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Poss to have an idiot's guide to methylation block theory?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by anniekim, Apr 19, 2011.

  1. anniekim

    anniekim Senior Member

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    Hi all,

    I was wondering whether anyone would be able to give me an idiot's guide to the methylation block theory in relation to CFS? I am not scientific and my concentration is poor, so if anyone was able to explain it in very simple terms, it would be so appreciated. I've looked through some of the threads on it, but am still pretty clueless.

    Also, does the methylation block theory link in at all to the current research on XMRV, other co-infections such as herpes virus' etc..? Are they two completely different treatment approaches/theories, or could there be a link?

    Many many thanks in advance.
     
  2. Freddd

    Freddd Senior Member

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    Hi Anniekim,

    Methylation is an important step in cell formation and a wide variety of things in the body. Lack of methylation is one of many effects from lack of mb12 and/or methylfolate. Cell formation can start or stop within hours depending upon what is taken and one's reactions. Methylation accounts for perhaps 1/3 or 1/2 of the mb12/adb12/methylfolate deficiency symptoms.

    In what I have seen, the viruses of many varieties, put a strain on the body and trigger a persistent b12/folate deficiency that a person typically can't recover from without supplements. One of the things with the active b12 protocol is that after it has affected lots of things, including helping the immune system, many things become "uncovered" by the responsive symptoms receding and what isn't affected. Some of the viruses are no longer present even though the effects have lasted for years. Some may still be active, I don't know. CFS/FMS has been blamed on many viruses over the years.
     
  3. richvank

    richvank Senior Member

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    Hi, anniekim.

    Here's something I wrote a while back in response to a similar request from another PWC. Maybe it will be of help to you:


    12/13/08 11:48 AM Simpler explanation of GD-MCB hypothesis for CFS

    1. To get an isolated case of CFS (I'm not talking here about the epidemics or clusters), you have to have inherited some genetic variations from your parents. These are called polymorphisms or single-nucleotide polymorphisms. We know what some of the important ones are, but we don't know all of them yet. This is a topic that needs more research.

    2. You also have to have some things happen in your life that place demands on your supply of glutathione. Glutathione is like a very small protein, and there is some in every cell of your body, and in your blood. It protects your body from quite a few things that can cause problems, including chemicals that are toxic, and oxidizing free radicals. It also helps the immune system to fight bugs (bacteria, viruses, fungi) so that you are protected from infections by them.

    3. Oxidizing free radicals are molecules that have an odd number of electrons, and are very chemically reactive. They are normally formed as part of the metabolism in the body, but if they rise to high levels and are not eliminated by glutathione and the rest of the antioxidant system, they will react with things they shouldn't, and cause problems. This situation is called oxidative stress, and it is probably the best-proven biochemical aspect of chronic fatigue syndrome.

    4. There are a variety of things in your life that can place demands on your glutathione. These include physical injuries or surgery to your body, exposure to toxic chemicals such as pesticides, solvents, or heavy metals like mercury, arsenic or lead, exposure to infectious agents or vaccinations, or emotional stress that causes secretion of a lot of cortisol and adrenaline, especially if it continues over a long time. Just about anything that "stresses" your body or your mind will place a demand on glutathione. All people experience a variety of stressors all the time, and a healthy person's body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed. However, if a person's body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low. When glutathione is properly measured in most people with CFS (such as in the Health Diagnostics methylation pathways panel), it is found to be below normal.

    5. One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins. If left unprotected, vitamin B12 is very reactive chemically. If it reacts with toxins, it can't be used for its important jobs in your body. A routine blood test for vitamin B12 will not reveal this problem. In fact, many people with CFS appear to have elevated levels of B12 in their blood, while their bodies are not able to use it properly. The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with CFS.

    6. When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins. Also, the levels of toxins rise in the body when there isn't enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low.

    7. The most important job that B12 has in the body is to form methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.

    8. When there isn't enough methylcobalamin, methionine synthase has to slow down its reaction. Its reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles.

    9. The methylation cycle is found in all the cells of the body (not counting the red blood cells, which are unusual in a lot of ways). The methylation cycle has some important jobs to do. First, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body. It is not a coincidence that these substances are found to be low in CFS, so that people try taking them as supplements. Not enough of them is being made because of the partial block in the methylation cycle. The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns. The "reading" of DNA is referred to as "gene expression." Methyl groups prevent or "silence" gene expression. Overexpression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression.

    10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with CFS.

    11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.

    12. That's the basic biochemical mechanism of CFS. I believe that everything else flows from this. As you know, there are many symptoms in CFS. I won't discuss all of them in detail here, but here's how I believe the fatigue occurs: The cells have little powerplants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells. For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.

    When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the "machinery" in the little powerplants, lowering their output of ATP. So the muscle cells then experience an energy crisis, and that's what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances. These have been observed in the ATP Profiles and Translocator Protein test panels offered by Acumen Lab in the UK.

    13. There are explanations that flow from this basic mechanism for other aspects of CFS. I haven't figured out explanations for all of the aspects of CFS, but I do think I understand a large number of them in some detail, and I've been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.

    14. The involvement of infections by bacteria, viruses and fungi appears to have two aspects in CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of CFS (such as at Incline Village in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.

    15. Second, when a person's glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the observation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.

    16. Third, when the immune system's defenses are down, a person can catch new infections from others or from the environment, and the immune system is not able to defeat them, so they accumulate over time. Dr. Garth Nicolson has found that the longer a person has been ill, the more infections they have, on the average.

    17. Other things that accumulate over time are various types of toxins, because the detox system depends to a large extent on the sulfur metabolism, and it will not be operating properly as long as the person has CFS. The body stores much of these toxins in fat, but as the levels get higher, they begin cause problems throughout the biochemistry of the cells. Many people with CFS have been tested for toxins (most commonly the heavy metal toxins, which are the most easily tested) and they are commonly found to be elevated.

    18. The longer a person is chronically ill with CFS, the more toxins and infections accumulate in their body, and the more symptoms they experience. This explains why the disorder changes over time, and why some people become extremely debilitated after being ill for many years.

    19. The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified treatment approach is designed to do, and so far, the evidence is that it does do these things in most people who have CFS. I recommend that people with CFS have the Health Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment. This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery.

    20. The main question I'm working on now is what else needs to be done to bring people to recovery? I don't have complete answers to this question yet. Many people may recover from this treatment alone, but it is proving to be a slow process, and we will need more time to see how this will work out. It does appear that people who suffer from illness due to toxic molds do need to remove themselves from environments where these are present. The small amount of evidence I have so far suggests that people who have Lyme disease will need to have that treated in addition. I'm not sure about certain viral infections. They may also need to be treated. We still have a lot to learn, but I'm convinced that the mechanism I have described above is the core of the abnormal biochemistry in CFS, and correcting it needs to be cornerstone of the treatment.

    I hope this is helpful.

    Rich Van Konynenburg
     
  4. anniekim

    anniekim Senior Member

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    Fredd and Rick, thank you both very much for your detailed replies, they were very helpful.

    Ten years back i had a test for gluthathione, it was I recall low. Money is tight so I am not sure whether I can afford to have the test you recommend Rich and if it's available in the UK etc...

    Last year I had to have two amalgam fillings removed, had them done separately 8 weeks apart. A few days after the second one i crashed badly (housebound again), from which I still haven't fully recovered 15 months on (still housebound). I take it the release of mercury vapour during the removal was the cause. Does not coping with the amalgam removal possibly suggest that this could be due to a partially blocked methylation cycle?

    Finally, Fredd and Rich, hope you don't mind if I ask for another idiot's guide, this time the difference between your protocols?

    Many many thanks for your time, it's hugely appreciated.
     
  5. maryb

    maryb iherb code TAK122

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    Dd you have the amalgams removed by a dentist using the rubber dam and air filtration? I did and still suffered the mercury dump a few months later.
     
  6. anniekim

    anniekim Senior Member

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    Hi Mary,

    I did have the rubber dam, but at the time wasn't aware of the importance of air filtration, very ignorant of me (I did check with Dr Myhill in the UK who insisted that having them out even without any precautions would be better than leaving them in. But I ignored that and arranged for the rubber dam. I think Dr M was mad to give me the advice she did and I wish I had just left them alone).
     
  7. Shellbell

    Shellbell Senior Member

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    Mary, have you recovered from your amalgam removal? I have two amalgams that need to be removed as my teeth are beginning to crack apart. If I don't do it now, she said I probably will lose the teeth.

    I have only been on Fred's protocol for 2 months and don't feel anywhere ready to do this. But my dentist is insisting. She is a biological dentist and does fantastic work. I had 6 removed last year by another dentist while being very sick at the time, and it took me 4 months to return to baseline. It was horrible.

    Last weekend, I crashed from accidentally ingesting MSG, I think, and am getting worse day by day. I also had a spot on my face sampled for skin cancer and think I may be reacting to the anesthesia too.

    Just last week I was getting ready to start doing mild exercising and seeing benefits from the protocol. I even volunteered a couple of hours at my old work in my husband's classroom. Now I am confined to my bed. Can't even be with my family as it is too overstimulating! So, I don't think I am ready for having my amalgams removed at this point.

    Any advice is appreciated. I am not sure how to procede with all of this.

    Shellbell
     
  8. Shellbell

    Shellbell Senior Member

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    Annikim, I also wanted to say sorry that you are going through all of this. I was absolutely miserable following my amalgam removal. I had it done with safe way, but it wasn't enough to stop the bad reactions I experienced after.

    I would definitely give the methylation protocol a try. I am hoping that it will pull me out of my current slump. It isn't easy to follow because there is a lot of adjusting of dosages, but I know it works. My family and doctors have been amazed at how well I "was" looking and feeling until this last episode. I would say as of last week I was feeling about ~60%+ recovered overall.

    Hang in there. It isn't an easy ride, but from what I hear, definitely worth it!

    Hugs,
    Shellbell
     
  9. richvank

    richvank Senior Member

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    Differences between Freddd's protocol and the Simplified Treatment Approach


    Hi, anniekim.

    I think that having a bad reaction to amalgam removal suggests that glutathione is depleted, because it is normally responsible for binding mercury for excretion. If glutathione is depleted, it is very likely that there is a partial block in the methylation cycle.

    With regard to explaining the differences between Freddd's protocol and the one I have suggested, I may be treading on difficult ground! :D I'll give you my impressions, but hopefully Freddd will correct anything I say that is not accurate.

    The protocol I have suggested was extracted from the full treatment program developed by Dr. Amy Yasko, used primarily to treat children who have autism. Her work in turn is based on her own experience as well as research, performed especially by Dr. S. Jill James and Prof. Richard Deth, which has shown that in autism there is a combination of glutathione depletion and an inhibition of the activity of an enzyme in the methylation cycle, methionine synthase. Dr. James et al. found that treating to lift the activity of methionine synthase also restores glutathione to a more normal level. I found that this same combination is present in ME/CFS, and that similar treatments to those used in autism by Dr. James, Dr. Yasko and the DAN! (Defeat Autism Now!) project will also help most people with ME/CFS.

    The substances needed by methionine synthase to carry out its reaction are homocysteine (which does not need to be supplemented) and L5-methyltetrahydrofolate as reactants, methylcobalamin (methyl B12) as a coenzyme, and some cofactor nutrients, including zinc. Methionine synthase is supported by another enzyme that "refreshes" it, called methionine synthase reductase, and this enzyme needs other cofactors, including vitamins B2 and B3. These enzymes are part of the methylation cycle and related pathways, and there are other cofactor nutrients needed by other parts of this cycle and associated pathways.

    This is the theoretical biochemical background. From this point, it's a question of deciding which supplements to include in a protocol to best help this part of the metabolism. This question is complicated by the fact that all we humans are unique, in that we have each inherited from our parents our own combinations of versions of the enzymes involved. These are called genetic polymorphisms or SNPs (single nucleotide polymorphisms). Furthermore, different people are deficient in different cofactor vitamins and minerals because of their particular genetics, diets, and health histories up to this point. If we had unlimited amounts of money and testing available, we could test each person thoroughly to see what their genetic polymorphisms are, and what nutrients are deficient, and then we could tailor the treatment to the individual. This is more or less what Dr. Yasko attempts to do in autistic children, and it has been pretty successful. However, it is complex and fairly expensive.

    In suggesting the so-called "Simplified Treatment Approach," I attempted to boil this down to a more manageable protocol that could be used by all PWME's/PWC's, without detailed testing. However, I still recommend getting the Health Diagnostics methylation pathways panel to see if there is in fact a partial block in the methylation cycle and glutathione depletion, and thus whether this type of treatment is likely to be of help to the person.

    I initially included 7 supplements, in January 2007, with the help of a PWC who was on the full Yasko treatment program. As time went on, I dropped two of them: quite a few people reported that they did not tolerate SAMe well, and others said that the Yasko Methylation RNA formula was too expensive for them. This left five supplements that included the Yasko multi vitamin/mineral formula, the phosphatidyl serine complex, a sublingual hydroxocobalamin supplement, FolaPro (5L-methyl tetrahydrofolate), and Intrinsi/B12/folate.

    The Yasko multi was included to supply the whole variety of vitamins and essential minerals, and hopefully to take care of whatever deficiencies different people might have in them. It also includes some nonessential supplements chosen by her particularly to support the methylation cycle and related pathways.

    The phosphatidylserine complex was included to supply a variety of phospholipids to repair the cellular membranes, especially the mitochondrial membranes, which are damaged by oxidative stress in ME/CFS. This supplement also supplies the essential omega-3 and -6 fatty acids that everyone needs.

    This combination thus supplies all the known essential nutrients for the human body except the essential amino acids, and my hope was that these would be supplied by protein in the person's diet.

    With this foundation, I then included B12 and folates, which are specifically needed by methionine synthase. I chose to use hydroxocobalamin on the basis that this would allow the cells to convert it to as much methylcobalamin and adenosylcobalamin that they needed.

    In the full Yasko program, Dr. Yasko characterizes certain polymorphisms to decide whether methylcobalamin or hydroxocobalamin are preferable for a given patient.

    In making this choice, I realized that there would probably be some people who would not respond as well as others, because of genetic variations. However, I was also concerned that high-dosage methylcobalamin might methylate inorganic mercury and move it into the brain. This is chemically possible, and has been observed in guinea pigs, though not demonstrated in the human body, and I knew that many PWCs have high body burdens of mercury.

    An additional concern I have is that high-dose methylcobalamin might overdrive the methylation cycle, since the amount of methylcobalamin will not be under the control of the cells themselves. The possible effects of overdriving the methylation cycle are not known. My concern is that it can prevent flow down the transsulfuration pathway, and thus affect the recovery of the balance of the sulfur metabolism.

    Also, if there is not effective control of the SAME/SAM ratio by glycine N-methyl transferase, this ratio may go too high, which would affect gene expression in general as well as other methyltransferase reactions in the body. Since this is unknown territory, I would prefer to avoid it by testing to see how the methylation cycle and related pathways are faring, and limiting methylcobalamin accordingly. But again, there is no proof that this is actually a problem for most people.

    This choice is one of the major differences between Freddd's protocol and the one I have suggested. Freddd uses high-dose sublingual methylcobalamin and adenosylcobalamin together, and finds that hydroxocobalamin is not helpful for himself and some others.

    For the folates, I included 5L-methyltetrahydrofolate, which is the form needed directly by methionine synthase (and which is also the folate form that Freddd uses), and, following Dr. Yasko, I also included folinic acid and folic acid.

    There is some folic acid in the multi, and both folinic and folic acids, as well as additional 5L-methyl tetrahydrofolate, were present in the Intrinsi/B12/folate. This supplement also included intrinsic factor and some additional B12. Over time, the manufacturer changed the formulation of this supplement, so I substituted Actifolate for it, which includes the three forms of folate, but no B12 or intrinsic factor.

    Since then, I have come to believe that folic acid does not contribute benefit and may interfere with absorption of the other folate forms, as well as using NADPH, which may be in short supply. I think Freddd has come to agree with this, also. So I have eliminated folic acid, except for what is in the multi, and I think Freddd is trying to eliminate it completely.

    I have retained folinic acid, following Dr. Yasko, because it is sort of a "buffer" form of folate that can be converted to other active forms, including those used to make DNA and RNA. I think there is advantage in supplementing this, especially until methionine synthase is more active, so that the 5L-methyl tetrahydrofolate can be converted to tetrahydrofolate, to be used to form other active folate forms. Freddd, on the other hand, has found that folinic acid causes his symptoms to worsen, so he is avoiding it.

    I want to emphasize that selecting the supplements for a protocol like this is not an exact science. The biochemical theory, combined with lab testing, gives us guidance about what is not working right, but it doesn't tell us exactly which supplements and at what dosages are most likely to help. And this will actually vary from one person to another because of genetic individuality. So it is a compromise and requires judgment, and what I have chosen is probably not optimum, but it is an attempt to simplify what was initially more complex and expensive than was feasible for many PWCs.

    A clinical study performed by Neil Nathan, M.D. and myself (reported at the IACFS/ME conference in 2009) found that this protocol gave significant benefit to at least two-thirds of the ME/CFS patients in the study, and a couple of them were able to return to full-time work.

    Freddd has begun from a much different starting point. He has been trying to achieve his own health for many years, and has based his protocol choices on his own experience and that of others, rather than on a theoretical framework or lab testing. Freddd himself has reported that he has an inborn genetic error of metabolism in his intracellular B12 processing enzymes. It is not clear how prevalent this is in the general population. The literature suggests that it is rare, but Freddd believes that it is fairly common. Freddd does not have confidence in lab testing, and relies on experience with trying various supplements and combinations of them, to see what the effects are on his symptoms and those of others. He has compiled an extensive list of symptoms and has assigned them to deficiencies of B12 or folate in the body as a whole or in the brain in particular, based on experience.

    It is not clear what the actual illness is in many of the people Freddd has worked with. Some may indeed have ME/CFS. Others may suffer from a variety of B12-deficiency conditions, including low B12 in the diet, pernicious anemia, transcobalamin deficiency, or the type of issue Freddd has himself, which involves the enzymes inside the cells that process B12.

    Freddd's protocol includes methylcobalamin (methyl B12), adenosylcobalamin (adenosyl B12), 5L-methyltetrahydrofolate, and some other cofactor supplements.
    He tends to use larger dosages than in the Simplified Protocol, and favors "pushing through" the symptoms that arise by continuing at the high dosages. He has found that this has led to success for himself and others. He does not believe that methyl B12 at high dosages will cause problems with mercury.

    I have taken what I believe is a more cautious approach, advising people to back off on the dosages or stop the protocol for a while if the symptoms become intolerable. In my view, the symptoms that arise on the Simplified protocol are due to restoration of the function of the body's detoxication system and immune system, and that these systems begin to work on the backlog of toxins and pathogens that have accumulated while the person has been ill. Mobilization of toxins into the blood on their way to the kidneys and liver for excretion bathes all the cells in toxins, and I think this is what causes the intensification of symptoms while on the protocol. Slowing down can give the body a chance to rid itself of some toxins before mobilizing more. Freddd attributes the symptoms during treatment to other causes than toxin mobilization, and his view is that backing off on the dosages will cause the person to "lose ground" and have to go through the same issues over again when they resume the treatment at full dosages.

    Freddd's protocol essentially bypasses the normal processes of absorption, transport and metabolism of B12 by using large dosages of the final two active coenzyme forms of B12, causing them apparently to diffuse directly into the cells. In principle, this approach is capable of compensating for a wide variety of B12-related disorders. Those benefiting from Freddd's protocol probably do have a wide variety of causes of their B12-related illnesses. My approach, on the other hand, has been directed at trying to understand the pathogenetic and pathophysiological mechanism of ME/CFS specifically, and to design a treatment that counters it, while working with the normal biochemistry of the body to the degree possible.

    Freddd's protocol has clearly helped many people, and based on the reports I've received over the past four years, I would say that the Simplified approach has done so as well. I don't have enough controlled treatment data to decide which approach might be best, and as I mentioned above, it probably varies with the individual.

    I might mention that there are also several other methylation-type treatments in use now, and they have all helped at least some people. They include the following:

    The S. Jill James and the DAN! project protocols
    The complete Amy Yasko treatment program
    The Alan Vinitsky protocol (which uses hydroxocobalamin and high-dose folic acid)
    The Derek Enlander protocol
    The Sarah Myhill protocol
    The Martin Pall protocol (which is moving toward including liposomal hydroxocobalamin and oral 5-methyl tetrahydrofolate
    The PamLab prescription "medical foods": CerefolinNAC and Metanx

    All these protocols are aiming at boosting the activity of methionine synthase, in my opinion, and all of them are helping some people. It would be helpful if there could be a controlled clinical comparison of these treatments on well-specified ME/CFS patients, but since for the most part these are non-patentable treatments, there is not likely to be funding available for this. In the meantime, we are operating on the basis of projections from available theory, limited clinical testing, and a lot of anecdotal reporting. It does seem to be true that methylation treatment in general is growing among the complementary and alternative physicians who treat ME/CFS and Lyme disease.

    One other thing that I want to emphasize is that my position is that a person needs to be under the care of a licensed physician when on methylation treatment. A small number of people have reported experiencing serious adverse effects while on the Simplified treatment, even though it consists only of nutritional supplements.

    I hope this is helpful.

    Best regards,

    Rich
     
  10. anniekim

    anniekim Senior Member

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    Shellbell, am sorry to hear about your dilemma. Am afraid I haven't really got any advice. One thought if the teeth are cracked, would removing the amalgam involve less drilling and thus less release of mercury vapour than teeth were perfectly ok? I don't know if there is any basis for this..., namely removing amalgams that are in perfectly good order involve more drilling than damaged amalgams? Never been able to get an answer on that.

    Rich, once again thanks heaps for your detailed reply, very appreciated. I have printed out your reply and will read when less exhausted than now.

    I appreciate you are not a doctor and are unable to give medical advice, but I have two questions you may have thoughts on. Bearing in mind that I reacted badly to my amalgam removal, is there a case to suggest that I should go under a mercury detox before attempting a methylation protocol? (I confess I don't fancy the idea of a mercury detox and have shied away from it).

    Secondly, in previous posts you acknowledge that some people do not respond to the simplified protocol and sadly make little improvement on it. You suggest that although there is no definite answers on this, it may be that they need to treat lyme or virus'. If after a few months of doing the protocol I am no better and decided to possibly go on anti-virals if tests indicated reactivated virus (something I am considering, having tests for hhv6 and ebv to see if reactivation is indicated), would it be best to stop taking the supps for the methylation protocol or continue taking the supps for meth protocol whilst concurrently taking anti virals? Should one even consider tackling the virus' first?

    Many thanks in advance.
     
  11. anniekim

    anniekim Senior Member

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    Rich, just found a blood test I had done a few years back at Biolab in London. I have this result:

    Red Cell: GSH PX: 49 U/ghb Ref Range: 67-90.

    Does it signifiy anything of use? Thank you.
     
  12. Freddd

    Freddd Senior Member

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    Hi Anniekim,

    I was as severly ill with these things as anyone here and maybe then some. I was dying from the accumulating malfunctions and my nervous system was failing. I come from the group healthcare software design and data analysis and consulting directions involving data mining, fraud detection, claims logic and of course reports of every variety and description for insurance management, plan trustees and outside supervisors/evaluators/auditors.

    Quite appropriately considering my background, I look to a solution that works more thoroughly for more people. I am certainly one of those that might be looked at in a worst possible example method because so many of the "ought to work" items don't for me.

    As to my genetic background, my maternal grandfather had MS and b12 deficiency and received injections from the time they were available. My mother appears to have had low level b12/folate deficiencies that were never diagnosed. I appear to have restricted, not absent, conversion of one type of cobalamin to another. How much more restricted I can't say as there is no money in this kind of study so it was never done. However, as the majority of people trying both find differential results with adb12 vs mb12 and that lot's of one doesn't fill up the need for the other I would say that some level of restriction is normal, at least amongst those who become ill with this wide variety of descriptions and names for various subsets of the 300 symptoms universe. So cyanob12 worked for a couple of symptoms out of a universe of 300. My MCV never went over 99.8 until glutathione induced deficiencies took it to almost 102. Mb12 never brought it down while Metafolin did. I have had folate deficiency symptoms my whole life, worsening dramatically when I started supplemented foods (cyanocbl and folic acid) like Metracal, Special K and Instant Breakfast.

    Because of the differential effects by dose size on my CNS and body, it appears that I share the likely genetic attributes that cause a limitation of the amount of cobalamins allowed into the CSF/CNS. This appears to be shared with those that research has identified with the same or similar characteristics; FMS, CFS, MS, Parkinson's, Alzheimer's, ALS and a few others.

    I had my worst; deepest and longest, crash after becoming vegetarian and depriving my body of both active forms of b12 and then getting sick. The crash occurred with an apparent viral infection whose results did go away until 17 years later with mb12/adb12.

    We don't know what percentage of people are affected to what extent by folic acid and/or folinic acid. I got very tired of it always being my health that got sacrificed as being part of those included in the "inevitable" write-off; the 20-50% for whom the chosen item doesn't work well. Rather than condemn maybe 20-50% (numbers suggested by research on genetic inability to convert folic acid to methylfolate) of those trying it to paradoxical folate deficiency or just plain ineffectiveness such as I and many others are now finding out they also have, I really can't continue suggestion of folic/folinic acid except as a conscious trial of it to see if there is a problem with the person then going on to Metafolin for a basis of comparison; maybe even 2-3 round trips until it is evident that there is no difference, or that there is.

    With cyanocbl and hydoxycbl there is a limit on effectiveness. They each work to some degree on up to 33% of the symptom universe for up to 2/3 of the people. The other third of people are 100% SOL and 2/3 of symptoms for 2/3 of people are SOL, the "inevitable" write-offs, sacrificed yet again on the alter of 60 years of research on inactive cobalamins (cyanocbl, hydroxcbl) and a statistical approach honed on decades of drug research indicating drugs don't work on everybody, why should vitamins? So with hydroxycbl and cyanocbl instead of mb12 and adb12, hundreds of symptoms then become mysterious untreatable conditions because the conclusion ends up "must not be b12 deficiency since b12 (hycbl, cycbl) didn't fix them". These untreatable symptoms will often continue to worsen even while others improve. Folic/folinic acid can do the same, allow many symptoms to continue to worsen despite the "right" thing. Not one of my approximately 100 docs through the decades were able to diagnose and treat my conditions. They virtually all jumped to the conclusion, "b12 deficiency" right off but then with questioning about supplements found out about cyanocbl and folic acid and threw out the right answer because "it is not possible to be deficient while taking b12 (cyanocbl) and folate (folic acid)". So, my non-responsive and worsening symptoms became mysterious untreatable diseases for decades. Because of all the studies proving that cyanocbl/hydroxycbl work a little, my doctors were all totally blinded to the possibility that they didn't work fully for everybody.

    While I don't seem to have any obvious jump out at you differences with p-5-p instead of b6, pantethinine instead of pantethenic acid, with 8 factor high gamma E instead of 100% d-alpha, D3 instead of D2, active vitamin A instead of carotene, many people have one or another problem with processing one or more of these. So again, going for the form that makes the fewest assumptions about the person and the hoops their bodies would have to jump through to make the inactive vitamers work, I choose to use the active and varied forms. This is again to increase the odds of response for any given person.

    I think that a full spectrum of basic vitamins and minerals and fats etc are needed for supporting all the intense healing and that without them healing grinds to a halt over and over. That is why there is no "simple" form. With the "simple" form it becomes a very complicated problem to figure out what each of the holdups are. As induced folate deficiency can cause open epilthelial sores in a matter of days and start IBS within a few more days one might assume that there is an impact on the ability to absorb many items from foods when transit time is closer to 12 hours than 36 hours. B12 deficiencies take longer to cause sores than the few days it takes with an induced folate deficiency

    Methylb12 and adenosylb12 work on virtually every one of universe of 300 symptoms for virtually 100% of people when the correct cofactors are in place. They don't have to be converted to anything else to be active because they are active from the first second. They are immediately available to all cells that can be reached by diffusion without waiting for the active transport system to dole them out according to some internally regulated triage pattern because they (limited cobalamins) are never enough this way. This produces a significant startup effect as hundreds of processes all try to start up at once, putting a strain on all resources. This can rapidly result in other deficiencies with low potassium (hypokalemia) occurring sometimes within a few days as methylation is rapidly restored and cell replication starts up in high gear. The active b12s, like the inactive, work better at fixing functional problems rather than outright long term damage of certain sorts. However, much of that damage can be repaired but it takes longer and requires a higher dose. Autoimmune damage doesn't appear to repair. Even in acting on so many "non-specific" symptoms, not all leave. This often includes discovering all sorts of specific co-morbidities that remain which includes mold sensitivities, lactose intolerance, gluten intolerance and an alphabet soup of other problems.

    I have watched hundreds of people become restored to decent health and able to go back to work on the active B12 protocol. I have watched a lot stall out on what now turns out to be paradoxical folate deficiency. Who knows how many others that never sign up or respond in writing are going down one road or another, such is one of the problems of the internet and knowing what the real statistics are.

    I think it is more important to make a start and then try various things and do one's own comparisons, to try folic/folinic acid and then try Metafolin in comparison, even to try hydroxycbl and then to try mb12/adb12 or the other way around. Without trying the things you won't know what works best for you. Rich mentioned that he thought 4 months is a reasonable time to get a feel for how any specific permutation of the supplements is going to work. I agree, that is long enough to be able to tell the large differences that there may be at any of several stages of healing. I think that several alternating 2-4 week periods for any single item can tell you a lot, whether folic/folinic acid alternating with Metafolin or hycbl alternating with mb12/adb12. You might not notice the difference the first time if it is subtle and the startup effects are much "louder". However, as one goes back and forth, the differences become increasingly obvious.

    It is better to start somewhere and build on that and improve it than not to start at all. Good luck.
     
  13. anniekim

    anniekim Senior Member

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    Thanks Fredd for your detailed reply. Is it possible to have the list of supplements in your protocol so I am clear what the different supplements are between yours and Rich's protocol. Your and Rich's help has been very appreciated. Thank you.

    Fredd, when you write 'I appear to have restricted, not absent, conversion of one type of cobalamin to another' and Rich has commented that you have shared you have an inborn genetic error of metabolism in your intracelluar B12 processing enyzymes, am I right in understanding you have deduced this not through tests, but through your own self treatment trials? Thanks.
     
  14. anniekim

    anniekim Senior Member

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    Rich, sorry another question, hope that's ok. In the thread 'The Three P's - A Closer Look at the middle One', you wrote, 'that the women who are treated in the study that Dr Neil Nathan and I carried out had already been treated for a variety of other issues for starting the methylation treatments'. Elsewhere you have written two thirds responded to your protocol. In light of this, I would like to clarify are you saying that the two thirds who responded in your study had done other treatments such as treating heavy metals, treating lyme, mold avoidance and anti-virals before having success on your protocol?
     
  15. Rockt

    Rockt Senior Member

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    I have watched a lot stall out

    Freddd, do you think "over-doing it" has anything to do with the stall some experience? I'm quite badly debilitated in terms of what I can do mentally and get really tired, (crazy?), of sitting in a dark room with my eyes closed all night, so as soon as I start to feel a bit better, I do more. I usually end up crashing and then whatever helped, doesn't anymore. I'm hoing to avoid this with the B12/methyfolate.
     
  16. richvank

    richvank Senior Member

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    Hi, anniekim.

    That's correct. However, these issues had not been absolutely resolved in all the patients prior to our study.

    The situation was that Dr. Nathan had been conducting a private medical practice in Springfield, MO, for about 12 years, and was seeing a large number of ME/CFS patients. Over time, he treated various of them for the issues you listed above. However, some may still have had one or more of these issues when our study began. He just picked the next 30 patients who came to his office and offered them the study. As we reported, not all of these patients fulfilled the strict Fukuda criteria plus having post exertional fatigue and malaise, so we did our statistical analysis only on the 21 patients who did, and the two-thirds figure is based on them. However, all 30 received the same protocol.

    After 6 months of treatment, additional individualized treatments were added, based on genomics, symptoms, and test results to that point, and in some cases they included treatment for heavy metal toxicity. This proved to be beneficial in at least one case, indicating that this woman still had a toxic metals issue during the study.
    I think this also showed (in this case) that it was necessary to treat the toxic metals issue specifically, in addition to the partial methylation cycle block, in order for this woman to recover sufficiently to go to Paris for a week with her friends. By the way, she was 84 years old!

    Best regards,

    Rich
     
  17. anniekim

    anniekim Senior Member

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    Rich, thanks. But sorry I am still not clear whether you would advise treating things like virus', metal toxicity before embarking on the methylation protocol? I get the impression - but I might be wrong so please correct me if I am - that if there are untreated problems like virus', lyme, metal toxicity, then the person will not respond/have any benefits on the methylation protocol? Or could one still experience partial benefit even if the other things have not been successfully treated? Thank you.
     
  18. richvank

    richvank Senior Member

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    Hi, anniekim.

    I think this is a very good question. My impression is that some of these things can prevent the lifting of the partial methylation cycle block, and are best dealt with before doing the methylation treatment, but I don't have much clinical data to back that up. One physician has told me that he had treated some of his "toughest" patients for all the issues he could find in them, and they were still not well. When he then found out about methylation treatment, and gave them that, it was the last thing they needed to recover.

    In our clinical trial, there were some people who were on the methylation treatment for 6 months, did not respond, and then were treated for heavy metal toxicity, and then they did respond.

    About a third of the people in our clinical study did not respond significantly to the methylation treatment. I don't know why. Perhaps they had one or more of these issues. If the heavy metals body burdens are high enough, these metals can block enzymes in the methylation cycle and related pathways, and I think that could prevent the methylation treatment from working. If there is untreated mold illness, at least one person's experience was that they were unable to tolerate the methylation treatment until it was corrected. It is known that the Lyme disease bacteria (Borrelia) cause glutathione depletion in their hosts. It may be that glutathione cannot be brought up by methylation treatment while there is active Lyme disease.
    I don't know about the viruses. Perhaps the immune system would be able to put some of them back into latency if the methylation cycle is brought back up by treatment, but perhaps others are able to hold down glutathione.

    That's about all I can say about this with the limited amount of data we have.

    Best regards,

    Rich
     
  19. richvank

    richvank Senior Member

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    Hi, Anniekim.

    Glutathione peroxidase (GSH Px) is an enzyme (actually a group of enzymes) that use glutathione to quench hydrogen peroxide and lipid peroxides, which form as a result of oxidative stress. Oxidative stress is a particular problems in ME/CFS, and has been the subject of quite a few published papers. In my hypothesis, it results from the depletion of glutathione in most cases. However, if there is a problem with the glutathione peroxidase enzymes, this can also allow oxidative stress to rise. Such a problem can be due to an inherited genetic polymorphism in the enzyme, or to a deficiency of selenium, which the main glutathione peroxidase enzymes require as a cofactor. I note that you are in the UK. It has been published that the population in the UK in general has been low in selenium since the 1970s, when the European Union was formed, and the UK began buying its grain from Europe, rather than from Canada and the U.S. The soils in Europe are low in selenium, so the UK population went low in selenium in general. Note that the Coxsackie viruses thrive under conditions of low selenium (as in Keshan disease in China, in an area where selenium is very low in the soil), and most of the published papers on Coxsackie in ME/CFS have come from the UK, though more recently, Dr. John Chia in southern California has been finding enteroviruses in general, and Coxsackie viruses are enteroviruses. Supplementation with selenium can correct this problem, if present.

    I have found that most PWMEs/PWCs are low in glutathione, but there is a subset that has normal glutathione levels, and though my data are limited, it looks as though these people have problems with the glutathione peroxidases or the glutathione transferases, or both. The latter are the enzymes that make use of glutathione to bind toxins for excretion.

    Best regards,

    Rich
     
  20. anniekim

    anniekim Senior Member

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    Rich, thank you so much for both of your replies, they were really helpful. Think i might buy me some selenium tablets :)
     

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