Rich -- few methylation questions (please :)

Discussion in 'Fibromyalgia Main Forum' started by Scapper, Jul 29, 2011.

  1. Scapper

    Scapper New Member

    Hi Rich: I was wondering if you could explain to me why people get headaches from the folates?

    And, why would my need for Potassium rise? What is the connection?

    I started taking 400mcg of Metafolin and I got the same reaction as I did in 2008 from Folapro. First few days I felt "sped up" and then I crashed. I took Potassium Citrate and this brought me back up for about 2 days and then I crashed again.

    I'm also taking 3mgs of sublingual Methylcobalamin (divided doses).

    I'm waking beyond exhausted......sick feeling w/ zero energy.....I mean no energy to even **move** and my brain fog is soooooo bad.

    I've also had this headache since starting the 400 mcg Metafolin.

    I tried to find old posts re: headache, but wound-up reading your older papers w/ my muddled brain, so I thought you might be able to shed some light on this for me and spare some of my brain cells :)

    As always, thank you for your time!

    scapper
  2. richvank

    richvank New Member

    Hi, scapper.

    The likely reason for the rise in the need for potassium is that potassium is the main ionic substance inside cells. When folate is taken by a person who has been low in intracellular folate, it is now possible to make DNA at a higher rate, and thus to make new cells at a higher rate. These new cells present a demand for potassium. There is no significant reservoir for extra potassium outside the cells, which contain 98% of the body's potassium inventory.

    I don't know for sure what would cause headaches. One possibility is sulfite. If you are low in molybdenum, that could slow your sulfite oxidase reaction and allow sulfite to build up. Headaches can be caused by sulfite.

    Another possibility might be that the detoxication system is beginning to operate more normally and is mobilizing toxins.

    The likely reason for the sequential crashes is that your body is deficient in some of the cofactor vitamins and minerals, so that as you begin to stimulate the methylation cycle toward more normal operation, these deficiencies begin to matter. I don't know if you are taking the multi that is included in the simplified prototol, but if not, you might consider adding it,and even starting on it first and building up the cofactor nutrients before going on to add the B12 and folates. Some of main cofactors needed by this part of the metabolism are zinc, magnesium, manganese, selenium, molybdenum and copper, and B complex vitamins. These are all included in the multi.

    I hope this helps, and I hope you will get relief soon. I see in your other posts that you are working with a physician, and I'm happy to see that.

    Best regards,

    Rich

    [This Message was Edited on 07/30/2011]
  3. mbofov

    mbofov Active Member

    I am a little concerned about the folic acid in the multivitamin used in the simplified methylation protocol, especially if someone has difficulty metabolizing folic acid, which I think I do and Scapper may well also. I've been doing a little research and find that Douglas Labs and Pure Encapsulations are both making multis now with Metafolin instead of folic acid.

    Also, we know that Freddd also has a great sensitivity to n-acetyl-cysteine, which is also contained in the simplified multi. And I do think I reacted badly to that multi. Whether it was to the folic acid or NAC or both, I don't know. I haven't done the experimentation that Freddd has.

    So I'm just wondering if it might be a good idea to switch multis, especially because of the folic acid and possibly also the NAC. From the little reading I've done, I think folic acid competes with folate (metafolin) for utilization by the body and may actually prevent utilization of metafolin, contributing to folate deficiency. Does this sound right to you?

    Also, I don't know if you saw the article I posted a couple of days ago about the relationship between B12 and folate (http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=1415873). A major point the article made was that high folate levels combined with low B12 can cause anemia and cognitive impairment. Here's an excerpt:


    “The tabulated data show that having low vitamin B-12 status, regardless of serum folate, was associated with a significantly increased prevalence of both anemia and cognitive impairment. Furthermore, compared with having normal status for both vitamins, having high serum folate but normal vitamin B-12 status was associated with a reduced prevalence of anemia and a significantly reduced prevalence of cognitive impairment. The worst combination was low vitamin B-12 status and high serum folate. Specifically, anemia and cognitive impairment were observed 5 times as often in the group with that combination as in the group with normal vitamin B-12 status and normal serum folate."

    One drawback of the article is that it talks only about folic acid, and not metafolin.

    Anyways, I'm wondering now if a possible problem with both your simplified protocol and Freddd's protocol would be that they might cause an excess of folate (whether in the fom of folic acid or metafolin), which could exacerbate any underlying B12 deficiency, possibly contributing to Scapper's crash and symptoms usually attributed to detoxing.

    I'd appreciate any thoughts you may have on all of this - thanks, Rich!

    Mary
  4. Scapper

    Scapper New Member

    Thank you so much Rich for helping this make some sense. I'm going to back off and begin w/ a multi.....I'm just not sure on which one at this time, since the debate of folic acid seems to be an issue.

    I came on to ask you to help this "debate" make sense to me and Mary has put my thoughts into words I never would have been able to find.

    Thanks Mary.

    I look forward to hearing Rich's comments and in the meantime, I'm hoping my body comes back up a bit (this is awful....insomnia kicked in hard last night) and I'd like to give my body the correct base before starting again.

    scapper

    p.s. Rich, my G.P. has asked me to bring in information regarding your protocol. Can you provide me w/ which updated papers you think would be appropriate for her? I was interested in asking her to write me a script for methylcobalamin (IM) daily......can you support this need?
    [This Message was Edited on 07/30/2011]
  5. richvank

    richvank New Member

    ***Hi, Mary.

    I am a little concerned about the folic acid in the multivitamin used in the simplified methylation protocol, especially if someone has difficulty metabolizing folic acid, which I think I do and Scapper may well also. I've been doing a little research and find that Douglas Labs and Pure Encapsulations are both making multis now with Metafolin instead of folic acid.

    ***One thing that Freddd and I agree upon, although perhaps for differing reasons, is that folic acid is not the best form of folate for PWCs to be taking. The reasons I am not in favor of using folic acid are first, that folic acid competes for absorption with the natural forms of folate that are in foods (5-methyl THF and folinic acid), and second, that many people are not able to utilize folic acid very well, because they have inherited a slow version of the DHFR enzyme, which is needed to convert it to THF, the basic chemically reduced form of folate from which the various active forms of folate are made. There is also some published research suggesting that folic acid can build up in the blood and can suppress the activity of the natural killer cells.

    ***It's true that there is some folic acid in Amy Yasko's multi, which is part of the simplified protocol. Whether there is enough in there to cause a problem probably varies from one person to another. If you have read the thread on Phoenix Rising that is entitled "Attention Freddd, etc." you are aware that I have suggested that Freddd has an unusual enzyme deficiency in MTHFS (methenyltetrahydrofolate synthetase), which would explain some of his response to various supplements, including folinic acid and folic acid. I don't know how common such an enzyme deficiency is, since I haven't found any reference to it in the published literature.

    Also, we know that Freddd also has a great sensitivity to n-acetyl-cysteine, which is also contained in the simplified multi.

    ***Yes, that is puzzling to me. He had a bad reaction to NAC and to glutathione, which NAC can help to produce. It seems that in addition to the MTHFS deficiency, he also has a deficiency in the intracellular B12 processing enzymes, such that if B12 binds with glutathione to form glutathionylcobalamin, the B12 is no longer available to his cells. It has been found in rat experiments that normally it is not possible for the cells to make methyl B12 without glutathione. So I think there is definitely something unusual in Freddd's B12 processing enzymes. This latter enzyme deficiency is more common. A recent review reports that about 400 people have been found to have this one.

    And I do think I reacted badly to that multi. Whether it was to the folic acid or NAC or both, I don't know. I haven't done the experimentation that Freddd has.

    ***It's difficult to say why it might have caused you problems, because there are so many ingredients in it. I've heard from some people that they cannot tolerate milk thistle, and that's one of the ingredients.

    So I'm just wondering if it might be a good idea to switch multis, especially because of the folic acid and possibly also the NAC.

    ***Perhaps so, and perhaps because of other ingredients as well.

    From the little reading I've done, I think folic acid competes with folate (metafolin) for utilization by the body and may actually prevent utilization of metafolin, contributing to folate deficiency. Does this sound right to you?

    ***It does compete for absorption into the blood by the gut, and also for transport into the cells from the blood.

    Also, I don't know if you saw the article I posted a couple of days ago about the relationship between B12 and folate (http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=1415873). A major point the article made was that high folate levels combined with low B12 can cause anemia and cognitive impairment. Here's an excerpt:


    “The tabulated data show that having low vitamin B-12 status, regardless of serum folate, was associated with a significantly increased prevalence of both anemia and cognitive impairment. Furthermore, compared with having normal status for both vitamins, having high serum folate but normal vitamin B-12 status was associated with a reduced prevalence of anemia and a significantly reduced prevalence of cognitive impairment. The worst combination was low vitamin B-12 status and high serum folate. Specifically, anemia and cognitive impairment were observed 5 times as often in the group with that combination as in the group with normal vitamin B-12 status and normal serum folate."

    ***I think that what is going on here is that low B12 is causing the folate to drain out of the cells into the blood serum via the so-called "methyl trap" mechanism. They are measuring folate in the blood serum, and a high level there is indicative of low intracellular folate levels. So it's not that high serum folate itself is a problem. The problem is that there is not enough folate inside the cells. When B12 is low in an absolute sense, or when there is a functional B12 deficiency, as in ME/CFS, the cells keep converting their folate pool into methylfolate, and because the methionine synthase reaction is not working at a normal rate (owing to not enough methyl B12 availability), the methylfolate builds up, and then exits the cells, into the blood serum. Over time, the cells go low in folates in general. We measure this with the methylation pathways panel.

    One drawback of the article is that it talks only about folic acid, and not metafolin.

    Anyways, I'm wondering now if a possible problem with both your simplified protocol and Freddd's protocol would be that they might cause an excess of folate (whether in the fom of folic acid or metafolin), which could exacerbate any underlying B12 deficiency, possibly contributing to Scapper's crash and symptoms usually attributed to detoxing.

    ***I do think that trying lower dosages of the folates might help, because bringing up the methionine cycle too rapidly might be causing too much mobilization of toxins. I don't think the problems are due to folate exacerbating B12 deficiency, if B12 is being supplemented at the same time.

    I'd appreciate any thoughts you may have on all of this - thanks, Rich!

    Mary

    ***You're welcome.

    ***Best regards,

    ***Rich
  6. Scapper

    Scapper New Member

    Can you provide me w/ a link to one of your papers that you feel would be appropriate for me to bring to my G.P.?

    I really want her to provide me w/ methyl B12 injections and I was hoping your literature would support the need.

    Anything......anything......

    Thanks.......scapper

    p.s. I had to back completely off the Metafolin to bring down my "sick all over" feelings (headache, insomnia, stomach ache, EXHAUSTION, brain fog)......I'll build up my co-factors and then try again (fyi).
  7. mbofov

    mbofov Active Member

    As always, thanks for all your input. Just a few comments -

    One, I've never had a problem with milk thistle. I've been taking it for several years ever since I did a major liver detox in 2003. I had some heavy exposure to chemical solvents when I was 19 (where I worked) and think that was affecting my liver. My digestion did improve a lot after the detox (e.g., prior to then one glass of wine would make me sick for an entire day, and 2 glasses would make me sick for 3 days, and now it doesn't).

    I am sure I have a MTHFS deficiency (which I know is not uncommon), primarily because I started feeling better after taking metafolin and cutting out folic acid. And I did have the methylation panel done which showed a deficiency.

    I don't know about Freddd's B12 processing enzymes deficiency - CFS is a such an unusual illness though, and B12 is inextricably involved, I would not be at all surprised if more PWCs had this deficiency. We're not being tested for it, of course.

    There's one more thing I've been wondering about. From what I read here, B complex vitamins are almost a staple for PWCs. It's one of our most basic supplements. All B complex vitamins contain folic acid (except for some of the newer ones which now have metafolin). Also, I believe a large percentage of PWC take some form of B12, either by injection or otherwise. I've done B complex vitamins and B12 shots (either hydroxocobalamin and methylcobalamin) for many years. The simplified methylation protocol is essentially folate and B12, which I've been taking for years. So why is there a block in the methyation cycle, both for me and all the PWCs who've been taking these supps for years? All I can figure is that the folic acid in the B complex and our fortified food is the culprit. It makes my head spin to think of all the years of taking a B complex perhaps causing more and more damage.

    My MCV on the CBC test has been at the top of the normal range for many years, but no doctor was ever knowledgable enough to piece things together and advise that folic acid might be hurting me and causing a folate deficiency.

    What do you think of all this?

    Mary
  8. richvank

    richvank New Member

    Hi, scapper.


    Here is a link to the poster paper reporting on the treatment study that Dr. Nathan and I carried out. That would probably be a good one to give to your G.P.

    http://www.mecfs-vic.org.au/sites/www.mecfs-vic.org.au/files/Article-2009VanKonynenburg-TrtMethylStudy.pdf

    In this treatment study, we used hydroxocobalamin rather than methylcobalamin, but many people do use methylcobalamin, in both autism and ME/CFS.

    In addition, my papers are now posted in the Wiki section of the Phoenix Rising ME/CFS forums site: http://forums.phoenixrising.me/forumdisplay.php?91-General-Wiki-Pages

    In Part 7 of my papers, there is one giving a "simpler" explanation of the hypothesis behind this treatment. I don't know if that would be too simplified for your GP or not. You can read it and see what you think.

    I think that backing off was a good thing to do, and I hope that the next trial, after building up cofactors, will go well.

    Best regards,

    Rich

  9. richvank

    richvank New Member

    ***Hi, Mary.

    As always, thanks for all your input.

    ***You're welcome.

    Just a few comments -

    One, I've never had a problem with milk thistle. I've been taking it for several years ever since I did a major liver detox in 2003. I had some heavy exposure to chemical solvents when I was 19 (where I worked) and think that was affecting my liver. My digestion did improve a lot after the detox (e.g., prior to then one glass of wine would make me sick for an entire day, and 2 glasses would make me sick for 3 days, and now it doesn't).

    ***O.K. Doesn't sound like milk thistle is a problem for you.

    I am sure I have a MTHFS deficiency (which I know is not uncommon), primarily because I started feeling better after taking metafolin and cutting out folic acid. And I did have the methylation panel done which showed a deficiency.

    ***You may be right. How have you responded to folinic acid? I think that would be the best test of whether there is an MTHFS deficiency. I guess I'm not quite ready to conclude that you have this deficiency, but I may be wrong. I think that folic acid can cause problems in other ways than via such a deficiency. If a person has a slow version of the DHFR enzyme, they will absorb folic acid, but they will not be able to utilize it very well, and in the meantime it will compete with absorption of the more active folates into the blood and into the cells. Another possibility is that folic acid could be putting a major demand on NADPH. Two NADPH molecules are needed to chemically reduce folic acid to the active form, and NADPH is also needed by both the MTHFR reaction and the MTRR reaction. Dr. Cheney wrote me that he has measured NADPH in many patients, and they are almost always low.

    I don't know about Freddd's B12 processing enzymes deficiency - CFS is a such an unusual illness though, and B12 is inextricably involved, I would not be at all surprised if more PWCs had this deficiency. We're not being tested for it, of course.

    ***That may be true. It may account for at least some of the cases that have not responded to the version of the methylation treatment that I have suggested.

    There's one more thing I've been wondering about. From what I read here, B complex vitamins are almost a staple for PWCs. It's one of our most basic supplements. All B complex vitamins contain folic acid (except for some of the newer ones which now have metafolin). Also, I believe a large percentage of PWC take some form of B12, either by injection or otherwise. I've done B complex vitamins and B12 shots (either hydroxocobalamin and methylcobalamin) for many years. The simplified methylation protocol is essentially folate and B12, which I've been taking for years. So why is there a block in the methyation cycle, both for me and all the PWCs who've been taking these supps for years? All I can figure is that the folic acid in the B complex and our fortified food is the culprit. It makes my head spin to think of all the years of taking a B complex perhaps causing more and more damage.

    ***That may be true. I'm glad that there are now some B-complex supplements available that use Metafolin rather than folic acid.

    My MCV on the CBC test has been at the top of the normal range for many years, but no doctor was ever knowledgable enough to piece things together and advise that folic acid might be hurting me and causing a folate deficiency.

    What do you think of all this?

    ***I'm glad that you have raised this issue. I encourage people to try testing out the folic acid hypothesis. It may pay off. I would like to have a firmer understanding before making more changes in the suggested protocol, because we know from our clinical study that most of the patients were helped by it. As you know, the only folic acid still remaining in the protocol is in the multi. If I abandon that multi, I also give up the other ingredients in it that are chosen to support the methylation cycle and related pathways. I'm concerned that other benefits would be lost in the change. So I have a bit of a dilemma. Ideally, controlled testing could be done to determine these things, but the funding is not there for that.

    Mary

    ***Thanks, Mary, and I hope the changes you have made in your own protocol will pay off for you.

    ***Best regards,

    ***Rich
  10. mbofov

    mbofov Active Member

    Someday when I have some energy to spare ;) I may try out folinic acid. I've had sort of a rough time lately, with my blood pressure dropping quite low (down in the 80's for the top number) and attributing it to the potassium supplementation I was doing in connection with Freddd's protocol. I also was feeling woozy and dizzy and tired and my vision was blurry. So I felt caught between a rock and the hard place - if I kept up with the metafolin, it meant keep taking potassium, but my BP was too low - so I stopped the extra metafolin and potassium, and my BP still would hardly get over 100 and was more often in the 90's and dropping occasionally down to teh 80's. grrrrr!!!!! I was feeling so frustrated, I can't tell you, at finally finding something that was helping and then feeling forced to stop.

    And then I discovered the real culprit - progesterone cream. I'm using a prescription progesterone cream and was doing it every other day and about a month ago my doctor told me to double my dose, do it every day, and it was shortly after that that my BP first dropped so low. So a couple of days ago I researched progesterone cream and sure enough, excess progesterone can cause all those symptoms, the blurry vision, low BP, woozy and tired. I stopped it, my BP is finally starting to go back up to normal levels, my vision is normalizing and the woozy feeling is gone. I sometimes feel like I'm being tested to see how much I can take by some being with a wicked sense of humor. (I think all of us on this board feel that way!)

    Anyways, I plan to restart the metafolin etc. in a day or two and hope to make progress on it (unless some new wrinkle pops up, of course). This is certainly a learning experience, to put a positive spin on things!

    Best wishes,

    Mary