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

  [ 1550 votes ]   [ 16 Comments ] • June 22, 2007

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.*

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.


* * * *

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.


* * * *

Q: What else can you explain about these illnesses?

Dr. Pall: Almost everything:

  • How many of the symptoms are generated,
  • Why these symptoms are variable from one individual to another,
  • Why these illnesses often occur together in the same individuals,
  • Why they also often occur with such diseases as asthma, migraine headache, tinnitus, lupus or rheumatoid arthritis,
  • And how they should be treated.


* * * *

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.


* * * *

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.


* * * *

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.]


* * * *

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.


* * * *

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".]

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.


* * * *

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.


* * * *

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.


* * * *

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.


* * * *

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 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"

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 ___
* 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.

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.

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Article Comments Post a Comment

Effectiveness of Treatment Protocol ?
Posted by: adonnay
Jun 13, 2007
This interview reports that five doctors (Dr. Paul Cheney, Dr. Garth Nicolson, Dr. Noboysa Petrovic, Dr. Jacob Teitelbaum, and Dr. Grace Ziem) have developed their own treatment protocols in consultation with Dr. Pall designed to down-regulate the NO/ONOO-cycle, which he believes is responsible for causing all the various symptoms of CFS, FM, MCS and PTSD. Dr. Pall says "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." (By cured, I assume Dr. Pall mean cases who met the diagnostic criteria for one or more of these diseases before their treatment but not after.) But so far no studies of these treatment protocols have been published. Could Dr. Pall please tell us how many cases of CFS, FM, MCS and PTSD these five doctors (or any other doctors) tell him they have seen cured with this treatment, and how many months of treatment on average were needed to achieve these cures? If no cases have yet been reported cured, can Dr. Pall please tell us which if any specific symptoms have been reported cured? In comparison, it also would be helpful to know how many patients these doctors say have tried their protocols but not been cured. Another important question not addressed in this interview is whether Dr. Pall believes that all cases of CFS, FM, MCS and PTSD may be cured by treatment protocols designed to down-regulate the NO/ONOO-cycle, or only cases that have some specific symptom(s) or abnormal test result(s), such as elevated NO in their exhaled breath. I invite anyone who has tried treating CFS, FM, MCS and/or PTSD with any version of Dr. Pall's protocol to post their own experience. Please tell us if you have you been cured of your disease or any symptom of it and how many months this took to achieve (or if it didn't work, how long until you quit). I'm sure I'm not the only one who looks forward to seeing some results! --Albert Donnay, MHS
Reply Reply

Working with my Internist
Posted by: bbrown1
Jun 13, 2007
Thank you for your time. I am currently on doctor prescribed meds for my CFS. Whenever I approach my physician regarding any natural treatments he will not discuss it as he states that there is no FDA approval for any of the herbs or supplements.

I have spoken to a pharmacist regarding fish oil capsules and flaxseed oil capsules along with garlic capsules which were recommended by a friend. It was recommended that I not take any of these three supplements with the meds I am already on. I am currently not taking my Trazadone for sleep as when I decided to try sleeping without them, I have been able to sleep. This is the first time that I have been able to sleep without the 100mg tablets in three years. However, I am back to needing 12-14 hours of sleep nightly.

Another improvement for me is the IBS. I am no longer needing fiber supplements to normalize my stools. I am quite regular.

My hopes are that I am possibly healing from the CFS.

The meds that I currently take are to treat other symptoms that I had prior to the CFS. These include:

Allegra for allergies Atenelol for HBP aspirin for mild congestive heart failure aciphex for acid reflux amitriptyline for pain (for CFS) cymbalta for depression and pain (for CFS) simvastatin for high cholesterol Calcitrate, 1000 mg daily multiple vitamin daily

I am a 54 year old post menopausal female. I know that you cannot make a suggestion either way most likely as it would be considered medical advice. However, I am hoping that you might be able to at least steer me in the right direction a little more than my PCP has with no comment at all.

Thank you.


Brenda Brown


Posted by: stristan
Mar 18, 2009
I will be very interested to find out if there have been any cures!


Hoorah! :D
Posted by: HazUK
Jun 28, 2007
This is great news. I had private tests done by my Chiropractor who is specialising in Neurology / also is a functional biochemist using nutrition to deal with this and improving pathways. He diagnosed this NO/ONOO cycle 2 years ago - things are much better since working with him but there is much further to go on this path. I have no money to buy what I need to help myself.

Great reading about the things available here on this site but if you are in this situation having to lay down all the time to do anything -there is no money to buy them. Even organic food is an expensive way to live when you are poor, no family to support you and unable to function well enough to work a few hours or reliably.

Now I hope this gets discussed further and a official clear path forward is found, we can get people out of feeling guilty for being ill with things not recognised so we can focus on just getting well instead of having to fight for help and support. Maybe there is room for funded treatment with dignity restored for us?

I have sent this article to my MP.

Perhaps others will do this.... even if you are not the ones dealing with it too?

Can I take this opportunity to give thanks for great work you are all up to to help us. x


nitric oxide cycle theory
Posted by: tonikelley
Jun 20, 2007
I think this may be one of the best, new breakthroughs to help us. I am very thankful to Martin Pall, PhD. for his work. I have kept up with every protocol and new research for past 8 years. Thanks to for making this an easier thing to do. My rheumatologist here in Mobile, Alabama told me in 1991 (16 years ago) that I should "go out and find things that are working and pursue them...that he could not do that and had very little to offer me." He said he knew of help out there, but he could not access it from traditional medicine practice. This is same good doctor who 10 years later wrote on his prescription pad for me the following I could try with proven results: Sam-E, St. John's Wort, Prozac, water exercise. Thank God for good doctors like this one. For the record, I decided NOT to try the Prozac.
Reply Reply

NO was proposed in 1999
Posted by: sregan
Jun 21, 2007 Search for "NITRIC OXIDE" almost half way down the page.
Reply Reply

Where to buy?
Posted by: liamn
Jul 3, 2007
Can someone tell me who makes MVM-A Take 2 capsules, three times daily, with or following meals. This is a multivitamin/mineral with acetyl-L-carnitine and R-alpha-lipoic acid. My MVM says take one a day. Is it safe to take 3? ProHealth does not have these products.
Reply Reply

Clarification for adonnay
Posted by: minnesota
Jul 12, 2007
The original wording of the bracketed editor's comment on the five Drs. who've developed protocols could be misread and has been revised for greater clarity. Drs. Cheney, Nicolson, Petrovic, and Teitelbaum have all apparently all developed protocols that included many of the agents which Dr. Pall predicts may downregulate the NO/ONOO- cycle biochemistry. But Dr. Pall has apparently cooperated only with the last named - Dr. Grace Ziem - in evolving a protocol.
Reply Reply

Nitric oxide
Posted by: rosedale
May 7, 2008
I've had ME since 1985 and fibro since 1994. Always reading and researching, and have found some things that help me some. I started taking Arginine since it made sense to me that more oxygen should help weak, fatigued muscles, and Arginine is a precursor of nitric oxide. Boy, was I wrong! I had a lot more muscle pain almost immediately, and stopped taking it. A few months later the newsletter started discussing the possible detrimental effects of nitric oxide. Hmmm...
Reply Reply

Martin Pall's theory works in practice--Highly Recommended
Posted by: ItWorks!
Jan 12, 2011
His book is technical, His explanation of what direction to take with supplements is as comprehensive as possible. And it is amazingly effective at least on two people (2 out of 2 people that I know have tried it). It works, I believe in situations where there has been ongoing physical, emotional trauma .... just because the effects on the body are the same. The results were rapidly observed in the above two cases. And I am thankful for his efforts in writing this book. It was a life changer. A game changer. I will never forget this scientist. When all medical help fails, yes, look for the devoted scientist who isn't a drug industry prostitute.
Reply Reply

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