Proposed relationship between Lapp-Cheney B12 treatment & methylation treatment

[Guest guest]

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. 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.

[The next section discusses a protocol developed by a guy who calls himself

" Freddd, " who posts to the Phoenix Rising ME/CFS internet group, and who

advocates a protocol that includes high-dose adenosyl B12, high-dose methyl B12,

and high-dose methylfolate. I don't know what fraction of the ME/CFS population

has the polymorpthism that Freddd apparently has. He and I have discussed this

at length on the public forum, so there is not a patient privacy issue in his

case.]

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