Forms of B12 and folate for treatment of CFS--pros and cons

Discussion in 'Fibromyalgia Main Forum' started by richvank, Mar 25, 2010.

  1. richvank

    richvank New Member

    Hi, all.

    Here is something I posted to a couple of the other CFS groups in response to questions, and I think it may be of interest to some people here as well.


    1. I think it is well established now that many and probably most cases of both autism and CFS have a partial methylation cycle block at the root of their biochemical abnormalities.

    I realize that many and perhaps most of the people in the research and clinical communities involved in these two disorders are not (yet!) on board with this concept, but I believe that careful study of the available research results and attention to the results of treatment based on this concept do bear it out.

    2. While a knowledge of the normal biochemistry of the methylation cycle and related pathways points in a general way toward the types of treatment that are likely to be effective, it does not uniquely identify the optimum treatment for either autism or CFS.

    For one thing, we humans all differ in terms of our particular sets of genomic polymorphisms, so that the same treatment is likely not optimum for all people who have autism or CFS.

    For another thing, a person who has one of these disorders does not have normally functioning physiology and biochemistry. The best path back to normal will probably have to be determined experimentally by each person, because normal biochemistry is not enough to tell us the best path back to normal. Because of this, I don't think that anyone can claim that a particular protocol is the "best" for use by everyone who has autism or CFS.

    3. What we can say on the basis of biochemical testing is that in autism and CFS there is a partial block of the enzyme methionine synthase, which is found in every cell of the body.

    We also know that this enzyme requires the reactants homocysteine and 5-methyl tetrahydrofolate, that it requires methylcobalamin (a biochemically active form of vitamin B12) as a coenzyme, and that the reaction it catalyzes produces methionine and tetrahydrofolate.

    We also know that in the liver and kidneys there is an alternate pathway that converts homocysteine to methionine, which is called the BHMT (betaine homocysteine methyltransferase) pathway.

    Both these reactions produce methionine, and a second reaction in the methylation cycle converts methionine to S-adenosylmethionine, which is the main source of methyl groups for methylation reactions in the body, of which there are a very large number.

    While the BHMT reaction does convert homocysteine to methionine, it does not involve the folate metabolism, and thus does not convert 5-methyl tetrahydrofolate to tetrahydrofolate, as the methionine synthase reaction does.

    Since the folate metabolism is important for other aspects of the overall biochemistry (including the synthesis of DNA and RNA to make new cells), and since the methionine synthase pathway is the only pathway that closes the methylation cycle in organs, tissues and cells beside the liver and kidneys, it is not sufficient to support only the BHMT pathway.

    4. Based on this, the main goal of treatment of autism and CFS must be to restore methionine synthase to normal operation. Since there is usually not a shortage of homocysteine, the substances that need to be raised in their levels in the body to stimulate the activity of methionine synthase are 5-methyl tetrahydrofolate and methylcobalamin.

    5. In addition to stimulating methionine synthase, there are other things that are needed by the methylation cycle and associated biochemical pathways for their operation.

    Other cofactors that are needed are other B vitamins (which are included in B-complex vitamin supplements) and some minerals (including zinc, magnesium, manganese, copper and selenium). In addition, certain amino acids are needed to feed this part of the biochemistry. These include methionine, serine, cysteine, glutamine and glycine.

    Whether or not these additional substances will need to be supplemented in treating a particular person will depend on the nutritional status of that person.

    6. Some of the toxic heavy metals, including mercury, are capable of blocking the activity of various enzymes in this part of the biochemistry. If the levels of these toxic metals are too high, they may prevent operation of the methylation cycle or associated biochemical pathways unless treatment is specifically used to lower their levels. Whether this is necessary for a particular person will depend on that person's body burdens of toxic metals.

    7. Getting back to the substances the levels of which need to raised to stimulate the activity of methionine synthase, there are various ways in which the levels of 5-methyl tetrahydrofolate and methylcobalamin can be raised. Possibilities to consider start from supplying the most common commercial supplemental forms of folate and B12, which are folic acid and cyanocobalamin. These are the least expensive and have the longest shelf lives.

    8. Folic acid is not a natural form of folate, and must be chemically reduced in the body before it can be used. People vary by a factor of five in their ability to do this, so that some people cannot utilize folic acid very well as a source of usable folate.

    One solution is to raise the dosage, so that more of the folic acid will be reacted by the DHFR enzyme to produce tetrahydrofolate, which can be converted by the cells to other forms of folate, including 5-methyl tetrahydrofolate.

    However, four sequential biochemical reactions are needed to convert folic acid to 5-methyl tetrahydrofolate, including two DHFR reactions, the SHMT reaction, and the MTHFR reaction. If a person has genomic polymorphisms in any of these enzymes that slow their respective reactions, this will interfere with the formation of 5-methyl THF from folic acid.

    If the folic acid dosage is increased in order to raise the amount of 5-methyl THF that is produced in the bodies of these people, the level of unreacted folic acid in their blood streams will rise. There have been some suggestions that this can increase the risk of cancer, but this is not well established at this time.

    I do not advocate using folic acid as the main source of folate in treatment to lift the methylation cycle block because it is an unnatural form of folate, because many people cannot use it readily because of their genomics, and because there is at least some evidence suggesting that high dosages of it can raise the risk of cancer. Also, I have seen in test results that many people with CFS have "normal" levels of folic acid in their blood, while their levels of 5-methyl THF are low.

    Nevertheless, high enough dosages of folic acid will likely work as the source of folate for many people who have partial blocks of methionine synthase, and I realize that this form of folate has been advocated and used with some success by Dr. Vinitsky. I think that the reason he uses such large dosages is that they are needed to overcome the problems I have discussed. I view this as a rather inefficient approach to raising 5-methyl THF, though if and when it works, I can't argue with success.

    9. If folinic acid is used, this will bypass the need for the DHFR reaction, which is slow in many people. Folinic acid is a natural form of folate, found in natural foods. It can be converted by the cells to the various coenzyme forms of folate, including 5-methyl THF.

    Three sequential reactions are needed to convert folinic acid to 5-methyl THF, including the MTHFR reaction. If genomic polymorphisms are present that will slow these reactions, the conversion to 5-methyl THF will be hindered. This can be compensated to some degree by raising the dosage of folinic acid. In spite of some claims, formaldehyde is not involved in the folinic acid reactions. Dr. Jon Pangborn has been a proponent of using folinic acid in the treatment of autism, and it is used to a considerable extent by the DAN! (Defeat Autism Now!) doctors. Dr. Amy Yasko has included folinic acid in her treatment as well.

    I think that one advantage of including folinic acid in the treatment of CFS is that it can be used by the cells to supply other forms of folate, especially initially, before the methionine synthase reaction is producing enough tetrahydrofolate to supply these needs. Thus, this should be able to help support the synthesis of DNA and RNA for making new cells, such as in the gut and the bone marrow, before the methylation cycle block has been fully lifted.

    10. The most direct approach to raising the level of 5-methyl THF is to take it directly. The correct chiral form for use by the body is sold as Metafolin or FolaPro or Deplin and comes from a manufacturing process that has been patented by Merck-Germany.

    There are other 5-methyl THF products that are made in different ways, and some of them may be racemic mixtures, which include forms that are not usable by the body, but I don't know about this in detail. Metafolin is the Merck trademark, which has been licensed to some suppliers. FolaPro is a Metagenics trademark, but the form of folate in it is the same as in Metafolin.
    Deplin is a "medical food" produced by PamLab under license from Merck-Germany. It has gone through FDA-approved testing as a treatment for depression. The dosage in Deplin is 7.5 milligrams (7,500 micrograms), which is much larger than the dosages in which Metafolin and FolaPro are sold (800 micrograms). Note also that I (following the lead of Dr. Yasko) have recommended a dosage that is one-quarter of that, or 200 micrograms, in addition to a smaller amount of 5-methyl THF in the Actifolate combined-folate supplement. So the dosage in Deplin is quite large compared to what I have suggested for use in treating CFS.

    Dr. Amy Yasko has been a proponent of using 5-methyl THF in the treatment of autism and other neurological disorders, and I have adopted it in the Simplified Treatment Approach for treating CFS, also.

    Dr. Jon Pangborn has argued against its use on the grounds that it is a "dead-end" form of folate that can be used only by the methionine synthase reaction. However, this is the reaction that needs to be stimulated in autism and CFS.

    In addition, it has been reported by Antoniades et al. that 5-methyl THF also reacts with peroxynitrite, which may be an additional advantage in CFS, and Prof. Martin Pall argues that this is the main role of 5-methyl THF in the treatment of CFS and related disorders, on the basis of his NO-ONOO theory.

    In my view, Dr. Yasko has the right approach, in using both folinic acid and 5-methyl THF. She also uses some folic acid, and I included that when I adopted the combined supplements she was using, though I don't think it is a necessary part of the treatment, and may be better omitted.

    11. There is also the question of which route should be used to supplement folate. Most people seem to be able to absorb folate if it is taken orally, and that is what I have recommended, but sublingual and injection routes may be necessary for some, if their digestive problems are severe.

    12. Moving on to the possible supplemental forms of vitamin B12 that can be used, they are cyanocobalamin, hydroxocobalamin (which is in equilibrium with aquocobalamin in the body)adenosylcobalamin (also known as dibencozide) and methylcobalamin.

    13. Cyanocobalamin is the least expensive and has the longest shelf life. However, in the cell, the cyanide group must be removed from the molecule before it can be converted to methylcobalamin, and this cyanide must be disposed of so that it does not rise to toxic levels, which can be life-threatening.

    The body has four ways of detoxing cyanide, and for low dosages (in the micrograms per day range), these usually do the job, except perhaps in people who have the rare Leber's hereditary optic neuropathy.

    However, in the larger dosages used for treating autism and CFS (several milligrams per day), detoxing the cyanide can be a concern, and I know of one case of CFS in which use of large dosages of cyanocobalamin led to cyanide toxicity.

    So I don't recommend using cyanocobalamin in milligram-level dosages by itself. If there is enough hydroxocobalamin used with it, that can help to protect against cyanide toxicity, but I still think it is better not to take large dosages of cyanocobalamin.

    14. Hydroxocobalamin must be converted by the cells into methylcobalamin before it can be used by methionine synthase.

    Unless a person has an inborn error of metabolism that involves the intracellular cobalamin processing enzymes, which is rare, their cells should be able to do this conversion, and this has the advantage that the cells can control how much methylcobalamin they make and retain so that they do not overdrive the methylation cycle.

    The cells can normally also convert this form to adenosylcobalamin, the other coenzyme form of B12 that they use (in the mitochondria).

    Hydroxocobalamin is the form of B12 that I favor for treating CFS. Dr. Amy Yasko also uses this form for treating some cases of autism, depending on the person's particular COMT and VDR polymorphisms.

    "Freddd," who posts to the aboutMECFS forum and the wrongdiagnosis forum, does not advocate use of hydroxocobalamin on the grounds that it is an "inactive" form of B12. It's true that it is not one of the coenzyme forms of B12, and must be converted to become one of these forms, but in all but a very few people, it is "active," in sense that the cells are equipped to use it effectively. Freddd himself has reported that he has a genetic mutation in his intracellular cobalamin processing enzymes.

    15. Methylcobalamin can be supplemented directly. At relatively low dosages, the cells will initially remove the methyl group from the molecule, and then will reform methylcobalamin and adenosylcobalamin as needed.

    At very high dosages (several milligrams per day) taken either sublingually or by injection, some methylcobalamin is apparently able to diffuse into cells and bypass the normal cobalamin processing enzymes, to supply itself to the methionine synthase enzyme directly.

    This is the approach advocated by freddd, and it seems to be helping some people with CFS. However, I have three concerns about this approach.

    One is that methylcobalamin is chemically able to react with inorganic mercury to produce methylmercury, which can readily enter the brain, where mercury acts as a potent neurotoxin. Many PWCs have high body burdens of inorganic mercury as a result of inhaling mercury vapor from amalgam fillings over extended periods in which their glutathione was depleted, so that they could not detox it well.

    I don't have proof that methylation of mercury occurs in CFS patients, though two or three anecdotal reports have suggested that it might, and guinea pig experiments have found that this can occur in them.

    Second, many PWCs have fairly high body burdens of a variety of toxins, and high dosages may cause rapid mobilization of these toxins, producing symptoms that are intolerable.

    Third, I have seen a couple of cases in which such high dosages of methylcobalamin, together with high dosages of 5-methyl THF, have apparently overdriven the methylation cycle, which I believe will prevent glutathione from coming up to normal as soon as it otherwise would.

    So while I think that methylcobalamin can be helpful, particularly in cases in which the person is low in methyl groups, I recommend caution with using multi-milligram dosages of methylcobalamin by sublingual or injection routes.

    Dr. James Neubrander has advocated use of subcutaneously injected methylcobalamin at a dosage of about 60 micrograms per kilogram of body weight every three days for the treatment of autism, and it is widely used by the DAN! doctors. Subcutaneous injection gives a slower release to the blood stream.

    16. Adenosylcobalamin (dibencozide) can also be used. This is the other coenzyme form of B12 used by the cells. In small dosages taken orally, this passes to the cells and the adenosyl group is first removed, and then both methyl- and adenosylcobalamin are made as needed by the cells.

    If taken in larger dosages (several milligrams per day) by the sublingual or injection routes, some adenosylcobalamin is apparently able to diffuse into the cells and be used directly.

    Dr. Amy Yasko recommends use of this form in addition to others by some people with autism and other disorders.

    Freddd advocates use of large dosages of this form sublingually.

    I haven't recommended use of this form, but it may be helpful in CFS.

    17. The question of what dosages of folate and B12 forms should be used to treat CFS is one that is not easy to resolve, and I think it varies with the individual PWCs.

    I have suggested some dosages based on Dr. Yasko's use in autism. Some people have found them to be too high, at least initially, and have had to start with lower dosages in order to be able to tolerate what appear to be detox and/or die-off related symptoms. Others have found that they need larger dosages.

    Freddd has advocated continuing with larger dosages and "pushing through" what he calls the "start-up" symptoms. I have advocated what I think is the cautious approach of backing off on the dosages until the symptoms are tolerable, and working up from there, as tolerated. Freddd's view is that that only delays the recovery.
    I don't have proof of which of these approaches is the best.

    18. I want to acknowledge Trina's help in choosing the initial supplements for the Simplified Treatment Approach back in January, 2007.

    19. I think there is still a lot more to be learned about how best to treat CFS. Basic treatment directed at lifting the methylation cycle block clearly seems to me to be an important aspect, but it does not appear to do the whole job for many PWCs. For those who receive limited help or no help at all from this treatment, I suggest considering the issues discussed in sections 5 and 6 above. If this still doesn't bring recovery, then I would suggest considering direct efforts to treat problems of the digestive system as well as exploring whether there are comorbid conditions, such as tick-borne diseases or mold illness, if this has not already been done.
    As always, I recommend working closely with a physician when doing treatment to lift a partial methylation cycle block.

    I hope this addresses the issues you raised.

    Best regards,

  2. elliespad

    elliespad Member

    So I can read it later. Thanks Rich !!
  3. Elisa

    Elisa Member

    Hi Rich,

    Great overview - interesting too...I so appreciate all your help and dedication!

    God Bless,

  4. richvank

    richvank New Member

    Hi, Elisa.

    Thanks for the response. I'm glad you found it interesting. I certainly would like to see you get better.

    God bless you, too!

  5. RunningAntelope

    RunningAntelope New Member

    Rich, your knowledge of biochemistry is impressive. I'm curious, have any of the PWCs you've consulted with achieved a "full" cure? You admit that the methylation block may be only part of the overall picture in CFIDS (which I think to be true), and how are you addressing other aspects of the pathophysiology of the illness?

    Thanks, Bill.
  6. ulala

    ulala New Member

    Are you familiar with CerefolinNAC? It's only available with a prescription. My doc has given me many samples and it seems to help me. It has NAC, L-methylfolate and Methylcobalamin.

    Years ago Dr. Susan Levine in NY gave me IV pushes of B12 and Magnesium. After those pushes I felt normal for about 2 ½ days. Unfortunately I haven’t been able to get this type of IV push now. I get b12 IM shots that seem to have no effect for me. I think the B12 shot is hydroxymethalcobalamin.

    What brand of B12 do your recommend taking? Perque B12. I can't really tell from your post above. Thanks!