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Input requested on possible changes to simplified methylation protocol

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, May 30, 2012.

  1. Lotus97

    Lotus97 Senior Member

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    That's interesting. When I was having problems with Jarrow's B Right B-complex I assumed it was the methylfolate since I had taken B Right for over a year without any problems until Jarrow added methylfolate to B Right (Summer 2012). However, I started taking the new B Right a few days after my amalgam was removed so I think being exposed to mercury and/or copper from the filling caused a partial block in the methylation cycle. I'm not saying the methylfolate didn't play a part, but now it seems possible that the methylcobalamin could also have been giving me problems even though there was only 100 mcg in each capsule and I took 2 capsules a day.
  2. dbkita

    dbkita Senior Member

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    Why does a methyl group drained down the CBS pathway lead to excitotoxicity. Sulfites? Ammonia?Aren't thiols in the diet just as dangerous if not more so?

    Yasko is mistaken in claiming AKG is formed, it is AKB, a very different and useful chemical in most cases. So glutamate while it may be a problem due to increased processing of histidine by THF with added folate, it is not from the CBS cycle. In fact taurine is one of the best anti-glutamate's in terms of inhibition next to GABA itself.

    Personally I think sulfites are a problem for me I never realized until recently, And I think Rich Vank's hypothesis about H2S gas produced from sulfate reducing bacteria may also be in play.

    Just curious what you think the main culprits are especially if you are talking really, really low doses of mb12 like in your case.
  3. caledonia

    caledonia

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    Those are the same as my SNPs. Yes, I'm testing with the urine strips - it's sulfate.
    My HDRI results are pretty wacked out. Most everything is either at the top or bottom end of the range.
  4. caledonia

    caledonia

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    What is your source for alpha keto glutarate not being formed?

    I have to take large amounts of GABA and taurine 3-4 X a day to keep things calmed down.

    I'm following the free thiol restriction list instead of the sulfur restriction list. According to this page, Yasko would be wrong about restricting actual sulfur: http://www.livingnetwork.co.za/chelationnetwork/food/high-sulfur-sulphur-food-list/

    Here is what Heartfixer says:
    The CBS defect is an up regulation. CBS is operating at up to ten times its normal rate. Homocysteine and all of the upstream methyl cycle precursors will be “pulled down the CBS drain” to produce toxic levels of cystathionine metabolites.....We treat CBS ( +) individuals with dietary animal protein and sulfate restriction and supplements designed to neutralize ammonia and speed up clearance of sulfite/sulfate.

    Biochemistry – The 10-fold up regulation in CBS generates sulfur breakdown products (sulfite and sulfate, which stimulate the stress/cortisol “fight or flight” response), excess ammonia (in the process wasting BH4 which is used up detoxifying ammonia), hydrogen sulfide (producing “brain fog”), and alpha-keto glutarate (leading to “excitotoxicity”). The G6PDH enzyme system may be affected, leading to abnormalities in sugar control. Methylation intermediates will “fall through this drain”, so the entire system suffers; our defenses against viral invasion and toxicity suffer. Co-Q10 and Carnitine generation will fall off due to impaired methylation, and ATP levels fall, robbing you of energy.

    Ammonia is produced during the metabolism of dietary protein. The CBS up regulation drains methyl cycle intermediates in to ammonia, more ammonia than your system can handle. Ammonia detoxification is metabolically expense, using up two molecules of BH4 per molecule of ammonia. BH4 is necessary to generate neurotransmitters (dopamine, serotonin, and norepinephrine) and nitric oxide, our key vasoprotective molecule. Thus it is easy to see how a CBS up regulation, by generating ammonia and depleting BH4, can set you up for neurological, psychological, and cardiovascular disease states.

    Sulfite is neurotoxic. Sulfite will be over produced by the CBS up regulation, and then requires conversion in to the less toxic sulfate molecule by the enzyme Sulfite Oxidase (SUOX). SUOX can easily be overwhelmed.

    While sulfate is less toxic than is sulfite, it will stimulate the adrenergic (fight or flight) limb of the autonomic nervous system and stimulate a cortisol stress response, revving you up into an unrelenting biochemical overdrive.

    Excitotoxicity – The CBS up regulation leads to excess production of alpha-ketoglutarate, which is converted in to glutamate, a stimulatory neurotransmitter. Under normal circumstances, glutamate will be converted in to GABA, a calming neurotransmitter, but the enzyme systems that convert glutamate in to GABA are compromised by lead and mercury, the clearance of which seems to be compromised in individuals with methyl cycle defects (here is a situation where dysfunction of a genetically abnormal enzyme leads to acquired dysfunction of a genetically normal enzyme system). The result is “excitotoxicity”, stimulatory behavior in autistic kids (“stims”) and anxiety and sleeplessness in adults.
  5. dbkita

    dbkita Senior Member

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    Yep I have read heartfixer as well. Nice site. But in this matter Yasko et al. are incorrect.

    I don't doubt that you are experiencing excitotoxicity (sulfites and H2S and ammonia can be big ones) and need to take GABA (which will work assuming your BBB is penetratable) or taurine (which I like myself).


    Ironically Rich Vank also pointed out this error on these very same forums some time ago but not many seem to have registered this key distinction.

    So here it goes:
    --------------------

    The enzyme that cleaves cystathione is known as cystathionine gamma-lyase.

    Source: http://en.wikipedia.org/wiki/Cystathionine_gamma-lyase

    As you can see the same enzyme also metabolizes cysteine into pyruvate, ammonia and H2S.

    So the figure that Dr Yasko has promulgated and others have taken up is really broken.

    I mean for example this figure:

    http://www.heartfixer.com/AMRI-Nutrigenomics_files/image004.jpg

    It is busted in two places.

    First the cystathionine gamma-lyase acts on cystathionine and this results in cysteine, alpha keto butyrate and ammonia.

    Then it the same enzyme that converts cysteine into pyruvate, ammonia, and H2S.

    Interestingly enough alpha keto butyrate is a very useful guy in that he eventually can be converted into forms that enter into the Krebs cylce as succinyl-COA.

    See http://en.wikipedia.org/wiki/Alpha-Ketobutyric_acid for more information

    I asked Rich Vank how this error got initiated and why it never got corrected. He had some notion that Dr Yasko had mis-copied it from some presentation or textbook and ran with the alpha-keto-glutarate. As far as why it has not been corrected, well my best guess is that we as humans like to hang onto memes even if they are wrong some times. But that is my two cents.

    Ammonia can certainly cause problems as it needs to be shipped out via the urea cycle, removed via BH4, or shuttled out using glutamine from the brain. All of these can have downstream neurotransmitter effects. And this could explain excitotoxicity (which I certainly experience as well).

    The sulfites and H2S and maybe even sulfates feeding sulfate reducing bacteria in the gut can also be big issues.

    Personally I notice I sleep better generally when my sulfates are lower (and it turns out I have oodles of alpha and gamma hemolytic strep in my gut so that fits). Molybdenum has been very useful as well so that fits with sulfites.
    My ammonia levels are normal but no doubt the load still compromises BH4 resulting in low dopamine and serotonin which also fits for me.

    As far as diet goes, I have already found personally the thiol rich avoidance diet is the key. Yes ratcheting up the methylation cycle can also cause enhanced levels of sulfates dependent on which CBS defects exist.

    I consume 4000 calories a day and eat a ton of protein (animal form, i.e. 230 grams a day). But if I eat thiol rich vegetables, say more than two servings a day, take a lot of ALA or NAC, or similar things, my sulfates go from 400-600 to 1200-1600 in a day. I still need to do a 24 hour urine sulfate test to correlate with the strips to be sure.

    But I still wonder then which is the actual trigger for the CBS excitotoxicity. Is it the ammonia or the H2S or maybe the sulfites.

    Or very likely it is the excess sulfates which trigger the adrenergic response. GABA and taurine fight with norepinephrine as well not just glutamate.

    Hope this helps :)

    Good luck and God bless!
  6. caledonia

    caledonia

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    I see your point, and it does look like you and Rich are correct. That's weird that Yasko would list AKG twice on that diagram anyway.

    So I think the ultimate question would be, where is the glutamate coming from, and why does reducing ammonia and sulfates help? In other words, regardless of whether Yasko is right or wrong with the explanation, the same treatment works.

    I think the answer might be on one of these pages somewhere, but I'm way brainfogged due to lack of sleep. If you can figure it out, let me know...otherwise I'll try and take a crack at it later.

    http://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid
    http://en.wikipedia.org/wiki/Glutamate

    I did see something about lack of B6 being the reason glutamate doesn't convert properly into GABA? Do ammonia and sulfite mess up B6?
  7. dbkita

    dbkita Senior Member

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    P5p is the cofactor for glutamic acid decarboxylase (an enzyme I know well since I have a very rare autoimmune disease that targets those enzymes specifically the 65 kildalton sub-type in the CNS). P5p is a cofactor for many other reactions as well as production of dopamine and serotonin.

    But for most people taking 25 mg of P5p is more than enough (probably less if sublingual).
    Remember P5p is the cofactor for cystathionine beta which is the driver of the trans-sulfuration pathway.

    Sulfites can cause a lot of problems including hitting people with arrythmias (my Mom), reflux (me), headaches (my brother), etc. But if you are having excitotoxicity with no heart issues then I would doubt sulfites. But anything possible I suppose.

    I doubt you will find the answer in the wikipedia for AKG and glutamate. There is no direct link for those reaction pathways from what I can tell.

    Methylation itself can create glutamate directly by metabolism of histidine into a one off version of glutamate by virtue of THF in the folate cycle and I would tender that is more of a problem than people on these boards recognize when it comes to potential over-methylation.

    One strong candidate may be the ammonia.

    Ammonia can lower BH4 and also overload the urea cycle. Ammonia in the brain is very toxic and can only be rectified by the glutamine shuttle from brain to body. An important enzyme to consider is the glutamine synthetase enzyme that converts glutamate into glutamine (the latter of which is BBB, whereas glutamate is not). Note excitotoxicity if indeed due to glutamate (and not say NE) must be then involve glutamate in the brain and not only in the body. So the BBB either has to be really leaky or their is conversion to glutamine prior to going either direction across the brain. One option then is the brain somehow loads up on ammonia and glutamate and is not able to convert to glutamine at an efficient enough rate and the shuttle across the BBB is too slow leading to excitiotoxicity.

    Personally though I don't think glutamate is always the only bad guy. NE is a huge player that many on these forums choose to ignore. And I believe they ignore at their own peril.

    There may for example be indirect links to norepinephrine due to a lifetime of CFS type symptoms and low energy production coupled with immune system dysregulation. Adreno and I have been discussing some of this in a couple of other active threads.

    Again I don't think a person with especially heterozygote CBS mutation(s) (remember the 10x is NOT for the heterozygote, single SNP,) necessarily will have pre-destined excitiotoxicity. There must be other forces at play as will. Just maybe clinically people with CBS mutations benefit from lowering ammonia giving them more BH4, ergo more dopamine and serotonin, which in turn better control the sympathetic nervous system.

    While others benefit from less sulfates feeding sulfate reducing bacteria in their guts and hence less H2S. I will admit the H2S is murky to me only in that I do not know enough about it to be able to assess its importance beyond that low levels are necessary and really high levels are toxic.

    In my own case I can tolerate much higher fluctuations in mb12 and p5p than I can in methylfolate or adb12.

    Lacking anything else atm, I would bet my money on ammonia and the stress that ammonia places on certain ammonia detox pathways. For people with sulfite sensitivity or sulfate reducing bacteria in the gut, they lean instead towards problems with thiols, and highly toxic sulfites, etc.

    To be honest this is all supposition at this point.
  8. adreno

    adreno 3% neanderthal

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    How do we get rid of ammonia? Would AKG be a good option? I know Yasko recommends Yucca, but I am a little worried about hemolysis. Restricting protein too much is not a good idea either, I believe. Proteins are very important, often PWMEs are in a catabolic state. Proteins stabilize blood sugar, are necessary for hormone production, source of methionine, builds muscle etc. I know I do better with moderate to high levels of protein. I literally crave meat.

    WRT excitotoxicity, or hyperstimulation, I must admit I'm starting to agree with dbkita. Glutamate seems to get blamed for just about every bad thing around here. I am personally finding that NE is a bigger problem. I can feel very anxious with tachycardia and cold limbs, while at the same time being completely dullminded, like my brain is totally switched off. It is a very weird sensation to be bodily hyped up, but mentally asleep. These symptoms, I believe, point towards high NE, not high glutamate.

    I am actually considering something to increase glutamate in the morning, because I believe my levels are too low. Coffee has worked for me in the past for this purpose, but the problem is that it also increases NE substantially. So I'm looking for other ways. Piracetam is perhaps an option. I am not recommending that everyone boost their glutamate, just saying that it can be a problem when glutamate is low also. I have found that it is actually quite easy to hammer glutamate down, if one wishes so.
  9. Lotus97

    Lotus97 Senior Member

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    Yeah, I also do well on a moderate to high protein diet. I tried a vegan diet once in attempt to "alkalize" and that was a disaster (thanks Tony Robbins). Even the Dali Llama eats meat.:thumbsup: I started taking Yucca for ammonia since Rich also recommended it although that might be because Yasko recommends it. What is hemolysis. Is that a likely risk?

    What is NE? I seem to have most of the symptoms you describe so I'd like to at least rule that out as a possible cause.

    I'm taking Ornithine AKG partially for ammonia although I don't know how much it's helping. I'm also taking Citrulline Malate and Arginine Pyroglutamate so I probably need to make sure I'm not boosting NO too much. I'm not sure if these charts are correct, but if they are then I'm more confused.

    [​IMG]


    [​IMG]
  10. adreno

    adreno 3% neanderthal

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    NE = norepinephrine

    Hemolysis = red blood cells burst, maybe low risk, I don't know.
    http://www.drugs.com/npp/yucca.html
    Lotus97 likes this.
  11. Lotus97

    Lotus97 Senior Member

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    What can cause elevated NE levels? I've tried to avoid things that increase norepinephrine in fear of overstimulation. I experienced symptoms from Effexor. I've also experienced symptoms from Prozac, but I didn't even consider it for NE since it's an SSRI. I thought I'd check just out of curiousity and found something interesting:
    http://www.biopsychiatry.com/fluoxdopnor.htm
  12. adreno

    adreno 3% neanderthal

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    I'm on fluoxetine. Fluoxetine is a 5-HT2C antagonist. 5-HT2C (a serotonin receptor) antagonism causes release of dopamine (DA) and NE in the prefrontal cortex (PFC). DA and NE normally helps with cognition in the PFC, although overstimulation is possible. Anxiety is mediated by other areas of the brain, namely the amygdala. Also, I doubt how strong the 5-HT2C antagonism really is. In any case, 5-HT2C receptors downregulate in response to both agonists and antagonists, so if there is any overstimulation, it is likely only in the beginning (2-4 weeks). That said, escitalopram (another SSRI) is probably more calming, and is the preferred choice if you have anxiety. It is the "cleanest" of the SSRIs. I found it intolerable, however.

    Effexor is a serotonin (5-HT) and NE reuptake inhibitor, which will increase 5-HT and NE levels across the brain (and in the periphery), so this can really cause side effects if you are sensitive to NE. There is of course a big difference between having a small increase in NE in the PFC, versus a very big increase in your entire body and brain.

    Several things can contribute to high NE levels; stress, immune system activation, low cortisol, low 5-HT, low ACh.
    Lotus97 likes this.
  13. dbkita

    dbkita Senior Member

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    Yes there is a big difference from having excess glutamate and excess NE. The former causes hyper-senses, nasty pain, racing thoughts, incredibly over-sharp thinking to the point things are mentally too fast, etc. NE is your fight and flight respons, tachycardia, high BP, pounding heart, amped body, can't settle down (body is essentially scared), can also cause pain but usually more muscle pain (complicated inter-connection with immune system) and so on and so on.

    Even the insomnia is different. In glutamate excitotoxicitiy your senses are so revved up you can't initiate sleep, you can hear a flea pass gas six miles away on the back of a dog six miles away (I exaggerate only slightly), you are completely mentally wired. With NE you heart is pounding, you can't get your body to stop moving, you roll over constantly, you wake every 15-20 minutes or even less if really bad. Yes the two neurotransmitters both feed into the hypothalamus and there is some overlap but there are in at least my own experience substantial differences.

    Both suck. I have had both at the same time due to my rare autoimmune disease. But they are not the same. When they both gang up on you at the same time it is generally lights out in the sense that you have no chance and you disintegrate.

    One of the easiest ways to bludgeon glutamate provided you can tolerate the sulfur and have ATP available, is to take NAC. I can take 750 mg of NAC twice a day and put my brain into a stupor. Problem is it is too much. It also causes reflux. Besides unless over-stimmed I don't think you want to wreck all glutamate at night. It is essential to dreaming.
    The goal is balance between the GABA and glutamate. Neither should be overly transcendent over the other for any extended periods of time.

    Maybe some of what CBS up-regulators experience is the result of increased trans-sulfuration leading to a fight or flight response and more NE. I know Yasko blames glutamate, ammonia, H2S, sulfites, and sulfates (the sulfates for the fight or flight, but I have not come across direct in vivo results that explain that link yet).

    I suspect again ammonia is bad. The body has several mechanisms to remove ammonia. The biggest in the periphery is the urea cycle. In the brain it is the glutamine shuffle with the body across the BBB. The urea cycle has many components but the key part relative to ammonia is glutamine production. Glutamine is the main nitrogen balancer in the body and I believe the 1st or 2nd most abundant amino acid.

    Having a proper functioning urea cycle and glutamine synthetase enzyme is going to be way more effective imho than sprinkling yucca powder on your food. The exception is ammonia made in the gut by bad bacteria. But the we are right back to immune system / gut dysbiosis and hence NE.

    I also agree that rationing protein can be dangerous for some. I would waste away via catabolism if I did not consume large amounts of protein. I worry some people on these forums blindly follow a low protein protocol and are doing themselves harm since they are not well enough to do their own protein synthesis let alone get enough of the essential amino acids.

    Dr Yasko has achieved much success but her primary original research was still derived from children with autism. She and others have extended it to adults who do not have autism but even Rich Vank was very cautious in how to apply some of Dr Yasko's methodologies.

    Again all I urge is caution.
  14. adreno

    adreno 3% neanderthal

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    [​IMG]

    So what we need is -- ATP? To drive the glutamine synthetase...?
  15. Lotus97

    Lotus97 Senior Member

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    I've actually started Prozac 3 different times in the past 6 months and you're right, the start-up period in the first month or so is when it hits hard. It's more of a physical symptom than mental anxiety though. Heart palpitations and feeling speeded up. It also causes insomnia. It works great for my mood though to the point where I sort of feel stoned. I was on it a long time when I was younger, but it wasn't nearly as effective as it is now. This generic brand I'm on now seems to be more potent and at a lower dose too. However, I didn't experience the side effects either when I took it in the past. I don't remember if I took the brand name or different generic. The first time I took it was 1997.
  16. caledonia

    caledonia

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    http://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid
    α-Ketoglutarate is transaminated, along with glutamine, to form the excitatory neurotransmitter glutamate. Glutamate can then be decarboxylated (requiring vitamin B6) into the inhibitory neurotransmitter GABA.

    http://en.wikipedia.org/wiki/Glutamate
    I had some fish sauce (umami/glutamic acid) on some vegetables last night, and about 15 minutes later started feeling overstimulated. The feeling lasted for about 30 minutes.

    I'm not tolerating much P5P (B6) right now. About 7mg. I'm only taking a very small amount of mfolate (about 8mg).

    That still doesn't quite explain how ammonia/sulfur turn into glutamate or increase levels of glutamate, but it does show that glutamate is stimulating/excitatory, and that AKG can turn into glutamate.
  17. Lotus97

    Lotus97 Senior Member

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    I might be more sensitive than most, but I think Yucca has been causing side effects for me due to it's estrogenic nature. I was taking a supplement with plant sterols and that caused the same effect. I wasn't sure until now and of course I'm still not 100% sure. It's so difficult attributing cause and effect to things.
  18. adreno

    adreno 3% neanderthal

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    Why would you start and stop an SSRI 3 times in the last 6 months? This will just mess up your neurochemistry.
  19. adreno

    adreno 3% neanderthal

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    Nice :) NAC and AKG together protects against ammonia toxicity:
  20. Lotus97

    Lotus97 Senior Member

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    The first time I hadn't actually stopped Prozac. I was switching from Zoloft to Prozac. The second time I was trying to skip a few days in between doses because I thought maybe I'd sleep better if there wasn't so much in my system. Since Prozac has a really long half life I was able to do this for about 3-4 weeks before I got depressed. It didn't help my insomnia though. The third time I tried switching to Paxil because I thought it was less likely to cause insomnia, but it turned out the generic brand I got was completely worthless. I had been on the Paxil brand name, but I was able to confirm this by reading some forums and found other people with the same experiences. Since I've gone back on Prozac my doctor was able to get my insurance to cover brand name Paxil, but I don't want to have to go through the whole starting and stopping thing again. My doctor added a low dose of Zyprexa in addition to Elavil which I was taking for sleep. I'm not really sleeping much longer, but so far I'm not waking up in the middle of the night as frequently as when I was just on the Elavil.

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