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Why would B12+folate cause GABA to reverse its effect?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by zanolachino, Mar 20, 2014.

  1. zanolachino

    zanolachino

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    Hello, everyone. I've been lurking for a long time, but this is my first post.

    I finally did the Health Diagnostics methylation panel, which showed low reduced glutathione, high oxidized glutathione, low SAM, high SAH, and low folate at every step of its path. I took this as a green light to begin folate/B12 supplementation.

    Two weeks ago I started 1mg m-B12, 4.3mg ad-B12, and 800mcg methylfolate daily. Basic cofactors were already in place, including lots of potassium.

    Around one week ago the negative effects began: psoriasis-like rashes, joint pain, loose stools, buzzing in the feet (a symptom from years ago which I considered cured), motor impairment, increased agitation and anxiety. Three days ago the tension became severe. In addition, I began to feel very foggy, weak, dizzy, nauseated, and cold. Yesterday, I stopped the folate and B12.

    I know that this raises conflicting opinions. Many would say that these effects mean that the methylfolate dose was too high, too fast, and the right thing to do is back off. Others would call this a donut hole and say press on.

    I welcome thoughts on what I have written thus far. But I have a more specific question:

    For years, one thing that has worked reliably to calm me down is GABA -- specifically, PharmaGABA, which is supposed to be able to cross the blood-brain barrier. When I wake up at night and cannot go back to sleep, a 250mg capsule of PharmaGABA usually does the trick. Sometimes I combine it with theanine. It takes about 10 minutes to kick in, and I feel the effect distinctly.

    Two nights ago, for the first time ever, supplemental GABA had a strong stimulatory effect. Last night I tried it again with the same unpleasant result. My nervous system has been raging ever since, and I would have to say that this is the worst I've felt in more than a year.

    Of course, I am alarmed that an indispensable ally has turned against me, and I worry about how I will be able to sleep. But it seems to me that this could be a crucially important clue -- if I could figure out what it means.

    Why would two weeks of m-B12/ad-B12/methylfolate cause GABA to reverse its effect?

    Guessing wildly, perhaps the B12/folate drove all of my dopamine to norepinephrine/epinephrine, and then the GABA inhibited dopamine further?

    Does anyone have a good enough understanding of the relevant systems to venture a hypothesis?
    ninauae likes this.
  2. PeterPositive

    PeterPositive Senior Member

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    You raise a very interesting question.
    I don't have an answer but I am in a similar boat. I don't take GABA directly but I use Valerian capsules (5-600mg) when I can't sleep well. (which in turn produce gaba)

    Methylfolate in particular improves my focus and attention but it also raises anxiety and excitability to a level that sometimes is excessive. 1200-1400mg can do that for me in 2-3 days. I have had several over-anxious episodes which would go away by discontinuing the supplement.

    Similarly Valerian doesn't work anymore.
  3. whodathunkit

    whodathunkit Senior Member

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    @PeterPositive: I can't remember...do you take lithium? Are you able to take it (that is, are you on any drugs or have any snp's that contraindicate lithium)?

    I've been experimenting with low-dose lithium orotate per @ahmo and some other's recs, and find it does pretty good to smooth out anxiety/over-excitation from increased methylation. TMG worked on the anxiety, too, but I think the betaine or something acted on my GI tract so I decided to try lithium. It's only been a couple weeks but so far it's working pretty well.

    There have been concerns raised about possible thyroid suppressing effects of lithium, but after some research I believe those effects are probably dose dependent and if you stay low you won't have to worry.

    Just mentioning in case you don't take it and might consider it.
    Last edited: Mar 20, 2014
  4. Lynn_M

    Lynn_M Senior Member

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    zanolachino,
    The symptoms you started experiencing around one week ago sound like they could be due to too much methyfolate for your system to handle. Because you started the mB12, aB12, and mfolate together, you could be experiencing methyltrapping, wherein you don't have enough mB12 at the cellular level to put the methylfolate to work. It's often advised to start the B12 at least a week ahead of the mfolate, to allow the B12 to build up in your system first. Also, you don't state if you're taking sublingual mB12, injections, or an oral form, nor do you state the brand. Those are all important variables, with the oral form being mostly useless, and only some brands of sublingual mB12 having any value. I personally now use the transdermal adenosyl/methyl B12 oil found at b12oils.com, which is comparable in efficacy to subcutaneous B12.

    A couple people had posted at MTHFR.net about developing rashes after starting mB12 and mfolate together. This was Dr. Ben Lynch's reply to those experiencing hives/runny nose after starting methylfolate/B12:
    "There is increased SAM production in the body when giving b12 and methylfolate – which is a bonus; however, the histamine may not be fully broken down if one is low in vitamin B1 or vitamin B5.

    For this reason, it is a good idea to start with a trace mineral complex (with food) and a b complex without folate and B12 to support all pathways prior to pushing SAM production. Talk with your doctor about this."

    Regarding the GABA and overstimulation, I think your theory about inhibited dopamine is wrong. According to nutripath Stephen Heuer, dopamine is a stimulant. Listen to a portion of this interview at http://oneradionetwork.com/health/s...health-diet-questions-answered-march-20-2014/, starting at 9 minutes in, where he's talking about dopamine and disturbed sleep. What came to my mind when I read your post was that niacin might be helpful in tamping down the anxiety and overstimulation, and Stephen recommends a particular form of niacinamide.

    Dr. Amy Yasko says a 2.5-3 mg. dose of lithium in the lithium orotate form helps the body with B12 uptake. Lithium orotate is sold in 120 mg. doses, and those contain 5 mg. of lithium.

    Once you're willing to start over again with a mB12 and folate regimen, I would start with just the methyl and adeno B12 for a week or two, and then if you have no symptoms, slowly titrate up your methylfolate doses.
    Last edited: Mar 20, 2014
  5. Vegas

    Vegas Senior Member

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    I will suggest that you have supplanted control of processes which are typically regulated by feedback inhibition. You jumped into a part of the metabolism that cannot be influenced by natural compounds, at least to the extent that you are doing with the supplements mentioned. You are artificially stimulating the biosynthesis of methionine and hence cysteine and cystathionine, which results in greater substrate availability to synthesize not only pyruvate (which can impair the metabolism of lactate making matters worse) but also ammonia. This also provides for more substrate for cystathionine beta synthase to yield hydrogen sulfide. So you are forcing these into a situation where you likely have an impaired nitrogen metabolism. How do I know about your nitrogen metabolism being impaired, well, this is inferred based simply by the fact that you find yourself needing GABA in the first place, and what you have done by adding cystathionine would negatively impact the glutamate-glutamine/glutamate-GABA cycles, creating a greater need for GABA.

    I hold the belief that these problems stem from intestinal dysbiosis, including an imbalance in species participating and contributing towards positive balance of the nitrogen metabolism, and the associated intestinal permeability that is maintained by this condition. Both which influence the impact of nitrogen accumulation and ones ability to render nitrogen metabolites into a more inert form and thus handle nitrogen influx. This process is necessarily tied to butyrate and propionate availability, and lactate metabolism, which is not coincidentally tied to cystathionine metabolism. Unfortunately for us humans, the microbial component is essential, we are not self-sufficient and must rely upon our microbes for nitrogen fixation, directly or indirectly.

    The conversion of glutamate to glutamine and glutamate to GABA is going to be negatively impacted by additional ammonia as well as via the catabolism of proteins. Glutamine synthetase and its regulatory mechanisms are wildly complicated, but they are going to be effected, I think, by your manipulation of the nitrogen metabolism. If you want to learn more, you can start by reading about ammonia homeostasis.

    I will say that over-riding your own systems for regulating cysteine is not particularly wise, at least in many cases, despite what you read on the Internet...of course unless some guy on the Internet told you otherwise. The bigger question is why do you respond to micronutrients which drive these methylation reactions. I believe there is a very important reason why your cysteine capacity was limited. Even if I didn't know what I was talking about, which is probably true, the KEAP-Nrf2 pathways would tell me biosynthesis of cysteine is not supposed to be in your hands. I
  6. whodathunkit

    whodathunkit Senior Member

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    @Vegas--interesting post. What would you recommend for someone like @zanolachino before moving on with methylation? Chelation & probiotics?

    For myself, I was interested enough in this post to go back and read some of your older posts, and saw you're into chelation. Are you still actively chelating? How is that going? Have things continued to improve or leveled off? Are you still of the opinion that DMSA and ALA are the best mercury chelators? Etc. Insights are welcome.

    I've chelated a few times myself, and it did me lots of good. Your older posts are inspiring, and I may give it another whirl. However, I'm in the process of correcting pretty severe anemia. I think the few rounds of chelation I did a few years ago are what completely tanked my iron levels, and because of ongoing "lady problems" I haven't been able to build them up again. This is the primary reason I haven't chelated since then, because I feel like I probably need to do some more. Any advice on dealing with anemia when chelating?
  7. Vegas

    Vegas Senior Member

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    @zanolachino Some things to consider: stop the methylb12, take a little Niacin, if necessary to help interrupt the current cysteine-driven show. Slow down but continue 5-MTHF, liberally use magnesium and B2 if tolerated, consider a small amount of Mn, try to acidify the colon by alkalizing the body, de-emphasize high-nitrogen foods/proteins and simple carbs, which more readily produce lactate, use only obligatively fermented LAB with extended fermentation, bifidobacterial strains innoculated in milk, and SBO, try resistant starch, consider Yucca Shig. w/ meals.

    I think heavy metal toxicity is in all probability a secondary consequence of dysbiosis, not the other way around. It wasn't until I foolishly integrated the 20 gram carb diet to control my hypoglycemia that I really became ill, and thus decimated my microbiome. I chelated 700 days to great improvement; however, it eventually became very clear that the effects mediated by Lipoic Acid were eventually largely unrelated to its ability to chelate metals. (Although HM toxicity is a very real problem and I don't want to discount the significance of this, I was plainly mercury toxic)

    In my opinion, FDC ALA is the most effective method of chelating mercury. Its effects, however, are generally viewed as being carried out by the chelating properties of lipoic acid. In all likelihood, for many this is not at all what is happening. I think, many of the effects are actually created by its abilities to much more broadly influence detoxification/redox balance/heme metabolism, etc. It has a potent ability to influence dehydrogenation and may be the most effective activator of nrf2 known. It is a great compound, but it wore me out over time as my cysteine levels normalized and I started to understand the bigger picture.
    froufox, Sidereal and Asklipia like this.
  8. PeterPositive

    PeterPositive Senior Member

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    Thanks.
    No, haven't tried lithium yet, although I have read similar suggestions. It looks interesting.
    What dose are you taking?

    Thanks
  9. whodathunkit

    whodathunkit Senior Member

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    @PeterPositive: just 5mg lithium/120mg total lithium orotate (Doctor's Best brand). I think I'm going to cut that in half to see how I do. Maybe you would want to start with just a half. Also, drink extra water. I read that lithium can cause extra urine output and dehydrate you, and I think it has me. Plus I haven't been drinking as much water past couple days because I've been busy.
  10. PeterPositive

    PeterPositive Senior Member

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    Thanks. Will talk about this with the doc and see what he says.
  11. zanolachino

    zanolachino

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    Thank you, everyone, for the responses. What a generous community this is!

    I am doing better now, but it took quite a few days after stopping 5-MTHF + B12 for things to start calming down, and I am still not back, by a long way, to where I was before I started.

    I remain entirely confused as to why PharmaGABA has reversed its action. I have not yet dared to try it again, but yesterday I attempted a dose of theanine, and it did not have the calming effect that it has always had. (Whether it had no effect or slightly increased anxiety, I cannot say for sure.)

    @Lynn_M,

    Thank you for all of the good points. I should have stated that the m-B12 was Enzymatic Therapy and the ad-B12 Source Naturals, both sublingual (really buccal: I kept them between cheek and gum for hours).

    It is funny that you bring up Ben Lynch, as he was influential in my decision to start 5-MTHF and m-B12 at the same time as opposed to pre-loading with B12. He has changed his tune on this over the years. Originally, he recommended pre-loading for the same reason you do, to avoid methyl trapping. Later, influenced by the work of RIchard Deith, he advised starting with folate to reduce risk of harm from B12 oxidation. Now, he recommends starting them simultaneously to avoid both problems.

    Speaking of Ben Lynch, just recently I got around to watching his YouTube videos. I wish that I would have done so sooner. I would not go so far as to say that they conflict with the material that he has provided in written form, but there is a definite shift in emphasis with regard to crucial issues. No question, on his website he discusses the side effects of too much 5-MTHF. But in the videos he goes much further: he states repeatedly that giving 5-MTHF + m-B12 to very sick people is a terrible idea as it will almost always make them worse. Instead, he says, the chronically ill should focus on repairing cell membranes, supporting mitochondria, and reducing oxidative stress. Methylation support should come much later. This is a somewhat different sense than one takes away from his written work -- and interestingly, it brings him in line with Amy Yasko's recommendations.

    Lithium is a good idea, but I have been taking 1 to 3 mg a few times a week for years, so I would be surprised if I am deficient.

    Niacinamide confuses me greatly. From the anxiolytic effects to the blood sugar effects (Dietrich Klinghardt, building on Jonathan Wright, prescribes niacinamide to reverse Lyme-induced insulin resistance), there are all sorts of good reasons, in theory, for me to take it. But whenever I have tried it, it has increased anxiety. I seem to have a paradoxical response to a lot of things.

    I admit that the dopamine idea is problematic, but I have always suspected that dopamine is involved in some way because when I am at my worst, some of my symptoms are Parkinsonian. Thankfully, it has been years since I was at my worst, but 5-MTHF + m-B12 brought these symptoms back.

    @Vegas,

    Your first message gives me a lot to think about. Thank you.

    I should stress that I did not arrive casually at the decision to tinker with my metabolism in this way. I was driven to it by years of frustration at health that was not improving no matter what I tried. Or more precisely: I was able to make great improvements for a few years, but for all of 2013 I plateaued, and recently I started to backslide in some ways.

    Did your first message get cut off? You were heading in such an interesting direction -- "I believe there is a very important reason why your cysteine capacity was limited" -- that I would hate to have missed anything.

    Regarding your second message, I am intrigued by your suggestions because you are right on the money with magnesium and lipoic acid. Magnesium helps me more than anything else -- indeed, I often feel that if I could only find a way to get more magnesium into my mitochondria, I would be healed. And lipoic acid has been helpful, too, particularly with my bizarre blood sugar problems.

    I understand that you do not view lipoic acid primarily as a chelator. Does this mean that you do not share Andy Cutler's view that it should never be taken in large single doses? I tried his protocol for many months, but recently I have resumed taking it in a large dose once per day.

    May I ask you to explain the thinking behind the B2 and manganese recommendations?

    Thanks again to everyone!
    Last edited: Mar 26, 2014
  12. Violeta

    Violeta Senior Member

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    It kind of unsetteled my mind that you said that your Parkinsonian symptoms returned from doing the B12/folate as I am having a hard time putting together all the issues that B12 and folate are obviously causing which can be seen by a lot of the recent posts on this forum. (Don't you love run on sentences?)

    Especially since Parkinson's has been said to be related to a pathogen. What's happening?

    I have been having some itchiness symptoms which I thought were immune/pathogen related, but at the same time seem to sound more like histamine issues, so I googled B12 and histamines. As you can guess, there are two opposing camps here, so I kept looking.

    Here's a link to a site about histamines and some of the issues that go along with it. (MS is one of them, cancer, chronic fatigue) Of course, histamines are not the root of the problem, but the information about histamine issues can provide good clues and also good ideas for relief, if that's what one needs.:grumpy:

    Well, here's the link:
    See what you think.

    http://thelowhistaminechef.com/these-probiotic-strains-lower-histamine-rather-than-raising-it/
    Tiger Lily 813 likes this.
  13. Violeta

    Violeta Senior Member

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    I can't find any reason for B12 or folate directly causing assault to the immune system; does anyone have any information concerning that or a direction that you can point me in?

    With respect to the Parkinsonian symptoms returning from B12/folate, I am still leaning in the direction that the B12 and folate increase histamine issues, and then the histamines congregate there and increase inflammation.

    What I'm wondering, though, is are the histamines attracted to metals or pathogens. Any help would be appreciated. I reduced histamines for a few days and then took a little bit of apple cider vinegar, and the itching on my spine came back almost immediately. I'm wondering what that indicates about my spine???

    Thanks for any input.
  14. Violeta

    Violeta Senior Member

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    This is a really good site for information about histamines, and it actually has a paragraph about Parkinson's disease.

    http://healthypixels.com/?p=1044

    With respect to Parkinson's disease:

    Parkinson’s Disease and brain degeneration – Accumulated histamine in the brain can cause damage to neurons through inflammation. Studies on patients with Parkinson’s Disease have shown abnormal, reduced ability to break down histamine in the brain and an accumulation of histamine methyltransferase. Furthermore, manganese exacerbated this altered histamine activity in lab rats.

    This study shows that supplementing folic acid (I do realize that's not the acceptable form) decreases excretion of zinc, but not copper. Therefore, I would jump to the conclusion that it would cause a relative deficiency of copper.

    http://www.ncbi.nlm.nih.gov/pubmed/6711464

    This is from the first link, and might explain why supplementing folic acid (in whatever form) would cause the increased release of histamines.

    Copper is required to form the DAO enzyme and copper deficiency associates with low DAO enzyme activity in animals. More research is necessary to confirm that copper supplementation increases DAO activity. Foods high in copper include fresh basil, cocoa powder, cashews, soybeans (mature), herbal tea, sesame seeds, sunflower seeds, garbanzo beans, and lentils.
    Last edited: Mar 30, 2014
    ahmo likes this.
  15. ahmo

    ahmo Senior Member

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    @Violeta Here's a fascinating vid re histamines in the brain. I'm not sure about whether Dr. Theoharides classifies it this way, but Dietrich Klinghardt and another researcher, Stephanie Seneff, link Parkinsons, ALS, MS, and others into the category of "adult autism". I like the look of the article you've linked, will get into it later. Thx. ahmo

    ‪‘Brain Allergy’ and ASD - T. Theoharides, MD, PhD‬
    https://www.youtube.com/watch?feature=player_detailpage&v=9QbZp3WcC1Q
    Violeta likes this.
  16. South

    South Senior Member

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    @Violeta

    Well not quite though, actually that study says, on the first page on the abstract: "Fecal zinc was significantly (p < 0.001) higher in the group that received folic acid supplements during the initial control and low zinc intake periods.
    No significant differences were seen during the period of high zinc intake. During all dietary
    periods urinary zinc excretion was reduced by about 50% by folic acid supplementation. No
    apparent changes occurred in iron or copper excretion."

    So, zinc was excreted faster in feces BUT slower in urine. Which looks a lot like the net zinc in the body may have stayed the same, IMHO. Just trying to save you some time in analyzing something, when there might not really be a cause or effect.

    If the link where you found the study doesn't show all the text, try this link instead:
    http://ajcn.nutrition.org/content/39/4/535.full.pdf
    Last edited: Mar 31, 2014
  17. Violeta

    Violeta Senior Member

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    @South, thanks for the complete text of that study. I have to reread it to see if I can figure out net zinc in all three parts of the study, but I see what you mean. At one point it even says that folate affects zinc nurtriture negatively. That's strange.

    So now I think I should keep looking for a reason for the effect of folate on immune system and histamine production. Any ideas?

    I need some help with this article. Does it mean folate makes zinc biounavailable?

    PS: I shouldn't have jumped to a conclusion:)
    Last edited: Mar 31, 2014
  18. Violeta

    Violeta Senior Member

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    @ahmo
    Thanks, It sounds interesting, I'm going to listen to it now.

    I just listened to this video, it's excellent! What hope for autism!!! Maybe for us, too. Isn't it amazing that the doctor and his group did all that 3 years of research on $65,000!
    Last edited: Mar 31, 2014
  19. Violeta

    Violeta Senior Member

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  20. Dannylingo

    Dannylingo

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    @Vegas I find your input in nitrogen metabolism interesting. My view on adverse affects of increasing methylation manual is this, when you increase cellular replication without adequate amounts of zinc, magnesium, copper, b6, and many more fundamental nutrients you are further eczaborating all these deficiencies at the cellular level wich are truly the issue at core here. It's like taking anabolic steroids if you ask me. When you stimulate cellular replication with a faulty Krebs cycle you are further depleting minerals and b vitamins that are most likely already low like biotin, thiamin, magnesium, manganese ect. This will produce side effects like rash/dermatitis since you are producing odd cells. About the gaba well I agree with Vegas. I believe that you are further aggravating an ammonia build up do to an impair urea cycle. Similar symptoms can be replicated by mega doses of b6 since it will stimulate amino acid catabolism. This will deplete a keto glutarate and glutamate in the brain wich is needed to produce gaba using b6. Hope that opens up some perspective.

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