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B-12 - The Hidden Story

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Cort, Jul 26, 2009.

  1. Sunday

    Sunday Senior Member

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    It's been said on this forum before, but high serum B12 levels may actually indicate a B12 deficiency; it's the cerebrospinal fluid that needs to be tested for the true story. Practical demonstration of my B12 deficiency is enough for me, I have no desire to have my spine tapped and also very little cash to spend on healing; I can think of a number of much more effective ways to spend money on healing than that. On the other hand, it's good some people are being tested so the medical community might have some of the kind of data it's used to.

    I think you kind of develop techniques for holding the lozenges in the mouth longer. I put them by my bed and slip them under my tongue when I first wake; I've never waked easily and CFS has made it even more difficult, so I doze off with them under my tongue and when I wake an hour or more later they are still there. I think getting them far enough under the tongue kind of puts them in a pocket where they are protected from excessive saliva and so forth. David, thanks for the upper lip tip, I'll try that; your upping-the-methylfolate tip was excellent so I regard you as a person whose advice should be considered! Maybe I have a dry mouth or something but under my tongue is mostly where my lozenges get parked, I move them around only if I get that weird sore-spot thing they sometimes cause. I've also been experimenting with taking the b12s in sequence, instead of all at once.
     
  2. Glutathione:

    This reference seems to contradict that gluathione is antagonistic to B12 absorption as I've read on this thread?? This seems to be for some sort of patent, so I'm skeptical when $$$ is involved.

    http://www.wipo.int/pctdb/en/wo.jsp?IA=US2006020826&DISPLAY=DESC

    Quote: Glutathione is required for the methylation of B12, and thus the continued formation of related products (Xia). Deficiency of glutathione thus results in deficiency of methylcobalamine and a number of disease states such as Autism.
     
  3. Freddd

    Freddd Senior Member

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    Hi Everybody,

    I Just want to say that I have some comments to make and answers to questions and correspndence that I have been very slow on this week, so please have patience. I have had a mild case of the flu, my first flu since about 1972 or so, the first time I've been sick in 7 years. Yuckkkk!
     
  4. Freddd

    Freddd Senior Member

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    I have taken that list of under and over methylators (sounds like some kind of rifle-shotgun combo) symptoms and categorized them as to type of b12 deficiency(s) by color and grouping them based on what symptoms I used to have.

    I have included the characteristics as listed on several sites of under and over methylators. They BOTH include depression which seems contradictory to me. Color red means mb12 deficiency symptom. Color pink means frequent mb12 deficiency co-correlate. Color red-brown means adb12 deficiency symptom. There are no hydroxyb12 deficiency symptoms or co-correlates because they don't exist as such because hydroxyb12 has no direct usage except to be converted to adb12 and/or mb12. Be aware that virtually all b12 deficiency symptoms, taken one at a time, may have multiple other causes.


    UNDER METHYLATORS


    My symptoms before taking b12 and cofactors

    1 - Depression - Depression
    2 - Poor tolerance of heat
    3 - Unexplained nausea
    4 - Frequent colds and flu
    5 - Poor pain tolerance
    6 - Joint pain
    7 - Joint swelling
    8 - Joint stiffness
    9 - Excess perspiration
    10 - Insomnia
    11 - Muscle pains - Muscle pains
    12 - Seasonal depression
    13 - Inhalant allergies
    14 - Oppositional –defiant -so my mother said but she was highly disturbed and psychotic and it was only her I was opposing and defying when she was irrational
    15 - Frequent headaches - Frequent headaches

    16 - Perfectionism
    17 - Competitiveness
    18 - Asthma
    19 - Vasomotor rhinitis
    20 - Allergic skin disorders
    21 - Pruritis
    22 - Sparse body hair - increased a lot to normal after mb12 and cofactors, especially on slick legs
    23 - Fatigue
    24 - Respond well to SAM-e

    25 - Anorexia/bulimia - physical, not psychological, no body distortion, no motivation to be anorexic except for b12 containing foods in some people
    26 - Prone to hives
    27 - Good tolerance of cold

    Not my symptoms/chraracteristics

    High salivary flow
    High tear flow
    Never dry eyes
    Hyperactivity
    Phobias
    Highly motivated
    Hard driving personality
    Addictive tendencies
    bipolar disorder
    OCD
    Schizophrenia
    Abundant or excess saliva in mouth
    Obsessive compulsive
    Slenderness
    Do worse on b12 and folates (4)
    Shopping/gambling disorders
    Excess stomach acid
    High libido
    Elevated absolute basophils
    Extreme internal anxiety despite outwardly calm
    Delusion thinking rather than hallucinations
    Respond well to SAM-e, methionine, avoid folic acid (1)
    Low serotonin
    Low dopamine
    Low norepinephrine
    Psychosis
    26 Total



    OVER METHYLATORS

    My symptoms before taking b12 and cofactors, except where noted


    1- High religiosity - if you include high spirituality instead of religiosity, I am anti-religiosity as such.
    2 - High artistic/musical ability
    3 - Auditory hallucinations
    4 - Absence of seasonal inhalant allergies - my seasonal inhalant allergies nave gone away with methylb12/methylfolate
    5 - Frequent dry eyes
    6 - Multitude of chemical sensitivities
    7 - Multitude of food sensitivities
    8 - Low libido - Low libido
    9 - Auditory hallucinations
    10 - Underachievement as child - so my mother would say
    11 - Nervous legs - Nervous legs
    12 - Depression - Depression
    13 - Despair
    14 - Respond well to b12

    15 - Upper body pain
    16 - Head pain
    17 - Low salivary
    18 - Low tears
    19 - Intolerance to SSRI drugs
    20 - Treatment revolves around folic acid, niacin, B12, and a high protein diet. (2)
    21 - Low motivation


    Not my symptoms/chraracteristics

    Elevated serotonin
    Elevated dopamine
    Elevated norepinephrine
    Self injury
    High anxiety evident to all
    Obsessions but not compulsions
    Paranoia
    Heavy body hair
    Hyperactivity
    Grandiosity
    Respond well to b12 but avoid SAM-e, inositol, methionine TMG and DMG (1)
    Panic attacks
    Nervous
    High pain tolerance
    “space cadet”
    Learning disabilities
    Low perspiration
    17 Total



    As you will note, I have approximately half of the characteristics of each category. So looking at these does that make me an under or over methylator? I was certainly a depleted (maybe blocked methylator if that is the same thing) methylator along with severe mb12, adb12 and methylfolate deficiencies. Can anybody bring some kind of sense to this from the "under/over methylator" hypothesis viewpoint? How about the some of you others? How do you stack up on these categories.
     
  5. aquariusgirl

    aquariusgirl Senior Member

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    Fredd
    I have a question about hypokalemia. Could someone have a tissue deficiency of potassium, but a high blood potassium reading?
    thank you
     
  6. Hysterical Woman

    Hysterical Woman Senior Member

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    Hi aquariusgirl,

    I am very interested in Freddd's response to this true. However, if everything I have read about minerals is true, then trying to measure them in the blood is not very accurate.

    Good Luck,

    Hysterical
     
  7. My first losenge of the 5mg Jarrow B12 seemed to make a significant change in my psychology. I was really up and switched on (compared to the way I felt before I took it). Since then, not much of any experience after taking. Normal? Should I increase the number of losenges per day after such a short time?

    .. I'm editing this five or ten minutes later (about an hour after taking the B12). I feel like my symptoms are worse -- difficulty standing/coordination, numbness coldness in feet. Not sure if this would of happened anyway without the B12, but assume this could also be normal effect? I was expecting a similar experience to the first time which was pleasant and uplifiing.

    Four hours after ingestions: Much worse. Really hard to coordinate, woobily. I think I read fearful people can experience fear as the uptake of b12 process starts. That has been my pattern and it is very strong now.

     
  8. Sunday

    Sunday Senior Member

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    michaeldfaulkner, the first time I took B12 I had a very pleasant experience. For a week early on, I felt like a real human being. Then came the two-month crash. I think it's pretty normal to be scared in the circumstances, we all know the terrors of the pit, and there are ways in which it's counterintuitive to throw ourselves in it. But there's healing in the pit this time, at least there is for me: I've gotten to the point (after 4 + months) that I think, "Oh, so that's going through another level of healing now," when I get a new symptom. Because that's how it's been for me. There is something deeper than all my fears: it doesn't work fast and it doesn't work painlessly or effortlessly, but it's working.

    freddd, wishing you well. Please rest! there's far too much viral-trigger involvement in this illness not to. (by the way I enjoyed the red variations for the mb12 denotations.)
     
  9. Sunday: Thanks. I'm certainly famliar with the term "healing crisis". So your symptoms got much worse? Are you expressing that after a time some things get better and then it appeared as if another layer was coming up to be worked on?

    Interested to hear other similar stories. You need to believe in this, or easy to back off (which I could try -- lowering the dose a bit).
     
  10. Freddd

    Freddd Senior Member

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    Hi Aquariusgirl,

    Tissue potassium is tied up in cells and has a large vloume of distribution. Serum potassium has a small volume of distribution and can move up or down very quickly as potassium is taken to form cells or as it is recharged via potassium intake. I really can't answer your question as I'm not sure how that might occur. However it is quite possible for serum levels to be well above tissue levels. The two are only losely coupled.
     
  11. Freddd

    Freddd Senior Member

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    Hi Hysterical,

    As serum potassium levels, either high or low, can cause problems, this is where it is measured, in the serum. This is where it can fluctuate relatively quickly and can be increased or decreased quickly. Potassium is the most common mineral in the body.
     
  12. Freddd

    Freddd Senior Member

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    Hi Michael,

    I have always been inclinded to describe this as "intensified symptoms" rather than "better" or worse". The symptoms are intensified. They stand out much more clearly. As the nervous system is what we perceive with, whether a symptom that is perceived more intensly is "worse" or not might be more of a philosophical or semantic matter than an actuality. Further they often can change dramarically, sometimes backstepping through the sequence backwards that they went trough first appearing. The intake of b12 upsets all the "it's the same so ignore it" type of function our nervous system has quite automatically. I've described it as playing double deck 52 pickup with the symptoms. Generally the things that intensify and change the most are the things that heal most quickly. I can't "prove" that but many have mentioned it and that is what I experienced. I had 3-4 pretty rocky months before things really started smoothing out. A few things improved in hours to a couple of weeks. After that it was 9 months before a large amount of healing was done.

    I definitely had a layered effect. After the biggest loudest layer was peeled back there was another layer underneath, and another and another.
     
  13. Freddd

    Freddd Senior Member

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    UNDER METHYLATORS


    My remaining symptoms and characteristics after b12 & cofactors

    2 - Poor tolerance of heat
    9 - Excess perspiration
    16 - Perfectionism
    17 - Competitiveness

    19 - Vasomotor rhinitis
    27 - Good tolerance of cold

    My symptoms before taking b12 and cofactors


    1 - Depression - Depression
    2 - Poor tolerance of heat
    3 - Unexplained nausea
    4 - Frequent colds and flu
    5 - Poor pain tolerance
    6 - Joint pain
    7 - Joint swelling
    8 - Joint stiffness
    9 - Excess perspiration
    10 - Insomnia
    11 - Muscle pains - Muscle pains
    12 - Seasonal depression
    13 - Inhalant allergies
    14 - Oppositional –defiant -so my mother said but she was highly disturbed and psychotic and it was only her I was opposing and defying when she was irrational
    15 - Frequent headaches - Frequent headaches

    16 - Perfectionism
    17 - Competitiveness
    18 - Asthma
    19 - Vasomotor rhinitis
    20 - Allergic skin disorders
    21 - Pruritis
    22 - Sparse body hair - increased a lot to normal after mb12 and cofactors, especially on slick legs
    23 - Fatigue
    24 - Respond well to SAM-e

    25 - Anorexia/bulimia - physical, not psychological, no body distortion, no motivation to be anorexic except for b12 containing foods in some people
    26 - Prone to hives
    27 - Good tolerance of cold

    Not my symptoms/chraracteristics

    High salivary flow
    High tear flow
    Never dry eyes
    Hyperactivity
    Phobias
    Highly motivated
    Hard driving personality
    Addictive tendencies
    bipolar disorder
    OCD
    Schizophrenia
    Abundant or excess saliva in mouth
    Obsessive compulsive
    Slenderness
    Do worse on b12 and folates (4)
    Shopping/gambling disorders
    Excess stomach acid
    High libido
    Elevated absolute basophils
    Extreme internal anxiety despite outwardly calm
    Delusion thinking rather than hallucinations
    Respond well to SAM-e, methionine, avoid folic acid (1)
    Low serotonin
    Low dopamine
    Low norepinephrine
    Psychosis
    26 Total



    OVER METHYLATORS


    My remaining symptoms and characteristics after b12 & cofactors

    1- High religiosity - if you include high spirituality instead of religiosity, I am anti-religiosity as such.
    2 - High artistic/musical ability

    4 - Absence of seasonal inhalant allergies - my seasonal inhalant allergies nave gone away with methylb12/methylfolate
    19 - Intolerance to SSRI drugs
    21 - Low motivation





    My symptoms before taking b12 and cofactors, except where noted


    1- High religiosity - if you include high spirituality instead of religiosity, I am anti-religiosity as such.
    2 - High artistic/musical ability
    3 - Auditory hallucinations
    4 - Absence of seasonal inhalant allergies - my seasonal inhalant allergies nave gone away with methylb12/methylfolate
    5 - Frequent dry eyes
    6 - Multitude of chemical sensitivities
    7 - Multitude of food sensitivities
    8 - Low libido - Low libido
    9 - Auditory hallucinations
    10 - Underachievement as child - so my mother would say
    11 - Nervous legs - Nervous legs
    12 - Depression - Depression
    13 - Despair
    14 - Respond well to b12

    15 - Upper body pain
    16 - Head pain
    17 - Low salivary
    18 - Low tears
    19 - Intolerance to SSRI drugs
    20 - Treatment revolves around folic acid, niacin, B12, and a high protein diet. (2)
    21 - Low motivation


    Not my symptoms/chraracteristics

    Elevated serotonin
    Elevated dopamine
    Elevated norepinephrine
    Self injury
    High anxiety evident to all
    Obsessions but not compulsions
    Paranoia
    Heavy body hair
    Hyperactivity
    Grandiosity
    Respond well to b12 but avoid SAM-e, inositol, methionine TMG and DMG (1)
    Panic attacks
    Nervous
    High pain tolerance
    “space cadet”
    Learning disabilities
    Low perspiration
    17 Total

    Once again, what remains after b12 and cofactors is approximately equal and down to 5 or 6 items in each category. Nothing distinguishing.
     
  14. Sunday

    Sunday Senior Member

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    This thread continues to be an education. Freddd, I'm impressed you can post so lucidly with the flu.


    michaeldfaulkner: "after a time some things get better and then it appeared as if another layer was coming up to be worked on" is an excellent pithy way of putting my experience. Yes. Healing crises, one after another and sometimes in a cluster (we won't go into the other word often associated with "cluster").

    For instance, I had constant nausea (as opposed to almost-constant nausea pre-B12) for my 2-month crash, then - wow, very infrequent very mild nausea - my god, the relief, so much brainpower goes into nausea. But now, in the middle of month 4, I'm having digestive stuff again, less nausea more pain and gut-rumbling. So to me it feels like it's a different part of the gut/digestive healing. Some of the reason I feel that is because there's starting to be a pattern to this, after going through it enough times. Some of it is because the way I was led to this protocol (a series of "coincidences") and my gut feelings about it - there's just some deep-down part of me that feels it's the thing for me to do. Now being borne out by actual symptom relief, even if it's on and off. I despair when I go down, I'm not going to lie to you, and yes I do wonder if I'll ever get up again. But that feeling underneath it all keeps me going.
     
  15. Sunday

    Sunday Senior Member

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    Btw Freddd, I've found your "healing backwards" description very helpful. It really does seem as though that's what's happening to me. And some of the things that are healing are things I wasn't even consciously aware of.
     
  16. Freddd

    Freddd Senior Member

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    Quote: Glutathione is required for the methylation of B12,

    methjylb12 doesn't require methylation, obviously assuming inactive b12.

    This reference seems to contradict that gluathione is antagonistic to B12 absorption as I've read on this thread??

    My experience was that glutathione (precursors) antagonized methylfolate producing immediate hard folate deficiency and immediately increased inflammation and inflammatory response throughout the body. Further it aqppeared to (and according to Rich biochemically

    accidently truncated - see my response to Rich for what I would have said and more
     
  17. maryb

    maryb iherb code TAK122

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    Hi Rich - just wanted to ask you do you think there is any point in me trying this protocol with still having 6 amalgam fillings? I don't feel well enough to go to have them removed at the moment but am desperate to try something.
     
  18. Hysterical Woman

    Hysterical Woman Senior Member

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    Hi Freddd,

    Yes, unfortunately docs frequently measure the minerals in the serum, but that doesn't give you any real information about what the minerals are doing in the tissues of the body where most minerals reside. That is why I chose to have an EXAtest which measures the levels in the cells by doing a scraping under the tongue. Potassium (and magnesium levels can be increased and decreased quickly in the blood but not in the tissue). In the case of magnesium, if you have a serious deficiency, it can take up to 1 year to return the levels to normal. If you have other problems such as malabsorption it can take even longer.

    And yes, both low and high potassium can be problems. From the EXAtest Interpretation Guide:

    "High Potassium: Tissue potassium may be elevated despite normal serum levels. THe EXA test reveals the tissue levels in the face of either excess or low potassium in the serumm can cause profound changes in membrane potentials and altered EKG readings.

    Elevated tissue potassium may be due to intravenous administartion, hormonal therapy (excess insulin), acidosis, or dietary intake. Cellular electrolyte levels and resting membrane potentials are affected by tissue potassium, sodium and calcium concentrations. Potassium in tissues is about 30-40 times greater than serum."

    and for

    "Low Potassium: Low magnesium leads to low tissue potassium since mangnesium is absolutely needed for potassium transport into tissue. Risk for cardiac irritability, irregulaity and hypertnesion have related to loss of cellular potassium. Depletion occurs when potassium output exceeds intake.

    Loss may be seen in adrenal insufficiency, excess sweating, diruretic use, steroid use, alcoholism, dietary loss, diarrhea, vomiting, renal disease, alkolosis, and malabsorption. High protein weight loss programs or diabetic keto acidosis can cause loss of potassium as well as magnesium due to excretion of ketones during the sudden mobilization of fats."

    Take care,

    HW
     
  19. richvank

    richvank Senior Member

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    Hi, maryb.

    Since I'm a researcher, not a licensed physician, I am not able to give individual treatment advice unless a physiciain is involved to review my suggestions.

    However, in terms of general information, not medical advice, I don't think the issue of whether to remove amalgams before or after treating the partial methylation cycle block in CFS has been resolved, at least to my satisfaction. I will give you the pros and cons as I understand them.

    First, it is kind of a basic principle of toxicology that when you are treating a toxicity, the first thing to do is to remove the source of the toxins. That is sort of common sense, and it's a good idea in general.

    However, the toxicity of mercury from amalgam fillings is a unique situation in that the removal of the source of the toxin tends to expose the person even more to the toxin, because drilling heats the filling and raises the vapor pressure of the mercury, which evaporates and is easily inhaled, because the fillings are located in the mouth.

    Precautions such as a good vacuum in the mouth and a separate supply of air to the nose are helpful, but there is probably still some additional exposure to the patient from the evaporating mercury.

    This situation is compounded by the fact that often the person's glutathione level has been depleted, partly by having to detox mercury in the past, as well as due to other causes, so if there is additional exposure to mercury, the person is not in a good status to deal with it, because of their low glutathione, and the result can be more serious toxicity, including neurotoxicity due to entry of mercury into the brain. So all of this argues to lift the partial methylation cycle block and thus bring glutathione up before removing the amalgams.

    On the other hand, the continued presence of the amalgam fillings will cause continued intake of mercury, which will have to be dealt with by the detox system, so that in a sense one is working against oneself by leaving the amalgams in while trying to increase the rate of removal by the detox system.

    Another factor is that mercury can inhibit the activity of several enzymes in the methylation cycle and related pathways, so that it may be difficult to lift the partial methylation cycle block in some cases unless some sort of chelation treatment is done first to lower the mercury levels.

    So the situation is somewhat complicated. I guess I find the first argument most compelling, especially since I have read several reports from people who had their fillings removed initially, even with precautions, and suffered because of it. So I guess I think that generally speaking there is merit in trying to lift the partial methylation cycle block and thus raise glutathione before disturbing the amalgams. But I can't say that I have proof that this is the best approach in all cases.

    If this doesn't work, then I think that some type of chelation should be considered next. I've read good things about MicroSilica and OSH#1 from Dr. Klinghardt.

    I hope this is helpful.

    Best regards,

    Rich
     
  20. richvank

    richvank Senior Member

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    I would like to comment on the interaction of glutathione and vitamin B12, both in the normal metabolism and in freddd's metabolism, as I understand it. I hope everyone understands that I am trying to be constructive in doing so, not trying to be argumentative.

    In the normal metabolism, glutathione is used by the cells to remove alkyl ligands, such as methyl or adenosyl, from incoming cobalamins. This has been shown in a recent study, the abstract of which is pasted below. Later in the normal processing of B12 in the cells, either a methyl group is reattached to the cobalamin after it is bound to the enzyme methionine synthase, or an adenosyl group is attached to it after it is transported into the mitochondria.

    In addition, although it is not yet clear in detail, it appears that between these parts of the normal processing, glutathione binds with cobalamin to form glutathionylcobalamin, and this serves to protect the cobalamin from reacting with other substances and being lost from its normal uses in the cells. Evidence for the presence of glutathionylcobalamin in cells has been reported in a recent paper by Hannibal et al., the abstract of which is also pasted below, and the reaction between aquocobalamin and glutathione has been found to be quite rapid (abstract below by Xia et al.). So in the normal metabolism of B12, glutathione plays a significant, positive role.

    Based on this, in the GD--MCB hypothesis I have suggested that CFS onset results when glutathione is sufficiently lowered by a variety of possible causes in a person with the appropriate genomic predisposition that B12 is sufficiently lost from production of methyl B12 so that a partial block in the methylation cycle occurs. This then reflects back on the ability to produce glutathione, keeping it depleted and causing CFS to be a chronic illness.

    freddd has reported that in his case, he found glutathione or its precursors to be deleterious. He has also reported information suggesting that he has inherited a mutation or inborn error of metabolism in his B12 processing enzymes. I suggest that based on his experience with glutathione, this mutation must be located in an enzyme that is involved in a step beyond the use of glutathione to remove the methyl group from cobalamin. Apparently, his cells are not able to replace the methyl group on cobalamin after it has been removed, or to add an adenosyl group to cobalamin. Thus, he has found that the only way his cells can get enough methylcobalamin and adenosylcobalamin is to supply these active, coenzyme forms directly as supplements, taken in large dosages. This is what might be referred to in the physical sciences as a "brute force" approach. I can understand that it is the only thing that works in a case like his, and I'm glad that he discovered it.

    However, I want to emphasize that this biochemical behavior is unusual, and it is not likely to be the case in most people who have CFS, because the mutations that can cause this are rare in the human population. Many people with CFS have reported that they have found glutathione to be beneficial to them. There are also some who have not reacted well to it. It isn't clear that this is because of interference with B12 utilization, as in freddd's case, however. It may result from utilization of glutathione by yeasts in the gut, mobilization of toxins into the blood by improved operation of the detox system, stimulation of the immune system, producing a Herxheimer effect, or breakdown of some of the glutathione to form sulfite, which is more than the sulfite oxidase enzyme can handle. I don't think we know which of these mechanisms could be involved in a given case.

    In order for freddd's approach to work, it must be true that by putting large concentrations of the coenzyme forms of B12 into the blood, enough of each of them diffuses into the cells and survives removal of their ligands to give the cells enough methyl B12 and adenosyl B12 directly to satisfy their needs for them. As far as I know, this is not described in the current research literature. Over the past weekend, I had the opportunity to talk personally to Prof. Barry Shane at a medical conference. He is from U.C.-Berkeley, and is an authority on folate and B12 metabolism. I asked him whether B12 could enter cells without being bound to transcobalamin, and he initially said no. Then I told him that there appears to be evidence that if large dosages are used, some unbound methyl B12 and adenosyl B12 are able to enter cells. He then conceded that if the concentrations were high enough, this might be possible. He compared this to the known ability of the body to absorb 1 % of B12 that passes through the gut, even without intrinsic factor. However. he said that occurs by diffusion through the tight junctions between the enterocytes that line the intestine, and that would be different from entry through a cell membrane. Anyway, this conversation confirmed to me that reserachers have not yet studied the direct transport of B12 through the cell membranes, which is apparently what happens in freddd's treatment. I don't doubt that it occurs. It just doesn't seem to have been studied.

    freddd has described, and the experiences reported by others here seem to confirm, that his treatment approach will work on people who have a wide variety of B12-related problems, including those who have CFS, which involves a partial block in the methylation cycle. This is understandable, because freddd's treatment bypasses all of the normal processes of absorption by the gut, transport by transcobalamin, and processing of B12 within the cells to form the coenzyme forms of B12, and it does this by supplying them directly in large dosages.

    However, I suggest (and freddd may not agree) that this approach is actually "overkill" for most people with CFS. I suggest that the reason is that most people with CFS have normal absorption, transport and processing of B12, except for glutathione depletion, which allows their B12 to be hijacked within the cells by reaction with other substances, including toxins. This is why hydroxocobalamin in high dosages, together with 5-methyl tetrahydrofolate to compensate for the methyl trap that resulted when their availability of methyl B12 decreased due to this hijacking, works for most of them. I suggest that the reason it did not work for nearly a third of them is not that hydroxocobalamin is not effective for them, but that they have had other issues that have prevented the methylation cycle function from being restored, such as depletion of vitamin and mineral cofactors for this part of the metabolism (such as zinc, magnesium, or other B-vitamins) or depletion of amino acids, including methionine, or high body burdens of toxic metals that block the enzymes in this part of the biochemistry.

    I want to reiterate that according to the literature, mutations in the intracellular B12 processing enzymes are rare. The most recent paper I've found reports that only about 400 people have been identified worldwide as having these mutations. Of course, there must be people who have not been identified, especially in the underdeveloped countries, but nevertheless, the evidence is that these mutations are rare. When this number is compared to the much larger number of people who have CFS (of the order of a million in the U.S. alone), it is clear that most people with CFS do not have these mutations. According to Prof. Shane, more of the problems with B12 involve transcobalamin deficiency, so that B12 cannot be properly transported from the gut to the cells. freddd's treatment should also work for people who have this problem, but I don't think they would respond in a negative way to glutathione, as he did, because very few of them would be expected to also have a mutation in their intracellular B12 processing enzymes.

    Another issue that continues to be discussed here is whether it is better to "push through" the symptoms and continue with large dosages of the coenzyme forms of B12, or whether it is better to start with lower dosages of folate and B12 ( such as hydroxocobalamin) as in the Simplified Treatment Approach that I have suggested, and work up as tolerated. I don't have a hard and fast answer to this, and it may depend on the individual and their body burden of toxins.

    I know that some people have been able to more or less continue with freddd's protocol and have been reporting benefits from doing so. I also know that there are people who have found this approach to be intolerable in terms of the symptoms that have arisen, and they have dropped back and have taken a slower approach.

    I don't think I am able to judge what people should do about this, because unless I were "in their skins," I have no way to know how severe their symptoms are. I also don't know if mobilizing toxins (such as mercury) at higher levels can move them to less desirable locations in the body, such as the brain, or whether large dosages of methyl B12 can eventually remove them from the brain.

    In view of these unknowns, my tendency is to advise caution, and to favor the more gradual approach, but I don't have personal experience with this, as freddd does, and I can't argue with his personal experience. He also reports that there have been a number of others who have had similar experiences, though I'm not aware of controlled studies with these higher dosages.

    The best data I have for the more gradual approach is from the clinical study that Dr. Nathan and I carried out with 30 women. Two-thirds of them improved, some markedly. Two of them were able to return to full-time work, and the 84-year-old was able to join her friends for a trip to Paris.

    Best regards,

    Rich



    J Biol Chem. 2009 Nov 27;284(48):33418-24. Epub 2009 Oct 2.

    A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins.

    Kim J, Hannibal L, Gherasim C, Jacobsen DW, Banerjee R.

    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5066, USA.

    Pathways for tailoring and processing vitamins into active cofactor forms exist in mammals that are unable to synthesize these cofactors de novo. A prerequisite for intracellular tailoring of alkylcobalamins entering from the circulation is removal of the alkyl group to generate an intermediate that can subsequently be converted into the active cofactor forms. MMACHC, a cytosolic cobalamin trafficking chaperone, has been shown recently to catalyze a reductive decyanation reaction when it encounters cyanocobalamin. In this study, we demonstrate that this versatile protein catalyzes an entirely different chemical reaction with alkylcobalamins using the thiolate of glutathione for nucleophilic displacement to generate cob(I)alamin and the corresponding glutathione thioether. Biologically relevant thiols, e.g. cysteine and homocysteine, cannot substitute for glutathione. The catalytic turnover numbers for the dealkylation of methylcobalamin and 5'-deoxyadenosylcobalamin by MMACHC are 11.7 +/- 0.2 and 0.174 +/- 0.006 h(-1) at 20 degrees C, respectively. This glutathione transferase activity of MMACHC is reminiscent of the methyltransferase chemistry catalyzed by the vitamin B(12)-dependent methionine synthase and is impaired in the cblC group of inborn errors of cobalamin disorders.

    PMID: 19801555 [PubMed - indexed for MEDLINE]



    Clin Chem Lab Med. 2008;46(12):1739-46.

    Accurate assessment and identification of naturally occurring cellular cobalamins.

    Hannibal L, Axhemi A, Glushchenko AV, Moreira ES, Brasch NE, Jacobsen DW.

    Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

    BACKGROUND: Accurate assessment of cobalamin profiles in human serum, cells, and tissues may have clinical diagnostic value. However, non-alkyl forms of cobalamin undergo beta-axial ligand exchange reactions during extraction, which leads to inaccurate profiles having little or no diagnostic value. METHODS: Experiments were designed to: 1) assess beta-axial ligand exchange chemistry during the extraction and isolation of cobalamins from cultured bovine aortic endothelial cells, human foreskin fibroblasts, and human hepatoma HepG2 cells, and 2) to establish extraction conditions that would provide a more accurate assessment of endogenous forms containing both exchangeable and non-exchangeable beta-axial ligands. RESULTS: The cobalamin profile of cells grown in the presence of [ 57Co]-cyanocobalamin as a source of vitamin B12 shows that the following derivatives are present: [ 57Co]-aquacobalamin, [ 57Co]-glutathionylcobalamin, [ 57Co]-sulfitocobalamin, [ 57Co]-cyanocobalamin, [ 57Co]-adenosylcobalamin, [ 57Co]-methylcobalamin, as well as other yet unidentified corrinoids. When the extraction is performed in the presence of excess cold aquacobalaminacting as a scavenger cobalamin (i.e. "cold trapping"), the recovery of both [ 57Co]-glutathionylcobalamin and [ 57Co]-sulfitocobalamin decreases to low but consistent levels. In contrasts, the [ 57Co]-nitrocobalamin observed in the extracts prepared without excess aquacobalamin is undetected in extracts prepared with cold trapping. CONCLUSION: This demonstrates that beta-ligand exchange occur with non-covalently bound beta-ligands. The exception to this observation is cyanocobalamin with a non-exchangeable CN- group. It is now possible to obtain accurate profiles of cellular cobalamin.

    PMID: 18973458 [PubMed - indexed for MEDLINE]


    Inorg Chem. 2004 Oct 18;43(21):6848-57.

    Studies on the formation of glutathionylcobalamin: any free intracellular aquacobalamin is likely to be rapidly and irreversibly converted to glutathionylcobalamin.

    Xia L, Cregan AG, Berben LA, Brasch NE.

    Research School of Chemistry, Australian National University, Canberra ACT 0200, Australia.

    A decade ago Jacobsen and co-workers reported the first evidence for the presence of glutathionylcobalamin (GSCbl) in mammalian cells and suggested that it could in fact be a precursor to the formation of the two coenzyme forms of vitamin B(12), adenosylcobalamin and methylcobalamin (Pezacka et al. Biochem. Biophys. Res. Commun. 1990, 169, 443). It has also recently been proposed by McCaddon and co-workers that GSCbl may be useful for the treatment of Alzheimer's disease (McCaddon et al. Neurology 2002, 58, 1395). Aquacobalamin is one of the major forms of vitamin B(12) isolated from mammalian cells, and high concentrations of glutathione (1-10 mM) are also found in cells. We have now determined observed equilibrium constants, K(obs)(GSCbl), for the formation of GSCbl from aquacobalamin and glutathione in the pH range 4.50-6.00. K(obs)(GSCbl) increases with increasing pH, and this increase is attributed to increasing amounts of the thiolate forms (RS(-)) of glutathione. An estimate for the equilibrium constant for the formation of GSCbl from aquacobalamin and the thiolate forms of glutathione of approximately 5 x 10(9) M(-1) is obtained from the data. Hence, under biological conditions the formation of GSCbl from aquacobalamin and glutathione is essentially irreversible. The rate of the reaction between aquacobalamin/hydroxycobalamin and glutathione for 4.50 < pH < 11.0 has also been studied and the observed rate constant for the reaction was found to decrease with increasing pH. The data were fitted to a mechanism in which each of the 3 macroscopic forms of glutathione present in this pH region react with aquacobalamin, giving k(1) = 18.5 M(-1) s(-1), k(2) = 28 +/- 10 M(-1) s(-1), and k(3) = 163 +/- 8 M(-1) s(-1). The temperature dependence of the observed rate constant at pH 7.40 ( approximately k(1)) was also studied, and activation parameters were obtained typical of a dissociative process (DeltaH++ = 81.0 +/- 0.5 kJ mol(-1) and DeltaS++ = 48 +/- 2 J K(-1) mol(-1)). Formation of GSCbl from aquacobalamin is rapid; for example, at approximately 5 mM concentrations of glutathione and at 37 degrees C, the half-life for formation of GSCbl from aquacobalamin and glutathione is 2.8 s. On the basis of our equilibrium and rate-constant data we conclude that, upon entering cells, any free (protein-unbound) aquacobalamin could be rapidly and irreversibly converted to GSCbl. GSCbl may indeed play an important role in vitamin B(12)-dependent processes.

    PMID: 15476387 [PubMed - indexed for MEDLINE]
     

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