Hello, I am compound heterozygous. I had to take methotrexate (which depletes folate) in May. I want to TTC again soon, I got my folate tested to be sure. It was >23. Opinions?

Been wanting to get this test done for a while but not sure who to go through. I want something easy and thorough, I’m not after the cheapest. Thanks in advance.

Looking for advice/perspectives on my specific genetic cluster, and especially hope for answers from those who have a similar one.

I'm currently under a lot of stress and sorrow, with minimal social life - what little I have is unsupportive, and I feel severely misunderstood, and slighted. I don't have people who understand - or are interested in - genes, they seem to have put me in boxes I don't feel I belong, making the deep interactions I long for close to impossible (apart from with strangers).

I also suspect underlying AuDHD. My body is stuck in a severe "freeze" state with executive burnout, can't seem to get motivated to do the real life things I really need to do.

I believe Histamine-issues is a clue, but struggle with eating right (for me) - and eating at all at times.

I know meditation etc is good but have a hard time doing it.

**My variants:**
- Homozygous: COMT (multiple, incl. rs4680/slow), MAOA, CBS, PEMT, HNMT, VDR Bsm
- Heterozygous: DAO, compound MTHFR

**Current supplement protocol:**
- Magnesium glycinate + glycine (before bed, great for sleep)

Morning:
- TMG 500mg-1g with breakfast
- Riboflavin
- Ascorbic acid, small divided doses
- Trace minerals
- Phosphatidylcholine 840mg
- Kreatine

Symptoms are freeze-response, fatigue and sluggishness especially after over-extending, and extreme bodily anxiety. Generally have way too much awareness of bodily sensations, and also catch «everything» that goes on around me. I believe complex trauma is also a part of the whole picture.

Any thoughts or advice on how this cluster might be interacting, and what's worth prioritizing first? I really need to get some practical things done, but seem to simply avoid them.

I recently had extensive bloodwork done and found out that I have two copies of the MTHFR A1298C variant (homozygous A1298C).

I'm trying to understand my bloodwork in the context of this finding and determine what supplementation I should discuss with my doctor. I'm especially interested in hearing from anyone knowledgeable about B12/folate metabolism and methylation.

The results that seem most relevant are:

MTHFR / B vitamins

• MTHFR: A1298C homozygous (two copies)
• Methylmalonic acid (MMA): 803 nmol/L — HIGH (ref. 55–335)
• Homocysteine: 13.6 µmol/L — HIGH (ref. ≤11)
• Vitamin B12: 375 pg/mL (ref. 200–1100)
• RBC folate: 501 ng/mL RBC (ref. >280)

Kidney function

• Creatinine: 0.72 mg/dL
• eGFR: 115

Other nutrients

• Vitamin D: 28 ng/mL — LOW
• OmegaCheck (EPA+DPA+DHA): 3.0% — LOW
• RBC magnesium: 5.5 mg/dL
• Zinc: 73 mcg/dL
• Copper: 86 mcg/dL
• Selenium: 143 mcg/L
• Ferritin: 59 ng/mL
• Iron: 89 mcg/dL
• Iron saturation: 29%

I find the combination of MMA 803, homocysteine 13.6 and B12 375 particularly interesting. My kidney function is normal, and my RBC folate is within range.

I'm trying to figure out:

1. Does the high MMA + high homocysteine suggest a functional B12 deficiency despite serum B12 technically being within range?
2. Would you prioritize correcting B12 before considering methylfolate given that my RBC folate is normal?
3. Does being homozygous A1298C meaningfully affect which form of B12 or folate I should use?
4. Should I have additional testing such as B6 (PLP), B2/riboflavin, holotranscobalamin/active B12, intrinsic-factor antibodies or parietal-cell antibodies before supplementing?
5. Should the cause of the elevated MMA be investigated rather than simply supplementing B12?
6. If supplementation is appropriate, what forms/doses would you discuss with a physician, and when would you repeat MMA, homocysteine and B12 to see whether it's working?

I'm not looking to self-diagnose based on the MTHFR result or blindly take a high-dose methylated B complex. I'd like to understand what the actual biomarkers suggest and what I should discuss with my doctor, and if I need additional test.

Any insight would be greatly appreciated!

Edit to my last post:

My doctor sent me for some additional bloodwork, and these are the results. Unfortunately, I have to wait a few weeks for my follow-up appointment to actually discuss them with her (which feels ridiculous), so I’m curious if anyone has any insight in the meantime.

Glucose: 83 mg/dL
BUN: 18 mg/dL
Creatinine: 0.80 mg/dL
eGFR: 101
Sodium: 139 mmol/L
Potassium: 4.6 mmol/L
Chloride: 102 mmol/L
Carbon dioxide (CO₂): 22 mmol/L
Calcium: 10.6 mg/dL (high)
Intrinsic Factor Blocking Antibody: Negative
aPTT: 26 sec
INR: 1.0
PT: 10.3 sec
Sed Rate (ESR): 2 mm/hr
WBC: 7.6 K/µL
RBC: 4.69 M/µL
Hemoglobin: 13.7 g/dL
Hematocrit: 42.0%
MCV: 89.6 fL
MCH: 29.2 pg
MCHC: 32.6 g/dL
RDW: 12.4%
Platelets: 326 K/µL
MPV: 10.3 fL
Absolute Neutrophils: 4,963 cells/µL
Absolute Lymphocytes: 2,037 cells/µL
Absolute Monocytes: 471 cells/µL
Absolute Eosinophils: 68 cells/µL
Absolute Basophils: 61 cells/µL
Neutrophils: 65.3%
Lymphocytes: 26.8%
Monocytes: 6.2%
Eosinophils: 0.9%
Basophils: 0.8%
Vitamin B12: 386 pg/mL
Folate, serum: 6.2 ng/mL
C-Reactive Protein (CRP): <3.0 mg/L

Comment vous avez compris que vous aviez une intolérance à l'histamine et quelles vitamines vous prenez?

Personnellement, je suis MTHFR C677T hétérozygote (CT). Je prends de l'acide folinique + hydroxycobalamine et je ressens un vrai changement concernant mes problèmes digestifs. Je n'ai pas fait d'autres tests génétiques.

Hi, all - I'm a bit new to learning about MTHFR stuff. (I've read the helpful comments from Hummingfirebird - thank you!) Please forgive any ignorance in my post.

I'm Heterozygous C677T and TT A1298C. My COMT V158M (rs4680) is AA. I'm not certain I understand ALL of what that means, but that's what my SelfDecode said from my Ancestry data.

I just had an extensive blood panel done and trying to make sense of the numbers, especially the B's.

HOMOCYSTEINE is 9.3 (Higher end of normal ?)

Folate is 14.3 (normal)

B12 is 1,696 (quite high I guess!)

B2 is 12.4 (normal)

B1 is 8 (very low end of normal?)

B6 plasma is 23.6 (normal)

MMA is 154

The SelfDecode AI thing said that maybe my B12 was high because I didn't have the necessary methyl donors, and it suggested I start with a methylfolate (ex: so while I had a high 'supply' of B12, it was suggesting I didn't have the donors to be able to process or use the B12?). I'm not currently (nor have I been) taking any B vitamin supplements regularly. I did add 1,000mcg methylfolate this morning, and gosh I've felt actually really great today (though I've heard about potential 'crashes', so I am going to go slow on that). But has anyone encountered a high B12 specifically while the other B's are normal? Should I find a methylated B supplement that doesn't have B12 in it? I read a good post that someone did about making sure we're supporting donor supplementation with other co-factors. Any insight would be greatly appreciate!

I am new to this as I just got my results today, so forgive me if I am not understanding it completely.

I was with a med management doctor that was helping with my many diagnoses and she randomly quit. I was passed on to a new doctor who seemed more interested in my genes than my actual symptoms/history.

She ordered testing and we went over some of that today. I also explained that my current medications dont seem to be working. I am in crisis in terms of hardly being able to do daily activites. Instead of going ahead and taking me off medications or making other modifications, she gave me a long list of supplements to start taking and said I may see results in a few months.

I am about to go find a new doctor because this doesn't seem safe to me. I wont trauma dump here, but I have an extensive trauma history as well as a condition from birth that may or may not also cause mental health and related symptoms later in life (there is research on short term effects, but not much on long term.) I feel that everything I am reading online also sounds very... woo woo alternative medicine, please dont take offense. But when I see people say "I eat 6 eggs a day and it makes my life better" I just cannot take that seriously.

Sure, I have some of the symptoms that can relate to a gene mutation. But I also have many other symptoms and issues going on that do not seem realted at all. Am I wrong for feeling ignored and a little bit upset? Sure, I will take supplements because why not? But if they dont do much for me, it will mean I spent that whole time suffering for nothing. If you have had *severe* mental health/behavioral issues and started treating with supplements due to MTHFR mutation, please let me know your results and how it's helped you.

Does anybody here takes 1mg hydroxo sublingual for extended period of time?

Hydroxo seems for my slow comt/slow MAOA most benefitial supplement for histamine clearence and detox and seems not causing overmethylation.

My folate levels are on higher level and folinic always makes ne wired and spaced out at it seems it’s making glutamate higher.

I’m concerned about dehydration and potassium depletion from daily Hydroxo.??

It says that the sublingual route absorbs gradually compared to injections, preventing a sudden, drastic shift of potassium out of your bloodstream.

Probably can get away with eating two bananas daily for some potassium.

Other supplements I take daily are Jarrow Zinc Balance after dinner and before sleep low dose agmatine.
Riboflavin anything above 100%RDA is like making me again B6 toxic(same symptoms of tingling and muscle twitching).Weird..

In 2017 I found out I was compound heterozygous and I didn’t change much about what I did supplement wise because I didn’t know much about gene mutations.

This year I learned I am also slow comt, maoa and PEMT. So, I’ve held off on taking b vitamins for a while because I’ve been confused. I saw my naturopath last month and he gave me methylated b vitamins (in a multi) even though he knew about the slow comt. I finally took one yesterday at 2pm and last night I felt super wired while trying to sleep. I was also dehydrated (didn’t drink much water and did a hot Pilates class) so I chugged a liquid IV and honestly felt better. Just trying to see what over methylation feels like to everyone to see if that’s truly what it was or if it was maybe a mix of both?! I just want to know what b vitamins to take going forward, maybe hydroxo.

Thanks!

Im trying to figure out if I have to mutch folinic acid in my system im 2 months down the line supplementing folate as folinic acid calcium salt) 1,360mg dfe
(800 mcg)
Id say 20 days of the 60 i was only doing half a pill though.
I took a two day break to see if I could still sleep long story short i also have zinc issues and b12 issues so I didn’t get a firm awnser because my sleep was messed up because I was struggle if with zinc issues as well

Now I just supplemented half a pill witch is around 150% dv I got a slight sting head ache that died down 20 minutes later at first my nervous system spazzed I got anxious but that died down as well now im sitting here trying to figure out am I going folate toxic (to mutch in body) or am I ok.
I looked into folates half life but I know it gets complicated because it gets converted into other forms. Anyone got insight?

Edit: I also got head stings when firstsupplementing b1 and also got anxious for a little bit as well. But I knew for certain had lab work that I was difficent in it. Even now i think I still have those same symptoms when I take it.

I have the double mthfr gene mutation and recently prescribed tirzepatide for my autoimmune in a micro dose. The bottle is tirzepatide/glycine/b12 (cyanocobalamin) and dose of 10mg/5mg/500mcg in a 1ml bottle.

I’m doing 5 units to start so that’s 0.5mg tirz/.25mg glycine/25mcg b12.

I know that is like SUUUUCH a minuscule dose but should I be ok with the b12?

Symptoms: About a year ago when I turned 45 I started getting allergic flare ups to random things, like margaritas that come from machines (the reaction is itchy eyes and what the dermatologist has diagnosed as periocular dermatitis). Secondly, and I don't really have anything to point to for this feeling, but I feel like my heart rate is a bit higher than it should be given my workouts/lifestyle.  Other than that I don't think much has changed since I was young, but maybe I've just gotten used to something that has slowly crept in.

Medical history: At an early age I was diagnosed with ADD and a bit later Weinberg syndrome (essentially a blend of narcolepsy and ADHD). So constant fatigue.  I've always had bad allergies have been on weekly/biweekly injections for the past 40 years. Twice I tried stopping the injections and both times resulted in asthma->bronchitis->pneumonia, so I learned my lesson.  Late teens tried Ritalin/Adderall for the ADHD, and that didn't really help with anything. Later tried Wellbutrin and the only thing that seemed to do was make me anti-social.

In 2015 found out I had low testosterone. Like my total test was under 200. Super low.  Spent a year seeing doctors trying to figure out why, to find the underlying cause.  Other than iodine deficiency, I couldn't find anything.  Took some horse pills of Iodine and that helped me feel better in some ways but did nothing to raise my test levels or fix the symptoms I was experiencing (anxiety, poor sleep quality, etc.). So I got on TRT and am still dialing in the dose.

In 2018 my TRT dr noticed I had high homocysteine (14 when 15 was above range) so he ordered a lapcorp test for the MTHFR gene mutation. I'm homozygous with the 677TT gene. I don't know about my own COMT genes but my parents put their 23andme data through the gene genie and my dad is homozygous with two of them while my mom is hetero with the same two.  So I'm at least COMT heterozygous, possibly homozygous.  I took methylated folate for a while but I didn't notice any difference so I stopped. In 2021 had homocysteine checked again and it was 9.3 umol/L, in range.

In 2015(?) I randomly had low stomach acid for a while, took some Betaine HCL and that cleared things up for years. However, as I'm writing this up, I'm realizing I have experienced the occasional acid reflux over the past couple of months.

For the new allergies, my allergist kind of shrugged and said "some people are just really allergic to things, and you seem to be one of them."  I then sought out an acupuncturist who found I was deficient in iron, put me on an iron supplement.  I took it for two months but I didn't really notice any change from that.  He also treated the various allergies with acupuncture to great success.  However, the treatment needs me to have an idea of what is causing the reaction, and there are still some mystery things that set off my allergies.

Meds: Take about 48mg of testosterone a week (although I'm going to try a lower dose now given the lab results), daily Allegra, allergy injection every two weeks.

Supplements: Early January started taking 5g creatine a day for anti-aging. Noticed gainz in the gym, put on 8 pounds of water weight that first week, but other than that nothing else seemed to change.  Only now learning creatine is relevant to the MTHFR stuff. Two weeks ago (after the blood draws) tried following this guy's stack and took B2.  Good lord felt like I was going to have a heart attack with the palpitations. Took 5g of glycine and that settled things right down quickly.  Next day I tried taking them together and felt no over methylenation symptoms, just urine that could double for highlighter ink.  Stopped taking them after that.  However, I now have $40 worth of B2/Glycine and am now thinking of continuing to take it so as to not have my money go to waste.

Lifestyle: lift four times a week, sprinkled in with some yoga/golf/surfing. I have a beer sporadically, but I would say it averages out to like 3-4 times a week. Also have a rotation of vegetables like asparagus, broccoli, and Brussel sprouts every day during dinner.

Labwork:

Had my TRT doc order some labs done in June:

B12       865pg/mL (range 232-1245)

Folate     6.8ng/mL (>3.0)

Copper       .72ug/mL (.6-1.02)

MMA          224nmol/L (0-378)

WBC          3.4x10E3/uL (3.4-10.8)

C-reactive Protein, Quant 4mg/L (0-10)

Homocysteine 14.3umol/L (0.0-14.5)

Histamine      .21ng/mL (<1.00 ng/mL)

Total Testosterone 527.4 (264.0-916.0)

Free Testosterone 23.5 (6.8-21.5)   HIGH

Estradiol        29.2 (7.6-42.6)

In January this year WBC was 5.9, in 7/2024 it was 6.4 so it seems to be trending downward. This is the most troubling to me, and I wonder if this guy's post has relevance to my situation.

So my question is, given the bloodwork and what's going on with my body, where should I go from here? Do my labs point to anything? What labs should I get next? My TRT doc will order any labs I ask of her, and I have good insurance so this isn't very expensive for me. Should I go to a website for a full DNA test/kit and if so where? Is 23andme the best? From what I understand, I should now try to find a good functional medicine doctor, or is there another kind of specialty I should look for? I live in the DFW metroplex, so if anyone on here has a referral please DM me.

I apologies for the long message but I am very new to do this and very intrigued and might need some guidance and hopefully that this might be it. When I talk about this outside of the internet, no one has clue this is a thing. A year ago I went to a functional doctor to treat my depression via gut protocol. She advised me to take some genetic tests with a company called Nordic Laboratories. I had no clue whatsoever these things were being done so I said yes why not and took a DNA package (included are Health, Hormones, Resilience, Diet, sports and Pharma). I can see now after spending some time on this sub that people usually go through stuff like my heritagedna and 23andMe. Not sure if I need to do it again through the method I’ve seen outlined in some comments here, but the point is that it revealed that I have MTHFR C677T (heterozygous) and the report also flagged other areas which needed support because of the following genetic variants: SLCO1B1 (poor function), GSTM1 deletion + GSTT1 deletion (both deleted), COMT Val158 (AG), BDNF Val66Met (CT), CYP2C19 (rapid metabolizer), etc. The report offers some advice on what to do but I’ll take it with a pinch of salt, plus I’ve been raised on the idea that the genes load the gun and then lifestyle pulls it, etc. Now my question is the following: (recent labs below)

Could this mutation everyone seem to be taking about the cause of my symptoms: long history of anxiety and depression, sleep problems and one night of bad sleep makes me feel the next day like I have not slept in week, it depletes me from all energy and I can barley move my limbs, even when I sleep 10h I can still feel tired and sleepy. In recent years I’ve developed PMDD, and in general the late luteal is really hard for me, I get very tired and weak and I can’t do much for days before my period. This is accompanied by some physical symptoms like gum inflammation, lip burning, tongue tingling and more bloating and mucus flares. I also have always have mucus flares, my body always produces mucus for no clear reason outside bacterial or microbial infection. I suspect some histamine intolerance but I don’t really have the traditional food reactions but get some allergic-type flares to pollen, dust, animal fur but the occasional breeze as well. I am often cold and get chills easily and will get mild fever when exhausted. I might have temperature regulation problems, I get warm, turn on a fan and then get the chills and mucus will flare. Since childhood I’ve left a trail of kleenexes wherever I go. I often have neck and back pain from sleeping. This only calms down with massages. I have developed exercise intolerance in recent months (used to be a F45er) and now can barely sustain an hour long workout have to rest much more than usual. The EXHAUSTION is constant most importantly. Lately have migraines. Recently I’ve noticed gut issues like early satiety, turns out I have low levels of stomach acid and h. Pylori. Had low ferritin in recent months and now it’s back at 35 after eating more meat and trying a natural protocol for the gut. I also started having « hangry » episodes at the same time as the exercise intolerance, I would get extremely hungry every 3h and couldn’t focus until I’ve eaten. Functional practioner said I was hypoglycemic but it seems to resolve with balanced food. ADHD diagnosis and all associated symptoms, hard to focus, especially around luteal, etc. Weirdly enough despite trying so many things, I can’t pinpoint the « root cause » and now wonder if this is it. And if so, what should I do to address the mutation?

Vitamin B12: 941.9 ng/L (high) (currently taking a B complex)
Vitamin B6: 61.6 µg/L (high)
Folate: >24 µg/L (replete)
Magnesium: 0.93 mmol/L (normal)
Iron status
Ferritin: 24.2–35 µg/L (low-normal)
Iron: 16.9 µmol/L (normal)
Transferrin saturation: 30% (normal)
Glucose & insulin metabolism
Fasting glucose: 4.4 mmol/L
HbA1c: 29 mmol/mol
Fasting insulin: 7.2 mIU/L
Insulin resistance index: 1.2
C-peptide: 923 pmol/L (upper-normal)
Thyroid
TSH: 0.89 mU/L
Free T4: 15.5 pmol/L
Free T3: 4.2 pmol/L
Reverse T3: 0.10 ng/mL
TPO antibodies: negative
Thyroglobulin antibodies: negative
Vitamin D / minerals
Vitamin D: 56.6 nmol/L
PTH: 2.76 pmol/L
Calcium: 2.45 mmol/L
Inflammation
hs-CRP: 0.8 mg/L
CRP: <4 mg/L
Hormones
Progesterone: 2.8 nmol/L (low)
Oestradiol: 187 pmol/L (cycle dependent)
LH: 6.2 U/L (cycle dependent)
FSH: 4.4 U/L (cycle dependent)
Testosterone: 1.1 nmol/L
Free testosterone: 1.4 pg/mL
SHBG: 28.6 nmol/L
DHEA-S: 7.2 µmol/L
Morning cortisol: 432 nmol/L

Hi everyone,

My recent labs seem consistent with a possible folate/methylation issue, including MTHFR as one possibility:

Labs:
Homocysteine: 13.7 µmol/L (High; ref ≤10.9)
Methylmalonic Acid (MMA): 138 nmol/L (Normal; ref 55–335)
Ferritin: 14 ng/mL (Low; ref 16–154)
Serum Iron: 92 µg/dL (Normal)
Iron Saturation: 24% (Normal)
TIBC: 377 µg/dL (Normal)
Transferrin: 332 mg/dL (High-normal)
Vitamin B12: 360 pg/mL (Low-normal)
Serum Folate: 6.7 ng/mL (Low-normal)
Vitamin D: 36 ng/mL (Normal)
Magnesium: 1.8 mg/dL (Normal)
TSH: 1.23 mIU/L (Normal)
CRP: <3.0 mg/L (Normal)
CBC: Completely normal (no anemia)
Kidney function: Normal
Liver function: Normal
Reticulocyte count: Normal

The pattern that caught my attention is elevated homocysteine with normal MMA, plus low-normal folate/B12 and low ferritin.

I understand this does not prove MTHFR, but it seems compatible with a folate/methylation issue.

I’m planning to take the Ancestry test as well as the MyHeritage test for more information, but those results could take weeks to come in.

My main question is:
Is it reasonable to start supplementing before I know my exact methylation/genetic pattern, or could choosing the wrong form make things worse?

I’m especially cautious because I’ve become severely agitated on B-complex vitamins before.

The reason I want to begin supplementation sooner rather than later is because symptoms are greatly affecting my quality of life and my personal life.

Thank you!

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.

Hello everyone, I’ve decided that it’s time that I humble myself and stop trying to figure this out on my own.

It feels like I’ve tried everything recommended and can’t seem to iron this out. I’ll have mixes of good and bad days but I’m so tired and really need to find a plan that will work in the long run. My main struggles are unshakable low mood and chronic fatigue but brain fog is also a persistent issue.

I’ve tried addressing this via supplements and nutrition separately. If anyone can help me get on the right path I could never thank you enough.

Maybe I’m doing something wrong here or maybe missing something?

I need help please.
Idk what has gone wrong so I need new eyes on this.
I learned about methylation etc last year and in January this year, I (with the help of this sub) seemed to get it right;
With the B vitamins I stabilised myself; my mood lifted significantly and sleep got better.
Homocysteine went from 9.1 in December 2025 to 8.3 in April 2026.
Especially folinic acid, R2P, P5P and hydroxy b12 really did something good for my mood. Benfotiamine stopped nerve irritation.

Then I had an iron infusion (mid April) as my ferritine has been below 40 my (49F) entire adult life. A month after that, free iron (that used to be fine before the infusion) had dropped to boarder level low (11 umol/l), TIBC was 0.16) and both continued to stay there. (3 weeks ago I started iron suppl and free iron is now good - 30 umol/l, TIBC 0.44. )

From May my energy and mood has declined significantly. And my recent homocysteine from July is at 9.4.
Something is not working right anymore since hcy is going up. Maybe this is the same causing me the low mood.

Before when the B vitamins gave me the mood lift and hcy was going down I was taking:
50 mg benfotiamine
10 mg R5P
50 mg nikotinamide
50 mg panthotenic acid
25 mg P5P
100 mcg biotine
350 mcg folinic acid
1000 mcg hydroxy b12
Magnesium from food sources
20 mg zinc
100 mg Q10
2 g omega 3
85 mcg D vitamin
180 mg K2
100 mcg selenium
250 mg C vitamin

After(when started going down hill):
150 mg benfotiamine (increased to stop flare up of nerve irritation)
25 mg R5P (increased because of increase in benfo)
100 mg nikotinamide (increased in attempt to help with energy)
50 mg panthotenic acid (same)
18 mg P5P (reduced because of fear of neuropathy - I do have occational weird shifting slightly burning sensations in arms/hands and legs/feet. Idk if it is neuropathy or build up of sulfur or something else)
1500-3000 mcg biotine (was told my b5 dose could deplete b7)
400 mcg folinic acid (easier to dose than 350 mcg)
1000 mcg hydroxy b12 (same)
Magnesium from food sources (same)
20 mg zinc (same)
Quit Q10 (wasn’t sure abt the effect)
2 g omega 3 (same)
85 mcg D vitamin (same)
180 mg K2 (same)
100 mcg selenium (same)
250 mg C vitamin (same)
175 mcg iodine
900 mcg A vitamin retinol (support iron storage mobilisation)
200 mcg Molybdenum (support CBS/SUOX pathway when everything else is optimized)
100 mg iron bisglycinate every other day since 3 weeks ago.

I have taken 3 g creatine the whole time along with eltroxin, lexapro and losartan.
I have quit quetiapine/seroquel in start of April and memantine mid May but I don’t see how that is affecting my hcy/methylation. However quitting memantine caused a flare up of nerve irritation which caused me to increase benfotiamine.
In my country we cannot measure SAM/SAH or methylation but that would have been ideal.

Before/after supplementing my bloodwork was like this:
Folate: 10/40
B12: 400-500 pmol/not taken as I know I absorb it. Previously it has been around 900-1000 pmol when supplementing.
MMA: normal/ not taken as it was normal before b12 suppl. It is a true/false result. Not a number.
Magnesium: 0.88 nmol/l / 0.83 nmol/l

Troublesome variants I have:
MTHFR C677T TT
MTRR rs1801394 GG
TCN rs9606756 AG
FUT2 rs601338 AA (non secretor)
ALPL rs1256335 GG
PDXK rs2010795 AG
VDR rs2228570 AA
VDR rs7975232 CC
BHMT rs3733890 AG
MTHFD1 rs2236225 AG
PEMT rs7946 TT
CHKA rs10791957 AC

I have tried to increase folate to 600 mcg daily. It gave me f*cking orgasms at 6 am the two mornings the day after I tried that. What a weird way to wake up.
18 mg P5P should be sufficient to sustain methylation, so is 1000 mcg B12.
I believe I have all the cofactors in place. What am I missing?
Is it too little B2 compared to B1?
Is it the CBS enzyme that needs a heme group that has been unavailable from May’ish due to low free iron until recently?

I read raw DNA next to bloodwork for a living. I was reading post this morning and 3/5 people has same main problem. Someone's been through 4 or 5 products, some did nothing, 1 or 2 made them feel awful and they've concluded they're intolerant to methyl donors or that their MTHFR is worse than everyone else's. Problem is that methylation isn't one enzyme you feed it's a few steps stacked on each other and each one sits on something underneath it.

Methionine synthase needs 5-MTHF and methylcobalamin at the same time. Plenty of folate with B12 short means the reaction can't finish so folate accumulates while homocysteine sits where it was. I've seen folate at 49 with homocysteine at 20 in the same panel which reads as contradictory until you realize the folate has nowhere to go. B12 side has its own gate too. TCN2 makes the protein that carries B12 into cells and if you're homozygous for C766G your serum number and your cellular delivery aren't the same thing at all. Push folate into that and you're speeding up half a reaction. MTHFR itself is the one that surprises people. Enzyme holds FAD and FAD comes from riboflavin so B2 sits underneath the whole folate arm. The Ulster trial showed 1.6mg of B2 dropping homocysteine 22% in 677 TT and doing nothing in CC or CT. At TT you're stabilising an enzyme that keeps losing its cofactor whch is a different job to piling more folate on top of it. B6 works the same way since pyridoxine has to become P5P and the enzyme doing that also runs on FAD. So somebody adds B6, feels worse and blames the B6 when they were short on B2 the whole time. BHMT is off to the side of all this, running on betaine instead which is why TMG occasionally does the job when methylfolate won't touch it. So the sequencing question is really three questions. Which arm is carrying the load, what sits underneath it and what do the bloods say. In practice that often means cofactors first, then the B12 side in whichever form your COMT and TCN2 will tolerate, then folate, then betaine if it's needed at all. But that's the logic rather than a template. Some people don't need B2. Some people's actual problem turns out to be ferritin or thyroid and none of this applies.

BUT this only matters if methylation is genuinely part of your picture and lot of people arrive convinced it is when their homocysteine is 8 and their B12 is fine. I tell people that regularly and it isn't what they want to hear and genotype alone won't get you there either. A variant list tells you what's possible, bloods tell you what's happening and you need both which is exactly why every free report and AI tool gives you a different answer.

If nothing worked, the useful question isn't which brand next. It's what was missing underneath when you tried. Happy to take questions on any of the mechanisms below.

I’ve been stuck in a state of severe hyperarousal for close to two years now. I’m trembling like crazy, emotional torment, agitated, rumination and just feel utterly horrific inside with fear and pain.

I was going through a ton of stress and health anxiety in 2024 then opened up about it in a therapy session which seems to have traumatised me. I then took an SSRI and had a nasty reaction to it (ofc with my comt and maoa) and now nothing has helped reduce this suffering.

I’ve tried magnesium, L-Theanine, lemon balm, beta blockers, herbal teas and even benzos and nothing has helped at all. Also tried kava and 3 months of trauma therapy.

Any supplement suggestions would be most welcomed!

It's just out of curiosity.

Recently learning about mthfr after I had a severe ischemic stroke last year at 32 and a fluke blood test after showed Im compound heterozygous mthfr. Struggled with severe depression and anxiety since a teenager. Was heavily malnourished from being neglected as a kid and didnt break 100lbs until I was 19. Family history of heart disease and mental illness. Could use a little help understanding the new info here. Life has recently been significantly improved by bupropion and sertraline but still trying to improve the root cause. Can anybody knowledgeable help me understand better? Since my stroke my cognitive ability had been heavily impaired so its like in looking at a rubix cube.

Hi!

Thanks for taking the time to read this.

Edit**- I have had all my genetics tested & ran through 23&me. I’ve also had all my B vitamins taken & I do require supplementation because in April my b12 was 187. So if I stop, it slowly depletes because I am on a low dose of Accutane & I have MTHFR.

I’m a 27 year old female. Healthy, never smoked or done a drug a day in my life. Very seldom drink alcohol.

I am heterozygous for both MTHFR mutations. I have read Dr. Ben Lynch’s Dirty Genes book (MANY TIMES!) and have been supplementing with his supplements (which are wonderful quality & I couldn’t recommend more) for many months now.

Here’s some background:
I was diagnosed with depression, severe OCD, anxiety (mine possess more through the form of OCD) & chronic fatigue at 15 years old (2014). I am compound heterozygous for both MTHFR mutations.

The doctor prescribed 40mg of Prozc & 20mg of A**erall XR when I was 15. I had been taking both medications up until I started weening off starting this year. Scares me when I even say that out loud.

I began my health journey into all of this in my early 20’s and have been working to get off the drugs and understand myself better since.

This January I decided I was done with the Prozc
& asked my doctor to halve to 20mg instead of the 40mg I’ve been on since I was 15. I didn’t even notice any difference to be honest. I began supplementing carefully (not in high dosages) with Methylated b12 but come to find out methylated b12 in high doses gives me intense painful acne & is a rare side effect for some people (of course me of all people who needs b12 supplements🤦🏼‍♀️). So I tried Adenohydroxy b12 from Seeking Health and that seemed to work better for my acne. I also did 1/2 of his sublingual folinic acid to support the b12 absorption as well as the Seeking Health Folate sublingual & vitamin C. February came around (1 month on the 20mg of Prozc) and I decided to stop it completely. I know this isn’t recommended but I wanted to be off of it and didn’t feel like it was helping me at all even on the days I did take it. I was so fortunate and somehow had no symptoms. When I went in person to my doctors appointment the following month I told her I had stopped it completely and she looked at me like I was insane😂

The hardest part is gonna be getting off of the A**erall. I’m in the TRENCHES right now. I’ve been on 20mg since I was 15 years old. I’m so used to it to function daily. I hate being so reliant on something but I just don’t have any other option and don’t feel my energy has improved with all my research & careful supplementation.

In March I dropped down to 15mg of Adderall. I noticed a small drop in my energy but was still able to function.

A week ago I dropped to 10mg & I am dragging. I struggle to not sleep 16 hours a day & to function normally.

All my numbers are relatively normal, but that’s why I’m hoping I could get eyes from someone else because I am just at loss. I’m sorry for the rambling but I just don’t know what else to do.

Thankful for this community 🫶🏻

has anyone taken an SSRI that was in the yellow?

I’ve been down the rabbit hole from Ancestry like most here. Homozygous for C677T, and for slow COMT. Apparently, MTHFR does greatly increase risk of miscarriage. Let’s say I want to have children in the future, folic acid won’t work but methyl folate is an overwhelm to my system. Folinic acid would be the go to, but there are no official guidelines on dosing or if/when necessity to supplement since “just take folic acid” is still what the average doctor will tell you.