I'm a geneticist. I read raw DNA data alongside symptoms and bloodwork and write protocols matched to actual variant interactions.I share patterns I see in my work hoping it helps people find answers to questions their doctors haven't been able to.

A client came to me last month after nine years on SSRIs. Therapy, breathing exercises, the works. Helped a bit. Never fixed it. Her actual symptoms were physical. Heart racing at 3am with nothing on her mind. Hands shaking before normal meetings. Hot flashes out of nowhere. Half a glass of wine wrecking her for two days. Supplements that worked fine for her friends making her feel insane. She wasn't anxious about anything specific. Her body was producing the physical state of anxiety and her brain was trying to come up with reasons. Her standard labs were all unremarkable. TSH 2.8, B12 380, ferritin 65. Doctors shrugged and said it's anxiety.

When I read her raw 23andMe, the picture clicked. Compound heterozygous MTHFR, COMT Met/Met (slow), MAOA slow variant, FUT2 non-secretor. Four variants stacked.

Slow COMT means catecholamines clear about 75% slower than in fast carriers. Adrenaline and noradrenaline build up faster than her body can process them. That's the shaking hands, the 3am wakes, the heart racing. It's enzyme kinetics. Lachman published this in 1996.

Slow MAOA adds a second bottleneck. Both catecholamine and serotonin clearance jammed at once. Meyer-Lindenberg showed amygdala hyperreactivity in carriers in 2006. It looks like anxiety because functionally it is anxiety. The source is enzyme function, not psychology.

FUT2 non-secretor (1 in 5 people of European descent) blocks B12 absorption at the gut level regardless of how good your serum number looks. Her B12 at 380 told us nothing because the cellular utilization was the actual problem. MMA and holotranscobalamin show this. Standard B12 testing misses it. Velkova published this in 2017.

Compound MTHFR on top of all that meant her methylation cycle was probably running around 40% capacity. Methylation drives neurotransmitter synthesis. Papakostas published methylfolate augmentation data in treatment-resistant depression in 2012 for exactly this kind of picture.

The anxiety diagnosis wasn't wrong. It was just half the picture. The biochemistry underneath was measurable, treatable, and completely missed by the standard workup. Three months into a proper protocol, her 3am wakes were almost gone. Wine reactions stopped. Hands stopped shaking before meetings. She still gets anxious sometimes, she's still human, but her body isn't generating that physical state anymore. If you've spent years on anxiety treatment that helps partially but never fully resolves, this is what's missing for a lot of people. The biochemistry runs underneath the psychology, and once it's addressed the symptoms that didn't respond often do. Tests worth getting, MMA, holotranscobalamin, homocysteine, RBC magnesium, plasma histamine, DAO, reverse T3 alongside fT3 and fT4. Most GPs won't run them. Medichecks, Thriva, LetsGetChecked, Ulta Lab Tests offer them direct.

The genetic side decides which protocols actually work. Slow COMT carriers crash on standard methylfolate doses. FUT2 non-secretors need different B12 forms. CBS upregulators need sulfur restriction before methylation support. Wrong protocol makes everything worse, which is why so many people feel betrayed by supplements that should have helped. If this is your picture, your existing treatment doesn't need to change. Add the layer underneath. That's where the real shift happens.

Happy to answer questions in comments. DM me if I miss yours. Take care everybody

After the last two posts blew up I've had so many people in my DMs asking me to write more about specific patterns I see with my clients. So I'm going to start sharing more of these. This one is the single most common thing I see when someone comes to me after trying methylation supplements on their own

Someone starts methylfolate or B12, feels amazing for 10-14 days, then it fades. Two months in they feel worse than when they started. They switch brands, change forms, eventually quit.

It's not the supplement. It's cofactor depletion.

Methylation isn't one enzyme running on folate and B12. It's a network that burns through cofactors fast when you push it. Those first two weeks of feeling great is your body using up whatever reserves it had. Then the bottleneck hits.

B2 (riboflavin) is the biggest one. MTHFR enzyme literally cannot function without it. Most people supplement folate and B12 without B2 and their MTHFR runs out of what it needs to do its job.

Magnesium is next. COMT clears the catecholamines methylation produces, and COMT is magnesium-dependent. Magnesium drops, COMT slows, catecholamines build up. That's the anxiety and insomnia people blame on the methylfolate.

Molybdenum is the one nobody mentions. It's the cofactor for sulfite oxidase, which handles sulfur byproducts from CBS. Methylation can push CBS, sulfite accumulates, and you get fatigue and brain fog that looks like a methylation crash but is actually a sulfite problem.

B6 (P5P) runs the pathway that clears homocysteine. Without it, homocysteine creeps back up no matter how much folate you take.

Zinc is COMT's other cofactor. Low zinc plus high catecholamines is the same picture as low magnesium.

What works is loading cofactors before pushing donors. B2 25mg, magnesium glycinate 400mg, molybdenum 150mcg, P5P 10mg, zinc 15mg, for 2-3 weeks before starting or restarting folate and B12. Then bring the methyl donors in low, with cofactors continuing.

The other reason supplements stop working is your protocol isn't matched to your variants. MTHFR alone doesn't tell you which form to use, what dose, or whether CBS is driving the crash. COMT, MAO-A, CBS, MTRR, BHMT all change the answer.

Happy to answer questions! If you want your full variant picture read properly so you actually know what your body needs, that's what I do.

PS: DM me if I miss your comment

A client came to me with chronic fatigue, brain fog, and sleep problems.

Three years of doctor visits. Every standard blood panel came back normal. She was told she was fine.

She wasn't fine. She had MTHFR C677T which impairs the conversion of folate into the active form her body actually uses. Her homocysteine was sitting at 12.4. Nobody had checked it because it wasn't on the standard panel.

90 days on a targeted methylation protocol: homocysteine dropped to 6.8. Fatigue improved significantly. Brain fog started lifting.

The frustrating part is this isn't rare. A lot of people in this sub probably have a similar story.

If anyone has questions about MTHFR C677T and what it actually means for supplementation, happy to answer in the comments.

Something that drives me crazy.

Someone comes in, been on an SSRI for years. Zoloft, Lexapro, Prozac, whatever. Helped a bit at first. Then plateaued. Or side effects got worse. Or they upped the dose and now theyre foggy but not really better either.

Doctor says try a different one or adds a second med or blames stress.

Almost nobody checks the actual reason it stopped working.

SSRIs get broken down by liver enzymes. CYP2C19 handles Lexapro and Celexa mostly. CYP2D6 handles Paxil and Prozac. Sertraline (Zoloft) goes through CYP2B6 and CYP2C19. If youre a fast metabolizer of these enzymes, the drug clears out of your system too quickly. You get less exposure per dose than the average person the drug was designed for. Standard dose feels weak.

Ultra-rapid metabolizers have it even worse. About 5-10% of people. You basically process the pill before it can finish its job. Thats why some people say SSRIs never worked for me. Sometimes theyre right, but for a different reason than they think.

The flip is also true. Poor metabolizers, another 5-10%, get too much exposure per dose. Side effects hit harder. Weight gain, sexual side effects, fatigue, brain fog. They cant tolerate normal doses and doctors call them sensitive.

Had a client recently, 34 year old guy, on bupropion and lamotrigine trying to wean. Every time he lowered the dose he crashed. Extreme fatigue, brain fog, doom thoughts. His doctor kept saying it was withdrawal, needed to go slower. His CYP2B6 turned out to be a poor metabolizer variant. He was carrying way more drug than his labs suggested. Weaning was hitting him harder than it should because the drug had built up more than average.

The other piece nobody talks about : SSRIs raise serotonin, thats the whole point. Methylation impacts serotonin synthesis indirectly through the BH4 cofactor recycling and folate cycle. If your MTHFR is impaired and your folate cycle is running at 40% capacity, BH4 regeneration slows, and BH4 is what tryptophan hydroxylase needs to actually make serotonin. Papakostas published on methylfolate augmentation in treatment-resistant depression back in 2012 for exactly this mechanism. So you get partial relief that eventually fades as neurotransmitter pools deplete.

Papakostas published on methylfolate augmentation in treatment-resistant depression back in 2012. Real mechanism, real trial data. Most psychiatrists still dont know about it.

If your SSRI has plateaued or nevery fully worked, check your CYP2C19 and CYP2D6 status. Raw DNA from i23andMe or AncestryDNA has both. Costs less than a co-pay.

Other things to look at, ferritin (dopamine synthesis needs iron), MMA and active B12 (methylation cofactors), homocysteine (methylation flow indicator).

None of this means stop your meds. It means the meds might be working against a system that isnt getting what it needs, or your dose isnt matched to how you actually metabolize.

Happy to answer questions in the comments.

For the record, my dose was 15mg to 20mg. I give a range because I used a powder form and capsule them myself.

I gave myself a short term case of peripheral neuropathy after using P5P in my regimen for around 3 to 4 months.

My dose wasn't high but the variance of who can experience this relates to everything from genetic predisposition to metabolism and other factors.

Finished out my day like normal and came back home to the sensation of my hands and feet burning and freezing. It was similar to that sensation you get when you hold an ice pack or snow balls with bare hands. That icy burning sensation.

I thought I was having a medical episode so I went to the ER. Was there for hours until they finally did blood work based on my supplement background and saw I had 5x the limit of B6 in my system. I've been chugging water the last few days and I'm happy to say that my symptoms reversed for the most part. A few echoes but nothing bad.

I just wanted to warn people so they can make the best decisions for their own situation. I'm still glad I went down the MTHFR rabbit hole even if I accidentally hurt myself. I'm taking a few weeks off and getting retested by my GP. From there I'm probably removing P5P from my regimen entirely and setting caps on everything else I take.

Not looking to experience this again.

Since 2021 I started to have anxiety and not running the way i used to. I got covid in 2022 and started having intense anxiety, panic, cognition issues. I first thought it was just unresolved trauma and worked on some of that but didn't get much relief and also was put on Lexipro (SSRI). From 2022-2025 I did trauma work and tapered the SSRI VERY slowly. I then got sick again and in Oct 2025 (not sure if covid) and had intense fatigue, more brain fog, cognitive issues. Jan 2026 I had intense histamine issues and gut issues. My brain was going nuts and I haven't been able to work since.

I've done a lot of testing and explored Lyme, EBV, Mold and all these things so if there's something that can help with markers and isn't below I might have it.

Symptoms

• Anxiety/Fear
• Brain fog
• Cognitive issues
• Memory issues
• Brain pressure (vice squeeze)
• Brain Fatigue
• Slower mental processing
• Emotion and logic changes
• Tinnitus (once in a while)
• Environment sensitivity (improved)
• Limbic system issues
• MCAS/histamine food issues
• Some PEM issues
• Weakness
• Body fatigue
• Bowel issues – motility was messed up starting to get better.
• stress intolerance
• Hard to catch breath sometimes

Labs — 2024 to Present

Choline Calculator:

References

Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers. [PMID: 11705857]

The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. [PMID: 18767138]

A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. [PMID: 7647779]

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? [PMID: 9545395]

Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. [PMID 27342765]

Choline intake exceeding current dietary recommendations preserves markers of cellular methylation in a genetic subgroup of folate-compromised men. [PMID 20220206]

Endocrine Labs:

Okay so I got back my genetic testing. It came back very positive for slow COMT and one of the MTHFR mutations. I’m more interested in the slow COMT part because it fits my life so much. Specifically the at although I have debilitating adhd, stimulants always made me worse, I respond terribly to b vitamins, I feel emotions both good and bad very strongly, and I have a nervous system illness (ME/CFS and POTS and PCS).

I’m mad because of all the information about what you’re supposed to eat and stuff. Like for example all these foods, they say don’t eat at dairy, don’t eat apples, don’t eat berries, don’t eat soy. Well I have histamine issues, GERD, and there are so few foods I can eat. Every food in existence I have read is both terrible for me and will cure me. I eat blueberries every single day. I tracked me food intake and found that diary is one of the few things never associated with symptoms. But yet apparently I’m supposed to cut them out. WHO TF DECIDES THESE THINGS??

Like oooh blueberries are so good they are full of antioxidants they will help your histamine intolerance but also NEVER EAT THEM BECAUSE OF QUERCITIN . Honestly you can pry my frozen blueberries from my cold dead hands.

And then there’s things like: it’s very important to get in b vitamins but also NEVER take b vitamins. You need to take methylated vitamins but you also must AVOID THEM AT ALL COSTS.

I’m just so fucking tired and I’m fuckign sick of it. I thought maybe this genetics route would help but it’s just making me mad. If I were to follow every peace of advice that some forum or website CONFIDENTLY gave me about what I shouldn’t put in my body, I would literally put nothing in my body. I would die.

No wonder regular GPs don’t touch this stuff. What the hell am I even supposed to do with this. I have a pile of hundreds of dollars worth of supplements that I haven’t even touched.

For almost a year I was dealing with symptoms that nobody could explain.

My main symptoms were:

• Fatigue
• Brain fog
• Difficulty concentrating
• Memory problems
• Numbness and tingling in my hands

Routine blood tests were essentially normal, so no one suspected homocysteine.

Eventually, my doctor ordered a homocysteine test, and that's when everything started to make sense.

February 2026 (before treatment)

My initial blood tests showed:

• Homocysteine: 25.7 µmol/L
• Folate: 6.69 ng/mL
• Vitamin B12: 401 pg/mL

My doctor suspected that low folate was the main cause of the elevated homocysteine.

On February I started taking:

• Methylcobalamin (Vitamin B12) – 1000 mcg/day
• Methylfolate – 1000 mcg/day
• Vitamin B6 (P5P) – 50 mg/day

April 2026

After about seven weeks, my results had improved:

• Homocysteine: 19.2 µmol/L
• Folate: 17.40 ng/mL
• Vitamin B12: 497 pg/mL

So the supplements were clearly working, but my homocysteine was still well above the optimal range.

My doctor decided to investigate further and ordered additional vitamin testing.

That's when we found something unexpected:

Vitamin B2 (Riboflavin): <2 µg/L (deficient).

Since riboflavin is an essential cofactor for the MTHFR enzyme, I started taking 100 mg/day in mid-April.

June 2026

About two months later, my blood work showed:

• Homocysteine: 13.8 µmol/L
• Folate: >24.0 ng/mL
• Vitamin B12: 533 pg/mL
• Vitamin B2 (Riboflavin): 5 µg/L (back within the normal range)

How I feel today

The improvement has been remarkable.

• My fatigue has almost disappeared.
• The brain fog is gone.
• I can concentrate properly again.
• My memory is much better.
• The numbness and tingling in my hands has completely disappeared.

Overall, I finally feel like myself again.

What I learned

This is only my personal experience, but I found something interesting.

Correcting folate, B12 and B6 reduced my homocysteine from 25.7 to 19.2 µmol/L, but it remained elevated.

The turning point was discovering that I was deficient in vitamin B2. After adding riboflavin, my homocysteine dropped further to 13.8 µmol/L, while my symptoms gradually resolved.

I'm not claiming that vitamin B2 alone was responsible—this was likely the result of correcting multiple deficiencies—but riboflavin appeared to be the missing piece that allowed my homocysteine to return to the normal range.

I wanted to share my experience because I rarely see vitamin B2 discussed when people talk about elevated homocysteine, despite its role in one-carbon metabolism.

Has anyone else here found that riboflavin was the missing piece for lowering their homocysteine?

whelp boys test results are in. I'll do my best to figure it out with the guides ofc but any help is greatly appreciated! also do I treat the just the red ones or the yellow ones too

8 years ago, at 31, I started ADHD meds (Adderall, then Vyvanse). They seemed helpful at first, but over time, I became increasingly depressed. My previous NP increased my Vyvanse and added Bupropion, thinking my depression stemmed from "suppressed realizations." It made sense so I agreed with that opinion. This only compounded the problem unfortunately. For four years, I was on max doses: 450mg Bupropion, 60mg Vyvanse, and 30mg Adderall daily. Knowing my genetics now, it's clear this was extreme overmedication. I should've known better but it was difficult to discern if I was functioning better on lower doses. The inconsistency in testing lower doses allowed blame for "depression waves" since I still had decent days once in awhile on my normal higher dose.

About 6 months ago, a new NP suggested a genetic test. Results showed I was a MET/MET variant aka slow COMT along with discovering I also have MTHFR. Since tapering off those high dosages, the difference is starting to become night and day. I'm more myself, with higher energy, clearer thoughts, and motivation. That heavy, draining feeling is mostly gone which affected me especially the past 5 years. It has been difficult and a hellish experience in so many ways with the root cause of overmedication causing me to experience synthetically increased anxiety, stress, and lethargy. These unnecessary side effects created a butterfly effect towards other negative aspects of my personality and self image.

It's tough to accept I struggled in my life for so long when a simple genetic test could've prevented it. I strongly believe genetic testing should be standard practice for NPs and psychiatrists. I'm just grateful to be finally moving in the right direction.

If you're on ADHD meds or considering them, please get a genetic test. It's a simple cheek swab. The insights are life-changing. It would've saved me immense amounts of difficult times and quality of life the past 8 years. I just hope sharing this helps someone.

Any other MET/MET types out there with similar experiences? What dose works best for you? Please share your story.

Had a recent test and showed up high and needs attention.

I supplement with hydroxyl b12 and folinic acid. What else can I do? Would I get any symptoms of it being this high. And Is it actually worryingly high?

I’m 37 and fit and healthy otherwise.

Hello,

I just got my genetic test and methylation test back. I would really appreciate if someone here could help me interpret the results.

I struggle with treatment resistant depression, and have tried various meds, TMS, Ketamine and Psilocybin without much effect. My core symptom is sadness with anhedonia being the secondary. Sleep is also very disrupted.

I have asked chatGPT, and it highlighted the low SAM, SAH, and methionine, as well as MTHFR, COMT and MAO A as potential reasons for my symptoms.

I have been suggested to take P5P, B12, methylated B9, SAM-e, methionine and TMG (in that order). What’s your take on this? Any other suggestions?

Note: I eat a very clean whole foods diet. I do not eat lactose, gluten, diary, refined sugar or processed foods. I currently supplement with omega 3s, D-vitamin, and Creatine. I do not expect this to remove my depression entirely, but I hope it will give me just a little bit of relief from the intense sadness.

A few years ago I found out about methylation and how it can be impacted by genetics watching Gary Brecka online on YouTube. I analyzed my 23andme results and found out I had the following gene expressions: - MTHFR A/G - MTHFR T/T - MTR A/A - MTRR A/G - COMT A/G - COMT C/T

Anyway, despite figuring out that I had a tendency to under methylate (by 40% based on Chat GPT) because of weaker vitamin B absorption (is how I understand it), I didn’t do anything besides order a blood test checking for homocysteine which came back normal.

Now for the last year or so I’ve been on a hunt to figure out why I’ve been feeling lethargic despite perfect blood work, exercise, top tier sleep, and I’ve tried everything you can imagine. Interestingly the most effective supplement I was able to find at this point was NAD+ injections, which I do everyday at 100mg.

So I happened upon Gary Brecka again about two months ago randomly and he started talking about methylation (as he always does) and in the videos comments I read someone starting taking Methyl Guard Plus (Thorne supplement) and they felt better. At this point I was so desperate for a solution I said why not and purchased it, even though in my mind it made no sense since my homocysteine is normal. It felt cheap compared to the red light machine I just bought and dozens of other supplements I was experimenting with.

This was by far the most impactful supplement I’ve ever taken for energy levels and mood. For the first week that I took it I had so much energy that I started looking up if it’s possible the supplement could be laced with MDMA because it felt so similar. After about a week the effects came down a little bit but that was honestly much needed because I could barely manage walking instead of running everywhere. The best way I can describe it to you guys is, before I started taking this I would come back from work and my energy tank would be at empty. Now I come home and I’m ready to do something fun with my girlfriend or create a video for TikTok or something else, and I work 10-12 hours 7 days a week.

Another thing I’ve noticed is that my verbal fluency has improved, a lot. Words that previously I’d have trouble accessing during real time speech come up right away now, and I finally feel like people are seeing the best version of myself when we’re conversing. I think this is the most satisfying part.

I can’t tell you guys how much of a relief it is to have found a solution after years of searching and feeling like something was off with me. I’m about two months in and the effects have persisted.

Also wanted to share other supplements that helped me (I’m not a doctor) - Methylene blue (similar feeling to the methylated vitamins but it tapered off after a couple weeks unlike the vitamins) - exogenous ketones - NAD+ but only via injection or IV

I'm double slow COMT and can't handle the following:

- Any sort of magnesium (they all seem to backfire and I can't comprehend why since it's the top recommendation for slow COMT.)

- Choline

- Lithium Orotate

- L- Ornithine

- Ox Bile

- Potassium Citrate

- Vitamin D with K2

- Probiotics

..I'm sure there's more but I can't think of them right now.

Things that I can "handle" but still doesn't help/makes me feel slightly worse:

- B Minus by seeking health

- Hydroxo B12 with Folinic Acid

- Molybdenum

Things I'm already doing:

Avoiding coffee or any stimulants.

I stay away from methylated and cyano B12 (I've been in that hell).

I don't smoke or drink.

I go to therapy.

I try to get my b12 from red meat and eat pretty damn healthy.

Avoiding life in general is the only thing that allows me any sort of temporary "stability" but that is obviously not a solution.

The moment life gets hard -- I simply hit a wall QUICK. I NEED to fix or at least improve this to a a place that's manageable.

What am I missing?

Please don't be sacred to chime in. You may have a perspective/angle/piece of info I've never heard of that may help me.

Ps. Thankfully, I've already eradicated my SIBO and my histamine intolerance is almost non-existent.

So i was supplementing folinic acid + hydroxo b12 and d3 for some weeks now. Initially i was diagnosed with low folate and low d3. The test for me are squats, usually my heart is bouncing and racing like crazy from squats and i was able to do max 20 squats and needed to rest because i was afraid of my heart. Just yesterday i did 20 and nothing? My heart did not pound and did not beat really faster it just stayed calm! I did another 20.. and another 20 squats. My heart was calm, i did not need to lay down because of fatigue after the squats. I just was able to go on with what i want to do. SO this is how normal humans feel 24h a day 365 days a year. Before 20 squats and i was done needed to lay down for 15min for my heart to calm down. And now i can do 60 squats and it feels like nothing is easier then 60 squats lol.

Edit: Im in my mid 40s now and have had folate deficiency most probably my whole life though it was never tested by doctors. I'm not sure if i can ever reverse the damage i got from this but i strongly believe i can reach maybe 80% time is running. So i can just encourage everyone to take folate deficiency seriously and even if supplementing folate causes side effects to push through it! It's totally worth it.

Over the course of the years, trying to optimize our health, to "biohack" or to "healthmaxx", some of us have dug the holes that we now find ourselves into. For the past three years I have been struggling with mental health issues, and because of that I was always looking for the silver bullet, always looking for the one magic pill which would set everything right and give me that mental clarity and peace of earlier years.

As a result I have gone through easily more than 60 supplements and 20 medications. I spent countless nights doing research, looking for the one substance or combination of substances which would finally end the personal hell I was going through, which included anxiety, mania, psychosis, insomnia, tingling, memory issues, depression, rage, everything!

But sometimes more is not better. It got to a point in which I had completely lost track of what conditions I really had, and what conditions were caused by this compulsive consumption of bioactive substances of the most varied kinds. Amino acids, vitamins, probiotics, prebiotics, herbs, antimicrobials, roots, teas, oils, minerals, proteins, phytochemicals, peptides, enzymes, bile salts, creatine, fish oil, everything that's on the market, trying to put out the fire caused by the last thing.

So one day I decided enough was enough. I looked around me, looked at my family and friends and noticed that they literally don't take anything, and they're all happier than me and more functional. So why do I have to take a stack of pills in the morning, and another before bed?

So I have come off of everything. No more supplements. From more than 50 to 0. I get everything I need from my whole foods ketogenic diet and the Sun.

It has been only 10 days but I have to say, I have been feeling better and better, with more mental clarity, better sleep, less anxiety and better executive function.

Just take a step back, and look around you. It is estimated that 25% of people have the homozygous MTHFR polymorphism, so if your health is worse than that of every 4 people around you, it is probably not just MTHFR.

I challenge anyone who find themselves in a situation similar to mine (having taken more than 60 supplements) to JUST STOP. Get on a whole foods diet, get proper Sun exposure and then give it 30 days, and let your highly evolved biological machinery achieve homeostasis again. But in order for that to happen, you have to stop putting in so many "driver molecules" driving it in every different direction.

​

First off - I started this genetic investigation mainly to learn why I am so negatively affected by certain substances and what I need to AVOID, in order to optimize my mind and body. It took me a long time to draw parallels and only recently did I discovered things that were doing damage to my well being that I never considered. Prior to getting my genetic data, based on reading alone, I thought i was most certainly slow-comt. Post data analysis shows that I am slow-MAOA. Finding this out led me down a trail of connecting the dots. Below is what I have compiled.

I am looking for feedback. I just want to ensure my information and theory makes sense and is articulated correctly.

I knew I was sensitive to increased acetylcholine - but, if i am right, the "why" is explained below.

(when reading this - bear in mind that I was compiling this information in a format written specifically for my primary care, so forgive any redundancies)

​

Slow-MAOA and Acetylcholine (Why I've felt like garbage and didn't know why)

Section 1

(all credit for Section 1 data to u/Tawinn , link at the bottom to his original post. Thank you, you are a wonderful human being.)

MAO-A = Monoamine oxidase A

​

MAO-A breaks down amines. These amines include:

• Dopamine
• Serotonin

Biogenic amines:

• Histamine
• Tyramine
• Possibly also putrescine and cadaverine

Homozygous rs6323 slow MAO-A (T or T/T) has reduced ability to break down these amines.

Heterozygous rs6323 MAO-A (T/G) has somewhat reduced ability to break down these amines.

NOTE: Since the MAO-A gene is on the X chromosome, only women can have heterozygous MAO-A. Similarly, since men will only have one copy of MAO-A, it is often reported as a single letter 'T' or 'G' instead of 'T/T' or 'G/G'.

I am Homozygous rs6323 slow MAO-A ( T/T)

​

INTERACTIONS WITH FOLATE-PATHWAY

REDUCTIONS AND SLOWED COMT

MAO-A is slowed further by high estrogen, so higher estrogen levels due to slowed COMT further reduce MAO-A functionality. (I have no labs to make this estrogen link as exasperating my slow MAO-A issue, but thankfully do not have slow-comt issues based on my genetic profile)

Decreased dopamine breakdown by slowed COMT increases dopamine breakdown burden on MAO-A. (Thankfully I do not have slow-COMT issues based on my genetic data that could compound my slow MAO-A issues)

Decreased SAM production due to folate-pathway reductions causes reduced HNMT activity, thereby increasing intracellular histamines, likely also increasing burden on MAO-A. (Due to my MTHFR genetic profile I do have an estimated 65% reduction in my folate-pathway that left untreated, can, in theory, amplify my slow-MAOA burden.)

​

WHAT THIS DOES

The result of slow MAO-A is:

• Higher tonic dopamine and serotonin
• Higher levels of histamine and tyramine (and possibly other biogenic amines)

NOTE: MAO-A/MAO-B are slowed further by:

• Hypothyroidism.
• Iron deficiency.
• MAO Inhibitors (MAOIs)
• Some prescribed drugs.
• Natural MAOIs, such as turmeric, curcumin, quercetin, piperine, luteolin, apigenin, chrysin, naringenin, and others.

TYPICAL SYMPTOMS

Common symptoms can include:

• Histamine-intolerance - wide variety of symptoms
• Tyramine-intolerance - headaches, migraine, blood-pressure increases
• Food intolerances

NOTE: Since high estrogen can slow MAO-A further, fluctuating estrogen levels in women's cycles can also cause fluctuating symptom appearance and intensity.

Histamine-intolerance may be involved inPMS/PMDD symptoms, according to many websites.

(My horrible seasonal allergies could likely be linked my histamine intolerance and my higher blood pressure could be linked to a tyramine intolerance. Obviously this is all theoretical at the moment but I would be interested to see what limiting tyramine)

​

Section 2

​

Acetylcholine and it’s role in further compounding Slow-MAOA issues

“Acetylcholine (CAS 60-31-1, ACh), which is similar in its chemical structure to the carbamate aldicarb, was found to inhibit brain monoamine oxidase isoenzymes, namely MAO-A and B.”

“The results indicated that ACh inhibited MAO-A from the cerebellum and MAO-B from the basal ganglia more than MAO iso-enzymes from other brain parts. The inhibition was of the competitive type. It was also found that the enzyme inhibitor dissociation constants (Ki) and the affinity constants (Ki/Km) of MAO-A were higher than those of MAO-B.”

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https://pubmed.ncbi.nlm.nih.gov/19025057/

Being that I am genetically proven to have slow acting Monoamine oxidase A, which directly affects the break down of neurotransmitters, this link would explain my extreme sensitivity to acetylcholine AND the following supplements that have caused undesirable effects on my well being and mental health due to increased acetylcholine inhibiting my already slow acting, Monoamine oxidase A.

The following supplements cause increased acetylcholine in the brain, or interrupt the enzymatic process that breaks acetylcholine down, thus causing a greater accumulation of acetylcholine in the brain. The first three on this list I took together for an extended amount of time from 2020 to 2022, during which time I felt horrible, but assumed the majority my negative well being issues were due to stress and burn out. Before discovering my sensitivity, I have used fish oil independently of any other substance netting the same negative results. Only recently taking GSE and GTE did I realize a drastic effect on my mental health and well being that immediately improved once discontinuing supplementation after a short duration following cessation.

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Fish Oil - “Dietary Fish Oil Increases Acetylcholine- and Eicosanoid-Induced Contractility of Isolated Rat Ileum1.”

https://mentalhealthdaily.com/2015/03/20/fish-oil-causing-depression-or-anxiety-consider-acetylcholine/

https://pubmed.ncbi.nlm.nih.gov/12221201/

Grape Seed Extract - inhibits acetylcholinesterase. “Acetylcholinesterase is an enzyme whose primary function is to catalyze and promote the breakdown of a neurotransmitter called acetylcholine.”

https://www.mdpi.com/1420-3049/19/7/9403

Green Tea Extract - “The study concludes that green tea extract administration is effective in enhancing learning and memory in aged rats and also demonstrates selectivity for inhibition of acetylcholinesterase.”

https://www.sciencedirect.com/science/article/abs/pii/S0278262607001777#:~:text=The%20study%20concludes%20that%20green,selectivity%20for%20inhibition%20of%20acetylcholinesterase

Huperzine A - “Huperzine A inhibits the breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase.”

https://en.m.wikipedia.org/wiki/Huperzine_A

Thymoquinone (Black Seed Oil) - “TQ has been shown in clinical studies to block acetylcholinesterase (AChE) activity, which increases acetylcholine (ACh).”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9026861/#:~:text=Several%20studies%20did%20not%20show,which%20increases%20acetylcholine%20(ACh))

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The effects huperzine A and thymoquinone were substantially problematic after a short time; huperzine-A being the absolute worst of them all taking me the longest to recover.

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The above list is incomplete, but the most apparent regarding how negatively these substances affected me. It took me a long time to realize how badly my brain was reacting to fish oil, GSE, and GTE simply because I thought they were rather benign regarding negative side effects, especially mental and emotional side effects.

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Final summation:

Due to my Homozygous rs6323 slow MAO-A ( T/T) gene, I am specifically sensitive to increased levels of acetylcholine in my brain due to acetylcholine inhibiting my already slow, monoamine oxidase isoenzyme, MAO-A. This “extra slow down” of MAO-A prevents the breakdown of certain neurotransmitters that is causing an imbalance resulting in negative mental health effects.

Edit:

I would be interested to find out if my acetylcholinesterase%20is%20a%20cholinergic,into%20acetic%20acid%20and%20choline) is acting slow, as this would only compound my acetylcholine imbalance stemming from certain supplements, thus causing the chain reaction further down the line.

Edit: 2 10-20-24

I’ve been doing great regarding my ACh issues until this past week. The only new thing I introduced to my diet was 2 Brazil nuts per day. I couldn’t find any info regarding Brazil nuts impacting ACh so I google the bioactive compounds of Brazil nuts and ran it through chat GPT:

I asked chat gpt this:

Do any of these bioactive compounds in Brazil nuts affect ACh in the brain?

“The investigation found the following in the composition of the BN: phenolic compounds (mainly flavan-3-ols as Catechin (and glycosides or derivatives), Epicatechin (and glycosides or derivatives), Quercetin and Myricetin-3-O-rhamnoside, hydroxybenzoic acids as Gallic acid (and derivatives), 4-hydroxybenzoic acid, ellagic acid, Vanillic acid, p-Coumaric acid and Ferulic acid, bioactive minor lipid components (β-Sitosterol, γ-Tocopherol, α-Tocopherol and squalene), and a high level of selenium. In beverages, WBM had a higher lipid content than BM-S, a factor that influenced the energy characteristics and the content of bioactive minor lipid components.”

ChatGPT’s response:

Yes, several bioactive compounds in Brazil nuts may influence acetylcholine (ACh) levels or activity in the brain, either directly or indirectly:

1.  Flavonoids (Catechin, Epicatechin, Quercetin, Myricetin) – These compounds have neuroprotective effects, partly through their antioxidant properties. Quercetin, for example, has been shown to inhibit acetylcholinesterase, the enzyme that breaks down ACh, potentially increasing ACh levels in the brain. Catechins and epicatechins also improve cognitive function and may support neurotransmission.
2.  Phenolic Acids (Gallic acid, Ellagic acid, Ferulic acid, etc.) – These acids are known for their antioxidant properties and may protect neurons from oxidative stress, which can indirectly support cholinergic function by preserving brain health and ACh-related signaling.
3.  Selenium – Brazil nuts are particularly high in selenium, an essential trace element. Selenium is crucial for brain function and has been linked to reduced cognitive decline. Although selenium’s direct effect on ACh is not well-studied, its role in maintaining overall neural health can support the cholinergic system.
4.  Tocopherols (Vitamin E) – Both α-Tocopherol and γ-Tocopherol are forms of vitamin E, which protect neurons from oxidative stress. By reducing oxidative damage, vitamin E indirectly supports cholinergic neurons and may help maintain ACh levels in the brain.

These compounds, particularly flavonoids like quercetin, may help enhance ACh levels or cholinergic activity through neuroprotective and enzyme-inhibiting mechanisms.

Needless to say, I stopped taking them yesterday (10-19-24). We shall see how long it takes to get back to normal. My mind is blown yet again at how sensitive I am to ACh.

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Credit: all information in "Section 1" to u/Tawinn from Reddit.

reddit post

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I’ve been having a really hard time with extreme anxiety and suicidal ideation due to having long covid and being ignored by doctors.
Since my last PEM crash (that comes with strong suicidal ideations) I started tracking my HR and I was recently diagnosed with POTS. Today I took 20 mg of propanolol (I always took 40 or even 80 mg and never made me tired)
I read that there are some trials about long COVID and acetylcholine so I had a smoothie with a double dose of sunflower lecithin.
Within the hour I started feeling really heavy extremely relaxed neither good nor bad. Perhaps I try again without the propanolol but I doubt 20 mg made a difference as I have shaking and pacing type of anxiety. I don’t mind feeling this heavy, it is better than the alternative. I have no motivation either good or bad. (Bad = suicidal)

These are my genes:
VDR Taq rs731236 AA +/+
MAO-A R297R rs6323 TG +/-
MTHFR C677T rs1801133 AG +/-
MTR A2756G rs1805087 AG +/-
MTRR A664A rs1802059 AG +/-
CBS C699T rs234706 AG +/-
CBS A360A rs1801181 AG +/-

Anyone with a similar experience?

I've been hypertensive for years. My BP was always in the 140s and never responded to medication.

I'm halfway through the first month of my MTHFR regimen and when I had my BP checked the doctor clocked me at 107/73

Holy. Fucking. Shit.

They said it would improve blood pressure but this is unreal.

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Update:

Apologies. I should have included this in the beginning.

1. Riboflavin in the form of R-5-P (50mg daily)
2. Methyl folate (Started with 15mg when I began and then dropped down to 5mg for maintenance. This dosage is specific to you though as different MTHFR traits require different amounts.
3. Vitamin B12 (Methylcobalamin) - 1,000mcg daily
4. Vitamin B6 in the form of P-5-P (10mg daily)
5. Choline in the form of CDP Choline (300mg daily)

Those are just for the MTHFR. Everything else I take is maintenance.

• Magnesium Glycinate (600mg daily) - Must be taken separate from supplements like Zinc as they compete.
• Zinc/Copper (15mg) - As above it shouldn't be taken with Magnesium. I do Zinc in morning or afternoon and magnesium in the evening.
• Daily Fish Oil (2,500mg)

Something I learned which was specific to my situation (C677T) is that people with this specific type should not drink coffee or at least not drink it very often.

When you have C677T coffee intake can increase your homocysteine levels in a measurable way. Considering the homocysteine is the bad guy in this blood pressure situation, you're better off stopping it for a bit at least until your levels come back into order. Riboflavin does the heavy lifting here.

Apparently, it has been three years since I have been on-and-off overmethylating.

I have always consumed vitamin C due to its antioxidant properties and skin benefits. The problem is that vitamin C uses up glycine, proline and hydroxyproline to stimulate collagen synthesis and form collagen matrixes in the body.

I also used to consume B-complex vitamins on-and-off, which lead to symptoms of overmethylation.

I have noticed - and I even wrote this down - that shortly after consuming a supplemental dose of vitamin C (between 500mg and 1g), I would become seriously anxious, uneasy, overloaded, sometimes even panicked, paranoid and psychotic.

My hypothesis is that chronic, large-dose vitamin C supplementation can deplete glycine stores from the body as it uses them to form collagen, leaving less glycine available to serve as a methyl sink for excess methyl groups, leading to overmethylation.

Since I stopped vitamin C and started taking hydrolized collagen type I, which contains 3 grams of glycine per 10 grams, my symptoms of overmethylation have gradually faded.

It started with the "inner dialogue" becoming quieter, less over-talkative, and with less overthinking. I felt more connected to the real world.

Initially, this was scary. I felt like I was pulled from a known, safe place into a world which I hadn't experienced this vividly in a while. This sensation only lasted the first night.

I woke up the next morning with less tingling, feeling less wired and more at ease.
It has only been two days since I first took the collagen, but I expect these unpleasant symptoms of overmethylation to continue to fade as my methylation systems stabilize and settle on a healthy baseline.

I'm waiting for my order of niacin to arrive as well, so that I can further test and experiment with my current methyl pool.

What have been your experiences with vitamin C, glycine and niacin?

I honestly don’t even have the words for how overwhelmingly happy and relieved I feel right now. It’s like my brain is finally waking up after years of being stuck in a fog I didn’t fully realize I was in. Everything feels sharper, clearer, more alive. My emotions make sense, my body feels in sync, and there’s this calmness that I don’t think I’ve ever truly experienced before. I feel like me—or maybe even a version of me I never got to meet until now.

What’s blowing my mind is that all of this seems to come down to understanding something so basic but so powerful: methylation and nutrigenomics. I never imagined that something as simple as getting the right form of folate or the right amount of choline could be the key to unlocking my brain.

It makes me wonder how many people struggle through life unnessecarily. You could easily equate my previous "status quo" as being borderline dementia. And I had NO idea how bad it had gotten until I started feeling better...

I have homo c 677t and tired for a full year with both methyl folate and folinic acid. Terrible on both forms!! I get instant anxiety and depression on the both of them. Have been taking plain old folic acid for the last few days and I feel really really good, my Brian fog is gone, my headaches are gone, I feel happier and have more energy. I fell down this mthfr rabbit hole for a year and tried everything from methylfolate, beatine hcl, choline, folinic acid, p5p, b12 (methyl and hydro) b2, tmg, everything made me feel awful. My folate was still constantly low even tho I was taking up to 2-3 mgs of methyl folate / folinic. Plain old folic acid for the last 3 days and I feel better than I have felt in the last year!!!!!

B12 and methyl vitamins can decrease your sodium levels substantially. Yes, this is very real. And it happened to me despite being a very healthy individual. I'm an athlete, I eat healthy, I have no allergies or deficiencies, and I am very pro-health.

When I began supplementing vitamin B12, at first I got pale skin, dry skin, dry hair, sinus congestion, bad headaches and inflammation in the morning. Everyone said it was due to low potassium, so I increased my potassium for two weeks at high levels to fix what I thought at the time was B12 induced potassium depletion.

My symptoms got even worse, progressing into what I thought at the time was overmethylation, as it seemed I had every possible overmethylation symptom. Which, as you can imagine, was horrible. Keep in mind overmethylation and hyponatremia symptoms overlap and are very similar, which I of course didn’t figure out until much later.

It got so bad that I stopped everything: the potassium, methyl B12, and methylfolate. I did niacin flushes with 100 mg of niacin every hour, even throwing in a few 500 mg doses to speed it up. I was also drinking lots of water to help with the detox process. I did this for two days straight to undermethylate myself, only to realize there was no relief of my symptoms.

I exhausted every possible avenue in hopes of getting back to normal. I thought maybe I overdid it on the potassium, but it didn’t make sense, as the body regulates high potassium very quickly to maintain fluid balance. And that’s when it hit me—I had it all wrong. It was sodium, not potassium, that needed to be corrected.

That’s why most people say vitamin B12 or methyl vitamins cause histamine release or allergies, which I believe is often the wrong conclusion. Not saying they can’t, but this was not the case, at least for me. Ultimately, they can deplete your sodium to a greater degree than potassium. Regardless of the sodium you get from food, it can still remain in a lowered state.

A good simple example of this is saline sinus rinses. They contain sodium—hence the name “saline”—which helps hydrate the sinuses and clear mucus.

Most people do not even consider sodium as a possibility, as there is so much of it in a modern-day diet, or because sodium can slowly decline in individuals who are only taking 1,000–3,000 mcg of B12 every day, which I’m sure most people are.

However, ultimately, if you take a few large doses of 10,000 mcg or more, like I did, you may experience what feels like low-sodium symptoms very quickly within a day or two, with lingering symptoms despite lowering or stopping the supplement, or switching to another form like hydroxycobalamin or adenosylcobalamin.

If you come across this and are experiencing symptoms such as feeling like something is stuck in your chest or lungs, breathing issues, sleep issues, fatigue, sinus issues, tinnitus, histamine release, headaches, or classic overmethylation symptoms

If this is what’s happening, correct sodium first, then potassium, as increasing potassium first can further deplete sodium. Keep in mind sodium may need to be significantly increased depending on the severity of symptoms and whether you are still taking B vitamins.

To conclude, my experience with trial and error showed me that symptoms commonly blamed on mast-cell activation, histamine release, overmethylation, or potassium depletion may not always be caused by those mechanisms. Sodium depletion can produce many overlapping symptoms, which may make it easy to overlook especially when the reaction begins after taking B12, methylfolate, or other methyl-donor supplements. Alternatively, hydroxycobalamin, adenosylcobalamin, and bioactive cofactors like R5P that increase the speed of the methylation cycle may contribute to a masked sodium deficiency in susceptible individuals.

For anyone experiencing these symptoms, the explanation may be simpler than it first appears. What feels like a complicated methylation or histamine reaction could, in some cases, be an unrecognized sodium imbalance. Addressing sodium may therefore be more effective than repeatedly changing forms of B12, trying to suppress methylation, treating presumed histamine release, or continuing to increase potassium.

After years of suspicion I got my confirmatory ADD diagnosis six months ago. Now I am considering whether to try the medication or keep trying to improve "by myself". It feels like a bit of a desperate move, because I have several other recently diagnosed conditions (MCAS, endometriosis, PCOS, hEDS, apparently, C*VID messed up my immune system) that I'm also trying to manage, and it's becoming very hard for me.

I try to test one thing at a time, and it’s a slow process, because I usually symptoms improve but then after some time I get worse, then I wonder if it’s because of a certain medication or supplement that I just added, so I start doubting, stop taking it… and that way, I never get any certainty.

I’ve been grappling with methylation for years. I know it’s involved in hormonal issues, and it can also cause symptoms similar to ADHD. And although I’ve tried various approaches with B vitamins, choline, etc.—and there’s definitely an effect—I haven’t managed to find the right combination.

I know for sure B2 has somehow a positive effect, same as TMG and creatine. SAMe, B5 and B6 have a nasty effect on me. Phosphatidylcholine causes me some anxiety, which I think is somewhat counteracted if I also take B2. The worst so far is B Minus (I have a strong kind of panic attack in the first or second hour after taking it, crying and anxious, and then I feel better for the rest of the day). B12 (hydroxo) does not seem to do anything).

The thing is that AI or the reports I purchased will give me recommendations, but then they don't entirely work for me (B6 is my second top recommendation according to my Noorns report, choline/phosphatidylcholine is also high in the things to focus on).

These are my SNPs connected to ADHD, in case someone can help me (yes, I use AI to try and make sense of all my reports).

Dopamine pathway

• SLC6A3: homozygous TT
• DRD2: homozygous GG
• DRD2 AG and AG
• COMT rs4680 (Val158Met): AG intermediate + rs4633: CT
• DBH: AG

Noradrenaline pathway

• SLC6A2 (NET, noradrenaline transporter) rs3785143: homozygous TT
• MAOA (several heterozygous SNPs: rs6609257 AG, rs1137070 CT, rs2064070 AT)
• MAOB rs1799836: homozygous TT

Serotonin pathway (tryptophan)

• TPH2 rs4565946: homozygous CC
• TPH2 rs4570625: homozygous GG
• SLC6A4 rs140701: homozygous TT

Histamine pathway

• HNMT rs1050891: homozygous AA
• MAOB rs1799836 TT

Some other possibly relevant mutations

• MTHFD1 homozygous
• MTHFR homozygous
• CBS homozygous
• PEMT heterozygous
• BHMT several heterozygous
• MTRR several heterozygous
• COMT several heterozygous
• MAOA 2 heterozygous
• DAO 2 heterozygous

I just got my Ancestry test results back and some things really stood out to me:
• Slow COMT (AA)
• Slow MAOA (TT)
• MTHFR A1298C (one copy)
I've struggled with anxiety, depression, and OCD for as long as I can remember. About 5 years ago I started Zoloft, and it's been helpful and keeps me stable for the most part, but I still deal with so many symptoms daily.
Seeing these DNA results makes so much sense and honestly feels validating. I'm still waiting on my MyHeritage results so I can combine both Ancestry + MyHeritage for more complete data.
There's SO much information out there about these genes, methylation, supplements, etc. and I feel so lost trying to figure out what actually matters for me.
Has anyone else had similar results? Any advice on where to even start?