Hi, Madie.
Here's a repost from another thread, yesterday.
Best regards,
Rich
Hi, all.
I very much appreciate the discussion going on here. As some of you know, for about 5 years (1999-2004) I advocated direct boosting of glutathione by a variety of modes. Most of this went on in the Yahoo CFSFMExperimental group. This was based on the experiences of Drs. Salvato, Cheney, and Enlander, which indicated that it could be helpful. Some people experienced temporary improvement in symptoms from this, while others found that it made their symptoms worse. For the ones for whom the symptoms got worse, some of us speculated about possible reasons, but we never knew for sure. The possibilities that were raised were: (1) a "herxheimer" reaction due to die-off of pathogens from activation of the immune system by glutathione; (2) catabolic breakdown of the glutathione, producing too much cysteine, which would auto-oxidize and make the oxidative stress more severe; (3) catabolic breakdown of the glutathione, which would present too much sulfite to the sulfite oxidase reaction, causing the sulfite to rise to toxic levels; (4) mobilization of toxins into the blood by the glutathione, and then dumping them, which would expose all the cells to the toxins; (5) oxidation of the glutathione to oxidized glutathione (GSSG), which would shift the redox potential in the oxidizing direction and deleteriously affect biochemical reactions that depend on it. Those are the ones that I can think of, and I'm not sure which if any of them explain what these people experienced. There hasn't been any clinical research to sort this out, unfortunately.
When I learned about the involvement of the partial methylation cycle block in autism from the work of Jill James et al. in late 2004, I shifted my focus to treating to lift the partial methylation cycle block, which was found to raise glutathione automatically in autism, and the same was later found in ME/CFS by the clinical study that Dr. Nathan and I carried out and reported in 2009. So then it seemed to me that it wasn't necessary to boost glutathione directly.
More recently, I have become concerned about the many reports of symptoms of excitotoxicity when people begin the methylation treatment. These include anxiety, nervousness, insomnia, a "wired" feeling, and hypersensitivity of the senses. Dr. Amy Yasko had already found this in autism, and had suggested protocols to deal with it. From reading some of her material, I learned that a lowering of glutathione in the astrocytes of the brain could account for the excitotoxicity, because it would cause the glutamate level to remain too high in the neuronal synapses, overstimulating the NMDA receptors. When I combined this with the experience reported by Dr. Cheney when he measured the IVRT changes in his patients on his echocardiograph machine, comparing the effects of methyl B12 with hydroxo B12, it dawned on me that raising the activity of the methionine synthase reaction would initially lower glutathione, and that could explain the initial excitotoxicity increase and the more severe change in IVRT caused by methyl B12 than hydroxo B12. The methyl B12 would have a more immediate effect on the methionine synthase reaction, because it did not need to be converted to serve as the coenzyme.
So at that point, I began to think that it might help to add some glutathione to the methylation treatment, especially early on, to counter this initial drop in glutathione, and hopefully to relieve the excitotoxicity increase. So far, I'm not sure this has paid off for the people who have tried it, and there are clearly some for whom it made things worse, as reported on this thread. Why did that happen? I think it goes back to trying to understand why some of the people did not respond well to glutathione by itself. As has been mentioned here, maybe it was due to mobilization of toxins, which were then redistributed rather than taken completely out of the body. How would this happen? I think it's always important to keep in mind that in chemistry there is the concept of the dynamic equilibrium. This means that bonds are continuously being made and broken, and the average effect of all of this is what is reflected in chemical reactions. More to the point, the bond between a glutathione molecule and a toxic metal ion is not necessarily permanent. It can be broken. If there continues to be enough glutathione present, the toxic metal ions can be rebound, and the overall net effect is that they will be carried out, on the average. This dynamic equilibrium effect is the same reason Andy Cutler recommends taking alpha lipoic acid every three hours to chelate mercury. That keeps its concentration up in the blood, so that a mercury ion that become unbound can be bound again by another ALA molecule.
So if this is what is going on, perhaps the application of glutathione would need to be more frequent. This may be why I.M. application of glutathione, as practiced by Dr. Salvato, might work better, because the release to the blood would be slower than by I.V.
On the other hand, if the glutathione is producing too much sulfite, maybe more molybdenum supplementation would help. 2000 micrograms per day is the upper limit recommended by the Institute of Medicine.
If glutathione is being oxidized, perhaps more supplementation with B-complex would help, because B2 and B3 are needed by the glutathione reductase reaction.
The other new thing that has come into this picture recently is the research published a few months ago from Korea, which showed that glutathione has a major effect on the affinity of part of the intracellular B12 processing system for the B12 molecule (the CblC complementation group). I think this is probably the reason why we have had to use such high dosages of B12 (compared to the RDA dosage) to treat ME/CFS, where glutathione has become depleted. This has suggested to me that if glutathione could be raised sooner in the cells during the methylation treatment, it might work better, because the B12 would be processed more rapidly by the cells. So that's another reason I've been thinking that adding glutathione might help.
As you know, Freddd has been adamantly opposed to supplementing with glutathione, based on his personal experience with it, and the experiences of some others. As I've posted in the past, I think that Freddd himself has a polymorphism in his CblC complementation group. This is the part of the intracellular B12 processing system that normally uses glutathione. In Freddd's case, I think that what happens is that glutathione binds his B12 to form glutathionylcobalamin, and his CblC group is not able to reclaim the cobalamin, to use it to make methy and adenosyl B12, which it normally does. I don't know how many people have such a polymorphism, but the published literature says it is rare. Nevertheless, this could be another way in which glutathione causes problems for some PWMEs.
With regard to the ways of boosting glutathione, most of them that have been used do not actually get glutathione into the cells in general. For example, I.V. glutathione is of course put directly into the blood, but it doesn't stay in the blood very long. About 80% of it is removed by the kidneys, and about 10% by the lungs. The rest goes to various other cells, tissues and organs. Most cell types do not import glutathione. Instead, it is broken down into its amino acids. Some of them are imported, and glutathione may be re-formed from them inside the cells.
To actually get glutathione into the cells in general, liposomal or acetyl glutathione are the forms that should work. Another approach is to give the cells the amino acids needed, so that they can make glutathione. The rate-limiting amino acid is usually cysteine, though I have seen quite a few PWMEs who are low in glycine, also. Cysteine can be given orally as N-acetylcyteine, which the liver cells will import. However, there has been controversy about use of NAC in ME/CFS, on the grounds that it can move mercury into the brain. There has not been a clinical study of this.
Selenium is needed by some of the glutathione peroxidase enzymes. These enzymes convert hydrogen peroxide to water, in the process oxidizing glutathione to GSSG. This is separate from the conjugation of glutathione to toxins by the glutathione S-transferase enzymes.
At this point, I'm not sure what to recommend about using glutathione together with the methylation treatment. It does seem to help some people, but I don't know how to predict whether it will help a given person or not. I appreciate people's input on this issue.
Best regards,
Rich
