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Why the increase in excitotoxity on the methylation block treatment?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Apr 8, 2010.

  1. richvank

    richvank Senior Member

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    Hi, all.

    I'd like to bounce something off you.

    As some of you know, when people start doing the methylation block treatment, many of them experience an increase in symptoms that appear to be associated with excitotoxicity ("wired" feeling, insomnia, anxiety, hypersensitivity to light, sound and touch). This is associated with more rapid firing of action potentials by neurons that incorporate NMDA receptors. I've wondered for a long time why this gets worse when a person starts to lift the partial methylation cycle block.

    O.K., here's what I suggest as the cause:

    When a person has a partial methylation cycle block, they experience draining of their sulfur metabolites excessively down the transsulfuration pathway, because homocysteine is not being recycled back to methionine as rapidly as normal. Over the course of time, this depletes methionine somewhat, and PWCs tend to be low in methionine.

    But even though this has occurred, there is still some draining down the transsulfuration pathway, and some of this serves to supply cysteine to make some glutathione. Glutathione is somewhat depleted, but some is still being made. If it weren't, the person would not survive.

    O.K., now consider what happens when the activity of methionine synthase is increased by raising the availability of methylcobalamin and 5-methyl THF to this enzyme. All of a sudden, more of the homocysteine is recycled back to methionine, and therefore, less is available to the transsulfuration pathway. I suggest that this results in temporarily lowering glutathione even further! Over time, this situation will improve, and we have observed in lab tests that glutathione does come up to normal over a period of some months, on the average. However, initially, I suspect that it goes down, worsening the glutathione depletion temporarily.

    Now here's how I think this impacts the excitotoxicity. Further glutathione depletion would increase the state of oxidative stress in the mitochondria of the neurons. This would intensify the partial blocks in the Krebs cycle and the respiratory chain, and that would further lower the rate of production of ATP. ATP is needed to power the membrane ion pumps in the neurons, and they normally maintain the electrical potential across the cell membranes.
    This potential in turn determines the firing threshold for action potentials (nerve impulses). When the potential is lowered, the neurons become more sensitive and fire more readily. Thus, this results in increased excitotoxicity.

    If this is actually what is going on, there may be some benefit to supporting the glutathione during treatment to lift the methylation cycle block, at least early on.

    I would be very interested to know what you think about the theoretical aspects of this, as well as whether any of you have experience in boosting glutathione more directly while lifting the methylation cycle block, and if so, whether it seems to have helped calm down the excitotoxicity.

    Thanks.

    Best regards,

    Rich
    Lotus97 likes this.
  2. Sunday

    Sunday Senior Member

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    Very interesting post, Rich. I think it would be real helpful to get a grip on the mechanism of these reactions, so people can determine whether it's a tough spot they should get through, or a too-big reaction they should step back the dosage for, or something that indicates they should stop the methylation protocol altogether, at least at that point (even though my own responses to methylation protocol have been partial, I still feel it's fundamental to this and possible many other neuro diseases).

    I need to ponder this and probably reread it a few times, but I'm going to think how this theory works (or doesn't) with my own experience. If I come up with anything coherent, I'll report back. I'll be interested to see what others say, too; there's certainly a lot of debate over this issue.
  3. dannybex

    dannybex Senior Member

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    Hi Rich,

    Thanks for posting this...very interesting as always. I was about to ask if excessive muscle twitching/spasms in PWC's might be related to taking 'too much' folate and/or b12 when I found this thread -- might this scenario possibly be an example of 'excitoxicity'? :confused:

    (I've been twitchy off and on for years, but really twitchy lately, especially below the knees. Overdid it big time about 3 days ago, so that's probably one of the main reasons, but also have been increasing my folate and b12 to come up to the ratio that Vinitsky has mentioned -- which means I've been taking more folate...about twice as much as a week ago.)

    When you suggest 'supporting' or 'boosting' glutathione, do you mean by undenatured whey products, or by taking individual aminos (glutamine, cysteine & glycine) to raise the levels?

    Also, maybe this is slightly off-topic, but I'm wondering if glycine itself has been found to be low in PWC's?

    It's my goofy-layman's understanding that glycine is a 'calming' amino acid, and has been successfully used in some excitotoxic conditions like OCD and ADHD. Plus, isn't it involved in liver detoxification as well? I'm just wondering if increasing the amount of glycine might help...?

    Many thanks in advance,

    Dan
  4. Dreambirdie

    Dreambirdie work in progress

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    Okay Rich, most of your theory is over my brain stupid head tonight, but I can tell you that I definitely have had issues with excitoxicity (new vocab word:cool:) whenever I tried adb12, even though Fredddd insisted that couldn't be possible.

    Now with the hydroxyb12 (perque), which I have dabbled with here and there, I notice my nervous system revving up even after 3 days on just 1/4 tablet. My thought was that the hydroxyb12 was causing the previously blocked pathways to begin to unblock, and thereby begin a detoxification of the many heavy metals in my system, and then the metals caused the excitoxicty.

    Whenever I get heavy metal detox symptoms, (like being on speed, heart racing/ skipping, mind in overdrive, etc), I do in fact up my dose of N-A-C to as high as 2000-3000 mg. It has been a LIFE saver! So I know that it is beneficial in relieving the excitoxicity.

    I know you've mentioned that this is a very high dose of N-A-C, but it always helps me feel better, so I don't doubt its effectiveness in those moments.
  5. xchocoholic

    xchocoholic Senior Member

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    Hi Rich,

    Please don't take this the wrong way but part of me wishes you had CFS/ME so that you could feel what we feel. You'd have a much better idea of how all this works if you could experiment on yourself. You're missing out on the all fun ... lol ...

    I'm still not up on all the terminology you use but here's my addition to this thread ...

    1/2 of a Metagenics Vessel Care (VC) sent me into a cleaning frizzy yesterday for at least 90 minutes straight and made my myoclonus and insomnia worse last night. Additional Theanine and 5HTP took care of my sleep issues though so I got plenty of sleep. I've been on VC off and on for over 6 months but I stopped VC because I've linked it to increased urinary symptoms. So this time, I took it with 2 AZO and some probiotics. So far so good on that front. No increased frequency of urination, burning, etc.

    I've noticed that VC helps me with energy off and on but nothing consistent.

    I took NOW brand 250 mg of glutathioine and drank alkaline water while I was working yesterday too in order to try to avoid PEM ... I'll let you know if it worked.

    I was thinking that these supplements can cause toxic reactions in some because of an inability to process B vitamins. Certain B vitamins have been linked to an increase in certain bacteria in the gut which can cause urinary symptoms. I've been taking AZO for UTI symptoms for a few months now and so far it's working. KOW... Taking it to avoid the complications I have with B vitamins is new so I'm now sure how well it's going to work.

    HTH ... Thanks for all you do for us ... Marcia
  6. serg1942

    serg1942 Senior Member

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    Hi Rich,

    Thank you so much for your input. As always, it is very useful for all of us.

    I am bouncing back to you! As you know I really had huge problems with excitotoxicity for nearly the whole year I was on the methylation supplements. Although I cannot be sure whether nebulized GSH helped me during that time, I know for sure that by taking Vit. C at intestinal (bowel tolerance) doses my neurotoxicity was amazingly reduced, shown by my ability to considerably lower the dose of clonazepam I was taking. So, given the fact that GSH is recycled by Vit C., (in this high dosing) maybe here is a connection, although, of course, the effect of Vit. C on its own as a “universal source” of electrons was a very important factor too.

    By reading your explanation of the reasons for developing excitotoxicity while on the methylation block cycle protocol, although it makes a lot of sense for me, it comes to my mind the perpetual question we have discussed many times: heavy metals; when we “feed” the MS enzyme we are allowing the body to produce more glutathione, more cysteine, and other necessary substances needed to form metallothioneins. In other words, we are allowing the body to synthesize all the substances needed to detoxify heavy metals and many other toxins.
    We all know, heavy metals produce neurotoxicty on their own--I think by affecting the balance of fatty acids on the cell membranes. Also, heavy metals are known to further block the enzymes you referred to in the Krebs cycle and on the respiratory chain of the mitochondria, thus producing more free radicals that in turn raise excitotoxicity even more.

    So, taking into account your proposed mechanism and my assertions above, my concern would be whether by taking more glutathione while on the methylation protocol we could be, indeed, augmenting the release of heavy metals, hence, increasing in turn excitotoxicity even more, creating in this manner a vicious cycle.

    What do you think about this? In your hypothesis, were you taking into account the effect of heavy metals?

    I am going to take advantage of this discussion to raise a question that you are aware of, but others reading this thread may not be: for myself and many others, taking LDN has been an invaluable tool for lowering excitotoxicity. I would very much like to hear from others who are trying both a version of the methylation protocol and LDN to know whether these two therapies together might be a good approach for reducing this very unpleasant, and sometimes limiting factor (excitotoxicity)--limiting in the sense that it determines whether you can tolerate the treatment to unblock the methylation cycle.

    Another related, and for me very important question, that this subject brings to mind, is whether it would be wise to take some chelator while on this protocol. The concern here would be whether by taking the chelator in question we would be excreting too high a level of heavy metals (thus worsening the situation), or, on the other hand, maybe we would be binding the heavy metals released by unblocking the methylation cycle, hence reducing the work of the liver and the rest of the detoxification system--therefore, diminishing the damage caused by these toxins.

    So, again, knowing that this is one of the perpetual quandaries, what would be your opinion here?

    Very best wishes,
    Sergio
  7. Dreambirdie

    Dreambirdie work in progress

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    Hi Sergio--thanks for asking these questions.

    Me too, Rich.... ?
  8. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Hi Rich,

    Thanks so much for opening these pesky questions again.

    My experience with supplementing glutathione in the early months of taking the methylation supplements is a bit atypical. I nebulized glutathione together with Hydrox B12 for several months and did find that this helped with my energy and ability to tolerate the supplements. After nebulizing for a while I started giving myself subcut injections of the two together. Again, my experience was good--I would immediately feel better. I also regularly took whey protein shakes.

    Then, after nearly one year on the methylation supplements, I began to be intolerant of both the injections and the nebulizing, and I have not tried again. On the other hand, before beginning the methylation protocol and before having taken the methylation panel from Vitamin Diagnostics (which confirmed that I had a methylation block and very low levels of reduced glutathione), I did well with fairly high doses of NAC--so I must have been supplementing glutathione through this.

    While I would not characterize my difficulties in following the methylation protocol as primarily excitotoxicity, this has certainly has been an ongoing problem. Just by guessing, I'd say that my difficulties were more from increased circulation of toxins which had been released through enhancing methylation. And, as a few others have mentioned, heavy metals come under suspicion when I mention toxins.

    This has been particularly evident to me as I have had brief intense bouts of these same symptoms after laser energetic detox treatments for heavy metals (brief being about 6 hours).

    My two cents!

    Sushi
  9. lostinthedesert

    lostinthedesert Killer, Clown, Priestess

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    GSH by neb or oral causes breathing trouble for me. NAC increases my fatigue. The thing that helps increased neuro symptoms when i use B12/folate is to increase dose/frequency of cholestyramine. Peace, S
  10. doveman

    doveman

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    I'd say I've had the symptoms you describe as excitotoxicity for a long time and I don't think they increased when I started MB12/Methyfolate/B-Right.

    When I started taking these last year, they actually gave me refreshing sleep and after about 6 hours sleep I was able to get up quite easily in the morning, which is completely unusual for me. Probably as a result of the quality sleep, I had more energy and was probably more relaxed and able to focus, so I'd say less excitotoxicity symptoms.

    When I added the AdB12, the next day I woke up feeling quite jolly, maybe euphoric, which lasted about half a day and again was quite unusual for me as I've been depressed for most of my life. I don't think I was manic though, I just felt that this was what I should feel like every day. Unfortunately, that was the only day that happened. I intend to experiment with higher doses of AdB12 soon to see if that makes it happen again.
  11. doveman

    doveman

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    Hi serg1942

    I know there's evidence that Vitamin C destroys B12 in the gut, but I'm not sure that's relevant if you were putting the B12 directly into your bloodstream with injections or sublinguals held in the mouth.

    Maybe the Vitamin C was destroying the B12 that the liver excretes into the bile, some of which is normally reabsorbed, and so reducing your B12 levels that way but I'm not sure if the evidence that Vitamin C destroys B12 in the gut supports that theory.
  12. serg1942

    serg1942 Senior Member

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    Hi Doveman,

    So you know evidence for the vitamin C destroying B12??? Would you mind to share it with me? I would like to read it!

    Anyway, like you point out, B12 is barely absorbed by the gut in the CFS, because of many factors involved, so we should take B12 usually sublingual, nebulized or IV.

    Regards,
    Sergio
  13. liverock

    liverock Senior Member

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    Rich

    I'm not doing the protocol but research has shown that Vitamin D can raise glutathione levels in the brain to protect neurons. It also appears to kill brain tumour cells.

    http://www.ncbi.nlm.nih.gov/pubmed/11893522
  14. aquariusgirl

    aquariusgirl Senior Member

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    Regarding Sushi's comment, I also find I can't tolerate supplemental glutathione at this point in my methylation program.
    I also think adding chelators or binders to the mix may help. I use some OSR 1 and edta complex and it clears the brain when I have too much metals kicking around, presumably released by the methylation supps.
  15. doveman

    doveman

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    Hi serg1942

    This is from page 1216S of Victor Herberts essay "Staging vitamin B12 (cobalamin) status in vegetarians" published in The American Journal of Clinical Nutrition. It can be downloaded here: http://www.ajcn.org/cgi/content/abs...NDEX=10&sortspec=relevance&resourcetype=HWCIT

    Effects of excess vitamin C on vitamin B-12 status

    Active vitamin B-12 can be destroyed by megadoses of vitamin C, which convert vitamin B-12 to analogue forms that are worthless to humans (8). Vitamin C acts as an antioxidant primarily at physiologic doses. At pharmacologic (or mega) doses, in the presence of iron, it is one of the most potent oxidants known and drives iron-catalyzed free radical generation (45), which can not only damage vitamin B-12 but can destroy IF (46).
  16. ukme

    ukme Senior Member

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    What would be considered a 'pharmacologic' dose of vitamin C?
  17. goldiland

    goldiland

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    Rich,
    I'm actually coming at this from the other side. I'm on a gluaththione precursor MAX GXL which is a combination of NAC, L-Glutamine and Vitamin C and combining it with 100mg CoQ10 (2X a day protocol) but am not on the methylation protocol. It's interesting that I've experienced a very similar excitotoxicity since starting the protocol about 2 1/2 weeks ago.... increased energy but somewhat wired and significantly increased insomnia. I've also been on many of the methylation co-factors in your protocol individually based on doctor recommendation but not synergistically and have done very poorly on methyl B-12 by itself (both shots and Jarrow sublingual) as well as phosphrylated serine (product called Seriphos). It would be interesting to hear your take on how the increased gluthathione could set off an excitotoxicity reaction as well. If the lab is up and running, I'm going to get tested for methylation block.... it may be a combination of the methylation protocol and the increased gluathione that is needed in synergy.

    Thanks,
    Gregg
  18. aquariusgirl

    aquariusgirl Senior Member

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    gregg
    rich will give u a much better explanation than I.. but the L-glutamine and the cysteine in the NAC are excitotoxic per Dr Amy Yasko.
    So it's the not the glutathione per se that is excitotoxic.. it's the components.
    I had an amino acid IV recently.. and it made my body feel better but messed up my brain.. I think because of the excitatory amino acids.
    You could read up on dr amy's site ...www.ch3nutrigenomics.com.. for more info ..or google autism, excitotoxicity....
    the autism ppl are years ahead of us.. and there's no point in reinventing the wheel. they've been there, done it.. for the most part.
  19. Lotus97

    Lotus97 Senior Member

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    NAC and Glutathione can cause detox symptoms in some people. Also, Vitamin C and CoQ10 can be overstimulating since they boost ATP, but they also can increase glutathione. Phosphatidylserine is a methyl donor and it can also increase norepinephrine in some people which also can be overstimulating.
  20. dbkita

    dbkita Senior Member

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    Vitamin C is a direct cofactor (with copper) of making norepinephrine. This is why high dose vitamin C seems helpful to those with fatigue issues with the double edged sword it raises the conversion of dopamine to NE. This is why it is never a good idea to supplement vitamin C in the evening.

    I disagree that supplements that raise ATP are by themselves overstimulating. ATP is what the body runs on .... even when the body is trying to relax or sleep. Yes a burst of energy late at night if supplements are taken late at night might push back one's sleep time but it not the same as CNS overstimulation. The two are often misconstrued. I have found that taking supplements like magnesium, D-ribose, CoQ10, etc. that this helps me to yes have energy but at the same time calms my system down.

    I wouldn't blame the Krebs cycle for overstimulation. Blame that on the immune system or neurotransmitters.
    Lotus97 likes this.

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