Hi, all.
The question of whether to supplement glutathione in some way in conjuction with treatment of the partial methylation cycle block in ME/CFS often comes up. There is some recent research that appears to shed some light on this issue, so I would like to
review the status of at least my understanding of it.
As I see it currently, there are three groups of people with respect to their response to
adding glutathione to methylation treatment:
1. There is a group who benefit from this addition, in terms of their symptomatic response.
2. There is a group who benefit initially, but as time goes on, it causes their symptoms to worsen.
3. There is a group who experience immediate worsening of their symptoms.
I dont know what fraction of the ME/CFS population is in each group.
I would like to suggest what I think is going on in each of these groups.
I suggest that the first group have inherited normal genotypes of their intracellular B12 processing enzymes, and they also have normal status of vitamins B2 and B3. In this group, the glutathione can be recycled at a normal rate when it becomes oxidized by reactive oxygen species that are part of the oxidative stress in ME/CFS, by the glutathione reductase reaction, which requires both B2 and B3. Furthermore, glutathione
is able to play its normal roles with respect to the intracellular processing of vitamin B12.
In particular, the Cblc enzyme (also known as MMACHC) uses glutathione to remove the upper ligand from incoming forms of B12 (cyano-, methyl- or adenosyl-) by the formation of glutathione conjugates of these ligands (PMID: 19801555).
In addition, it appears that glutathione also reacts with the resulting aquocobalamin to form glutathionylcobalamin. Glutathionylcobalamin is chemically more stable than the other forms of B12, but Cbcl is normally able to retrieve cobalamin from glutathionylcobalamin so that the cobalamin can be used to form methylcobalamin and adenosylcobalamin in the amounts needed by the cell (PMID: 21429294).
Thus, glutathione appears to serve not only as a reactant in the metabolism of B12, but also as a protector of B12 from reactions with toxins, and a buffer to store B12 until it is needed by the cell.
I suggest that the second group have inherited normal genotypes of their intracellular B12 processing enzymes, but they have a deficiency in B2 or B3 or both, so that the rate of the
glutathione reductase reaction is too slow to keep up with the oxidation of the glutathione. As a result, though the supplemented glutathione is initially beneficial to them, over time it becomes a detriment, because the ratio of reduced to oxidized glutathione drops too low, and this worsens the oxidative stress of the cells.
I suggest that the third group has inherited an inborn error of metabolism involving the Cblc enzyme. As a result of this, when glutathione reacts with B12 to form glutathionylcobalamin, their genotype of the Cblc enzyme is unable to retrieve the cobalamin from the glutathione to use it to form methylcobalamin and adenosylcobalamin. If glutathione is supplemented, this situation is made worse for this group. In addition, this group is unable to make use of hydroxocobalamin as their B12 supplement
(PMID: 21497120), because it is converted to glutathionylcobalamin in their cells (even without supplementing glutathione) and is therefore made inaccessible. I suggest that Freddd is in this group, and this explains why he cannot tolerate supplementing glutathione, why he cannot make use of cyanocobalamin or hydroxocobalamin, and why he must use high dosages of methylcobalamin and adenosylcobalamin, applied either sublingually or by injection. This raises the concentration of these species in the blood stream, and enough of them is able to diffuse into the cells through their plasma membranes to be used directly without intracellular processing, thus supplying the need of his cells for methylcobalamin and adenosylcobalamin.
Best regards,
Rich
Hi Rich,
I may not have been posting for a while but I haven't been asleep. I have found some additional questions to ask you, some additional understandings in this area, we can hopefully hash out.
I suggest that the third group has inherited an inborn error of metabolism involving the Cblc enzyme. As a result of this, when glutathione reacts with B12 to form glutathionylcobalamin, their genotype of the Cblc enzyme is unable to retrieve the cobalamin from the glutathione to use it to form methylcobalamin and adenosylcobalamin
There are several problems with that as a freestanding explanation. First that could hardly account for the relatively large number of people who have this response. Second, there is the cobalamin dumping that occurs. While nobody has done a peer reviewed study of serum and body levels of cobalamin with and without glutathione, the effect I'm speaking of is as obvious as Jimmy Durantee's nose. I ran a number of urine colorimetry trials that allowed me to calibrate injected dose of mb12 to the color of urine from sublingual doses because cobalamin is intensly colored and shows up very clearly. It is almost pure magenta in coloration which no other nutritional factor affects. The amount of magenta is directly proportionate to dose of cobalamin. Concentration doesn't affect the relative color because the yellow components are equally diluted. It is purely the relative amount of magenta to yellow and cyan. Further it is a very easy naked eye comparison. The glutathione causes the amount of cobalamin excreted in the urine at 30mg injected daily to approximately match the urine excretion of 120-160mg of daily injection. RustyJ noticed this change
"I did notice my urine contained much more b12," as do others who are taking enough to be above the threshold of naked eye visibility. If nothing else this dramatically lowers serum and probably tissue level and limits the amount of diffusion that can take place, even if it does nothing more than cause it to exit 4-6 times as rapidly. In me that caused a lack of penetration to the CNS and provoked rapid neurological deterioration.
Then in looking at the actual process of conversion of inactive cobalamins to methylb12 there are several potential roadblocks. This requires an enzyme that is available in limited quantities. This conversion also requires ATP. This produces a potential deadlock preventing conversion. If the person in question has certain types of muscle pain and severe fatigue (as in FMS and CFS) indicating mitochondrial failure from lack of adenosylb12 or l-carnitine fumarate or other causes, the ATP may not be available for the conversion. As many processes break down for all we know the enzyme, which is severely limited in quantity at best, itself might not get made without mb12. I haven't been able to track that down yet. As the conversion pathway is generally inactive cobalamin + enzyme + ATP >> methylb12, methylb12 + enzyme + ATP? >> adenosylb12, the ATP needed for the conversion from inactive to mb12 might not happen without priming the pump with adb12 and/or l-carnitine fumarate and/or D-ribose and/or unknown other factors, in the first place.
In my own case, I certainly converted some mb12 to adb12, enough to knock me for a loop de loop (in noodle soup?). However, it was nowhere near complete no matter how much mb12 I took for 9 months thereby producing a completely separate startup effect from Adb12. And another huge further startup with l-carnitine fumarate. So I had three ramp-ups of ATP. Without sufficient ATP I could NOT convert inactive cobalamins more than just a little for all those years. I did however convert cyanocobalamin all those years sufficiently to keep my MCV < 100 which is more than 1/3 of subjects in studies can't do. So I doubt the complete lack of the enzyme in my body. I did not die as a child. I did not have failure to thrive as an infant. The problem may not have occurred at all except that I became a vegetarian robbing my body of that pump-primimg amount of ATP. Before becoming a vegetarian I could jog 5 miles in 40 minutes and 10 miles in 90 minutes. I was a professional ski patrolman and could ski 2600 vertical feet without stopping and could do that all day every day. My EARLY symptoms, before becoming vegetarian were mostly methylfolate deficiency, CNS-mb12 and CNS-adb12 symptoms and a weak immune system which vitamin C strengthened at age 23 when I started vit C.
As I see it currently, there are three groups of people with respect to their response to
adding glutathione to methylation treatment:
1. There is a group who benefit from this addition, in terms of their symptomatic response.
2. There is a group who benefit initially, but as time goes on, it causes their symptoms to worsen.
3. There is a group who experience immediate worsening of their symptoms.
I dont know what fraction of the ME/CFS population is in each group.
I would generally agree with this but think that there may be another group or two, or maybe actually subgroups of one or more specified above. Let me try a different logical grouping. An assumption is that potassium is given as needed so that doesn't have to be dealt with as a response. This may be a sparsely populated matrix without all positions filled
I. There is a group who have a large startup response to each of mb12/adb12/Metafolin with a large reduction of symptoms over a period of a year or more.
A. There is a group who experience immediate worsening of their symptoms, typically a RETURN OF SYMPTOMS, specifically folate deficiency symptoms intially followed by mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
B. There may be a group who benefit initially, but as time goes on, it causes their symptoms to worsen as mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
C. There may be a group who benefit from this addition, in terms of their symptomatic response
II. There is a group who have a large startup response to each of mb12/adb12 with a large reduction of symptoms over a period of a year or more.
A. There may be a group who experience immediate worsening of their symptoms, specifically folate deficiency symptoms intially followed by mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
B. There may be a group who benefit initially, but as time goes on, it causes their symptoms to worsen as mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
C. There may be a group who benefit from this addition, in terms of their symptomatic response
III. There is a group who have little or no startup response to each of mb12/adb12/Metafolin with a little reduction of symptoms over a period of a year or more.
A. There may be a group who experience immediate worsening of their symptoms, specifically folate deficiency symptoms intially followed by mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
B. There may be a group who benefit initially, but as time goes on, it causes their symptoms to worsen as mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
C. There may be a group who benefit from this addition, in terms of their symptomatic response
IV. There is a group who have some or no startup response to each of hycbl/cycbl/Folic-folinic acid with perhaps some reduction of symptoms over a period of a year or more.
A. There may be a group who experience immediate worsening of their symptoms, specifically folate deficiency symptoms intially followed by mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
B. There may be a group who benefit initially, but as time goes on, it causes their symptoms to worsen as mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
C. There may be a group who benefit from this addition, in terms of their symptomatic response
D. There may be a group with no change at all as their folate, mb12 and adb12 deficiency symptoms continue unchanged
V. There is a group who have "DETOX" symptoms (methylfolate deficiency) in response to hycbl/cycbl/Folic-folinic acid.
A. There may be a group who experience immediate worsening of their symptoms, specifically severe worsening of folate deficiency symptoms intially followed by mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
B. There may be a group who benefit initially, but as time goes on, folate deficiency symptoms remain about the same and their symptoms to worsen as mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
C. There may be a group who benefit from this addition, in terms of their symptomatic response, despite the continuing folate deficiency symptoms.
D. There may be a group with no change at all as their folate, mb12 and adb12 deficiency symptoms continue unchanged
Vi. There is a group who start glutathione or precursors prior to starting any cobalamin or folate.
A. There may be a group who experience immediate worsening of their symptoms, specifically folate deficiency symptoms intially followed by mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
B. There may be a group who benefit initially, but as time goes on, it causes their symptoms to worsen as mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
C. There may be a group who benefit from this addition, in terms of their symptomatic response
D. There may be a group with no change at all as their folate, mb12 and adb12 deficiency symptoms continue unchanged
VII. There is a group who start glutathione or precursors prior to starting any cobalamin or folate who then later start mb12/adb12/Metafolin.
A. There may be a group who experience immediate worsening of their symptoms, specifically folate deficiency symptoms intially followed by mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
B. There may be a group who benefit initially, but as time goes on, it causes their symptoms to worsen as mb12 deficiency symptoms followed by adb12 deficiency symptoms which are typically called DETOX.
C. There may be a group who benefit from this addition, in terms of their symptomatic response
D. There may be a group with no change at all as their folate, mb12 and adb12 deficiency symptoms continue unchanged.
E. There may be a group who benefit from this addition, in terms of their symptomatic response and then improve again after starting amb12/adb12/Metafolin
F. There may be a group who benefit from this addition, in terms of their symptomatic response and then no change after starting amb12/adb12/Metafolin