Hi, all.
I think I now understand better why Drs. Lapp and Cheney found in the 1990s that a high dosage of injected vitamin B12 (they initially used cyanocobalamin) gave their ME/CFS patients an increase in energy, stamina, or well-being within 12 to 24 hours, which lasted for two to three days, and why the dosage had to be so high compared to the RDA for B12 (2,000 to 2,500 micrograms per injection, compared to 2.4 micrograms per day). I also think I now understand better how this fits in with the methylation-type treatments, which can bring greater improvement on a more permanent basis, and also how Freddd’s approach meshes with the above two types of treatments.
Here’s my suggested explanation:
It is known that normally after vitamin B12 is absorbed by the gut, it is transported in the blood to the body’s cells, bound to the carrier transcobalamin. After entering the cells, the B12 normally passes through an intracellular processing pathway, which produces the appropriate amounts of the two active coenzyme forms of B12 needed by the cells, i.e. adenosylcobalamin and methylcobalamin.
Adenosylcobalamin acts as a coenzyme in the mitochondrial methylmalonate pathway, which feeds certain substances into the Krebs cycle to be used as fuel for making ATP. These substances are isoleucine, valine, threonine, methionine, the side-chain of cholesterol, and odd-chain fatty acids.
Methylcobalamin acts in the cytosol as a coenzyme for the methionine synthase reaction, which links the methylation cycle with the folate metabolism and also helps to govern the flow into the transsulfuration pathway, which feeds the synthesis of glutathione, among other reactions.
One of the key parts of the intracellular processing pathway for vitamin B12 is called the CblC complementation group. This group normally binds cobalamin in order to carry on its processing. The strength of this binding, called the affinity, depends strongly on the presence of glutathione. A recent study by Jeong and Kim (2011, PMID: 21821010) using bovine CblC and cyanocobalamin, found that glutathione, which is normally present in the cells, raised this affinity by a factor of over one hundred.
In ME/CFS, we have found that glutathione becomes depleted. That being the case, we can expect the affinity of CblC for cobalamin to drop considerably. The effect of this would be to lower the rate of production of both adenosylcobalamin and methylcobalamin. The effect of lowering adenosylcobalamin is to decrease the fuel supply to the Krebs cycle and hence to lower the rate of production of ATP. The effect of lowering methylcobalamin is to partially block the methionine synthase reaction, lowering the methylation capacity, and draining the methylation cycle and disrupting the sulfur metabolism in general. The methyl trap mechanism then continues to convert other forms of folate into methylfolate, and this is partly catabolized by reaction with peroxynitrite which forms as a result of the glutathione depletion. The folates thus become depleted, and a chronic vicious circle mechanism is set up.
Now, consider what happens when a high dosage of B12 is injected, as in the treatment discovered by Lapp and Cheney. When the dosage is high enough, the low affinity of the CblC complementation group for cobalamin is overcome, so that the rates of production of adenosylcobalamin and methylcobalamin are able to come up, perhaps even to normal levels. I suggest that this affinity problem is the reason for the need for such a high dosage of B12 to obtain a therapeutic effect.
The added adenosylcobalamin would support the methylmalonate pathway, and more fuel would be supplied to the Krebs cycle, which would raise the rate of production of ATP. I suggest that this is what causes ME/CFS patients to experience a boost in energy, stamina or well-being on the high-dose injected B12 treatment. This is particularly significant in ME/CFS, because carbohydrate and fat metabolism is hindered due to the effect of glutathione depletion on the aconitase reaction, early in the Krebs cycle. Note also that deficiencies in some of the B-complex vitamins can interfere with obtaining this benefit, because they are also needed by the methylmalonate pathway.
However, I suggest that even though methylcobalamin production would also rise, the partial block of the methionine synthase reaction would remain if B12 alone is given, and this is the reason for the limited benefit of that treatment. The reason why B12 treatment alone will not correct the partial block in methionine synthase is that there is insufficient methylfolate available to feed this reaction. The reason for that, as Prof. Martin Pall has pointed out, is that the level of methylfolate has been lowered by reaction with peroxynitrite. Peroxynitrite has risen because of the state of oxidative stress that ensues when glutathione is depleted.
If methylfolate is added in addition to adding high-dosage B12, the partial block of methionine synthase can be lifted, which can then break the vicious circle mechanism that holds glutathione down. Over time, as glutathione rises, the affinity of CblC for cobalamin will also rise, and supplementation of high-dosage B12 will no longer be necessary. Likewise, peroxynitrite will drop as glutathione is restored, so that supplementation of methylfolate will no longer be necessary, either.
In Freddd’s case, I suspect that there is an inherited polymorphism in the CblC complementation group. While normally glutathione supports this group and helps it to process B12, in Freddd’s case this does not work. Glutathione binds cobalamin and his CblC complemention group is unable to retrieve it and convert it into the two coenzyme forms of B12. Freddd has found that if he uses large dosages of both adenosylcobalamin and methylcobalamin (applied sublingually or by injection) and if he avoids glutathione or precursors to form glutathione he can overcome this problem. Apparently these two coenzyme forms of B12 are able to diffuse directly into the cells and bypass the normal B12 processing pathway, so that both the mitochondria and the methionine synthase reaction are supplied directly with the cofactors they need. In addition, he supplies methylfolate in high dosage as well, which overcomes the deficiency in this reactant.
I suspect that the reason why Freddd has observed an independent benefit by adding adenosylcobalamin is the same as the reason why the Lapp and Cheney treatment brought benefit to their patients, i.e. it causes a boost in fueling the mitochondria.
I think this explains the results reported by Drs. Lapp and Cheney, the reason for the increased benefit of adding methylfolate as in the methylation-type protocols, and the basis for the success of Freddd’s approach.
Best regards,
Rich
I think I now understand better why Drs. Lapp and Cheney found in the 1990s that a high dosage of injected vitamin B12 (they initially used cyanocobalamin) gave their ME/CFS patients an increase in energy, stamina, or well-being within 12 to 24 hours, which lasted for two to three days, and why the dosage had to be so high compared to the RDA for B12 (2,000 to 2,500 micrograms per injection, compared to 2.4 micrograms per day). I also think I now understand better how this fits in with the methylation-type treatments, which can bring greater improvement on a more permanent basis, and also how Freddd’s approach meshes with the above two types of treatments.
Here’s my suggested explanation:
It is known that normally after vitamin B12 is absorbed by the gut, it is transported in the blood to the body’s cells, bound to the carrier transcobalamin. After entering the cells, the B12 normally passes through an intracellular processing pathway, which produces the appropriate amounts of the two active coenzyme forms of B12 needed by the cells, i.e. adenosylcobalamin and methylcobalamin.
Adenosylcobalamin acts as a coenzyme in the mitochondrial methylmalonate pathway, which feeds certain substances into the Krebs cycle to be used as fuel for making ATP. These substances are isoleucine, valine, threonine, methionine, the side-chain of cholesterol, and odd-chain fatty acids.
Methylcobalamin acts in the cytosol as a coenzyme for the methionine synthase reaction, which links the methylation cycle with the folate metabolism and also helps to govern the flow into the transsulfuration pathway, which feeds the synthesis of glutathione, among other reactions.
One of the key parts of the intracellular processing pathway for vitamin B12 is called the CblC complementation group. This group normally binds cobalamin in order to carry on its processing. The strength of this binding, called the affinity, depends strongly on the presence of glutathione. A recent study by Jeong and Kim (2011, PMID: 21821010) using bovine CblC and cyanocobalamin, found that glutathione, which is normally present in the cells, raised this affinity by a factor of over one hundred.
In ME/CFS, we have found that glutathione becomes depleted. That being the case, we can expect the affinity of CblC for cobalamin to drop considerably. The effect of this would be to lower the rate of production of both adenosylcobalamin and methylcobalamin. The effect of lowering adenosylcobalamin is to decrease the fuel supply to the Krebs cycle and hence to lower the rate of production of ATP. The effect of lowering methylcobalamin is to partially block the methionine synthase reaction, lowering the methylation capacity, and draining the methylation cycle and disrupting the sulfur metabolism in general. The methyl trap mechanism then continues to convert other forms of folate into methylfolate, and this is partly catabolized by reaction with peroxynitrite which forms as a result of the glutathione depletion. The folates thus become depleted, and a chronic vicious circle mechanism is set up.
Now, consider what happens when a high dosage of B12 is injected, as in the treatment discovered by Lapp and Cheney. When the dosage is high enough, the low affinity of the CblC complementation group for cobalamin is overcome, so that the rates of production of adenosylcobalamin and methylcobalamin are able to come up, perhaps even to normal levels. I suggest that this affinity problem is the reason for the need for such a high dosage of B12 to obtain a therapeutic effect.
The added adenosylcobalamin would support the methylmalonate pathway, and more fuel would be supplied to the Krebs cycle, which would raise the rate of production of ATP. I suggest that this is what causes ME/CFS patients to experience a boost in energy, stamina or well-being on the high-dose injected B12 treatment. This is particularly significant in ME/CFS, because carbohydrate and fat metabolism is hindered due to the effect of glutathione depletion on the aconitase reaction, early in the Krebs cycle. Note also that deficiencies in some of the B-complex vitamins can interfere with obtaining this benefit, because they are also needed by the methylmalonate pathway.
However, I suggest that even though methylcobalamin production would also rise, the partial block of the methionine synthase reaction would remain if B12 alone is given, and this is the reason for the limited benefit of that treatment. The reason why B12 treatment alone will not correct the partial block in methionine synthase is that there is insufficient methylfolate available to feed this reaction. The reason for that, as Prof. Martin Pall has pointed out, is that the level of methylfolate has been lowered by reaction with peroxynitrite. Peroxynitrite has risen because of the state of oxidative stress that ensues when glutathione is depleted.
If methylfolate is added in addition to adding high-dosage B12, the partial block of methionine synthase can be lifted, which can then break the vicious circle mechanism that holds glutathione down. Over time, as glutathione rises, the affinity of CblC for cobalamin will also rise, and supplementation of high-dosage B12 will no longer be necessary. Likewise, peroxynitrite will drop as glutathione is restored, so that supplementation of methylfolate will no longer be necessary, either.
In Freddd’s case, I suspect that there is an inherited polymorphism in the CblC complementation group. While normally glutathione supports this group and helps it to process B12, in Freddd’s case this does not work. Glutathione binds cobalamin and his CblC complemention group is unable to retrieve it and convert it into the two coenzyme forms of B12. Freddd has found that if he uses large dosages of both adenosylcobalamin and methylcobalamin (applied sublingually or by injection) and if he avoids glutathione or precursors to form glutathione he can overcome this problem. Apparently these two coenzyme forms of B12 are able to diffuse directly into the cells and bypass the normal B12 processing pathway, so that both the mitochondria and the methionine synthase reaction are supplied directly with the cofactors they need. In addition, he supplies methylfolate in high dosage as well, which overcomes the deficiency in this reactant.
I suspect that the reason why Freddd has observed an independent benefit by adding adenosylcobalamin is the same as the reason why the Lapp and Cheney treatment brought benefit to their patients, i.e. it causes a boost in fueling the mitochondria.
I think this explains the results reported by Drs. Lapp and Cheney, the reason for the increased benefit of adding methylfolate as in the methylation-type protocols, and the basis for the success of Freddd’s approach.
Best regards,
Rich
