Chronic fatigue syndrome: oxidative stress and dietary modifications – Brief Article
Alan C. Logan
Chronic fatigue syndrome (CFS) is an illness characterized by persistent and relapsing fatigue, often accompanied by numerous symptoms involving various body systems. The etiology of CFS remains unclear; however, a number of recent studies have shown oxidative stress may be involved in its pathogenesis. The role of oxidative stress in CFS is an important area for current and future research as it suggests the use of antioxidants in the management of CFS. Specifically, the dietary supplements glutathione, N-acetylcysteine, alpha-lipoic acid, oligomeric proanthocyanidins, Ginkgo biloba, and Vaccinium myrtillus (bilberry) may be beneficial. In addition, research on food intolerance is discussed, since food intolerance may be involved in CFS symptom presentation and in oxidation via cytokine induction. Finally, recent evidence suggests celiac disease can present with neurological symptoms in the absence of gastrointestinal symptoms; therefore, celiac disease should be included in the differential diagnosis of CFS.
(Altern Med Rev 2001;6(5):450-459)
Chronic fatigue syndrome (CFS) is a relatively common disorder, particularly in women, affecting 522 women and 291 men per 100,000. (1) In addition to the characteristic persistent fatigue, CFS patients often complain of a number of symptoms including headache, joint pain, gastrointestinal (GI) disturbance, cognitive dysfunction, visual disturbance, and paresthesia. (2, 3)
Pathological changes have been observed in CFS patients, including white matter lesions in the CNS (4-6) and cerebral hypoperfusion. (7-9) Other findings that suggest CNS involvement include vestibular dysfunction (10,11) and gait abnormalities. (12,13) Immune response also appears to be impaired; specifically, elevated levels of interferon alpha, transforming growth factor beta, interleukin-4, interleukin-6, interleukin-1 alpha, and tumor necrosis factor alpha (TNF-[alpha] have been observed. (14-19)
The purpose of this paper is to integrate various branches of current research in an effort to highlight the importance of antioxidant capacity and food intolerance in CFS. First, recent studies will be reviewed that indicate oxidative stress is involved in the pathogenesis of CFS. This suggests antioxidants may be beneficial in the management of CFS. Glutathione (GSH), N-acetylcysteine (NAC), [alpha]-lipoic acid, oligomeric proanthocyanidins (OPCs), Ginkgo biloba, and Vaccinium myrtillus (bilberry) would therefore be dietary supplements with potential therapeutic benefit. Second, the literature will be reviewed that suggests food intolerance may be involved in CFS symptom presentation and in oxidation via cytokine induction.
Although food intolerance can be an important consideration in the presentation of this heterogeneous disorder, evidence also suggests celiac disease should be included in the differential diagnosis of CFS. Celiac disease may present primarily with neurological symptoms in the absence of gastrointestinal symptoms.
Current Research on Oxidative Stress in CFS
The role of oxidative stress in CFS is an emerging focus of research. Although it is uncertain whether oxidative stress is a cause or a result of this illness, recent studies have demonstrated that oxidative stress contributes to the pathology and clinical symptoms of CFS. Theoretically, oxidative stress can be caused by an increase in the generation of reactive oxygen species, of which mitochondrial dysfunction is believed to be a main source, or it can be caused by a decline in the efficiency of antioxidant enzyme systems. (20) Recent studies have examined both of these possibilities by looking for markers of oxidative stress and protective antioxidant systems.
Fulle et al observed evidence of oxidative damage to the DNA and lipids of biopsy samples from the vastus lateralis muscles of CFS patients. (20) In addition, they found an increase in the activity of antioxidant enzyme systems, including glutathione peroxidase, an increase they suggest is a compensatory measure in response to oxidative stress. The researchers noted a similarity between increased oxidative damage in CFS patients and age-related changes in healthy individuals, concluding that antioxidants have therapeutic potential to reduce oxidative damage.
Pall suggests the level of the oxidant peroxynitrite is important in CFS patients. (21) He contends elevated peroxynitrite causes mitochondrial dysfunction, lipid peroxidation, and, by way of positive feedback, elevated cytokine levels. The cytokines, in turn, cause the formation of nitric oxide that combines with superoxide to form the potent oxidant peroxynitrite, thus continuing the cycle. Peroxynitrite targets the mitochondria and Pall notes this may help explain mitochondrial dysfunction in CFS. As support for the peroxynitrite theory, Pall cites evidence that the mitochondrial enzymes succinic dehydrogenase and cis-aconitase are inactivated by peroxynitrite. (22,23) This makes for an interesting finding because decreased succinic dehydrogenase activity has been found in CFS patients (24,25) and urine levels of the intermediates metabolized by these enzymes have been found to be elevated in CFS patients. (26,27) Pall proposes a number of nutritional and botanical interventions that may reduce peroxynitrite and cytokine levels; among them, the soy isoflavone genistein, epigallocatechin-3-gallate from green tea, and vitamins C and E.
Keenoy et al found impaired antioxidant capacity in a sample of CFS patients with “subclinical” or moderate magnesium deficiency. (28) The impaired capacity involved both the total antioxidative capacity of plasma, as measured by Trolox Equivalents Antioxidant Capacity (TEAC), and the antioxidant component dependent on albumin. While no improvement was observed in these parameters after oral or intravenous magnesium supplementation, some patients demonstrated increased serum vitamin E and an associated decrease in lipid peroxidation. This finding, according to the authors, is likely due to the sparing effect of magnesium on vitamin E by preventing its in vivo oxidation. In addition, the researchers postulated that an elevated concentration of inflammatory cytokines might indirectly cause diminished antioxidant capacity by inhibiting albumin transcription in the liver.
A subset of patients whose magnesium body stores did not improve after supplementation also had lower blood glutathione levels, suggesting a relationship might exist between intractable magnesium deficiency and low glutathione. (28) Interestingly, RBC magnesium levels have previously been reported to be decreased in CFS patients, some of whom had adequate dietary intake of magnesium. (29)
Some of these same researchers further examined the role of oxidative stress in CFS. They found an increased susceptibility of LDL and VLDL to copper-induced peroxidation in CFS patients. (30) They conclude this might indicate the impaired lipoprotein antioxidant capacity in CFS, causing accelerated lipid peroxidation.
Richards et al found CFS patients had elevated levels of methemoglobin (MetHb), a marker of oxidative stress. (31) Formation of MetHb, a product of iron oxidation, is regulated by NADH-MetHb reductase. Consequently, levels of MetHb may increase when there is an alteration in this reducing system within the erythrocyte. The researchers reported the increase in MetHb correlates with the presence and severity of several CFS symptoms, including photophobia, irritability, and GI complaints. MetHb also requires glutathione and cysteine to be reduced in normal cells. It is interesting to note that both glutathione (28) and cysteine (32) levels have been found in decreased levels in CFS patients.
Additional evidence supporting the role of free radical damage in CFS patients and the efficacy of antioxidant treatment comes from a recent study. (33) In a three-month, double-blind, placebo-controlled crossover study, 22 CFS patients were given a Swedish pollen extract high in antioxidant polyphenols. Statistically significant improvement was observed in the treatment group, notably in fatigue, sleep disturbance, GI complaints, and hypersensitivity. In addition, there was a highly significant improvement in erythrocyte fragility, a marker of oxidative damage. The researcher acknowledged the synergistic effect of antioxidants, as in the Swedish pollen extract, and suggests future research using antioxidant combinations.
Implications for Antioxidant Treatment
The above findings on oxidative stress suggest that supplementing with certain antioxidants, in addition to vitamins C and E, may be valuable in a CFS treatment protocol (Table 1). A number of supplements should be considered for potential therapeutic intervention, including selenium (necessary to support glutathione peroxidase activity), (34) GSH, NAC, and [alpha]-lipoic acid. Although there is conflicting evidence, a number of studies have shown oral administration of GSH can directly increase plasma and tissue GSH concentration. (35-37) Alternately, NAC and [alpha]-lipoic acid can increase GSH concentration indirectly; (38,39) NAC provides cysteine for GSH synthesis, and [alpha]-lipoic acid is believed to increase intracellular GSH levels by reducing extracellular cystine to cysteine, bypassing the cystine transporter. (40) GSH is neuroprotective and may play a role in preventing additional CNS lesions. (41) [alpha]-Lipoic acid is also neuroprotective, scavenges nitric oxide and peroxynitrite, and may be especially promising as an antioxidant against mitochondrial dysfunction. (40) The supplement coenzyme Q10 has similar neuroprotective qualities and has the ability to improve mitochondrial function. (42)
The botanical antioxidants OPCs and Ginkgo biloba should also be considered. Bagchi et al found that OPCs are highly bioavailable and provide significantly greater protection against free radical damage than beta carotene and vitamins C and E. (43) These authors also reported the ability of OPCs to provide protection from radical-induced lipid peroxidation and DNA damage, which is of particular importance to CFS patients.
Ginkgo biloba is a powerful antioxidant, (44) demonstrating strong neuroprotective properties in animals. It has been shown to reduce mitochondrial reactive oxygen species, in particular peroxynitrite. (45) The capacity of Ginkgo to increase cerebral blood flow (46) and improve memory and cognition associated with cerebral insufficiency (47) suggests it may be useful for CFS symptoms related to hypoperfusion.
Plant-based antioxidant support should be maximized through dietary intake. Cao et al found that a diet high in fruits and vegetables can increase plasma antioxidant capacity in humans, as measured by oxygen radical absorbance capacity (ORAC) assay. (48) Blueberries have the highest ORAC scores among thirty fruits and vegetables tested, (49,50) and may be of significant benefit due to their high potential antioxidant activity, (51) neuroprotective properties, (52) and specific ability to protect red blood cells from in vivo oxidative damage. (53) Of the blueberry species, Vaccinium myrtillus has the highest combined anthocyanidin, phenol, and ORAC scores. (51)
In a recent double-blind, placebo-con trolled, crossover study, administration of pure anthocyanidins (80 mg daily) showed a small but statistically significant benefit in a group of patients with the related disorder of fibromyalgia. (54) The trial was three months in duration for active treatment and involved an anthocyanidin combination derived from grape seed, bilberry, and cranberry. Improvements were observed in sleep quality and fatigue. Based on these findings a similar trial is warranted in CFS patients.
Food Intolerance, Cytokines, and CFS
Food intolerance is implicated in the presentation of symptoms in CFS. Nisenbaum et al presented an abstract at the American Association for Chronic Fatigue Syndrome conference in Seattle in January 2001, showing that 54 percent of a sample of CFS patients had attempted unspecified dietary modifications. Of these individuals who modified their diet, 73 percent reported dietary changes were beneficial in reducing fatigue. (55) It remains speculative whether these improvements were due to increased dietary antioxidant intake or the elimination of certain foods. Although further research is necessary, it appears diet plays an important role in CFS, in contrast to previous suggestions. (29)
Recent research published in Lancet by Jacobsen et al suggests that eliminating food intolerances by dietary modification may reduce the release of inflammatory cytokines. (56) The investigators demonstrated that individuals with food intolerance, a condition distinguished from IgE-mediated food allergy, had a significant elevation in inflammatory cytokines (interleukin-4, interferon gamma, TNF-[alpha]) when given a dietary challenge of dairy and wheat. The authors noted that cytokine elevations can account for post-challenge symptoms such as headache, myalgia, joint pain, and GI disturbance, symptoms clearly similar to those observed in CFS patients.
Prior to the Lancet study, researchers had made assumptions regarding food intolerance and chronic fatigue. Manu et al, without conducting an elimination and challenge diet or evaluating for the presence of inflammatory markers, suggested that patients with chronic fatigue who report food intolerance are merely manifesting somatization traits. (57) Food intolerance was identified by asking patients to name foods causing adverse reactions. This is not a reliable method, since the inflammatory response is neither as immediate nor as extreme as in classic food allergy, making self-identification of offending foods difficult. The landmark study by Jacobsen et al (56) validates the symptoms of those with food intolerance and thereby negates those false assumptions of the presence of psychiatric pathology.
There are a number of diagnostic methods to detect the presence of food intolerance, the “gold standard” being the elimination and challenge diet. (58) Research has shown the use of a food and symptom diary during the elimination and challenge diet further helps to identify problem foods. (59) In addition to being an inexpensive method to determine whether a food or chemical intolerance is contributing to the symptoms of CFS, subsequent elimination of the offending foods or additives from the diet may be an effective treatment. This protocol has been successful for other illnesses, including asthma, (60) ulcerative colitis, (61) Crohn’s disease, (62) irritable bowel syndrome (IBS), (63) and perennial rhinitis. (64)
In an Australian study, CFS patients eliminated wheat, milk, benzoates, nitrites, nitrates, and food colorings and other additives from their diet. (65) The compliance rate was approximately 50 percent, with 37 patients completing the protocol. Of the CFS patients who complied, the results were remarkable: 90 percent reported improvement in the severity of symptoms across multiple body symptoms, with significant reduction in fatigue, recurrent fever, sore throat, muscle pain, headache, joint pain, and cognitive dysfunction. Furthermore, the elimination protocol resulted in a marked improvement in IBS-like symptoms among all patients; a significant finding because CFS patients have a high rate of IBS. (66,67)
The results of this study support the findings of Borok published in the South African Medical Journal over a decade ago. (68) Borok cited a strong correlation between CFS and the presence of food intolerance. He reported alleviation of chronic fatigue among CFS patients (n=20) after removing certain foods from the diet, with milk, wheat, and corn among the top offenders.
Gibson and Gibson explored the effect of intolerance to wheat on CFS symptoms in a pilot study. (69) They used a multi-therapeutic protocol that included a wheat-free diet, nutritional supplementation, and homeopathy. After four months, 70 percent of the 64 patients enrolled in the study showed improvement in physical symptoms and mental outlook. Unfortunately, due to the study design, it is impossible to know what effect elimination of wheat alone might have had.
Another study concluded that choosing organically grown dietary fruits and vegetables is important for CFS patients, since they have elevated serum levels of chlorinated hydrocarbon pesticides compared to normal control subjects. (70) The authors noted that certain chlorinated hydrocarbon pesticides, such as 1,1-dichloro-2,2-bis(P-chlorophenyl)ethene (DDE), are lipid compounds that can accumulate in cell membranes and may alter cell membrane integrity and inhibit functional membrane-bound proteins. Moreover, they are capable of crossing the blood-brain barrier to affect neurological activity. With respect to food intolerance, exposure to pesticides may be involved in the loss of innate or natural tolerance for chemicals, including those in foods. (71)
Interestingly, Komaroff et al found 60 percent of CFS patients reported alcohol intolerance at the onset of CFS. (3) This is similar to the experience of those having the related illnesses of multiple chemical sensitivity (MCS) and Gulf War syndrome (GWS). Miller and Prihoda found MCS and GWS patients frequently report alcohol and food intolerance. (71) They discussed the possibility that alcohol intolerance may be related to food sensitivity to the grain or fruit from which the alcohol is derived.
Celiac Disease May Mimic CFS
Keeping in mind that CFS is a disorder of exclusion and that there have been reports of improvements with wheat elimination, all patients should be assessed for the presence of celiac disease (CD). Investigators have found CD to be an under-diagnosed condition in the general population (72) and may present with only mild enteropathy or no GI symptoms at all. (73) Neurological dysfunction is a known complication of CD and ataxia, and cognitive difficulties may be the first manifestations of clinically-silent celiac disease. (74)
In an article published in Lancet, Hadjivassiliou et al demonstrated that 57 percent of 53 individuals with neurological dysfunction of unknown cause had positive antigliadin antibodies. (75) Most of these patients did not manifest major GI symptoms that would lead a clinician to consider CD.
Luostarinen et al, in a recent review article on celiac disease published in European Neurology, stated that CD should be considered in all patients presenting with neurological disturbances such as memory deficits and ataxia of unknown etiology. (76) Assuming that GI complaints, gait abnormalities, cognitive difficulties, and other neurological complaints are common among CFS patients, an investigation into CD is warranted. A preliminary investigation has not established a clinical link between CFS and CD; (77) however, the prevalence of CD may be higher among CFS patients than in the general population. (77,78) The current case definition for CFS (79) has been criticized for not suggesting lab work to determine the presence of celiac disease, resulting in CD being overlooked and presumed to be CFS. (80) Clinicians should be aware that reduced levels of serum ferritin and decreased red cell folate are sensitive laboratory observations (88 percent and 82 percent, respectively) in routine screening of celiac patients. (81)
Despite extensive international research, both the etiology and pathogenesis of CFS are far from clear. A number of recent studies demonstrate that oxidative stress is a component of the illness, although further research is needed to elucidate whether the oxidative damage is the cause or an effect. Since it is apparent from the research presented that some degree of oxidative stress is present in CFS patients, various antioxidants show promise as part of a CFS protocol. The antioxidants glutathione, N-acetylcysteine, [alpha]-lipoic acid, oligomeric proanthocyanidins, Ginkgo biloba, and Vaccinium myrtillus very possibly hold promise, although clinical studies are necessary to demonstrate their efficacy among CFS patients.
With respect to diet, information on food intolerance and CFS remains limited. Perhaps new research will determine if food intolerance plays a direct role in cytokine induction among CFS patients. Until this research is conducted and the mechanisms behind this complex illness are more fully understood, elimination and challenge diets combined with the synergistic effects of multiple dietary and supplemental antioxidants may be beneficial in a CFS treatment protocol.
The authors wish to thank Robert Marshall of the Learning Resource Centre of the Canadian College of Naturopathic Medicine for help with the preparation of this manuscript by securing many of the difficult to find journal articles.
Table 1. Antioxidants in the Treatment
of CFS and Their Mechanisms
Antioxidant Mechanism of Action
Selenium Supports glutathione peroxidase activity, a
Se-dependant antioxidant system (34)
Glutathione Reduced glutathione (GSH) directly increases
glutathione levels (35-37)
N-acetylcysteine Provides cysteine for GSH synthesis (38)[alpha]-Lipoic acid Increases intracellular GSH by reducing
extracellular cystine to cysteine (40)
CoQ10 Improves mitochondrial function;
Oligomeric Protects against radical-induced lipid
proanthocyanidins peroxidation and DNA damage (43)
Ginkgo biloba Powerful antioxidant; increases cerebral
perfusion and associated memory and cognitive
deficits; neuroprotective (45-47)
Vaccinium myrtillus Neuroprotective; (52) protects RBCs from in
(bilberry) vivo oxidative damage (53)
(1.) Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med 1999;159:2129-2137.
(2.) Komaroff AL, Buchwald D. Symptoms and signs of chronic fatigue syndrome. Rev Infect Dis 1991;13:S8-S11.
(3.) Komaroff AL, Fagioli LR, Geiger AM, et al. An examination of the working case definition of chronic fatigue syndrome. Am J Med 1996;100:56-64.
(4.) Buchwald D, Cheney PR, Peterson DL, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med 1992;116:103-113.
(5.) Natelson BH, Cohen JM, Brassloff I, Lee HJ. A controlled study of brain magnetic resonance imaging in patients with the chronic fatigue syndrome. J Neurol Sci 1993;120:213-217.
(6.) Lange G, DeLuca J, Maldjian JA, et al. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J Neurol Sci 1999;171:3-7.
(7.) Schwartz RB, Komaroff AL, Garada B, et al. SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. AJR Am J Roentgenol 1994;162:943-951.
(8.) Costa DC, Tannock C, Brostoff J. Brain stem hypoperfusion in patients with myalgic encephalomyelitis-chronic fatigue syndrome. Eur J Nucl Med 1992;19:733.
(9.) Ichise M, Salit IE, Abbey SE, et al. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nucl Med Commun 1992;13:767-772.
(10.) Furman JM. Testing of vestibular function: an adjunct in the assessment of chronic fatigue syndrome. Rev Infect Dis 1991;13:S109-S111.
(11.) Ash-Bernal R, Wall C 3rd, Komaroff AL, et al. Vestibular function test anomalies in patients with chronic fatigue syndrome. Acta Otolaryngol 1995;115:9-17.
(12.) Boda WL, Natelson BH, Sisto SA, Tapp WN. Gait abnormalities in chronic fatigue syndrome. J Neurol Sci 1995;131:156-161.
(13.) Saggini R, Pizzigallo E, Vecchiet J, et al. Alteration of spatial-temporal parameters of gait in chronic fatigue syndrome patients. J Neurol Sci 1998;154:18-25.
(14.) Ho-Yen DO, Carrington D, Armstrong AA. Myalgic encephalomyelitis and alpha-interferon. Lancet 1988;1:125.
(15.) Bennett AL, Chao CC, Hu S, et al. Elevation of bioactive transforming growth factor-beta in serum from patients with chronic fatigue syndrome. J Clin Immunol 1997;17:160-166.
(16.) Linde A, Andersson B, Svenson SB, et al. Serum levels of lymphokines and soluble cellular receptors in primary Epstein-Barr virus infection and in patients with chronic fatigue syndrome. J Infect Dis 1992;165:994-1000.
(17.) Chao CC, Janoff EN, Hu SX, et al. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with chronic fatigue syndrome. Cytokine 1991;3:292-298.
(18.) Patarca R, Klimas NG, Lugtendorf S, et al. Disregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression. Clin Infect Dis 1994;18:S147-S153.
(19.) Hanson SJ, Gause W, Natelson B. Detection of immunologically significant factors for chronic fatigue syndrome using neural-network classifiers. Clin Diagn Lab Immunol 2001;8:658-662.
(20.) Fulle S, Mecocci P, Fano G, et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med 2000;29:1252-1259.
(21.) Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses 2000;54:115-125.
(22.) Radi R, Rodriguez M, Castro L, Telleri R. Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 1994;308:89-95.
(23.) Castro L, Rodriguez M, Radi R. Aconitase is readily inactivated by peroxynitrite, but not by its precursor, nitric oxide. J Biol Chem 1994;269:29409-29415.
(24.) Edwards RH, Newham DJ, Peters TJ. Muscle biochemistry and pathophysiology in postviral fatigue syndrome. Br Med Bull 1991;47:826-837.
(25.) Vecchiet L, Montanari G, Pizzigallo E, et al. Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome. Neurosci Lett 1996;208:117-120.
(26.) McGregor NR, Dunstan RH, Zerbes M, et al. Preliminary determination of a molecular basis of chronic fatigue syndrome. Biochem Mol Med 1996;57:73-80.
(27.) McGregor NR, Dunstan RH, Zerbes M, et al. Preliminary determination of the association between symptom expression and urinary metabolites in subjects with chronic fatigue syndrome. Biochem Mol Med 1996;58:85-92.
(28.) Manuel y Keenoy B, Moorkens G, Vertommen J, et al. Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. J Am Coll Nutr 2000;19:374-382.
(29.) Grant JE, Veldee MS, Buchwald D. Analysis of dietary intake and selected nutrient concentrations in patients with chronic fatigue syndrome. J Am Diet Assoc 1996;96:383-386.
(30.) Manuel y Keenoy B, Moorkens G, Vertommen J, De Leeuw I. Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci 2001;68:2037-2049.
(31.) Richards RS, Roberts TK, McGregor NR, et al. Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep 2000;5:35-41.
(32.) Aoki T, Miyakoshi H, Usuda Y, Heberman RB. Low NK syndrome and its relationship to chronic fatigue syndrome. Clin Immunol Immunopathol 1993;69:253-265.
(33.) Ockerman P. Antioxidant treatment of chronic fatigue syndrome. Clin Pract Altern Med 2000;1:88-91.
(34.) Arthur JR. The glutathione peroxidases. Cell Mol Life Sci 2000;57:1825-1835.
(35.) Aw TY, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact 1991;80:89-97.
(36.) Jones DP, Hagen TM, Weber R. Oral administration of glutathione (GSH) increases plasma GSH concentration in humans (abstract). FASEB J 1989;3:A1250.
(37.) Favilli F, Marraccini P, Iantomasi T, Vincenzini MT. Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters. Br J Nutr 1997;78:293-300.
(38.) Kelly GS. Clinical applications of Nacetylcysteine. Altern Med Rev 1998;3:114-127.
(39.) Han D, Tritschler HJ, Packer L. Alpha-lipoic acid increases intracellular glutathione in a human T-lymphocyte Jurkat cell line. Biochem Biophys Res Commun 1995;207:258-264.
(40.) Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 1997;22:359-378.
(41.) Bridges RJ, Koh JY, Hatalski CG, Cotman CW. Increased excitotoxic vulnerability of cortical cultures with reduced levels of glutathione. Eur J Pharmacol 1991;192:199-200.
(42.) Matthews RT, Yang L, Browne S, et al. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci USA 1998;95:8892-8897.
(43.) Bagchi D, Bagchi M, Stohs SJ, et al. Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology 2000;148:187-197.
(44.) Diamond BJ, Shiflett SC, Feiwel N, et al. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil 2000;81:668-678.
(45.) Bastianetto S, Ramassamy C, Dore S, et al. The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci 2000;12:1882-1890.
(46.) Krieglstein J, Beck T, Seibert A. Influence of an extract of Ginkgo biloba on cerebral blood flow and metabolism. Life Sci 1986;39:2327-2334.
(47.) Rai GS, Shovlin C, Wesnes KA. A double-blind, placebo controlled study of Ginkgo biloba extract (“tanakan”) in elderly outpatients with mild to moderate memory impairment. Curr Med Res Opin 1991; 12:350-355.
(48.) Cao G, Booth SL, Sadowski JA, Prior RL. Increases in human plasma antioxidant capacity after consumption of controlled diets high in fruit and vegetables. Am J Clin Nutr 1998;68:1081-1087.
(49.) Cao G, Sofic E, Prior RL. Antioxidant capacity of tea and common vegetables. J Agric Food Chem 1996;44:3426-3431.
(50.) Wang H, Cao G, Prior RL. Total antioxidant capacity of fruits. J Agric Food Chem 1996;44:701-705.
(51.) Prior RL, Cao G, Martin A, et al. Antioxidant capacity as influenced by total phenolic and anthocyanin content, maturity, and variety of Vaccinium species. J Agric Food Chem 1998;46:2686-2693.
(52.) Joseph JA, Shukitt-Hale B, Denisora NA, et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 1999;19:8114-8121.
(53.) Youdim KA, Shukitt-Hale B, MacKinnon S, et al. Polyphenolics enhance red blood cell resistance to oxidative stress: in vitro and in vivo. Biochim Biophys Acta 2000; 1523:117-122.
(54.) Edwards AM, Blackburn L, Christie S, et al. Food supplements in the treatment of fibromyalgia: a double-blind, crossover trial of anthocyanidins and placebo. J Nutr Environ Med 2000;10:189-199.
(55.) Nisenbaum R, Reyes M, Jones A, Reeves WC. Course of illness among patients with chronic fatigue syndrome in Wichita, Kansas. Abstract #49 presented at the American Association for Chronic Fatigue Syndrome conference. January 2001. Seattle, WA.
(56.) Jacobsen MB, Aukrust P, Kittang E, et al. Relation between food provocation and systemic immune activation in patients with food intolerance. Lancet 2000;356:400-401.
(57.) Manu P, Matthews DA, Lane TJ. Food intolerance in patients with chronic fatigue. Int J Eat Disord 1993;13:203-209.
(58.) Kitts D, Yuan Y, Joneja J, et al. Adverse reactions to food constituents: allergy, intolerance, and autoimmunity. Can J Physiol Pharmacol 1997;75:241-254.
(59.) Kueper T, Martinelli D, Konetzki W, et al. Identification of problem foods using food and symptom diaries. Otolaryngol Head Neck Surg 1995;112:415-420.
(60.) Baker JC, Ayres JG. Diet and asthma. Respir Med 2000;94:925-934.
(61.) Candy S, Borok G, Wright JP, et al. The value of an elimination diet in the management of patients with ulcerative colitis. S Afr Med J 1995;85:1176-1179.
(62.) Workman EM, Alun Jones V, Wilson AJ, Hunter JO. Diet in the management of Crohn’s disease. Hum Nutr Appl Nutr 1984;38:469-473.
(63.) Nanda R, James R, Smith H, et al. Food intolerance and the irritable bowel syndrome. Gut 1989;30:1099-1104.
(64.) Asero R. Perennial rhinitis induced by benzoate intolerance. J Allergy Clin Immunol 2001;107:197.
(65.) Emms TM, Robers TK, Butt HL, et al. Food intolerance in chronic fatigue syndrome. Abstract #15 presented at the American Association for Chronic Fatigue Syndrome conference. January 2001. Seattle, WA.
(66.) Gomborone JE, Gorard DA, Dewsnap PA, et al. Prevalence of irritable bowel syndrome in chronic fatigue. J R Coll Physicians Lond 1996;30:512-513.
(67.) Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 2000; 160:221-227.
(68.) Borok G. Another answer to yuppie flu? SAMJ 1989;76:176.
(69.) Gibson SL, Gibson RG. A multidimensional treatment plan for chronic fatigue syndrome. J Nutr Environ Med 1999;9:47-54.
(70.) Dunstan RH, Donohoe M, Taylor W, et al. A preliminary investigation of chlorinated hydrocarbons and chronic fatigue syndrome. Med J Aust 1995;163:294-297.
(71.) Miller CS, Prihoda TJ. A controlled comparison of symptoms and chemical intolerances reported by Gulf War veterans, implant recipients and persons with multiple chemical sensitivity. Toxicol Ind Health 1999; 15;386-397.
(72.) Unsworth DJ, Brown DL. Serological screening suggests that adult coeliac disease is underdiagnosed in the UK and increases the incidence by up to 12%. Gut 1994;35:61-64.
(73.) Troncone R, Greco L, Auricchio S. Gluten sensitive enteropathy. Pediatr Clin North Am 1996;43:355-373.
(74.) Wills AJ. The neurology and neuropathology of coeliac disease. Neuropathol Appl Neurobiol 2000;26:493-496.
(75.) Hadjivassiliou M, Gibson A, Davies-Jones GA, et al. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996;347:369-371.
(76.) Luostarinen L, Pirttila T, Collin P. Coeliac disease presenting with neurological disorders. Eur Neurol 1999;42:132-135.
(77.) Petri H, Graffelman AW, Knuistingh-Neven A, et al. Coeliac disease and chronic fatigue syndrome. Int J Clin Pract 2001;55:71.
(78.) Skowera A, Peakman M, Cleare A, et al. High prevalence of serum markers of coeliac disease in patients with chronic fatigue syndrome. J Clin Pathol 2001;54:335-336.
(79.) Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121:953-959.
(80.) Empson M. Celiac disease or chronic fatigue syndrome — can the current CDC working case definition discriminate? Am J Med 1998;104:79-80.
(81.) Pare P, Douville P, Caron D, Lagace R. Adult celiac sprue: changes in the pattern of clinical recognition. J Clin Gasteroenterol 1988;10:395-400.
Alan C. Logan, ND – Associate Director, CFS/FM Integrative Care Centre. Correspondence address: 3600 Ellesmere Road, Unit #4, Toronto, ON M1C 4Y8; alancloganND@excite.com
Cathy Wong, ND (Cand.) – 4th year intern at the Canadian College of Naturopathic Medicine
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