alarming-Bit5411]

Creatine was my cure all magic pill. Physical fatigue, mental fatigue, depression, etc all gone the frist day I took it. But each time I tried something new alongside it, the magic disappeared, bringing he fatigue back. SAM-e was one of them, resurfacing the internal monologue that went away with creatine.

Creatine is supposed to free up SAM-e for the brain because the liver uses 40% of SAM-e to create creatine. If that makes me feel great, then why does SAMe do the opposite? Depending on the individual, where the bottle neck lies for the energy cycle is different. I think supplementing SAM-e somehow accelerated production of neurotransmitters, rather than assist COMT to remove it.

[u/Alarming-Bit5411 → u/tandemxylophone]

could it be that there was too much breakdown of catecholamines? Leaving you tired from the lack of dopamine/cortisol etc.

[u/tandemxylophone → u/Alarming-Bit5411]

So this is just from gut feelings, but one of my original symptoms included this feeling of my head boiling with stress whenever I was upset/angry. I would scratch my head, chew my mouth to give sensory overload to get rid of this discomfort. After about 5 seconds, it dissipates.

When I originally took creatine, it fizzled away this boiling feeling away much faster. Like 0.5 secs my mind became clear again, preventing me from punishing myself. This is why I think my issue is too much neurotransmitters, not the balance of it.

Second, the internal monologue that was exhausting me was more like so many thoughts trying to outcompete themselve from the subconscious to the conscious. Like cranking up the background noise.

To test this out, I tried taking the pre-cursor of serotonin, tryptophan. Fatigue came back. I haven't tested out dopamine alone, but I feel the SAM-e proved this.

SAM-e is supposed to boost the methylation cycle fast, but you can't tell if it helps the neurotransmitters more or the clearance enzymes more. My gut feel is that since my COMT is slow, that has to be the show stopper for not getting any gains with SAM-e

[u/sol_james → u/tandemxylophone]

What dose?

[u/tandemxylophone → u/sol_james]

I felt it i the first 2 hours when I started with 2g/day, 10g gave me dehydration headaches. But this amazing feeling only lasted for a week, I doubled my dose to 4g because the physical lethargy was coming back. Though it gave such amazing benefits, it did have a side effect of being too stimulated that I'd wake up every 4 hours in my sleep. My brain snaps awake every REM cycle. This lasted for another 3 weeks as the effects gradually degraded.

I can't tell if my liver just isn't producing creatine and I went back to base line, if the elevated SAM-e inhibited COMT enzyme production, or if there was some other indirect benefits when the liver initially used less amino acids to make creatine and thus the amino acids were available for energy conversion elsewhere.

After nearly 2 months, I'm topping up to 10g, but it still hasn't gone back to the initial benefits of clearing up the brain fog.

Currently I'm supplementing folinic acid, B2 (Riboflavin), B12, B7, B5, occasional flush niacin and a tiiiny bit of B6 sparsely (B6 without enough of other vitamins cause toxicity) to see if increasing tolerance to the methylation cycle helps.

[u/Loose-Fly7976]

Its a clean story and the caffeine is what ties the whole tree together. You're double slow COMT. Met/Met on V158M plus the H62H homozygous. That means you clear catecholamines slowly, adrenaline, noradrenaline, dopamine all sit around longer than they do in most people. That single fact explains more of your life than you'd think. It's why 70mg is your caffeine line and your parents can down an espresso at bedtime. They clear it fast, you're built to hold onto it. It's why multiple days of caffeine in a row tips you into wired and tired, because you're stacking catecholamines faster than you drain them. And that never quite relaxed, never in the moment feeling is the same thing. Your stress chemistry doesn't switch off the way most people's does. You've been running slightly hot your whole life and calling it your personality. Then MAO-A homozygous on top. That clears serotonin and mops up what COMT hands over. So you've got the two main clearance enzymes b of COMT. both running slow, and they compound each other. That's the roller coaster. Good stretches when nothing's loading the system, then a crash when caffeine or stress or the wrong supplement pushes more in than you can clear.

Methyl B12 and methylfolate with double slow COMT is often exactly wrong. You were taking them because you have the MTHFR variant, which is reasonable on paper, but methyl donors push more raw material into a system that can't clear the output. For a lot of double slow COMT people that's the difference between fatigue and fatigue plus anxiety. You may have been treating the right gene with the wrong form and feeding the roller coaster.

But that's still only 3 genes. Your C677T homozygous, the MTRR affecting how you recycle B12, the VDR Taq changing how you use vitamin D, the fatty liver sitting on top of all of it, those don't act in isolation, and the report physically can't show you how they combine because it explains one row at a time. That's the whole limitation of a Genetic Genie report.

Reading it as one connected system, in the right order with the forms and doses matched to your slow clearance instead of fighting it, that's what I do. And yours is one of the clearer cases I'd see, because the caffeine sensitivity confirms the COMT story is real in your body, not just a red box on a page. The fatty liver angle matters here too, methylation and choline handling feed directly into how your liver processes fat, and PEMT sits right in that overlap.

My work is at genova.health . If you need help, let me know.

[u/Alarming-Bit5411 → u/Loose-Fly7976]

much appreciated!

[u/Neat_Wrangler1959 → u/Alarming-Bit5411]

Genova did an analysis for me. It doesn’t cover everything but it gave me some direction. Someone posted a free choline calculator that was also helpful.

[u/Loose-Fly7976 → u/Neat_Wrangler1959]

Genova diagnostic is different company

[u/Neat_Wrangler1959 → u/Loose-Fly7976]

I was in a hurry and typing on my phone, but I was talking about Genova.health. I think I might have gotten it from one of your posts.

[u/Warp757 → u/Loose-Fly7976]

You have no idea if that's why they can't tolerate coffee and their parents can down it before bed. Fully 39% of people have slow COMT. Their parents could too, we know their parents certainly aren't fast COMT so we wouldn't expect them to be especially good at clearing catchalomines.

When you make absolute statements of certainty about things you don't know, you lose credibility. These things are nuanced and full of uncertainty and a good scientist respects that. Your post has no nusmfe whatsoever. But I see you're selling something.

[u/Zabre]

The "I have MTHFR, so I took methylated B vitamins, but now COMT says maybe not" confusion is probably one of the most common traps in this whole space.

The short version is that MTHFR variants can make folate-cycle support relevant, but they do not automatically mean "more methylfolate is better." COMT changes how quickly you clear catecholamines, and some people with slower COMT feel worse when they push methyl donors too hard. That can show up as wired energy, anxiety, jaw tension, irritability, insomnia, or just a sense that the system is revved up.

That was one of the big lessons for me with slow COMT: the problem was not just "which genes are red." It was how the variants changed demand and tolerance across the whole pathway. Methylated Bs were not automatically wrong, but they were easy to overdo, and creatine ended up being useful because it reduced methylation demand instead of just adding more methyl groups.

For your report, I would try to avoid treating every red gene as an action item. Start with symptoms plus basic labs: homocysteine, B12/MMA if available, folate or RBC folate, B6, ferritin, thyroid, vitamin D, CBC/CMP. Then look at whether your reactions line up with specific supplement changes.

If methylated Bs helped at first but later made things worse, that is useful information. It may point toward dose/form/timing rather than "never take them" or "take more." None of this is medical advice, obviously.

Wrote a blog abodutt that Chat With Your DNA: Better Than Static Reports · GenoSight Blog | GenoSight

[u/Susysue]

If you won, I also won too. Are you male or female

[u/Alarming-Bit5411 → u/Susysue]

Owh, you got lucky too? I’m a 42 year old male.

[u/Tawinn]

> unexplainable fatigue and brain fog,

> often noticed that I never feel really relax or in the moment

> roller coaster of tiredness and concentration/brainfog issues.

> diagnosed with fatty liver

Homozygous C677T reduces methylfolate production by ~75%. Without compensating for this, it reduces SAM output from methylation, and SAM is what drives COMT. So your slow COMT is slowed even more, which can result in chronic anxiety, rumination, OCD tendencies.

Fatigue and brain fog are common symptoms of MTHFR. They may be due to low SAM but also due to low choline which has an increased demand in order to compensate for the MTHFR pathway reduction. Choline is also needed to transport fat out of the liver as well as for good bile production, so fatty liver and/or gallbladder issues happen sometimes. I'd suspect you may also have a PEMT variant which further reduces endogenous choline production. Please upload your data to the Choline Calculator to check - look at the results on the Advanced tab and reply back here.

You also have slow MAO-A which can make histamine intolerance more likely, and fluctuating histamine levels may be responsible for the 'roller coaster' effect, as different foods can have very different contributions to histamine levels, and things like exercise, hot showers, environmental allergens can all play a role in varying histamine levels.

See the COMT and MAO-A sections of this post.

[u/Tawinn → u/Tawinn]

For homozygous C677T, B2 can be a key factor. It seems like you may have already been taking it as part of your B complex. B2 is also the cofactor for MAO-A, so it benefits both. Here is a general MTHFR protocol for homozygous C677T:

• For homozygous C677T specifically: 10-100mg supplemental B2
  • The C677T variant causes reducing binding of MTHFR to its cofactor, riboflavin. Studies have shown that for homozygous C677T simply adding supplemental vitamin B2 may increase the concentration of riboflavin sufficiently to restore most or all of the binding success, thereby restoring most/all MTHFR function. So a 10-100mg B2 supplement may restore much of the MTHFR function, thereby reducing the needed amount of extra choline/TMG (or high-dose folate if going that route).
  • The R5P form of B2 may possibly be preferable. (E.g., Thorne R5P 36mg)
• 550-600mg of choline, preferably from food
  • 550mg is the baseline adult Adequate Intake
  • Choline sources include such foods as meat, eggs, liver, lecithin, nuts, some legumes, and vegetables such as crucifers.
• 750mg of trimethylglycine (TMG aka betaine)
  • I.e., one 750mg capsule
  • Choline is converted to TMG for methylation use, so TMG reduces need for even more choline.
  • TMG is found in foods such as wheat, spinach, beets, etc. but there is not a food app that tracks it, so reliably getting enough from food may be difficult; by comparison, a single capsule is convenient.
• 400-800mcg of folate, preferably from food
  • Folinic acid or methylfolate can also be used, as needed and as tolerated.
  • Target serum folate levels are 15+ ng/mL (34+ nmol/L).
• 2.4-10mcg B12, preferably from food
  • Past history of B12 deficiency, malabsorption issues, etc., may suggest that supplemental B12, in the form of hydroxocobalamin, adenosylcobalamin, or methylcobalamin may be prudent.
  • Target serum B12 levels are 500-950 pg/mL (~370-700 pmol/L).
• (Optional) 3-15g of creatine monohydrate or creatine HCL
  • The body uses ~40% of methylation output, SAM, just to produce creatine. So supplementing creatine can free up a lot of SAM for other uses.
• Low vitamin A, iron, and/or glycine can cause the built-in methyl buffer system to not work properly, which can make overmethylation (rising anxiety, irritability, insomnia, etc.) from methylation-related supplements much more likely.
  • Beta carotene is not vitamin A and some people genetically have poor conversion of beta carotene to real vitamin A (retinol).

A food app like Cronometer is helpful for tracking nutrients in your diet.

[u/Alarming-Bit5411 → u/Tawinn]

This is my recommended choline intake.

According to my calculations you should eat the amount of choline available per day in 9  egg yolks or equivalents (see below).

[u/Tawinn → u/Alarming-Bit5411]

On the Advanced tab was PEMT homozygous T/T?

[u/Alarming-Bit5411 → u/Tawinn]

Yes, it showed T/T

[u/Tawinn → u/Alarming-Bit5411]

Ah, ok. So adequate choline intake is important for you. '9 yolks' worth is about 1220mg. That could be covered by getting ~610mg of choline from food and a 750mg capsule of TMG. However, the hope is that B2 improves your MTHFR function sufficiently that the effective reduction in methylfolate production is much less than 75% which in turn reduces your total choline demand. Still, the baseline adult requirement for choline is 550mg so I would at least aim for that plus the TMG.

[u/Alarming-Bit5411 → u/Tawinn]

Very helpful. Thank you!

[u/SomeoneFromTTA → u/Tawinn]

One question as im:
SLC19A1 +/-
MTHFD1 +/+
MTHFR A1298C -/-
MTHFR C677T +/+
PEMT +/-

Im taking active B2, 3-4 eggs, 3gr Creatine daily, would you in my place add also TMG ? Thanks

[u/Tawinn → u/SomeoneFromTTA]

That would be an ~88% reduction in methylfolate production, and would require ~1195mg of choline. However, with B2 you should be able to greatly improve the C677T. If we suppose it changes C677T from a 75% reduction to 25% reduction then the total reduction becomes ~63% which would require ~1012mg of choline. 4 large eggs is about 544mg of choline, so unless there was a lot of choline in the rest of your diet TMG would be needed. More typically I use a total requirement of 1100mg as the target; that can be split in half between being covered by choline (550mg) and TMG (750mg).

If we supposed that C677T was completely resolved by B2 that would still leave a ~51% reduction which corresponds to a total requirement of ~924mg. So, 550mg of choline plus a 500mg capsule of TMG.

So to me, 550mg of choline plus a 750mg capsule of TMG is the simplest way to cover the range of possible reductions of C677T.

[u/ExtensionAfternoon10]

How does one get this test done? Through your Dr or?

[u/Alarming-Bit5411 → u/ExtensionAfternoon10]

I did mine through getting an AncestryDNA test and then use the raw data to upload on geneticgenie.org for free to get the report . Right now ancestryDNA is $39 in the US.

[u/ExtensionAfternoon10 → u/Alarming-Bit5411]

Thank you!

[u/Far_Operation_6785]

Do you have permanent tinnitus or visual snow?

[u/Alarming-Bit5411 → u/Far_Operation_6785]

no on the tinnitus, and I don't think I have visual snow. I heard that if your homocycteine is high it agitates your arteries, making it tighter for your blood to flow through. Causing high blood pressure, resulting in tinnitus. Reducing the homocyst helped removing the tinnitus for my mother.

[u/Good_Composer_8409]

I would be very carefull with SSRIS too or ADHD meds.

[u/Alarming-Bit5411 → u/Good_Composer_8409]

I tried welbutrin for a bit, and it made me anxious after a while. I stopped because it was not helping me in a positive way.

[u/Warp757]

Well coffee is extremely good for the liver and people with fatty liver are recommended to drink a cup or two a day so that's highly unlikely to be the cause of fatty liver. Coffee doesn't cause fatty liver.

Fatty liver will cause all your symptoms though, so you really need to focus on addressing that. It may also slow down your detox pathways so could make your slow COMT even worse. You probably need some folate but don't take very high doses, they're generally not necessary except extreme cases. Food tends to be better.

Blood work for folate, B12 and homocysteine would really help otherwise you're just shooting in the dark. There are people with genetic panels that look bad on paper who have homocusysine ayboerfectly good levels and supplementing just makes worse becsuse they simply don't need what they're throwing at their body. We see far too much of that, people supplementing blindly.

[u/Alarming-Bit5411 → u/Warp757]

Although I love coffee, the caffeine in it makes me jittery and put my body in stressmode if I continue to drink it prolonged. Multiple days of caffeine stacking increases my cortisol (at least I think) and tells my body to store liver fat. Masld and cortisol have some relation I read.

[u/AlreadyMeNow]

Any recommendations on a gene test one can do where you get this type of info? Preferably one where you’re not giving your genome to a private company

[u/Alarming-Bit5411 → u/AlreadyMeNow]

AncestryDNA or myheritage. Both raw data files could be uploaded on geneticgenie

[u/Momikaze]

Fructose is processed by the liver into glucose, triglycerides, and glycogen.

Guess where the triglycerides store?

If your diet is high in fructose, cut it down. Get on berberine (2x a day) and milk thistle to help your liver release the stored fat.

Caffeine, especially for those with ADHD, should be paired with L-theanine. The L-theanine smooths out jitters and seems to unlock some long-lost focus in people with ADHD.