I am hearing and experiencing more and more people who are responding poorly to folic acid whether it be folic acid or methylfolate.

Why are people with MTHFR mutations responding poorly to methylfolate!?

It doesn’t make sense right?

People with MTHFR mutations and high homocysteine – especially those who are homozygous MTHFR – should respond favorably to methylfolate.

In researching this and looking closely at the biochemistry, it makes sense why some react poorly to methylfolate, methylcobalamin or folic acid.

(By the way, methylfolate in this case means 5-MTHF or L-5-MTHF.)

Today, I received yet another question about this and I felt it important to share with you.

My husband is + for MTHFR compound heterozygous gene mutation. He reacts very unfavorably to folate supplementation, actually deteriorated while on IV injections of folate. We are trying to get his metabolic MD/neurologist to engage in further testing and having a difficult time in having him understand the problems my husband is having with his prescription Folbic medication.

Hello –

Thank you for sharing your story. This, unfortunately, is all too common a scenario.

It is VERY important to know which MTHFR mutations he has.

I do not recommend obtaining the L-5-MTHF for your husband. It may make him worse if given right now. From hearing the symptoms, other things have to be addressed first.

I highly recommend you get tested for MTHFR along with your husband’s family members. It is serious and must be addressed. Do not try and get pregnant without being tested for MTHFR and having the possible mutations dealt with.

If you are having trouble obtaining a lab test for MTHFR, you may obtain the test from me as long as you are not living in NY. I can only provide the test for you, I cannot diagnose anyone or prescribe treatment for MTHFR. Your physician has to do that.

IMPORTANT!! Increased methylation may cause – and does cause – neurological symptoms.

Methylation reactions increase in aging, the symptoms of Parkinson’s Disease (PD) are strikingly similar to the neurological and functional changes seen in advanced aging, and Parksinson’s Disease is age-related. For methylation to be regarded as important in PD it means that, along with its biochemical reactions and behavioral effects, increased methylation should also cause specific neuronal degeneration . . . Most of the SAM-induced anatomical changes that were observed in the rat model are similar to the changes that occur in PD, which further support a role of SAM-dependent increased methylation in PD.[1]

and . . .

Increased methylation can deplete dopamine, norepinephrine and 5-HT; increase acetylcholine; and cause hypokinesia and tremors. These effects are similar to changes seen in PD, and interestingly also, they are similar to some of the changes that are associated with the aging process. It is suggested, therefore, that increased methylation may be an inducing factor in parkinsonism. Accordingly, the effects of an increase in methylation in the brain of rats were studied. S-adenosylmethionine (AdoMet), the limiting factor in the methylation process, was injected into the lateral ventricle of rats. Specific behavioral changes that resemble changes seen in PD were investigated. The results showed that AdoMet caused tremors, rigidity, hypokinesia, and depleted DA.[2]

So if your husband’s level of SAMe increases, I would assume his symptoms worsen. Based on what you told me about his negative response to certain foods (very helpful information by the way), I am assuming his methionine is elevated and therefore so is his SAM.

SAMe comes from Methionine and Methionine is highest in these foods:

  • Egg
  • Fish
  • Elk
  • Chicken
  • Turkey [3]

These are all the foods which are causing your husband to worsen which makes total sense – if you step back and think about the biochemistry.

If given methylfolate, methylcobalamin or folic acid, your husband’s methionine will increase.

I have a hunch that your husband may do well with Vitamin B6 and magnesium.

Talk with your doctor about stopping Folbic and lowering homocysteine with Vitamin B6 and magnesium.

Magnesium Plus contains active B6 and magnesium. Consider 2 capsules twice a day.

The biochemistry also shows the importance of Vitamin B6.

Vitamin B6 as pyridoxal-5-phosphate actually converts homocysteine into much needed nutrients.

  1. Taurine
  2. Cysteine
  3. Sulfate
  4. Glutathione

If vitamin B6 is low, the production of these critical nutrients is severely limited. These critical nutrients are absolutely essential in those with neurological disorders as they help with neurological function and protection from neuronal oxidation/damage.

My guess is your husband is quite low in Pyridoxal-5-phosphate and may actually have another mutation which prevents the conversion of inactive Vitamin B6 (pyridoxine HCl to active vitamin B6 (pyridoxal-5-phosphate).

Taking about 20 mg of Niacin twice a day may help as well as this ‘eats up’ excess methyl groups – which may be elevated right now due to taking Folbic.

Do let me know how he does.

In time, he likely will need to get on L-5-MTHF by Seeking Health – or HomocysteX by Seeking Health – but currently, I do not think it is correct – but I am just guessing based on your comment.

Summary for your husband:

  1. Stop eating foods with methionine!
  2. Talk with your doctor about stopping vitamin B12 and folic acid immediately
  3. Lower homocysteine with Pyridoxal-5-Phophate
  4. Consider taking Nicotonic acid (50 mg) 2 to 3 times a day for a week to remove the excess methyl groups.

It is impossible for me to diagnose, treat or prescribe – so I am not. I am merely providing you information which may be beneficial – or it may not.

Hopefully it is!

In health,
Dr Lynch

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9 years ago

I just found this study that suggests that b12 deficiency resulted in lower acetylcholinesterase (the enzyme that breaks down acetylcholine) levels. I wonder how this relates to your mention of acetylcholine and SAMe above?

This would be helpful for some of us who react badly to any sort of choline supplement or foods high in choline. Plus a study of CFS patients showed they had high levels of choline.

I’d be curious what you think of this Dr. Lynch.

9 years ago

Your mag link doesn’t work 🙂

9 years ago

I have OCD, anxiety/depression, and autoimmune issues. I recently found a doctor specializing in brain biochemistry trained by Dr. Walsh (mentioned in Pete’s above post). He suspects I’m severely undermethylated. I am waiting for lab results on histamine, zinc, copper, ceruloplasmin, TSH, and homocystene, as well as heavy metals and pyrrole. He did not test me for MTHFR.

He says folate is a serotonin reuptake promoter, so if I’m undermethylated and suffer with depression, etc., folate will strip more methyl than it provides, making me feel worse. I will need to avoid folate-rich foods (my favorite), eat more protein (I’m vegan), and start extraordinarily high doses of B6 and other vitamins/minerals, excluding methylfolate.

I’m so confused because everything I’m reading on this site states methylfolate as the primary treatment. Moreover, the compounded vitamins he gave me to use while waiting for my results has made me ill: Vitamin C 500mg, Vitamin D3 1,500 IU, Vitamin B6 75mg (pyridoxine HCI 50mg and pyridoxal-5-phosphate 25mg), Zinc 25mg, Selenium 15mcg. I’m actually supposed to increase dosing over 4wks from 1 capsule to 4 capsules a day! I couldn’t even tolerate a week on 1 capsule a day (I suspect the B6 and/or Zinc).

I thought I had finally found someone who could successfully treat my issues, and now I’m not so sure I’m on the right path.

9 years ago
Reply to  K

K, I’m sorry to hear this. Are you feeling better now? Curious to hear how your progress is going. I too reades Dr. Walsh’s book as well as this site and am confused about exactly what process to take while I wait to see a doctor in a few weeks.


9 years ago
Reply to  Sue

Soe, I am overwhelmed with too much conflicting information, which is causing a lot more anxiety and also unintentional weight loss. My histamine level came back normal so apparently I’m not undermethylated even though I act like it, but I think it’s due to my folate-rich diet. So I got tested on my own through 23andme and I’m homozygous for C677T. Then I contacted a practitioner through the MTHFR Support site and he thinks my OCD, anxiety and depression are related instead to the COMT and MAO A genes (both homozygous) which are creating elevated dopamine and adrenalin levels. He recommended I start with the basics, including probiotics, DHA, digestive enzymes, adaptogenic herbs, and a protein powder (which has 80 mcg folic acid per serving – I thought I’m supposed to avoid this). I also have a significant copper/ceruloplasmin deficiency which apparently could be the cause of my spinal demyelination. The frustrating thing is that my neurologist knew 5yrs ago that I was deficient, but told me not to supplement with copper because it’s toxic, and when I tested negative for Wilson’s disease, he dropped the issue. So I’m not sure who to listen to because I really don’t want to start taking this protein powder enriched with copper and folic acid (Metagenics UltraInflamX 360) if it’s going to make me feel worse.

7 years ago
Reply to  K

hey k i have ocd too, i want to chat to you, see how you are doing

6 years ago
Reply to  K

K – are all the nutrients you mentioned in each capsule and increasing the capsules increases the dose? By the way, I hope you found that increasing the Zinc was probably what the problem was since it causes a copper dump.

5 years ago
Reply to  K

K – I’ve been working with a nutritionist who was trained by Mensah Medical…..who for the most part is in alignment with Dr. Walsh. How are your copper levels? I’m am an undermethylator and I stay away from folate too, but copper has been my biggest obstacle, I had too much of it biounavailable. I had to start eating meat again a few years back AND taking zinc around the same time, both of these made me feel ill and more vulnerable as I started flushing copper out of my system (zinc is an antagonist to copper). It was hard morally to go back to meat and the process took around 2 years but now all of my levels are in the perfect range and I’m a new person. I was diagnosed bipolar when I was in my 20s and also diagnosed depression and anxiety (different stages of life, different doctors etc). The biggest change I experienced was I literally feel like my brain has been cleaned and detailed. I’m so thankful now!! After being medicated for 13 years, living like a hermit for another 8….I’m still figuring out what to do with this new information. How did no one know to look into this before? Anyway I wish you heaps of luck and mostly faith! It was strange to stay the course when NO ONE I know even gets it remotely and I made big changes to my lifestyle. My friends and family knew I struggled so much of my life yet when I now say I’m healed now by nutrients, well I feel like they gloss over and space out (like they can’t possibly believe it). I guess I wouldn’t have either if it didn’t work! Aloha!

3 years ago
Reply to  Persus

Hello, so happy to hear you are feeling well! Very inspiring. How long did you feel worse before better with the copper unload. Could you share your protocol. I have high copper and am about to start my journey getting it back to normal. I am mire then a little anxious. Any tips. Thank you

9 years ago

I am one of those people who had extremely high histamine from methylfolate, b12, P5P, D3, Iron, Copper, all sorts of foods, and many other supplements. After 8 weeks on methionine, I am so much better and it keeps getting better slowly. I can take Vitamin D3, P5P, Iron and Copper now without excessive histamine although I am still severely deficient in all of those after years of being unable to tolerate them. MB12 and methylfolate still give me excessive histamine. Major improvements didn’t start until a month after starting methionine at 1.5g/day.

Walsh was right all along about high histamine, even though his ideas have fallen out of “fashion”. High histamine is dependent on the body’s ability to produce sufficient SAM-e, and for severely histamine intolerant people like us, it does not happen with mb12/methylfolate but has to be accomplished by methionine.

I’m also starting to add back some foods. For more than a year, I was eating only 3 foods because everything else made my histamine worse.

9 years ago
Reply to  Dr. Ben Lynch

I eat a lot of protein, close to a pound a day of lean meat, and I do take enzymes with every meal.

It’s not a deficiency of methionine in the diet. Walsh recommends 3-4g/day of methionine for undermethylators, and I am currently in this range now. It would be difficult and expensive to achieve this intake of methionine from diet alone without causing other issues.

The crux of the issue is that those who are high in histamine and get worse with mb12/folates are presenting the classic symptoms of histadelia that Walsh wrote about. It doesn’t apply to the majority of people with methylation issues.

Walsh recently published two seminars on youtube that explain undermethylation in more detail, and why increasing the folic acid cycle is detrimental in histadelia

3 years ago
Reply to  Dr. Ben Lynch

While I agree that Walsh’s terminology, ‘undermethylator’ and ‘overmethylator’ are almost nonsensical, I think Dr. Lynch would agree that he was wrong 10 years ago when he said:

“If given methylfolate, methylcobalamin or folic acid, your husband’s methionine will increase.”

Methionine, as you noted in this reply, is a key part of making SAMe. If one takes too many methyl donors like methylfolate or MB-12, without sufficient protein, they could eventually deplete methionine stores, not increase them.

This is explained well in this paper on the methyl-folate trap:

6 years ago
Reply to  Sero

I know this is an old post- I wanted to ask if the Walsh Protocol still working for you? I am an undermethylator with high histamines. I wanted to start the methionine- but very confused about what to eat. Between the foods that are high histamine and supposedly not eating folate rich foods- I am at a loss for what to eat. Do you have any suggestions? Thanks!

9 years ago

Hi Dr. Ben,

I am desperate for some advice. I am waiting for results from Amy Yasko’s Methylation test- but I know I am positive for the 1298c gene.

I have had 3 minor surgeries prior to getting pregnant 4 years ago exposing me to nitric oxide, and I also had my mercury amalgams out prior to getting pregnant improperly – since I have had 2 children, and have been steadily losing weight since. I am 99lbs now, and have gone from burning arms to now shaking everywhere. I know I have some major nutrient deficiencies. I am not absorbing the nutrients from the foods I eat, and I am eating very clean, organic, mostly paleo.

When I take Folate – my eyes burn… when I take methyl b12… I still get some of that eye pain, yet when I take a B complex, I do feel some temporary relief in my shaking. So I have to choose, eye pain, or relief from shaking.

Since messing around with the B vitamins, I have noticed I am getting SO thirsty. I tried taking Magnesium, but either I am not taking enough or it’s something else.

I need some direction… I really want this shaking to stop, and to start gaining weight… it is seriously driving me insane and it makes sleeping at night very difficult! Please help me. I would love to have a consult, but I am waiting for the rest of my test results before I bother booking an appt.

8 years ago
Reply to  Kim

Kim, are you doing any better? Have you tried posting in MTHFR groups on Phoenix Rising.

8 years ago
Reply to  Kim

I have battled internal shaking, like shaking you can’t see but can feel everywhere for 8 years. It’s been terrible. I’m working with Dr. Yasko, which i recommend, but let me tell you what has helped me…getting my lithium levels up, sam e drops, refrigerated royal jelly, folinic acid….small doses and experiment with combinations, but im finally getting better….start with lithium, less than 1mg, see how you feel, sam e drops worked way better for me than pills, these are the two big first steps for me, phosphatidyl serine complex helps too but makes me sleepy, folinic acid is my newest helper…this shaking stopped me life for years, also i can’t take b’s, makes me really sleepy but yasko says you need lithium to transport b’s….try little bits of lithium, she sells drops, like 50mcg, micrograms, it works, it takes time to find the right combo of all these things, but these listed supplements have saved me!

Kim Marino
7 years ago
Reply to  Victoria

I had horrible internal shaking for almost 2 years. If you would like some advice on how to make it go away feel free to email me.

8 years ago
Reply to  Kim

Kim, i forgot to mention, lots of this shaking for me seems to be tied to high blood ammonia levels, sam e reduces ammonia, and carnitine is also helping, acytel l carnitine helps me more than plain carnitine but yasko recommends plain carnitine, but i have learned to try and go with what works! Great luck to you!

7 years ago
Reply to  Victoria

Victoria, I’m really interested to read that you’ve found a link between high ammonia and shaking. Recently my daughter developed slight shaking. Around this time we changed from brand name Acetyl l Carintine to a compounded version. But initially they gave me just L Carnitine (I noticed before opening). I rang and complained and they replaced it, but I’m suspicious their Acetyl L Carntine may not be up to scratch. My daughter is quite dependant on it to resolve brain fog. Have you found any research regarding high ammonia and shaking?

6 years ago
Reply to  Kim

Try Ben’s supplement for dehydration. I know I had to go through a series of protocols. I continued to improve when I focused first on removing sulfur, then food intolerances, then bringing back sulfur, then on my liver, then later on autism. (This was MY protocol, just giving it as an example). My supplementation has gone through changes as has my diet…over years of time. Focus on liver health definitely helped me with severe dehydration and high blood pressure, but as I learned more some of my supplements were changed to more benefit my methylation defects. It is a long process. To me it has been like treating one layer, then the next, etc.

8 years ago

I do poorly on Folate, but I’m pregnant! 9 weeks. Should I still take it? It gives me terrible insomnia. At first I’m OK but as days pass it gets worst and worst, probably as methyl groups start to collect. I stopped for a few days, it got better, but now even taking 1/4 of the dose will keep me awake. Will niacin help?


I get very weak muscles, heart palpitations, anxiety and other symptoms when taking both methyl-folate and methyl-b12, which i believe are related to low magnesium and potassium levels.

I was wondering if you have ever encoutered others developing these low magnesium/potassium symptoms on the methyl-supplements ?


7 years ago

I’m having similar problems. I took 1000mcg of folate and 1000 mcg sod methyl B12 for about three months before starting horrible anxiety symptoms. The symptoms stopped with niacinamide. So I took the advice on this page mad decided to find a basic B supplement as I probably should’ve done that beforehand. I bought Thorne Research Two Per Day. I started on half the recommended dose and woke in the night with heart racing and terrible nightmare, however I felt energised without the usual brain fog. The next day I took a quarter dose. I had insomnia and anxious feeling. Today I took an eighth of a dose and still those horrible feelings! Tomorrow I will stop.
I have only been tested for MTHFR (I am heterozygous C677T), but my son has had the full range of tests and also has the MAO- A +\+, two COMT +\-, VDR Taq +\-, MTR +\+, MTRR+\-, and two CBS +\-. His doc says his profile is complicated and we can’t just introduce the B12 immediately, we have to investigate first. I think, because of the reactions I am having, I may also have some of these genes.

7 years ago

can you advise me on what I might do for my son who just got tested for MT HFR and he is positive. His Homosystine is 14 but he does not have any other symptoms. Like I do. Any suggestions on something he can take. He’s only 24 years old. Thank you

7 years ago

Dear Dr. Lynch,

I have MTHFR A1288 C (+/-) and MTRR A66G (+/-) and various COMT mutuations and CBS mutation (+/-). I am very sensitive to sulfur foods.

I respond well to adenosyl and HydroxyB12, not methycobalmin. However, I respond very poorly to methlyfolate and methtlcobalamin. I use to be able to tolerate little bit of methlyfolate, now the smallest amount taking it daily causes (severe insomnia, heart palpitations, anxiety, severe depression- just 100mcg). My heart races fast in 30 mins after taking it and insomnia becomes really bad. So, my doctor told me to take a break for a week. I notice in 5 days without any folate I had the same symptoms that I had with overmethylation.

So, I started taking it again small amount again and in 5 days symptoms of methylfolate return again causing severe insomnia and heart palpitations. I read your articles and advice here, so I started to take niacin you suggested, and it helps. Dr. Lynch, do I need not to take methyfolate everyday for sensitive people like? I know I need it some b/c lack of it causes the same problems. Is there a special kind of folate for people like me? It seems over accumulation causes inflammation of some sort. Any suggestions will be helpful. I get your products b/c they are less complicated and more easily tolerable to people who are very sensitive to supplements. Thanks – Preet

[…] to reduce the risk of a one-a-day supplement potentially being harmful instead of helpful. [3, 4] Some people may do better taking a trace mineral supplement and eating split pea soup and other […]

Karen Gee
6 years ago

My daughter’s seizures were horrific. Tonic clonic seizures with status events multiple times a day. Leucovorin was increased to 30mg twice a day and the seizures improved. Changed her diet by removing oats, which she had showed an elevated IGM reaction. Seizures have STOPPED. Miraculous to see, but my daughter is still fatigued and can hardly hold her head up. Giving her B6P5P 200mg, 250mg Magnesium but no Niacin. Chicken and salmon and peaches and green beans are ground and given to her. So many other foods cause seizures. I suspect she might be overmethylating and needs Niacin. Ideas? Wish I could find a doctor to help me that takes health insurance near Dalas Texas!

5 years ago
Reply to  Karen Gee

I’d ask your doctor about stopping the B6/p5p. That’s an insanely high dose for an adult let alone a child, and can cause the neurological symptoms you described.

6 years ago

Is this in any way associated with a porphyria polymorphism? I have hemochromatosis and for decades now my liver tanks if my ferritin goes over 20. A few years ago I became quite ill with multiple advanced food intolerances and my doctor (who kept my iron low)retired at the same time. As everyone ignored his previous practices, I developed multiple severe porphyria symptoms. At first I controlled it with extremely high levels of sugar, salt and potassium. Over time I’ve reversed a lot of this with your and Yaskos information (yes I think I’m an aspie). I can now eat sulfur but yesterday I ate cabbage (thiols) and these symptoms came roaring back. I’ll be doing some of what you’ve mentioned here, but these symptoms are so porphyria specific I’m wondering if it might be a porphyria polymorphism. Any light you can shed is appreciated.

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