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TMG makes me very depressed why?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by wiltedflower77, Jun 23, 2016.

  1. wiltedflower77

    wiltedflower77

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    Hi everyone, I'm pretty new to posting but been following threads and info on here for ages now. Just wondered if any of you clever science Boffs out there might be able to help me? I'm totally confused as usual but am desperate to try and gain some understanding into what's going on in my brain and body. These are my main SNPs

    MAO rs6323 +/+
    MTHFR c677T +/-
    MTRR A66G +/-
    CBS A360A +/-
    VDR Bsm +/+
    SOD2 A16V +/-

    Supplements I take every day -
    Multi b (without b12)
    Vitamin C/D
    B2 fmn
    Multi minerals and extra zinc
    Coq10
    Turmeric
    DHEA 5mg

    On my Doctors Data methylation profile my methylation was apparently 'normal' but every now and then (about every 2 weeks)when I take about 200mcg methylfolate I start to feel better mentally and physically within 2 hours. This also happens when I occasionally take sam-e 200mg but sam-e also makes me feel more relaxed than methylfolate. Inositol powder also helps my mood but can't take it much as it gives me a dodgy stomach.

    Last week and at other times I tried taking about 200mg TMG powder in the morning. By day 2 I am severely depressed, suicidal, very tearful, and angry. The next day after stopping it I feel better mentally. I just don't understand what's happening?? I would be so grateful for anyone's advice. NAC also seems to make me low but not to same extent. I have suffered from anxiety and low mood for many years prior to CFS but it's all got alot worse since then. Anti depressants don't help anymore.
    Thankyou

    Annie ☺
     
  2. dannybex

    dannybex Senior Member

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    RIch told me years ago that 'too much TMG (betaine) could interfere with parts of the methylation cycle:

    " The betaine will stimulate the alternative BHMT pathway in the liver and kidneys, and that may make it difficult to lift the partial block in the methionine synthase pathway, which is linked to the folate metabolism, and which needs to be operating normally to bring glutathione up and also get the folate metabolism back to normal. So if you don't notice much change after being on the simplified treatment approach for a couple of months or so, then you could consider adding some DMG (dimethylglycine), which will slow down the BHMT pathway and hopefully shift more of the flow to the methionine synthase pathway. I think this has to be done by trial and error, because different people may respond differently, based on genetics."
     
  3. Critterina

    Critterina Senior Member

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    This totally makes no sense to me. Why would you prefer one pathway to the other for methionine formation? That "hopefully" shift more flow to the pathway that uses B12 seems like "wishful thinking". BTW, I am +/+ for both MTRR and BHMT-08 and for me, DMG is awful.
     
  4. dannybex

    dannybex Senior Member

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    They're both beneficial though, I think. All about balance.

    In my case, I was taking high doses of betaine HCL for low stomach acid, so that's why I asked him if this would affect methylation. Since I thought I needed that much in order to digest anything, I kept it up for years -- it's just been in the last 3-4-5 months that I've finally backed off to about 1/3rd of what I was taking and my digestion isn't worse. It isn't better either, but am trying to address that in other areas.

    TMG was one of the components in Jill Jame's study w/autistic kids that showed a significant improvement. It also helps lower s-adenosylhomocysteine (SAH).
     
  5. Hip

    Hip Senior Member

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    I also experience significant depression when taking TMG (tri-methyl-glycine), betaine or SAMe (S-adenosyl-methionine).

    I found a possible explanation for this, which I posted here: basically TMG, betaine or SAMe increase the interferon alpha response, and interferon can cause depression.

    This is unfortunate, because interferon alpha induces intracellular antiviral effects that may be useful and important in ME/CFS for clearing out viral infections from cells.
     
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  6. wiltedflower77

    wiltedflower77

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    Thanks for all your replies. My brains not too good with all the biochemistry stuff so find it difficult to understand. I don't get why Sam-e really helps just after one dose. But TMG which makes Sam-e makes me very depressed after one or two doses. :vomit:
     
  7. MacGyver

    MacGyver

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    I have the exact same problem, in fact I'm just coming out of a week-long Phosphatidylcholine, TMG and possibly Betaine HCL induced depressed week where I go into complete freak-out and tunnel vision mode and seem to lose enough of my brainpower to no longer be able to see the very obvious, heh. Doesn't help that the amount of pain I then experience goes up to nearly unbearable proportions (low dopamine!).

    I share a bit of the same SNPs (MAO A, MTRR, CBS, SOD2 but not MTHFR) but I don't know how important that is, I like to be guided by responses in the first place over theoretical stuff although we need theory to figure stuff like this out of course.

    What I understand so far (which is common knowledge around here but still, want to spell this out so we can crack this and if anyone spots something wrong, please do correct me):
    1. Phosphatidylcholine becomes TMG after oxidation
    2. TMG is Glycine with three methyl groups attached
    3. TMG 'stimulates' the BHMT pathway which is the 'backup' or 'short' route to recycle Homocysteine into Methione
    4. Betaine HCL is TMG with HCL attached so will contribute to the TMG-'pool'
    5. Taking TMG will spare (and thus increase) Choline since less Phosphatidylcholine needs to be oxidized into TMG
    Stuff that I've gathered over the past months that is less clear to me or from less reliable sources:
    1. Taking TMG raises Carnitine levels
    2. Taking TMG raises the need for Methylfolate
    3. Increasing BHMT pathway activity lowers the amount of homocysteine available for the 'main' or 'long' route to recycle homocysteine to methionine via methionine synthase (MTR) and methionine synthase reductase (MTRR).
    *Insert commercial break*

    Pondering about this I've reviewed my documentation which pointed me to this pubmed article: http://www.ncbi.nlm.nih.gov/pubmed/6115113
    And this has me intrigued: "5-methyl-THF, the form in which almost all folate is transported in human plasma, must react with intracellular homocysteine before it can be retained by the cell as a polyglutamate. Since homocysteine is derived entirely from methionine, methionine deficiency will cause intracellular folate deficiency, and the rate of mitosis of rapidly dividing cells will be reduced"

    Thus by taking anything that stimulates the BHMT pathway we in effect create a Folate deficiency on a cellular level. It doesn't matter how much Methylfolate (or Methylcobalamin) you take at that (/a certain) point since that's not the main issue, it's a lack of Homocysteine (/Methionine) that causes the issue!
    So that means Homocysteine isn't just a waste product but a necessary part of proper Folate metabolism!?! You mean Homocysteine isn't the boogie man I thought it was?!? Awww :( ;)

    In hindsight this is just what the whole methylation cycle does but it's obvious it wasn't clear to me how it worked exactly! In my mind Homocysteine was just the thing being recycled by Methylfolate and Methylcobalamin, not contributing to Folate metabolism itself!

    So that would mean anything that increases Homocysteine would help here which means:
    1. Taking Methionine
    2. Taking things that spare Methionine:
      1. Cysteine (might increase urea excretion so not the best idea initially) (hello NAC btw, although that would contradict your experience, maybe exactly because it increases the urea burden EDIT: NAC lowers homocysteine, see my post below)
      2. Carnitine which is methionine + lysine
    3. Taking SAMe
    4. Taking things that spare SAMe:
      1. Creatine
    5. Increasing absorption of Methionine from food via a properly working digestive system:
      1. Digestive enzymes to break down protein
      2. Stimulate bile so endogenous enzymes are released
      3. Increasing stomach acid if low since bile is released in response to correct acidity of food
      4. SAMe is know to increase bile...
    6. Eating a protein rich diet, preferably meat
    7. Making the CBS pathway function normally since it otherwise might be a drain on homocysteine as well
    One other thing that I think (hope) is related to this is that I have issues taking Magnesium and Carnitine (Fumarate). I've had great results with Boron and Manganese (and Calcium) and then being able to take Magnesium but I can never sustain it. After a while I have to stop taking it as it causes increased pain and depression and/or just a general crash of everything. Maybe Boron, Manganese and Calcium were just increasing my need for Magnesium and thus reducing availability of it for other processes. Hmm.
    Now I'm wondering if Magnesium is such an issue because it is increasing ATP production and then leading to a Methionine deficiency because that is what is used to convert Methionine into SAMe? Or it's because of an overall increase in metabolism.
    Not sure why Carnitine would be such a problem at the moment, maybe because it would spare TMG and thus in effect increase available TMG for the BHMT pathway? Unsure of TMG - Carnitine connection though.

    I guess I'll find out when I try it all! Something tells me I'll finally experience hypokalemia symptoms which I haven't with taking Methylfolate, Methylcobalamin, Adenosylcobalamin or Carnitine.

    So to summarize: TMG induces a Homocysteine deficiency and thus induces a Folate deficiency when there is insufficient Homocysteine(/Methionine) to feed both pathways which leads to several issues like depression and, you know, basically everything we're trying to solve with methylation!?!

    I know this has been mentioned and done before (trying Methionine etc.) but I've never seen it's relation to TMG spelled out like I did above.

    I've got some SAMe on the way, as well as several amino acids including Methionine as wel as digestive aids. I guess some part of me was still functioning when I ordered it all last week ;)

    But as always; the proof is in the pudding!
     
    Last edited: Jul 26, 2016
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  8. MacGyver

    MacGyver

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    Some more insights that seem to confirm my conclusions in the post above:
    1. NAC lowers Homocysteine levels (will have to dig a bit deeper to see exactly how; so far I found a few references to NAC displacing Homocysteine on its carrier protein) so it has the same effect as TMG in this case. That's two things that point in the same direction and confirm your experience @wiltedflower77!
    2. Several people have noticed that if they experience jitteryness when taking Carnitine, they can reduce the effect by taking TMG. My guess at this time is that the jitteryness they experience is related to the 'long' pathway of recycling Homocysteine and thus sufficient intracellular Methylfolate and by taking TMG they steel Homocysteine from that pathway thereby reducing some of the 'long' pathways effect and thus less uptake of Methylfolate inside cells. In other words the effect of Carnitine is dependent on sufficient Methylfolate inside cells (the answer why is probably somewhere on these boards, more sleuthing required :))
    3. TMG raises the need for Methylfolate in case there is sufficient Homocysteine (/Methionine) since more Homocysteine will be recycled back to Methionine and back to Homocysteine and thus be available for Methylfolate uptake inside cells. Which will lower plasma Methylfolate levels.

    This really explains a lot of unanswered questions!
     
    Last edited: Jul 26, 2016
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  9. Lilmaz

    Lilmaz

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    This is really interesting. I tried TMG for first time yesterday, just a pinch, but ended up very depressed, OCD-like and hesitant with feeling in an awful bubble but different to the brain fog I experience with high ammonia.

    I'm told I'm UM so I'm confused why this reaction. I thought OCD was an UM symptom so requires more mb12 not folate. However, on my current regime I get the acne type lesions in my hairline and around my neck, I think it's related to low folate to mb12 ratio.
    I wanted to try TMG as an alternative to SAMe. I also have poor reactions to SSRIs (worse depression but not OCD). I was also very, very cold which is one of my hypokalemia flags.

    I have SNPs in A1298c, MTR++, MTRR++, MAOA++, both CBS, BHMT, SOD2.
     
  10. MacGyver

    MacGyver

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    Excuse my ignorance but what is UM @Lilmaz?

    I recognize the OCD thing I think, it's not the typical close-the-door-three-times you mean but more being stuck on something/thoughts and not being able to stop, no?

    Well under my current understanding TMG would have caused a Homocysteine deficiency and then a Methylfolate deficiency. But taking more folate wouldn't do anything since it's the transport of folate inside cells that is an issue, not the amount of available folate.
    By taking TMG all available homocysteine was funnelled away from folate metabolism which means you'll start getting folate deficiency symptoms. The solutions I currently see are what I mentioned above, all with the purpose of increasing available Homocysteine so Methylfolate can continue to be absorbed. There's going to be a certain point where TMG becomes beneficial instead of harming. The pool of SAMe just needs to be increased up to a point where both pathways can hum along I think.

    The order I see now that one would approach mending the methylation cycle is as follows:
    1. Take Methylcobalamin, this seems the safe starting point
    2. Take Riboflavin or FMN to recycle available Methylfolate (talking saturation here, not 25mg a day)
    3. In case ammonia is a problem I think it would manifest here already, look into ammonia support*
    4. Take B6 or P5P to recycle available Methylfolate
    5. Take Methylfolate to increase available folate
    6. Possibly take Creatine to increase available SAMe and thus Homocysteine
    7. Take Methionine and/or SAMe to increase available Homocysteine
    8. I can imagine ammonia manifesting itself here in increased amounts or for the first time, look into ammonia support if needed*
    9. Take Phosphatidylcholine and/or TMG to increase recycling of SAMe
    10. In case Phosphatidylcholine/TMG are still an issue more Homocysteine is required via step 7
    11. At any of the steps (more) Methyfolate/Methylcobalamin might be required but having B2 and B6 in place first will temper that requirement I think but anything is possible.
    * Bit fuzzy on ammonia support still since I'm pretty sure I haven't encountered it yet, I guess Ornithine, alpha ketoglutaric acid, yucca etc. would do it.

    Besides taking Methionine supplements it also makes sense to support absorption from food, maybe even starting there, but as mentioned previously Betaine HCL contributes to the TMG pool so can only be used after TMG becomes beneficial.

    Where Adenosylcobalamin and Carnitine fit in I don't know yet. All I know is I can't take either TMG or Carnitine at this point. I know both (Adenosylcobalamin and Carnitine) are involved in energy production in the mitochondria. Carnitine having to do with fatty acid transport inside the mitochondria.

    I'll have to take a look at the relation of the Krebs cycle, Carnitine, Adenosylcobalamin and the mitochondria to increase my understanding.
     
  11. Lilmaz

    Lilmaz

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    Sorry UM - undermethylated.

    Ammonia definately a problem for me, seems to be one of my primary issues. Reluctant to try yucca due to its hormonal properties but lactulose syrup helps.

    Started Carnitine (ALCAR) with good response.

    My ND wanted to move to SAMe but I was suspicious it'd go bad so wanted try TMG first.

    The 'OCD' feeling was more like repetitive checking (not locks etc but I was sure I hadn't got my APA formatting right on an assignment, went over & over it lol) and also general indecision, lack of feeling competent.

    But stumped where to from here or if I just write off TMG.

    Also have mb12 4000mcg/adb12 1000mcg, 1.25mg lithium orotate, & seeking health b complex plus that supplies 20mg riboflavin, 20mg P5P, 400mcg mfolate among others. I did not increase the b2 as I thought it increased MAOA activity and could cause depression. Also take the other basic support indicated by @Freddd like C, E zinc, omegas. Was good on this regime few months ago but not now!
     
    Last edited: Jul 26, 2016
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  12. MacGyver

    MacGyver

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    @Lilmaz How do the ammonia problems manifest? (this is for my own selfless understanding here :))

    Didn't know about yucca hormonal properties. Thanks!
    What things have you tried (with and without success) regarding ammonia?
    Do you have gut issues?

    What's the good response to ALCAR you get? I'm assuming you're getting benefit from it instead of nothing or feeling worse. Freddd has mentioned it several times that most people tolerate either ALCAR or Carnitine Fumarate but rarely both. That's something I need to look into, specifically their functional difference.
    Maybe I need to try some ALCAR as well. Hmm.

    Well I think in your case I'd try some SAMe. But slooooowly. That should increase the available pool of Homocysteine which in turn should result in an increased uptake and highly likely an increased need for Methylfolate (and Methylcobalamin).

    Well don't write off the TMG, it's not because of your (and my) bad response to it that TMG itself is bad, it isn't. In fact it's a good way to 'measure' if you've got sufficient Homocysteine and thus Methionine/SAMe in your body. That said I'd hold off on it until you've tried increasing all the other things like SAMe and Methionine and got the 'long' pathway humming along. After that TMG should improve our health.

    Maybe I need to spell it out again more differently and hopefully more clearly:
    The most import and primary goal is getting sufficient Methylfolate inside cells. For that we need sufficient Homocysteine. But, taking TMG will lower Homocysteine available for Methylfolate absorption.
    I know it's a bit counterintuitive but it makes perfect sense...to me...now...after a year :)!
    Taking TMG is very good to increase SAMe, our secondary goal, but at the expense of getting Methylfolate inside cells IF there is insufficient Methionine available. So that needs to be resolved first.

    Regarding B2; taking it will actually 'normalize' MAO A functionality so your mood should become more stable. For me it just makes me happy :) I'd recommend you try FMN as well though again, start slooowly with it since that form is a lot more potent than regular B2, which is good but can induce/expose other deficiencies more heavily.

    20mg B2 in a B complex won't yield the effect you're after, you'll need more than that to feel the mental effects. Try separate doses of max 25mg each to test that out.

    Also, if you feel worse with taking SAMe in terms of ammonia then that increased Homocysteine is being funneled into the CBS pathway. Though the body should prefer the other pathways. Having enough Methylcobalamin and Methylfolate available is a requirement for that so you might end up with some startup symptoms before you find the right balance.

    I've been taking some ammino acids (Now foods 9 essential aminos) and I do feel an improvement though I'm taking it slowly. Will have Methionine separately and SAMe today.
     
    Last edited: Jul 27, 2016
  13. MacGyver

    MacGyver

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    Took some SAMe (Now Foods 100mg) and I got the exact same response to it as with the 9 aminos: a relaxed feeling. Mood is slightly better as well. The noticeable effect tapers off pretty quickly but hours later there is still a more relaxed feeling overal than 'normal'. That is with the 9 amino's, pretty sure the SAMe will yield the same effect but since I'm now taking both I won't be able to separate longer term effects like that.
    Will be testing some extra Methionine away from everything else tomorrow.

    Also, it dawned on me that taking magnesium very likely results in an increased need for SAMe. Need to look into this but it would explain my problems with it. So again magnesium would be causing a 'drain' of SAMe and thus Homocysteine. But that would only be the case if the SAMe is used but can't be recycled. Or it might be tied up elsewhere for a while. Hmm.
     
  14. MacGyver

    MacGyver

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    Well, I did some more research on the Homocysteine depletion theory I posted before and its impact on folate metabolism and it looks like what I said is exactly what is happening! In fact this is the methyl-trap @Freddd has been talking about all along but it happens for another reason that nobody seems to have been paying attention to or made the link with TMG as far as I can tell.

    The common thinking here is that the methyl-trap can only happen because of insufficient Methylcobalamin. But in our case it happens because of insufficient Homocysteine!

    The main metabolite in the folate cycle is THF or Tetrahydrofolate.
    This is used in several pathways of which we all know the effects of a deficiency of.
    One of these is that THF is eventually (via 5,10 Methylenetetrahydrofolate) converted into Methylfolate.
    Then Methylfolate is used to create Methylcobalamin (from a protein bonded form) and at the same time AND together with Methylcobalamin converts Homocysteine back to Methionine.
    In this process Methylfolate is converted back to THF. (and Methylcobalamin back to another protein bonded cobalamin form). Key here is that Methylfolate doesn't just create Methylcobalamin but is involved in the conversion of Homocysteine to Methionine together with the Methylcobalamin it creates. It's both or none.

    The caveat here is that Methylfolate can ONLY be used for this pathway. It has NO OTHER purpose in folate metabolism.

    So what happens when there is insufficient Homocysteine?
    THF keeps being converted into Methylfolate but it (Methylfolate) can't be used since, even if there is sufficient (Methyl)cobalamin it can NOT be converted back to THF since Homocysteine is a required COFACTOR of this process. In this way THF becomes 'trapped' as Methylfolate since it has no other purposes in this form. Thus inducing a folate deficiency!

    Homocysteine is a COFACTOR to recycle Methylfolate into THF!

    And what happens when you take TMG or NAC? Exactly; they lower Homocysteine!
    And that leads to a deficiency of folate and thus a slowed down folate cycle and metabolism BUT ONLY when there is insufficient Methionine.

    This brings about another interesting thing: taking Folinic acid would help since it is converted into THF which would keep feeding the folate cycle. Taking more Methylfolate would do squat since that is what is already building up in excess. It's probably even excreted in high quantities at this point.
    Now I get Rich van K's insistence on using Folinic acid along with Methylfolate, although it would only be a bit of a band aid. But it doesn't sound like a bad idea to include it to make sure the folate cycle keeps going no matter what.

    Hmm, in theory taking TMG + Folinic acid would result in both cycles (folate and methylation) humming along nicely. Sounds more like a hack though.

    Whew! Like I said before: this is a huuuge eye opener for me!

    Oh yeah, one last thing: a human adult produces 6-8 grams of SAMe per day. Not sure if this includes recycling but I guess it would. Still, if taking 100mg of SAMe has a noticeable effect you know there's a big crater to fill!
     
    Last edited: Jul 27, 2016
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  15. aaron_c

    aaron_c Senior Member

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    Very interesting @MacGyver!

    Do you eat a low protein diet? I'm just trying to figure out why you would have low methionine. That seems like the most obvious hole to fill to me.
     
  16. Lilmaz

    Lilmaz

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    I certainly don't eat low protein. I feel quite weak if I don't eat meat and I have PCOS so I try to avoid spiking my insulin with a high carb diet. However, mb12 increases my appetite and cravings for carbs :(

    Quick question @MacGyver is there an FMN form b2 on iherb you can suggest? I live in NZ and find iherb best for shipping.
     
  17. MacGyver

    MacGyver

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    Nope, I like meat, but I wouldn't go so far as to say I eat tons of it. My apetite has been low for quite a while. I eat because I know I have to, not because I feel hungry. I think I just eat regularly like most 'healthy' people.
    Regularly have (canned) fish as well; sardines, tuna, mackerel, salmon. Vegetable wise: beans, chickpeas, peas.

    Not exactly low protein I think :)

    I think improving digestion is going to be the most important thing longterm for me.

    I don't think I'm draining it all via the CBS-ammonia pathway either, otherwise I should now be feeling worse instead of better with the amino's and SAMe I've taken. At least I'm assuming that.
    Will have to look and see if there are other Methionine/SAMe drains.
    EDIT: One of them is Glutathione of course!

    Source naturals Coenzyme B2 definitely works. I can vouch for it. It does have a very bitter taste to it but you get used to that after a few times. That's unavoidable since that comes from the FMN and not some filler/flavor.
     
    Last edited: Jul 27, 2016
  18. Lilmaz

    Lilmaz

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    I found with ALCAR that my cognition was sharper and more sustained during the day. However, I am considering the last few weeks critically and I have deteriorated. Whether that is simply due to stressful events or the ALCAR is draining a co-factor I am not sure. I think I should remove it, go back and increase methylfolate and try SAMe before adding it back in (and the FMN as you suggested). I am very foggy, low mood, achey, zero drive again at the moment. How I was before mb12.

    My ammonia symptoms - well my sulphur symptoms are similar however not as severe, they're brain fog and anxiety but quite quickly relieved by activated charcoal and lowering dietary sulphur and strictly avoiding sulphur preservatives and supplements.
    Ammonia starts with anxiety then proceeds to severe brain fog, anxiety/depression, body aches, vertigo, derealisation, difficulty stringing sentences together/word finding and pronounciation, feeling of impending seizure, unable to drive/walk around a store etc, despair really. It truly has been the most debilitating aspect of my ME/CFS.

    lactulose syrup is used for hepatic coma due to hyperammonia It is quite inexpensive and relatively benign as far as side effects. It reduces ammonia by a few mechanisms but centres in the gut.
     
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  19. alicec

    alicec Senior Member

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    This distorts the situation somewhat.

    Homocysteine is the substrate for methionine synthase (MTR). This reaction is the key to methyltrap and the metabolic consequences discussed in the paper you linked and in your analyses above.

    Homocysteine has no special role, it is simply the recipient of the methyl group transferred by the enzyme via its methylfolate (MeTHF) and B12 co-factors. In the process, methionine is produced and MeTHF is transformed into a form which can be used within the cell -THF.

    The enzyme is responsible for these transformations, homocysteine is just a passive recipient of a methyl group.

    As the paper you linked discusses, when this reaction is compromised, the cell prioritises its limited resources and directs folate back to the MTR reaction, suppressing other avenues for folate utilisation (eg nucleotide synthesis). At the extreme, when the MTR reaction comes to a virtual halt, the cell responds to the build up of MeTHF, which cannot be used because it cannot be transformed into THF, by expelling it from the cell. This is the methyltrap phenomenon that Freddd discusses.

    Anything that limits the MTR reaction will have these consequences. Lack of substrate (homocysteine) is just one possibility.

    This complicated enzyme has four binding domains, all of which must function correctly for it to carry out its function. Two are for the MeTHF and B12 cofactors already mentioned, a third is for homocysteine with zinc playing a critical role in the interaction, while the fourth site introduces an even further layer of complexity.

    This site mediates the interaction with another enzyme system (methionine synthase reductase, MTRR) which is required to ensure that the cobalt in the B12 cofactor remains in a reduced state. SAMe and a flavoprotein are required for this reaction.

    So problems with any of these many cofactors could compromise the enzyme, in addition to shortage of substrate.

    For the sake of completeness we should also consider a related source of problems, namely that THF generated by MTR cannot be recycled to MeTHF (via MTHFR) and so cannot fuel another cycle of MTR reactions.

    Some SNP combinations may make a contribution by altering protein structure of the enzymes. Except in very rare cases, this would be only a relatively small contribution - don't fall for Yasko's exaggerated and often erroneous claims - but for some people the contribution could be important.

    These are most of the direct influences that I can think of off the top of my head. Then there are indirect influences - eg nitrosative stress which inhibits MTR, compromised Kreb's cycle limiting ATP production and thus formation of SAMe from methionine - and so on.

    You are right of course that all the emphasis has been on high homocysteine and we shouldn't forget that low homocysteine has it's own set of problems. We just need to place homocysteine into its proper context. It is simply an indicator of how well or badly various intersecting metabolic pathways are proceeding. In itself, it doesn't do anything important, it simply acts as a stepping stone in the process of making things which do have consequences.
     
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  20. alicec

    alicec Senior Member

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    Australia
    I eat a high protein diet (including meat), don't have digestive problems and have low methionine - along with most other amino acids.

    Based on OAT and UAA tests, I believe that the source of my problem is that glycolysis and Kreb's cycle are stuffed and I'm burning amino acids as a major source of energy.

    In desperation I tried supplementation with essential amino acids. Yes it would be better to fix the blocked energy pathways but so far nothing I have tried has been successful. I thought this might be a helpful stop gap.

    It did work for a few weeks in that I had a bit of an energy boost and felt a little better - but this soon petered out and if anything I soon felt worse.

    I'll be interested to know how this goes with time.

    Unfortunately biological systems have this pesky habit of undergoing negative feedback inhibition.
     
    Valentijn and Gondwanaland like this.

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