I've known and interacted with Marty Pall for quite a few years. I value his work, and I have learned a lot from him. Most recently, he is the person who helped me to explain why the methylfolate in the blood plasma goes down instead of up in ME/CFS. Our most recent interaction was documented in the Townsend Letter in first part of this year.
Marty was one of the first ME/CFS researchers, along with Paul Cheney, Sarah Myhill and myself, to believe that ME/CFS is fundamentally a metabolic disorder in its pathophysiology, which I believe is increasingly being shown to be true.
All that having been said, it's also true that Marty and I have had, and continue to have, disagreements about the basic mechanism in the pathophysiology of ME/CFS. My view is that the reactions involving nitric oxide and peroxynitrite that he has described do in fact occur in ME/CFS, but that they are not the most fundamental in the pathophysiology. Peroxynitrite has been part of the model I have suggested since the beginning, but I see its rise as a consequence of the depletion of glutathione, which I view as the trigger for the onset of ME/CFS, in response to a variety of possible stressors that place demands on glutathione.
In his suggestions for treatment, Marty has emphasized antioxidants. He has also included hydroxocobalamin and more recently, methylfolate. He has suggested that the role of hydroxoB12 is to scavenge nitric oxide, and the role of methylfolate is to scavenge peroxynitrite. In my view, these are parasitic reactions that hinder these two from performing their fundamental roles in ME/CFS treatment, which are to support methionine synthase, to overcome the functional B12 deficiency, and to lift the partial block in the methylation cycle.
As far as I know, Marty does not believe that there is a functional B12 deficiency or a partial block in the methylation cycle. As far as I know, he is still not recommending a high enough dosage of hydroxocobalamin, applied in a way that will achieve a high enough level in the blood, to have significant therapeutic effectiveness.
In my view, the reason for the rise in nitric oxide is that because of the partial methylation cycle block, the resulting methylation deficit lowers the production of assymetrical dimethylarginine (ADMA), which is normally the main inhibitor of the nitric oxide synthase reaction. I believe that the rise in peroxynitrite is a consequence of depletion of glutathione, which goes hand in hand with a rise in oxidative stress, which allows superoxide to rise. There is a spontaneous reaction between superoxide and nitric oxide that produces peroxynitrite.
So, in some sense, it's a matter of disagreement about which is the cart and which is the horse.
I should note that both Marty's model and mine are focused on the pathophysiology of ME/CFS. Neither deals in much detail with the etiology (or etiologies), i.e. the root causes. I think Marty and I basically agree on the general categories of the etiologies, though. I call them stressors, and within that I include physical, chemical, biological and psychological/emotional stressors. The toxins are included within the chemical stressors, and the infectious pathogens are included within the biological stressors. I believe that the combination of stressors that bring the onset of ME/CFS differ from one person to another. I am very gratified to see the increased research effort by several groups now to look at the infectious pathogens as possible etiological agents for ME/CFS.
As far as I know, the improvements people have experienced when treating on the basis of the GD-MCB model have exceeded the improvements when treatment has been based on the NO-ONOO model. I don't disagree that antioxidants can help to lessen the oxidative stress in ME/CFS, but I have not found that the core of the pathophysiology, which I believe lies at a partial block in methionine synthase, can be addressed effectively with antioxidants.
Marty has gone on to apply his model to a number of other disorders besides ME/CFS, including MCS. I have not suggested that the GD-MCB model explains these other disorders. It may be that Marty's model is more applicable to MCS than to ME/CFS, but I have not studied MCS in detail, as he has.
Again, I want to emphasize that though Marty and I don't agree on some things, I very much appreciate the work he has done.
Best regards,
Rich