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Nitric Oxide Cycle Theory: Will It Explain CFS, FM, and Other ‘Unexplained’ Illnesses? – Q&A with Martin L. Pall, PhD

Martin L. Pall, PhD, is generating excitement in scientific communities worldwide with his theory that a "stressor-initiated" biochemical mechanism – the nitric oxide/peroxynitrite (NO/ONOO-) cycle – may be responsible for CFS, FM, and other syndromes.

The attention began with publication of his new book, Explaining 'Unexplained Illnesses': Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others [1].*

In the following Q&A, Dr. Pall, Professor of Biochemistry and Basic Medical Sciences at Washington State University, explains his theory in lay terms. Simply put, Dr. Pall proposes that the complex NO/ONOO- cycle he describes may result in high levels of oxidants, which affect different tissues in different individuals, accounting for a “stunning” variety of symptoms. Dr. Pall also believes a well-chosen regimen of antioxidants and other agents may help the body “downregulate” the NO/ONOO- cycle biochemistry.


Q: Dr. Pall, you suggest that cases of chronic fatigue syndrome (CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS) and post-traumatic stress disorder (PTSD) may all get started (get “initiated”) by similar mechanisms. What led you to that conclusion?

Dr. Pall: Cases of each of these are initiated by certain short-term stressors. These include both bacterial and viral infections in CFS and FM, exposure to three types of pesticides or to organic solvents, in MCS, to physical trauma in FM or PTSD, or to severe psychological stress for PTSD or any of these others. There are others, totaling 12 or 13 such stressors.

Each of these diverse stressors can increase levels of a chemical compound called nitric oxide in the body. So I proposed that nitric oxide is likely to have a role in the initiation of chronic illness.


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Q: So how can nitric oxide act to initiate chronic illness?

Dr. Pall: That is a very important question. I proposed that nitric oxide, acting via its product peroxynitrite, a potent oxidant, acts to initiate a biochemical vicious cycle which is the cause of illness.

This cycle, which we now call the NO/ONOO- (pronounced no, oh no!) after the structure of nitric oxide (NO) and peroxynitrite (ONOO-) is based on many well documented biochemical mechanisms, and the combination of such mechanisms is a complex vicious cycle which can propagate itself over time, producing chronic illness.

So for each of these cases of illness, we have an initial cause, one or more stressors, and an ongoing cause, the NO/ONOO- cycle mechanism. The pronunciation no, oh no reflects both the role of these two chemicals and the way people who suffer from these illnesses feel.


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Q: What else can you explain about these illnesses?

Dr. Pall: Almost everything:


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Q: You have discussed five principles that summarize the NO/ONOO- cycle mechanism as a model of disease. Please describe these.

Dr. Pall:
n The first principle, which we have discussed, is that NO/ONOO- cycle illnesses are initiated by stressors that can raise levels of nitric oxide or other cycle elements.

n The second principle is that the chronic illness is caused by the NO/ONOO- cycle and that ill people will, therefore, have raised levels of various cycle elements.

n The third is that the symptoms and signs of illness must be generated by the elements of the cycle.

n The fourth is that the basic mechanism is local. This local nature is caused by the fact that the three chemicals that have central role in the NO/ONOO- cycle, nitric oxide, peroxynitrite, and a third chemical – superoxide – all have relatively short half lives in biological tissues, so that they don’t travel very far from where they are produced to where they are destroyed. And the mechanisms of the cycle act at the level of individual cells of the body.

The consequences of these are that one person may have certain tissues of their body impacted by this local NO/ONOO- cycle biochemistry, but others may have different tissues impacted, leading, in turn, to much variation in symptoms and signs from one individual to another.

This variation in symptoms and signs of illness has been one of the greatest puzzles of this group of illnesses, and this can be explained easily with the current model.

n The fifth principle, the one that most sufferers as well as most physicians should find of the most interest, is how to treat these illnesses.

We should treat these by lowering (down-regulating) the NO/ONOO- cycle biochemistry. In other words we need to treat the cause of illness, not just the symptoms.


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Q: We’ll get back to therapy shortly. You suggest that the complexity of the cycle is the most difficult aspect in the effective treatment of these illnesses. Why is that?

Dr. Pall: The cycle involves at least 22 different mechanisms, by which one element of the cycle leads to an increase in another element of the cycle. It is the combination of these mechanisms, diagrammed by arrows in Figure 1 on my website and in my book.

The cycle involves many such mechanisms, as stated here, and also such variables as the activity of a “transcription factor” called NF-kappa B, which turns on the inflammatory cytokine genes and a gene that encodes the inducible nitric oxide synthase (iNOS), the levels of superoxide, the levels of calcium in the cytoplasm of cells, and the levels of two receptor systems that act mainly in the nervous system, the vanilloid receptors and the NMDA receptors.

The cycle also involves decreased ability to make energy in the form of ATP, due to the attacks of peroxynitrite on proteins and other components in the mitochondria.


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Q: So how does this explain what we need to do for effective therapy? Dr. Pall: It is the complexity of the cycle that makes treatment such a challenge.

I discuss many “agents” that are predicted to lower the NO/ONOO- cycle biochemistry in the chapter of my book on therapy (the longest chapter in the book). Twelve or 13 classes of such agents that have been reported to produce significant improvement in CFS, FM, or MCS in clinical trial studies and others may also be useful, albeit with less evidence.

However, individual agents produce only modest improvements.

Five physicians have produced complex treatment protocols having 14 or more agents predicted to down-regulate the NO/ONOO- cycle biochemistry, and these complex protocols appear to be much more effective than are the individual agents. It is these complex combinations of agents that have the most promise in the treatment of these illnesses. Most of these agents are nutritional, but some are conventional pharmaceuticals and some are “herbals.” [Dr. Pall refers to protocols developed by Dr. Paul Cheney, Dr. Garth Nicolson, Dr. Noboysa (Nash) Petrovic, Dr. Jacob Teitelbaum, and Dr. Grace Ziem. Dr. Pall has cooperated with Dr. Ziem in his own efforts to evolve a protocol.]


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Q: This treatment approach seems to be almost the opposite of that usually used in modern medicine. Is that so?

Dr. Pall: You are quite right – this approach is opposite to the predominant current approach to treatment. That predominant approach dates from the development of wide spectrum antibiotics in the 1940’s and 1950’s. That “magic bullet” approach is still very effective in the treatment of many acute bacterial infections. But it has been a failure with most chronic diseases, which are rarely cured; and often one cannot even greatly slow their progression.

The evidence of these five physicians suggests that we may be able to get a good clinical response with our group of four illnesses. Our goal should, in my view, be to get a substantial number of cures and it is my hope that by improving this approach, we will be able to do so.


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Q: We understand you have designed a protocol that is available over-the-counter, is that right?

Dr. Pall: Yes, I have designed [working with a leading supplement research company] an approach to down-regulating the NO/ONOO- cycle biochemistry that involves only over-the-counter supplements. [See "Antioxidant Suggestions for Down-Regulation of the NO/ONOO- Cycle from Dr. Martin Pall, PhD" [2].]

Let me just caution that I am a PhD, not an MD, and none of this should be viewed as medical advice, and that the supplements included in the protocol are not sold as a treatment or cure for any disease.


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Q: You argue, we take it from the title of the book, that these four illnesses are true diseases and that the NO/ONOO- cycle is a disease mechanism.

Dr. Pall: Exactly. I propose that the NO/ONOO- cycle is the tenth paradigm of human disease, adding it to the nine well-accepted disease paradigms described in Chapter 14 of my book.

It is unusual, however, primarily because the local nature of the cycle leads to much variation of symptoms of illness, depending on which tissues are impacted by the cycle and how severely they are impacted. What we are dealing with here with CFS, MCS, FM and PTSD is a huge spectrum of disease, with stunning variations in different individuals.


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Q: Are there any other important breakthroughs proposed in your book?

Dr. Pall: One very important breakthrough is that there are other diseases that are good candidates for NO/ONOO- cycle diseases. I suggest 14 additional diseases/illnesses that appear to be good candidates for NO/ONOO- cycle diseases, including such diseases as multiple sclerosis, tinnitus, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and asthma.

Each of these six has the apparent involvement of the NO/ONOO- cycle in different tissues. Another disease that is a candidate as a NO/ONOO- cycle disease is autism, where the early onset and the impact of the cycle on the developing brain may produce the characteristic properties of autism. Autism also has a huge spectrum of disease, the autistic spectrum disorders.

The criteria for other diseases/illnesses being candidates for inclusion under the NO/ONOO- cycle paradigm are their fit with the five principles we discussed earlier.

The possibility that this single mechanism may explain many different diseases is truly stunning. But it should not be completely surprising. There are dozens of diseases that are chronic inflammatory diseases, and the NO/ONOO- cycle involves inflammatory biochemistry, much the same biochemistry that occurs in inflammation. Thus the NO/ONOO- cycle may explain many of the diseases that are so predominant in medicine.


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Q: What response has the scientific community given to your theory?

Dr. Pall: The response has been truly amazing. I have just returned from giving five talks in Europe, two in Britain, and three in Spain. And the response at each of these talks has been extraordinary. I have already been invited back to both countries to give more talks. I am scheduled to give a talk in Mexico and five others in the U.S. this year. My book sold out within a week, with a second printing scheduled. I have had nine radio interviews to date and still more will occur fairly shortly.

I have to say that I am amazed at how positive the responses have been to date, especially when you consider how conservative science tends to be and how difficult it usually is to get acceptance of new scientific paradigms.


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Thank you very much, Professor Pall, for your responses to our questions, and we hope to hear more about your ongoing work in the future. For More Information

To read the transcript of a Live Chat with Dr. Pall, held in the ImmuneSupport.com Chat Room – where he answers scores of patient questions about his theory and protocol – go to "Live Chat with Martin L. Pall, PhD – July 6, 2007" [3]

If you are interested in reading a more detailed synopsis of Dr. Pall’s NO/ONOO- cycle concept – including a chart detailing “plausible mechanisms” for the different signs and symptoms associated with multisystem illnesses, from fatigue and memory dysfunction to chronic pain and IBS – visit Dr. Pall’s website at http://molecular.biosciences.wsu.edu/Faculty/pall/pall_main.htm [4] ___
* Dr. Pall's book, Explaining 'Unexplained Illnesses': Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Posttraumatic Stress Disorder, Gulf War Syndrome and Others (Haworth Press, 2007) is available in the ProHealth bookstore [1].

Note: This information has not been evaluated by the FDA. It is not meant to prevent, diagnose, treat, or cure any illness, condition, or disease. It is very important that you make no change in your healthcare plan or regimen without researching and discussing it in collaboration with your professional healthcare team.