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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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    http://www.ncbi.nlm.nih.gov/pubmed/6462327

    Also, this from Rich. Interesting what he says about ammonia and mitochondria because Carnitine is supposed to improve mitochondrial function.

     
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  2. adreno

    adreno 3% neanderthal

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    Lotus97

    I don't know why you would want Paxil over fluoxetine. Paxil has some nasty anti-cholinergic side effects. Anti-cholinergics are generally bad news for your heart and autonomic nervous system. The only SSRIs I would consider are escitalopram, sertraline or fluoxetine. If you're also on Zyprexa (antipsychotic) and Elavil (TCA) you're on a pretty serious polypharmacy cocktail, with lots of potential side effects. The antipsychotics and TCAs are like pharmaceutical shotguns, blasting so many receptors and other systems that it is practically impossible to predict how you're going to react to them, especially when you throw in ME/CFS and dysautonomia in the equation. I suggest you be careful. Personally I wouldn't mix all those drugs. If you're worried about the 5-HT2C antagonism of fluoxetine (and subsequent NE release), it's nothing compared to the actions of the drugs you take. Don't kid yourself that the doctors actually know how the drugs they prescribe work, or how they interact.

    Zyprexa is an antagonist of the following receptors:
    Elavil (amitriptyline):
    You're learning fast Lotus, getting a crash course in neuroscience, biochem and endocrinology here :)
    I guess we'll soon be able to write our PhDs on this stuff...at least we already know ahellofalot more than any doctor I've ever met -- when people ask me if I'm on Facebook, I answer: "No, I'm on PubMed".
     
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  3. Lotus97

    Lotus97 Senior Member

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    adreno

    Yeah, my med situation is a bit unusual. A few years ago I started getting acid reflux from SSRIs so I switched to Risperdal. This was my idea. My doctor had prescribed Risperdal for sleep because I though Elavil was causing side effects. When I stopped the SSRI I was on I tried Risperdal during the day and it seemed to work for depression. I've tried 3 different SNRIs and they didn't do anything for me. Although my doctor was hesitant to let me take Risperdal during the day, but she's flexible and I like that about her. For the next year and a half I took Risperdal during the day and Elavil at night. I slept very well during that period and I made a significant recovery to the point where I was able to work out at the gym almost every day although I should add that after I got back from the gym I spent the rest of the day either in bed or at the computer and my mom still did my laundry, dishes, cooking, and grocery shopping. I did gain 30 lbs over that year and a half which is why I went back to SSRIs. This time I took Prilosec for acid reflux caused by SSRIs, but my sleep got a lot worse. I went from sleeping 10-11 hrs a night to 5-6 hrs. I attribute a huge part of my recovery to getting enough sleep (and also limiting activities during the day). I had been on Paxil briefly and remember it making me really drowsy so I thought if I took that instead of Prozac I would sleep better. After a problem with generic Paxil I went back to Prozac and asked my doctor about a low dose of Zyprexa (2.5 mg) along with Elavil. I had been on Zyprexa in the past for sleep and slept really well. The psychiatrist who put me on Zyprexa back then did it for other reasons which I won't mention because I believe she misdiagnosed me and another psychiatrist thought the same thing as me. I have some concerns about the generic brands of Zyprexa and Elavil I'm on right now. Although there are forums discussing the effectiveness of various generic brands of drugs I have a hard to finding them with a Google search.

    hehe, I'm on Facebook, but I only log on like 3-4 times a year. Phoenix Rising and an anime site I use which are pretty much my Facebook.
     
  4. Lotus97

    Lotus97 Senior Member

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    I should say up front that Rich did decide to go with the Neurological Health Formula (Holistic Health, Inc.) instead of the Thorne multi so if anyone is planning on following Rich's protocol exactly then that's what you should go with.

    That said, Thorne actually makes another multi that might work for those looking for an affordable multi-vitamin with very low doses of methylfolate, folinic acid/calcium folate, methylcobalamin, and adenosylcobalamin/dibencozide and without folic acid.
    http://www.iherb.com/Thorne-Research-Children-s-Basic-Nutrients-180-Veggie-Caps/18435

    This reason I suggest this is because many people here (including Dan and myself) are very sensitive to methylation and it would be a good idea to start slow. The components for methylation build up in your system over the course of days and weeks so if you start at a high dose you might feel fine for a few days or even a week or two, but then you'll start overmethylating and it might take a couple of days or even weeks before things settle down. Even the 200 mcg folinic acid + 200 mcg methylfolate dosage that Rich recommends might be too much for some people. Although the Neurological Health Formula that Rich recommneds has some things that Thorne's multi doesn't, Thorne's is cheaper, doesn't contain Folic Acid, and does contain active B vitamins along with some non-active B vitamins. Keep in mind the values listed in the product description are for 6 capsules which is a good thing because they can be spaced throughout the day and there's also some evidence that the absorption rate of B vitamins increases for lower doses of B vitamins taken orally. Also, it allows people to start out with a very low dose of active folate (one capsule) that can be built up to 6 capsules if tolerated. The recommended daily dose of 6 capsules would provide exactly the amount of methylfolate and folinic acid that Rich recommends (200 of each). In addition to the non-active B-vitamins included in this multi (I'm not listing them there, but you can check the product description for the amount of those), the amount of active B vitamins in one capsule are as follows:

    Vitamin B2 (as Riboflavin 5'-Phosphate [R5P]) - 0.55 mg
    Vitamin B6 (as Pyridoxal 5'-Phosphate [P5P]) - 0.5 mg
    Folate (33.3 mcg as Calcium Folinate and 33.3 mcg as L-5-Methyl-tetrahydrofolic Acid, Glucosamine Salt)
    Vitamin B12 (11.25 mcg as Adenosylcobalamin and 11.25 mcg as Methylcobalamin)
     
  5. dbkita

    dbkita Senior Member

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    I not sure I understand why the focus on alpha-keto-glutarate. It is not made in the trans-sulfuration cycle. It a very important part of the Krebs cycle and is the result of deamination of glutamate. The only way alpha-keto-glutarate piles up in the cell (to my knowledge) is if the Krebs cycle is blocked before transforming into succinic acid and yes then some of the excess AKG would convert to glutamate which is excitatory but such conversion has nothing to do with the CBS pathway.

    Also converting alpha-keto-glutarate to glutamate locks up one free ammonia. Just like conversion of glutamate to glutamine locks up another free ammonia. One cannot simply view reactions individually, they are all in chemical equilibrium and most are reversible provided co-factors exist for each enzyme in charge of a particular reaction direction. If pile-ups happen it is because something is imbalanced, not because something like AKG is being made as part of the Krebs cycle.

    If you had that sort of reaction to fish sauce (btw no MSG right? since that is a very different thing than simple glutamate), then you probably have a leaky blood brain barrier and I am sorry since that can lead to all sort of brain inflammatory problems and neurotransmitter imbalances. The reason I bring this up is MSG is BBB penetrable, glutamate (and GABA) normally are not.

    Provided there is no heavy inflammation in the CNS or other liabilities (e.g. metals), 7 mg of p5p while maybe not optimal is more than enough to prevent a deficit in the glutamic acid decarboxylase (GAD) reaction to make GABA. I have SPS (meaning a rare autoimmune disorder where antibodies attack my GAD enzymes) and a quality sub-lingual P5p of say 12.5-25 mg is plenty assuming I keep it there for awhile in the mouth).

    On the other hand 8 mg is a lot of methylfolate. Did you mean 8 mcg perchance? Because if you are taking 8 mg there is a very possible glutamate source imo. High levels of methyfolate (especially with low doses of B12) will drive THF like gangbusters to process histidine into oxo-glutarate(?) instead of histamine and eventually glutamate. That is one of the classic symptoms of over methylation in addition to over-excessive norepinephrine production (also very excitatory). Sadly many people on these forums assume they are detox or start-up effects and keep paying a heavy price.

    You are right it doesn't explain how ammonia/sulfur turn into glutamate. And yes AKG can turn into glutamate ... but so can other things, like say for example glutamine.

    I don't see a direct connection to the CBS pathway especially for hetero-zygotes where up-regulation is not that large.
    The stated logic of Dr Yasko is simply wrong in this regards. AKG is not made in the trans-sulfuration pathway. Somehow the error has propagated and hung around for far too long. Something Rich Vank also posted on in these forums.

    If there is a connection it is very indirect and would also likely impact many other variables such as other neurotransmitters or hormone production, cytokine signaling, liver efficiency, etc. Again you want AKG turning into glutamate and then glutamate into glutamine if you have high ammonia which CBS sufferers have in spades.

    Yes glutamate is excitatory. It is your main excitatory neurotransmitter in the brain. It is needed for focus, memory, thought, nerve impulses, etc. not to mention many other things most of them overwhelmingly positive. For sure, when out of balance, glutamate can cause problems in the CNS especially with the NMDA glutamate receptors.

    But imbalances in dopamine and serotonin also cause problems (bipolar for example). GABA relaxes you but too much also inhibits all other neurotransmitters and makes you feel depressed or like a vegetable (think of all those people on Valium over the decades). Too much acetyl-choline can cause hideous pain patterns, sensory overload, and even psychoses.

    But one neurotransmitter, that should only be high if someone is under stress, is the fight or flight neurotransmitter norepinephrine. That neurotransmitter should only be made adaptively produced on the fly based on the bodies needs (like kicking your heart rate up slightly when you get up from a chair to an erect position, or reacting to a potential threat, or revving up when you are excited, etc.). If it is chronic then all bets are off and it also certainly means one or more of the other aforementioned neurotransmitters 'chains' of the NE beast along with key hormones) are broken or too low.
     
  6. dbkita

    dbkita Senior Member

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    From the abstract the benefit of NAC is as an anti-oxidant, right? But I think it is a little more sophisticated.
    The AKG converts to glutamate eating ammonia. Then the glutamate is coupled with cysteine (NAC makes it accessible in the brain) as part of making glutathione and then the glutathione is helpful on its own. Unfortunately this is done in rodents, so I would be a little cautious especially for those with CBS defects since I am not sure there is a guarantee the glutathione is made. That being said it is interesting.

    Oh and to answer your other question about glutamine synthetase, yes it needs ATP (like many other enzymes).
    But the other co-factors are biotin, Mn, and Mg (not sure).

    http://www.uniprot.org/uniprot/P15104
    http://www.rcsb.org/pdb/101/motm.do?momID=30

    Having trouble confirming the biotin elsewhere, suspect it is hypothesized by homology modeling to one or more biotin regulated enzymes.

    Rich Vank spoke about this another post:

    "Excitotoxicity seems to be a complex phenomenon. Lowering the intake of foods high in glutamate is one thing that can be done. Taking supplements that calm the NMDA receptors is another, and Amy Yasko has given lists of them. I've suggested that L-cystine (not L-cysteine) might raise glutathione in the brain, and help with this (but not if there is a high mercury body burden, because it can move mercury into the brain). Another possibility would be supplementing manganese, if it is low, because it supports glutamine synthetase, which converts glutamate to glutamine. I don't think it's a good idea to try to "push through" excitotoxicity, because it may be killing neurons."

    Hope that helps.
     
  7. caledonia

    caledonia

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    Lol - yes - 8mcg NOT 8mg.

    So you're proposing that instead of some connection to glutamate, there is a connection to norepinephrine causing the exitotoxicity feeling?

    I think I'm going to take the easy way out and simply pose this question over at Yasko's forum and see if I can get her to take another look at this. I'll make a post here if I get an answer.
     
  8. caledonia

    caledonia

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    I just found something on Yasko's forum. Here is a page with an updated pathway diagram (#7). http://www.ch3nutrigenomics.com/phpBB2/viewtopic.php?t=314

    In this diagram, AKG has been corrected to show AKB instead. There is a linkup to cortisol. So I guess you could say it's more of a fight or flight response rather than excitotoxicity. (Or are those considered to be one and the same?)

    A quote at that point in the diagram says: "When the need is for energy and not for cysteine, homocysteine is metabolized to AKB, NH3 and H2S."
     

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  9. caledonia

    caledonia

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    Okay, I think I have it.

    Here is a quote from Heartfixer: 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”). "

    We now know that there is no AKG, and therefore no excitoxicity coming through the transsulfuration pathway. However, there is still the cortisol (fight or flight response) coming from the excess sulfur. So that is where the "excitoxicity" feeling is coming from.

    This should now more properly be called the "CBS fight or flight response" or the "CBS cortisol response".

    There may also be glutamate excitotoxicity going on, but that is due to lack of B6 which causes it not to be converted to GABA; it's not coming from the transsulfuration process.
     
  10. dbkita

    dbkita Senior Member

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    I am glad the diagram is corrected. If you see my earlier post the exact sequence of reactions is laid out.

    I guess their assumption is cysteine turns into AKB + ammonia + H2S instead of glutathione and taurine. That seems plausible but I have not seen a direct source that supports that uet.

    Fight of flight response and excitoxicity are not the same things at all. Fight or flight is by definition catecholamines and specifically norepinephrine and epinephrine. It can also result from low cortisol or low other hormones but that simply since they pave the way for the norepinephrine generated by the sympathetic nervous system (not simply the adrenal glands).

    But where is the link to cortisol down-regulation? Increased cortisol signaling does the reverse and corrals fight or flight.
     
  11. adreno

    adreno 3% neanderthal

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    Yeah, in theory NAC and AKG could have a nice synergistic effect in balancing the ammonia and glutamate. Rodent studies yes, but to my knowledge neurons (and glial cells) work very similarly in rodents and humans, whereas some other biological systems do not.

    I've added 1g AKG in the morning. So far, not much of difference. On the other hand biotin had a huge effect on me, so maybe now my glutamine synthetase in running ok...
     
  12. dbkita

    dbkita Senior Member

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    I think AKG is blood brain penetrable but I am not sure (my memory is not what it used to be sadly). It would have to be to have any benefit for the ammonia in the brain.

    What were the doses in the article you linked? 1 gram of AKG seems very small to actually turnover much in the way of ammonia. I think giving the synthetase enzyme what it needs is a more effective way to handle things.

    Neurons and glial cells may be similar but the pharmacokinetics for a substance can be very different.

    One thing to make sure of is that you are not manganese depleted. Not sure best way to do that precisely. Doubtful I suppose if you eat nuts for example.
     
  13. dbkita

    dbkita Senior Member

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    Yeah I have read that paragraph (I like the heartfixer site, nicely put together).

    I just wish I knew exactly how sulfites and sulfates create a stress / cortisol "fight or flight" response. I mean sulfites are toxic so yeah they can do cellular damage and need to be processed into useful sulfates by SUOX. Sulfites I can see but why sulfates unless at really high levels?

    There is no way I can see someone (regardless of CBS mutation) who has a urine 24 hour sulfate load well within normal (let's say do to diet changes, etc.) that will have a problem with sulfates causing severe stress reaction (sulfates are essential to life) with the one exception: that would be sulfate reducing bacteria which lead to H2S in the gut and we are right back at H2S again.

    Here is a link from the Mayo Clinic about the fight / flight response:

    http://www.mayoclinic.com/health/stress/SR00001

    Remember noradrenaline and adrenaline are surrogate names for norepinephrine (NE) and epinephrine.

    By definition when you are subjected to stress your body releases norepinephrine and epinephrine but also cortisol to deal with the damage possibly posed by those two. Low cortisol leads you right open to a world of hurt when the fight - flight response takes off.

    Anyways if we accept that sulfites / excessive sulfates can trigger fight / flight and especially if a person's adrenal are "burned out" and can't support the bad effects then we are again talking about NE not glutamate.

    There is a simple way to tell. What are your cardiovascular symptoms like? The NE signature is fairly different from glutamate in terms of how it hits the heart.
     
  14. adreno

    adreno 3% neanderthal

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    I did not look at the study. Just taking one tab of this:
    http://www.iherb.com/Source-Naturals-K-Mag-KG-1185-mg-60-Tablets/1313

    I wasn't depleted on mineral test, but somewhat low. I can't eat nuts (allergies) so I probably need to supplement some. 2.5 - 5mg should be enough, I reckon.
     
  15. dannybex

    dannybex Senior Member

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    That does sound like a decent possibility Lotus, thanks for posting that. I wish they would make a children's 'b', without the other stuff...but like you say, if one takes less than the six capsules per day, one can regulate the amount of any of the nutrients.

    I'm trying to limit my beta-carotene (and other carotenes I suppose) after probably getting way too much over the past 4-5 years -- basically eating carrots and/or sweet potatoes almost every day, a I was avoiding regular potatoes and other nightshades.

    Getting excessive amounts of carotenes, may have helped deplete my zinc (zinc is needed to convert carotene into vitamin A), and also excess carotenes can build up if thyroid function is slowing down...

    Thanks again!

    d.
     
  16. Lotus97

    Lotus97 Senior Member

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    You can just take 1/3 of a capsule of this B-complex.
    http://www.iherb.com/Thorne-Research-B-Complex-5-60-Veggie-Caps/18132
     
  17. dbkita

    dbkita Senior Member

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    If you tested low I would start with 5 mg for a while and see how it goes. I get about 3-5 mgs per day in my diet depending on absorption efficiency so 5 is probably reasonable to supplement. Eventually you may be ok with 2.5 but that only be if your test results normalized in parallel. Some people take really high doses thinking it will aid joint health but that can have some negative ramification too, like that article I linked before regarding glutamate release and less GABA in animal testing.
     
  18. Lotus97

    Lotus97 Senior Member

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    That looks like a good supplement, but I'm already stocked up on Potassium, Magnesium, and AKG right now so I just added it to my iHerb wishlist. Do you take that with a meal like the instructions say? I'm asking because I've been reading not to take potassium tablets because they can cause damage, but is that with all types of potassium?

    Manganese is in whole grains like oat bran and brown rice. Or are you on the caveman Paleo diet? I couldn't tell because of your avatar...

    I've been wondering what to supplement in terms of minerals because I haven't had any tests and I doubt my doctor will be willing to have me tested although my HCB and HCT were low so that means I'm low in iron? I was reading something about taking B2 causes the liver to release iron, but taking manganese blocks that. I was taking relatively high amounts of manganese, zinc, and molybdenum and no copper except for what I get from my diet because I thought I might have copper toxicity. I am getting a decent amount of manganese from my diet though so I should probably cut back on my manganese. Molybdenum seems important for a lot of things so I'll probably keep taking high doses of that.
     
  19. adreno

    adreno 3% neanderthal

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    I take it with breakfast. I believe the scaremongering about potassium is overblown. I think it is mostly the chloride that can be hard on the GI tract.

    Lol yeah, I try to follow a paleo diet, but I do not some carbs to function. At the moment my choices are mostly brown rice, quinoa, sweet potatoes and some fruit. So it looks like a do get some manganese from my food.
     
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  20. Symptomatic

    Symptomatic Senior Member

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    caledonia

    Thanks for posting the updated Yasko sheet, I'm not a member of her site and couldn't follow the link, so the .pdf you posted was very helpful.
     

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