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No love of B2 here - a warning about riboflavin

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by South, Jul 25, 2014.

  1. aaron_c

    aaron_c Senior Member

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    I feel like I am just adding to the chaos, but:

    This book reports on page 141 that "high doses of B2 can also cause a rise in catecholamine levels (Keiser, 1995; Koller, 1988)."

    So on one hand, low b2 can inhibit MAO, raising catecholamines plus seritonin (am I forgetting anything) and on the other hand high b2 can increase catecholamines, which might be what @Tunguska is reporting?
     
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  2. Gondwanaland

    Gondwanaland Senior Member

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    @South what is your MAO status?
     
  3. Kimsie

    Kimsie Senior Member

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    This might be a long shot, but I have been studying the pathways with the B vitamins intensely the past couple of days and I might have come up with something that explains why B2 could cause a reduced amount of serotonin.

    B2 is used in 3 very important enzymes, or actually enzyme complexes that are related to energy production, and that also use B1(thiamine): the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, and the branched chain ketoacid dehydrogenase complex (which allows valine, etc, to enter the TCA cycle as intermediates or acetyl CoA).

    If a person is low on thiamine, then taking B2 without thiamine (and you need more of the thiamine than the B2, in our experience), they could drive their thiamine levels even lower because taking B2 will push these enzymes, which also use thiamine.

    Thiamine is also used in the Pentose Phosphate pathway, or PPP, which provides NADPH for glutathione reductase, among other things. With low thiamine, I believe that the NADPH production from the PPP is reduced and then the body has to make up the difference through the folate cycle. It isn't well known that the folate cycle can produce NADPH, but here is a visual I made to illustrate the pathway: simplified folate cycle.jpg
    I had to do a lot of studying of diagrams of the folate cycle to understand this so if you feel confused, I'm not surprised. Edit: I just realized that I misspelled glycine decarboxylase, sorry!

    Now notice in the diagram that when glycine is used to make 5,10-methylene THF, ammonia is released. What do you need to get rid of ammonia? BH4. What is one of the things you need to make serotonin? BH4.

    I think that what can happen is that the other amino acids are shunted into making serine and glycine for NADPH synthesis and so the urine amino acids are low, except for taurine, which can't enter the TCA cycle. (The amino acids enter the TCA cycle and when they become malate they can enter the pathway to make serine and glycine). This is what showed up on my husband's urine amino acids test, with all the essential amino acids very low except taurine.

    My husband has had minor depression for years, and also high ammonia for years (we can smell it in his sweat and it comes out on urine tests.) It doesn't matter whether he has a high protein or low protein diet, his sweat smells, or smelled, like ammonia. We felt that it might cause a problem with his BH4, but we couldn't see what to do about it. Well, 3 days ago he started taking 1000mg of thiamine, instead of 100mg, along with his other vitamins, and last night he came in after exercising (and sweating like crazy. He doesn't have CFS, I am just using him as an illustration.) and he said, "My shirt doesn't smell like ammonia now when I exercise!" And it didn't!.

    So I thought that was a little confirmation about what I have written above. I hope I have written this clearly enough to make sense. Hopefully it will make him feel better in other ways, too, but it is too soon to tell.
     
    Last edited: Nov 8, 2014
  4. aaron_c

    aaron_c Senior Member

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    Wow @Kimsie, that is some dense reasoning! (Dense like a fudge cake, not like "bad.")

    I am not a biochemist or any such, but I do have a question about part of your theory: You suggest that as we become low on thiamine we would start to lose out on NADPH, and that the folate cycle would basically creatively contort itself in a cycle that produces NADPH and ammonia, but uses up serine. My question is about serine: As I understand it, we can synthesize serine (and in a case like this where we are using more of it, I will assume that we are synthesizing it), and serine synthesis uses an ammonia donated from glutamate. So it seems like the reaction you have described--which still seems like a theoretically good way raise nadph--would not end up producing excess ammonia in the long run. Although perhaps in the short run?

    [​IMG]
    Of course, then there is the question of why do people with chronic fatigue generally have low NADPH if this cycle can come into play? Is it blocked in some way? Is something else limiting it? Is serine synthesis limited in some way?

    You know, the glycine decarboxylase complex might account for why Rich Van K found low glycine in a lot of people with chronic fatigue. Maybe it was all eaten up to provide more NADPH! (Or else synthesis was blocked along with the rest of the folate cycle, and then we supplemented lots of MTHF, which bypassed the need to move THF to methylene THF, thus preventing glycine synthesis.)

    I hope you continue to let us know what you find out. It would be very interesting if B2, by using up active B1, was increasing ammonia somehow.

    And obviously, perhaps I have missed something somewhere.

    What do you think?
     
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  5. South

    South Senior Member

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    @Gondwanaland I don't know my mao status. Thanks for bringing up the point though.

    @Kimsie thanks for posting that. I'm not smart enough to understand much of it. I think one thing I got from it is that a next experiment I could try is using B2 and thiamine at the same time, to see if I again experience low serotonin from the B2...and if I don't, then perhaps a thiamine deficiency caused the B2 to give me low serotonin last time I tried B2.

    FWIW, I don't have any ammonia odor issues.
     
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  6. Gondwanaland

    Gondwanaland Senior Member

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  7. SDSue

    SDSue Southeast

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    Wow. A mitochondrial "specialist" put me on 100 mg riboflavin per day for nearly a year. Looking back, that was the darkest year of my life - I experienced a deeply severe depression, which hadn't occurred before or since. Now I know why!

    This is yet another example of the need for balance of with supplements.
     
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  8. Gondwanaland

    Gondwanaland Senior Member

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    :eek:
    Yet another example of medical incompetence and irresponsibility :bang-head:
     
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  9. Kimsie

    Kimsie Senior Member

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    What I put into the post in this thread isn't really complete without some other information about what I have been learning in the past few months. I am pretty sure that there are some blockages in the glycolysis pathway and the availability of pyruvate is more limited in a lot of people with certain chronic illnesses than in healthy people. I theorize that the reason for this is because there is a problem with sulfite oxidase and sulfite levels are higher than normal and the sulfite is causing problems. If a person does not have any problem with this particular pathway to make serine, then using serine and glycine for NADPH synthesis should not create a problem with ammonia. This is how the pathway is supposed to work.

    Here is an interesting study where they found that people with all kinds of chronic illnesses, including some with CFS, had a high cysteine/sulfate ratio, and I think that this must be caused by a problem with sulfite oxidase. Unfortunately, they didn't check the sulfite/cysteine ratio in this study, because I think that is what causes the problem, if I am right. Here is a study which talks about how sulfite interferes with glycolysis. So the point of this is that sulfite interferes with glycolysis in at least two places, and it could interfere in the pathway for serine synthesis that you mention because 3-phosphoglycerate comes from that pathway. Another possible problem with making serine from this pathway is that it uses an aminotransferase and all aminotransferases requires B6, so if a person is low in B6, they could have problems making serine in this way. That could be another reason why B2 can cause depression, because the SHMT can drain B6 and the aminotransferases are vital to neurotransmitter function. I can think of a lot of possible ways that B2 could cause depression, and they all involved an imbalance of B vitamins. I have researched this a lot because of my son with depression.

    The reason I hypothesize that this process is causing more ammonia to be released is because the urine amino acids are so low, and so they must be being broken down more than they would have been normally, which releases ammonia. (My husband was eating a diet quite high in animal protein when his urine tested so low in amino acids, so his levels were not low from low dietary intake.)

    The folate cycle isn't contorting itself when it makes NADPH. It's normal for the pathway to run that way, (see the article I mention in my post above). Probably most people here haven't taken a good look at the whole folate cycle; the version that is seen a lot, that Amy Yasko uses, is super simplified and makes it look like the folate cycle is simpler than the methionine cycle, when it is actually about 10 times more complicated than the methionine cycle and it has a lot of loops going different ways. Making methionine is just one of the many important things that folate does. Most likely, in a healthy person, only excess serine and glycine is used in this pathway.

    Another pathway to make serine and glycine is from malate, which can be used to make pyruvate, and the malate can come from the amino acids which can enter the TCA cycle as intermediates, i.e. glutamine, histidine, proline, arginine, valine, isoleucine, methionine, tyrosine, phenylalanine, asparagines, and aspartate. The other amino acids, except taurine, can mostly enter the TCA cycle as acetyl CoA. So the loss of amino acids could be mainly from the use of amino acids to fuel the TCA cycle because glycolysis is inhibited, and it might not have anything to do with low thiamine. However, the difference with ammonia in the sweat of my husband gives support to the idea that at least in his case, his amino acids are being used to make serine/glycine for this pathway. Actually, now that I think about it, it isn't that ammonia is released particularly in the glycine reaction that would cause the higher ammonia, it is that amino acids are being catabolized (broken down) that would not be broken down other wise. With more thiamine my husband doesn't catabolize as much protein and he has less ammonia. It was really cute, while I was writing this he came in and held out his wet shirt for me to smell; he just can't get over the difference!

    It might be that some people are having difficulty with this serine/glycine pathway and so can't make enough NADPH even with the alternative pathway. This is probably the case with a lot of CFS people because I think they are low in a lot of cofactors. This alternative pathway requires not only folate, but B6 also, so low B6 will inhibit this pathway at SHMT. In fact, part of my hypothesis is that in some people with chronic illness, this pathway causes people to lose B6. This is what happened to my son with depression - about a month after he started taking a lot of folate he started getting depressed, but before he started the folate he had terrible fatigue. I think that if we had been giving large doses of B6 and thiamine (and he was taking 50 mg of P5P but that wasn't enough) along with the folate and other vitamins he was taking, he would not have become depressed.

    If a person knows that they are low in NADPH, then I think that they may want to try taking a pretty large dose of thiamine, but not without the other B's. Our experience is that a much lower dose of riboflavin is needed than thiamine, so I can see why taking B2 without thiamine caused a problem. There could be some people who need more riboflavin, though.

    Supplementing with a lot of folate wouldn't stop any pathway from going, except if it caused another vitamin to be drained, such as I think it can cause a drain of B6 in certain instances, as I mentioned above. In these pathways each molecule of folate (this is true with other cofactors also) is used over and over many thousands of times, and the pathway is not regulated by the availability of folate, but by other things such as the amount of substrate and product (what the enzyme works on and what it produces), etc. A shortage of a cofactor will inhibit a pathway, and so people seem to draw the conclusion that an abundant amount of a cofactor will do the opposite and make too much of something, but this can only happen for a short while until the body adjusts the levels of the enzymes. For instance, in the case of MTHFR high levels of SAMe inhibit MTHFR in just a few minutes. Other enzymes might take a few hours to be adjusted. Some take a few days.

    If a vitamin causes symptoms immediately, then I think that is a sign that another vitamin is lacking, such as when a person gets anxiety from taking a large dose of folate - because they don't have enough niacin. If it takes more time, then probably another vitamin is getting drained and one can look at the pathways involved to try to figure out which one it might be, such as in the case with B1 and B2 being used together in several very important enzymes. Another cause of symptoms is that, in chronic illness, often glutathione and other toxin clearing pathways are being affected and sometimes taking vitamins improves these toxin clearing pathways and the person can have nausea and other symptoms associated with detoxification.
     
    Last edited: Nov 9, 2014
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  10. Kimsie

    Kimsie Senior Member

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    Probably you needed something like 600 mg of thiamin HCL, 500 mg of B5, 100-200 mg of P5P (activated B6) and 250-500 mg of niacinamide, along with 3-10 mg folate and some B12 to balance out 100 mg of riboflavin. (This is based on our experience.)

    I don't think there is too much reason to fear taking larger doses of vitamins, as long as you take enough of all of them. The only real problem, I think, when you take enough of all of them, is that you can end up with some pretty severe detoxification when you open up the pathways and suddenly your glutathione is working like it should after not working for so long.
     
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  11. SDSue

    SDSue Southeast

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    I spoke with my ME doctor, and apparently they've learned the hard way to give charcoal prior to glutathione, for that very reason. When administered IV glutathione some time ago, I had the most severe, and apparently permanent, crash.

    I like your proportions for the B's. If I get brave enough to try again, I'll be referencing this post. I've learned the hard way to take this all really slowly! Thanks so much.
     
  12. Kimsie

    Kimsie Senior Member

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    I had 1 gram of IV glutathione once a few months ago and the next day I felt like I had the flu and I even threw up! And I don't even have CFS, but I have a few symptoms that are probably related to toxic buildup.

    But my husband (who has high lead levels) and both of my sons that have problems didn't have any problem with IV glutathione.

    I think the proportion of B's I listed would work OK for most people. My sons take this much several times a day, and my son with schizophrenia takes 2 grams of niacin 3 times a day so what people need can vary a lot. Large doses of niacin are particularly common for schizophrenia. That's what works for him now, but I think we might be able to bring that down after he gets his levels up on thiamine and B6.

    Most likely people with ME/CFS have had years to build up toxins and so they need to build up the dose slowly.
     
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  13. Tunguska

    Tunguska Senior Member

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    All that is great info. I'll just add this quickly as an anecdote. I did have mental complications possibly related to a B2 protocol, but was already taking B1 and tried mega-dosing it to no avail (also tried high dose B3, B6, B12). In the end it seems to be about folate. I had to take something like 10mg of methylfolate to see any relief effect at all. I guess this goes with what Freddd says, except I avoid methylation (B12 is always negative for me and negates folate effects so I take most of it away, at night, with only small dose with the folate; inspired by someone's post on this forum). It seemed more about B2 and folate for me from the start.
     
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  14. picante

    picante Senior Member

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    Here, I'll add another mystery to the pile of riboflavin reactions. I haven't studied the B-vit. pathways, so I'm clueless.

    I started taking sublingual riboflavin, but it's the FMN form (Source Naturals coenzymated B2). I picked that one because I was told (and I read) that T4 is needed to convert riboflavin to FMN to FAD, and I don't have much T4 in my body, having taken T3 for 5-6 years for my hypothyroid condition.

    I'm 2 months into Freddd's protocol. Convinced that I needed B2, I asked my ND for some dessicated thyroid and started taking 1/2 grain on Nov. 25th, along with my T3. Then on Dec. 6th I started the sublingual B2 (FMN), hoping I would be able to convert it to FAD. (I'm not taking B1 or B3, just some P5P every 2-3 days and 300 mg pantethine daily.)

    Initially I didn't notice much, but to further complicate the picture, on the 9th I switched my dose of Ad/MeB12 oil to the evening. I had insomnia around 3-5 am and woke up with low back inflammation. This was the unwelcome return of a symptom that had dwindled to practically nothing on Freddd's protocol. Same response the next night, so I reverted to dosing my Ad/MeB12 oil in the morning (btw, it has vitamin D3 in it -- this might be relevant). The low back inflammation had been continuous, and it persisted through yesterday, the 12th. Also, my mood had taken a slow dive. I was quite discouraged.

    Last night I was once again awake around the same time. I had decided to take the B2 in the middle of the night, just because I hadn't managed to fit it in during the day. My back hurt. I was thinking "Well, crappola, what should I try now? Maybe I should just undo all my recent changes in reverse order. That sounds good." Then I made the connection between the B2 in my mouth and my itching face & scalp (a brand-new experience!). I took the B2 out -- it dissolves very slowly, so most of it was still there. My face & scalp stopped itching and I went to sleep.

    Today my low back inflammation has started to ease up and my mood is improving.

    The advice I got that led me to try this seemed pretty logical:

    "Possibly your [three] NOS2 +/+ alleles in combination with VDR bsm mean that you hare a lower potential to fight EBV.

    "Your hypothyroid problem would make this worse as you need FAD (from riboflavin) to make functional NOS. Mutations in NOS generally involve the ability to bind FAD/FMN, BH4, and heme. You NOS2 activity would be greatly depleted by an odd combination.
    Thus, hypothyroidism leads to low conversion of dietary riboflavin to FMN, then FAD. This has a big effect on a massive number of enzymes, but it in can lead to low B12 levels (due to poor functioning of MTHFR and MTRR). Low MeB12, means poorer folate cycling. This leads to lower amounts of BH4 (an essential requirement for NOS). Low FAD also leads to improper production of heme - this doesn't seem to have surfaced on any chat site as yet, and it certainly took some digging, but FAD is required in the last step in heme synthesis. You may have seen a thread on porphyria and CFS. Porphyria is the bit that is left if you can't make heme. This to me once again suggests that low riboflavin, FMN,FAD either dietary or from hypothyroidism is a major contributor to CFS."
    Does anyone have any thoughts about my experience?
     
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  15. aaron_c

    aaron_c Senior Member

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    @picante,

    One nitpick: Instead of hypothyroidism causing low B12, I think you meant low function of methionine synthase, caused by low B12 levels, which would (potentially) be exacerbated by your MTHFR and MTRR mutations, and a deficiency of B2 (MTHFR needs B2). Although I suppose that low thyroid could cause low stomach acid which would lower one's absorption of B12...from the gut, at least(?). But the consensus I have encountered at phoenixrising (including from Rich Van K) is that inflammation and lack of glutathione causing oxidation of B12 is the reason many of us do well supplementing some amount of B12. (Please, someone chip in if yall have heard otherwise!)

    I have also wondered about b2's role with high porphyrins I see reported from time to time for people with ME.

    The one clue I might have is that if the depression that is accompanying your other symptoms is related to ammonia, perhaps the riboflavin is allowing NOS to function better, thus allowing it to use up BH4 as it moves ammonia towards urea. About a year ago I was on a thread discussing if NOS uses up BH4, and if so, how. My experience at least points towards it doing so, but we never did find out how.

    It could be something else entirely, of course.

    I believe that Freddd suggests relatively low doses of B2 with his protocol, although I have seen it in the context of "because then you will need WAY more potassium." For what it is worth, I had diarrhea when I took large amounts of B12 but did not limit my B2 to under 12 mg per day.

    It doesn't sound like you've had any improvement from B2, would that be accurate?
     
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  16. Gondwanaland

    Gondwanaland Senior Member

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    lack of molybdenum?
     
  17. picante

    picante Senior Member

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    By all means, pick a bunch of nits and send them up here to the northern Rockies. They don't grow here.
    That was a quote from someone else, explaining that low FMN & FAD can lead to low B12. This quote appears to include both what you said and what he said:
    "The enzyme methionine synthase (EC 2.1.1.13), which converts homocysteine to methionine, is dependent on 5-methyltetrahydrofolate as a methyl donor but also on vitamin B-12, as methyl cobalamin (139). The synthesis of methylcobalamin appears in turn to be dependent on flavoproteins. Despite this interrelation between riboflavin and vitamin B-12, there is no clear evidence that riboflavin deficiency leads to a functional deficiency of vitamin B-12."
    http://ajcn.nutrition.org/content/77/6/1352.full
    However, this is an example of the kind of research Freddd is always mentioning, because the title of that section is:
    Cyanocobalamin (vitamin B-12)
    :lol::lol::aghhh: In other words, there's no clear evidence that it leads to a functional deficiency of cyanocobalamin!

    However, if it is true that the synthesis of methylcobalamin is dependent on flavoproteins, then it's a Catch-22, ┬┐no?

    I can't tell you how many websites I've been on where they claim that a methylation protocol can cure Hashimoto's/hypothyroidism. Is it true, or is everyone just repeating the same "information"?

     
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  18. picante

    picante Senior Member

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    This FMN supplement contains 18 mg riboflavin from 25 mg flavin mononucleotide. It's not a lot, and I could easily cut it in half. And no, I didn't experience a greater need for potassium while I was taking it, including the one day when I took 2 tablets.
    What concerned me was the inflammation. I still don't understand why it would trigger inflammation. It has continued to diminish today. The depression is gone, so presumably that was from the B2 as well.
    If the B2 was helping me make nitric oxide, I would have felt better, not worse. I assume, then, that I'm missing a co-factor, which could be T4, or B3, or both, or....
     
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  19. picante

    picante Senior Member

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    Hi izzy, I'm taking ionic molybdenum drops. Possibly not enough, since I've got sulfur issues, too.
    The itchy face & scalp had a hot quality, so I'm thinking that was more inflammation. How the B2 would cause that, I don't know.
     
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  20. pogoman

    pogoman Senior Member

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    There are several mitochondrial diseases that improve with supplemental riboflavin, tagged with the term riboflavin responsive.
    One such is RR-MADD that involves FAD, long name Multiple Acyl-CoA Dehydrogenase Deficiency.
    http://www.ncbi.nlm.nih.gov/pubmed/3930843
    http://omim.org/entry/231680#clinicalFeatures
     
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