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Study: Folinic acid beneficial to 81% of CFS patients...plus biomarker?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by dannybex, Feb 8, 2013.

  1. dbkita

    dbkita Senior Member

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    Understood. To be clear though I was implying that the 81% probably can mobilize folinic acid at some level (they used big dosages if I remember right). And that the 19% left over may NOT be able to do so.

    In other words if we view folinic acid as a storage intracellular buffer form which is perfectly natural, that most people at some level can shuttle around and convert for multiple uses. While not as optimal as taking straight methylfolate for methylation they would get some conversion dependent on MTHFR status and of course there are other reasons folates are used than just methyation, i.e. dUMP, thymidine synthase, etc. (though those other uses I doubt need high levels). Clearly the 81% were at some level able to deal with a stockpile of folinic acid.

    But for those who cannot it could be really devastating. Folinic acid levels when they rise high enough without proper activity of MTHFS will strongly downregulate SHMT1 and more importantly SHMT2 in the mitchondria. At which point you can kiss the folate cycle goodbye, since you are stuck at THF. Sure you could massively dose methylfolate but that will only last so long, if SHMT is blocked. This would lead to a folinic acid / methylfolate arms race which would not be good.

    In any event I don't see why high dose folinic acid would ever be a good thing. If you want methylation then take l5mthf and bypass a lot of issues. If you want some folates for other uses and want some regulatory control of SHMT and other folate enzymes, then take small amounts of folinic acid. Folinic acid as you know has a long half-life and can sit right in the CNS and take days to clear out. Overdoing it with say 800 mcg folinic acid (imo over doing it) could really "pile-up" over time. But 200 mcg? I doubt that is a big issue with most people based in part on the 81% study and the .high frequencies of many MTHFS and SHMT1 haplotypes.
     
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  2. Freddd

    Freddd Senior Member

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    Hi Dbkita,

    Understood. To be clear though I was implying that the 81% probably can mobilize folinic acid at some level (they used big dosages if I remember right). And that the 19% left over may NOT be able to do so.

    I do and do understand exactly that. I was speculating that perhaps the slowness of processing itself could be a source of some level of insufficiency as the RATE of conversion couldn't keep up with the rate of demand. It would make sense in that 200mcg of l-methylfolate can't keep up with the folate demand it starts. It could be that the more effective the folinic acid the bigger the donut hole insufficiency it starts. That's one problem with folinic acid from one viewpoint anyway, that one doesn't know what is going on, there are too many possibilities.


    more importantly SHMT2 in the mitchondria.

    Can you explain that please? What would the effect be? I was wondering what difference methylfolate makes for AdoCbl. Would this be perhaps some part of that connection?
     
  3. greenshots

    greenshots Senior Member

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    I always remember it as
    Folinic = SHMT
    Methylfolate = mthfr

    It has to go thru shmt before it goes to mthfr c677t and then on thru the methionine synthase areas (MTR & MTRR) so you may need both but only the 5 MTF version can get you past the c677t


     
  4. dbkita

    dbkita Senior Member

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    There are two isoforms for SHMT. SHMT1 in the cytosol runs the reversible reaction of serine +THF = glycine + 5,10 methylene THF. In the mitochondria the isoform is SHMT2. This preferentially drives the forward reaction of serine + THF = glycine + 5,10 methyleneTHF (the precursor to 5mthf).

    The SHMT1 enzyme is part of a system to make sure the cell has ample THF hanging around but also enough 5,10 methyleneTHF and helps the SHMT2 enzyme makes glycine (very important). A secondary function of SHMT1 is to make intracellular folinic acid (5 formyl thf) from 5,10 methenylTHF (not 5,10 methylene THF) if there is sufficient glycine (meaning the forward primary reaction is working well already) and place it in store as a buffer for down the line production of thymidine, etc.

    See:
    http://www.ncbi.nlm.nih.gov/pubmed/2201683

    I have to assume this takes place at another active site on the enzyme than the reversible serine-glycine site but maybe I am wrong. Anyways, MTHFS taps this store to re-make 5,10-methenyltetrahydrofolate (NOT 5,10 methyleneTHF). Note: the methenyl variant (often confused; for example the heartfixer.com and Yasko diagrams have it wrong) goes on to make thymidine via thymidine synthetase and dUMP. People with Smith-Magenis disease are missing SHMT1 entirely (like a knockout mouse) but still have 50% SHMT activity because SHMT2 is partially redundant if needed.

    That is known. Now what is hazy or is speculative is another thing entirely.

    Hypothetically, I could imagine a scenario where a pile-up in folinic acid down-regulates SHMT1 & maybe SHMT2 (a big IF that I am not certain of at present). This could then potentially start choking the input to MTHFR. For a regular person this probably doesn't arise as folinic acid never rises above some level and can be managed with some sort of alacrity. I think this is where Rich (and others) thought MTHFS comes into play. I still think this is hypothetical.
    I will admit I am still in the process of studying SHMT. The SHMT1 C1420T SNP listed by Yasko et al is pretty conclusively now shown to NOT be the only “player” as it by itself does NOT lower or raise enzyme activity. But it does appear from correlations in older studies with other indications that it may be part of a fragile haplotype where some other mutations we do not know about makes things go askew and enzyme activity drops. There is a lot of confusion about SHMT1 SNPs and their significance. No one really knows.

    For example:
    http://journals.lww.com/psychgeneti...ations_in_folate_metabolic_pathway_and.2.aspx

    Note how the non-autistic children have more of the “risk” A allele and the thinking is A is protective vs autism. Yet SHMT is a cornerstone mutation of the Yasko protocol with first priority. Eh?


    Yet SHMT activity IS important:
    http://ajcn.nutrition.org/content/93/4/789.full

    But here -/- means literally no gene as in deletion. Not the same as a single SNP C1420T.
    The exact balancing act between SHMT1 and SHMT2 is complicated further by that SHMT2 encodes its own variant of SHMT1 if necessary for expression. i.e. redundancy. Like I said complicated.

    In her book Autism Pathways to Recovery Chapter 6, Dr Yasko says:
    “Supplementing with nucleotides, which are a form of our DNA bases, can help to both support thymidine, while maintaining appropriate methylation cycle activity. In addition, both iron and a form of folate called “5 formyl THF ” help to regulate SHMT activity. That’s why using lactoferrin (which helps to control iron levels) along with low doses of 5 formyl THF (found in the product, ActiFolate) help shift methylation activity back to the short and long routes around the cycle.”

    So autistic kids who in reality tend to have the wild type ‘G’ allele as we saw conclusively above, are viewed as having too much ‘diversion’ from methylation by thymidine synthase or is it just too little production of both? Not clear to me by that paragraph. The folinic acid “regulates” SHMT. Up or down? We assume in reality ‘down’ by negative feedback. But SHMT1 and SHMT2 or only SHMT1? Yet even worse the folinic acid and nucleotides, etc. are being presumably given to patients with the A ‘risk’ allele. Again, eh? (Note the MTHFR c677T and MTHFR A1298C haplotype is very loaded towards autism as an aside).

    But ignoring that, let us say regardless of SNPs, a person really has a down regulated, poorly functioning SHMT1 then a natural conclusion would be to supplement the end products of that enzyme. Right?

    Supplementing methylfolate, whether SHMT2 is down regulated or not, is not an issue if we are tackling MTHFR after all. The folinic acid would be in principle be a back channel to the "warehouse" to help the dUMP and other cycles. THF will spin back from methylfolate if not in a methyl trap.

    But … at what dose does supplementing folinic acid do only the “good” things listed above vs. suddenly start to further down-regulate already anemic SHMT1 production? Does SHMT2 re-balance to fit the bill or is it squashed. Can cytosolic folinic acid even cross into the mitochondria? Or is it all regulation at a transcriptional level?

    However, I cannot at present imagine that large doses of folinic acid serve these purposes well. That seems more about flooding the folate cycle and hoping everything shakes out. If you will forgive me, seems more like a bit of using blunt forced trauma on the patient at high enough doses. But low doses may be a different story having more to do with augmenting DNA production and purine synthesis than boosting methylation capacity. Maybe that is for the 81%. The 19% may be kind of screwed for lack of a better term.

    Personally I am staring a SHMT1 C1420T homozygote SNP in the face. But right now I am pretty sure I have not much of a clue what that really means. It puts me at risk (risk only) for impaired SHMT1 activity. But from what I have researched, in no way guarantees that. And like I said some of the existing information how it interacts as per autism, methylation, etc. is very suspect. I suppose I am not surprised after the researching the whole VDR SNP notational debacle. At some point I will try to post a SHMT thread, but there are like 15 papers lurking on the topic and I really can’t find a direct definitive connection for some of the stuff regarding the tested SNP.

    Anyways I have a bad head cold and am going to try and get some sleep.
     
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  5. Xara

    Xara Senior Member

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    First: I hope you'll recover from that bad cold soon, and you'll wake up feeling better.

    Second. Thanks for this most interesting post, though hard to grasp for any layman of course.

    Third. I remember you once explained folinic acid is not the same as the form that's in vegetables. Could you please explain how that vegetable form fits in to this SHMT1 and SHMT2 activity? Thank you in advance.
     
  6. dbkita

    dbkita Senior Member

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    Thanks Xara. I hope so to. My worry is my daughter though is fighting a bacterial infection with a 10 day course of Augmetin. She is getting better but I am worried with my glucocorticoids this may be a problem if I indeed got her bug. Ugggh.

    While every living thing has folates of various types which you will absorb when you ingest food, the dominant dietary folates are not to my understanding folinic acid. Folinic acid will of course be there. Strictly speaking dietary folates are THF and all derivatives but the usage generally associated with "Folate" in foods is the non-oxidized variants of folic acid (folic acid is synthetic) packed in multiple glutamates. So when a nutrition site is saying how much "folic acid" in a non-fortified food, they really mean how much of these polyglutamate folates (i.e. natural source B9).

    These "folates" are stripped of glutamates in the intestinal lumen and then run through the processes to reduce it to DHF and then THF. SHMT only knows about serine, glycine, THF, 5,10 methyleneTHF and on the secondary track 5,10 methenylTHF and folinic acid. It does not directly interact with other folate derivatives. So the more you raise THF via methylation support or taking in dietary folates (assuming DHFR works well), then the more fuel for SHMT in principle. I think though the actual regulatory dance is very complicated.

    This link might be useful although I have not scrutinized all of it carefully. You would be surprised how many people mix thing up in the folate cycle.

    http://www.altmedrev.com/publications/3/3/208.pdf
     
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  7. dannybex

    dannybex Senior Member

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    Dbkita -- just wanted to thank you for your posts.

    You're so smart and knowledgeable about these intricate, complicated genetic issues, and I appreciate they way you try to make them comprehensible to mushy-brained types like myself.
     
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  8. Victronix

    Victronix Senior Member

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  9. Lotus97

    Lotus97 Senior Member

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    There's a thread in the SNP forums about which SNPs have a problem with folinic acid (although I'm not sure it's been completely mapped out yet).
    http://forums.phoenixrising.me/inde...d-intolerance-request-for-genetic-data.19168/

    There's another way you could test it. If you're familiar with the effects of taking too much methylfolate, you could just take a high dose of folinic and see how you feel. If you feel the same as when you take methylfolate then that would mean you're converting it to methylfolate.
     
  10. Lotus97

    Lotus97 Senior Member

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    Were you taking folinic acid and/or methylfolate when you tested low on them? If so, did you not feel the effect of them until you stopped folic acid? Or if you were only taking folic acid then, were there any specific symptoms you attribute to taking folic acid? Also, do you remember what dose of folic acid you were taking?
     
  11. Lotus97

    Lotus97 Senior Member

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    As for dietary folate I would recommend reading through the last couple pages of this thread starting here:
    http://forums.phoenixrising.me/inde...ients-plus-biomarker.21745/page-3#post-340037
    You'll see that folinic acid from dietary folate isn't processed exactly the same supplemental folinic acid. I admit that I have yet to completely grasp the significance of all of this, but it seems that if dietary folate is your main source of folate you might not get the same results as you would if you took supplemental folate. There's a lot of information in this thread and I appreciate dbkita for laying it all out for us, but it might be some time before I digest all of this (no pun intended).
     
  12. Lotus97

    Lotus97 Senior Member

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    I'm confused because dbkita said mthfr c677t didn't affect folinic acid. I admit that I understand very little of what dbkita said (although I hope one day I will understand) and know little about SNPs in general.
     
  13. Lotus97

    Lotus97 Senior Member

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    I need to ask you about another of Rich's quotes. He said something about supplemental folinic acid being polyglutamated and therefore it would help with glutamate excitotoxicity. I just checked and he only said it once and it was back in 2010 so I'm wondering if this is the same thing as how he initially thought it was MTHFR and then realized later it was MTHFS and/or SHMT (I'm still confused on those too). Since that post in 2010, Rich has talked about excitotoxicity and methylation many times, but he never mentions folinic acid which is strange especially since folinic acid is in his protocol. I'm assuming he was wrong and then realized it later which is why he never mentions it again. I just posted that quote in another thread so I would like to know if it's incorrect so I can edit my post.
     
  14. Lotus97

    Lotus97 Senior Member

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    The thing I'm confused about is when people say folic acid and/or folinic acid "block" methylfolate. I don't understand how I felt the effects of methylfolate when I was taking 1500 mcg of folic acid and only 100 mcg of methylfolate. Was it just that a tiny bit of methylfolate was able to sneak past the folic acid and get absorbed? I get that a deficiency can cause certain symptoms, but the symptoms lasted 5 weeks until I finally stopped the methylfolate. And the symptoms were the same as I got from taking too much B12 so it seems like it was overmethylation. I think the Quatrefolic methylfolate might be more potent because I tried Thorne's b complex with methylfolate more recently and it didn't seem to have the same effects. I mostly took it with vitamin c and/or potassium, but there were a few days where I didn't and I was also taking B12 at the time (I wasn't with the Quatrefolic). As dannybex said, folic acid could cause a folate deficiency, but a B12 deficiency could also cause a folate deficiency. I'm too sick to do any tests now so I'm just going to take B12 and limit my folate. Then when I'm ready I guess I'll try one folate at a time and see how it goes.
     
  15. greenshots

    greenshots Senior Member

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    Thats right, folate is converted to folinic at the SHMT enzyme and then its converted to methylfolate or 5 MTHF at the MTHFR c677t. So folinic doesn't override the c677t at all. But if you have trouble at the SHMT, you'll have problems with folinic and then there will be less methylfolate for the next step at the c677t. Its all interrelated. The pathway for folate is SHMT to MTHFR and on to MTR/MTRR for converting to homocysteine. I'm not sure about Rich's comment on pyroglutamate but I know if you have defects in these areas, plain folate becomes more problematic because it is a glutamate. This is also probably one of the reasons folic acid can cause cancer in some people.
     
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  16. Victronix

    Victronix Senior Member

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    My SHMT is one of the few normal ones, but 2 of my 3 MTHFRs are +/-, and most of my MTRRs are +/-. I had my homocysteine checked and it was normal, just about in the middle of the range (but I also take 7 mg of B-12 per day since I developed a B-12 deficiency in 2008, don't know what my homocysteine would be without the B-12). So hopefully folinic will not be too much of a problem.
     
  17. dannybex

    dannybex Senior Member

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    I was taking -- from time to time -- off and on for years -- folic acid, when I thought there was only 'one' folic acid.

    It came as part of a sublingual b12/folic acid combo. Did seem to help, but I think it was most definitely the ad-b12 in it, and not the folic acid. Country Life brand...think it was 400mcgs folic and 500 mcgs ad-b12.

    p.s. I personally don't think folinic blocks methylfolate. Not sure, but believe it slowly converts to methylfolate if you don't have various genetic issues others have mentioned.
     
  18. dbkita

    dbkita Senior Member

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    Folinic acid is not polyglutamated. It is monoglutamated like many folates. He may have crossed that up with the dietary natural folates I described above. I see no reason directly that folinic acid would raise glutamate. That form is stable. It does not get broken down to cross membranes. The only possible indirect link is that really high TH4 levels can lead to over-processing of histidine into a glutamate derivative (this is the same reason that histamine levels are low in high methylation states). But how much that actually impacts excitotoxicity is not clear to me.

    Also I am sorry but that idea that the amount of glutamate in supplemental folates (remember they all get reduced to monoglutamate form in the intestinal lumen) is a significant impact on someone is unlikely to say the least. The reason is simple. The amounts. If you take 800 mcg of folic acid or folinic acid, you get about 1/3 of that as glutamic acid. You get a ton more glutamate in simple protein foods. Even if you take 3200 mcg of folic or folinic acid you get like 1 gram. 1/4 lb of ground hamburger has 3.3 grams or so.
     
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  19. dbkita

    dbkita Senior Member

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    Just to clarify, in that thread I was actually trying to make it clear that most dietary folates are NOT folinic acid.
    I guess I did not make that clear enough.

    Here is what I posted in the thread you linked:

    "Folinic acid is a 5-formyl derivative of THF. The folates in vegetables are not folinic or folic acid (a fully oxidized synthetic folate, i.e. pteroylmonoglutamic acid). This is a notorious misconception in the research community. The folates in food are metabolites of THF packed within polyglutamates. In the intestinal lumen these polyglutmate dietary forms are broken down into monoglutamate variants which can then be converted to DHF and then THF by their respective enzymes. The DHFR enzyme is not present in humans for the synthetic folic acid it is present for processing dietary folates. Folinic acid is readily converted to 5,10 methylene THF without use of DHFR. That being said dietary folates parallel more with folic acid than with folinic acid with one crucial difference ... they can be processed in the intestinal lumen and the liver. Folic acid (I am pretty sure) being fully oxidized must be converted in the liver.

    I don't think this changes the fact that high dietary folates could be an issue for some people who can not make use of them, have intestinal wall damage, or critical needs for 5mthf but let's be honest while maybe garden feasts are not a good idea, it is not wise probably to eschew vegetables entirely as a general rule."

    Technically that was a little strong in the sense that animal and plant cells will have folinic acid in them. Just like TH4, L5mthf (say in liver), or 5,10 methylene THF, etc. But the dominant form that is ingested as dietary folates is the natural, non-oxidized folate (folic acid is the oxidized, synthetic version that can only be processed in the liver). Again this is cleaved of most glutamates in the intestine and further reduced to DHF in the intestines or liver. From there DHFR takes it to THF.
     
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  20. Freddd

    Freddd Senior Member

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    I want to make clear I eat plenty of veggies. They contain a lot of important nutrition way beyond folates. I just have to balance and time my doses of methylfolate. I may be able to distinguish at least one subset of persons. There are those who have had folate insufficiency symptoms since infancy or childhood. In my age group, 65 or thereabouts, there was no folic acid in childhood so any reaction was to veggie folates. I had those symptoms. Things got a lot worse very rapidly when I added folic acid in Special K and other such products. Now there are people who got sick as infants from formula right off so the natural problem with veggie folates isn't as easily distinguishable.

    As adults what is happening may not be the same. It may be that we are getting hung up on a "rate of availability". if folinic acid does act for many as a "time release" it just may not be accessible when needed in an amount that fully satisfies that need when healing is going strong. As usual, people get confused with some layers healing and some layers demonstrating insufficiency at the same time.

    Confusing folate insufficiency with glutamate toxicity doesn't help anybody. Distinguishing amongst all the different responses is difficult and confusing but is the only way to get useful answers. So if a person starts wrestling with glutamate toxicity hypothesis when they have folate insufficiency they will not find the answers, floundering around and maybe never finding a helpful solution. Bad questions get bad answers when taken as a given. GIGO
     
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