Am I Overmethylated? MTHFR Questions.

Overmethylated vs. undermethylated seems to be one of those things that everyone defines a different way, so let’s talk about it and see if we can bring some clarity. The terms overmethylation and undermethylation make the most sense to me as the Walsh Research Institute uses them.  These are general physical tendencies based on the sum of your genetics, nutritional status and body burden. There isn’t one gene or genetic defect alone that can account for them – so just because you have an MTHFR C677T mutation doesn’t actually mean you’re over or under methylated (although it would be one factor that might push the balance to undermethylation).  Dr. Walsh describes one’s methylation status as being like a tug of war between opposing factors. Many of those are genetic and some are nutritional or environmental.

Overmethylation MTHFR

This is less common than undermethylation. According to Dr. Walsh’s research, 70% of the population are normal methylators, 22% are undermethylators and 8% are overmethylators. Overmethylation in this context means that the methylation cycle as a whole is sped up, or downstream reactions that use SAMe (the ultimate product of the methylation cycle) are compromised in such a way that there is too much SAMe floating around wanting to methylate something.

  • Clinically overmethylators are more likely to have agitated or anxious conditions. Frequently panic or anxiety attacks (64% of panic/anxiety clients at the Walsh Research Institute), paranoid schizophrenia (52% of paranoid schizophrenic clients at WRI were overmethylators), ADHD (28%), behaviour disorders (23%), depression (18%). Depression  can occur in under, normal or over methylators but 18% of depressed clients of Dr. Walsh are overmethylators.
  • Mutations most likely to contribute to overmethylation are AGAT, GAMT, CBS and MT. MTHFR mutation usually pushes towards undermethylation (but I myself am compound heterozygous MTHFR and an overmethylator) Remember that the presence of one or more of these mutations isn’t enough to say if you’re an over or under methylator. The combination of all of your genetic factors as well as your nutritional state must be taken into account. The best way to determine is through symptoms and traits.
  • Other contributing factors are impaired creatine synthesis. This is because Approximately 70% of the SAMe from the methylation cycle is used by creatine synthesis, so if this is impaired the SAMe is used more slowly. This can be due to genetic factors (AGAT or GAMP) or due to deficiencies of arginine or glycine. Also impaired cystathione synthesis, or other polymorphisms in methyltransferase SNPs that account for the rest of the SAMe use.
  • Overmethylation leads to excessively high activity of dopamine, norepinephrine and epinephrine in the brain.

    If this reminds you of you, you could be overmethylated. A photograph of Robin Williams taken by Michael Dressler in 1979, later used as a cover photo for Time magazine to highlight Williams.

    If this reminds you of you, you could be overmethylated. A photograph of Robin Williams taken by Michael Dressler in 1979, later used as a cover photo for Time magazine to highlight Williams.

  • Symptoms and traits of overmethylation include:
    • High anxiety
    • Sleep disorder
    • High energy, restless, must move and fidget
    • Verbose or talkative
    • Often high artistic or musical ability
    • Antihistamine intolerance (makes anxiety or restlessness worse)
    • Overly empathetic with others
    • Non-competitive in sports
    • Tendency towards food and chemical sensitivities
    • Less likely to have seasonal allergies
    • Histamine Intolerance (or HIT – this is essentially a food sensitivity to high-histamine foods)
    • Low libido
    • Dry eyes and mouth
    • Adverse reaction to SSRI drugs, SAMe or methionine (typically all make anxiety or depression much much worse.
    • An easy way to picture this type is by using Robin Williams as an example.

Is Overmethylated the Same as Over-supplemented?

No, although it seems that in a lot of popular literature on the subject people use the term interchangeably. So often you’ll see someone say that you might  be “overmethylated” if you are taking too much 5-MTHF or SAMe.  I feel that these are different things entirely.  If you have a tendency to be overmethylated then certainly you would probably feel worse taking something like SAMe, but even without that you are still an overmethylator (in my opinion).  Likewise taking too much 5-MTHF, doesn’t make you suddenly “overmethylated” it just means you’re taking too much.

Okay! I’m Overmethylated. Now What?

Interestingly the best way to balance the consequence of overmethylation, is still 5-MTHF.  This seems strange, because it is also the answer if you’re’ undermethylated, but the effects are actually coming from a different mechanism. Folate actually reduces activity at serotonin, dopamine and norepinephrine synapses. 5-MTHF is the active form of folic acid, and you can also get it from foods, especially if you have some trouble taking the supplement.  Trouble taking the supplement is surprisingly common, although I think less common clinically in overmethylators (in my experience) than in undermethylators. Niacin or niacinamide can also be helpful for overmethylators as they quench some of the excessive methylation. Again, start slowly.

I Want to Start Taking 5-MTHF. How Do I Make This Easy?

Any time you start taking 5-MTHF, or increase your dose, there will be an adjustment period.  Here’s a whole post on it.  Just remember, start with a low dose and increase really slowly. This is changing the way your neurotransmitters work and doing some heavy detox work, so it’s vital not to overdo it because that is crazy-making. Start low and go slow.

28 thoughts on “Am I Overmethylated? MTHFR Questions.

  1. David

    Thank you for providing this information. Much appreciated! I had never considered how glycine could impact methylation through creatine synthesis.

    This makes me wonder. I’ve noticed I tend to react poorly in the same way to both niacin and alpha-lipoic acid, both of which requires SAM-e to metabolize (from what I’ve read). I also react similarly to glycine, which has puzzled me. But now it strikes me, could it be because it increases creatine synthesis, and therefore also uses up SAM-e? Would love to hear your thoughts on this.

    1. amyneuzil Post author

      Hi David,
      Interesting (and astute!) observation. Glycine does require SAM-e for creatine synthesis, although not for many other uses, so ??? Here’s a link to the creatinine synthesis pathway for your reference. Out of curiosity, have you tried taking SAM-e? I’d be curious to see what happens there. It’s entirely possible that your SAM-e is deficient, hence the issues with niacin, ALA, and glycine. But, being (I’m assuming) an MTHFR person, you could be struggling to keep up with SAM-e generally. Let me know, I’m curious. 🙂

      1. David

        I did try SAM-e, with mixed results. Maybe I just need to go very slow. What dose do you generally suggest for a person who is sensitive to most supplements (especially anything stimulating)?

        Anyway, yeah, I suspect undermethylation. It would surely explain a lot of things! I’m trying to get properly tested, which is a bit of a hassle where I live. But I figure better safe than sorry…

  2. Michael D

    Hi Dr. Amy,

    I’ve been reading a lot about overmethylation lately and have become quite confused over some conflicting info. Some doctors are saying to avoid methylfolate because the methyl group could worsen overmethylation. What is your opinion on this?

    1. amyneuzil Post author

      Hi Michael,
      My opinion is that overmethylation or undermethylation are both equally maladaptive ways that our body adjusts to the functional folate deficiency caused by having the MTHFR mutation. So, overmethylation isn’t about having too many methyl donors or too much methylfolate, it’s actually the way your body deals with the lack. I am an overmethylator, with a compound heterozygous mutation, and for me, taking a moderate dose of methylfolate (usually between 1500 and 2000 mg daily in addition to food sources) actually helps me to reduce my symptoms and feel more balanced. Having said that, finding the right dose for you is key, because taking too much for me is awful. No sleep, hyper, wound up, just well too much. Does this make any sense?

  3. Jamie

    Doc started me on deplin for compound heterogeneous mthfr. Within two days I lost the feeling in the backside of my head, starting seeing stuff that wasn’t there, anxious, agitated, beyond talkative… Good grief.. Severe muscle weakness and numbness.

    I thought I was freaking dying.

    No joke.

    So did the doctor. They tested me for everything under the sun. Mris blood work.. You name it. All clear.

    Doctor says u have to take the deplin to lower your sky high homocystine levels!!!

    I stopped taking deplin four days ago. I’ve got some of the feeling back in my head.

    Is this a common response to over methylation??

    1. amyneuzil Post author

      Hi Jamie,
      Some of it is common and some of it is not. Certainly, if people start on too high a dose too quickly it’s really common to see things like anxiety, agitation, and near-mania. The hallucinations, weakness and numbness are less common, but not unheard of. Isn’t it nuts? The methylfolate is a great idea for you, but it’s probably better to start your body a bit slower. Deplan is a kick-in-the-pants dose. It’s either 7.5 or 14 mg and I’ve been taking 5-LMTHF for years and I can’t go past 3 mg or I keep my whole house awake all night with me because I turn into a lunatic. Try starting at a lower dose and adjusting really gradually – this article will help give you an idea. Wait until your symtpoms from the Deplan completely clear – your body will need a break to deal with all of that.

  4. Jayne

    I’m reacting to every supplement i take. Methyl b12 adeno, hydroxy multi vitamins. I used ro take it fine although always hd an issue with stimulants. Neve been able to do caffeine. Wondering what changed. I typically feel great for a couple days and then bam. Panic, anxiety, high blood pressure and other symptoms. Ive been told im probably deficient in a vitamin and that’s why I can’t handle the b12. I haven’t done 23 and me yet but wondering if im overmethylating for some reason and everything I’m taking is just to much. I have most of the Overmethylation symptoms. I just bought folinic acid snd i also have methyfolate are either one of those ok to take or do you think i should try 5-LMTHF i also need b12 as its low. I have hashis so what amount of folate should i start with and what b12 and how much should i take. Any suggestions?

    1. amyneuzil Post author

      Hi Jayne,
      Wow. Yes, when you’re so sensitive I honestly think the best way to go is a multivitamin with tiny doses of everything. Start SUPER slow. I really like the Thorne Research Basic Nutrients III or IV (depending on whether or not you need iron), but any good one that has a very low dose of everything will do. Now, as I say that, when you look at the label information on those vitamins it looks like a really high dose, but that is per SIX capsules (6!!). So if you start with one capsule then it’s a really low dose. My hope there is that we can start with just one capsule for a few weeks, then try increasing to two if you’re tolerating it well.

      When I hear ” I typically feel great for a couple days and then bam. Panic, anxiety, high blood pressure and other symptoms.” that says to me that your body needs those nutrients, but can’t keep up with the intake or is getting bottlenecked somewhere. If we can start with a lower dose, we might not run into the same problems (hopefully). Also, when you’re sensitive like this, strip away everything that you don’t absolutely need. Don’t take any extra vitamins or supplements and keep things simple. Only ever add one thing at a time so that if you react oddly to it, you know what you changed. Does that make sense? Good luck!

  5. Aura

    Thank you so much for the reply. I hadn’t found that article on my own. It makes a lot of sense! I was considering switching my children to methylated folate. Is there a recommended dosage for children based on age or weight?

  6. Aura K.

    Should b12 be supplemented with the 5-MTHF got overmethylators? And if so, should the b12 also be methylated?
    Thanks so much for all the great info!

  7. Nancy

    Wow! I think I finally get this… seem to really know your stuff. Many thanks. I purchased B-Healthy by Emerald. Taken it for two days, it really seems to be working? I always thought I was an under methylation but now after reading ur description I realize I’m an over! Feeling much calmer today! Amen

      1. Rosemary Lane

        Hi Amy, THANK YOU for this opportunity to clear things up. I have a double MTHFR mutation C677T + A1298C. I had a high homocystine level so I asked for folic acid Rx and methylcobalamin (2,500 mcg, but only take half). Now I am concerned that the folic acid is the wrong thing to be taking. I was on Barroca plus from my shrink years ago. I have blood clots and a hip replacement so take Coumadin. Please tell me what PROPER SUPPLEMENTS I should be on?

        1. amyneuzil Post author

          Hi Rosemary,
          Make sure you work with your doctor because Coumadin is a very dangerous medication and any changes you make to the rest of your supplement routine can influence it. Folic acid is typically the wrong thing for MTHFR mutants. Having the MTHFR mutation means that we don’t efficiently convert folic acid to the active form, 5-LMTHF. So for us, it is generally more effective to take folate in the active form already. Here is some good background reading on the mutation in general and on getting enough methylfolate. Please work with your doctor to make sure you switch safely to a methylfolate that will work for you! Keep me posted – I’d love to hear how it all goes and if you notice a difference between the folic acid and the methylfolate.

  8. Kimberly

    I’m homozygous MTHFR among other SNP mutations evolving Serotonin. COMT is normal. I have trouble with Methyl donors or any Serotonin co-factors like Mag, Vit C, B6, Vit D etc.. I will get agitated, panic attacks, shaking,insomnia etc.. My Organic acid tests have shown high Dopamine turnover and low Serotonin turnover so, my ND kept pushing 5htp, methylfolate etc. I got so depressed, yet so agitated I thought I was going crazy. She did a blood test and my Serotonin was very high. I took Methionine and began sobbing and having anger fits. We did a DNA test and it turns out due to my MAO mutations (among others) I cannot tolerate any Serotonin co-factors and I’m wondering how that plays out with under/over methylation? What does adverse reaction to Methionine tell us? Thanks in advance!

    1. amyneuzil Post author

      Hi Kimberly,
      It sounds like even though you have the MTHFR and a number of mutations that normally lead to low Seratonin, because of the low turnover your Seratonin is actually high so every time you supplement something that might compensate for the mutations you’re getting a really mild form of serotonin syndrome or other intolerable side effects. Huh. That isn’t easy. Obviously, your ND who is actually working with you will have much more detailed knowledge here than I do because they have seen your full genetic panel and know your history and symptoms. My guess based on what you’re describing is that you’re overmethylated, also methionine is typically used as a treatment for undermethylators so that might make sense. Have you tried the methylfolate by itself at a very low dose? HEre’s a great article that gives more information about some of the supplements used for over/undermethylation. I hope this helps!

      1. Kimberly

        Thank you. Great article. I have tried methylfolate many times, but probably not on it’s own. I know I used a brand that had methylb12 with it, but I believe I was taking Magnesium and B6 around the same time, that was a disaster. I will try adding it in on it’s own in tiny amounts. Thanks again!

  9. Jessica

    Hi there! I’ve suffered with depression and anxiety for most of my life. I’ve tried everything including psychiatry, which had disastrous results. I reacted badly to every drug. Now I use St. John’s Wort with good success but it caused strong photophobia. My friends swears by his sam-e, so I tried it. By day three I was extremely depressed. It drastically increased my depression! Reading online about thousands of experiences, I’ve only come across one person that said it increased their depression. Usually people complain that it causes anxiety or agitated states. Usually I am easily agitated, yet felt nothing but tired and deeply depressed. Does this mean I’m an overmethylator? I don’t really relate to the above list, as I’m more introverted.

    1. amyneuzil Post author

      Hi Jessica,
      Actually, I think it means that you have an MTHFR mutation with extremely low serotonin. Check out this article and see if it makes any sense (it’s not directly about the SAMe thing, but I think it makes sense…) Let me know what you think!

      1. Jessica

        Thank you! So, whether I’m an over or under, I should take 5-L methyltetrahydrofolate? I’m a little scared after the sam-e experience. Just when you think you can’t feel worse, volia! I definitely identify with the over more than under. I tend to have bad reactions to practically everything, which is very disheartening. Ive tried everything. 🙁 Thank you for answering my questions. 🙂 I found a new kind of saint John’s Wort (perika) standardized to hyperforin instead of hypericum, and it doesn’t give the photo toxic effects…but it also doesn’t work. 🙁 So, maybe I imagined St John’s wort working (just normal mood shifting, as it tends to do). 5-htp has some small positive effect. Anyway. Now I’m taking advantage. 😉

        1. amyneuzil Post author

          Yes to 5-LMTHF, just start REALLY slowly. Especially when you have bad reactions to a lot of things. Start slowly and listen to your body. Remember the first few days feel a bit weird even if you’re on the right track so hang in there.

  10. patricia

    Are headaches and extreme sleepiness a detox reaction or an over supplementation issue. I only take 400mcg methyl folate daily.

  11. Ab

    Is there a mistake in this post? It seems like it should be
    “Symptoms and traits of OVERmethylation include” and not UNDERmethylation.
    Am I right? Thank you

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