Taking Folate and Feeling Badly? Methylation Requires Balance

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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40 Responses to “Taking Folate and Feeling Badly? Methylation Requires Balance”

  1. Barbara R. Moser,RN February 24, 2012 at 5:04 pm # Reply

    Which mutations warrant you to avoid foods high in methionine?

    We started my mother on folgard & aspirin last July. Prior to that she has been experiencing Rheumatoid Arthritis like pain with elevated RA factors…Now that we switched from coumadin to folgard with aspirin her RA factor levels have gone very high.

    Thank you,

    Barbara (homozygous A1298c)
    (My mother is compound heterozygous A1298c & c677T)

    p.s. I am working on writing our story for your site….have so much to share but want to be succinct. Thanks for all your hard work. You have truly blessed me with valuable information – I hope we can reciprocate.

    • Dr Ben February 24, 2012 at 5:40 pm # Reply

      Barbara –

      Please – share all in your story. No need to be succinct.

      If homocysteine levels are high, that warrants limiting foods high in methionine – especially if one is unable to tolerate nutrients which help lower homocysteine – such as betaine, B6, B12 and methylfolate.

      I highly recommend you mom stop eating gluten and dairy immediately – along with healing her digestive system and balancing her immune system.

      My wife had RA – now gone.

  2. Janis Bell May 2, 2012 at 1:34 pm # Reply

    I know that ramping up is important, but I’m not quite sure whether we do this to reach our ideal amount or, because as the body gets healthier, it is able to handle a greater quantity of B12 and methylfolate.

    I’ve tried to increase my supplements several times, and each time, I reach a point where I feel good for awhile and then start to have sleepless nights and the feeling of too much stress in my body. The way life is, one an always find an outside source of stress at the time, so it usually takes me a few days before that ‘aha’ moment sets in. “I increased my B12 3 days ago.” or “I added an extra dose of folate.”

    Most recently, I shifted from Metafolin to Quatrefolic. I started at the same dose I had worked up to (1600 mg) and increased one 500mg pill the 2nd week. I did fine for several days. Then I increased my methyl B12. Oops! I got symptoms of feeling like I was getting a cold. I had several nights of poor sleep, even after I cut out the methyl B12 and cut down on the Quatrefolic.

    I am COMT++ as well as hetero for C677 and A1298 and CBS, MAO, NOS. I’m slow to break down dopamine and other catecholamines, easily get a backlog of methyl groups. Will I always need to support with low doses of folate and B12, or will I be able to build up a tolerance for higher doses as I remove toxins from the body?

    • Sam Miller December 13, 2012 at 4:01 am # Reply

      I had the similar question as Janis. I react strongly to even low doses of methylfolate (e.g., 100mcg)–mainly dull, achy pain-like symptoms all over the body. Dr Ben, would you suggest trying an even lower dose (e.g, 50mcg)? Do you find that people that initially react to methylfolate are able to build up tolerance to it and increase the amount slowly over time?

      I haven’t done any blood tests for any MTHFR mutations. I plan to discuss the possibility of getting the test with my doctor next week (I am not sure if we have the test in Canada). I thought I would try taking methylfolate since I have many of the symptoms of MTHFR mutation–severe chronic fatigue, GI distress (crohn’s), anxiety, depression, etc. Have you found that people can react to low doses of methylfolate even if they don’t have a MTHFR disorder?


      • Dr Ben December 13, 2012 at 6:06 am # Reply

        Sam –

        The methylfolate may be increasing levels of nitric oxide and/or hydrogen sulfide.

        Consider taking Niacin, Molybdenum and stopping the methylfolate for a few days. Discuss with your doctor before making changes.

        Yes – people can have unbearable symptoms initially and work through it. This may also be caused by an increase of microcirculation in areas that have not seen adequate blood flow for some time due to lower hydrogen sulfide and/or nitric oxide levels. It could also be caused from elevated peroxynitrite or nitrotyrosine levels.

        This is all theory at this point; however, I do know that methylfolate increases both nitric oxide and hydrogen sulfide – and thus microcirculation. It could also be that you are low in choline and need to support first with choline before methylfolate. Again, theoretical.

        People can definitely react to methylfolate ESPECIALLY if they don’t have a MTHFR disorder.

        • Sam Miller December 19, 2012 at 11:20 pm # Reply

          Thanks for your reply. Interestingly, I am also quite sensitive to niacin. It’s probably a good idea that I do the MTHFR genetic test before I proceed with any more supplemental methylfolate, at least anything above 50mcg, which is the dose I can seemingly tolerate. If I do not have a MTHFR genetic disorder, why put myself through the painful process of trying to build up a tolerance to methylfolate?

          • Dr Ben December 20, 2012 at 5:58 am #

            Sam –

            Simply having the MTHFR mutation does not necessarily mean that you are needing more methylfolate.

            You may have adequate levels already – especially if your diet and lifestyle are good – along with your digestive health.

  3. Kris December 16, 2012 at 4:18 pm # Reply

    I too am having the same problems as the above persons with hetero for MTHFR and COMT ++ for both. Could it be that we have enough methyl groups hanging around to take regular folate? Would the extra methyl groups make methylfolate out of regular folate?
    I really can’t tolerate any methyl groups and am taking hydroxy b12, but need to get some folate into my system.

    • Sam Miller December 20, 2012 at 3:25 am # Reply

      I’ve been wondering the same, too. Aren’t most people with a MTHFR mutation still able to convert folate into methylfolate to some degree, just not efficiently? For those of us who are hypersensitive to methylfolate, what about supplementing our diet with natural food folate at a higher than normal dose to make up for any MTHFR inefficiencies? I wouldn’t want to take synthetic folic acid based on the preliminary evidence of the potential negative effects of unmetabolized folic acid.

      According to this highly informative article “Folic Acid is Hazardous to Your Health. What About Food Folate?” (http://www.doctorsresearch.com/folic-acid.htmll)
      “Food folate is natural and is absorbed through a different pathway than folic acid, long-term consumption of folate does not result in an accumulation of a foreign substance in the body, but instead has many benefits.”

      Surprisingly, I have not been able to find natural food folate in supplement form on the internet. You would think that there would be a big market for it.

      • janis bell December 20, 2012 at 5:06 am # Reply

        Natural folates are unstable, which is why folic acid was invented, which I believe was very close in time to the FDA’s authorization of white bread, for the removal of the germ depleted bread of important B vitamins.

        So what about folinic acid? It is converted to methylfolate and available in supplements.

        • Dr Ben December 20, 2012 at 5:53 am # Reply

          Janis –

          Folinic acid is more stable; however, it still has to be put through the MTHFR enzyme in order to be converted to methylfolate.

          Folic acid also gets converted to methylfolate but it has to go through more folate-transforming enzymes in order to do so.

      • Dr Ben December 20, 2012 at 5:56 am # Reply

        Sam –

        As Janis said, methylfolate is unstable.

        Uncooked leafy green vegetables contain methylfolate. They are a great source of methylfolate – and other folates. There are a couple hundred different types of food folate.

  4. Kris December 25, 2012 at 8:07 pm # Reply

    So, are you saying that for those of us that can’t tolerate methylfolate, we could get enough from eating a lot of leafy green vegetables?

    • Dr Ben December 26, 2012 at 2:48 am # Reply

      Kris –

      If you cannot tolerate methylfolate you need to find out why.

      Your SAMe levels normal? Your demand for additional methylation normal? You have a CBS upregulation? You have a COMT or MAOA inhibition?

  5. janis bell December 26, 2012 at 6:18 am # Reply

    Dr. Ben, In your last response to Sam, you listed some of the things that could be a cause of an inability to tolerate methylfolate. What can one do about some of the things your mention?
    For example, I know I’m COMT++ and CBS+-, don’t tolerate SAMe but in previous testing it was normal or low, have high serum folic acid and high serum B12 but also high MCV and MCH. So what would you recommend to support methylation?

    • Marsha August 27, 2013 at 3:55 am # Reply

      Serum folic acid suggests that you’re not able to convert the synthetic folic into active folinic or folate. CBS — most now suggest that it isn’t a problem — that Yasko is wrong about ‘upregulation’.

  6. Kris December 26, 2012 at 6:45 pm # Reply

    Hi Dr. Ben,
    In answer to your question, yes, I do have reason not to tolerate methyl groups, and also have some other major problems. I have a lot of symptoms, which get worse every day. Will you be doing consultations again, any time soon? My daughter on the other hand responded incredibly to mb12 and methyl folate, it was like a miracle! So I know that it can work.

    1ACAT rs3741049 + –
    2CBS rs234706 C6999T + –
    3COMT-61 rs769224 + –
    3COMT rs 4680 V158M++
    3COMt rs4633 H62H ++
    taq VDR rs 1544410 – –
    4MTHFR C677T + –
    4MTHFR A1298C – +
    4MTHFR 03 rs2066470 P39P + –
    4MTR rs1805087 A2756G + –
    4MTRR rs10380 H595Y + –
    4MTRR rs162036 K350A + –
    4MTRR rs1801394 A66G + –
    4BHMT04 rs617219 + –
    4BHMT 02 rs567754 + –
    AHCY 02 rs819134 + –
    AHCY1 02 rs3741049 + –


  7. Kris December 27, 2012 at 2:18 am # Reply

    adding to the above, I just looked up my MAOA status and I am SLC6A4++. And I am always pretty happy, but what else does that mean in relation to methylation?

    • Gretchen Axelson February 1, 2013 at 8:11 pm # Reply

      Kris, I have a similar genetic profile and complaints. I would be interested in anything you find that helps. .
      Gretchen age 55
      +/+ COMT V158M, COMT H626H, VDR Bsm, MAO A
      +/- MTHFR A1298C, MTHFR C677T, BHMT-02 BHMT-04, BHMT-08, SHMT1 C1420T

      • Kris February 3, 2013 at 9:41 pm # Reply

        Hi Gretchen,
        I have done a lot more research about folate since I posted the above, and came across some good information that said that if you are +- for MTHFR A1298C and c677T you can take regular folate, 200mg at breakfast and 200mg at dinner and your body will have no problem converting it to methyl folate. I am doing this, along with supplementing with hydroxy b12 and am slowly seeing improvement in my symptoms.
        Hope this helps.

        • Kb April 10, 2013 at 8:55 pm # Reply

          How much mb12 and when do you take it?
          Right now I’m taking methylfolate 200mcg and methylcobalim 125mcg in the am and have trouble falling asleep–will wake with a start, sometimes heart racing, right after dozing off and also some anxiety. I dont know what to do.

        • Kelly December 15, 2013 at 5:28 pm # Reply

          Hi Kris,

          What do you mean by “regular folate”? Methylfolate or folinic acid?


  8. Pete April 7, 2013 at 4:39 pm # Reply

    Dr. Ben,

    I ran across the whole Methyl cycle after reading Dr. William Walsh’s “Nutrient Power”. After having completed that book, I have been trying to get a clear idea of how the methyl cycle works. One thing Dr. Walsh emphasizes in his book, in particular for people treating for neurological disorders is that folate actually enhances acetylation and demethylation at certain parts of the histone tails that regulate neurotransmitters/ transporters. What is your take on folate and acetylation? I have seen information on your site regarding methyl trapping causing issues and accidental overmethylation, but nothing about folate and it’s effect on acetylation and demethylation. This might be of some use to people who are treating for depression/anxiety and other neurological disorders more than people who are suffering from other issues.

    • Karen November 22, 2013 at 10:25 pm # Reply

      I’d be very interested in Dr. Lynch’s reply to this as well. Thanks for asking this question Pete.

    • Dr Lynch November 23, 2013 at 1:00 am # Reply

      Pete – I will look into this. I understand methylation really well but not acetylation. It is on my to do list. I am looking into it. Thank you for the insight.

      Definitely may help answer some of the ‘overmethylation’ and ‘undermethylation’ issues – and I do not like using those terms – I think they are not helpful at all. There is something else going on and acetylation may be a component of this –

      Thanks again

      • Janis Bell November 23, 2013 at 6:33 am # Reply

        I’ve also been looking into and interested in acetylation since it seems to play an important role in dealing with toxicants. Looking forward to Dr. Ben’s answer on how it relates to methylation and how to support it. I am one of those with MTHFR snps who can’t tolerate even small amounts of 5MTHF. I always thought it was due to my hetero COMT snps but the fact that I developed chemical sensitivity, and that I have some acetylation snps, makes me think it could be more complicated. I’ve tried just about every methylation product out there and finally settled on folinic acid and hydroxycobalamin (Perque) because everything else leaves me wired and tired.

      • Karen December 15, 2013 at 5:29 pm # Reply

        Hi Dr. Lynch,

        Were you able to find out more about acetylation?

        • Dr Lynch December 17, 2013 at 1:26 am # Reply

          Still researching – read a bit but not enough.

          • Karen July 12, 2014 at 4:29 am #

            Hi Dr. Lynch,

            Any follow-up info on acetylation?

  9. Kelly October 16, 2014 at 10:01 pm # Reply

    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.

  10. Sally Oh November 24, 2014 at 3:29 am # Reply

    Your mag link doesn’t work :)

  11. K December 3, 2014 at 5:03 am # Reply

    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.

    • Sue February 13, 2015 at 3:17 pm # Reply

      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.


      • K February 22, 2015 at 9:28 pm # Reply

        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.

  12. Sero February 15, 2015 at 8:23 am # Reply

    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.

    • Dr Lynch February 16, 2015 at 7:44 pm # Reply

      Sero –

      Were you not eating much protein or having digestive issues so not able to absorb methionine?

      One has to have all the building blocks for SAMe in order process histamine – and have all the downstream enzymes working as well.

      Methionine is a key part of SAMe production.

      • Sero February 28, 2015 at 9:07 pm # Reply

        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


  13. Kim March 17, 2015 at 4:30 pm # Reply

    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.


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