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L-cystine may help to lower excitotoxicity on methylation protocol

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Aug 1, 2012.

  1. richvank

    richvank Senior Member

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    Quite a few PWMEs who have tried the methylation protocol have reported that they have experienced an increase in symptoms associated with excitotoxicity when they began (anxiety, insomnia, nervousness). In the past, I have suggested trying acetyl glutathione or liposomal glutathione to counter this. One or two people reported that they thought this helped them.

    Now I would like to suggest something else that I think would help with this, which is less expensive: L-cystine. Note here that I do mean L-cystine, not L-cysteine. (Cystine is the oxidized form of cysteine, consisting of two cysteine molecules bound together by a disulfide bond.) Douglas Laboratories is one producer of L-cystine, and there are at least a couple of suppliers of it
    on the internet advertising 60 capsules, 500 mg each, for $16.50. I would suggest starting with a dosage of 500 mg and increasing to as much as 1,500 mg, depending on the response. L-cystine should not be taken by people who have a tendency to develop cystine kidney stones, or people who suspect that they have a high body burden of mercury, because L-cystine may move mercury around. And as always, I recommend working with a physician while on this protocol.

    Here is the rationale:

    I believe that the increase in excitotoxicity results from a further drop in the glutathione levels in the astrocytes (helper cells) in the brain, when the protocol is begun. (We know
    from the recent MRS measurements of Shungu et al. that glutathione is already somewhat depleted in the brain in ME/CFS.) The further drop in glutathione lowers the production of ATP by the mitochondria of these cells, and they then have less energy for pumping glutamate out of the synapses and recycling it. When glutamate builds up, it overexcites the NMDA receptors, and that produces excitotoxicity.

    If this is true, then it would seem that we may be able to lower the excitotoxicity if we can support the glutathione levels in the astrocytes as this protocol is begun.

    According to the Dringen model, the astrocytes make their glutathione using cystine as their source of cysteine. Cystine is obtained from the blood, and is able to pass through the blood-brain barrier.

    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.

    It would therefore seem that if L-cystine were supplemented, it would augment the cystine in the blood and increase the supply available to the brain, and hence to the astrocytes. Hopefully, this would raise the glutathione levels in these cells, and increase their ability to remove glutamate from the synapses, lowering the excitotoxicity. Ingested cystine is not metabolized significantly by the liver, because it does not import cystine readily.

    If anybody decides to try this, I would be interested to hear the results, whatever they turn out to be. Thanks.

    Best regards,

    Rich
     
  2. Adster

    Adster Senior Member

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    Thanks Rich. Would there be any issues with trying this if a person suspects mercury toxicity?
     
  3. richvank

    richvank Senior Member

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    Hi, Adster.

    I've just looked into this, and I think you have a good point. I've added a note about this to my post. Thank you.

    Best regards,

    Rich
     
  4. August59

    August59 Daughters High School Graduation

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    Thanks Rich as always for your continuing quest to take things to the next step!

    Your opinion about something. I had the notion that I probably had some elevated mercury levels, but was not sure because I have had a lot of amalgam fillings in the past and still have a few. About 6 months ago I saw an intergrative doctor and he initially did a 24 hour urine metals test and suprisingly nothing was really elevated out of the normal range. A few weeks later he had me do a "provoked" urine metals test using DMSA, glycine and potassium.

    The outcome of this test was a little surprising in that mercury did not move from the unprovoked test, but nickel really went into the elevated range followed by elevations of lead and cesium just barely out of the normal range. Of course I was curious as to why the mercury didn't go up since I still had amalgam fillings. His response was there is some opinions that DMSA or any other chelator will not pull mercury out of an amalgam filling and that they will only remove mercury that has already been methylated into the body.

    He also said some don't prescribe to this opinion, but if you look at your situation over the last 30 years and approximately 40 amalgam fillings later, (most of those in the first 5 or so years) you would expect to see mercury levels go up during the provoked test if in fact strong heavy metal chelators remove mercury from the actual fillings.

    Thanks again!
     
  5. richvank

    richvank Senior Member

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    Hi, August59.

    I've always doubted that a chelator like DMSA would extract mercury from fillings. In order to do that, I think it would have to be in the saliva. I've never heard of a measurement to see if it passes from the blood to the saliva via the saliva glands, but I doubt that it does. If it does do that, then it would enter the digestive system. Would it be broken down there, and release the mercury for possible reabsorption by the gut? The absorption fraction of inorganic mercury by the gut is pretty low. I guess those are my thoughts on this, but I'm not aware of measurements having been made.

    Best regards,

    Rich
     
  6. Gestalt

    Gestalt Senior Member

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    Isn't the methylation protocol supposed to increase glutathione levels....not decrease them? I am a bit confused by your logic.

    I have a different theory. The increased excitotoxicity from starting a methylation protocol may come from CBS defects that become more pronounced as more stuff is getting drained down the transsulfuration pathway because the methylation cycle is pushing through more. Ammonia production increases and the excess in ammonia is what's causing the increase in excitotoxicity. In this case yucca may help more so, and or supporting the urea cycle with ornithine & citrulline malate.

    However I am still willing to try cystine. I'll do anything to help reduce excitoxocity.
     
    greenshots likes this.
  7. richvank

    richvank Senior Member

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    Hi, Gestalt.

    Yes, ultimately the methylation protocol does increase glutathione. We have documented that with lab testing.

    However, the very first thing that happens when B12 and folate are applied together, which is the real essence of this protocol, is that the activity of the methionine synthase enzyme is increased. This enzyme converts homocysteine to methionine. When that starts, there is initially less homocysteine available to enter the transsulfuration pathway, and that ends up lowering the production of cysteine and hence, glutathione.

    Over time, the methylation cycle is able to fill by recycling homocysteine to methionine, and then there is more homocysteine available to enter the transsulfuration pathway.

    In our clinical study, our first test point after starting the protocol was at three months, and at that point the glutathione level had increased significantly. But at early times, it makes sense that glutathione would initially drop, and that does seem to correspond to the increased excitotoxicity that many people report.

    If you do try L-cystine, I'll be interested to hear how it goes.

    Best regards,

    Rich
     
  8. Dreambirdie

    Dreambirdie work in progress

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    This is interesting and potentially useful for me. I have consistently had problems with excitotoxicity whenever I try the methylation protocol and have had to back WAY OFF it for that reason.

    Thanks Rich, for sharing this info with us.
     
  9. place

    place Be Strong!

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    This is very interesting. if I take too much b12 I get ICI and more sinus issues. II t back off, but it is inflamtion, is what it is. I stop taking B12 and up my anti-inflamitory type suppliments and it goes away in 24 hours. But after several times of trial and error, this same reaction occurs. I have been trying to figure out where in the process it is getting bottled necked. This topic is very timely of course as I am going through it now.
     
  10. LynnD

    LynnD

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    Hello,
    Dont have ME/CFS but while online search to see why had 3x's higher then upper test parameters.
    Found one site said could be from low thyroid. (hi RT3, low FT3, toward lo end of TSH, but reacted to iodine and cytomel). also very high carotine blood test. Had weight loss that no one knew cause , so when heard of SCD (specific carbohydrate diet ) to rid of bad bugs in digestive tract tried it and helped immensely. also one Dr prescribed MB12 shots, which helped greatly with energy and brain concentration. Then noticed needed it 3x's /wk. So now on sublingual.
    Did notice it causes weightloss for me, and feels like getting infection or myabe as someone commected, immune ssytem was more balanced. Lately , things taste bitter, espec water ,unless put salt or K or Mg in it.
    Try to get nutrients from food but still on small amount often of MB12, fermented cod liver oil, and L-Cysteine .
    and go for a walk in the morning if can.
    So saw a mention of paradoxical folic acid deficiency and wondered (lost the page) if I might
    have that or a form of it. how to find what symptoms, what try and what test to tell the Dr.(or will he give me that blank look often get?) of a test. still trying to learn about methylation and acetylation (think might have trouble with that) .
    Thanks for helping me find or where to look for this info
    Lynn D
     
  11. greenshots

    greenshots Senior Member

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    Hi Dr. vank,

    Wouldn't this lost homocysteine apply more for those without the CBS then those who do? Also, I'd have to figure that if you have a bunch of defects like the MTHFR C677T, BHMT, and MTR, which cause higher homocysteine, that you'd have higher levels than someone who didn't, so this also might not apply?

    Seeing as how so many sick people have alotta these defects, it seems like the theory on lost homocysteine might be less common in people who are sicker. What do you think?


     
  12. richvank

    richvank Senior Member

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    Hi, Angela.

    I don't know. These would all be good things to study!

    It would be interesting to know whether the people who experience the worst excitotoxicity on starting the simplified methylation protocol have certain patterns of SNPs.

    My approach in recent years has been to suggest the simplified protocol for everyone, regardless of SNPs, and then try to deal with whatever issues arise. Many people do not have the finances to afford the nutrigenomic panel, and prefer just to try the treatment. Sometimes this pays off. Other times, more work is needed.

    If people have the resources to run one test, I prefer the Health Diagnostics methylation pathways panel.

    When I see the results of the Health Diagnostics methylation pathways panel on someone who has also run the nutrigenomic panel, the results in the biochemistry don't always match what one might expect on the basis of the
    SNPs. I prefer to go with the actual biochemistry. The SNPs are helpful for showing tendencies, but they aren't always very predictive.

    Best regards,

    Rich
     

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