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 published in 2000,* it remains sound and relevant. To read PART 1 of this article, discussing vitamin and mineral deficiencies in ME/CFS, see “Nutritional Strategies for Treating ME/CFS: The Big Six Vitamins and Minerals.” The following explanation of other nutrients important for ME/CFS concludes with Dr. Werbach’s Nutritional Supplementation Protocol for CFS. It outlines the doses and trial periods usually required to determine if individual nutrients may be beneficial.
Nutritional Strategies for Treating Chronic Fatigue Syndrome:
Other Nutritional Factors
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.
OTHER NUTRITIONAL FACTORS FOR TREATING CFS
Two separate clinical notes have reported that L-tryptophan was depressed in the plasma of 80% of a group of CFS patients, a larger percentage than all other amino acids analyzed.(67,68)
Fibromyalgia patients have similar findings. For example, in a study of patients with a severe level of pain, plasma free tryptophan levels were inversely related to pain severity.(69) Also, when fibromyalgia patients were compared to controls, plasma tryptophan levels tended to be lower in the patient group, and their transport ratio of tryptophan to other competing amino acids was significantly decreased, suggesting that brain serotonin levels may be depressed.(70)
Tryptophan is the dietary precursor of serotonin, a neurotransmitter intimately connected with mood.
For example, a low tryptophan diet may cause relapse in recovering depressives,(71) while low tryptophan concentrations may rise when depression remits.(72) However, the efficacy of tryptophan supplementation in treating fatigue and depression in CFS patients is unknown.
Tryptophan supplementation usually provides a mild degree of analgesia and may be especially effective for the subset of chronic pain patients with a disorder of serotonergic transmission.(73)
While its analgesic efficacy in CFS has not been explored, there has been some interesting work reported in patients with fibromyalgia.
In one study of fibromyalgia patients with severe musculoskeletal pain, plasma free tryptophan levels were measured and found to be inversely related to the severity of subjective pain.(69)
Evidence that tryptophan has a causal relationship to pain comes from an open trial involving 50 fibromyalgia patients. They received 100 mg three times daily of 5-hydroxytryptophan, a metabolite of tryptophan and immediate precursor of serotonin.
After three months, half of the group had a fair-to-good degree of overall improvement, with highly significant improvements in fatigue, number of tender points, pain intensity, anxiety, and sleep quality.(74) These results were similar to those of an earlier double-blind study by the same group of investigators.(75)
There is enhanced degradation of tryptophan in infectious diseases, possibly due to the increased formation of gamma interferon during activation of cell-mediated immunity.(76)
However, it is not known whether correcting a tryptophan deficiency will enhance cell-mediated immunity in virally-mediated illnesses.
Carnitine and its esters prevent toxic accumulations of fatty acids in the cellular cytoplasm, and of acyl CoA in the mitochondria, while providing acetyl CoA for mitochondrial energy production.
Because of its important role in muscle metabolism, carnitine deficiency may well impair mitochondrial function. If so, it could cause symptoms of generalized fatigue along with myalgia, muscle weakness, and malaise following physical exertion.(77)
The evidence to date suggests some CFS patients may suffer from a clinically-relevant carnitine deficiency. While findings concerning free serum carnitine levels have been mixed, studies have found significant decreases in serum acylcarnitine.(7-79)
Moreover, a third study found an increased ratio of acylcarnitine to free carnitine,(25) a finding which suggests insufficient carnitine is available for metabolic requirements.(83)
Most importantly from a clinical perspective, one of these studies found:
• Both total and free serum carnitine levels were inversely correlated with patient symptoms [lower carnitine, more severe symptoms],
• And serum carnitine levels were directly correlated with capacity to function.(79)
Moreover, another of these studies found a similar relationship between serum acylcarnitine, symptoms, and functional capacity.(77)
In other words, in CFS, serum carnitine levels appear to be a biochemical marker for both symptom severity and ability to function.
Clinical trials of oral L-carnitine, using up to 1 gm three to four times daily, have shown mixed results.(79,80,82) Plioplys believes this is because only one-third of CFS patients are carnitine responders. Of the responders, some improve so dramatically that, even if they were fully disabled initially, they return to normal functioning and remain well if they continue taking the supplement. Unfortunately, he found baseline serum levels of L-carnitine failed to predict who would respond.(79,80)
Studies with AIDS patients suggest the possibility that another measure may better identify carnitine-responsive patients.
Similar to CFS patients, AIDS patients tend to have low serum carnitine, although some have elevated levels. However, mononuclear carnitine levels are low in both the low- and high-carnitine subgroups.(83) When a group of AIDS patients with low mononuclear carnitine took six grams L-carnitine daily, an improvement in metabolic and immunological parameters was noted, and the response occurred after only two weeks of supplementation.(83)
CFS patients also have low mononuclear cell carnitine levels,(84) so possibly mononuclear cell carnitine will prove to be a better predictor of carnitine response. And, six grams daily may be a more effective dosage.
Of course, because the metabolic and immunologic parameters in AIDS are quite different from those of CFS, it is premature to assume that what applies to one patient population will also apply to the other.
Since CoQ10 facilitates cellular respiration, and because clinicians believe it is of therapeutic value, it has long been prescribed to CFS patients.(85,86)
Judy presented a formal study of 20 female patients who required bed rest following mild exercise. They were compared to 20 sedentary sex-, age-, and weight-matched normal controls.
Eighty percent were deficient in Coenzyme Q10, which further decreased following mild exercise, or over the course of normal daytime activity. Three months following supplementation with 100 mg of CoQ10 daily, exercise tolerance (400 kg-meters of work) more than doubled; all patients had improved.
Ninety percent had reduction and/or disappearance of clinical symptoms, and 85% had decreased post-exercise fatigue.(87)
ESSENTIAL FATTY ACIDS
Low levels of essential fatty acids (EFAs) appear to be a common finding in chronic fatigue syndrome.(26,88)
It has been theorized this finding is due to abnormalities in EFA metabolism. Gray and Martinovic found changes in the ratio of biologically active EFA metabolites such as would be expected as an exaggeration of normal physiological response to excessive or prolonged stress.
They postulated these changes in EFA metabolites, in turn, could cause the immune, endocrine, and sympathetic nervous system dysfunctions seen in CFS.(89)
Horrobin has noted that viruses, as part of their attack strategy, may reduce the ability of cells to make 6-desaturated EFAs, while interferon requires 6-desaturated EFAs in order to exert its antiviral effects.(90)
In addition, it is quite possible that supplementation with essential fatty acids may improve the hemorrheological abnormalities found in CFS alluded to earlier. [See research on vitamin B12 and vitamin C benefit for microcirculation, discussed in PART 1.] The formation of prostaglandin E1, for example, can be enhanced by increasing intake of omega-6 fatty acids. This prostaglandin has been shown to improve erythrocyte membrane fluidity(91) and filterability;(92) i.e., the ability of erythrocytes to pass through a small membrane filter.
Early research suggests EFA supplementation may be effective for the treatment of CFS. The best study to date concerned a group of 63 patients with a good employment and mental health history who had post-viral fatigue syndrome for at least one year. As expected, their baseline plasma EFA levels were found to be low. They randomly received four capsules twice daily of either an olive oil placebo or a mixture of 80% evening primrose oil and 20% concentrated fish oil (35 mg GLA and 17 mg EPA per capsule). After three months, 85% of treated patients rated themselves as better than at baseline compared to 17% of those on placebo, a highly significant difference. Without exception, the individual symptoms, including fatigue, aches and pains, and depression, showed a significantly greater improvement on the fatty acid supplement than on placebo.
Moreover, in the treated group only, plasma EFA levels rose to normal and monounsaturated and saturated fatty acid levels, which had been elevated, normalized.(91)
A recent attempt to replicate these results was unsuccessful.(95) However, there were positive findings in an open trial of a group of 29 CFS patients who had been ill for an average of 5.9 years. They received essential fatty acid supplements along with psychological help and graded exercise. Only two of these patients showed any improvement in the 12 months prior to starting the program, while 27 of them significantly improved within the program’s first three months.
Twenty-eight of the 29 patients were followed-up an average of 16 months later. All but one of them were still improved compared to before treatment, and 20 of 28 had made further progress.(89)
OVERVIEW – RECOMMENDATIONS & A PROTOCOL
Any of the nutrients discussed above could be marginally deficient in CFS patients, a finding that appears to be primarily due to the illness process rather than to inadequate diets.
In one study, for example, CFS patients had a similar dietary quality to that of healthy volunteers. Moreover, they reported the use of vitamin/mineral supplements containing 100% to 200% of the RDA significantly more frequently, and their intake of iron, magnesium, and zinc was greater.(25)
It is likely that marginal deficiencies not only contribute to the clinical manifestations of chronic fatigue syndrome, but also are detrimental to the healing processes. Therefore, when feasible, they should be identified by objective testing and their resolution should be assured by repeat testing following the initiation of treatment.
Moreover, because of the rarity of serious adverse reactions and the difficulty in ruling out marginal deficiencies, and because some of the therapeutic benefits of nutritional supplements appear to be due to pharmacological 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. (See protocol, below.)
DR. WERBACH’S NUTRITIONAL SUPPLEMENTATION PROTOCOL FOR CFS
(Suggested amounts and time generally required to test for benefit)
• Tentative protocol – 1 to 10 mg a day for 3 month trial
• Possible benefits – Reduction of fatigue & depression; improved immune function
• Tentative protocol – Total of 6,000 to 70,000 micrograms intravenously for 3 week trial. [Note: formulations allowing effective sublingual delivery of B12 to the bloodstream have since been developed]
• Possible benefits – Reduction of fatigue, depression and pain; improved microcirculation
• Tentative protocol – 10 to 15 grams daily
• Possible benefits – Improved immune function; reduced pain; improved microcirculation
• Tentative protocol – If RBC magnesium is low, 100 mg intravenously each week for 6 weeks. And malic acid with magnesium 600 mg a day by mouth; Malic Acid 2400 mg a day by mouth, 8-week trial
• Possible benefits – Subjective improvement, reduction of muscle pain
• Tentative protocol – If diagnosed with neurally-mediated hypotension (faint/dizzy on standing), increase sodium intake moderately
• Possible benefits – Subjective improvement
• Tentative protocol – 135 mg a day for 15 days
• Possible benefits – Increased muscle strength and endurance; reduction of pain and fatigue; improved immune function.
• Tentative protocol – In fibromyalgia: 5-hydroxytryptophan 100 mg 3 times a day, 3 month trial.
• Possible benefits – Reduction of pain and fatigue
• Tentative protocol – 1 to 2 grams 3 times a day, 3 month trial
• Possible benefits – Improvement that can be dramatic
• Tentative protocol – 100 mg a day, for 3 month trial
• Possible benefits – Marked improvement with increased muscle endurance
Essential Fatty Acids
• Possible benefits – General Improvement
[Note: ProHealth has reproduced this article with kind permission from Alternative Medicine Review, 2000;5(2):93-108. © Alt Med Review, all rights reserved. To read the Part 1 of this article, which reviews common vitamin and mineral deficiencies in ME/CFS, see “Nutritional Strategies for Treating Chronic Fatigue Syndrome: Vitamins and Minerals.”]
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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.