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What Does Overmethylation Feel Like?

Discussion in 'Genetic Testing and SNPs' started by ktred, Mar 7, 2013.

  1. ktred

    ktred

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    I am+/+ for COMT V158M, COMT H62H, VDR Tak & MTHR C677T. This grouping of homozygous mutations leaves me very confused about how sensitive I am might be to methyl donors.

    I have been sick for so long that it's hard for me to tell when or if I have been over-methylated. I have gone through phases where I have taken lots of methyl B-12 & methyl folate, but don't recall feeling any worse than usual. To what degree does my ++ VDR Taq cancel out my two ++ COMT mutations?

    Thanks
  2. Lotus97

    Lotus97 Senior Member

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    I know the feeling. My earlier attempts at methylation left me significantly sicker than before I started. It didn't help that I was already starting to relapse from working out at the gym over the summer. Now my adrenals are so fried I can't tell how much of my symptoms are from overmethylation/overdriving the methylation cycle and how much is from cortisol and/or norepinephrine from my adrenals and also how much is from ammonia induced excitotoxicity.

    Aside from low potassium symptoms (which need to be dealt with immediately), it would mainly be a wired/anxious feeling. Rich attributed the latter symptoms to excitotoxicity caused by glutamate and a drop in glutathione. I just posted about this in another thread, but I'll repost it here. I just want to make it clear that I'm not advocating Rich's protocol over Freddd's (and neither is Rich in these quotes), but Rich have a major disagreement over the issue of overdriving the methylation cycle and there's no way around that fact. Also, Freddd doesn't agree with Rich's theory about his cobalamin issue, but for whatever reason Freddd does seem to need atypically high doses of methylcobalamin (and methylfolate). This is from my earlier post:
    ------------------------------------------------------------------------------------
    Rich actually suggest L-Cystine (not L-Cysteine or NAC), but not if you have mercury issues. NAC, cysteine, and cystine can all cause problems if you're mercury toxic. There's more about L-Cystine and methylation in this thread:
    http://forums.phoenixrising.me/inde...excitotoxicity-on-methylation-protocol.18721/
    How does cystine normally get into the blood? The liver produces glutathione from the constituent amino acids that it receives from the diet via the intestine and the portal vein blood flow. The liver exports some of its glutathione to the circulating blood, and enzymes break down the glutathione into its constituent amino acids. The cysteine is mostly oxidized to cystine, and some of this is taken up from the blood by the brain.
    When the methylation protocol is begun, the activity of the methionine synthase enzyme in the liver is increased by supplementing B12 and folate forms. This causes more of the homocysteine to be converted to methionine, so less is available to support synthesis of glutathione. One result of this is that the cystine level in the blood goes down, so that less of it is available to the brain.
    At one time Rich had also suggested glutathione for excitotoxicity. I've more or less stopped glutathione recently, but I've noticed when I do take it it calms me down. I take Source Naturals' sublingual (orange flavor is best). More recently, Rich has suggested other supplements
    A lot of people experience it when they start this protocol. It's due to too much glutamate in the synapses of the neurons in the brain. The glutamate is supposed to be pumped out and converted to glutamine by the astrocytes, and sent back to the neurons for re-use, but this takes ATP, and when glutathione is low, the mitochondria do not produce ATP as fast as normal. When this protocol is started, I suspect that glutathione initially drops even more, and that is what causes the excitotoxicity. Various things have been recommended by Amy Yasko to counter this, including GABA, theanine, magnesium, Valerian root, grape seed extract, pycnogenol, progesterone cream, and taurine.
    Of course, it's better to avoid excitoxicity rather than have to deal with it which is why Rich recommends starting at low doses and doing things slowly.
    As you know, I have suggested a somewhat different approach to treating the methylation cycle partial block than Freddd has suggested.
    There seem to be more and more people who are exhibiting effects of overdriving the methylation cycle from taking high dosages of methylfolate and methyl B12 together. I do not recommend this approach.
    When high dosages of methylfolate and methyl B12 are taken together, the cells are no longer able to control the rate of the methylation cycle, and it becomes overdriven.
    One result of this is a rapid buildup of folates in the cells, because of the rapid production of tetrahydrofolate by the methionine synthase reaction.
    Tetrahydrofolate is readily converted to the forms of folate needed to support DNA and RNA synthesis, and this releases cells from a block at the S phase of the cell cycle.
    They rapidly start dividing, and this produces a strong demand for potassium.
    As Alex has noted, it has been shown that the intracellular potassium levels are low in CFS (likely because of an ATP deficit at the membrane ion pumps, due to mito dysfunction, in turn due to primarily to glutathione depletion), so there is no reserve there.
    The reason I don't recommend going much higher on methylfolate when it is combined with several milligrams of methyl B12 is that this combination takes control of the rate of the methionine synthase enzyme away from the cells and drives it too fast. The result is that too much of the homocysteine is converted to methionine, and there is not enough left to flow into the transsulfuration pathway to support synthesis of glutathione and other sulfur-containing substances that the cells need.
    The result is that the methylation cycle gets going well, but glutathione does not come up, as it needs to do for full recovery. There are excess methyl groups produced because of overdriving the methylation cycle. These are shunted off to the folate metabolism by sarcosine, which is produced by the glycine N-methyltransferase reaction, and then they come back to the methylation cycle via methylfolate. It's sort of like a futile cycle, like a squirrel in a rotating cage.
    This is not just based on biochemical theory, though it is supported by that. It is based on lab tests that people who have been on this regimen have sent me.
    For most PWMEs, this does not work very well in the long run. In Freddd's own case, because of the genetic variations that he apparently has in the CblC complementation group and in MTHFS (not to be confused with MTHFR), it is necessary for him to use a high dosage of methyl B12 to overcome the CblC problem, and it is necessary for him to use a high dosage of methylfolate to feed his folate metabolism, since he cannot use folinic acid or folic acid. (I'm not sure why he cannot use folic acid. Perhaps he has a polymorphism in the DHFR enzyme, also). Freddd cannot tolerate raising glutathione, because it binds cobalamin to form glutathionylcobalamin, and his version of the CblC complementation group is not able to retrieve cobalamin from glutathionylcobalamin. As far as I can tell, this is a rare genetic variation. Most PWMEs are depleted in glutathione, and this is responsible for a large number of the symptoms.
    There may be other PWMEs who have one or more of these genetic issues as well, since Freddd reports that there are some others who respond to these supplements in the same way he does, but most do not seem to have them, based on our clinical study and anecdotal reports from quite a few PWMEs.
    Best regards,
    Rich
  3. ktred

    ktred

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    I really appreciate your reposting this for me. So much of this information I have yet to fully comprehend! My methylation supplementation has for the most part helped me, but I do feel something like anxiety; it's hard to put a name on what I'm feeling. Like you, my adrenals get fried very easily. That in and of itself produces and wired and anxious feeling, but I know that problems with the methylation cycle effects the adrenals.
    warriorseekspeace likes this.
  4. adreno

    adreno 3% neanderthal

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    Signs of overmethylation IME: increased pain and inflammation, SNS overdrive, feeling wired, headache, anxiety, hypokalemia, insomnia, malaise. B3 can effectively bring down overmethylation.
    The Spitfire likes this.
  5. ktred

    ktred

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    Very interesting. I've had a few of those symptoms, but not most of them. I also take thyroid medicine (T3) combined with Armour and hydrocortisone for my non functioning adrenal glands. When those meds are off a bit, the symptoms seem similar to overymethlyation.

    Do you think heart palpitations could be the result of overymethyltion?

    Thanks
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  6. adreno

    adreno 3% neanderthal

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    There are many reasons for heart palpitations, but yes I believe overmethylation could cause this, especially if you're already sensitive towards changes in your biochemistry. Remember also that methylation also increases the demand for potassium.
  7. Lotus97

    Lotus97 Senior Member

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    I've been experiencing heart palpitations more often recently. I assume for me it's probably either from fatigue and/or norepinephrine. When I had been taking too high a methylation dose I did experience severe heart palpitations, but now I'm taking a very low dose and supplementing with potassium. What are some other causes? I wonder if there's something I've overlooked.
    I've been experiencing malaise and sometimes also flu-like symptoms since restarting methylation a few months ago, but I don't think those are necessarily from overmethylation since like I said I'm taking a very low dose.

    Rich said that one of the causes of inflammation from methylation could be from an infection. I assume there are other causes of methylation related inflammation. If someone knows what they are I'd like to hear them.

    There are also toxins released during methylation although that happens even if you're not overmethylating. This subject is kind of controversial as far as how much it happens or even whether or not it happens at all, but I've heard from 2 people who had their metals tested a week or two after starting methylation and both were releasing toxins.

    My health is at the point where even spending time at the computer causes a worsening of symptoms so when methylation makes me even more wired than usual I'm less likely to stay in bed and more likely to spend my time at the computer so it would be counterproductive to healing. Maybe for others the extra energy would be preferable.
  8. Misfit Toy

    Misfit Toy Senior Member

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    I felt anxious and unstable with heart palipitations. Also, I had severe pain. Fibro out of control and the back of my head and jaw was killing. My doctor said, "Get off the protocol" and I felt better in 2 days. So, that was what it was. Interesting. Off the protocol, which I was on back in 2007...for 3 months, my brain was more clear than it had been in
    awhile. I had been on the protocol for 4 months, but extremely high doses. Bottom line, it worked with my head and it felt nice to be a little bit clearer in the mind. Testing to go back on it again.
  9. adreno

    adreno 3% neanderthal

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    Electrolyte and hormone imbalances would be first on my list. Some drugs can cause it too. SNS overdrive. Probably a million reasons. You have to look at what you changed when it started.
  10. Lotus97

    Lotus97 Senior Member

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    Well, my adrenals are probably the main reason, but I noticed they got worse this past week after increasing my dose of Paxil. I had the same symptoms from Prozac and Zoloft, but after finding some evidence that those two raised norepinephrine I concluded it was the NE rather than my response to SSRIs. As far as electrolyte balance goes, I remember you said something about too much potassium and not enough sodium causes you to urinate a lot. I'm definitely doing that a lot, but I also drink a lot of water. I'm not sure if I have a question unless you know how I can figure out. I'm really hesitant to raise my sodium since I'm experiencing heart palpitations, but extra potassium doesn't seem to help them.
  11. Lotus97

    Lotus97 Senior Member

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    What happened between now and then? Did you try methylation with a lower dose? I find that I can't even tolerate the starting doses in Rich's protocol right now.
  12. Misfit Toy

    Misfit Toy Senior Member

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    Lotus97, being tested all over again. I will see if I can handle it now. I am sicker now than then so it should be interesting.
  13. Lotus97

    Lotus97 Senior Member

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    My early methylation attempts made me sicker which I think is why I'm having a hard time now. I was already starting to relapse even before methylation. I was planning on posting this earlier, but this seems like a perfect time. I've gathered some posts from Rich about the possible negative effects methylation has on the body. I would advise anyone who is in especially poor health to be careful with methylation.
    =========================================​
    One physician I know gives all his patients the methylation treatment, and then watches the response. If they experience some symptoms that appear to be caused by detox, but they are able to tolerate them, he continues with this treatment. If they have intolerable symptoms that appear to be related to mobilization of toxins, then he stops the methylation treatment and works on improving the status of the gut. When that is working better, he moves on to supporting the liver. His thinking is that the toxins that were being mobilized were being reabsorbed by the gut and sent back to the liver. In order to properly process and excrete the toxins, the gut and liver must both be functioning well enough to handle them.

    My guess is that when there is an inflammation response to methylation cycle treatment, there is an infection. If the inflammation continues without resolution, then my guess is that the immune system has been reactivated, but is not capable of defeating an existing infection. In such cases, I think that treating to support the immune system would be one approach. Another would be to test to determine what pathogen is causing the infection, and then treating it with an antibiotic, antiviral or antifungal, depending on the pathogen.

    I think it's important to note that a healthy person would not have any reaction to the supplements used in the methylation protocols, because their methylation cycle, detox system and immune system would already be functioning normally. So the fact that there is a response, even though it may seem to be deleterious, means that the methylation cycle was partially blocked and that these supplements were needed. However, the way one should proceed from that point on probably depends on the type of response that the individual person has.

    So far, I'm pretty sure that if the following are present, they will need specific treatment, in addition to treating the methylation cycle partial block: biotoxin (including mold) illness, Lyme disease and its coinfections, well-entrenched viral infections, and high body burdens of toxic heavy metals, such as mercury. There may be others of which I'm not aware, but there is some experience with these, at least, which people have reported

    I believe that the partial methylation cycle block is the pivotal abnormality in the pathogenesis and pathophysiology. With respect to the root cause or causes (etiology) of ME/CFS, I have suggested that this disorder arises from a combination of a genetic predisposition and some combination of a variety of stressors, which can be physical. chemical, biological, or psychological/emotional. I've suggested that this combination leads to glutathione depletion, which leaves B12 unprotected, which causes a decreased production of methylacobalamin, which inhibits methionine synthase, which forms a vicious circle with glutathione depletion, making ME/CFS a chronic condition. The retroviruses would fit within the biological stressors in my hypothesis, and certainly could be a root cause. If effective treatment of the retroviruses ends up bringing about recovery from ME/CFS, that will be very convincing as to its role as an etiologic agent. I hope that turns out to be the case for at least some of the PWMEs/PWCs. It may not be true for all of them, though, because this population seems to be very heterogeneous.

    The reason I have included the variety of stressors as etiologic agents is that I have studied the published "risk factor" studies, and have also queried quite a few PWMEs/PWCs as to the events that preceded their onset, and I've found a variety of precursors. The common factor seems to be that they are all things that would be dealt with by the body's nonspecific stress response systems, and these in turn are known to place demands on glutathione.

    In addition to this, there are now many PWMEs/PWCs who have taken the Health Diagnostics methylation pathways panel, and nearly all of them show evidence of a partial methylation cycle block or glutathione depletion, and usually both.

    And when treatment was given in our clinical study that is directed toward lifting the partial methylation cycle block, we observed by testing that this does in fact occur, and that glutathione also comes up automatically. This was accompanied by improvement in symptoms in at least two-thirds of those who were treated.

    Putting all of this together, I think the GD-MCB hypothesis is consistent with the observations and with known biochemistry and physiology. That doesn't mean that I believe that it is scientifically proven, which is a very high standard to meet, and requires considerable investment in time, money and effort, but that it is a valid working hypothesis. I'm hoping to interest researchers and fundors in this model so that it can be more thoroughly tested.

    The methylation cycle is at the beginning of the sulfur metabolism. It is fed by methionine, which comes in as part of protein in the diet. Homocysteine is produced from methionine (via SAMe and SAH) in the methylation cycle, and then methionine synthase "decides" how much should be converted back to methionine, to stay in the methylation cycle. In the liver and kidneys, the BHMT reaction also converts some homocysteine back to methionine. The rest of the homocysteine enters the transsulfuration pathway, which is downstream.

    The way that methionine synthase does its "deciding" is that the cobalt ion in the cobalamin that is its cofactor gets oxidized at a rate that depends on the state of oxidative stress in the cells. The more oxidizing this state is, the more often the cobalt ion gets oxidized, and that temporarily shuts down the methionine synthase reaction and diverts the homocysteine flow into the transsulfuration pathway, which helps to make more glutathione, which counters the oxidative stress. Unfortunately, in ME/CFS this delicate mechanism gets overwhelmed, and the oxidative stress becomes more severe, so that glutathione doesn't recover and get control of it. The result is that methionine synthase becomes partially blocked, and the sulfur metabolites drain down the transsulfuration pathway, into sulfoxidation, and get excreted too much as taurine and sulfate, which depletes methionine. The whole sulfur metabolism becomes dysfunctional, and that takes down the cell-mediated immune response as well as the detoxication system. As well, everything that depends on methylation reactions is affected, including gene expression, synthesis of several needed substances, and the neurotransmitter metabolism. Also, this drains the folates from the cells via the methyl trap mechanism, and that affects things that depend on folate, such as synthesis of new RNA and DNA. The latter is what cause the red blood cells to be too big and too few in number.

    The methylation cycle is so fundamental to so many parts of the body's biochemistry that when it becomes dysfunctional, it causes a host of problems, and this is why people experience so many symptoms, involving so many body systems and organs, in this disorder.
  14. Misfit Toy

    Misfit Toy Senior Member

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    Lotus97, my question is...our livers aren't working properly or else we wouldn't be having this problem and so many have guts that are whacked, like me. So, I agree, that sometimes this can make things worse if your liver and kidney's aren't working right, but really....they aren't working right to begin with because otherwise we would be able to detox...correct? My phase liver 2 is shit.
  15. Lotus97

    Lotus97 Senior Member

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    I don't think Rich was necessarily saying to do what that doctor does. I assume his point was just that if our liver and gut are in bad shape then methylation might be more difficult. It's a sad irony that the people who need various medical treatments the most are the ones who have the hardest time. From what I understand it's that way with cancer treatment. When I tried "detox baths" a few years ago my health got worse rather than better. It didn't help that I lost 40 lbs around the same time so all the toxins stored in my fat cells were released. It almost certain that I have Lyme disease, but my health is too poor to do the treatment now.
    Ailsa likes this.
  16. Misfit Toy

    Misfit Toy Senior Member

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    Lotus97, that is a lot of weight to lose. And you know, I wouldn't want to have to take the antibiotics with lyme. So many get so sick. Some don't even get better with antibiotics. I am so sorry you are so sick. I really am. The whole methylation deal is worrisome. We shall see. I will be posting for sure, once I get my protocol.
  17. adreno

    adreno 3% neanderthal

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    Low sodium can definitely cause heart palpitations, and if you urinate a lot you likely need more of it.
    Lotus97 likes this.
  18. Lotus97

    Lotus97 Senior Member

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    I'm almost six feet, but yeah it's still a lot of weight. I was drinking a lot of ginger tea which an Ayurvedic method for detoxification and weight loss. I was also on a low calorie diet. The low cal diet was unintentional. Now that I count calories I realize that my past diets were way too low. Normally low cal diets aren't good for weight loss because the metabolism slows down, but I think the ginger tea sped up my metabolism. After that I made a slow, but gradual recovery until last summer when I started working out at a gym. Now I'm almost back where I started 2 1/2 years. I don't think I'm going to make a lasting recovery until I can treat my underlying health issues which seem to be adrenals and Lyme.
    I look forward to hearing about your experience with methylation. We seem to hear mostly the success stories and from people who have no problem taking higher doses, but we don't hear much from the people for whom methylation didn't go well. I had a very hard time with just a tiny bit of methylfolate. I had no idea what was going on until I came across a quote by Rich where he said some people had to wet a toothpick and pick up a tiny bit of methylfolate when they started methylation and even that was too much at first. I don't think I would have done methylation if it wasn't for Rich. And he describes his protocol as "a gentler approach to lifting the partial methylation cycle block, and many PWMEs need such an approach." Don't get me wrong. Some people have great success with Freddd's protocol, but as I said before I can't even tolerate Rich's dosage recommendations right now.
  19. Misfit Toy

    Misfit Toy Senior Member

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    Lotus97,,,right now. I get it. Believe me, I am worried myself. People a lot of times don't write what is going on with them. They only write positives. I think they are afraid someone will pounce on them or tell them what to do if they say something negative. Also, even on here, people don't like when something doesn't work for you unless they have the same experience. They would rather not say anything. We are so different and all are going to have different experiences.
    Lotus97 likes this.
  20. Lotus97

    Lotus97 Senior Member

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    In the past few weeks I've seen 2 different people who described herx-like symptoms from methylation being told that the solution to their problems was more methylfolate. I won't mention any names, but you can guess who told them that.

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