Dr. Melvyn Werbach, long-time Assistant Clinical Professor at UCLA School of Medicine, is a world authority on nutritional medicine, and has published scores of articles, books and textbooks on the subject. Though this summary was first published in 2000,* the information remains sound and relevant. The cited sources, information on other nutritional factors important for ME/CFS patients, and an overall protocol with time required to test for benefit, are included in PART 2 of this article.
Nutritional Strategies for Treating Chronic Fatigue Syndrome:
Vitamins and Minerals
Despite considerable worldwide efforts, no single etiology has been identified to explain the development of chronic fatigue syndrome (CFS). It is likely that multiple factors promote its development, sometimes with the same factors both causing and being caused by the syndrome.
A detailed review of the literature suggests a number of marginal nutritional deficiencies may have etiologic relevance. These include deficiencies of various B vitamins, vitamin C, magnesium, sodium, zinc, L-tryptophan, L-carnitine, coenzyme Q10, and essential fatty acids.
Any of these nutrients could be marginally deficient in CFS patients, a finding that appears to be primarily due to the illness process rather than to inadequate diets.
It is likely that marginal deficiencies not only contribute to the clinical manifestations of the syndrome, but also are detrimental to the healing processes. Therefore, when feasible, objective testing should identify them and their resolution should be assured by repeat testing following initiation of treatment.
Moreover, because of the rarity of serious adverse reactions, the difficulty in ruling out marginal deficiencies, and because some of the therapeutic benefits of nutritional supplements appear to be due to pharmacologic effects, it seems rational to consider supplementing CFS patients with the nutrients discussed above, along with a general high-potency vitamin/mineral supplement, at least for a trial period.
The disorder we call chronic fatigue syndrome (CFS) does not appear to be new. The current interest in attempting to define and treat it stems from several studies in the mid-1980s that found elevated levels of antibody to Epstein-Barr virus in people with CFS-like symptoms, most of whom had a history of infectious mononucleosis a few years earlier.
When it later became apparent that healthy people could also have elevated Epstein-Barr virus antibody titers while some CFS sufferers had normal titers, the US Centers for Disease Control and Prevention developed a research case definition that defined the syndrome by its most common presenting characteristics. In 1994, the International CFS Study Group published a revised and more inclusive case definition [The ‘Fukuda’ Definition](1) which defines chronic fatigue syndrome. See Table 1.
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Table 1: International CFS Study Group Definition of Chronic Fatigue Syndrome
I. Clinically evaluated, unexplained persistent or relapsing chronic fatigue that:
• Is of new or definite onset (has not been lifelong).
• Is not the result of ongoing exertion.
• Is not substantially alleviated by rest.
• Results in substantial reduction in previous levels of occupational, educational, social, or personal activities.
II. The concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue:
• Self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities
• Sore throat
• Tender cervical or axillary lymph nodes
• Muscle pain
• Multi-joint pain without joint swelling or redness
• Headaches of a new type, pattern, or severity
• Unrefreshing sleep
• Postexertional malaise lasting more than 24 hours.
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Despite considerable worldwide efforts, no single etiology has been found to explain the syndrome. It is likely that multiple factors promote its development, sometimes with the same factors both causing and being caused by the syndrome. Many of these factors constitute specific pathophysiological entities that characterize certain subsets of chronic fatigue patients. See Table 2.
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Table 2: Suspected Etiologies for Chronic Fatigue Syndrome
• Viral infections and the post-viral fatigue syndrome
• Neurally-mediated hypotension
• Psychogenic biological dysfunction
• Low natural killer cell syndrome
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Numerous factors appear to promote the development of the syndrome. See Table 3.
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Table 3: Factors Suspected of Promoting Chronic Fatigue Syndrome
• Hypoxemia [low blood oxygen]
• Endocrine dysfunction
• Immune dysfunction
• Stress-related dysfunction
• Somatoform disorder
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This review of the nutritional literature focuses on those nutrients for which the evidence most strongly supports relevance to treatment. The scientific literature is fairly sparse, and promising nutritional treatments usually lack adequate scientific proof. For these reasons, in addition to examining studies of CFS patients, this review will also focus on studies of patients presenting with individual aspects of the syndrome, such as fatigue or an impaired immune response to viral infections.
VITAMINS FOR TREATMENT OF CHRONIC FATIGUE SYNDROME
A subset of CFS patients appears to be deficient in folic acid. Based on established norms, half of a group of 30 male and 30 female patients had deficient serum folate concentrations, while another 13% had low borderline concentrations.(2)
What makes this finding particularly interesting is the fact that serum folate is highly correlated with the folate level of the cerebrospinal fluid. While erythrocyte folate is usually a better indicator of folate deficiency,(3) serum folate is a better indicator of cerebrospinal fluid folate.(4)
Although the brain maintains adequate folate levels longer than most tissues,(4) a chronically low serum folic acid level - and thus a chronically low cerebrospinal fluid folic acid level - would be a reasonable basis for suspecting that brain folate could be diminished in CFS, causing impairment in brain function.
Is this consistent with the clinical presentation? Fatigue and depression, common findings in CFS, are also prominent features of folate deficiency.(5) Moreover, several experimental studies found folate supplementation to be effective for improving mood in folate-deficient members of the general population.(5,6)
Folate deficiency can cause immunodepression, and CFS often presents with evidence of immune activation, so the contribution of a marginal folate deficiency to the immunological picture in CFS should be considered unknown until it is formally studied.
While we can surmise that folate supplementation would be effective in chronic fatigue patients with a marginal folate deficiency, its efficacy in this population has been investigated only in a small, double blind crossover study that failed to find benefits from supplementation with daily, intramuscular injections of 800 mcg of folate for one week.(7)
It should be noted that the study was of very short duration. In addition, this dosage, although often considered adequate to correct a folate deficiency, is small when compared to the folate dose used in another study to successfully treat a group of patients who, although they did not have CFS, presented with easy fatigability and minor neurological signs. These patients received a minimum of 10,000 mcg of folate daily, yet it took two to three months for their fatigue to respond.(8)
Therefore, if folic acid supplementation is effective in CFS, it is possible that substantially larger dosages will have to be prescribed for a substantially longer period of time.
In an informal study of more than 100 CFS patients, 30% showed elevations of methylmalonic acid,(9) a urinary metabolite believed to be considerably more sensitive than serum vitamin B12 for diagnosing cobalamin deficiency.(10)
Moreover, a study of 12 women who fulfilled the criteria of both CFS and fibromyalgia found the levels of vitamin B12 in the cerebrospinal fluid were significantly correlated with measures of fatigability and neurasthenia.(11)
Is a B12 deficiency consistent with the presentation of chronic fatigue syndrome?
As in the case of folic acid, fatigue and depression are features common to both disorders,(5,12) suggesting inadequate B12 nutriture could contribute to the clinical picture in a subset of patients.
Also, as already noted in regard to folic acid, there is no scientific data proving the efficacy of vitamin B12 supplementation in CFS patients. There is data supporting the theory that the vitamin, given by injection [or now by formulations allowing sublingual B12 delivery], is therapeutic.
Similar to the situation with folic acid, these data suggest the total dose of B12 necessary for a response is massive when compared to the dose considered adequate to correct a B12 deficiency. An accepted regimen for treating vitamin B12 deficiency is to initially administer 1000 mcg of the vitamin IM weekly. The patient usually responds rapidly, and the dose is then decreased to 1000 mcg each month for as long as needed.
Drs. Charles Lapp and Paul Cheney shared their observations from treating more than 2,000 patients in a clinical setting. Initially, they administered relatively small amounts of vitamin B12, but the results were inconsistent, so the dosage was increased to 2,500-5,000 mcg cyanocobalamin (subcutaneous or IM) every two to three days.
Fifty to eighty percent eventually responded with an increase in energy, stamina, or wellbeing, usually within two to three weeks of treatment.(9,13)
Although these results are promising, the same double-blind crossover study alluded to earlier in regard to its failure to find folate supplementation to be effective, also failed to find evidence that vitamin B12 supplementation provided anything more than a placebo effect. In this instance, the CFS patients received daily intramuscular injections of 2 ml of a solution containing 200 mcg cyanocobalamin or placebo for one week.(7) Since, however, the dosage utilized was less than one quarter of the minimal effective dosage in Lapp and Cheney’s report, the question of the efficacy of higher dosages for treating depression and fatigue in this disorder arguably remains unanswered.
Some additional data comes from two studies of people who felt poorly but had not been specifically diagnosed as having chronic fatigue syndrome or any other specific disorder.
The first, a double-blind crossover study, concerned men and women who complained of chronic tiredness but had no physical findings and normal serum B12 concentrations. They received intramuscular injections of 5,000 mcg of vitamin B12 or placebo twice daily for two weeks, each in random order with a two-week rest period in between.
The vitamin injections resulted in a significant increase in feelings of well-being. The placebo injections had no effect, so long as placebo was given first. If, however, vitamin B12 was given first, there was no change between the B12 and the placebo period, suggesting the effect of the vitamin lasted at least four weeks.(14)
An informal study found a substantial proportion of patients with normal serum B12 concentrations felt better following injections of hydroxocobalamin but not following injections of sterile water. The maximum feeling of well-being, which was established through open trials, occurred using dosages ranging from 3000 mcg four times weekly to 9000 mcg daily.(15)
In comparing the total weekly dosages of vitamin B12 in the four studies, it is arguable that the dosage of the only negative study was so low that the study failed to disprove the hypothesis that administration of higher vitamin dosages may be an effective treatment intervention.
A substantial amount of vitamin B12 appears to be necessary to relieve the symptoms of CFS, compared to the amount needed to correct a B12 deficiency; thus, the vitamin appears to exert a pharmacologic effect.
As a drug, vitamin B12 seems to have substantial analgesic properties.
Indeed, in open trials, patients with vertebral pain syndromes,(16) degenerative neuropathies,(17) and cancer(17) noted excellent pain relief with injections of 5,000 to 10,000 mcg daily.
While analgesia achieved in open trials may be attributed to the placebo effect, rat experiments have offered some objective confirmation. Using an animal model of pain, not only did orally-administered vitamin B12 have an analgesic effect, but the effect was dosedependent.(18)
Thus, the improved feelings of well-being in CFS patients following vitamin B12 supplementation could be at least partly due to the analgesic effect of the vitamin when administered at pharmacologic dosages.
A very interesting theory proposes a mechanism by which B12 pharmacotherapy may reduce CFS symptoms.
Both Mukherjee and Simpson have provided evidence that CFS symptoms are associated with an increased percentage of abnormally-shaped erythrocytes (non-discocytes).(19-21) Mukherjee has found that, in CFS sufferers, 40% to 100% of their erythrocytes are grossly deformed and can be identified as rigid stomatocytes and dimpled spherocytes.(22)
Erythrocytes normally measure eight microns in diameter, while the diameter of the vessels through which they flow may be only three microns. Mukherjee and Simpson have each postulated that loss of the normal biconcave form impairs the ability of erythrocytes to change shape in order to traverse the microcirculation. The result is a reduction in blood flow on the microcirculatory level, causing an oxygen deficit and an accumulation of by-products of cellular respiration.
This pathophysiological change could help to explain why CFS patients often present with symptoms referable to multiple organ systems.
In an open trial, Simpson administered 1,000 mcg cyanocobalamin intramuscularly to a group of patients with myalgic encephalomyelitis who also exhibited an increased percentage of non-discocytes. Half of the patients noted an improved sense of well-being within 24 hours and their improvement was found to correlate with a reduction in non-discocytes. By contrast, patients who failed to improve showed no change in red cell shape.
The author has suggested that vitamin B12 administration may relieve CFS symptoms by reversing the erythrocyte abnormalities leading to improved tissue oxygenation.(23)
Other B Vitamins
Other B vitamins for which there is evidence of reduced nutriture in CFS include riboflavin,(24) thiamine,(24-26) and pyridoxine.(24)
While niacin nutriture in this disorder has not been studied, there is evidence that supplementation with nicotinamide adenine dinucleotide (NADH), the reduced coenzyme form of the vitamin, may be beneficial.
In a double-blind crossover study, 10 mg daily of the reduced form of NADH was significantly more effective in reducing symptoms than placebo. Moreover, these patients were found to have elevated urinary concentrations of 5-hydroxy-indoleacetic acid, the major metabolite of the neurotransmitter serotonin, and the concentrations returned to normal following NADH supplementation.(27,28)
Depression is the first symptom of experimental scurvy,(29) and a marginal deficiency of vitamin C may cause fatigue, lassitude, and depression(30) which responds to supplementation.(5,31) Although an early report failed to find evidence of decreased serum ascorbate levels in CFS patients,(25) no current assay technique for ascorbic acid is entirely satisfactory(32) and therefore this single report of serum ascorbate levels arguably does not eliminate the possibility that a subset of CFS patients is vitamin C-deficient.
Since vitamin C deficiency causes capillary fragility, perhaps the best method of assaying vitamin C stores is to perform the Rumpel-Leede test in which a tourniquet is applied to the arm for five minutes to see whether petechiae appear.(33) As to assay techniques, the best is probably the ascorbic acid saturation test which measures the body’s efforts to conserve vitamin C following a loading dose.(34) Data on the results of these tests in CFS has yet to be reported; therefore, the issue of whether vitamin C is marginally deficient in a subset of patients remains unsettled.
Like vitamin B12, ascorbic acid appears to exert a substantial analgesic effect at pharmacologic dosages.
In a double-blind crossover study, supplementation of normal volunteers with 1 gm vitamin C three times daily reduced delayed-onset muscle soreness following strenuous exercise.(35) Under double blind conditions, severely ill cancer patients receiving 10 grams daily experienced a significant reduction in pain(36) while, in an open trial, 10 grams daily reduced the sensitivity of teeth to air and water.(37)
However, whether the analgesic effects of ascorbic acid supplementation extend to patients with chronic fatigue syndrome is not known.
Results of a study published only in abstract form suggest vitamin C supplementation may also share with vitamin B12 the ability to reverse erythrocyte membrane abnormalities seen in CFS and thus improve capillary blood flow.
Using high resolution, phase contrast microscopy, 25 chronically disabled CFS patients were all found to exhibit two or more membrane abnormalities in over half of their red cells, while only 10% of red cells of the control subjects hospitalized for elective surgery met this criterion.(38,39)
They received an intravenous infusion containing 15 grams of ascorbic acid. Fifteen minutes later, post infusion blood samples showed that over 80% of the membrane abnormalities had disappeared. Moreover, based on changes seen in colliding cells, there was a higher degree of pliability in the cell wall.(38,39) Whether these findings coincided with clinical improvement was not reported.
Vitamin C supplementation also bolsters immune responses.
Normal volunteers supplemented with 1-3 grams vitamin C daily showed enhanced immune function, including increased neutrophil motility(40) and chemotaxis,(41) increased immunoglobulin levels,(42,43) and increased lymphocyte blastogenesis in response to mitogens.(41)
In persons with recurrent infections due to primary defects of phagocytic function, vitamin C is considered to be the specific therapy.(44) [Phagocytes are white blood cells that ‘eat’ invading bacteria and dead or dying cells such as those infected by viruses and attacked by other immune cells.]
Vitamin C has considerable antiviral activity which may be due, at least in part, to enhanced interferon activity.(45) However, in CFS, ability of vitamin C to normalize immune responses or to bolster antiviral defenses is unknown.
MINERALS FOR TREATMENT OF CHRONIC FATIGUE SYNDROME
Stress hormones, including both catecholamines and corticoids, can promote a reduction in tissue magnesium levels.(46) Seelig noted that many of the symptoms and findings in CFS resemble those of magnesium deficiency.(46) See Table 4.
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Table 4: Magnesium Deficiency or CFS?
(Based on Seelig M presentation to 37th Annual Mtg., American College of Nutrition, Oct 13, 1996)
1. Neuromuscular and psychiatric disorders
• Symptoms - chronic fatigue, weakness, paresthesias, depression, anxiety, sleep disturbances, migraine & tension headaches.
• Objective findings - EEG abnormalities, electromyographic abnormalities, sensorineural abnormalities.
2. Immunologic disorders with an inappropriate response to viral infections including:
• Both higher and lower antibody responses.
• Depressed natural killer cell responses.
• Altered cytokine and interleukin release.
• Abnormal delayed skin sensitivity.
• Mild immune dysfunctions.
• Hypereosinophilia (only with myalgia).
3. Increase in substance P. (Substance P is a neuropeptide isolated from brain tissues and the gastrointestinal tract. It promotes inflammation and inflammatory pain, brochospasm, and capillary permeability. The result may be edema, chronic uticaria, rhinitis or any of several neuropsychiatric disorders.)
4. Increase in NMDA (n-methyl-d-aspartate) receptor activity. (The NMDA receptor is part of the brain's neuroexcitatory pathway. Upregulation of the receptor is found in CFS and causes a variety of neuromuscular and psychiatric symptoms. It is also found in magnesium deficiency, as magnesium inhitbits the NMDA receptor.)
* * * *
Several studies of magnesium nutriture in CFS have been published. The findings have been mixed,(25,26,47-52) although two studies published in major peer-reviewed journals found lower erythrocyte magnesium levels in CSF patients than in controls.(25,51)
Among CFS patients seen in clinical settings, magnesium deficiency appears to be common.
For example, a referral center that evaluated several hundred CFS patients noted half of their patients were magnesium-deficient.(26) Testing for magnesium retention following a magnesium load is a more sensitive assay than simply examining blood or urine levels. Specifically using this test, 45% of a group of 97 patients were found to be magnesium-deficient,(53) while an unpublished study found evidence of a magnesium deficiency in 38% of a group of 1,300 patients.(52)
Although the literature is too sparse to draw firm conclusions, many CFS patients who are magnesium-deficient could possibly derive benefit from magnesium supplementation.
Perhaps the best clinical study to date involved patients with low erythrocyte magnesium levels who randomly received 100 mg magnesium IM or placebo each week for six weeks. Twelve of the 15 patients who received magnesium felt better compared to only three of the 17 patients who received placebo. Moreover, erythrocyte magnesium levels returned to normal in all of the patients receiving magnesium, but in only one patient who received placebo.(51)
These findings are consistent with a report that CFS patients who were not magnesium-deficient failed to benefit from an injection of 580 mg magnesium, six times the dosage received by the group of magnesium deficient patients.(48)
Particularly when fibromyalgia is a substantial component of the clinical picture, magnesium has often been combined with malic acid, since malate plays an important role in energy metabolism; specifically the generation of mitochondrial ATP.
Abraham and Flechas originally proposed using the magnesium-malic acid combination and presented the results of an open trial in which primary fibromyalgia patients were treated for an average of eight weeks with 200-600 mg magnesium and 1,200-2,400 mg malate daily.
The subjects exhibited a significant decrease in mean tender point index from 19.6 to 6.5.
Two days after 6 of the 15 patients were switched to placebo, they reported muscle pain had worsened. After two weeks, their mean tender point index had risen from 6.8 to 21.5.(54)
While these results are promising, a subsequent double-blind crossover study of primary fibromyalgia patients who received 300 mg magnesium and 1200 mg malic acid or placebo in random order for four weeks, each with a two-week washout period in between, failed to find significant improvements in pain, tenderness, and functional or psychological measures.(55)
If this study were to be repeated using twice the dosage, lasting eight weeks, and including CFS patients, the results might be different. In the meantime, we have only the informal observations of some clinicians who find that, while pain from fibromyalgia appears to respond in about two days, fatigue may take two weeks to respond.
According to one clinician, 40% of patients with CFS show improvement after starting supplementation.(56)
Sodium (Neurally-Mediated Hypotension)
Neurally-mediated hypotension, a term that refers to an abnormal neurocardiogenic reflex in individuals with structurally normal hearts, is a common cause of recurrent lightheadedness and fainting.
When venous pooling during long sitting or standing causes a reduced ventricular preload, susceptible people respond with an increased catecholamine response, resulting in augmented inotropic activity and excessive stimulation of mechanoreceptors in the left ventricle. This causes an exaggerated parasympathetic response, resulting in vasodilation, bradycardia, hypotension, and possibly syncope/faintness.(57) After the episode, fatigue is prominent and may last for an extensive period of time.(58)
Neurally-mediated hypotension has now been identified as a common finding in chronic fatigue syndrome.
In one study, 23 CFS patients were tested on a table designed to tilt them upright at various angles. Twenty two of the 23 patients showed evidence of neurally-mediated hypotension as compared to only 4 of 14 normal controls; moreover, 9 of the 23 patients reported complete or nearly complete resolution of CFS after this pathophysiological response was adequately treated.(59)
Of particular interest was the finding that nearly two-thirds of the CFS patients in this study reported they usually or always tried to avoid salt and salty foods. Symptoms associated with inadequate sodium intake include undue fatigue after moderate exertion, lassitude, headache, sleeplessness, and inability to concentrate;(60) this symptom complex has even been reproduced with experimental salt restriction.(61)
The ability of sodium intake to affect blood pressure regulation through its effect on blood volume is well known, suggesting this subgroup of CFS patients may benefit by moderately increasing their salt intake.
Zinc is another mineral often marginally deficient in CFS. In one study of 28 women, mean red-cell zinc concentrations, although within the normal range, were significantly lower than in a group of healthy controls.(25) A second informal, clinical study found that, of 1,300 CFS patients, nearly one-third had evidence of zinc deficiency as manifested by low blood-zinc concentrations, or leukonychia.(52)
It is interesting that zinc deficiency can cause immunodepression(62) and produce muscle pain and fatigue.(63)
While a marginal serum deficiency would be unlikely to reduce muscle zinc nutriture, changes in extracellular zinc levels have been reported to influence the twitch-tension relationship in muscle, presumably due to a direct effect at the level of the cellular membrane.(64)
Leukonychia, a term referring to white spots on the fingernails, is believed to be a sign of marginal zinc deficiency and has been found to be correlated with frequent feelings of drowsiness.(65) However, its prevalence in CFS is unknown. Also, erythrocyte zinc levels were found to be abnormally low in over half of a group of randomly selected patients who reported having chemical sensitivities,(68) suggesting that zinc deficiency may be more likely in CFS patients who are chemically sensitive.
Unfortunately, the results of zinc supplementation in CFS have yet to be reported, so its potential contribution to treatment can only be speculated. When normal volunteers with no evidence of zinc deficiency were supplemented with 135 mg of zinc daily for 15 days, they developed increased isokinetic strength and isometric endurance in their leg muscles.(63)
If normals can improve muscle function with zinc supplementation, supplementing marginally zinc-deficient CFS patients may promote improvement in muscle physiology.
*ProHealth has reproduced this article with kind permission from Alternative Medicine Review, 2000;5(2):93-108. © Alt Med Review, all rights reserved. See also Dr. Melvyn Wernbach's research-based review of the other nutrients most important for people with ME/CFS and fibromyalgia (L-tryptophan, L-carnitine, CoenzymeQ10, and essential fatty acids), plus his overall Nutritional Supplementation Protocol for CFS - "Nutritional Strategies for Treating Chronic Fatigue Syndrome: PART 2, Other Nutritional Factors"]
Disclaimer: This information has not been reviewed by the FDA. The information is general and is not intended to prevent, 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.