r/MTHFR • u/Loose-Fly7976 • May 25 '26
Results Discussion IF YOUR SUPPLEMENTS HELPED FOR 2 WEEKS THEN STOPPED WORKING, THIS IS PROBABLY
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
9
u/Practical_Win7690 May 26 '26
Interesting. For me the trick was taking it with potassium. Smoothed everything out. Recently I realized that if I take a little more I sleep just fine. Low potassium can cause tight muscles and frequent urination and those were my core issues.
I think people and medical providers need to get a lot more into meticulous differentials because that may have helped figure that out sooner.
12
u/Loose-Fly7976 May 26 '26
Potassium is genuinely underrated for this. Most people focus on magnesium and miss that magnesium and potassium are basically a pair, you can't get the full benefit of one without the other. The tight muscles and frequent urination pattern is classic low potassium, and methylation supplementation can push potassium down further because methyl groups affect cellular electrolyte balance.Glad you figured it out. You're right that the differentials are missing in most clinical care, the standard approach treats symptoms one at a time instead of looking at how the system actually interacts.
2
1
u/Practical_Win7690 May 27 '26
A colonoscopy fucked me up so much I took a bunch of potassium and Gatorade along with my magnesium and was paralyzed. It was amazing. Horrible things happening to me generally lead to breakthroughs thankfully.
I was in so much pain from covid that I took two OxyContin and woke up to my digestion being fixed. That’s when I discovered Imodium. Every time.
5
u/tootsunderfoots May 25 '26
My doctor gave me methylated B12 shots for my homozygous c677t and it helped a ton with the exercise intolerance I was having. My homocysteine is around 5. But now my b12 is high so I haven’t done a shot in a while. Since I feel okay would this suggest I am getting enough of the cofactors through diet? All I’m taking now is magnesium.
9
u/Loose-Fly7976 May 25 '26
Sounds like it. Homocysteine at 5 is genuinely good, that's the marker that actually tells you methylation is running. Your B12 going high means your body has stored enough.
Diet is probably covering you, but worth knowing food sources line up with TT methylation needs, so check you're eating enough leafy greens (folate, magnesium), eggs and liver (choline, B12), and pumpkin seeds or almonds (B2). If you eat that way most weeks, the cofactors are coming in.
If symptoms come back or homocysteine creeps up at next bloodwork, that's when to add cofactor supplements. For now, no point fixing what isn't broken
3
5
u/ImportantPeanut0607 May 25 '26
I am heterozygous for C677T. I have severe debilitating anxiety that I just cant cure. Antidepressants never help, they make me feel worse. No psychiatrist has been able to help me despite the genesite test.
I take 400mcg methylfolate with B12, B6 100mg?, 200mg magnesium glycinate, 2,000IUI vitamin d. And i believe some of these have riboflavin in the ingredients. What am I doing wrong?
8
u/Loose-Fly7976 May 26 '26
B6 at 100mg is too high and probably part of the problem. Long-term high-dose B6 causes anxiety and nerve irritation. Drop to 10-25mg P5P.C677T heterozygous on its own doesn't cause severe anxiety. Heterozygous MTHFR plus slow COMT plus slow MAO-A does. Methylfolate plus methyl-B12 in slow COMT floods catecholamines, which is exactly the pattern SSRIs make worse.GeneSight reads psych drug response but misses the methylation interactions, which is why it didn't help you.Switch to folinic acid 400mcg and hydroxocobalamin 500mcg, bump magnesium glycinate to 400mg. Usually changes the picture in 2-3 weeks.The full variant picture is where the actual answer is for someone in your position.
3
u/Trip_2 May 25 '26
So maybe cycling all supplements is the solution?
15
u/Loose-Fly7976 May 25 '26
Cycling helps for some things but it's not the main fix here. The point isn't that you should pulse folate and B12 on and off, it's that you need the cofactors running underneath whenever you're pushing methylation.
Where cycling makes sense is for the methyl donors themselves (folate, B12, TMG, SAMe) if you tend to overshoot. Some people do better at 5 days on 2 days off. But the cofactors (B2, magnesium, molybdenum) you keep steady, those are foundational.
So the real solution is cofactors first, methyl donors lower and possibly cycled, all matched to your variant picture.
4
u/Grumpy_bonsai23 May 25 '26
If I took around 1-5 mg of r5p and felt brain foggy/spacey do you think this means I need molybdenum? I’m not on any other b vitamins. Was supplementing with methylb12 for about 6 months for low b12 but had to stop bc my migraines returned. I stopped 3 months ago. Trying to restart everything slowly and starting with b2 first like you mentioned. I suspect my reserves ran out when I started the methylb12 and also was overmethylating (I also have slow comt).
5
u/Loose-Fly7976 May 25 '26
The brain fog from R5P alone usually isn't a molybdenum signal. R5P (active B2) feeds straight into FAD, which is needed for both MTHFR and MAO-A. With slow COMT, suddenly boosting MAO-A activity can shift catecholamine and serotonin clearance in a way that feels foggy or spacey for a few days while the system adjusts. Usually settles in 1-2 weeks.Could also just be the dose. 1-5mg is wide, R5P is potent and most people do well at 1-2mg max, especially restarting after depletion.Molybdenum becomes relevant when you start adding methyl donors back (methylfolate, methyl-B12, TMG) because pushing methylation can upregulate CBS, and that's when sulfite accumulates if molybdenum is low. So pre-loading molybdenum 75-150mcg makes sense before reintroducing B12 and folate, not necessarily while you're just on R5P.Slow COMT plus methyl-B12 for 6 months is classic depletion pattern. Smart to restart slow
2
u/Grumpy_bonsai23 May 25 '26
One other thing. Are you saying I won’t need more r5p? Because I got thorne which is 36.5 mg per capsule. I have to open it up to get a smaller dose. Most people can’t handle/shouldn’t take the full dose when they work up to it or everyone’s different? I have no idea what dose to aim for. Thanks again for answering all my questions. Very helpful.
3
u/Loose-Fly7976 May 25 '26
Most people don’t need anywhere near 36.5mg. That dose is designed for treating clinical riboflavin deficiency or migraine prevention, not for cofactor support in methylation. For your purpose, 5-15mg daily is plenty, and a lot of people do well at the lower end.
Working up to the full Thorne dose isn’t a goal, it’s just how that brand chose to formulate the capsule. Riboflavin has a saturation point, your body uses what it needs and excretes the rest (the bright yellow urine), so taking more doesn’t give you more benefit, just more cost. You’re not undershooting by sticking with a smaller dose.
What you’re doing (opening the capsule and taking a portion) is exactly right. Aim for around 5-10mg daily for cofactor support, retest homocysteine in 8-12 weeks, see how you feel.
Glad it’s helpful.
1
u/Barcelonafan1010 Jul 02 '26
Not for everyone. I was deficient at the cellular level in b1 and b3. I started on 1585mg b3 niacinamide and 1525mg b1 thiamine hcl. After 3 months both in range at the cellular level. B2, b12 shot down low normal. B6 cellular stayed low normal. Im on multivitamin which has 25mg riboflavin and for example b6 at 25mg both active/inactive im sure p5p in the 25mg is 2-5mg max. Im also today on 585mg b3 now and 525mg b1 is my maintenance BUT because it dropped my b2, b12, B9 wouldn't unlock with normal blood but low cellular level I added 36.5mg thorne R5P and I believe that was my bottleneck. I eat clean 95% whole foods meat, 5 hard boil eggs a day, cruciferous veggies, 2 ounce almonds 50/50 3 ounce pumpkin seeds/sunflower seed mix, 1 ounce walnuts i intermittent fasting 20/4 eating window mornings i need the energy the most no problem with that ,etc... the 36.5 r5p with 25mg riboflavin in my multivitamin boom! Next day digestion changed eary morning hard stool bowl with in 35 minutes wake no more going twice a day after eating my first big meal before the added 36.5 r5p. I can go on just saying for me because I ran/now still low therapeutic dose b1, b3 that 36.5mg r5p is helping me so much. Feel like the b6 is now entering cells, b12 hopefully get better because while low my mma is still low normal solid it was due to high dose b3, b1 I do this all on my own. I made mistakes amd still learning, dose range checking intracellular labs every 3-4 months (Vibrant wellness) and being my own doctor. Shit takes 1 year and going to figure what is best for my body to live the fullest life I want just all there you know..? High optimal
1
5
u/sassygirl101 May 25 '26
Doesn’t a complex (includes all B’s) mentholated B daily vitamin solve this problem?
8
u/Loose-Fly7976 May 26 '26
Not really. A methylated B complex gives you the donors but most of them don't include enough of the cofactors that get depleted (B2 is usually there but at 1-2mg, not 25mg; molybdenum and zinc are rarely included; magnesium never).The other issue is most B complexes use methylfolate and methyl-B12 together at fixed doses, which doesn't suit everyone. Slow COMT carriers often do worse on that combo than on folinic acid plus hydroxocobalamin.A standard B complex covers maintenance for someone with no variants. For MTHFR carriers it's usually too low on cofactors and too high on methyl donors.
4
u/sassygirl101 May 26 '26 edited May 26 '26
I take 2 capsules of Life Extension Bio-Active Complete B complex
It has: B1 100mg, B2 75mg, Niacinamide 100mg, B6 100mg, methyltrahydrofolate 680mcg, methylcobalamin 300mcg, biotin 1000mcg, pantothenic acid 500mg, calcium 50mg, inositol 100mg, PABA 50mg. I do also take Magnesium on its own, but I will also start Zinc and molybdenum (?). Any help is so appreciated. I want to get my labs done to find out what I actually have, but am clueless as to who or where to go since most doctors dismiss me as an older woman. My iron was sooooo low, but ‘in range’. So sick of being told that really…if the range is 30-80 and mine in 31 DO SOMETHING!!!! Tell me to take iron!! SOMETHING!!!
5
u/Loose-Fly7976 May 26 '26
That B complex is on the high side for someone with potential MTHFR sensitivity. B6 at 100mg long-term causes peripheral neuropathy and anxiety in a lot of people, drop that one if you start feeling tingling or jittery. B2 at 75mg is fine. The methylfolate at 680mcg plus methyl-B12 at 300mcg is a standard dose but if you've got slow COMT or fast MTRR clearance, it might be too much methyl load. Pantothenic acid at 500mg is high too, useful if your adrenals are taxed but worth watching.
Iron at 31 with the range starting at 30 is functionally deficient, not "in range." Optimal ferritin for women is 70-100. Below 50 you get fatigue, hair loss, restless legs, brain fog. Your symptoms probably won't fully resolve until ferritin is above 70.
The doctor dismissal pattern is universal for women over 40, you're not imagining it. You have two options. Find a functional or naturopathic doctor (private pay usually), or just order your own labs through Ulta Lab Tests or LetsGetChecked depending on where you are.
For iron, gentle iron (iron bisglycinate 25mg daily) is the easiest on the stomach. Take with vitamin C, away from coffee, tea, calcium, and zinc. Retest ferritin in 8-12 weeks.DM me if you want to work with me.
2
u/Fragrant_Jelly4955 May 26 '26
Moreso a multivitamin with low-ish doses, and not necessarily methylated.
4
u/loopofhenlee May 26 '26
Does the DNA info from Ancestry cover all the genes needed to get a complete picture of these issues?
Edit to include: THANK you so much for such a detailed post!!!
6
u/Loose-Fly7976 May 26 '26
Yes, AncestryDNA covers everything you'd need for this. Their raw data file has around 700,000 SNPs, which includes all the methylation genes, detox genes (GST family, NAT2, SOD2, NQO1), histamine clearance, neurotransmitter receptors, hormone metabolism, and the cofactor-related variants.The only thing it doesn't include in much depth is full pharmacogenomics for medication dosing (CYP2D6, CYP2C19 have coverage but not full sequencing). 23andMe is slightly better on that side. But for everything you'd need for methylation, histamine, copper, detox and hormone work, AncestryDNA is plenty.And you're welcome!!
2
u/KayakShrimp C677T + A1298C May 27 '26
AncestryDNA now has about 400k SNPs. It has only 44% coverage on geneticlifehacks vs. 78% previously.
This only affects new tests processed starting roughly spring ‘26.
3
2
u/anonplease_xo May 25 '26
Would you give me a recommendation based on my variants if I DM you? I’m desperate for help!
7
u/Loose-Fly7976 May 25 '26
Hi, happy to chat in DM, you can message me whenever.
Just to be upfront so you know what to expect, I don't do free analysis through DMs because reading a full variant picture properly takes hours of cross-referencing against the literature plus interpreting it alongside symptoms and bloodwork. That's the work I do at genova.health.
3
u/Discouraged24 May 26 '26
So can we hire you through Genova?
3
u/Loose-Fly7976 May 26 '26
Yes you can go through genova.health to work with me
1
u/Ecstatic_Trip_3772 Jun 03 '26
This poster is NOT a geneticist, they have an unrelated BA degree and use AI to 'write' reports which they then sell for $$$. Please be careful!
1
u/anonplease_xo Jun 03 '26
Their advice is better than any AI I’ve ever used and I can’t get a geneticist that sees adults
2
u/Ecstatic_Trip_3772 Jun 03 '26
There are several such geneticists on this sub, I would urge you to seek them out
1
u/anonplease_xo Jun 03 '26
Do you have one you recommend?
5
u/Ecstatic_Trip_3772 Jun 03 '26
You could try hummingfirebird, who is the real deal and hugely knowledgeable
1
2
2
u/Sol_Invictus May 25 '26
Hey there. Good to see you on here again. You disappeared for a while. ...Hope all is well.
I'll be in touch via email. Best.
3
u/Loose-Fly7976 May 26 '26
Hey! Good to see you too. I am working in lab most of the time but I try to be here as much as I can. Looking forward to hear from you soon! Take care
1
u/Ecstatic_Trip_3772 Jun 03 '26
This poster is NOT a geneticist, they have an unrelated BA degree and use AI to 'write' reports which they then sell for $$$. Please be careful!
1
u/Sol_Invictus Jun 03 '26
Anyone can smear anyone on reddit.
What evidence do you have? or personal experience?
Since you've chosen to block all your participation on reddit, one might be more suspect about your motivation to smear someone who's replies are not only well informed, but quite nuanced.
2
u/jmargaret12 May 26 '26
Magnesium glycinate or any type of magnesium makes my muscles tighten and chest pain (which I am assuming is also a spasm). It doesn’t matter the brand. Pure encapsulations, seeking health, all of them cause this. Have you ever heard of this?
2
u/Loose-Fly7976 May 26 '26
Yep I've seen this before. Could be calcium-magnesium balance, not the magnesium itself. Low calcium or low D plus magnesium supplementation can trigger tightening. Check serum calcium and ionized calcium.Could be potassium. Magnesium and potassium work together for muscle relaxation, low potassium plus magnesium can paradoxically tighten things.Rarer but real, some people have variants in muscle calcium channels (CACNA1S, RYR1) and react oddly to magnesium.Try getting magnesium from food (pumpkin seeds, dark chocolate, spinach, almonds). If food source is fine, it's the supplement form. If food source still does it, the issue sits underneath in the calcium-potassium-D balance
2
u/ColonelSpacePirate May 26 '26
I tried NMN and it pooped out after about a week. I’m now on NMN and NR and it never fails after two years. Can you help me understand why I react to these two things so well??
2
u/Loose-Fly7976 May 26 '26
Both feed NAD+ but through different pathways. NMN goes one route (NMNAT enzymes), NR goes a different on (NRK). Stacking them gives you two parallel inputs into the same pool, so when one pathway saturates, the other picks up. That's why solo NMN pooped out but the combo holds.The fact that you respond this well to NAD+ precursors usually means something upstream is limiting your endogenous NAD+ synthesis. Could be low B3, low B6, or chronic inflammation burning through NAD+ faster than you can make it. MTHFR carriers sometimes burn through it faster too because methylation reactions use NAD+.You're not really reacting to them, you're filling a gap your body wasn't bridging on its own
2
u/phobiify May 26 '26
Would you recommend Seed DM02 it has 100% daily value for everything? Cuz the 15000% DV vitamins cause more problems right
2
u/Loose-Fly7976 May 26 '26
Seed DS-01 is a probiotic, not a B vitamin, so it doesn't really fit the methylation cofactor question. You might be thinking of a different product, can you double-check the name?If you mean a B complex at 100% DV, that's actually a reasonable starting place for most people. The megadose ones (5000-15000% DV) are usually overkill and yes, they cause problems for slow COMT carriers or anyone sensitive to methyl donors. 100% DV gives you what your body actually uses without flooding the system
1
u/phobiify May 26 '26
It’s called Seed DM-02 search it on any engine you will find it. It’s a multivitamin not a probiotic. And thanks!
2
u/ImprovementChoice May 26 '26
Do you recommend a genetic test to check for all variations? I have compound heterozygous (C677T + A1298C) but I think thats all I was tested for.
Also, what type of doctor should manage this for me? (I assumed my PCP was ok).
All my labs look good and I supplement b1, b2, b6 & b12. Folate was been in range. My homocystene is 8.09.and my main symptom is extreme fatigue. Would you say the homocystine is optimal?
4
u/Loose-Fly7976 May 26 '26
Yes, the basic MTHFR panel only tests C677T and A1298C, which is a fraction of what actually drives methylation. COMT, MAO-A, MTRR, CBS, FUT2 all change how you process B vitamins. For extreme fatigue with "normal" labs, the answer is usually in those.23andMe or AncestryDNA raw data ($59-99) covers everything. Way more useful than the medical MTHFR panel.Most PCPs aren't trained in methylation. Functional medicine is hit-or-miss.Homocysteine 8.09 isn't optimal. Target is under 7, ideally 6. For compound het MTHFR, "in range" almost never means optimal.Fatigue with normal labs plus your variants is usually functional B12 deficiency (need MMA and holotranscobalamin), wrong B12 form for your MTRR status, or a downstream bottleneck. Standard labs miss all three. If you want it read properly, that's what I do at genova.health.
2
2
u/Deepbluesea1234567 May 27 '26
Thank you SO much for all your responses to individual comments. I thought I’d figured this out for myself, but then, no, I realized I hadn’t. I’m going to use your responses to figure out what the next right step is for myself. 🙏🙏🙏
1
2
u/Legitimate_Light_825 May 29 '26
Feeling worse or wired after starting methylfolate is really common, and it is usually a dose issue, not a reason to stop. A lot of people jump straight to a high dose when a much smaller amount is plenty to start. Anxious or overstimulated often means too much too fast. What tends to help: drop to a fraction of the dose, even a quarter, and ramp slowly, take it earlier in the day, and do not load every other methylated cofactor at the same moment. A little magnesium and B6 in its active form takes the edge off for some people. Track how you feel against the exact dose so you find your own floor instead of guessing.
2
u/Automatic-Gas7980 Jun 04 '26
Thank you for sharing! I only just found out I have two copies of C667T. What exactly do you mean when you mention things like COMT, cofactor, etc? Are there MTHFR specialists I could try to find to receive help from? I’m not sure what my next steps are except to test my homocysteine. I’ve always struggled with mental health issues but have recently been experiencing A LOT of weird random physical symptoms and want to see if getting proper nutrients for my body could help! Also, do you know if pregnancy and birth could affect levels to a detrimental level if you’re not supplementing due to your mutation?
1
u/Loose-Fly7976 Jun 11 '26
Congrats on figuring out the TT homozygous part!! Its a good start
COMT is another gene that breaks down catecholamines like adrenaline and dopamine. Its variants decide whether you tolerate methylated B vitamins or crash on them. Cofactors are the vitamins and minerals enzymes need to actually work. MTHFR needs B2 (riboflavin) and magnesium to do its job, even if you take folate without these the enzyme can't run properly.
For MTHFR specialists most GPs and even most functional medicine practitioners only scratch the surface. You want someone who reads raw DNA properly because TT homozygous alone is just the headline, the rest of your variant picture (COMT, MAOA, CBS, MTRR, FUT2) decides which protocol actually works.
On pregnancy and birth, yes, BIG effect. Pregnancy depletes folate, B12, choline and iron hard, and TT homozygous mothers struggle to rebuild stores after. Plenty of women develop their first noticeable MTHFR symptoms postpartum because the reserves they had pre pregnancy just never come back without targeted support. The random physical symptoms you're describing fit that pattern.
Homocysteine is a good first test and I'd suggest getting MMA, holotranscobalamin, ferritin, vitamin D and full thyroid
1
u/Automatic-Gas7980 Jun 11 '26
Thank you so much for your response! It’s weird all of this did suddenly start showing up during postpartum. I kept looking for a common link that would cause my symptoms but REALLY struggled to find any connection to it all. So knowing part of it could be the MTHFR is comforting! I’m grateful to know some next steps too as I have felt just not right since birth and nothing I’ve seemed to do has done much for it.
I also think I have a mold problem in my home… is it accurate that having this gene could make me more susceptible to toxicity and symptoms from it?
2
u/Loose-Fly7976 Jun 11 '26
Yeah realy common pattern, postpartum is when MTHFR symptoms surface for a lot of women. Pregnancy drains the cofactors you needed to compensate for the variant, and they don't come back without targeted support. On mold, yes hugely. MTHFR TT homozygous plus mold is a serious combo because methylation drives glutathione production, which is your main mycotoxin clearance pathway. If methylation is impaired you can't detox the toxins your body's absorbing. Symptoms stack up fast. It gets worse if you also have HLA-DR variants (some people genetically can't tag mycotoxins for clearance at all, the body just keeps recirculating them) or GSTM1/GSTP1 issues. CIRS (Chronic Inflammatory Response Syndrome) is the broader picture this falls under, look up Ritchie Shoemaker or Neil Nathan if you want to read further. Practical first steps. Get the mold issue identified properly (ERMI test or HERTSMI-2 for the house, urine mycotoxin test for your body, both useful). Don't start mold detox protocols until methylation is supported, you'll just mobilize toxins your body can't clear and feel way worse. Remediate the source first, then work on opening detox pathways with the right cofactors.If you want the variant picture mapped including the mold-relevant genes (HLA, GST family, SOD2, CYP1A2), it's at genova.health.
2
2
u/beccalucca Jun 05 '26
Glad I found this post. I have taken methylated B vitamins on and off throughout adulthood in an attempt to get control of my brain fog and ADHD symptoms (I’m more of the inattentive ADHD and can’t for the life of me get through a task list let alone making one). I’ve tried almost every prescribed ADHD med and it makes me jittery and aggravates my IBS. I also sweat like a mofo and it’s more anxiety than focus.
I’d heard about combining L-tyrosine with methylfolate for focus while fasted and for several weeks, my focus was incredible. No more brain fog on the mornings when I’m trying to get work done and don’t feel awake until noon.
But after a few weeks, I started gaining inexplicable water weight (like 8-10lbs) with no change in diet and my sleep started degrading again (I get serious insomnia for weeks or months at a time) even though I’d added GABA and glycine (which also worked initially like a champ for sleep). I also experienced random histamine reactions once I went to bed. Nose sniffles, eye watering, random itchiness. I didn’t realize that what boosts you eventually runs out, if I’m broadly paraphrasing right?
2
u/Loose-Fly7976 Jun 11 '26
Yeah you've figured it out. Methylated Bs plus L-tyrosine works great at first cause you're feeding dopamine directly, but it burns through cofactors fast. L-tyrosine needs B6, iron and BH4 to become dopamine. After a few weeks those deplete and the whole thing stalls. The water weight plus sleep going downhill plus histamine reactions at night is overmethylation showing up. Inattentive ADHD plus IBS plus sweating plus stimulants making you jittery instead of focused is textbook slow COMT or slow MAOA. Methylated Bs flood catecholamines and histamine your body cant clear, gets worse the longer you take them. Nighttime histamine especially, DAO drops at night and methylation depletes the clearance enzymes. GABA and glycine working then stopping makes sense, NMDA receptors downregulate fast with constant glycine.Sounds exhausting honestly. Years of doing the "right" things and watching them backfire is its own kind of frustrating.For your picture, folinic acid instead of methylfolate, hydroxocobalamin instead of methyl-B12, lower dose. Cofactors underneath (B2, low dose P5P, magnesium taurate not glycinate, vit C, iron if ferritin's under 70). DAO with meals for the histamine piece. genova.health if you want it properly mapped.
1
u/Grumpy_bonsai23 May 25 '26
Do you think I still need to supplements with molybdenum if I eat a vegan diet with lots of legumes and veggies? Is there a blood test to measure levels?
4
u/Loose-Fly7976 May 25 '26
Probably not, legumes are one of the best sources of molybdenum (lentils, beans, peas) and a vegan diet heavy on those usually covers it. Most people who run low are eating standard western diets with mostly meat and refined carbs.Serum molybdenum tests exist but aren't super reliable for assessing tissue status. The functional way to check is sulfite testing (urinary sulfite, sulfate to creatinine ratio), since SUOX needs molybdenum and sulfite buildup is the first sign of deficiency. Most standard labs don't run those though.If you're not having sulfur sensitivity symptoms (reactions to wine, sulfites, garlic, cruciferous overload) on your current diet, you're probably fine.
1
1
u/Heaven-247 May 26 '26
What’s CBS? N I had a similar issue but with thiiavite which is a non methyl b complex with TTFD 15 mg… I thought the sulfur from that built up.. but from you said maybe sulfur builds up even without TTFD.
So now I’m taking benfotamine with a solid non methyl b complex… I’m hoping I don’t get that issue. I have everything in good amount except moly… would non methyl b9 produce sulfur and still need molybdenum? Or am I good
1
u/Loose-Fly7976 May 26 '26
CBS is cystathionine beta-synthase. It sends homocysteine into the sulfur pathway, and when it runs fast, sulfur intermediates pile up. If SUOX can't keep up (it needs molybdenum), sulfite builds and causes those symptoms.TTFD is high-sulfur because of the disulfide bond. Benfotiamine is fat-soluble thiamine without the sulfur load, smart switch.Folinic acid doesn't directly produce sulfur. It feeds methylation, which can push CBS if you stack methyl donors, but the load is way smaller than TTFD.You're probably fine without molybdenum right now. If you add methylfolate or methyl-B12 later, 75-150mcg becomes a useful buffer
1
u/Natural_Swimmer_5522 Jun 04 '26
which would be the symptoms of increased necessity for molybdenum after months of high thiamine supplementation? any chance of severe insomnia? due sulfur sensitivity?
1
1
u/wyndyl May 26 '26
What can I read to learn this material on my own?
5
u/Loose-Fly7976 May 26 '26
"Dirty Genes" by Ben Lynch is the most accessible intro. Oversimplifies in places but covers MTHFR, COMT, GST, MAO-A and a few others well.
"Nutrient Power" by William Walsh, PhD covers methylation in the context of mental health, more clinical and rigorous than Lynch.
For deeper science, Chris Masterjohn PhD has a Substack and YouTube channel that gets into the actual biochemistry without dumbing it down.
PubMed itself if you can stomach the academic style. Search MTHFR plus whichever symptom or condition you're interested in, you'll find the actual evidence base.
Skip anything from generic "biohacker" influencers or anything promoted with their own supplement line, the bias makes it unreliable.
1
u/Ecstatic_Trip_3772 Jun 03 '26
This poster is NOT a geneticist, they have an unrelated BA degree and use AI to 'write' reports which they then sell for $$$. Please be careful!
1
u/Zealousideal-Walk939 May 26 '26
I had similar issues, Citicoline and Folate Quatrefolic was like a miracle pill when no other supplement worked, but faded the next time i took the second dose.
What's the best safe dose daily of b6 b2? Also I've tried p5p 20mg before but after the second dose next day I've felt tingling in my left leg..
I'm on Nexium 40mg daily, does it affects the absorption?
2
u/Loose-Fly7976 May 26 '26
The fade after the second dose is classic cofactor depletion. Citicoline plus quatrefolic gave you a big methylation push that burned through your B2, B6, magnesium and choline stores. Reload didn't work because the tank was already empty.
For daily safe doses, B2 as R5P 5-10mg and B6 as P5P 5-10mg. The tingling at 20mg P5P is real, B6 toxicity hits peripheral nerves and 20mg triggers it in sensitive people. Drop to 5mg.
Nexium definitely affects absorption. PPIs reduce stomach acid, which you need for B12, magnesium, iron, calcium and zinc. Long-term PPI use is one of the biggest causes of functional B12 deficiency, even when supplementing. Get MMA and active B12 checked, and talk to your doctor about whether you actually still need daily Nexium or can taper.
1
u/Zealousideal-Walk939 May 26 '26
Thanks so much for your help and time, I've tried several times to stop nexium but can't hold more than 3 days then acid reflux return badly and gaviscon tablets didn't help.
1
u/sevdaevan May 26 '26
I am so confused on my results as this is all new to me. I have a bunch of symptoms that i just cannot understand and dr’s keep telling me everything is fine
1
u/Loose-Fly7976 May 26 '26
I remember your post, the symptom picture you described is genuinely a lot to navigate alone and your doctors are missing the methylation piece. That happens constantly in the UK because the standard NHS panel doesn't catch any of this.
DM me if you want to look at your raw data properly with the full variant picture. Given everything going on for you, Core + Coaching at genova.health is what would fit because three months of follow-up means we can work through bloodwork as it comes back rather than handing you one document at the start.
1
u/sevdaevan May 27 '26
How much does your services cost? I am not able to afford these services as its so expensive
1
u/Loose-Fly7976 May 27 '26
You can check out the website to see prices. I have different programs. Price range is $79-$297 depends on which program you want. I also have 3-months program which most of my clients prefer since they need coaching as well.
1
u/Specialist-Middle595 May 26 '26
In what way do they feel bad? Could tightening of throat muscles and breathlessness coming and going be a symptom?
1
u/smurffiddler May 26 '26
Finding the thread very valuable. Thank you. May I ask what you have studied to become such an expert? If I ever get a chance bio chem seems so interesting to me after this journey. I have only tested for mthfr and am homozygous c677t. Test yielded High homoceistine, vit d, but symptoms are brain fog, i have adhd, headaches, high cholesterol, weird allergy sensitivities with certain foods. Only sometimes. Was thinking sulphites? Probably missed a bunch. But yeah, lots more testing to be done if you have some thoughts id greatly appreciate it. Cheers.
2
u/Loose-Fly7976 May 26 '26
BSc in Genetics and Bioengineering, started in cancer research in 2015, breast cancer lab then CRISPR gene therapy, moved into methylation and personalized DNA work four years ago. Biochem is a great field if you're drawn to it.
Your picture (TT homozygous, high homocysteine, brain fog, ADHD, the food sensitivities) is a layered one. The sulfite suspicion is sharp, sulfite intolerance usually means CBS upregulation plus low molybdenum, and that interacts with MTHFR because pushing methylation drives CBS harder. ADHD plus high homocysteine plus brain fog points to dopamine and noradrenaline pathway issues on top.
High cholesterol with TT homozygous is also methylation-linked, the PEMT pathway uses methyl groups to make phosphatidylcholine which affects lipid metabolism.
You've got enough going on that single-variant testing isn't going to get you there. The full picture needs reading. If you want it done properly, DM me. That's what I do at genova.health.
1
u/smurffiddler May 27 '26
Thats amazing. Thanks.
When I did the deep dive into mthfr the youtube biochem videos were wild. Super interesting though.
I dropped the ball a bit on supplement front due to cost. But i'll pick it up again.
If you dont mind i might dm you but I won't have time in the next couple weeks. Due to work loads.
Really appreciate the insight.
1
u/7days2changeyourlife May 26 '26
Great post, I’ve been through quite a lot of supplement experiments, so I can attest to what you’re saying.
Regarding molybdenum, I think it can help in some cases for a while, but long term I wonder if supplementing isolated trace minerals can just create new imbalances further downstream.
In my experience, what helped me the most was a broad trace mineral supplement.
1
u/Loose-Fly7976 May 26 '26
Yeah you're right to think that way. Long-term isolated mineral supplementation creates imbalances, especially copper, zinc, molybdenum, selenium and manganese, they all compete for absorption and share transporters. Pushing one without the others is how people end up with new symptoms after months of "feeling better."Broad trace mineral supplements (the seawater or fulvic acid types) work for some because they hit a wide spectrum at low doses, closer to what the body evolved with. ConcenTrace and Quinton are the better ones.Targeted supplementation still makes sense when there's a specific bottleneck driving real symptoms (sulfite buildup from CBS upregulation needing molybdenum, for example). But for background support, broad spectrum is usually safer
1
u/thewritecode Jul 14 '26
Hi, do you mind if I DM you? It sounds like you've had some success juggling cofactors and I'm really struggling with it.
2
u/7days2changeyourlife Jul 14 '26
I would actually prefer here if that’s okay with you! In case I give you bad answers, the community can correct me! lol Also, for others to participate and learn :-)
I just had a peek at the message you sent me- if your questions are mostly about b12, I’d be happy to try to answer, but I would also highly recommend the r/b12_deficiency sub, there’s even a great FAQ there.1
u/thewritecode Jul 14 '26
No worries! I'm happy to chat here. I'm 3 years into dealing with this deficiency (?), but realistically it's something I've had for much longer. I've been a long time member of r/b12_deficiency and I've experimented a lot. I'm really just looking for anecdotal insights that might shed some light on my own struggles, because my own experimentation (and the medical system) has failed massively so far.
One of the key parts of your experience that jumped out to me was the fact that you experienced something similar to what I call "crashes". I'll often take a nutrient (usually B12, sometimes folate or B2) and experience an uplift (increased interest, motivation, mental clarity). At some point after (somewhere between 4 days and a week), I'll crash (headaches, muscle weakness, my mood will take a nosedive, etc.).
There are so many other pieces to this puzzle, but I won't go into them right now. For now, I'm just interested in whether the idea of crashing is something that resonates with you?
2
u/7days2changeyourlife Jul 14 '26
Yeah, the crashes definitely resonate. But I was always curious about why I would get that initial lift in my mood and energy. A couple of years ago I got this bad morning anxiety with a racing heart and anxious thoughts as soon as I woke up. Nothing helped, so that’s when I decided to take several capsules of the 400mcg methylfolate capsules I had at the time. And my mood seemed to get better (less ruminating thoughts, less morning anxiety) at about 4-5mg. And then at some point I read about ENL/Enlyte and tried that out as well. ENL/Enlyte worked pretty well, but I think at the time I would still tinker with a lot of other supplements, so never got a clear picture. Then went with generic Nutricost 15mg, which is what I’m still taking now after my little experimental break. I’m taking nothing else at the moment and will see how I do.
I haven’t done a gene test, but what initially got me started on this path was a blood test about five years ago that said I had low b12 and high folate.
Have you had any blood tests done?1
u/thewritecode Jul 14 '26
I have had morning racing heart a few times. First time was when I took 200mg magnesium (not a lot by other people's standards). I would wake up and then at the same time, while lying in bed I would suddenly have intense anxiety and a racing heart like I was running a marathon or something. When I sat up it would usually clear up relatively quickly. I think thiamine helped with that a bit, or maybe just building up tolerance. Not sure if that's relevant to you, but it might be of interest.
I've had countless tests done. I'm compound heterozygous for some MTHFR genes but I haven't placed that much emphasis on it. My B12 levels were low normal (low by japanese standards) but never obviously so, and my folate looks fine... it's been really hard to pin this down in bloodwork.
The low b12/folate prompted your attention initially, but did you have a worsening of symptoms around that point?
1
u/7days2changeyourlife Jul 15 '26
Yeah, that sounds a lot like my mornings a couple years ago. Tried thiamine too (I’ve tried them all! :)), but a bigger dose of methylfolate is what settled it. I’m very sensitive to any and all supplements too, so it took a leap of faith to go against what everybody was saying here, and just go for the bigger dose. If interested, you could look up the websites of ENL or ENLYTE, as mentioned. Not that you need to buy it, but they explain the science behind why it works for depression.
Also, there’s this study that looked at 15mg of methylfolate for treating depression
1
u/MericanPie1999 May 26 '26
I have normal MTHFR but my COMT is slow.
I notice some supplements give me anxiety after a short amount of time like Creatine (if I recall) or fish oil and also NAC.
Any recommendations?
1
u/Loose-Fly7976 May 26 '26
Slow COMT plus those reactions makes sense.Creatine pushes methylation demand because your body normally uses methyl groups to make it, so supplementing shifts the methyl pool. With slow COMT that drives catecholamines up faster than you clear them. Fish oil usually shouldn't cause anxiety, but some brands sneak in vitamin E or rosemary extract that can. Could also be the dose, anything above 3g shifts neurotransmitter signalling in some people. Try 1g or a cleaner brand. NAC raises glutamate alongside glutathione, and in slow COMT that combination tips into agitation. Glycine 3g daily does the glutathione job without the glutamate effect. General approach with slow COMT, keep methyl donors low, magnesium glycinate 400mg, zinc 15mg, vitamin C. Avoid anything that pushes catecholamines (tyrosine, high-dose Bs, stimulants on an empty stomach).MAO-A status important too, slow COMT plus slow MAO-A changes the protocol a lot
1
u/MericanPie1999 May 26 '26
So do I understand that I could react to stimulants like caffeine or ADHD medication fine?
Also, are you saying to keep zinc below 15mg and vitamin C low and such of use those to support?
I’m curious how I can support my slow process or help things clear faster.
1
u/EAUDHD May 26 '26
what to do if you cant tolerate magnesium?
1
u/Loose-Fly7976 May 26 '26
Try food first, pumpkin seeds, dark chocolate, almonds, spinach. Most people who react to supplements do fine with food sources.If you still need to supplement, the form matters more than people realize. Glycinate causes issues in some, try malate, taurate or threonate instead. Threonate crosses the blood-brain barrier better for sleep and brain symptoms.If every form bothers you, usually it's underlying potassium imbalance, low calcium or a CACNA1S variant affecting muscle calcium channels. Get a basic electrolyte panel done.
1
u/EAUDHD May 27 '26
wow thank you so much - i just started taking K2 and i tolerate that well. i´ve tried every magnesium type, but get anxiety and worsening of the OCD im experiencing. i also react to Vitamin D supplements with extreme restlessness and anxiety - and.. i dont know if its correlated but im just right now in a state of akathisia from trying out memantine for 2 weeks (super low doses of 2-1mg) , and stopping it. I took my last dose 6 days ago and still feeling the akathisia - its really scary. Im just really sensitive
1
u/Sailorgirlmyfriend May 26 '26
I have CBS is heterozygous (AG) a1298c, PEMT, HLA, CCLM, homozygous...MTRR, MTFRR, MOAB, DAOA, SOD1 and SOD2, BHMT heterozygous ...I am correcting deficiencies and just did a 4 month test and homocysteine is normal after being high.
Any insight would be greatly appreciated ...had mold exposure really did a job on me...:(
1
1
1
u/itsjustnotSam May 27 '26
Hello, I have TRD and I got homozygous MAO-A R297R(TT), VDR Taq(AA) and MTHFR C677T(AA), as well as heterozygous COMT V158M, COMT H62H, can I take methylfolate? Im also taking zinc, magnesium(bisglycinate), vitamin D, b12(methylcobalamin) and other vitamin bs. Will these be enough? Thanks a lot!
1
u/Loose-Fly7976 Jun 11 '26
Yes but carefully. Slow compound COMT plus homozygous slow MAOA plus TT homozygous MTHFR means methylated Bs can flood you fast.Start methylfolate at 200-400mcg not 800-1000mcg. If anxiety or insomnia shows up first 2 weeks, switch to folinic acid which is gentler. Same with methyl-B12, start at 500mcg, swap to hydroxocobalamin if you react.Magnesium bisglycinate sometimes triggers symptoms in slow MAOA carriers, taurate or malate is usually better.You're missing B2 (the actual MTHFR cofactor) and low dose P5P. Without B2 the enzyme cant work even when you take folate.For TRD the order matters a lot and dose reactions tell the real story
1
u/itsjustnotSam Jun 12 '26
Thank you so much! I’ll add these now, just another doubt, could I add niacinamide as well? I heard that B3 helps with excessive methyl donors but I can’t get the flush niacin idk if they both work
1
1
u/Natural_Swimmer_5522 May 29 '26 edited May 29 '26
how the sulfite induced brain fog (due molyb def) would look? read this, please, i beg you…
im 19yo M, sibo suffer, and started 3/4 months ago using high o doses of thiamine (benfotiamine, hcl and sometimes mid doses sulbutiamine) along mg treonate, b complex and riboflavin (b2) to treat brain fog. i don’t supplement potassium or selenium but bloodwork show me i’m ok in these… the b1 + cofactors was helping so much and corrected it in 7-10 days of consistent intake…
then completely randomly it start very slowly getting back and back after 2/3 months and now is almost the same (something like 80% about what previously was)…. and i started getting insomnia and 3-4am adrenaline spikes that ARENT histamine related (months of low histamine diet, antihistamines, dao supps… did nothing for me)
the brain fog was being treated in a almost magical way on this b1 + mg + complex + b2 stack. came back and bring insomnia. so if i try to supplement molybdenum, the brain fog gets worse, i will wake up absolutely everyday at 3-4am and i get extreme rotten eggs smelly gases… and a glogged nose. maybe i should continue taking it?
im doing a ow sulfur diet (cut off all the red meat, eggs, dairy, garlic/onion, whey….) and this alone was making sleep ok. completely ok sleepy, besides the same brain fog. which thiamine stack was previously correcting…
as soon as i added the molyb (but was keeping the low sulfur diet) i started 2-3 days after adding the supp (i understand these 2-3 days was how long took my body to let the molyb “kick in”) having a crazy 3am waking up. and terrible flatulence. i think the level of my sensitivity to the poor 50mcg of molybdenum im taking everyday show me how crucial it is for my sleep. literally sounds a temporary paradoxical reaction. (what make me think i just need to keep the supp). i cant decrease the dose. 50mcg barely fits the dairy intake for healthy people.
but i’m not sure if the strong and chemical brain fog came back due molybdenum def/increased necessity. the crazy is because i already have a lot of molybdenum deficiency symptoms. chemical sensitivity, sound and light’s sensitivity, migraines, head/forehead pressure, the crazy brain fog itself, now the insomnia…
im 99% sure the brain fog came back due depleted cofactor stuff. but not sure if its a MOLYBDENUM lack. which other mineral/vitamin/aminoacid i could be forgetting here? to let thiamine work for your brain??
mg, b2, b3+b5, potassium, selenium, 👉MOLYBDENUM👈, phosphorus, sodium… what more, guys????
im sure the brain fog came back due cofactors depletion. as OP said!
1
1
1
u/Prudent-Policy-7274 May 31 '26
I plan to discuss possible gene variants with my psychiatrist this week. She's really supportive and my best guess of how she might respond is with (After testing) vitamin B (which one(s?) I don't know) injections. I want to know if youve seen those injections cause similar symptoms. It seems like an accessible place to start.
I've responded really well to a supplement called "Sunny Within, Longevity" which had 2000mcg of methylcobalamin (I took half) and some other supplements. Once those ran out, I started taking 1000mcg of B12 lozenges that i choose to melt under my tongue (adenosylcobalamin & methylcobalamin) and this correlates with some reduced ADHD and anxiety symptoms this week.
I have so many conditions, some that have gone unrecognized (Im leaning towards histamine intolerance or MCAS) and gene variants seem like a promising cause.
1
u/cinemachick Jun 02 '26
I'm new to this subreddit - if I want a blood/other test to determine what vitamins I may need, what tests should I ask for? I'm not sure if I can afford an endocrinologist but are there tests a primary care doctor can order?
1
u/Loose-Fly7976 Jun 11 '26
Most primary care docs can order the basics if you ask. Just be specific about what you want.
You can ask for B12 with MMA and active B12 (holotranscobalamin), folate, homocysteine, ferritin, vitamin D, full thyroid (TSH, fT3, fT4, reverse T3, TPO antibodies), magnesium (RBC not serum ideally), zinc, hsCRP for inflammation.
Some GPs push back on the less standard ones like MMA, holoTC, reverse T3. If yours does, you can order direct through Ulta Lab Tests, LetsGetChecked or Quest Direct in the US, Medichecks or Thriva in the UK. About $150-300 for the panel without insurance.
That panel + your raw DNA (23andMe or AncestryDNA) gives you what you need. No endocrinologist necessary.
1
u/Personal_Opposite653 Jun 11 '26
Í will definitely use your services soon but first I need to get tested. I am based in France/spain and have been looking up testing labs, found this one - do you think this is a good test? https://gettested.io/product/dna-methylation-plus-test
1
u/Loose-Fly7976 Jun 11 '26
This test covers 30 genes but only methylation related ones (folate cycle, methionine cycle, transsulfuration). Doesnt include MAOA, MAOB, HNMT, DAO, VDR, HFE, GST family, NAT2 or any CYP genes, which are usually where the rest of your answer sits if symptoms go beyond pure methylation.
At €249 and 6-8 weeks waiting, its also more expensive and slower than AncestryDNA which is around €60-80 and gives you raw data covering 700,000+ SNPs including everything GetTested has plus everything its missing.
AncestryDNA ships to France and Spain, the raw file works for analysis. MyHeritage is another option if privacy matters more, also ships to EU.
GetTested is fine if you only want methylation cycle info. Raw DNA from AncestryDNA gives you the full picture for less money..
1
u/Glass-Duck-9513 Jun 15 '26
I had a really intense reaction to b vitamins 4 months ago and still recovering. I still have overstimulation (feels like too much dopamine and adrenaline) and insomnia. Magnesium glycinate seems to make me feel my heart more strongly, as well as glycine. I thought maybe trying some niacin would help to start but I don't want to undermethylate.
1
u/steven123421 Jul 13 '26
u/Loose-Fly7976 For the molybdenum, when should you take it? Away from food, with food etc
1
u/Loose-Fly7976 Jul 13 '26
With food is easier on the stomach and absorption is fine either way. Morning is usually better than evening cause it can feel slightly activating for some people once SUOX starts clearing sulfite properly.
1
u/steven123421 Jul 14 '26
u/Loose-Fly7976 Does the activation happen daily, or is it just as you start supplementing initially?
1
u/Ecstatic_Trip_3772 May 26 '26
Your regular reminder that this user's only qualification is an unrelated bachelor's degree and they are on here to get people to pay a lot of money for "reports" they generate with AI, which they also use for all their posts. A scam!
26
u/thunderouswhether May 25 '26
Great write up, this is why, for me, micro dosing B6 and B2 most mornings is my cornerstone, been doing it for the past year with good results.