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.



11 thoughts on “Am I Overmethylated? MTHFR Questions.

  1. Kimberly

    HI,
    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!

    Reply
    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!

      Reply
      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!

        Reply
  2. 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.

    Reply
    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!

      Reply
      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. 😉

        Reply
        1. amyneuzil Post author

          Ha!
          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.

          Reply
  3. patricia

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

    Reply
  4. 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

    Reply

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