What is the Best B12 for MTHFR Mutants?

The best B12 for MTHFR mutants is… not easy. Just like everything else about being an MTHFR mutant – but the good news is that there is a logical process of discovery that you can go through to find the best B12 for your own brand of mutant-hood.  Also, if you’re a little fuzzy on the MTHFR particulars this is a great place to start for the basics and this article will help you figure out if you’re an MTHFR mutant.

Obviously the Best B12 for MTHFR Mutations is Methyl-B12 (methylcobalamin) Right?

Nope. At least not for everyone.  It makes sense on the surface that if you can’t methylate well then you probably don’t methylate B12 any better than you methylate folate. The problem is that nothing about methylation issues is “on the surface.” Let’s look at a diagram from Dr. Amy Yasko’s awesome website, which focuses on MTHFR mutations and autism,  to help to understand this further:

Awesome (and kind of intense) view of that methylation cycle that helps to show the best B12 for MTHFR mutants from Dramyyasko.com

Awesome (and kind of intense) view of that methylation cycle that helps to show what B12 is best for MTHFR mutants from Dramyyasko.com

Just to clarify, what you’re looking at is a huge, complex, multi-step chemical reaction. Each of the green arrows signifies a vitamin or co-factor that is important for that step of the reaction.  The boxes are particular genes that also influence that step of the reaction. You’ll notice the MTHFR gene that we all know and love at the bottom left of the diagram. You’ll also probably notice that the whole picture is so much bigger than just those two genes (eek!).

The big green arrow for B12 comes straight down between the two big wheels of the methylation cycle.  There are two genes that can change that step of the process, which are called MTR and MTRR. Both MTR and MTRR genes code for enzymes that convert homocysteine to methionine. Both of these enzymes need methyl-B12 to work and your body especially needs B12 support if you have the MTR or MTRR mutations. So, in theory, the best B12 for MTHFR mutants should be methyl, and this is a great place to start but sometimes clinically this doesn’t pan out. Often clinically hydroxycobalamin, which is a slower-release, longer-acting form does much better.

Methylcobalamin, or methyl-B12, is still the best first choice. It makes the most logical sense, it’s the most rapidly active form and it’s already methylated so your body doesn’t have to convert it to anything for it to work.  It’s also the most rapidly acting (and therefore rapidly broken down form) and because of this some people with MTHFR mutations have problems with it. Especially the MTHFR mutants who have severe side-effects from taking 5-MTHF. If you’re not sure if that’s you then read more here.

Signs Hydroxycobalamin (hydroxy-B12) Could Be Better For You:

  • You take methyl-B12 and don’t notice any difference in energy level, mood or really anything else.
  • You have the MTR or MTRR mutations but don’t respond to methyl B12.
  • You have started slowly taking methylfolate but quickly started having side effects.
  • Your blood levels of B12 show up too high, but you still have symptoms of B12 deficiency.
  • Even taking a good dose of methylfolate and methylcobalamin your homocysteine levels don’t come down.
  • You take methyl-B12 and kind of start to freak out.
  • You’re taking good methyl-folate, other good B-vitamin support, and you don’t feel better at all, or feel worse.
  • You take methyl-B12 and on blood tests you still show up B12 deficient.
  • You also have the COMT or MAO mutations,  that change the way some of your neurotransmitters are broken down.

The bottom line is that if you start a good protocol with methylfolate and methyl B12 and don’t feel any better, or feel worse then either you started with too high a dose, or hydroxycobalamin (hydroxy B12) would be a better choice than methyl B12.

The Benefits of Hydroxycobalamin or Hydroxy B12

  • Hydroxycobalamin is used more slowly by your body and so can help to maintain steadier levels of B12
  • It helps prevent methylfolate from forming too much nitric oxide in your body, which helps to reduce side effects of 5-MTHF.
  • It easily converts to methyl B12
  • It helps reduce cyanide in the body (totally unrelated, but it’s a bonus!)

So does this mean hydroxycobalamin is the best B12 for MTHFR mutants? Well – no. The best B12 for MTHFR mutants is always unique to that particular person. It means that your total picture determines what’s best for you.  The logical place to start is with a methyl B12, but if that isn’t giving you the results you want or if you’re having a lot of side effects from the mthylfolate you’re taking then try switching to a hydroxycobalamin form. For many of you it will help to get you feeling energetic and happy and all the things we should feel every day.

32 thoughts on “What is the Best B12 for MTHFR Mutants?

  1. Gabriel

    Hello, Dr. Neuzil. I’m taking my chance writing to you hoping for a little advice… I’m 47 yo male (Romanian, so please excuse my English wording) struggling with what I thought it was bad anxiety for the last 17 years. Few years ago I ordered a genetic report from 23andme, just for fun, and only yesterday I found out this can be a tremendous tool in terms of healing myself. I uploaded my raw data to geneticgenie and I received a methylation profile. Needless to say that… we have a saying in Romanian: I look at it like the goat looks at the woods. Anyways: I have this report with some mutations, and I would kindly ask for an advise from your side in terms of supplements/dosages to incorporate into my regime. Do you think we can work this out as I REALLY need to feel… human again? My mutations:
    VDR Taq AA +/+
    MTHFR C677T AG +/-
    MTRR A66G GG +/+
    BHMT-02 CT +/-
    Currently (since last week) taking L-Methionine and TMG, do NOT feel any better from Methyl B12 and I will start adding 5-MTHF tomorrow.
    Thank you very much for your patience in reading my message, wishing you a nice day!

    1. amyneuzil Post author

      Hi Gabriel,
      I *love* the expression “like the goat looks at the woods.” Hilarious!
      It can be really overwhelming to see your genetic reports, but it sounds like you’re taking some good steps forward. How did adding the 5-LMTHF go? Do you feel alright with it? Also, did you feel worse with the methylB12 or just not better?

      1. Gabriel

        Hi, Dr. Neuzil,

        Thank you for your reply, much appreciated.
        Adding 5-LMTHF surely did make a difference in the way I “feel”. The change is not dramatic but, after a few weeks of administration, I can definitely state that I feel better. Yet, I simply know that the methylcobalamine is not making any difference whatsoever, considering the things I’ve read it should do – I expected to lift the brain fog, for example. The brain fog (agoraphobia symptoms like) is my main issue right now, almost all the other symptoms I attributed to anxiety are almost gone and I’m clearly getting better day by day.
        Currently I’m taking HomocysteX plus (1 cps) + TMG 1 g + Liposomal Glutathione (15 mg) + some Basic Minerals + Calcium D Glucarate (500 mg) or DIM – all on daily basis in the morning prior to meal. I’m adding Vitamin D 5000 every other day.
        That’s it… I wish you all the best and please receive my warmest regards!
        Wishing all the best to all the people reading here, too, and hope all to feel better soon!


  2. Jennifer

    Hi Dr Amy! I really appriciate your blog and helpful information that is within it!
    I, too, have a MTHFR mutation however my genetic test report doesn’t state anything more then that but gives information about it and how to help it. I had the genetic report done in 2013 because I wasn’t responding well to bipolar 1 medications anymore. Having this report has been literally a life saver. Anyway, since 2013 I was instructed to take 15mg of Deplin prescription but now I can just buy the methylated folate otc. So, since 2013 give or take a few months here and there, I’ve been taking it. Fast forward to now…I feel horrible, and I have for quite a long time. I haven’t gotten far with my PCP besides more antidepressants so I’ve been ordering my own labs and trying to help myself the best I can. I’m planning to see a Functional Medicine Practitioner but I can’t get in until Aug. My b12 is 1979 pg/mL, my folate is >20 ng/mL. I have been very cautious about which type of L-methylfolate I buy but it seems it’s not methylating…? I have other labs that are abnormal but that seems to worry me the most. What are your thoughts, ma’am?
    Thank you

    1. amyneuzil Post author

      Hi Jennifer,
      Jeez. It sounds like you’ve been on a journey with this! So – when you started the deplane and methylfolate, did you notice a difference? Did it make you feel better? My thought is that you might actually not need such a hefty dose anymore. Did the functional medicine practitioner help at all? I started a podcast on MTHFR, called To Health With That! – you can find it here on apple podcasts or really on any podcast service. That might be a decent place to start. Also, I have a dedicated website specifically about MTHFR that might be helpful as well. Here’s a good place to start. Thanks so much for being here and I’ll keep a better eye on these comments – reach out if I can help at all.

  3. olivia

    Hello, great information. My daughter is 5 has autism and receptive/expressive disorder. She was prescribed to take 0.5ml Hydroxy B12, however the times she does she starts mumbling more, her speech is not as clear.. on days she is off hydroxy she seems better more focused and much clearer speech.. i’m concern if this is right for her. she is also taking O.N.E. multivitamin which contains methyl B12 and that doesn’t seem to have much positive or negative effect. the hydroxy b12 is liquid form .. any thoughts greatly appreciated.

    1. amyneuzil Post author

      Hi Olivia,
      Yes – when the hydroxy form is interfering with her speech it might be better to try different forms. Of course, if the hydroxy is prescribed then talk with the prescribing physician before you make any changes. Usually, the methyl form, although it’s technically the form we use best, is also the most difficult to tolerate because of it’s rapid use – essentially any problems it is going to cause, it causes in a rush. The cyano form is much maligned just because the cyano group is the same cyano as in cyanide, but it’s not actually toxic and it is reasonably easy for the human body to metabolize, plus it’s the most readily available form and will be easy to find in a liquid. You might try that at a low dose and see if it’s helpful. The other option is a topical B12 – there are a number of patches and creams that might be decent just because absorption is slower. Outside of that, food sources are great but can be difficult to get into any kids, let alone kids on the spectrum. I wish I had a solid answer for you, but honestly it will come down to trial and error. Let me know what works.

  4. lesley

    It all started with high homocysteine levels so had vit levels done. according to dr all within normal limits.
    B6 – 19.6 (high normal)
    b12 – 248 (low normal)
    folate 7.5 (low normal)
    Vit D total 44 (middle range)
    d3 44
    I had read something that made me wonder about MTHFR and I had genetics done by 23andme la.st year so uploaded to Genie
    It came back with following results
    Have VDR taq +/+
    mthfr 677t hetero
    mthfr a1298c hetero
    comt v158m "
    comt h62h " also comt p199p which is -/-
    mtr a2756g "
    mtrr a66g "
    bhmt 02 "
    shmt1 c1420t "
    thought good I just need to add vit d, methyl b's etc. then on further reading saw not! if have vdr taq homo along with compound comt hetero (but I also have comt p199p -/- ()does that make a difference. Then having the mtr and mtrr!!!!!! the more I read the more confused I am. I have been depressed and have no energy for the last couple of years and thought now this is the answer Vit D def and low b's but b6 high normal (not need more b6). I am now so lost. what i think now is need vit D and k2 and potassium, magnesium but what for the B's and to help depression (have also had social anxiety since young) now in 70's. concerned about homocysteine levels. should I just start on low dose methyl b. I would appreciate your help. I am so confused.

    Rest are +/-
    comt v158

    1. amyneuzil Post author

      Hi Lesley,
      It is so confusing, isn’t it? I agree the vit D is necessary. potassium and magnesium are deficient for most people in the modern world because we tend to not eat enough of the veggies and plant-based foods so I think those are probably a safe bet too. Instead of trying to piece together the B vitamins, I think it would be easier for you to start with a great quality multivitamin. I love the Thorne Basic Nutrients III for people who don’t need extra iron. Just check the dosage – if you take it as labeled, it’s 6 capsules daily. Once you are sure you tolerate that, then adding a separate methylfolate on top of it would be the next best step. Just don’t push too quickly. This is all an adjustment for your body, so take it slow. If it’s still confusing, then make an appointment with me or someone else who can help you sort through it. I hope this helps!

  5. Roxanne

    Hi Amy, I am homozygous for MTHFR A1298C and trying to figure out what to start taking for it. My NutraHacker report says to take and to avoid Methyl B-12. Where should I start? Here are the reports.
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    /Users/roxanneseverson/Desktop/Screen Shot 2018-07-24 at 8.08.54 AM.png
    /Users/roxanneseverson/Desktop/Screen Shot 2018-07-24 at 8.09.05 AM.png

    Thanks, Roxanne

    1. amyneuzil Post author

      Hi Roxanne,
      I can’t see your specific reports for some reason, but honestly, for most MTHFR folks I think the Methyl B-12 is pretty hard to take. Hydroxy B-12 is probably the next best option. It metabolizes more slowly and doesn’t cause as many symptoms (for most people) as the methyl does. If the hydroxy isn’t a good fit then just keep trying other forms until you find one that suits.

  6. David


    Thank you for this article and hopefully you could help with a question I have on the best form problem ive been having.

    I received injections for b12 deficiency many years ago but have been traveling and I believe the deficiency has been creeping back over many years.

    With Methyl i notice a big increase in energy and mental concentration but using just a little bit, over several days, will send me into anxiety and feeling restless. So I tried hydroxo sublingual.

    This started alright but after several weeks i became lethargic, had aching muscles and headaches.

    But I did notice some real benefits from hydroxo like vastly improved smell, being able to put on weight easily for the first time in years, and improved sight.

    I read from forums online that hydroxo can lower pottasium in its process of creating more red blood cells and perhaps this is causing these negative, and only initial, effects from hydroxo?

    Would you suggest continuing with hydroxo and taking pottasium supplements? Could this lowered pottasium sort itself out after the body has reached an level of not being anemic?

    Thanks alot!

    1. amyneuzil Post author

      Hi David,
      I certainly think the hydroxy form is the best for you given your reaction to methyl and the improvements you’ve seen. I think there are two possibilities for the symptoms that you have been having. Potassium is one of them, and I think the simplest one to remedy. The other is that actually having enough B12 is allowing your body to detox more rapidly, but that the toxins are getting bottlenecked somewhere else in the detox pathway. So I think there are two things to try. The first is potassium supplementation because it’s inexpensive, easy and very low risk. Kind of a no-harm, no-foul solution. It should work reasonably quickly and be very uncomplicated. If it doesn’t work quickly, then I’d suspect the toxin issue. If that is the case then it’s a bit more tricky. Decrease the dose of hydroxy B12 and boost some of the things that can help with the detox process (water and fiber are probably the most important, but some liver support might not go amiss as well.) Fingers crossed the potassium will work and it will all be easy easy. Keep me posted!

  7. Lisa

    Hi, my 11 yo son has been recently diagnosed with both mutation of MTHFR (c677T and A1298C) heteroz.
    His blood shows high levels of B12, normal levels of other B vitamins. Low level of folid acid ( 3.8) and low hormones. Should he be taking Methyl B12 supplements? Homocistein level is 8 ( normal range here is Europe) for now. Thank you for your help, Lisa

    1. amyneuzil Post author

      Hi Lisa,
      I would say he should certainly be taking methylfolate since his folic acid is low, but talk with his doctor about it as well. Homocysteine isn’t a great marker for some people because there are a lot of different ways to reduce that level that don’t depend on the MTHFR enzyme. The B12 seems like it is a really important piece for some people with MTHFR mutations and for others it doesn’t make much of a difference. I would stay start with the methylfolate and if you’re not seeing the changes and results that you would like to see then maybe add either a methyl- or hydroxy-B12. I hope this helps!

  8. amber

    Hi there! Thank you for the great article.

    I’ve read that its recommended ,based on my own mutations with MTHFR, COMT and VDR, that I should be taking “All three types with less methyl B12” do you know which 3 types of, I assume b12, she is speaking about possibly know a vitamin that would be a good fit for those requirements? Thanks so much for any info, these mutations are a confusing map to navigate.

    1. amyneuzil Post author

      Hi Amber,
      Yeah – it’s super confusing to navigate. And honestly, I don’t think there’s really any “one size fits all” protocol, so generally, I’d suggest trying different products to see what feels best for your body. I haven’t seen a mixed B12 product that I like but my guess would be that they are talking about the three most common forms of B12, which are cyano-, methyl- and hydroxy-. It’s easy to find inexpensive B12 of all three types individually, so maybe try to cobble together something that works for you from those? Do keep in mind that some people with MTHFR mutations don’t respond tremendously well to methyl-B12. Keep me posted – I’d love to know what your experience is!

  9. Tina Coyle

    I recently started taking a supplement with b12 as “Glycoprotein Matrix”. I have avoided all supplements in the past due to my crazy reactions to them, including terrible headaches and anxiety spikes with any and all forms of b12. I started on a low dose and am getting a light headache and noticing a small uptick in anxiety. I was wondering if this was a detox response and I should stick it out and wait for symptoms to pass before increasing, or if it is something I should avoid all together. I am currently being treated for chronic lyme and this supplement came highly recommended to help my body with the treatments in general.

    1. amyneuzil Post author

      Hi Tina,
      So – certainly talk with the practitioner who is managing your lyme because sometimes the lyme also can give odd reactions to things. My feeling about it would be to try to look for food sources of B12 but potentially avoid the supplements. There can be a detox-type reaction with B12, but there are also people who just react incredibly badly to it for mysterious reasons. I would guess you might be one of those. Do you know if you have any mutations involving MTRR or the more B12 concerned part of the pathway? For some poeple with B12 issues it helps to also take methylfolate, but again talk with your practitioner because it might not be recommended for the rest of your protocol. Let me know what you decide and how it all works out!

  10. Lynn

    I am compound hetero MTHFR. Normal COMT. I was told that I would do better on a mix of B12 such as methyl and adenos.

    Would it be better to purchase individual L-Methyl Folate (like Metafolin) and B12 (Methyl/adenos mix) or is it ok to buy them combined into one pill/tablet?

    Trying to make up my mind between separate or single or if that is even an issue.


    1. amyneuzil Post author

      Hi Lynn,
      Generally, I like B12 separately because the absorption through the stomach is really low (REALLY LOW) so it’s always best to get that one sublingually. The 5-MTHF absorbs better through the stomach, so I would say separately.

  11. Ana Rodriguez

    Thank you for this awesome, thorough information and recommendation.
    Recently I discontinued all of my physical health supplementation. In some respects I feel better and in other respects I feel a need to resume supplementation.
    Researching MTHFR is shedding light on why discontinuing my supplementation may have had a positive effect on my mental and physical health. Of course I have also taken other measures recently to reduce my exposure to sources of stress and triggers.
    One thing that is becoming clearer and clearer to me is that I need to be working with a competent practitioner. My body is one-of-a-kind and I need a practitioner that will partner with me as I explore what is best for me as a unique individual.
    Finances are proving to be a significant hurdle. Over the last 15 years my health has deteriorated to the point of limiting my outings/activities to two hours Maximum. In addition almost all of my money making activities are now out of the question due to the rapid onset of pain when I engage in them. Sewing, carpentry, design work, juice bar… Even engaging in physical therapy can be more debilitating them beneficial at times.
    Hoping to reengage in life and puzzled as to how best to go about it!!!

    1. amyneuzil Post author

      Hi Ana,
      I completely agree – anybody who says that there is one answer for everybody has not talked with very many sick people! We’re all so different. And honestly, I think for a lot of people it’s easy to get into a situation where you take every supplement that sounds good and then end up doing as much harm as good. Taking a break from them sounds like a great idea and of course reducing your stresses and triggers will help. Sounds like you’re on the right path! Keep me posted. 🙂

  12. Anna

    Thank you for your posting. It really helps me.
    I have a 5 yr old (born in 2011) son on the autism spectrum.
    My son has got a MB12 injection twice recently. He weighs 17 kg and was shot with 0.04 cc. But after the second shot (Nov 30), he showed very frequent urination, which he has not usually done before. He peed every 20-30 minutes, and seemed not to be in control of it! It lasted about a week ( during the week, I didn’t add a shot to him) and stopped just yesterday (Dec 7). Now I am just wondering if he should be given MB12 again at lower dosage or switch to HB12.
    He showed both good effects and bad effects after MB12 shot: Longer eye contact and more focused, less hyperactivity vs Increased stimming (mouth-seeking in particular) behavior and extraordinary frequent urination which is explained above.
    I am in dire need of your advice. Look forward to hearing from you!

    1. amyneuzil Post author

      Hi Anna,
      So – with such a mixed response I would certainly talk with the doctor who prescribed the B12. I haven’t heard of the frequent urination before, but as you know with autism spectrum everyone seems to break down at their weakest points and that could just be a vulnerable spot for your son. My gut feeling would be to try a lower dosage first because it might just be a detox reaction (not that this makes it easy, but it does mean we’re on the right track). If that isn’t successful then switch over to HB12. Of course talk with the prescribing physician about all of this, but that would be my gut feeling. Great luck and keep me posted – I’d love to know how he does!

  13. rose

    i took methyl b12 and got severe side effects that i still havent recovered from

    headaches etc which have improved but not completely

    what can you recommend please

    detoxing seems to help somewhat

    1. amyneuzil Post author

      Honestly I’d take a break from all B12 until your symptoms subside and do everything you can to take extra care of your body – clean diet, lots of water, as much sleep as possible, detox baths or sauna. Anything like that. Once the symptoms decrease then maybe try starting a tiny dose of tydroxycobalamin, which can be an easier form for MTHFR folks to tolerate. Crazy how taking the methyl form can kick off such a horrible cascade of symptoms, isn’t it? Honestly it really just pushes all of those pathways too quickly and kick-starts detox and that can feel bad if we do it too quickly. So take great care of you and pamper yourself a little until things calm down, then start again and slowly with the hydroxy form

  14. Leslie

    MY 18 yr old daughter has Lyme and is Compound Heterozygous. Her doctor had her take Methylcobalamine shots. She began swelling especially in the legs and ankles. No correlation was made until several weeks had gone by. Now the doctor has prescribed the Hydoxycobalamin which we are still waiting to be shipped. I was told that this should resolve my daughter’s swelling. Is this all we really need to do to reduce the swelling that she has had for what is now almost two months? It is concerning to me that we may not be doing all we can to reduce this swelling. She also has a bruise on her leg that is taking an extraordinarily long time to heal. Is swelling a common occurrence for people with this mutation and methylcobalamine? Thank you.

    1. amyneuzil Post author

      Hi Leslie,
      It isn’t a common reaction that I’m aware of, but the Lyme might also have a hand in how she responds to the injections. It’s so hard to say because with a complex picture like MTHFR on top of Lyme disease we don’t really know what is doing what. My only suggestion for the swelling would be lukewarm epsom salt baths just to encourage circulation and drainage. Also the usual things like elevating her legs whenever possible. With the swelling any bruising on her legs will take longer to heal because the swelling compromises her circulation a bit so that is to be expected. Did the doctor suggest waiting for the swelling to go down before starting the hydroxycobalamin? It might be a good idea to talk with the doctor about it – partly to give her body a chance to calm down and partly so that when you start the hydroxy you can tell if it also causes swelling (because there is always a chance that it could if the methyl form did). Hopefully the hydroxy will be far easier for her body, but really we never know 100%. Good luck and keep me posted please! I’d love to know how she feels with the hydroxy.

  15. Michael (NW)


    I’m MTRR ++ (I have one that is ++ and one that is +-). I do feel better with Methyl-B12. In fact, it took 5000mcg to 10,000mcg to notice a big difference. But, I’ve been reading that B12 can increase histamine? Yet, I thought it helped to convert Homocystein to Methionine which is anti-histamine… I just wondered how much Methyl-B12 is recommended for MTRR. I haven’t read much on recommendations.

    Thank you.

    1. amyneuzil Post author

      Hi Michael,
      Great question, and not an easy one to answer. Because you have the MTRR mutation that really changes the way your body uses and methylates B12 specifically we don’t really have a good idea about how much you might need. To be honest, it seems the dosage even in non-mutants is highly variable as well because so much depends on absorption. I’ve seen patients who respond to 1000 mpg and I’ve also seen patients who get nothing out of any oral dose but will respond to injectables. It’s just all over the map. If 10,000 mcg is making a difference for you then stick to it – in this case there isn’t a “right” dose. In terms of the B12 increasing histamine thing, I’ve seen it on other websites but when I dig into the research, I can’t find any links between taking B12 and high histamine. There are clearly links between B12 deficiency and higher histamine levels, but none in published medical research (as per pubmed search) that show the reverse. My guess would be that some website made a correlation in error and everyone else has just parroted that assuming that they did their research and it’s accurate information. I hope this is helpful!

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