Welcome to our Live Chat Event with Dr. Martin L. Pall, PhD, a Professor of Biochemistry and Basic Medical Sciences at Washington State University, and author of the acclaimed new book Explaining “Unexplained Illnesses.”*
Dr. Pall has concluded that a single complex biochemical cycle which elevates levels of potent oxidants in the body – the nitric oxide/peroxynitrite cycle (NO/ONOO- cycle) – is responsible for causing CFS, FM, MCS, PTSD, and other chronic diseases. He believes this vicious cycle is initiated by a range of short-term stressors including viral and bacterial infections, toxic chemicals, physical trauma, and severe psychological stress. And a well-chosen regimen of antioxidants and other agents may help the body down-regulate that cycle. (For an expanded explanation of these concepts, click here. And for details of Dr. Pall’s antioxidant protocol, click here.)
Importantly, as Dr. Pall cautions, “I am a PhD, not an MD, and none of this information should be viewed as medical advice. The supplements included in the antioxidant support regimen I have designed are not meant or sold as a treatment or cure for any disease.”
Q: Dr. Pall, do you or someone close to you have one of these illnesses?
Dr. Pall: I had Chronic Fatigue Syndrome, but unlike most such people, I had a full recovery over a period of about a year and a half. I consider myself cured and have had no relapses over the past 8 years.
Q: Was your illness directly related to something you could identify?
Dr. Pall: It was caused by a Varicella zoster infection – basically a bad case of shingles. Herpes group viruses are common initiators for cases of CFS, so this should not be surprising. They probably are active in this because they are very active in producing an inflammatory response.
Q: What did you do to recover from your CFS?
Dr. Pall: I did three types of things. I was very careful to pay attention to what my body was telling me – specifically to avoid exercise. I think that response to exercise and perhaps other stress seems to be a specific defect in CFS. I talk in my book about what is the probable mechanism here. So this may be a good thing to observe but I think, in general, it is always good to pay close attention to many of the things your body is telling you.
I was very careful about my diet, knowing much about the biochemical properties of different foods, trying in general to give my body everything it might need in order to recover. I also took a number of nutritional supplements including antioxidants, magnesium, Co-Q10. However, it should be noted that you never know when you look at one person, what is producing a favorable response. So I think these things were important, but you can’t say as a scientist that this has any validity.
Q: How did you get started thinking about this cycle? What gave you the idea?
Dr. Pall: Peroxynitrite has a role in many different diseases, but what got me started on the vicious cycle idea was the work of Dr. Joe Beckman on the inactivation of the enzyme superoxide dismutase (in mitochondria) an enzyme that helps get rid of superoxide. His work suggested a possible vicious cycle – and what I have done is to look for other possible elements in cycles that can further contribute. Having identified additional elements in the larger cycle, the next step was to look to see if there was evidence for a role in the group of multisystem illnesses. [Note: Joseph Beckman, PhD, is a professor in the Department of Biochemistry and Biophysics, Director of the Environmental Health Services Center, and Principal Investigator of the Linus Pauling Institute at Oregon State University.]
Q: Do you think there’s a difference in the specific types of stress that cause the different illnesses?
Dr. Pall: Yes, there are stressors that are most commonly involved in the initiation of one illness but rarely involved in the initiation of others. For example the organic solvents and the pyrethroid and organochlorine pesticides seem to be most commonly involved in the initiation of Multiple Chemical Sensitivity (MCS). However, there is a fair amount of cross-talk, where stressors initiate more than one illness.
Q: How is a “stressor” different from stress?
Dr. Pall: The term stress is used in two different ways, and is, therefore, ambiguous. Some people use the term to refer only to psychological stress, whereas others refer to stresses as being anything that perturbs the body. The term “stressor” is therefore clearer, referring to many different things that may perturb the body.
Q: Why do you think some people develop this cycle after a stress, and not everyone?
Dr. Pall: There are important genetic, hormonal, and nutritional effects which, along with the strength of the stressors involved, determine who becomes ill and who does not.
Q: So you think the nitric oxide cycle affects different tissues in the body rather than all at once?
Dr. Pall: Yes, it is local. And where it is localized in the body determines what symptoms and signs affect a particular individual.
Q: Dr. Pall – I am confused about the nitric oxide [NO] cycle theory. I have heard that NO is good for our health. Can you explain a little more about it?
Dr. Pall: Nitric oxide has important functions in the body. It serves to dilate the blood vessels, it has an important role in the nervous system, and in controlling the immune system. However, when there are excessive levels and specifically when a lot of it is generating peroxynitrite, it can cause lots of problems. Let me say that one should not look at the NO/ONOO- cycle just in terms of nitric oxide – there are many different elements involved that are important.
Q: What stabilizes the “vicious circle” of oxidative stress so the person has CFS [for example] but does not die?
Dr. Pall: The body still has protective mechanisms – it is just that they are not working adequately.
Q: Dr. Pall, have you taken into consideration the possibility of genetic damage done by chemical, bacterial, or viral agents?
Dr. Pall: Yes, and peroxynitrite will break down to release hydroxyl radical that will cause genetic damage. There was a report that in CFS, damage to the mitochondrial DNA accumulates at a greatly increased rate, and this might be caused indirectly by elevated peroxynitrite.
Q: Many people believe that the illness Myalgic Encephalomyelitis has, in this country, inaccurately ended up under the umbrella term ‘Chronic Fatigue Syndrome’. Does your theory treat them as one and the same (possibly differing only in severity and organs affected), or would you tend to believe that (the possibly infectious disease) M.E. is one of many stressors that can lead to chronic illness (chronic NO/ONOO- cycle) in its aftermath?
Dr. Pall: I treat them as being either similar or identical. I would say, in general, that this whole group of illnesses, with cases being so variable from one individual to another, constitute a whole spectrum of illness. Presumably this spectrum is generated by variations in the tissue distribution of the NO/ONOO- cycle biochemistry among different individuals.
So what we have are different diagnostic criteria or case definitions that basically identify some fraction of this spectrum as being some specific disease or illness. But the divisions are more or less arbitrary. A different case definition will change which part of the spectrum is included. This is important. These different illnesses don’t fall into discrete categories, in the same way that, for example, tuberculosis infection is different from an influenza infection or a cholera infection.
Q: You mentioned exercise. Everyone tells us “all you need to do is exercise.” How do we explain that is the wrong thing to do?
Dr. Pall: The phenomenon of post-exertional malaise in CFS is very well documented. So exercise leads to increases in the whole spectrum of symptoms in CFS. The question is why? I argue that it actually up-regulates the NO/ONOO- cycle mechanism by producing increased iNOS induction (more nitric oxide). You might look at the section of my CFS chapter on developing specific biomarker tests for CFS.
Q: Do you talk at all about Fibromyalgia?
Dr. Pall: Chapter 8 in my book is on Fibromyalgia. It discusses both features that are similar to these other illnesses and also how the widespread excessive pain, the most characteristic feature of Fibromyalgia, appears to be generated.
Q: Why do people with Fibromyalgia have more problems with free radicals versus the average population?
Dr. Pall: That is true for people with CFS and the other illnesses as well. Any time you have elevated levels of superoxide and peroxynitrite, you are going to have oxidative stress and excessive free radicals.
Q: What causes the pain that no doctor seems to be able to find?
Dr. Pall: There is a difference between the Fibromyalgia pain and the pain found in this whole group of illnesses. The latter pain is similar to what is called hyperalgesia – excessive pain that has been studied extensively and which involves all of the elements of the NO/ONOO- cycle. So the presence of pain in these multisystem illnesses should not be surprising.
Q: Would this protocol work for myofascial pain syndrome?
Dr. Pall: That would be my guess – we need data on this.
Q: How does the cycle correspond to the presence of multiple infections like HHV-6, Epstein-Barr virus, etc.?
Dr. Pall: These are probably opportunistic infections caused in part by the changes in immune function produced by superoxide, oxidative stress, nitric oxide, and the inflammatory cytokines – all of which are part of the cycle.
Q: How does reducing the NO toxic levels in the body get rid of the infections that we have accumulated over the years?
Dr. Pall: One needs to normalize not just nitric oxide, but the whole cycle. However, normalizing the cycle should restore normal immune function. I think the question you raise is whether we should also be treating the opportunistic infections that often accompany CFS and related illnesses. They are likely to exacerbate the NO/ONOO- cycle, so such treatment is likely to be helpful.
Q: Do you think there is a link between sleep and CFS, FM, and other illnesses?
Dr. Pall: Yes. The question is, what is the mechanism? I think it may involve peroxynitrite oxidation of a compound called tetrahydrobiopterin. Tetrahydrobiopterin deficiency has an important role in the production of serotonin and melatonin, both of which help control sleep
Q: I have severe MCS [multiple chemical sensitivity] with CFS and have been having terrible breathing difficulties when exposed to various things ever since I came down with walking pneumonia recently. These reactions seem to get worse each year. [Might the antioxidant regimen you designed provide a benefit?]
Dr. Pall: Dr. Ziem finds that many of her patients with “reactive airways disease” respond well to the protocol that she and I developed, when they simultaneously avoid chemical exposure. So I think it is likely that these approaches can produce substantial normalization of lung function – but again, one needs to also avoid chemical exposure, and that is difficult in our society. [Note: this refers to Dr. Grace Ziem, MD, DrPH, who specializes in the diagnosis and treatment of chemical injury, and with whom Dr. Pall cooperated in his work to evolve a nutritional protocol for support of patients with unexplained illnesses.]
Q: How do you rid the body of these pesticides?
Dr. Pall: I’m not sure you need to. I think the main focus needs to be on how to recover from the effects of pesticides and other toxicants. Most of the damage – presumably through the initiation of the NO/ONOO- cycle – is produced by toxicants that are long gone in the chronic phase of illness. This shows up in MCS, because MCS people react very quickly to new chemical exposure; so it is primarily their sensitivity to chemicals that is the problem, not stored toxicant chemicals in the body.
Q: Why are so many Gulf War vets ill?
Dr. Pall: Because of the NO/ONOO- cycle mechanism. Gulf War syndrome is basically a combination of CFS, Fibromyalgia, MCS and PTSD initiated by at least a dozen stressors that the Gulf War military were exposed to.
Q: There are confirmed cases of transmission of the illness (CFS-like) from Gulf War vets to their families. How is this possible? The initial stressor was already non-existent and OH/ONOO state is not considered contagious, is it?
Dr. Pall: That is a good question, but I can’t really answer it. I think it needs more study to confirm that this is really going on.
Q: Please explain how PTSD [Post Traumatic Stress Disorder] relates?
Dr. Pall: The severe psychological stress that initiates cases of PTSD can also, like the other stressors, produce increases in nitric oxide. So the initiation can involve the same mechanism as in these other illnesses. PTSD shares many symptoms and signs with these other illnesses, as well – this is reviewed in Chapter 3 of my book. The question about PTSD is whether you can explain the characteristic psychiatric symptoms as being a consequence of the NO/ONOO- cycle. I do make arguments in my book that these can be explained as being caused by the cycle, but you will have to read the PTSD chapter to see what the arguments are.
Q: What part do you think diet and antioxidants can play in controlling depression then, Dr. Pall?
Dr. Pall: I’m not sure I can answer that, although I think that by down-regulating the NO/ONOO- cycle, all of the symptoms should improve at some point. I suggest in my book that excessive nitric oxide in certain parts of the brain has a role in generating depression, so this suggests that the nitric oxide scavenger hydroxocobalamin (a form of vitamin B12) may be especially useful in lowering depression. Not sure if there is any data on this.
Q: Realistically, how much benefit do you think the antioxidants you recommend can offer patients? And is there any research showing evidence of benefits yet?
Dr. Pall: I think there is much benefit. But the combinations of antioxidants must be well-chosen. Many people have had the notion that antioxidants are largely interchangeable and that one antioxidant is likely to be as useful as another. In fact, it is much more complex than that. And I think that the antioxidant trials that have been focused on using high dose synthetic alpha-tocopherol (the most commonly used form of vitamin E) and high dose synthetic beta-carotene have not been well thought out.
Q: Does a treatment plan for the cycle require a physician, or can it be implemented and maintained by the person suffering from the illness?
Dr. Pall: I have worked with a leading supplement research company to develop an all over-the-counter nutritional protocol to lower the NO/ONOO- cycle biochemistry. [See “Antioxidant Suggestions for Down-regulation of the NO/ONOO- Cycle from Dr. Martin Pall, PhD.”] ProHealth is working with this company to help make these preparations available. Again I must caution that these suggestions are intended as nutritional support, not as a replacement for medical treatment of any condition. Any decisions regarding a change in your healthcare plan or regimen should be made in collaboration with your professional healthcare team.
Q: How long does it take on the protocol to observe favorable results?
Dr. Pall: I think as we have gotten better at this, the response has become more rapid. I’d expect to see a response in a few weeks, certainly in less than three months. I would add, however, that the approach requires that one avoid stressors that will otherwise up-regulate the NO/ONOO- cycle biochemistry. In CFS, that would include exercise as such a stressor – and many individuals may also have to avoid foods that they are allergic to, and psychological stress.
It is important that the approach not only involves taking certain nutritional supplements but also avoiding anything that might otherwise up-regulate the cycle biochemistry.
Q: Must all of the supplements from your protocol be taken to get full benefit, or can you take only a few?
Dr. Pall: I would expect that there will be a better response to all of them, or at least all of them that a person tolerates well. But individual components may, nevertheless, be helpful. For example, I have gotten some feedback from a group of people in Spain who are only taking the MVM-A part of the protocol and report favorable responses to that. I don’t suggest that, but it nevertheless seems to be helpful to them. [Note: the MVM-A formulation is a multivitamin/mineral with acetyl-L-carnitine and R-alpha-lipoic acid.]
Q: In your protocol, do supplement dosages differ? In other words, do you make any distinction between a 200 lb man and a 110 lb woman? Often supplements don’t make a distinction, and those of us who are small have problems.
Dr. Pall: No it does not, but clearly you may wish to consider this when deciding on your personal regimen.
Q: Can you over-use antioxidants?
Dr. Pall: Some antioxidants, especially when used alone and at high dose, can cause problems. And I criticize the use of high dose synthetic alpha-tocopherol (form of vitamin E) as well as high doses of synthetic beta-carotene, in my book. We have tried to consider possible negative effects of antioxidants in developing the Allergy Research Group protocol.
Q: I am a CFS patient. My uric acid level is typically below normal range. I understand that uric acid in the blood helps protect against peroxynitrite, and that the purine inosine can boost blood levels of uric acid. Do you think that supplementing with inosine might be helpful too?
Dr. Pall: There are three types of agents that may be expected to raise uric acid levels, and they may all be helpful. One is inosine – others are D-ribose and RNA [ribonucleic acid]. Each has some positive aspects, but each may well have some drawbacks as well. I think that one or more of these may be worth trying.
Q: During a lecture by Dr. Paul Cheney he said he had seen adverse reactions to NAC [N-acetyl cysteine] supplementation. What dosage of NAC do you consider to be helpful?
Dr. Pall: NAC – N-acetyl cysteine – is well tolerated in most people, but Cheney has found that some of his patients do not tolerate it. We are using a low dose (about 40% of the usual dose) in the Allergy Research Group protocol, and suggest using it after starting to take magnesium. Magnesium should lessen any sensitivity to NAC.
Q: What can you do if you develop reactions to drugs, herbs, or various vitamins?
Dr. Pall: Avoid them or cut the dose. In some cases reactions may be due to impurities, in which case finding a purer source may be helpful.
Q: Are there certain amino acids that can be taken which will help the mytochondria to produce more energy?
Dr. Pall: Yes. I have tended to stay away from suggesting using amino acid supplements because they have so many complex interactions. But I may be wrong about this. The Petrovic protocol uses such amino acid supplements. [Note: This refers to a nonprescription CFS protocol developed by Nash Petrovic, MD, that reportedly includes “a complex mixture” of more than 200 microantioxidant compounds.]
Q: Could you please explain the use of Ecklonia cava extract (SEANOL-F)? It was recommended as a supplement that you use but it was not covered in your book. Thanks.
Dr. Pall: I’ve gotten some recent feedback from physicians that this polyphenolic antioxidant is very useful. It may well act in similar fashion to other phenolic antioxidants discussed in my book.
Q: Dr. Pall, is cod liver oil a good way to slow down the NO/ONOO- cycle?
Dr. Pall: Cod liver oil contains long chain omega 3 fatty acids, and these lower the induction of the inducible nitric oxide synthase. They should be helpful in this way.
Q: Do you have an opinion on the use of malic acid for FM and/or CFS?
Dr. Pall: I suggest that magnesium malate may be the best form of magnesium to take.
Q: How does NO/ONOO- theory compare to Dr. Paul Cheney’s model of a deficiency of 3 main enzymes, presented on video from 2006?
Dr. Pall: Dr. Cheney and I have spent many hours on the phone discussing CFS. Our views on it are very similar. This is apparent from the comments he kindly made for my book. [Note: Dr. Cheney stated in his review, “A stunning expose on what is surely a central thesis of chronic, unexplained, and fatiguing illness; namely that oxidative stress mechanisms hold the key to any holistic viewpoint….This book could easily mark the end of the beginning of a more complete understanding of this complex field, which is a trillion dollar nightmare of human misery and bio-political inattention.”]
Q: What have other CFS and FM researchers said about your new ideas so far?
Dr. Pall: I got some great responses from the CFS people in England when I presented this recently. I have been invited back to keynote another CFS meeting in October.
Q: Does this abnormal NO/ONOO- cycle chemistry have any connection to the theory of the abnormal methylation cycle that some Drs. are talking about? [Rich Van Konynenburg, PhD’s glutathione depletion-methylation cycle block theory of CFS.]
Dr. Pall: This methylation concept is a very different concept from the NO/ONOO- cycle. I do think that a number of the agents suggested by those discussing methylation will help to lower the NO/ONOO- cycle – so they may be useful for reasons that have nothing to do with methylation. In addition, the biochemistry involved in the methylation cycle is impacted by the NO/ONOO- cycle biochemistry. For example, the enzyme methionine synthase is inhibited by nitric oxide.
Q: Comparing Dr. Rich Van Konynenburg’s methylation cycle theory & the OH/ONOO- cycle, which concept do you think holds most promise for CFS & FM patients, and why?
Dr. Pall: We have communicated on this. The NO/ONOO- cycle mechanism is very extensively documented in my book, which contains about 1,500 references to the scientific literature. I have also published 16 papers on this mechanism. It is also much more complete than is Rich’s proposal, and provides detailed explanations for many features of these illnesses that have never been explained previously.
Q: I am on the Rich Van Konynenburg protocol. Can I combine yours for MCS with this?
Dr. Pall: There are a lot of overlaps between the two. I’d have to look at them in more detail to see if there any incompatibilities between them, but I suspect they are compatible.
Q: Isn’t peroxynitrite a radical scavenger, which could greatly disrupt the energy production in the mitochondria? Do you think Dr. Robert Suhadolnik’s work on the RNase L antiviral pathway could be the trigger which chews up the messenger RNA as well as the viral RNA – could be what is causing the NO and peroxynitrite problem?
Dr. Pall: Peroxynitrite attacks multiple components of mitochondria, and this is an important part of the NO/ONOO- cycle, and also contributes to symptoms. I don’t think we know how the 37 kD RNase L is involved – at this point, we have a wide ranging explanation of CFS without involving this factor, but that does not mean it does not have a role.
Q: Do you think a pharmaceutical company could make and patent a drug that would break the free radical cycle?
Dr. Pall: I think there are drugs that are helpful, and others may be developed in the future that may be more so – I talk about one possibility in my book that has substantial promise. But I think that the “magic bullet” approach to dealing with chronic diseases in general is dysfunctional.
Q: Is it possible to repair the superoxide dismutase production in the body?
Dr. Pall: There is a lot of experimental work on what are known as “superoxide dismutase mimics” – relatively small molecules that get rid of superoxide. I don’t know what the prospects are for these being developed as effective drugs.
Q: Dr. Pall, do you believe the pharmaceutical company industry will lobby the drug insurance companies to block funding for supplements, or do you expect the medical industry in general to embrace your system?
Dr. Pall: The lobbying has been going on vigorously for quite a while. You should look at Dr. Jerome Kassirer’s book entitled On the Take – it is very enlightening.
Q: Do you think the NO/ONOO- protocol might change any over time?
Dr. Pall: I certainly hope so. I hope we will learn rapidly how to get an improved clinical response. And I think that many physicians and scientists will be involved in this process in the future, as they have been in the past.
Closing Chat Remark:
Thank you, Dr. Pall, for all your hard work, and for helping those of us with MCS [and other unexplained illnesses] have real answers behind a perplexing illness that is “not all in our head.” Bless you!
ProHealth also wishes to thank Dr. Pall – and all the patients, researchers, and advocates who participated so generously in this Live Chat Event. Hopefully the information exchanged here will help advance the work to find a cause and a cure.
* 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, May 2007), is available through the ProHealth bookstore.
Note: This information has not been evaluated by the FDA. It is not medical advice and 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 health support regimen without researching and discussing it in collaboration with your professional healthcare team.