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The myths of overmethylation

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Kimsie, Jan 7, 2016.

  1. Kimsie

    Kimsie Senior Member

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    It is a common belief that taking too much folate can cause “overmethylation” leading to symptoms such as anxiety. While taking too much folate isn’t a good idea and it is possible to have a state of overmethylation, I believe that there are some incorrect ideas circulating that need to be examined.

    I have been modifying my hypothesis, and I am hoping that some of you here will respond by giving me helpful criticism of my ideas so that I can continue to improve them. I will respond by either modifying my hypothesis or by defending my ideas, as it seems appropriate to me.

    Myth #1. Niacin helps symptoms of overmthylation by mopping up methyl groups.

    Niacin does mop up methyl groups, especially in the niacinamide form, but normally if the levels of neurotransmitters get too high they are quickly degraded by enzymes such as MAO. Without sufficient niacin (NAD) for the aldehyde dehydrogenase enzyme reaction, MAO will become inhibited – leading to an excess of neurotransmitters. So if a person has sufficient niacin in the body, they will not get a buildup of neurotransmitters (assuming they do not have some other block in that pathway). Magnesium is also used in this pathway. The common symptoms of overmethylation are caused by niacin deficiency, so niacin or niacinamide relieves them. Notice that I am saying there is a deficiency of NAD here, something I have said before in other posts. Obviously this is important for energy production because if a person does not have enough NAD for the MAO pathway then they don't have as much as they need for the TCA cycle either.

    I realize that a number of people here have problems taking niacin or niacinamide. I believe that this must be due to insufficient amounts of other substances, such as vitamins or minerals, or other factors that are interfering with normal pathways in the body. By examining the symptoms an individual has, it may be possible to figure out what is going on and compensate.

    Myth #2. Too much folate can cause a person to have too much SAM-e, leading to overmethylation.

    Although MTHFR, which is the rate controlling enzyme for the methionine cycle which produces SAM-e, can be inhibited by a lack of folate there are several feedback mechanisms which normally control the amount of SAM-e produced regardless of folate availability, such as high levels of SAM-e inhibit MTHFR. The liver has a mechanism for getting rid of too much SAM-e through the glycine N-methyltranferase enzyme which requires glycine. The body makes glycine using SHMT, a folate enzyme. So an increased need for glycine might increase production of SAM-e. Insufficient glycine could be the cause of high SAM-e. Other possible causes might be found in the MTHFR feedback pathways of the individual person.

    Note: I don't think the answer is taking glycine. More about that later.

    I think this is enough to get a conversation started, if anyone is interested. I can put up lots of references and diagrams if anyone wants to see them, but I don’t have enough time today. I have a lot of other ideas that I would like to discuss but if I try to put everything into one thread it would be too long and complicated so I am planning to gradually start other threads about them.
     
    Last edited: Jan 7, 2016
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  2. Beagle

    Beagle

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    Great post Kimsie! Your references and diagrams would be great to see, and I'm looking forward to your other threads.
     
  3. South

    South Senior Member

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    @Kimsie For real life useage for non-science-minded people like me, aren't the two explanations in your niacin/niacinamide section similar enough to each other? in other words, is there something that I, as a brain-fogged person, need to know about the semantics between those two explanations, or can I just pop my niacinamide capsule when I feel I need to slow methylation, without struggling to understand why it helps? (not being lazy here, just not good at understanding science diagrams)

    And when you said "Notice that I am saying there is a deficiency of NAD here"...is increasing NAD going to be an upcoming topic, with steps to take to increase it ...or am I way off?
     
  4. Kimsie

    Kimsie Senior Member

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    I already have made a thread about how to increase NAD but right now I think that increasing NAD is only a piece of the solution. Adding D-ribose to your supplements might help you to make more NAD. I think that you can go ahead and pop the niacinamide as long as you don't get any adverse effects from it.

    I see that you do not have ME/CFS. Can I assume that you are not very likely to get adverse reactions when you take supplements?

    I understand that many people here have brain fog and energy issues and of course everyone doesn't need to try to understand what I am writing. There are a number of people here who like to talk about these pathways, though, and I am hoping some of them will get a chance to give me input.
     
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  5. nandixon

    nandixon Senior Member

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    But remember that methylfolate is an inhibitor of GNMT, similarly to the way that SAMe is an inhibitor of MTHFR. So an excess of methylfolate will inhibit the disposal of SAMe via GNMT, thereby increasing SAMe in that respect.
     
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  6. picante

    picante Senior Member

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    Helena, MT USA
    Ooooh, that is exactly what I've been thinking! I'm very excited about your post; you've gotten much further in your hypothesis than I have. More tomorrow!
     
  7. South

    South Senior Member

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    @Kimsie Thank you for the info; I'm looking forward to more reading on this thread from you.

    Despite that I do not have ME, I actually do get negative reactions to some supplements, but niacinamide isn't one of them.
     
  8. GhostGum

    GhostGum Senior Member

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    @Kimsie You might be interested in this thread here on Nicotinamide Riboside, NAD and presursors,

    http://www.longecity.org/forum/topic/75094-nicotinamide-riboside-current-news-and-updates/

    An interesting looking supplement, especially maybe for the ones who need B3, like myself. I wish I understood the science better, so I could relate what you are talking about to myself but after a couple of years juggling methylation supplements I just feel it is hard to connect theory with practise (I suspect there is much guessing going on); it has just turned out to be endless refinement of supplements until they all seem to sit together. No matter how well I seem to have the co-factors covered, one dose too many of B12 (1000mcg+ a day) or methylfolate (500mcg+ a day) and I get 'over-methylation' symptoms, too much B12 is especially not nice.

    I was diagnosed as an 'over-methylation', and I fit the 'psychiatric' profile, history of psychosis. And the bad response to too many methyl donars fits, so hard not to believe there is a lot of truth in the theory.
     
  9. roller

    roller wiggle jiggle

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    isn't it a bit too strange, that we all have that B12, B9, D deficits?

    Bacteria may eat them away.

    Of course, when you don't supplement the B-range you are done, but if you do you are, too.
    As you are feeding the culprit, who is always a bit faster than you.
     
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  10. Kimsie

    Kimsie Senior Member

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    Yes, but since SAMe inhibits MTHFR, when SAMe levels are high, then 5mTHF levels drop.
    The binding of 5mTHF to GNMT Zamierowski and Wagner [15] discovered that the GNMT is a major folate binding protein. 5mTHF binds to GNMT and tends to inactivate it; see Fig. Fig.1.1. Thus, when SAM starts to rise, the inhibition of MTHFR causes the concentration of free 5mTHF to fall causing some of the boundGNMT-5mTHF complexes to dissociate. This makes more free GNMT so the GNMT pathway runs faster preventing the SAM concentration from rising too much. Conversely, if SAM starts to fall, the inhibition of MTHFR is partially relieved creating more 5mTHF. The increased 5mTHF binds to more GNMT, lowering the amount of free GNMT available for the GNMT reaction, thus moderating the decline in SAM concentration. Because of these ideas, Wagner and others refer to the GNMT reaction as a “salvage pathway”. When SAM is high many of the excess methyl groups are carried away in the GNMT reaction and when SAM is low the GNMT reaction is constricted to save the methyl groups for the other MT reactions. This view is consistent with the fact that the product of the GNMT reaction, sarcosine, has no known physiological function.
    Thank you! You got me researching GNMT more and it clears up a puzzle I just came across last night. It appears that one purpose for GNMT is to allow the body to get rid of excess methionine. People with a genetic deficiency of GNMT have very high methionine levels even though other components of the pathways are working normally. In other words, they don't have defects in the methylation cycle or in the transsulfuration pathway.

    This means that depending on diet, a person will not usually be able to pull enough methionine into the cycle to remove all the excess through transsulfuration without using up some extra SAMe. GNMT is what uses up the extra SAMe and allows the excess methionine to be metabolized. GNMT-deficient individuals have elevated serum methionine and SAMe. I would like to propose that insufficient glycine could have a similar effect as the GNMT mutations, but to a different degree. Since high levels of folate will allow the cycle to run unhindered, this will allow the methionine levels to normalize, but SAMe level might still be high, depending on whether other parts of the folate pathway are blocked in some way. This is something I need to think about more. Here is my folate diagram with changes to reflect these thoughts.
    Folate and glycine.jpg
     
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  11. nandixon

    nandixon Senior Member

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    That's not going to be true, though, when people are taking large/excess amounts of supplemental (exogenous) methylfolate. In that case, the inhibition of MTHFR by SAMe will only prevent the formation of endogenous methylfolate, and methylfolate levels will remain high due to the supplementation.

    There will be over-methylation in people taking excess amounts of methylfolate, and that will include some methylation of DNA, among numerous other potential methylation reactions which use SAMe and that may be affected. And that may be good or bad depending on the individual person and how things balance out among those different reactions.
     
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  12. Kimsie

    Kimsie Senior Member

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    Our oldest son has had schizophrenia for over 11 years, so we are no strangers to psychosis. I have been able to take away his symptoms with supplements, but after about 2 months they came back. This time around we have learned that he has high urinary pyrroles so we have recently switched to sublingual P5P. We have found that high dose folate gradually drains their (our sons) B6 stores even more. It doesn't seem to me that your folate dose would be a problem that way, though.

    I am not saying that there is not truth in the theory of overmethylation, I am just saying that I think some ideas about it are not correct, so I am exploring alternative ideas.

    Does taking B3 resolve your over-methylation symptoms, even with too much B12?
     
  13. Kimsie

    Kimsie Senior Member

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    How much exogenous methylfolate are you talking about? Usually 5 mg is considered a large dose. Doesn't each molecule get cycled thousands of times? And after the 1st time it is endogenous?
     
  14. nandixon

    nandixon Senior Member

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    After the conversion of homocysteine to methionine, only the tetrahydrofolate (THF) portion of the methylfolate molecule can be recycled and then be thought of as endogenous.

    The methyl group portion ("moiety") of methylfolate, which is ultimately used by SAMe in the different methylation reactions, is not recycled in that way. Once a methyl group has been used in a methylation reaction it is not going to be readily available again to make more SAMe.

    (The THF portion, on the other hand, can be used again as part of the process to make more SAMe - by the action of the enzyme serine hydroxymethyltransferase, SHMT, which adds a 1-carbon unit to THF that is converted to a methyl group by MTHFR.)

    Thus by supplementing an excess of methylfolate, an exogenous supply of methyl groups is made available that bypasses the inhibition of the endogenous production that will have occurred (due to the inhibition of MTHFR by SAMe). And the excess methylfolate will also inhibit GNMT. So not only will more SAMe be made (within the constraints of various feedback mechanisms) but also less SAMe will be disposed of, and overall methylation capacity will be increased.
     
    Last edited: Jan 9, 2016
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  15. Kimsie

    Kimsie Senior Member

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    SAM has a molecular weight of about 400 and methylfolate is about 460, so 5 mg of methylfolate will make about 6 mg of SAMe. I am trying to find info on how much SAMe is synthesized a day to see what the impact would be but I don't have time right now. Do you know how much SAMe we normally produce a day?
     
  16. nandixon

    nandixon Senior Member

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    The endogenous production of methyl groups would not be completely shut down with inhibition of MTHFR (and other enzymes) by increased SAMe, which I think is what your question may be implying.

    I think it's better to view the effect of excess methylfolate from a concentration standpoint, rather than absolute quantity amount.

    For example, the increased concentration of methylfolate will drive the methionine synthase (MTR) reaction and also decrease the GNMT reaction (the main way SAMe is degraded, I believe), both of which will increase methylation capacity.

    Just to be clear, too, as to the effects of excess methylfolate, as I mentioned on another thread recently:
     
  17. Kimsie

    Kimsie Senior Member

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    This is what I was referring to; My original statement was about whether this kind of overmethylation (as opposed to methylation of histones, which is a different subject) could be caused by a lack of glycine which would interfere with GNMT, which is a major way for the body to get rid of excess SAMe. You were saying that taking methylfolate will inhibit GNMT, and I am wondering if 5mg of methylfolate can inhibit GNMT significantly for more than a short period of time.
    I hope no one thinks that I am trying to say that this statement isn't true, because I know that it is true.

    I am just exploring the idea that if a person has overmethylation problems when they take folate, they might be significantly low on glycine. I don't think low glycine is the cause of their problems; I think that low glycine might be a factor in their symptoms. I am trying to figure out if it is a good idea to take glycine as a supplement in this case or not.
     
    Last edited: Jan 9, 2016
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  18. nandixon

    nandixon Senior Member

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    I'm not sure about time frame, and especially if the person is taking that 5mg every day, but I do know that GNMT is very sensitive to inhibition by methylfolate at very low concentrations (less than 1 micromolar, I believe). Since taking 5mg of methylfolate will cause a very significant increase in the concentration of methylfolate in the human body, there should be a clear impact (physiologically) on the ability of GNMT to dispose of SAMe.

    Sorry I can't be of more help than that. I was interested in this a year or two ago because I had found that taking 400-800 mcg of methylfolate consistently caused arthritis-like symptoms to appear a few hours later, and I was trying to figure out why.
     
  19. Kimsie

    Kimsie Senior Member

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    It isn't clear to me how significant 5mg of methylfolate is but I think what you say about the arthritis-like symptoms you had could be significant. Did you ever try taking 400-800mcg of folinic acid at that time to make a comparison?
     
  20. Kimsie

    Kimsie Senior Member

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    Has anyone here ever suddenly (without gradual buildup) taken several grams of glycine? What happened? How much folate were you in the habit of taking?

    A couple of days ago I gave about 5 grams of glycine to my son with schiz and although he had taken a total of about 8 mg of folate (folinic acid) over the past few days (but no folate for months beforehand) he became very nauseated. I realized from smelling his breath that he was trying to get rid of a lot of cysteine (I accidentally overdosed my other son on methionine once and learned by experience that if a person has more cysteine to get rid of then his sulfite oxidase can handle they try to get rid of it through the lungs and it makes a peculiar smell).

    So I gave him (my son with schiz) 1 mg of molybdenum (to help make more sulfite oxidase), and it didn't take too long to relieve his nausea. Because of this and because of now learning that GNMT is how we get rid of excess methionine, I am certain that he is low in glycine, which I had already hypothesized for other reasons, and that methionine had built up in his body. A couple of years ago I gave him a lot of glycine for a while, but this was when he had been taking a lot of folate so it didn't have this effect. It might also be that he is low on molybdenum because there was a time when he was very low on RBC moly-b but after taking it for a while he was very high and I stopped giving it to him and since that was over a year ago his levels might have dropped again.
     

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