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Methylation 101?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by ixchelkali, Jun 18, 2011.

  1. ixchelkali

    ixchelkali Senior Member

    Long Beach, CA
    Can somebody (Rich?) explain methylation to me in simple terms? I've read Rich's simplified methylation block protocol, and it's straightforward enough, but what IS a methylation block? My sister developed symptoms similar to ME/CFS following chemotherapy for cancer. It started with peripheral neuropathy and has slowly progressed. She recently had a tilt-table test and tested positive for orthostatic hypotension, but her doctor doesn't seem to know much about it. She's sleeping 12 hours a day and is very fatigued, has brain fog, pain, etc. It sounds very similar to my ME/CFS. I mentioned methylation block to her, but I couldn't explain it because I don't understand it myself.

    Can someone explain the concept in a way that I can understand through the brain fog, and maybe give me some links about it that I could pass along? Thanks.
  2. hogwild


    Hear hear! As you know, even those of us who have done some homework on CFS/ME/MCS etc. can
    find it imppossible to keep up with all the different developments and theories. I would really appreciate
    a "Methylation for Dummies" post.

    Simple pictures or diagrams would be helpful too, though I know that may be too much to ask.

  3. LaurieL

    LaurieL Senior Member

    Here, here, I'd like to third that. Here we have two of the brightest minds with methylation block protocols, and not one thread devoted to actually teaching the methylation cycle to go along with them. I came here this morning with the intention of asking for the same type of thread to be started. Great minds think alike!!!

    I can't tell you how frustrating it is to learn when you don't feel well in the first place and there is nothing here on this forum devoted to such. Just protocol recommendations. We sure would be appreciative of the additional effort it would take to actually learn "How methylation works".

    And by mentioning the specific two, I certainly don't mean to count out all the great minds that already understand the cycles to chime in too. We need something like this here.

  4. anniekim

    anniekim Senior Member

    I started a thread asking for an idiot's guide to the methylation block theory. Rich kindly replied. Sorry don't know how to put in a link, but If you do a search you should find it. Only did it a few weeks ago
  5. caledonia


    Cincinnati, OH, USA
    You need B12 and folic acid to methylate. Normally your body takes in these nutrients from food, then starts converting them to an active form that the body can actually use.

    If you have a methylation block, you will be unable to convert the vitamins which will stop the methylation process. If you take the active forms of B12 and folic acid, you will be able to jump over the block and start methylating again.

    Methylation creates glutathione which helps with detoxification, energy in the mitochrondia in your body's cells, adrenal function and many other important processes.

    A methylation block is caused by a chronic stressor, ie viruses, toxins, severe stress from abuse, etc. Chemo would be a perfect example of a chronic stressor.

    Your sister should be on Rich Vank's protocol. She has classic symptoms of B12 deficiency (neuropathy) and adrenal fatigue (hypotension, fatigue), if not ME/CFS.
  6. Wayne

    Wayne Senior Member

    Ashland, Oregon
    Stab at Describing the Methylation Cycle

    Good description Caledonia... as far as I can tell anyway. :)

    Whether correct or not, this is how I tend to think about methylation:

    The methylation cycle "recycles" various key nutrients to maintain adequate/normal glutathione levels, which is our bodies' most important detoxification component. If we can't maintain normal glutathione levels, we are in deep doo doo. Less than normal levels adversely affects many critical systemic functions in our bodies, including our immune systems.

    This cycle "break down" or "partial block" can result from any number of stressers as Caledonia points out. These stressers can cause a very significant draw down of our glutathione levels at any given time and create a "chronic shortage" of key nutrients necessary to the cycle. Different chronic shortages are to a large degree determined by our own genetic makeup.

    Disclaimer: I could be totally wrong about all of this. ;):angel:

  7. aprilk1869

    aprilk1869 Senior Member

    Scotland, UK
  8. Sushi

    Sushi Moderation Resource Albuquerque

    And here is the text of Rich's response so you don't have to scroll through the whole thread:

    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
  9. anne_likes_red

    anne_likes_red Senior Member

    Also, here is a link to Sarah Myhill's website info on The "Methylation Cycle" and treatment - although her protocol may differ slightly from Rich's. I think she does a good job of explaining and it's set out in an easy to read way in her wiki format.


  10. LaurieL

    LaurieL Senior Member

    To the moderators and to Cort,

    Would it be possible to get a sticky thread for those looking for information and easily found in a brain fog stupor like state?

    ooops...forgot to say.....pretty please with sugar on top?

  11. Freddd

    Freddd Senior Member

    Salt Lake City
    I would like to add to the methylation block considerations. Eight years ago I came up with a "depleted methylation capacity" hypothesis. This was based on the observation that with cyanocbl and hydoxycbl that there was an initial startup effect, sometimes dramatic, that faded quickly with repeated injections. This lack of repeatability and sustainablity caused the AMA to label ANY PERCEPTABLE EFFECT from cyanocbl (the ONLY kind at the time) to be purely "placebo" effect. Physicians were threatened with sanctions for giving injections of cyanocbl for any reasons except high MCV with low serum cobalamin. Having more "energy" was considered placebo. All of the effects most of us have from mb12, adb12 and hydroxycbl would all have been considered placebo effect and hence a forbidden usage. I'm not making this up. Go read history. This is how many of us got to be suffering from these stealth deficiency diseases. The AMA and it's policy on B12 is a major cause of the lack of recognition of CFS and FMS as complexes of b12 deficiency symptoms.

    So, "depleted methylation capacity" hypothesis in hand, I started investigating on that basis. I quickly came across methylb12 (available commercially by then) and methylfolate (not available at all in any form). Whether "depleted methylation capacity" is identical with "methylation block" I can't tell you. I suspect that it isn't.

    So, cell reproduction slows down considerably because of lack of methylb12 and methylfolate, the two forms absolutely needed for the DNA replication to occur. This can happen in the normal routine of eating with no supplements for probably any number of reasons. It can also occur BECAUSE of taking cyanocbl, hydroxycbl and/or folic acid which depletes whatever other methyl groups are available. I have watched b12 deficient persons change to "cyanocbl (or hydroxcbl) sufficient but methyl group depleted" and unable to convert cyanocbl (hydroxcbl) to methylb12. These people have some b12 effectiveness from cyanocbl/hydroxcbl but it disappears after a while.

    In the absence of glutathione, NAC, folic acid, folinic acid and for a few persons, vegetable food folate, there is no evidence at all that "methylation block" or "depleted methylation capacity" is possible in the presence of methylb12 and methylfolate. Because the DNA methylation function can be inhibited (blocked) by folic acid, folinic acid, possibly vegetable food folate, glutathione and NAC even with mb12 and methylfolate, it is a decidely different thing than an actual lack of methyl groups.

    In my case and some others, glutathione and/or NAC and/or folic acid and/or folinic acid and/or vegetable food folate can actually block the active mb12/methylfolate from working. This appears to be able to start the "methylation block" within hours. With enough Metafolin and methylb12 and the lack of the blockers methylation can be restarted within hours as well. The "methylation capacity depletion" appears to take much longer to occur but can be restarted just as quickly. There may be any number of reasons for either or both methylation defects. Rich has other theories about how the methylation block can come about. There might be a dozen reasons that are all occurring for one group or another. However, in the absence of actual actively blocking agents such as various forms of folate other than methylfolate, NAC and glutathione (precursors), methylb12 and methylfolate will prevent the methylation depletion or methylation block and restore methylation to normal functioning rapidly.
  12. ixchelkali

    ixchelkali Senior Member

    Long Beach, CA
    I lost track of this thread while I was off for a while having a mini crash. Now that I've found it, I'd like to thank all who responded. Your answers were very helpful; just what I was looking for. Thank you.
    Anju likes this.
  13. Anju


    Hartford, CT
    Thanks a lot Freddd, for this explanation, it is a START for me, but I really need to find a good doctor , practitioner to help me

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