Nutritional Strategies for Treating ME/CFS: PART 2, Other Nutritional Factors
By Melvyn R Werbach, MD •
July 20, 2011
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.
Moreover, supplementation with both evening primrose oil, a source of omega-6 fatty acids,(93) and fish oil,(94) a source of omega-3 fatty acids, has been shown to improve erythrocyte filterability.
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
• Tentative protocol - 135 mg fish oil (EPA) a day; 280 mg evening primrose oil (GLA) a day, 3 month trial
• 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.
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Dr. Werbach's recommendations in the light of the GD-MCB hypothesis
|Posted by: richvank
Jul 21, 2011
I would like to comment on how the GD-MCB hypothesis explains the need for the nutrients that Dr. Werbach has found to be helpful to supplement in ME/CFS.
The GD-MCB (Glutathione Depletion-Methylation Cycle Block) hypothesis for the pathogenesis and pathophysiology of ME/CFS essentially proposes that the onset of sporadic cases of ME/CFS result from the combination of a genomic predisposition with some combination of stressors, which can be physical, chemical, biological or emotional/psychological.
The response to the stressors causes cortisol and adrenaline to rise initially, and in combination with the genomic predisposition, they lead to depletion of glutathione. The glutathione depletion causes a functional deficiency in B12, and this leads to a partial block of the enzyme methionine synthase in the methylation cycle. Folates drain from the cells via the "methyl trap" mechanism. The other features of ME/CFS result from the vicious circle mechanism that is established between the partial block in the methylation cycle and the depletion of glutathione, which makes ME/CFS chronic.
Looking at Dr. Werbach's recommended supplements in the light of this hypothesis, note that the first two he mentions are folic acid and B12. These are the two nutrients which the GD-MCB hypothesis predicts to be the most essential, because both are needed by the partially blocked methionine synthase enzyme, which is the core of the pathophysiology according to this hypothesis. B12 is needed because of its functional deficiency, caused by glutathione depletion. Folate is needed because folate has drained from the cells as a result of the B12 functional deficiency. The key to lifting the partial methylation cycle block is to take folate and B12 simultaneously.
We have actually found that it is better to supplement the active, natural forms of folate rather than the synthetic, oxidized form folic acid, because folic acid competes with the active forms for absorption, it requires often deficient NADPH for its conversion to active forms, and some people have a slow version of the DHFR enzyme which does this conversion. The best folate form is 5L-methyltetrahydrofolate, and folinic acid is also helpful for many PWCs. When these forms are used, the dosage can usually be somewhat less than the range Dr. Werbach has suggested.
The best B12 forms are hydroxocobalamin, methylcobalamin and adenosylcobalamin. Cyanocobalamin should not be taken alone in large dosages, because of the cyanide it contains. While most people are able to detox the cyanide, especially if high-dose hydroxo B12 is taken with it, cyano B12 does not add anything to what is supplied by the other B12 forms. Whether hydroxocobalamin or methylcobalamin is preferable depends on the genomics of the individual. The dosages Dr. Werbach has suggested may be somewhat high if taken together with the active folates.
The next supplement recommended by Dr. Werbach is vitamin C at a fairly high dosage. While this will help to address the oxidative stress that results from the depletion of glutathione, it may be counterproductive to take it when treating with folate and B12 to lift the partial methylation cycle block, because it is normally recycled by glutathione, and adding vitamin C when glutathione is depleted may hinder its rise, which we have found to be automatic when the methylation cycle block is treated. So while vitamin C may be somewhat helpful as a stand-alone support for countering the oxidative stress, it is probably best not taken in such high dosages when treating the methylation cycle partial block.
Intracellular magnesium is depleted in ME/CFS, and this seems to be associated with the glutathione depletion. Supplementing it can have some benefit, but until glutathione is raised by treating the partial methylation cycle block, intracellular magnesium levels do not seem to be maintained.
Malate is helpful to support the Krebs cycle, which is partially blocked at aconitase by the depletion of glutathione and its oxidation.
Sodium chloride can give some temporary benefit, but it does not address the cause of the low blood volume in ME/CFS, which is diabetes insipidus (not to be confused with diabetes mellitus), in turn likely caused by glutathione depletion in the hypothalamus and pituitary, causing low secretion of antidiuretic hormone. Lifting the partial methylation cycle block raises glutathione and should correct this problem.
Zinc is essential for the methionine synthase enzyme as well as many others. Supplementing it as a cofactor may be necessary to bring up the methylation cycle.
L-tryptophan is low in many PWCs, as are other amino acids. According to the GD-MCB hypothesis, this occurs because of the partial block early in the Krebs cycle due to glutathione depletion and oxidation. The result of this is that PWCs are not able to burn carbohydrates and fats as fuels as well as normal, and thus amino acid are burned for fuel more than normal. In addition, the gut problems that develop, either initially or as consequences of the methylation cycle partial block, can hinder the absorption of amino acids by the gut. Supplementing amino acids can be helpful, especially those needed to get the methylation cycle and glutathione back up to normal.
L-carnitine and coenzyme Q10 are both needed by the mitochondria, which are dysfunctional in ME/CFS, and both are deficient. The reason they are deficient is that both require methylation for their synthesis, and there is a partial block in the methylation cycle. These deficiencies contribute to the mitochondrial dysfunction, but the main cause is glutathione depletion, which inhibits both the Krebs cycle and the respiratory chain in the mitochondria. Supplementing these two can be somewhat beneficial, but restoring methylation and glutathione are necessary to correct the mitochondrial dysfunction.
Essential fatty acids are depleted in ME/CFS because they are the most vulnerable molecules in the cells to the oxidative stress that results from glutathione depletion. Supplementing them can be helpful, but it should be combined with treating the methylation cycle and thus raising glutathione. Otherwise, the added essential fatty acids will be vulnerable to peroxidation, which is a chain reaction process.
The main points I would like to make are that the Glutathione Depletion--Methylation Cycle Block hypothesis is able to explain very well the deficiencies in ME/CFS that have been noted by Dr. Werbach, that its predictions agree well with his findings, and that this model adds some qualifications to his recommendations for supplementation.
I hope this is helpful.
Rich Van Konynenburg, Ph.D.
|Posted by: brooklynbred
Oct 19, 2012
#1 We miss you Rich!
and #2: ME/CFS/FM folks MUST look into MTHFR genetic testing to determine if they have an issue with Folate and B-12 utilization/conversion! It's paramount! If you test + for one or both of these mutations (A1298C and C677T) You are faced with a serious Methelation Pathway issue which must be corrected. If you are taking non-bio-active formes of Folate or B-12, you are not only not helping yourself but actually potentially doing harm. This MTHFR test is a SIMPLE commercial lab test that can be requested through your doctor.
Here is more info: