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B-12 - The Hidden Story
- Thread starter Cort
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Hi Rich
Wow! - and there I was expecting to be told to take more calcium or zinc!! I really appreciate the indepth reply, and I love finding out what is really going on. It's encouraging to find it IS something to do with getting methylation going. So I'm on the right track.
When you say detoxing requires a lot of sulfur, does that mean we should be eating a lot of sulfur foods? I have eliminated a lot of sulfur foods which has been helpful for controlling yeast and made me feel better all round. I definitely have a problem with leeks, cabbage and coffee.
Just another question on the orthostatic tachycardia and methylation. I saw a cardiologist last week who gave me a clean bill of health as far as my heart is concerned. I even muttered about left ventricular dysfunction, and he told me that it was working fine. He told me I had classic POTS, as my heart rate raced away as I was on the exercise bike. He gave me a different beta blocker, which worked beautifully, but I will only take it when I know I'm going to be on my feet a lot. I have been reading alot about choline, which needs to be methylated to convert to acetylcholine, and the process also requires B1, preferably transdermal. I am thinking that it makes sense to supplement these, as presumably the body needs more than what is available through diet in order to overcome a deficiency that has led to autonomic dysfunction? Have you got any view on this? Should I be taking lecithin / choline?
thanks again - your input is helping me piece all the bits of the jigsaw together.
Nicola
Sunday,
Zinc really helped me with nail growth as my level was borderline based on my Spectracell lab test. Also my skin did not heal before taking 50 mg zinc a day. But I still have ridges on my nails and the moon parts are no longer there.
Nicola,
Could I ask how much B12 and folate you take per day?
Zinc really helped me with nail growth as my level was borderline based on my Spectracell lab test. Also my skin did not heal before taking 50 mg zinc a day. But I still have ridges on my nails and the moon parts are no longer there.
Nicola,
Could I ask how much B12 and folate you take per day?
Hi Sara
Currently I am taking 600mg folate and between 5-7.5mg methyl B12 a day, in divided doses. The half moons started coming back almost as soon as I had my amalgams out, and have slowly been reappearing in the 3.5 years since, but theye have definitely had a spurt since starting on the mB12. I am also taking 50mg zinc / day, and took it up to 100mg for a week or so, but didn't notice any difference.
Nicola
Currently I am taking 600mg folate and between 5-7.5mg methyl B12 a day, in divided doses. The half moons started coming back almost as soon as I had my amalgams out, and have slowly been reappearing in the 3.5 years since, but theye have definitely had a spurt since starting on the mB12. I am also taking 50mg zinc / day, and took it up to 100mg for a week or so, but didn't notice any difference.
Nicola
Nicola, do you find better benefits from splitting up your mb12 doses? I have been experimenting with doing that and also with taking them more at once (I'm up to 15mg, and I just can't fit three of those and the adb12s in my mouth all at once!). I'd be curious to know what led you to split the doses.
Rich, I finally had the plasma amino acids test. Elevated methionine (2.9), leucine (18), isoleucine (8.9), valine (27), sarcosine (1.4). Low homocystine (< dl), cystathionine (< dl), taurine (4.7). Cystine was in range (5.4).
The top recommendations under presumptive needs were for B6, folate, B12, and magnesium. The supplementation schedule also listed 755mg of methionine.
Does that make any sense?
The top recommendations under presumptive needs were for B6, folate, B12, and magnesium. The supplementation schedule also listed 755mg of methionine.
Does that make any sense?
Hi Sunday
I think it was Freddd who suggested that if you were having problems with start-up to aim for length of B12 intake, rather than depth, ie, taking in small doses over a longer period, rather than a big dose all at once. As I wanted to go gently, I took my doses during the course of a day, and stuck with it. I think he recommends doing a challenge dose (ie a big dose all at once) as a means of testing whether you have any further reaction once you have reached your top dose. Freddd - if I have this wrong please feel free to correct me!!
Nicola
I think it was Freddd who suggested that if you were having problems with start-up to aim for length of B12 intake, rather than depth, ie, taking in small doses over a longer period, rather than a big dose all at once. As I wanted to go gently, I took my doses during the course of a day, and stuck with it. I think he recommends doing a challenge dose (ie a big dose all at once) as a means of testing whether you have any further reaction once you have reached your top dose. Freddd - if I have this wrong please feel free to correct me!!
Nicola
Hi Nicola,
I think he recommends doing a challenge dose (ie a big dose all at once) as a means of testing whether you have any further reaction once you have reached your top dose.
This is approximately what I have said. As a dose approaches approximately 3mg injected sc, say about 15mg sublingual, maximum effect is reached. However, there is a separate additional effect in the CNS when the dose reaches approximately 7.5mg sc injected (50mg sublingual single continuous dose over 3 hours or so). This is hypothecized to be when the CSF/CNS is penetrated by diffusion in those who normally have a problem getting sufficient cobalamin into the CSF/CNS. Significantly low cerebral spinal fluid cobalamin levels independently of serum levels have been found in people with CFS/FMS/Alzheimer's. Many people have no response to the 50mg sublingual challange dose. Some people have a response to each adb12 and mb12 separately. The people who have a response generally will experience some improvement with the larger doses usually achieved through injections. These tend to be the people who will benefit from injections rather than or in addition to sublinguals. The challange dose however should only be done after all the body level responses are done because the body responses are generally much "louder" and will mask the more subtle CNS reponses.
On injections I was unable to tell the difference between 2.5mg injection and 5mg. However 7.5 was very noticably different. I had the same effects with sublinguals at proportionate doses.
I think he recommends doing a challenge dose (ie a big dose all at once) as a means of testing whether you have any further reaction once you have reached your top dose.
This is approximately what I have said. As a dose approaches approximately 3mg injected sc, say about 15mg sublingual, maximum effect is reached. However, there is a separate additional effect in the CNS when the dose reaches approximately 7.5mg sc injected (50mg sublingual single continuous dose over 3 hours or so). This is hypothecized to be when the CSF/CNS is penetrated by diffusion in those who normally have a problem getting sufficient cobalamin into the CSF/CNS. Significantly low cerebral spinal fluid cobalamin levels independently of serum levels have been found in people with CFS/FMS/Alzheimer's. Many people have no response to the 50mg sublingual challange dose. Some people have a response to each adb12 and mb12 separately. The people who have a response generally will experience some improvement with the larger doses usually achieved through injections. These tend to be the people who will benefit from injections rather than or in addition to sublinguals. The challange dose however should only be done after all the body level responses are done because the body responses are generally much "louder" and will mask the more subtle CNS reponses.
On injections I was unable to tell the difference between 2.5mg injection and 5mg. However 7.5 was very noticably different. I had the same effects with sublinguals at proportionate doses.
I most certainly do agree, methylcobalamin and adenosylcobalamin far far far surpasses cyanocobalamin and hydroxycobalamin in every way possible for adults in healing muscles, nerves, methylation defects etc etc etc. They go way beyond merely correcting methylation defects, which mb12 actually does whereas the other forms don't supply methyl groups but rather consume then requiring additional methyl sources. My recovery from way past the edge, dying rapidly, is a living breathing demonstration of that every day. My doc said he had never seen anybody recover like this from being so far gone.
Here is an interesting article that tells more about what b12 does.
http://emedicine.medscape.com/article/1152670-overview
The neurologic manifestation of cobalamin deficiency is less well understood. CNS demyelination may play a role, but how cobalamin deficiency leads to demyelination remains unclear. Reduced SAM or elevated methylmalonic acid (MMA) may be involved.
SAM is required as the methyl donor in polyamine synthesis and transmethylation reactions. Methylation reactions are needed for myelin maintenance and synthesis. SAM deficiency results in abnormal methylated phospholipids such as phosphatidylcholine, and it is linked to central myelin defects and abnormal neuronal conduction, which may account for the encephalopathy and myelopathy. In addition, SAM influences serotonin, norepinephrine, and dopamine synthesis. This suggests that, in addition to structural consequences of vitamin B-12 deficiency, functional effects on neurotransmitter synthesis that may be relevant to mental status changes may occur. Parenthetically, SAM is being studied as a potential antidepressant.
Another possible cause of neurologic manifestations involves the other metabolically active form of cobalamin, adenosylcobalamin (see image below), a mitochondrial cofactor in the conversion of L-methylmalonyl CoA to succinyl CoA. Vitamin B-12 deficiency leads to an increase in L-methylmalonyl-CoA, which is converted to D-methylmalonyl CoA and hydrolyzed to MMA. Elevated MMA results in abnormal odd chain and branched chain fatty acids with subsequent abnormal myelination, possibly leading to defective nerve transmission.
More recent studies propose a very different paradigm: B-12 and its deficiency impact a network of cytokines and growth factors, ie, brain, spinal cord, and CSF TNF-alpha; nerve growth factor (NGF), IL-6 and epidermal growth factor (EGF), some of which are neurotrophic, others neurotoxic. Vitamin B-12 regulates IL-6 levels in rodent CSF. In rodent models of B-12 deficiency parenteral EGF or anti-NGF antibody injection prevents, like B-12 itself, the SCD-like lesions.
In the same models, the mRNAs of several cell-type specific proteins (glial fibrillary acidic protein, myelin basic protein) are decreased in a region specific manner in the CNS, but, in the PNS myelin, protein zero and peripheral myelin protein 22 mRNA remain unaltered.
In human and rodent serum and CSF, concomitantly with a vitamin B-12 decrease, EGF levels are decreased, while at the same time, TNF-alpha increases in step with homocysteine levels. These observations provide evidence that the clinical and histological changes of vitamin B-12 deficiency may result from up-regulation of neurotoxic cytokines and down-regulation of neurotrophic factors.
N2 O pathomechanisms in vitamin B-12 deficiency
N2 O can oxidize the cobalt core of vitamin B-12 from a 1+ to 3+ valance state, rendering methylcobalamin inactive, inhibiting HC conversion to methionine and depleting the supply of SAM. Patients with sufficient vitamin B-12 body stores can maintain cellular functions after N2 O exposure, but in patients with borderline or low vitamin B-12 stores, this oxidation may be sufficient to precipitate clinical manifestations.
http://emedicine.medscape.com/article/1152670-overview
The neurologic manifestation of cobalamin deficiency is less well understood. CNS demyelination may play a role, but how cobalamin deficiency leads to demyelination remains unclear. Reduced SAM or elevated methylmalonic acid (MMA) may be involved.
SAM is required as the methyl donor in polyamine synthesis and transmethylation reactions. Methylation reactions are needed for myelin maintenance and synthesis. SAM deficiency results in abnormal methylated phospholipids such as phosphatidylcholine, and it is linked to central myelin defects and abnormal neuronal conduction, which may account for the encephalopathy and myelopathy. In addition, SAM influences serotonin, norepinephrine, and dopamine synthesis. This suggests that, in addition to structural consequences of vitamin B-12 deficiency, functional effects on neurotransmitter synthesis that may be relevant to mental status changes may occur. Parenthetically, SAM is being studied as a potential antidepressant.
Another possible cause of neurologic manifestations involves the other metabolically active form of cobalamin, adenosylcobalamin (see image below), a mitochondrial cofactor in the conversion of L-methylmalonyl CoA to succinyl CoA. Vitamin B-12 deficiency leads to an increase in L-methylmalonyl-CoA, which is converted to D-methylmalonyl CoA and hydrolyzed to MMA. Elevated MMA results in abnormal odd chain and branched chain fatty acids with subsequent abnormal myelination, possibly leading to defective nerve transmission.
More recent studies propose a very different paradigm: B-12 and its deficiency impact a network of cytokines and growth factors, ie, brain, spinal cord, and CSF TNF-alpha; nerve growth factor (NGF), IL-6 and epidermal growth factor (EGF), some of which are neurotrophic, others neurotoxic. Vitamin B-12 regulates IL-6 levels in rodent CSF. In rodent models of B-12 deficiency parenteral EGF or anti-NGF antibody injection prevents, like B-12 itself, the SCD-like lesions.
In the same models, the mRNAs of several cell-type specific proteins (glial fibrillary acidic protein, myelin basic protein) are decreased in a region specific manner in the CNS, but, in the PNS myelin, protein zero and peripheral myelin protein 22 mRNA remain unaltered.
In human and rodent serum and CSF, concomitantly with a vitamin B-12 decrease, EGF levels are decreased, while at the same time, TNF-alpha increases in step with homocysteine levels. These observations provide evidence that the clinical and histological changes of vitamin B-12 deficiency may result from up-regulation of neurotoxic cytokines and down-regulation of neurotrophic factors.
N2 O pathomechanisms in vitamin B-12 deficiency
N2 O can oxidize the cobalt core of vitamin B-12 from a 1+ to 3+ valance state, rendering methylcobalamin inactive, inhibiting HC conversion to methionine and depleting the supply of SAM. Patients with sufficient vitamin B-12 body stores can maintain cellular functions after N2 O exposure, but in patients with borderline or low vitamin B-12 stores, this oxidation may be sufficient to precipitate clinical manifestations.
N
Hi, can someone please confirm for me that this is still the current treatment protocol because I would like to try it.:
SIMPLIFIED TREATMENT APPROACH
FOR LIFTING THE METHYLATION CYCLE BLOCK
IN CHRONIC FATIGUE SYNDROME (Revised)
(Extracted from the full treatment program
developed by Amy Yasko, Ph.D., N.D.
which is used primarily in treating autism [1])
SUPPLEMENTS
1. FolaPro [2]: ¼ tablet (200mcg) daily
2. Actifolate [3]: ¼ tablet daily
3. General Vitamin Neurological Health Formula [4]: start with ¼ tablet and work up dosage as tolerated to 2 tablets daily
4. Phosphatidyl Serine Complex [5]: 1 softgel capsule daily
5. Activated B12 Guard [6]: 1 sublingual lozenge daily
SIMPLIFIED TREATMENT APPROACH
FOR LIFTING THE METHYLATION CYCLE BLOCK
IN CHRONIC FATIGUE SYNDROME (Revised)
(Extracted from the full treatment program
developed by Amy Yasko, Ph.D., N.D.
which is used primarily in treating autism [1])
SUPPLEMENTS
1. FolaPro [2]: ¼ tablet (200mcg) daily
2. Actifolate [3]: ¼ tablet daily
3. General Vitamin Neurological Health Formula [4]: start with ¼ tablet and work up dosage as tolerated to 2 tablets daily
4. Phosphatidyl Serine Complex [5]: 1 softgel capsule daily
5. Activated B12 Guard [6]: 1 sublingual lozenge daily
Hi Nexus,
It depends, and I don't mean diapers.
Are asking about The simplified methylation protocol with the inactive hydroxyb12 that are you speaking about or the active b12 protocol that was the basis of this thread being started? That one usses both methylb12 and adenosylb12 and is more complicated and far more effective.?
It depends, and I don't mean diapers.
Are asking about The simplified methylation protocol with the inactive hydroxyb12 that are you speaking about or the active b12 protocol that was the basis of this thread being started? That one usses both methylb12 and adenosylb12 and is more complicated and far more effective.?
N
I was talking about the simplified protocol because that's what I managed to find in this maze of a thread.
Can you outline what needs to be done on the active b12 protocol?
Sorry my comprehension skills are very bad. I couldn't read the whole thread or really understand the parts I did.
Can you outline what needs to be done on the active b12 protocol?
Sorry my comprehension skills are very bad. I couldn't read the whole thread or really understand the parts I did.
Hi, freddd.
This is good stuff. There are at least three components in myelin that require methylation for their synthesis: phosphatidylcholine, myelin basic protein, and certain plasmalogens.
One more thing that can be added to the items discussed above is the work of Prof. Richard Deth and his group at Northeastern University in Boston. They have found that methylation is required for the operation of the dopamine D4 receptor in the brain. This receptor is involved in the focusing and maintenance of attention. This probably explains some of the deficits that people experience when they have a partial block in their methylation cycle.
Rich
This is good stuff. There are at least three components in myelin that require methylation for their synthesis: phosphatidylcholine, myelin basic protein, and certain plasmalogens.
One more thing that can be added to the items discussed above is the work of Prof. Richard Deth and his group at Northeastern University in Boston. They have found that methylation is required for the operation of the dopamine D4 receptor in the brain. This receptor is involved in the focusing and maintenance of attention. This probably explains some of the deficits that people experience when they have a partial block in their methylation cycle.
Rich
Hi, Nexus.
As the person who extracted the simplified treatment approach from the full Yasko treatment program, I can tell you that yes, this is the current version of that protocol. As you have seen from freddd's response, he favors a somewhat different treatment approach. If you would like to read a report on a clinical study of the simplified treatment approach, you can find it in at least three places on the internet. The newest one is Nico Vanden Eynde's reactivated website: http://www.cfsresearch.org When you get there, click on M.E./CFS, and then on my name, and you will find it listed as the treatment study.
Best regards,
Rich Van Konynenburg
As the person who extracted the simplified treatment approach from the full Yasko treatment program, I can tell you that yes, this is the current version of that protocol. As you have seen from freddd's response, he favors a somewhat different treatment approach. If you would like to read a report on a clinical study of the simplified treatment approach, you can find it in at least three places on the internet. The newest one is Nico Vanden Eynde's reactivated website: http://www.cfsresearch.org When you get there, click on M.E./CFS, and then on my name, and you will find it listed as the treatment study.
Best regards,
Rich Van Konynenburg
Hi Rich,
They have found that methylation is required for the operation of the dopamine D4 receptor in the brain. This receptor is involved in the focusing and maintenance of attention. This probably explains some of the deficits that people experience when they have a partial block in their methylation cycle
A key component of brainfog and certainly one I have had too much experience with for too many years. So that might explain partly why Provigil can have such a huge effect. I found 1/4 of the normal dose to be quite excellent in improving funtion and preventing narcolepsy. A whole tablet was way too much. I found it very helpful for maintaining focus and clear thought.
An additional factor, adb12 increased my mental clarity in a differnt way and separately from mb12. There are clearly several different things going on though I couldn't tell you what. This is where the higher doses, at or above 7.5mg Sc injection comes into play in some folks. These are also the doses at which the damage from subacute combined degeneration is affected and retreats. And again, each of adb12 and mb12 has their own effects and both are improved with methylfolate. If you have any ideas on this I would be very interested in hearing them. If you have any ideas of how to improve these reponses I would be very interested.
Hi, freddd.
As you probably know, the main fuel for the brain is glucose, and the secondary fuel is ketones. As you probably also know, when a person does not have enough adenosylcobalamin in their mitochondria, methylmalonate and propionate rise, because the pathway that normally feeds them into the Krebs cycle at succinyl Co A is partially blocked.
Below is an abstract of a paper describing a study in rats in which elevated methylmalonate and propionate were found to block the metabolism of the ketones by the brain. This would take away one of the main sources of fuel for the cells of the brain. I suggest that this is the reason you obtain better brain function from your high-dose supplementation of adenosylcobalamin, given that you have a genetic mutation that prevents the normal formation of adenosylcobalamin in the cells.
As you probably know, glucose normally first passes through the glycolysis chain in the cytosol of the cells, and is converted to pyruvate. Pyruvate then normally enters the mitochondria and is converted to acetyl-CoA, which enters the "top" of the Krebs cycle. In CFS, because the methylation cycle is partially blocked due to an intracellular functional deficiency of methylcobalamin and 5-methyl tetrahydrofolate, glutathione becomes depleted. The partial methylation cycle block and the depletion of glutathione are linked in a vicious circle mechanism.
(I'm not totally clear on the mechanism of this vicious circle, but the synthesis glutathione is downstream in the sulfur metabolism from the methylation cycle, and we have good evidence now in both autism and CFS that a partial block in the methylation cycle is linked to depletion of glutathione. So it's an experimentally observed phenomenon, even though I don't think anyone completely understands its mechanism yet.)
At any rate, the depletion of glutathione causes a rise in concentrations of oxidizing free radicals, which are produced as a normal part of oxidative metabolism in the mitochondria, but are normally taken care of by the antioxidant enzyme system, of which glutathione serves as the basis. There is abundant evidence of elevated oxidative stress in both CFS and autism.
When the oxidizing free radicals rise, they react with the enzymes that have iron-sulfur clusters, deactivating a fraction of these enzymes. One of these enzymes is aconitase, which lies early in the Krebs cycle, after citrate. This puts a partial block at this point in the Krebs cycle. Since the pathway for the overall metabolism of glucose must pass through this enzyme, the result is that the functional deficiency of methylcobalamin partially blocks the use of glucose for fuel by the cells, including the cells of the brain. The evidence for the partial block at aconitase comes from the urine organic acids test results that I have reviewed from many people with CFS, which often show a bottleneck between citrate and the following Krebs metabolites.
Succinyl CoA lies beyond aconitase in the Krebs cycle, so that the injection of the ketones pathway into the latter part of Krebs cycle is not impacted by the partial block at aconitase. I suggest that even though there is a partial block at aconitase, it is still possible to get some energy to drive ATP synthesis by injecting substrates at succinyl CoA and utilizing only the latter part of the Krebs cycle. I think this is why adenosylcobalamin is able to help with ATP production, even though low glutathione due to a partial methylation cycle block is still causing a partial block at aconitase. The point is that the Krebs cycle is not a closed cycle. Things can come in and out of it at various points in the cycle.
The result of all this is that methylcobalamin affects the use of glucose for fuel by the brain, while adenosylcobalamin affects the use of ketones. I suggest that when you supplement both at high dosages, you help feed both of the brain's fuels into the Krebs cycle, thus raising the rate of production of ATP, which is needed to drive the membrane ion pumps in the neurons, as well as other reactions in the neurons and the other cells of the brain.
I suggest that the reason you experience separate benefits from these two forms of B12 is that your cells are not able to interconvert them because of the genetic mutation in your intracellular B12 processing enzymes.
I think it is possible (and there is some evidence for this in the literature) that the relative use of glucose and ketones as fuel may differ for the neurons and the glial cells (such as the astrocytes), and this may also be involved in your differing responses to the two forms of B12. Furthermore, I think there could be differences between different major parts of the brain in terms of their relative use of these two fuels, and that may also be contributing to the differing effects on mental clarity that you experience from these two B12 forms.
I don't currently see how adenosylcobalamin could interact directly with 5-methyl tetrahydrofolate in your case. In cases in which the cells are able to interconvert the forms of B12, I suggest that the availability of sufficient 5-methyl tetrahydrofolate would make the use of methylcobalamin more efficient, so that more of the B12 resources could be directed toward synthesis of adenosylcobalamin. Thus, there would be an indirect interaction between 5-methyl THF and adenosylcobalamin. But I don't know of a direct connection between 5-methyl THF and adenosyl B12.
In a previous post, freddd, you encouraged me to visit the B12 deficiency thread on the "wrong diagnosis" website to look into the success that people there have experienced from your treatment protocol. I was happy to see that people there had benefited, and I think that you were able to do some very good things for some of them. However, here's my problem: I can't tell how many of these people actually had chronic fatigue syndrome, which is what I am specializing in, and to which this forum is devoted. In my view, B12 deficiency is not the same as chronic fatigue syndrome, and I think the formal case definitions would support me in that view. As I've acknowledged in the past, your treatment protocol is capable of helping people who have a wide variety of B12 problems, since it bypasses the normal absorption, transport and processing of B12 in the body. As such, it does help people who have a partial methylation cycle block as a result of the vicious circle mechanism that is present in CFS. But I claim, based on clinical experience, that it is not necessary to use methylcobalamin and adenosylcobalamin to help these people, because their cells are capable of converting between the various forms of B12 to satisfy their needs for the two active coenzyme forms.
I know that you have cited the experience of many people from this other website, in terms of the need to use high dosages of both these coenzyme forms in order to achieve successful results, and have applied this experience to chronic fatigue syndrome cases. However, I question the relevance of this part of the experience, because I don't see evidence that these other folks actually had CFS, as opposed to other B12-related problems, such as pernicious anemia or transcobalamin deficiency, or, as in your case, genetic mutation of the intracellular B12 processing enzymes. As far as I know, most people who have CFS do not have these other problems, based on the fact that CFS is defined as an acquired, rather than a lifelong disorder, and the observation that most are helped by hydroxocobalamin.
As I've reported in the past, the simplified treatment protocol, which uses hydroxocobalamin rather than the coenzyme forms methylcobalamin and adenosylcobalamin, has been found to help at least two-thirds of the people with CFS who have tried it. I realize that you have suggested that the reason that the other nearly one-third do not respond to this treatment is that hydroxocobalamin is "inactive." I think that that might be a possible explanation for some of those with CFS who do not respond, but I also think that some don't respond for other reasons, such as lack of enough of the vitamin and mineral cofactors, lack of high enough levels of the amino acids that are needed, or high body burdens of toxic heavy metals, which are known to be able to block enzymes in this part of the metabolism. So I would say that it is far from proven that the non-response of this nearly one-third is due to the "inactivity" of hydroxocobalamin, as you have repeatedly claimed. I have studied some of the nonresponding cases in detail with lab testing, and I have identified cases in which it appears that one of these other factors is involved in the nonresponse. Until we have more measured data, I don't think it is justified to make the claim that all of the nonresponse is due to "inactivity" of hydroxocobalamin.
I'm bringing these things up not to pour cold water on your efforts, but just to try to clarify the issues as well as we can at this point. I can't say that I know what the optimum protocol is for treating CFS. It may be that some people need to go a bit more slowly, while others will do better by "pushing through" the symptoms by continuing with high dosages. I can't say. It may depend on the sizes of their body burdens of toxins.
I think we still have a lot to learn about this. I appreciate being able to interact with you about these things in an objective way.
Rich
Biochem Med Metab Biol. 1991 Feb;45(1):56-64.
Effects of methylmalonate and propionate on uptake of glucose and ketone bodies in vitro by brain of developing rats.
Dutra JC, Wajner M, Wannmacher CF, Dutra-Filho CS, Wannmacher CM.
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Methylmalonate (MMA) and propionate effects on glucose and ketone body uptake in vitro by brain of fed and 30-hour-fasted 15-day-old rats were studied. In some experiments cerebrum prisms were incubated in the presence of glucose and either MMA or propionate in Krebs-Ringer bicarbonate buffer, pH 7.0. In others, the incubation medium contained beta-hydroxybutyrate (HBA) or acetoacetate (AcAc) instead of glucose. We verified that MMA increased glucose uptake by brain of fasting animals, whereas propionate had no effect. In addition, MMA diminished HBA but not AcAc incorporation into brain prisms, whereas propionate provoked a diminished utilization of both ketone bodies by brain. The in vitro effect of MMA and propionate on brain and liver beta-hydroxybutyrate dehydrogenase activity was also investigated. It was shown that MMA but not propionate significantly inhibited this activity. Rats were also injected subcutaneously three times with a MMA buffered solution, and the in vivo effects of MMA on the above-mentioned parameters assessed. Results from these experiments confirmed the previously found in vitro MMA effects. Methylmalonic acidemic patients accumulate primarily methylmalonate and secondarily propionate and other metabolites in their tissues at levels comparable to those we used in our assays. Most patients who survive early stages of the disease show a variable degree of neuromotor delay. Since glucose and sometimes ketones are the vital substrates for brain metabolism, it is possible that our findings may contribute to a certain extent to an understanding of the biochemical basis of mental retardation in these patients.
PMID: 2015109 [PubMed - indexed for MEDLINE]
As you probably know, the main fuel for the brain is glucose, and the secondary fuel is ketones. As you probably also know, when a person does not have enough adenosylcobalamin in their mitochondria, methylmalonate and propionate rise, because the pathway that normally feeds them into the Krebs cycle at succinyl Co A is partially blocked.
Below is an abstract of a paper describing a study in rats in which elevated methylmalonate and propionate were found to block the metabolism of the ketones by the brain. This would take away one of the main sources of fuel for the cells of the brain. I suggest that this is the reason you obtain better brain function from your high-dose supplementation of adenosylcobalamin, given that you have a genetic mutation that prevents the normal formation of adenosylcobalamin in the cells.
As you probably know, glucose normally first passes through the glycolysis chain in the cytosol of the cells, and is converted to pyruvate. Pyruvate then normally enters the mitochondria and is converted to acetyl-CoA, which enters the "top" of the Krebs cycle. In CFS, because the methylation cycle is partially blocked due to an intracellular functional deficiency of methylcobalamin and 5-methyl tetrahydrofolate, glutathione becomes depleted. The partial methylation cycle block and the depletion of glutathione are linked in a vicious circle mechanism.
(I'm not totally clear on the mechanism of this vicious circle, but the synthesis glutathione is downstream in the sulfur metabolism from the methylation cycle, and we have good evidence now in both autism and CFS that a partial block in the methylation cycle is linked to depletion of glutathione. So it's an experimentally observed phenomenon, even though I don't think anyone completely understands its mechanism yet.)
At any rate, the depletion of glutathione causes a rise in concentrations of oxidizing free radicals, which are produced as a normal part of oxidative metabolism in the mitochondria, but are normally taken care of by the antioxidant enzyme system, of which glutathione serves as the basis. There is abundant evidence of elevated oxidative stress in both CFS and autism.
When the oxidizing free radicals rise, they react with the enzymes that have iron-sulfur clusters, deactivating a fraction of these enzymes. One of these enzymes is aconitase, which lies early in the Krebs cycle, after citrate. This puts a partial block at this point in the Krebs cycle. Since the pathway for the overall metabolism of glucose must pass through this enzyme, the result is that the functional deficiency of methylcobalamin partially blocks the use of glucose for fuel by the cells, including the cells of the brain. The evidence for the partial block at aconitase comes from the urine organic acids test results that I have reviewed from many people with CFS, which often show a bottleneck between citrate and the following Krebs metabolites.
Succinyl CoA lies beyond aconitase in the Krebs cycle, so that the injection of the ketones pathway into the latter part of Krebs cycle is not impacted by the partial block at aconitase. I suggest that even though there is a partial block at aconitase, it is still possible to get some energy to drive ATP synthesis by injecting substrates at succinyl CoA and utilizing only the latter part of the Krebs cycle. I think this is why adenosylcobalamin is able to help with ATP production, even though low glutathione due to a partial methylation cycle block is still causing a partial block at aconitase. The point is that the Krebs cycle is not a closed cycle. Things can come in and out of it at various points in the cycle.
The result of all this is that methylcobalamin affects the use of glucose for fuel by the brain, while adenosylcobalamin affects the use of ketones. I suggest that when you supplement both at high dosages, you help feed both of the brain's fuels into the Krebs cycle, thus raising the rate of production of ATP, which is needed to drive the membrane ion pumps in the neurons, as well as other reactions in the neurons and the other cells of the brain.
I suggest that the reason you experience separate benefits from these two forms of B12 is that your cells are not able to interconvert them because of the genetic mutation in your intracellular B12 processing enzymes.
I think it is possible (and there is some evidence for this in the literature) that the relative use of glucose and ketones as fuel may differ for the neurons and the glial cells (such as the astrocytes), and this may also be involved in your differing responses to the two forms of B12. Furthermore, I think there could be differences between different major parts of the brain in terms of their relative use of these two fuels, and that may also be contributing to the differing effects on mental clarity that you experience from these two B12 forms.
I don't currently see how adenosylcobalamin could interact directly with 5-methyl tetrahydrofolate in your case. In cases in which the cells are able to interconvert the forms of B12, I suggest that the availability of sufficient 5-methyl tetrahydrofolate would make the use of methylcobalamin more efficient, so that more of the B12 resources could be directed toward synthesis of adenosylcobalamin. Thus, there would be an indirect interaction between 5-methyl THF and adenosylcobalamin. But I don't know of a direct connection between 5-methyl THF and adenosyl B12.
In a previous post, freddd, you encouraged me to visit the B12 deficiency thread on the "wrong diagnosis" website to look into the success that people there have experienced from your treatment protocol. I was happy to see that people there had benefited, and I think that you were able to do some very good things for some of them. However, here's my problem: I can't tell how many of these people actually had chronic fatigue syndrome, which is what I am specializing in, and to which this forum is devoted. In my view, B12 deficiency is not the same as chronic fatigue syndrome, and I think the formal case definitions would support me in that view. As I've acknowledged in the past, your treatment protocol is capable of helping people who have a wide variety of B12 problems, since it bypasses the normal absorption, transport and processing of B12 in the body. As such, it does help people who have a partial methylation cycle block as a result of the vicious circle mechanism that is present in CFS. But I claim, based on clinical experience, that it is not necessary to use methylcobalamin and adenosylcobalamin to help these people, because their cells are capable of converting between the various forms of B12 to satisfy their needs for the two active coenzyme forms.
I know that you have cited the experience of many people from this other website, in terms of the need to use high dosages of both these coenzyme forms in order to achieve successful results, and have applied this experience to chronic fatigue syndrome cases. However, I question the relevance of this part of the experience, because I don't see evidence that these other folks actually had CFS, as opposed to other B12-related problems, such as pernicious anemia or transcobalamin deficiency, or, as in your case, genetic mutation of the intracellular B12 processing enzymes. As far as I know, most people who have CFS do not have these other problems, based on the fact that CFS is defined as an acquired, rather than a lifelong disorder, and the observation that most are helped by hydroxocobalamin.
As I've reported in the past, the simplified treatment protocol, which uses hydroxocobalamin rather than the coenzyme forms methylcobalamin and adenosylcobalamin, has been found to help at least two-thirds of the people with CFS who have tried it. I realize that you have suggested that the reason that the other nearly one-third do not respond to this treatment is that hydroxocobalamin is "inactive." I think that that might be a possible explanation for some of those with CFS who do not respond, but I also think that some don't respond for other reasons, such as lack of enough of the vitamin and mineral cofactors, lack of high enough levels of the amino acids that are needed, or high body burdens of toxic heavy metals, which are known to be able to block enzymes in this part of the metabolism. So I would say that it is far from proven that the non-response of this nearly one-third is due to the "inactivity" of hydroxocobalamin, as you have repeatedly claimed. I have studied some of the nonresponding cases in detail with lab testing, and I have identified cases in which it appears that one of these other factors is involved in the nonresponse. Until we have more measured data, I don't think it is justified to make the claim that all of the nonresponse is due to "inactivity" of hydroxocobalamin.
I'm bringing these things up not to pour cold water on your efforts, but just to try to clarify the issues as well as we can at this point. I can't say that I know what the optimum protocol is for treating CFS. It may be that some people need to go a bit more slowly, while others will do better by "pushing through" the symptoms by continuing with high dosages. I can't say. It may depend on the sizes of their body burdens of toxins.
I think we still have a lot to learn about this. I appreciate being able to interact with you about these things in an objective way.
Rich
Biochem Med Metab Biol. 1991 Feb;45(1):56-64.
Effects of methylmalonate and propionate on uptake of glucose and ketone bodies in vitro by brain of developing rats.
Dutra JC, Wajner M, Wannmacher CF, Dutra-Filho CS, Wannmacher CM.
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Methylmalonate (MMA) and propionate effects on glucose and ketone body uptake in vitro by brain of fed and 30-hour-fasted 15-day-old rats were studied. In some experiments cerebrum prisms were incubated in the presence of glucose and either MMA or propionate in Krebs-Ringer bicarbonate buffer, pH 7.0. In others, the incubation medium contained beta-hydroxybutyrate (HBA) or acetoacetate (AcAc) instead of glucose. We verified that MMA increased glucose uptake by brain of fasting animals, whereas propionate had no effect. In addition, MMA diminished HBA but not AcAc incorporation into brain prisms, whereas propionate provoked a diminished utilization of both ketone bodies by brain. The in vitro effect of MMA and propionate on brain and liver beta-hydroxybutyrate dehydrogenase activity was also investigated. It was shown that MMA but not propionate significantly inhibited this activity. Rats were also injected subcutaneously three times with a MMA buffered solution, and the in vivo effects of MMA on the above-mentioned parameters assessed. Results from these experiments confirmed the previously found in vitro MMA effects. Methylmalonic acidemic patients accumulate primarily methylmalonate and secondarily propionate and other metabolites in their tissues at levels comparable to those we used in our assays. Most patients who survive early stages of the disease show a variable degree of neuromotor delay. Since glucose and sometimes ketones are the vital substrates for brain metabolism, it is possible that our findings may contribute to a certain extent to an understanding of the biochemical basis of mental retardation in these patients.
PMID: 2015109 [PubMed - indexed for MEDLINE]
Hi Rich,
Thankyou for your reply. Would you object if I posted it over at wd as well because there are a lot of imterested folks there.
In my view, B12 deficiency is not the same as chronic fatigue syndrome
You are ccorrect in assuming that many of the folks there do not yet have a CFS/FMS diagnosis though many do and some are well on their way. True pernicious anemia is very rare there, at least amongst any that post. In several years there has been only a handful. Most go for years without a useful diagnosis or treatment but not as long as here. It took me 13 years of bad treatment to get the FMS/CFS diagnosis because so many considered it an imaginary woman's disease.
The broader view from where I sit CFS looks like one specific subset of b12 deficiency symptoms which I did have in it's entirety including sudden onset with a viral infection, possibly coxsackie. My wife had it too and it was going around lioke wild fire. The difference was that she got better after 6 months and I didn't even start recovering for 16 years. The difference I see here is that on the whole folks here have been deficient longer and are generally sicker then at WD. On the whole the people here respond very strongly and separately to both mb12 and adenosylb12. Their additional symptoms also fit into the set of all b12/folate deficiency sysmptoms. There may also be additional specific factors either present (ie heavy metals) or lacking, such as l-carnitine and D-Ribose but not limited to them.
Your hypothesis of my specific response caused by genetic situation doesn't hold water. Too many people, possibly the majority, here and at WD, have such strong and specific different responses to each adb12 and mb12 that it is very unlikely to be because of genes causing a rare enzyme defect. Also, please don't ignore the research showing depressed cerebral spinal fluid level of cobalamins in CSF/FMS. Again, the separate strong responses of many people to the CSF/CNS threshold dose (7.5mg sc injection or 50mg long duration sublingual). Some folks only have a threshold response to one but not the other cobalamin regardless of order given. That is they will either have the threshold response to only mb12 or only adb12 no matter which one is first. And again, this effect is slightly stronger if Metafolin is given at same time the b12 dose is started for a substantial percentage of people but not everybody.
All of these things are purely pragmatic, as that is the only level I can do this on, but I could assemble a panel that will demonstrate any or all of these things over and over in a reliable and predictable fashion. You could make this bet all the way to the bank. I have no idea what the biochemical explanations may be for all of this. All I can work with is naked eye observation. I'm sure a lot might show up on tests if the right things are even tested for.
I think that that might be a possible explanation for some of those with CFS who do not respond, but I also think that some don't respond for other reasons, such as lack of enough of the vitamin and mineral cofactors, lack of high enough levels of the amino acids that are needed,
Without a doubt lack of cofactors is a major factor. My best estimate of non-responders to mb12/adb12 alone is about 25%, which is right in that 20-40% range. With methylfolate that goes up to perhpas 85-90%, from 75%, responders. With all the basics, b-complex, a, d, e, c, zinc, omega3 oils, calcium, magnesium, zinc plus critcal cofactors; SAM-e and L-carnitine fumarate, response goes up to essentially 100%.
The cofactors in all however, probably accounts for close to 65-75% of total extent of effect. Certain cofactors , and combinations, can be like switching everything on at once, including zinc, vitamin D3, l-carnitine fumarate (usually fumarate, occasionally acetyl), methylfolate, SAM-e, possibly magnesium (not enough clearcut returns on that one yet) in no specfic order.
I don't currently see how adenosylcobalamin could interact directly with 5-methyl tetrahydrofolate in your case. In cases in which the cells are able to interconvert the forms of B12, I suggest that the availability of sufficient 5-methyl tetrahydrofolate would make the use of methylcobalamin more efficient, so that more of the B12 resources could be directed toward synthesis of adenosylcobalamin. Thus, there would be an indirect interaction between 5-methyl THF and adenosylcobalamin. But I don't know of a direct connection between 5-methyl THF and adenosyl B12.
None the less there is something clearly going on. After the glutathione (precursor, some used precusors some did infusions) trials were discontinued the adb12 had zero effect when taken with the 800mcg Metafolin dose and the symtoms it affects were unaffected, even by 51mg sublingual. However as soon as 4800mcg of Metafolin was taken the next dose of 7.5mg injected sc mb12 and separately, the next adb12 51mg dose was very strongly effective in the way not seen since the initial such dose. That can be duplcated only by not taking any adb12 for 3 months or so. Additionally, taking 800mcg of Metafolin (daily dose 4000-4800mcg) on an empty stomach at the same time as the sublingual or injected doses which allows the serum peaks to coincide. makes the mb12 or adb12 just barely noticably more effective. It's not gangbusters, but it is noticable. Believe me, the reaction of my subacute combined degeneration symptoms makes things very noticable as they are right on the pivot point. Aside from traumatic injury damage, those SCD symptoms and signs are all I have left. I'd like to see everybody have that quality of results.
What do you think about recrutiing sponsers for teams to have let's say 5km race 3 days in a row and other criteria, evaluated on the entire team basis, easily done by somebody who is actually healed, impossible for somebody who isn't, after 3 years of treatment by whatever protocol each team chooses using matched pair (set) design expanded to include as many teams as might choose to enter. Make the prize significant, like the X-prize competitions and raise substantial money for research. Maybe make it some sort of TV reality show (sponsers and money). We would want to start with people so verifiably sick and disabled that even walking 5km on one day much less 3 in a row is impossible so there is no doubt what so ever about the magnitude of change being looked for. Include a control group not receiving one of the special protocols, but maybe a pharmacutical team takinf drugs to alleviate symptoms as are currently being pushed, and matched teams assembled by an independent panel. Would that be a worthwhile way to raise money for research and determine effectivness of treatments?
Thankyou for your reply. Would you object if I posted it over at wd as well because there are a lot of imterested folks there.
In my view, B12 deficiency is not the same as chronic fatigue syndrome
You are ccorrect in assuming that many of the folks there do not yet have a CFS/FMS diagnosis though many do and some are well on their way. True pernicious anemia is very rare there, at least amongst any that post. In several years there has been only a handful. Most go for years without a useful diagnosis or treatment but not as long as here. It took me 13 years of bad treatment to get the FMS/CFS diagnosis because so many considered it an imaginary woman's disease.
The broader view from where I sit CFS looks like one specific subset of b12 deficiency symptoms which I did have in it's entirety including sudden onset with a viral infection, possibly coxsackie. My wife had it too and it was going around lioke wild fire. The difference was that she got better after 6 months and I didn't even start recovering for 16 years. The difference I see here is that on the whole folks here have been deficient longer and are generally sicker then at WD. On the whole the people here respond very strongly and separately to both mb12 and adenosylb12. Their additional symptoms also fit into the set of all b12/folate deficiency sysmptoms. There may also be additional specific factors either present (ie heavy metals) or lacking, such as l-carnitine and D-Ribose but not limited to them.
Your hypothesis of my specific response caused by genetic situation doesn't hold water. Too many people, possibly the majority, here and at WD, have such strong and specific different responses to each adb12 and mb12 that it is very unlikely to be because of genes causing a rare enzyme defect. Also, please don't ignore the research showing depressed cerebral spinal fluid level of cobalamins in CSF/FMS. Again, the separate strong responses of many people to the CSF/CNS threshold dose (7.5mg sc injection or 50mg long duration sublingual). Some folks only have a threshold response to one but not the other cobalamin regardless of order given. That is they will either have the threshold response to only mb12 or only adb12 no matter which one is first. And again, this effect is slightly stronger if Metafolin is given at same time the b12 dose is started for a substantial percentage of people but not everybody.
All of these things are purely pragmatic, as that is the only level I can do this on, but I could assemble a panel that will demonstrate any or all of these things over and over in a reliable and predictable fashion. You could make this bet all the way to the bank. I have no idea what the biochemical explanations may be for all of this. All I can work with is naked eye observation. I'm sure a lot might show up on tests if the right things are even tested for.
I think that that might be a possible explanation for some of those with CFS who do not respond, but I also think that some don't respond for other reasons, such as lack of enough of the vitamin and mineral cofactors, lack of high enough levels of the amino acids that are needed,
Without a doubt lack of cofactors is a major factor. My best estimate of non-responders to mb12/adb12 alone is about 25%, which is right in that 20-40% range. With methylfolate that goes up to perhpas 85-90%, from 75%, responders. With all the basics, b-complex, a, d, e, c, zinc, omega3 oils, calcium, magnesium, zinc plus critcal cofactors; SAM-e and L-carnitine fumarate, response goes up to essentially 100%.
The cofactors in all however, probably accounts for close to 65-75% of total extent of effect. Certain cofactors , and combinations, can be like switching everything on at once, including zinc, vitamin D3, l-carnitine fumarate (usually fumarate, occasionally acetyl), methylfolate, SAM-e, possibly magnesium (not enough clearcut returns on that one yet) in no specfic order.
I don't currently see how adenosylcobalamin could interact directly with 5-methyl tetrahydrofolate in your case. In cases in which the cells are able to interconvert the forms of B12, I suggest that the availability of sufficient 5-methyl tetrahydrofolate would make the use of methylcobalamin more efficient, so that more of the B12 resources could be directed toward synthesis of adenosylcobalamin. Thus, there would be an indirect interaction between 5-methyl THF and adenosylcobalamin. But I don't know of a direct connection between 5-methyl THF and adenosyl B12.
None the less there is something clearly going on. After the glutathione (precursor, some used precusors some did infusions) trials were discontinued the adb12 had zero effect when taken with the 800mcg Metafolin dose and the symtoms it affects were unaffected, even by 51mg sublingual. However as soon as 4800mcg of Metafolin was taken the next dose of 7.5mg injected sc mb12 and separately, the next adb12 51mg dose was very strongly effective in the way not seen since the initial such dose. That can be duplcated only by not taking any adb12 for 3 months or so. Additionally, taking 800mcg of Metafolin (daily dose 4000-4800mcg) on an empty stomach at the same time as the sublingual or injected doses which allows the serum peaks to coincide. makes the mb12 or adb12 just barely noticably more effective. It's not gangbusters, but it is noticable. Believe me, the reaction of my subacute combined degeneration symptoms makes things very noticable as they are right on the pivot point. Aside from traumatic injury damage, those SCD symptoms and signs are all I have left. I'd like to see everybody have that quality of results.
What do you think about recrutiing sponsers for teams to have let's say 5km race 3 days in a row and other criteria, evaluated on the entire team basis, easily done by somebody who is actually healed, impossible for somebody who isn't, after 3 years of treatment by whatever protocol each team chooses using matched pair (set) design expanded to include as many teams as might choose to enter. Make the prize significant, like the X-prize competitions and raise substantial money for research. Maybe make it some sort of TV reality show (sponsers and money). We would want to start with people so verifiably sick and disabled that even walking 5km on one day much less 3 in a row is impossible so there is no doubt what so ever about the magnitude of change being looked for. Include a control group not receiving one of the special protocols, but maybe a pharmacutical team takinf drugs to alleviate symptoms as are currently being pushed, and matched teams assembled by an independent panel. Would that be a worthwhile way to raise money for research and determine effectivness of treatments?