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

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Mar 25, 2010.

  1. richvank

    richvank Senior Member

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    Hi, all.

    Here's something that I have just posted to some other CFS groups in response to questions. I think it may be of interest to some people here, also.

    Rich


    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,

    Rich
  2. JanisB

    JanisB Senior Member

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    Rich,
    Have you read Vinitsky's patent? It is online and very interesting. I think he has a few ideas which are valuable and which could contribute to the great work you are doing for those of us with ME-CFS. Also, Dr. V has over 6 years of clinical experience with his methylation protocol with chronically ill adults rather than autistic children.

    The first new idea is called MPP - methylation priority principle -- theorizes that methylation resources of the body are allocated by higher priority toward stress response at the expense of routine bodily functions whenever there are inadequate resources to sustain methylation for all functions. It is the first explanation I've read that makes sense of my symptoms, of the order (and disorder) in which they appeared, of relapses, and of the path of my current process towards recovery.

    The second is his discovery that the ratio of 5 folate to 2 OH B12 seems to unblock methylation more quickly than any other ratio. He has apparently tested this using HRV to measure SNS and PNS, to bring them into a healthy relationship, and to see other lab tests fall into place afterwards. The high doses are not the starting point for treatment; in fact, he starts with a dosage not too far from what you have recommended, i.e. 0.5 mg folate and 0.2 mg OH B12.

    In the patent, he indicates that natural folates (not folic acid) are preferable and lists several kinds. However, he also notes [0039] that "folate scavenges for aldehydes and glutamate and recycles aldehydes through hydroxocobalamin to homocysteine." As there aren't footnotes, I don't know if this is h is idea or, what seems to be the case from the context, it is widely known in current biochemistry. His pathway diagram differs from the ones I have seen in Yasko's work, and in yours, making it a little difficult to understand with my minimal chemistry background.

    Finally, you will be pleased to read [0042] that he recognizes insufficient or dysfunctional GSH as one of two causes for methylation inadequacy. The other is insufficient OH B12, and he sees the insufficiency of folate function, the folate trap, as the major block in the dysfunctional system that leads to chronic illness.

    I hope you'll read his work and consult with him to see what kind of patient data he has kept over the years. We adults with ME-CFS differ from autistic kids in a number of ways, one of which is that our PNS response is more attenuated, or rather less able to offset SNS overactivation. Part of this could be due to the increased toxicity we've accumulated from metals, chlorinated hydrocarbons, solvents, etc; part perhaps from an infectious agent still to be identified. The bottom line though, is that those of us getting improvements with the Yasko protocol are not getting the obvious and dramatic changes that autistic kids are getting. Vinitsky's theory makes sense of this.
  3. JanisB

    JanisB Senior Member

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    Sorry Rich, as a bit more research reveals you know Dr. Vinitsky's patent. Here's what you wrote in 2008 on ProHealth at http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=1321755
    So do you know if PWC's have tried Vinitsky's 5:2 ratio, and what kind of results they've had?
  4. dmholmes

    dmholmes Senior Member

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    Houston
    Hi Rich. What would your opinion be on each of the following cobalamin dosages compared to 2mg hydroxocobalamin per day? (minus the methylmercury issue)

    • 1mg methylcobalamin and 1 mg adenosylcobalamin per day
    • 2mg of methylcobalamin per day
    • 2mg of adenosylcobalamin per day

    Thanks,
    David
  5. richvank

    richvank Senior Member

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    Overdriving the methylation cycle, elevated sarcosine and prostate cancer

    Hi, all.

    I just learned something that I think I should pass on to you.

    As you know, I have expressed concern in the past about the possibility that high dosages of 5-methyl THF together with high dosages of methyl B12 could overdrive the methylation cycle in people with CFS.

    I have now received plasma amino acids test results from two people who have been on this type of protocol for some time (names withheld because of patient privacy rights), and this is the pattern they have both shown:

    1. MethionineHigh

    2. HomocystineBelow detection limit

    3. Methionine sulfoxide--Detectable to elevated

    3. SarcosineVery high

    4. Serine/Glycine ratio--Low

    5. CystathionineBelow detection limit

    6. TaurineLow-normal


    This is how I interpret this pattern:

    The high methionine level is unusual in CFS, as it is usually low. This suggests that it is being recycled rapidly from homocysteine, unless it is being supplemented.

    The undetectable homocystine, which is the oxidized form of homocysteine, suggests that homocysteine is also very low. This inference can be made because the presence of methionine sulfoxide gives evidence of a state of oxidative stress, which suggests that if homocysteine were present in significant amounts, homocystine would also be detected.

    The combination of inferred low homocysteine and high methionine suggests that the conversion of homocysteine to methionine is rapid, thus inferring that the methylation cycle is running faster than normal.

    The very high sarcosine confirms that the methylation cycle is running faster than normal. The formation of sarcosine from glycine by the enzyme glycine N-methyl transferase serves as sort of a pressure relief valve for the methyation cycle, dissipating methylation capacity by forming sarcosine when the ratio of S-adenosylmethionine to S-adenosylhomocysteine is tending to become too high.

    The low ratio of serine to glycine suggests that the serine hydroxymethyltransferase (SHMT) reaction is running faster than normal, which suggests that tetrahydrofolate is higher than normal, which in turn suggests that the methionine synthase reaction is running faster than normal.

    If the methionine synthase reaction is running faster than normal, the cystathionine beta synthase reaction would not be expected to be able to compete as well as normal for homocysteine, and thus the flow down the transsulfuration pathway would be expected to be lower than normal. Evidence that this true is the undetectable level of cystathionine.

    Additional support for low flow down the transsulfuration pathway comes from the low-normal level of taurine.


    What would be the consequences of overdriving the methylation cycle?

    I think that one would be that the sulfur metabolism, including cysteine, glutathione and taurine would not be able to recover as rapidly as they would if the methylation cycle was not running so fast. This could slow the overall recovery, I think. It would leave the person in a state of oxidative stress longer, and would slow the recovery of the detox system and the immune system, as well as maintaining the symptoms caused by low glutathione for a longer time.

    The other consequence is that sarcosine remains high in an effort to control the SAMe to SAH ratio, which is being pushed higher than normal. Does this matter?
    It looks as though it might, from a paper published last year, abstracted below (the full paper is available from PubMed, by entering the PMID number in their search box, and then clicking on the colored box at the upper right of the abstract page.) Note especially the paragraph that begins with the word "sarcosine":


    Nature. 2009 Feb 12;457(7231):910-4.
    Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

    Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM.

    The Michigan Center for Translational Pathology, Ann Arbor, USA.

    Comment in:

    * Nature. 2009 Feb 12;457(7231):799-800.

    Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease.

    Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells.

    Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.

    PMID: 19212411 [PubMed - indexed for MEDLINE]


    I think this is something to be concerned about. In particular, I think it would be wise for any men who have been on this protocol for an extended time to have a digital rectal exam and a PSA test to check for prostate cancer. If prostate cancer is present, I think it would be wise to lower these dosages to allow sarcosine to come down.

    Beyond that, I continue to have doubts about the advisability of use of this high dosage protocol. If sarcosine stimulates prostate cancer, it might stimulate other types of cancer as well. I continue to believe that people should proceed more slowly with treatment, and should monitor the status of their methylation cycle by lab testing during the treatment, aiming to restore it to normal status, rather than to overdriven status.


    Best regards,

    Rich

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