The myths of overmethylation

[nandixon]

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?

Yes. Folinic acid causes the same problem for me, so it's not specific to methylfolate, and perhaps might be related to purine synthesis.

Oral methylfolate is about 90% bioavailable, if I recall correctly, and 5mg will increase the concentration of methylfolate in the blood about 5-fold at the peak. (Easy numbers to remember.) [Edit: Apparently not that easy, as I just realized it's actually 5mg of folinic acid that produces a 5-fold increase in methylfolate.] I'm not sure how that translates into precise intracellular numbers, but it should increase significantly there too.

 

[Kimsie]

Yes. Folinic acid causes the same problem for me, so it's not specific to methylfolate, and perhaps might be related to purine synthesis.

Oral methylfolate is about 90% bioavailable, if I recall correctly, and 5mg will increase the concentration of methylfolate in the blood about 5-fold at the peak. (Easy numbers to remember.) [Edit: Apparently not that easy, as I just realized it's actually 5mg of folinic acid that produces a 5-fold increase in methylfolate.] I'm not sure how that translates into precise intracellular numbers, but it should increase significantly there too.

It looks like the first pass liver changes most of the folinic acid to 5-MTHF before it reaches the general circulation. It doesn't appear to me as if there is usually any difficulty for the body to find methyl groups (since they can be made from glucose through serine through SHMT) if a person has sufficient folate for SHMT. It must be the increase in the folate pool that is causing the symptoms, and not the amount of methyl groups that are found in the methylfolate, that is leading to symptoms of overmethylation. This leads me to say again that if a person has this type of overmethylation symptoms - anxiety or excessive adrenaline - they should consider the possibility that they have insufficient glycine and/or niacin.

Note that I say insufficient because maybe they have normal amounts of these but they have an increased need for them; maybe they would not test low so normal labs might not tell the story.

Your arthritis type symptoms could have come from some other part of the folate cycle, as you mention, and not have anything to do with methylation. If so it is a mistake to call it overmethylation. It bothers me that when people get symptoms from taking folate, they always call it overmethylation, but methylation is only about no more than 20% of what folate does, and we need to remember everything that folate is involved in. B12, on the other hand, is only used for methylation and the pathway to change branched chain amino acids so that they can enter the TCA cycle, so symptoms from B12 are probably related to methylation. Does B12 cause any symptoms for you?

Have you ever taken glycine? Did it make any notable changes?

Regarding purines, how is your zinc? Low zinc blocks purine salvage.

 

[nandixon]

Your arthritis type symptoms could have come from some other part of the folate cycle, as you mention, and not have anything to do with methylation. If so it is a mistake to call it overmethylation. It bothers me that when people get symptoms from taking folate, they always call it overmethylation, but methylation is only about no more than 20% of what folate does, and we need to remember everything that folate is involved in. B12, on the other hand, is only used for methylation and the pathway to change branched chain amino acids so that they can enter the TCA cycle, so symptoms from B12 are probably related to methylation. Does B12 cause any symptoms for you?

I never said the peculiar arthritic symptoms I experience from methylfolate or from folinic acid was due to overmethylation. I don't know what that's from. I also get arthritic symptoms from any dairy (milk-derived) products and all of the nightshade vegetables. (The dairy products also cause a severe exacerbation of my fatigue.) But in the case of the food items, it seems to be more of an immunological or inflammatory process, and is delayed by 1-3 days.

More than about 125-250 mcg/day of either methylcobalamin or hydroxocobalamin (hydroxycobalamin) makes my fatigue and PEM worse. (More than about 400mcg of methylfolate or folinic acid also does that after several days, but the arthritic symptoms I mentioned appear in just hours.)

It's probably not surprising that niacin may be particularly helpful for your son with schizophrenia. And if that's the case, it wouldn't be surprising that too much methylation might eventually make things worse for him - as it gradually depletes the niacin. (Niacinamide can also be made from tryptophan so the process could be gradual.)

It's going to be less likely the case for people with ME/CFS, though, that niacin will be so singularly helpful.

 

[nandixon]

It looks like the first pass liver changes most of the folinic acid to 5-MTHF before it reaches the general circulation. It doesn't appear to me as if there is usually any difficulty for the body to find methyl groups (since they can be made from glucose through serine through SHMT) if a person has sufficient folate for SHMT. It must be the increase in the folate pool that is causing the symptoms, and not the amount of methyl groups that are found in the methylfolate, that is leading to symptoms of overmethylation. This leads me to say again that if a person has this type of overmethylation symptoms - anxiety or excessive adrenaline - they should consider the possibility that they have insufficient glycine and/or niacin.

Note that folinic acid already has a built-in "latent" methyl group and requires no 1-carbon addition by SHMT. The formyl group (-CHO) of folinic acid is transformed into a methyl group by cyclization with MTHFS followed by reduction with MTHFR to make methylfolate.

 

[Kimsie]

Note that folinic acid already has a built-in "latent" methyl group and requires no 1-carbon addition by SHMT. The formyl group (-CHO) of folinic acid is transformed into a methyl group by cyclization with MTHFS followed by reduction with MTHFR to make methylfolate.

I was wondering where it entered the cycle. Thanks. I don't think that changes anything that I said regarding glycine and GNMT since it enters before MTHFR.

 

[Kimsie]

I never said the peculiar arthritic symptoms I experience from methylfolate or from folinic acid was due to overmethylation. I don't know what that's from. I also get arthritic symptoms from any dairy (milk-derived) products and all of the nightshade vegetables. (The dairy products also cause a severe exacerbation of my fatigue.) But in the case of the food items, it seems to be more of an immunological or inflammatory process, and is delayed by 1-3 days.

More than about 125-250 mcg/day of either methylcobalamin or hydroxocobalamin (hydroxycobalamin) makes my fatigue and PEM worse. (More than about 400mcg of methylfolate or folinic acid also does that after several days, but the arthritic symptoms I mentioned appear in just hours.)

Thanks for the data. Is the type of arthritic symptoms you get in hours from folate the same as from food items or does it seem different to you? Do you take P5P? How much do you take and how does it affect you? Does the b12 take days to make fatigue and PEM worse or is it the same as with too much folate? I gather you haven't taken glycine? If you are ever feeling Guinea pigish maybe you could take some and let me know how it affected you.

Have you ever had your zinc checked? Methionine synthase requires zinc.

Is there anything that has made your fatigue and PEM better, but only for a limited time and then it stopped working? Anything make it better and keep on working?

I hope you don't mind all the questions, but I appreciate getting more data. I really wish I could figure out why folate and B12 affect you and others here the way they do and although it appears unlikely that I will figure it out, I can't help trying.

It's probably not surprising that niacin may be particularly helpful for your son with schizophrenia. And if that's the case, it wouldn't be surprising that too much methylation might eventually make things worse for him - as it gradually depletes the niacin. (Niacinamide can also be made from tryptophan so the process could be gradual.)

It's going to be less likely the case for people with ME/CFS, though, that niacin will be so singularly helpful.

Niacin by itself does not help my son with schiz. It might be helpful in combinations, but it is hard to be sure because there are so many factors to take into account. I know that folate drains his P5P and this is related to his having pyrroles in his urine. It may be that he has a mutation in his heme pathway which produces a certain percentage of a defective product which combines with P5P in the liver. I know he has something that combines with P5P.

 

[Kimsie]

OK, I have come to the conclusion that taking high doses of methylfolate can significantly inhibit GNMT and this is why it can cause overmethylation symptoms from high SAMe. Taking folinic acid would probably be a better choice for most people, unless they can't metabolize folinic acid.

If a person gets symptoms from too much SAMe when they take folinic acid, they are probably low in glycine, which would also inhibit GNMT.

GNMT is the enzyme pathway which regulates methionine levels in the body and prevents excess SAMe from accumulating. Taking niacinamide will also get rid of excess SAMe and methionine, but it doesn't have the same regulation as GNMT and could drain too much SAMe if the person is not able to methylate freely. Taking niacinamide will have a sparing effect on glycine, if glycine levels are low. Taking high dose niacin would probably drain more glycine than it spares because large doses of niacin are generally metabolized by combining with glycine (unlike niacinamide).

Sometimes when people talk about "overmethylation", I think they are really referring to symptoms relating to the other parts of the folate cycle. Here is my folate cycle chart showing the main parts of the folate cycle to illustrate the ideas presented in this post.

 

[Violeta]

@Kimsie , I appreciate your theory about overmethylation.

While reading through this thread some things came to mind. It is a different way of possibly looking at the subject, but I am not up to speed on this with you and Nandixon.

When reading in the methylation forum when I first came here I noticed that more than one person had difficulty with methylfolate and at least one person said they developed Parkinsonian symptoms.

While reading about aldehyde dehydrogenase I found that: "Aldehyde dehydrogenase: The 3 substrates of this enzyme are aldehyde, NAD+, and H2O,"


Aldehyde dehydrogenase peculiarities in Parkinson's.
ALDH + Parkinson's
http://www.ncbi.nlm.nih.gov/pubmed/25298080

Could a pathogen such as candida be causing high levels of aldehydes and causing this sort of combination?
Folate, alcohol, ALDH polymorphism
http://www.ncbi.nlm.nih.gov/pubmed/21946912

Biotin deficiency causes heme deficiency:
http://jn.nutrition.org/content/137/1/25.full

Getting more interesting as I go along!

Epigenetic synergies between biotin and folate in the regulation of pro-inflammatory cytokines and repeats.
http://www.ncbi.nlm.nih.gov/pubmed/24007195

I don't want to go overboard, although I probably already did, but there is also the biotin suppressing fungal candida which would cut down on aldehydes, biotin helping Parkinson Disease, possible relationship of fungal pathogen to pyroluria.

I am only looking for helpful criticism of this information being helpful for the overall theory that you are wondering about.

Edit in: http://www.alternativementalhealth....ia-bipolar-depression-and-anxiety-symptoms-4/
with respect to biotin:"Preliminary data from Austria (Lauda) demonstrate a modest negative correlation between red cell glutathione and urinary Mauve by colorimetric assay. A significant inverse correlation exists between GST and urinary Mauve by colorimetric assay, and pends publication (correlation coefficient -0.65087, p<0.02). Audhya found very strong inverse correlation (coefficient -0.973) between OHHPL by HPLC/MS and biotin concentration, also pending publication. It is observed that biotinidase, which maintains biotin levels, is very sensitive to oxidative stress."

 

[BadBadBear]

I am an overmethylator and have poor night time sleep. I started on a fairly high dose of glycine - 3 gm recently. It makes me really sleepy. If I take a gram in the morning, I am dead all day so I stopped trying that. Last night I tried sublingual niacinamide - which I've not taken in a couple of years - to see if that would help squash high night time adrenaline. Also I'm finally tolerating molybdenum and had a dose of that (dealing with high copper issues which can go with overmethylation). It used to make my feel overstimulated, now molyb makes me calm. My sleep tracker shows I barely moved all night. Probably one of the most calm nights of sleep I've had since I started tracking. I take Cytomel around 3 AM and was able to go to sleep after taking it, which is not usually the case. Not sure if the effect will hold, but I am hopeful that I'm onto something useful.

 

[Sherpa]

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?

I have taken 3 to 4g of glycine without any gradual buildup. I was in the habit of taking approx 1600mcg methylfolate and Folinic blend per day. I tried taking glycine at night for insomnia but it kept me awake - slightly stimulated me.

Taking a lower dose, 2g, on subsequent nights helped me fall asleep.

 

[Vanessa_M]

This is not what I've heard about overmethylation, what are your main sources of information? I've heard that taking too much folate can be a problem for people who are UNDERMETHYLATED because they already have too much of it in their system and it strips methyl groups. But it is actually recommended for people who are overmethylated (8% of the population is) See https://www.samanthagilbert.com/folate-friend-foe/
The source material I rely on for my info on over /undermethylation is Dr. William Walsh of the Walsh Research Institute. He has a lot of YouTube videos that discuss this as well as a few published works. Has spent a good part of his career testing thousands of people for these kinds of issues. Might be worth checking out.

 

[Vanessa_M]

I am an overmethylator and have poor night time sleep.

Hi there, I've heard that certain nutrients like molybdenum and manganese can cause copper dumping at first, maybe why you didn't tolerate it right away? Interesting to hear your comments, I've been on a copper detoxing protocol for a while now but mainly zinc. I might give these other nutrients a try. Was taking things one step at a time rather than all at once. I also found out I'm overmethylated, so will commence other nutrients and supplements for that too.