The Pall Protocol for Fibromyalgia Chronic Fatigue Syndrome

Is Nitric Oxide Behind these Conditions?

Some researchers speculate that chronic fatigue syndrome (CFS or ME/CFS) and fibromyalgia (FMS) could have a common cause. One researcher says that cause is nitric oxide and that it is also responsible for multiple chemical sensitivity (MCS) and post-traumatic stress disorder (PTSD).

Martin Pall, ​PHD, is a professor of microbiology at Washington State University and started looking into ME/CFS after he was diagnosed with it.

The essence of his theory is that short-term stressors cause a build up of naturally occurring nitric oxide, which starts a vicious cycle and leads to long-term illness.

It's important to remember that this protocol is experimental and has not been scientifically proven. A growing number of studies, however, support the theory of dysfunctional oxidative pathways, and some people who've tried the protocol say it has worked for them.

The information here is not intended to either support or refute Pall's theory but is here to inform you about available theories and treatment protocols so you can make informed decisions. It's important to include your doctor in your treatment decisions and to be monitored for any changes to your health.

Nitric Oxide in Your Body

Nitric oxide (NO) is all over your body and plays important roles such as influencing oxygen transport to your tissues and transmitting nerve impulses.

Until the late 1990s, however, it was considered a toxin and Pall considers it a toxin in his theory. Multiple studies show changes to the central nervous systems of people with FMS and ME/CFS, and Pall says those changes would require high levels of NO.

Pall says high NO levels in the central nervous system, in turn, lead to elevated levels of peroxynitrite, which causes tissue damage.

How do you get too much NO in your body? Pall lays out 12 possible stressors, 8 that lead to a direct increase, 4 that lead to an indirect one. The direct stressors are:

  • Viral infection (ME/CFS, FMS)
  • Bacterial infection (ME/CFS, FMS)
  • Physical trauma (ME/CFS, FMS, PTSD)
  • Carbon monoxide exposure (ME/CFS)
  • Organophosphorus pesticide exposure (ME/CFS, MCS)
  • Toxoplasmosis infection (ME/CFS)
  • Volatile organic solvent exposure (MCS)
  • Autoimmune diseases (secondary FMS)

The other 4 stressors trigger a response that leads to increased NMDA receptor activity, which is known to increase levels of NO and peroxynitrite (ONOO-). (NMDA receptors send signals in the brain and may be involved in cell damage.) These stressors are:

Note: NO levels also increase as a result of certain positive things, such as when you exercise, eat a low-fat diet, improve your nutrition or quit smoking, all of which experts consider a benefit to people with FMS and ME/CFS. Many researchers consider high NO levels to be good for your health.

The Vicious Cycle

Pall proposes that once a stressor causes a build up of NO, it puts in motion a vicious cycle that consists of several self-perpetuating loops.

From there, it gets extremely technical and difficult to understand unless you're really knowledgeable about biochemistry. If you are, Pall has a complete diagram on his website. For the rest of us, here's an example of how just one 5-step loop works:

  1. High NO level increases peroxynitrite level;
  2. Peroxynitrite increase causes oxidative stress (a build up of molecules that damage cells. Studies link oxidative stress to ME/CFS);
  3. Oxidative stress stimulates NF-kB (which controls expression of genes involved in immunity and cellular function);
  4. NF-kB increases production of the enzyme iNOS (inducible nitric oxide synthase);
  1. iNOS increases NO level, and we're back to step one.

Pall has named the vicious cycle the NO/ONOO- cycle (pronounced "no, oh no!"). He says it happens at a cellular level, which is why one tissue can be in pain while the ones around it are fine. It also explains why symptoms can vary so vastly from one person to another.

Shared Symptoms

Pall says elements of the NO/ONOO- cycle can explain a host of symptoms shared by CFS, FMS, MCS and PTSD. (He offers them as plausible causes, not established ones.) These symptoms include:

Breaking the Cycle

To break the cycle, Pall says it needs to be "down regulated," which essentially means slowing it down by eliminating things that trigger it. For example, if stress makes you feel worse, it needs to be reduced or managed. Beyond that, he believes the complexity of the cycle requires multiple types of treatment.

Pall's paper on the NO/ONOO- cycle outlines a multitude of things -- many of them nutritional supplements -- that he predicts will down regulate the cycle. (Remember that this theory is unproven and these agents untested for treating this group of illnesses.) He also lists the treatment regimens used by five doctors who've found success treating one or more of these conditions and says the treatments all are likely to down regulate the cycle. As with all treatment options, you should talk to your doctor about what is right for you.

Pall's not the only one pointing to nitric oxide as a possible cause of these illnesses. Several researchers examining NO's role, particularly in fibromyalgia, are calling for studies into whether antioxidants are an effective treatment.

The Research

Since Pall's book outlining his theory came out in 2007, a fair amount of research has been done on the role of nitric oxide in these conditions.

In ME/CFS, several studies (Sachdeva, Kumar, Gupta) have appeared to support the theory, at least in mouse-models.

Some human studies also lend credence, including a 2010 study (Suarez) that showed abnormal NO metabolites after exercise in ME/CFS. Research published in 2014 (Morris) suggests that oxidative and nitrosative stress may drive immune-inflammatory and autoimmune pathways that sustain the disease mechanisms of the disease.

However, at least one study (Meeus) has found no interaction between the amount of NO in the blood and activity in ME/CFS.

Several studies (Cimen, Fatima, Sendur) also support the theory of nitric oxide involvement in FMS. Another (Kim) found no significant difference in NO levels between the FMS group and healthy controls.

Is the Pall Protocol Right for You?

Only you can decide which treatment is right for you, and you should be sure to discuss your treatment options with your doctor. In addition to many aspects of this protocol requiring a doctor's participation, you also should be closely monitored to ensure the treatment does not have a detrimental effect on your health.


Cimen OB, et al. Pain medicine. 2009 Jul-Aug;10(5):813-8. Arginase, NOS activities, and clinical features in fibromyalgia patients.

Fatima G, Das SK, Mahdi AA. Clinical and experimental rheumatology. 2013 Nov-Dec;31(6 Suppl 79):S128-33. Oxidative stress and antioxidative parameters and metal ion content in patients with fibromyalgia syndrome: implications in the pathogenesis of the disease.

Gupta A, Vij G, Chopra K. Journal of neuroimmunology. 2010 Sep 14;226(1-2):3-7. Possible role of oxidative stress and immunological activation in mouse model of chronic fatigue syndrome and ita ttenuation by olive extract.

Kim SK, et al. Clinical and experimental rheumatology. 2010 Nov-Dec;28(6 Suppl 63):S71-7. Arterial stiffness and proinflammatory cytokines in fibromyalgia syndrome.

Kumar A, et al. Indian journal of pharmacology. 2011 May;43(3):324-9. Nitric oxide modulation in protective role on antidepressants against chronic fatigue syndrome in mice.

Martin L. Pall, School of Molecular Biosciences, Washington State University. All rights reserved. "Novel Disease Paradigm Produces Explanations for a Whole Group of Illnesses."

Meeus M, et al. In vivo. 2010 Nov-Dec;24(6):865-9. Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study.

Morris G, Maes M. Current neuropharmacology. 2014 Mar;12(2):168-85. Oxidative and nitrosative stress and immune-inflammatory pathways in patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS).

Sachdeva AK, Kuhad A, Chopra K. Brain research bulletin. 2011 Oct 10;86(3-4):165-72. Epigallocatechin gallate ameliorates behavioral and biochemical deficits in rat model of load-induced chronic fatigue syndrome.

Sendur OF, et al. Rheumatology international. 2009 Apr;29(6):629-33. Serum antioxidants and nitric oxide levels in fibromyalgia: a controlled study.

Suarez A, et al. Journal of women's health. 2010 Jun;19(6):1073-7. Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study.