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The “triggers” that initiate ME/CFS and other multi-system illnesses - Fibromyalgia (FM), Multiple Chemical Sensitivities (MCS), Lyme disease, Post Traumatic Stress Disorder (PTSD) and Gulf War Syndrome - are numerous and varied. However, because these diseases ultimately have consistent and often-overlapping symptoms, researchers believe there may be biochemical abnormalities common to all sufferers.
If a common biochemical abnormality can be identified, treatments directed toward this alteration might hasten resolution or at least provide significant improvement for those afflicted.
In the quest for a “unifying theory” of ME/CFS and related multi-system diseases, two models have emerged that have gained much scientific credibility. Research is revealing a connection between these complicated and misunderstood diseases and an equally complicated and misunderstood vitamin that may hold the key to improved health for many.
The Vitamin B-12 - ME/CFS/FM Connection
In searching for common biochemical threads among ME/CFS and FM victims, researchers have noted that symptoms of vitamin B-12 deficiency closely parallel those of ME/CFS and other multi-symptom diseases. In fact, symptoms overlap to such a great extent that many respected ME/CFS/FM researchers and physicians - including Drs. Paul Cheney, Charles Lapp, Kenny DeMeirleir, Jacob Teitelbaum, and Martin Pall - consider vitamin B-12 a mainstay of supportive treatment.
One study found improved energy levels even in people who were not deficient in vitamin B-12 but were administered the vitamin anyway. B-12 (2,500–5,000 mcg) administered every two to three days was associated with improvement in 50% to 80% of a group of people with ME/CFS. Most improvement was seen after several weeks of vitamin B-12 administration.
The Curious Symptoms of Vitamin B-12 Deficiency
Best known for participating in the manufacture of red blood cells, B-12 is also needed for production and maintenance of the myelin sheath that surrounds nerve cells, and for manufacture and maintenance of DNA. Participating in nearly every function of the body, vitamin B-12 deficiencies have widespread consequences.
Energy. Even minor deficiencies of vitamin B-12 can cause anemia, fatigue, shortness of breath and weakness.
The Nervous System. Deficiencies of B-12 can cause neurological changes including numbness and tingling in the hands and feet, balance problems, depression, confusion, poor memory and Alzheimer's-like symptoms. Long-term deficiencies of B-12 can result in permanent impairment of the nervous system.
The Gastro-Intestinal System. B-12 deficiency can cause decreased appetite, constipation, diarrhea or alternating constipation/diarrhea (also called Irritable Bowel Syndrome), weight loss and abdominal pain.
The Immune System. Vitamin B-12 is necessary for normal functioning of white blood cells. Studies show that B-12 helps regulate Natural-Killer T-cells and prevents chromosome damage.
The Cardiovascular System. Vitamin B-12 participates in the conversion of homocysteine to methionine. Elevated homocysteine levels are a known independent risk factor for heart attack, stroke and thrombosis. Without adequate B-12 levels, homocysteine levels typically rise.
Special Senses. Degenerative changes in the central nervous system caused by B-12 deficiency can also affect the optic nerve, resulting in blue-yellow color blindness.
Other Symptoms of vitamin B-12 deficiency include sore mouth or tongue
In Infants and Children, signs of vitamin B-12 deficiency include failure to thrive, movement disorders, delayed development, and megaloblastic anemia.
So Is ME/CFS a Simple Vitamin B-12 Deficiency?
Although B-12 deficiency symptoms share many commonalities with ME/CFS and other multi-system diseases, researchers do not suggest that these diseases are simply a vitamin B-12 deficiency.
Two emerging theories of biochemical abnormality are believed to be heavily involved in ME/CFS and other multi-system diseases. In fact, either or both of these models of biochemical abnormality might be a central cause of ME/CFS. Interestingly, both of these abnormalities are related to forms of vitamin B-12 deficiency.
The Nitric Oxide/Peroxynitrite (“No, Oh No!”) Model of ME/CFS
ME/CFS and other multi-system diseases appear to be “triggered” by a wide variety of factors. Sufferers often report an initial viral, bacterial or other infection, a physical or psychological trauma, chemical exposure or other stressor before onset of symptoms. In this regard, ME/CFS shares similarities with Fibromyalgia (FM), Lyme disease, Multiple Chemical Sensitivities (MCS), PTSD and Gulf War Syndrome.
According to the theory of noted researcher Dr. Martin Pall, PhD, detailed in his book Explaining ‘Unexplained Illnesses', ME/CFS and other multi-system diseases overlap in symptoms and initial triggers because they share a common metabolic origin, a ‘vicious cycle’ related to nitric oxide (NO-) and peroxynitrite (ONOO-) over-production.
Because of the chemical abbreviations for these two substances (NO- and ONOO-) Dr. Pall calls this vicious cycle the "No, Oh No" cycle, and he presents solid evidence to make a case for this cycle as an underlying cause of ME/CFS and other multi-system diseases.
Dr. Pall has observed that virtually every known initiator of ME/CFS and other multi-system diseases either increases nitric oxide (NO) or the superoxide radical (O2-) or both. These two molecules quickly react to form peroxynitrite (ONOO-), a potent oxidant that is capable of damaging a wide range of biological molecules.
Peroxynitrite (ONOO-) then acts through multiple mechanisms to regenerate O2- and NO-, the very molecules that create it. In this way, the NO-/ONOO- cycle becomes self-perpetuating, and a vicious cycle is initiated. Unless something intervenes to break the cycle, it is possible that this biochemical "endless loop" could self-perpetuate indefinitely.
There is increasing evidence to support this pathway as a primary underlying abnormality in ME/CFS and other multi-system diseases.
This runaway NO-/ONOO- cycle has also been associated with increased perception of pain.
[See Figure 1: The NO-/ONOO- Cycle, and Figure 2: Independent Consequences of Increased Superoxide (O2-), Nitric Oxide (NO-) and Peroxynitrite (ONOO-)]
Figure 1: The NO-/ONOO- Cycle (Click on image to enlarge.)
Key to Figure 1: The NO-/ONOO- Cycle "Players"
- Nitric oxide (NO-) is a naturally occurring "messenger molecule" in the body and also a pro-oxidant and free radical. Depending on the amount and where it is released, NO- can be either beneficial or toxic. Nitric oxide is known to play a role in blood pressure regulation, blood clotting, immunity, digestion, the special senses (sight and smell), and possibly learning and memory. Abnormal levels of NO- may play a role in diseases such as atherosclerosis, diabetes, stroke, hypertension, impotence, septic shock, and long-term depression. In ME/CSF/FM and related multi-system diseases, research suggests that excess NO- may be a primary contributor to long-term energy depletion and immune dysfunction.
- Superoxide (O2-) is a potent free radical. Like nitric oxide (NO-), has independent deleterious effects when expressed in excess. Superoxide reacts with NO- to form ONOO-.
- OONO- (peroxynitrite) is a potent oxidant that damages cells. It is formed when NO- and O2- react with each other. Peroxynitrite in turn acts through multiple mechanisms to regenerate its precursors, NO- and O2-. In this way, a “vicious cycle” of damage creating more damage begins.
Figure 2: Independent Consequences of Increased Superoxide (O2-), Nitric Oxide (NO-) and Peroxynitrite (ONOO-).
Consequences of Superoxide (O2-) Excess:
- Endothelial dysfunction
- Associated with retinal cell death, pulmonary hypertension, general hypertension, atherosclerosis, neurodegenerative disease, type II diabetes
- Decreased cellular respiration
- Cell death
Consequences of Nitric Oxide (NO-) Excess:
- Cellular energy depletion
- DNA damage
- Neurotoxicity, neuronal cell death and brain injury
- Hypersomnolence and sleep apnea
- Lung injury
- Increased pain perception and lowered pain threshold
- Lowered blood pressure
- Inhibition of the methylation cycle
- Formation of carcinogenic substances
- Increased inflammation
- Modification of cellular proteins
- No is associated with Alzheimer's, Arthritis, Parkinson's, stroke, hemorrhagic shock, cancer, viral infections
- Damaged mitochondria
- Suppressed immune system
- Assisted viral replication and pathogenesis
Consequences of Excess Peroxynitrite (ONOO-)
- Increases lipid peroxidation
- Retinal cell death
- DNA damage
- Decreased mitochondrial respiration (cellular oxygen)
- Increase viral replication
- ONOO- is associated with Alzheimer's disease, rheumatoid arthritis, atherosclerosis, lung injury, amyotrophic lateral sclerosis, HIV, multiple sclerosis, kidney damage, Parkinson's disease, Huntington's disease, Sjögren's syndrome, septic shock and other diseases.
Dr. Bell, one of the first physicians to recognize ME/CFS as a discrete medical condition, proposes in his book Cellular Hypoxia and Neuro-Immune Fatigue that cellular hypoxia (decreased oxygen to the cell) may be the underlying factor in ME/CFS/FM and related multi-system diseases. This is consistent with the NO-/ONOO- theory, because injuries of many types result in decreased oxygen to the cell, thus potentially initiating such a destructive runaway cycle.
Hydroxocobalamin Breaks the NO-/ONOO- Cycle
Hydroxocobalamin (cobinamide), a unique form of vitamin B-12, is a potent nitric oxide (NO-) scavenger. It is the only form of vitamin B-12 that effectively neutralizes the NO- molecule. Hydroxocobalamin is the preferred form of vitamin B-12 required to break the NO-/ONOO- vicious cycle of cellular damage.
The Methylation Cycle and ME/CFS
The methylation cycle is a biochemical pathway required for the manufacture of DNA, RNA, phospholipids (myelin sheath of nerves), neurotransmitters, adrenal hormones and more than 100 enzymes. A fully functional methylation cycle is also required for numerous detoxification reactions.
A defect in the methylation pathway is a second proposed mechanism in the development of ME/CFS. The research of Dr. Rich van Konynenburg has been instrumental in development of a theory involving an intricate interrelationship between the methylation cycle and ME/CFS.
Methylation defects cause reduced detoxification ability, decreased production of serotonin, dopamine, melatonin and other neurotransmitters, decreased production of adrenal hormones, increased levels of toxic homocysteine, and decreased cellular energy production.
This reduced production of vital neurotransmitters may explain the feelings of depression and despondency that frequently strike ME/CFS victims and would explain the positive effects often achieved with the use of SSRI and other mood-altering pharmaceuticals.
Unfortunately, many clinicians interpret the improvement seen with antidepressant medications as “proof” that ME/CFS is a psychiatric illness when in fact an understanding of the methylation pathway defect offers solid evidence of a biochemical basis for depression and low energy in ME/CFS.
[See Figure 3: The Methylation Cycle]
Figure 3: The Methylation Cycle (Click on image to enlarge.)
- The overlap between the NO-/ONOO- cycle and the methylation cycle where excess NO- blocks methionine synthase, a critical enzyme in the methylation cycle.
- The methylcobalamin form of vitamin B-12 is a required nutrient in the methylation cycle. If any one step in the methylation cycle fails, the entire cycle fails.
Vitamin B-12: Which Form is Best?
What we know as vitamin B-12 is actually a collection of four related but different cobalt-containing molecules. Each of these forms plays a distinct role in the body as follows:
Hydroxycobalamin is a unique form of B-12 that quenches excess nitric oxide (NO-), the precursor to peroxinitrite (ONOO-). Hydroxocobalamin (and methylcobalamin) also play a more important role in addressing neurological disorders than cyanocobalamin.
Hydroxocobalamin participates in detoxification, especially cyanide detoxification. Cyanide levels are typically elevated in smokers, people who eat cyanide-containing food (like cassava) and those with certain metabolic defects. Excess cyanide in the tissues blocks conversion of cyanocobalamin to methylcobalamin or adenosylcobalamin. In such instances, hydroxocobalamin is the vitamin B-12 of choice. Hydroxycobalamin is FDA- approved as a treatment for cyanide poisoning.
Methylcobalamin is considered by many researchers to be the most active form of vitamin B-12. It is the requisite form of vitamin B-12 in the methylation cycle. Methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity and promotes nerve cell regeneration. Methylcobalamin is the only form of vitamin B-12 that participates in regulating circadian rhythms (sleep/wake cycles). It has been shown to support improved sleep quality and refreshment from sleep, as well as increased feeling of well-being, concentration and alertness.
Adenosylcobalamin (dibencozide), another highly active form of vitamin B-12, is essential for energy metabolism and is required for normal myelin sheath formation and nucleoprotein synthesis. Deficiencies are associated with nerve and spinal cord degeneration.
Cyanocobalamin, the most common form of B-12 found in nutritional supplements, is a synthetic form of B-12 not found in nature. It has the lowest biological activity and must be converted in the liver to more biologically active forms. This conversion is inefficient and some people who may not benefit from cyanocobalamin due to lack of assimilation or conversion. However, the cyano form of B-12 is needed to balance hydroxycobalamin in performing its NO-quenching function and should therefore be included in hydroxocobalamin supplements.
Who is Vitamin B-12 Deficient and Why?
Research shows that a much larger segment of the general population is vitamin B-12 deficient than previously thought. Recent studies indicate that up to 78% of seniors are deficient.
Irritable bowel syndrome (IBS), seen in as many as 77% of CFS patients and 78% of FM patients is a major cause of vitamin B-12 deficiency. This leads one to ponder the “which came first, the chicken or egg” nature of this: Are ME/CFS patients B-12 deficient because of IBS, or is IBS a result of cellular or neurological insult caused by B-12 deficiency?
Other high-risk groups for B-12 deficiency include:
- Those who use acid-blocking or neutralizing drugs (such as Prilosec, Prevacid, Nexium and others);
- Those who use drugs which impair intestinal absorption (such as Metformin, Questron and Chloromycetin);
- And people who have had gastric surgery.
Bacterial overgrowth of the small intestine, which occurs frequently in people with ME/CFS and low stomach acid, is a predisposing factor for B-12 deficiency because the bacteria themselves use vitamin B-12.
The most recent and disturbing studies suggest that vitamin B-12 deficiency is more prevalent in young adults than previously thought. One study found that vitamin B-12 deficiency was similar in three age groups (26-49 years, 50-64 years, and 65 years and older), but that early symptoms were simply less apparent in the young. This study also found that those who did not take a vitamin B-12-containing supplement were twice as likely to be deficient as supplement users, regardless of age.
Secondly, unlike other water-soluble vitamins, B-12 is stored in the liver, kidneys and other tissues. Deficiencies of B-12 often appear so slowly and subtly as to go unnoticed, and blood tests for vitamin B-12 levels miss early deficiency states at least 50% of the time.
Why Many People Need to Obtain Vitamin B-12 From Supplements
Medical science once believed that few people were vitamin B-12 deficient. This false assumption may stem from the fact that vitamin B-12 is produced in the body by a normal, healthy population of bowel bacteria.
Foods are not a significant source of vitamin B-12 in most diets. Meat, milk, eggs, fish, and shellfish contain the highest amount of B-12, but only 50% of this is absorbable even in a healthy gut. Vegetarian sources of vitamin B-12, such as algae, are not bio-available and do not make significant contribution to dietary vitamin B-12 levels.
Further, absorption is hampered by low stomach acid, IBS, and bacterial overgrowth of the small intestine - conditions which are common in ME/CFS sufferers. The US Institute of Medicine recommends that adults over 50 obtain vitamin B-12 from supplements.
Oral vs. Injectable: Which is Best?
Although vitamin B-12 has previously been given by injection, it is now accepted in conventional medicine that oral & sublingual vitamin B-12 is equally as effective as injection in treating pernicious anemia and other B-12 deficient states.
According to The National Institutes of Health (NIH), oral vitamin B-12 supplementation is extremely safe. It is also as effective as injections, and inexpensive and more convenient compared to injection.
All Roads Lead to B-12: Conclusions and Recommendations
The suffering from ME/CFS and other multi-system diseases is widespread and devastating. This affliction is beginning to receive more attention, perhaps because of the activism of those affected and the dedication of ME/CFS researchers and clinicians. Current research is providing us with new insights into the underlying mechanisms of this complicated illness.
The Nitric Oxide/Peroxynitrite model (NO-/ONOO-) and The Methylation Cycle have emerged as two likely contributory mechanisms to ME/CFS and other multi-system diseases including Fibromyalgia, Lyme disease, Multiple Chemical Sensitivities, PTSD and Gulf War Syndrome. Deficiencies of either of two forms of vitamin B-12 - hydroxocobalamin and/or methylcobalamin - play a significant role in these biochemical processes.
Since vitamin B-12 (especially the hydroxocobalamin and methycobalamin forms) offer such potential benefits for ME/CFS and other multi-system disease sufferers - without known risks - it seems reasonable to suggest that anyone suffering with ME/CFS or other multi-system illness should consider taking a supplement containing these two important forms of vitamin B-12.
Furthermore, because of the balancing effect that cyanocobalamin has on hydroxycobalamin and the protective and regenerative effect that adenosylcobalamin exerts on the myelin sheath of nerves, these forms should also be considered as an important part of any complete vitamin B-12 supplement.
* Dr. Dana Myatt, NMD, is a practicing naturopathic family physician, educator, author, and speaker with a special interest in nutrition. She lectures widely to medical and lay audiences, and hosts a website. Mark Ziemann, RN, Dr. Myatt’s husband and collaborator, is also an educator, author, and speaker specializing in holistic nursing practice and patient education.
Note: This information has not been evaluated by the FDA. It is generic and is not meant to prevent, diagnose, treat or cure any condition, illness, 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.