Chronic Fatigue Syndrome
Magnesium is an essential mineral involved in hundreds of enzymatic reactions in humans, and its deficiency may be linked to chronic fatigue (Wicks 1999; Rude 2009). Magnesium deficiency is a common and often underestimated problem (Rosanoff 2012). For example, a nationwide US survey reported that adult women consumed an average of 71% of the US Recommended Daily Allowance (RDA) of 320 mg (Rude 2009).
Some, but not all, studies have reported that supplemental magnesium is helpful for people with CFS or fibromyalgia. One study reported that 20 adults with CFS had significantly lower red blood cell magnesium levels compared to 20 healthy controls. In a follow-up placebo-controlled clinical trial, 15 CFS patients were randomly chosen to receive a weekly 1 g intramuscular injection of magnesium sulfate for six weeks. Members of the treatment group had significantly improved energy levels and less pain, were less emotionally reactive, and perceived significant overall improvement compared to the subjects receiving placebo. Eighty percent of magnesium-treated subjects reported benefit from the treatment versus 18% of controls (Cox 1991). Although not a CFS study, an uncontrolled trial of up to 600 mg magnesium and 2400 mg malic acid daily in 24 fibromyalgia subjects reported significant declines in pain and tenderness (Russell 1995).
The traditional test for magnesium levels (ie, serum magnesium) can be misleading. Serum magnesium levels are considered unreliable, as they only show fairly severe deficiency, which has created confusion in some studies that test serum magnesium and conclude that magnesium status is adequate (Ismail 2010). While the perfect test for magnesium status has not yet been developed, red blood cell magnesium is the preferred method for assessing stores of this important mineral (Witkowski 2011).
B-complex vitamins such as B1 (thiamine), B2 (riboflavin), and B6 (pyridoxine) play a critical role in many energy-producing reactions in the body, while other B vitamins, such as folate and B12 (methylcobalamin), are important for the creation of new cells, repair of damaged ones, and normal function of the central nervous system (Woolf 2006; Reynolds 2006). One study found significantly lower vitamin B1, B2, and B6-related enzyme activities in 12 CFS patients compared with 18 age- and gender-matched controls (Heap 1999). Another study reported that serum folate was abnormally low in 30 of 60 CFS patients (Jacobson 1993). Yet another trial compared placebo to treatment with a daily low potency multivitamin/mineral supplement containing B vitamins in 38 women aged 18-50 years who had CFS. Along with other nutrients, the supplement contained B vitamins in the following amounts: 4.2 mg B1, 4.8 mg B2, 6 mg B6, 54 mg niacin, 600 mcg folate and 3 mcg B12. After two months, the women receiving the supplement had significantly less fatigue, better sleep, and fewer and less intense headaches compared to women receiving placebo (Maric 2014). A multi-nutrient intravenous nutrition formula (ie, “Myer’s cocktail”) that includes B-vitamins, magnesium, and other nutrients has been reported to help CFS patients (Gaby 2002).
Zinc is a mineral involved in immunity, wound healing, protection against oxidative damage, and other essential functions (Tate 1999; Rostan 2002). A study that compared 21 CFS patients to healthy controls found significantly lower blood zinc levels in patients; moreover, lower zinc was positively correlated with markers of inflammation and immune activation (Maes 2006). A study in 10 healthy but sedentary young men reported that daily zinc supplementation at a dosage of 3 mg/kg bodyweight prevented an exercise-related decrease in thyroid hormone and testosterone. The author concluded that this result indicates supplemental zinc may improve performance (Kilic 2007). Another author, reviewing integrative treatments for CFS, wrote that despite a lack of clinical trials of supplemental zinc for CFS, it is a worthwhile candidate for further investigation (Brown 2014).
While a number of studies have reported that supplemental vitamin C can improve immunity, reduce inflammation and oxidation damage, and improve blood vessel health, research examining vitamin C supplementation in CFS is sparse (Qian 2001; Bryer 2006; Werbach 2000). A study of 25 disabled CFS patients reported that intravenous treatment with 15 g of vitamin C corrected, within a matter of minutes, red blood cell abnormalities in 100% of CFS patients compared to only 10% of controls (Werbach 2000).
One study of 221 people with CFS demonstrated average vitamin D blood levels of only 18 ng/mL – significantly lower than healthy controls (Berkovitz 2009) and far below optimal levels of 50–80 ng/mL. It has also been found that, among people with CFS, low vitamin D levels correlate with markers of increased cardiovascular risk, inflammation, and oxidative stress. The authors underscored the complex relationship between vitamin D levels and CFS symptoms; they also highlighted the need to perform additional studies with different methodological approaches to better understand this correlation (Witham 2014). Vitamin D supplementation may benefit those affected by CFS; a small case series reported that fatigue was reduced in four adults with CFS who were treated with 5000-10 000 IU of vitamin D plus minerals and trace elements daily (Hock 2000). Other researchers have proposed that vitamin D may be a useful treatment for CFS by modulating inflammatory pathways thought to be involved in the condition, namely the NF-κB pathway. Vitamin D’s active metabolite, 1,25-dihydroxyvitamin D, represses activation of the NF-κB pathway, which drives inflammation and whose chronic activation has been implicated in CFS symptomatology (Hoeck 2011).
Omega-3 Fatty Acids
Omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are abundant in marine oils such as fish and krill oil, effectively modulate inflammatory pathways in the body (Flock 2013). They are also important for supporting the integrity of cell membranes and can favorably impact blood lipid levels (Riediger 2009; Ginter 2010).
In a study on 63 adults with postviral fatigue syndrome, subjects were treated daily with either a 4 g mixture of evening primrose oil and fish oil or 4 g of sunflower oil (placebo). The total daily dose in the evening primrose/fish oil group was 288 mg of the omega-6 fatty acid gamma-linolenic acid (GLA) from evening primrose oil, 136 mg EPA, 88 mg DHA, and 80 mg vitamin E. At three months, 85% of the evening primrose/fish oil group reported significant improvement compared to only 17% of the placebo group (Behan 1990). An uncontrolled study in four CFS patients found that 12 weeks of daily supplementation with 1116 mg EPA, 348 mg DHA, and 120 mg GLA resulted in symptomatic improvement in all subjects (Puri 2004).
CFS May Respond Best to a Multifaceted Treatment Approach
CFS appears to have many interrelated causes and triggers that affect multiple organs and systems in the body, making multifaceted treatment more likely to produce noticeable and sustainable improvement (Teitelbaum 2001). Several published studies have investigated the effects of multiple nutrient and herbal extract combinations or nutrient/drug combinations.
In a pilot study, 34 adults (average age 50 years) suffering from severe fatigue took a comprehensive, multi-nutrient supplement two or three times daily. Each supplement pack contained a broad range of ingredients including vitamins, minerals, herbal and plant extracts, amino acids, and essential fatty acids. After eight weeks of treatment, fatigue levels fell by 33% (Ellithorpe 2003).
An earlier study of a multiple nutrient and drug intervention protocol in 72 adults with fibromyalgia randomly assigned 38 subjects to receive treatment ; 96% of subjects also met CDC criteria for CFS. The reported average duration of CFS symptoms, before entering the study, was 8.3 years. Chronic fatigue and fibromyalgia symptom outcomes were analyzed using subject interviews and indexes of tender points and disability (Teitelbaum 2001).
The multi-faceted treatment program included:
At the end of the trial, the treatment group had significantly fewer symptoms of fibromyalgia and chronic fatigue and significantly fewer tender lymph nodes than the placebo group; side effects were comparable between the two groups. Ninety-one percent of treated subjects assessed their conditions as “better” or “much better” versus only 36% of placebo subjects (Teitelbaum 2001). Further studies are needed to help identify effective multifaceted treatment regimens for CFS, fibromyalgia, and similar conditions.
Amino acid deficiencies may be linked to CFS. An analysis of 25 CFS subjects demonstrated that levels of the following amino acids were below reference values: tryptophan (80%), phenylalanine (72%), taurine (64%), isoleucine (60%), leucine (52%), arginine (24%), and methionine (20%). In an uncontrolled trial, a 15 g free form amino acid mixture was prescribed based on individual test results. Of the 20 who completed the three-month treatment phase, 15 reported a 50-100% improvement in symptoms, three reported a 25-50% improvement, and two reported no improvement (Bralley 1994).
Cocoa Bean Polyphenols and Flavonoids
Dark chocolate is made from cocoa beans, which contain a wide range of phytochemicals (such as polyphenols and other flavonoids) that have a variety of health benefits, including possibly reducing the risk of cardiovascular disease and cancer. Dark chocolate may have a role in the treatment of CFS. A study treated 10 adults with CFS using 15 g of polyphenol-rich dark chocolate three times daily. After eight weeks of treatment, fatigue, depression, and anxiety scores all declined significantly. Then, following a two-week period of no treatment, participants were given another preparation of 15 g of low-polyphenol, simulated chocolate three times daily. During this time, their condition deteriorated significantly. The simulated chocolate had other differences besides the lower polyphenol content; it contained whole milk powder (active treatment contained none) and almost twice the percentage of sugar and more than twice the percentage of carbohydrate as the active treatment. Chocolate has been shown to increase neurotransmitters (eg, serotonin), and an imbalance of neurotransmitters has been reported in CFS subjects. The researchers hypothesized that by modulating neurotransmitters, polyphenol-rich chocolate reduced symptoms of CFS (Sathyapalan 2010).
Melatonin is a natural hormone produced by the pineal gland in the brain (Arendt 1998; Wu 2005). It regulates the sleep-wake cycle and is an efficient antioxidant (Cipolla-Neto 2014; Romero 2014). An analysis of 14 published studies revealed that melatonin taken shortly before bedtime significantly reduced sleep latency (time to fall asleep) in persons with delayed sleep phase syndrome, or difficulty falling asleep (Buscemi 2005). One promising study gives reason to suspect that melatonin may be helpful for some people with CFS. In an uncontrolled trial in 29 adults with CFS who had chronic fatigue for at least 12 months, subjects were administered 5 mg melatonin daily. After three months of treatment, subject scores on a standardized assessment of fatigue, concentration, and activity all significantly improved. Excessive fatigue was eliminated entirely in eight of the subjects during treatment (Van Heukelom 2006). Individuals with Parkinson’s disease often develop chronic and unremitting fatigue that meets the diagnostic criteria for CFS. In a study on 30 Parkinson’s patients with CFS symptoms, treatment with melatonin led to a significant reduction in fatigue and anxiety scores on standardized assessments as well as improvements in quality of life; sleep quality also improved following melatonin treatment (Datieva 2013).
A number of studies have found that probiotic bacteria such as Lactobacillus and Bifidobacterium may decrease symptoms of CFS. A controlled trial in 29 healthy adults aged 60-81 years reported that daily consumption of 100 g of a fermented milk drink containing live Lactobacillus helveticus for three weeks significantly improved sleep compared to a placebo beverage that contained no probiotics (Yamamura 2009). A study of 15 subjects who met the CDC criteria for CFS reported that treatment with 20 billion colony forming units (CFUs) of Lactobacillus paracasei, Lactobacillus acidophilus,and Bifidobacterium lactis bacteria twice daily for 30 days reduced CFS-related symptoms in 40% of subjects (Sullivan 2009). In a placebo-controlled pilot study of probiotics for CFS, 39 adults were given a probiotic mixture containing eight billion live Lactobacillus casei bacteria three times daily. Treatment significantly reduced anxiety compared to placebo (Rao 2009).
Ribose plays a key role in synthesizing many important compounds such as RNA and DNA (the cell’s genetic material), as well as many compounds involved in energy production (such as CoA, ATP, NADH, and FADH). A pilot study analyzed 36 subjects with CFS and/or fibromyalgia who took 5 g of D-ribose three times daily. After an average of 25 days of treatment, subjects reported experiencing significantly less fatigue and improved overall well-being, better sleep, increased mental clarity, and a decreased pain threshold (Teitelbaum 2006).
Adaptogenic Herbs for Chronic Fatigue
Several medicinal plants, known as adaptogens, have shown a non-specific ability to enhance the body’s overall resistance to mental and physical stress. Although the precise mechanisms are unclear, there is evidence that they may influence the HPA axis and several biochemical pathways involved in the body’s stress response (Panossian 2009).
Adaptogenic herbs are of particular interest in CFS due to their reputation for boosting energy as well as their possible effects on the HPA axis and on supporting healthy immune system function. Some adaptogens considered promising for CFS include:
Additional information on adaptogens can be found in the Stress Management protocol.
Nutrients to Support Mitochondrial Function
The mitochondria are the energy powerhouses of cells; they generate chemical energy in the form of ATP, which is used to fuel cellular reactions throughout the body. Thus, supporting mitochondrial function may be beneficial in conditions involving diminished energy or fatigue, such as CFS (Maassen 2002; McBride 2006; Nicolson 2013).
NADH. NADH is a coenzyme and cellular metabolite related to niacin (vitamin B3) (Jones 1996); it is involved in many energy-producing reactions within the body. In an open-label trial, 20 individuals with CFS were randomized to treatment as follows: 12 subjects received 5 mg of oral NADH daily, escalating to 10 mg if not symptomatic improvements were noted, and eight subjects received other nutritional supplements plus psychotherapy. After three months, the NADH group had a significantly greater reduction in mean CFS symptom score (Santaella 2004). Another study of 26 subjects who met CDC criteria for CFS reported that 31% responded favorably to four weeks of daily supplementation with 10 mg NADH compared to only 8% of subjects given placebo (Forsyth 1999).
Coenzyme Q10 (CoQ10). CoQ10, a nutrient with potent antioxidant properties, is a crucial component in the production of ATP within mitochondria (Maes 2009). CoQ10 is found in meat and synthesized in small quantities in the body, though in healthy individuals it is abundant in the mitochondria (Molyneux 2008). A study of 58 people with CFS reported that up to 45% had blood CoQ10 levels below normal (ie, below 0.49 µg/mL), while none of the 22 healthy controls had blood CoQ10 levels below this level. CFS subjects with very low CoQ10 levels (ie, below 0.39 µg/mL) had significantly more problems with fatigue, concentration, and memory compared to CFS subjects with higher levels (Maes 2009). A randomized, controlled trial in fibromyalgia subjects reported significantly lower levels of fatigue, pain, and tender points in 10 subjects who received 100 mg CoQ10 three times daily for 40 days compared to 10 placebo-treated fibromyalgia subjects (Cordero, Alcocer-Gómez, de Miguel 2013). Other researchers have reported that CoQ10 supplementation reduced production of pro-inflammatory interleukins IL-1β and IL-18 in subjects with fibromyalgia (Cordero, Alcocer-Gómez, Culic 2013).
L-carnitine. L-carnitine is an amino acid derivative that plays two important roles in energy production. First, L-carnitine and its derivatives acetyl-L-carnitine and propionyl-L-carnitine transport fatty acids into the mitochondria where they are oxidized for energy. Second, L-carnitine also upregulates several enzymes involved in energy production (Scioli 2014; Kudoh 2014; Huertas 1992; Mingorance 2011; Mazzio 2003; Kuratsune 1994). Some evidence suggests that L-carnitine may be useful for people with CFS or other conditions characterized by fatigue. Two studies reported significantly lower blood carnitine and acylcarnitine in CFS patients compared to controls (Kuratsune 1994; Plioplys 1995). In the second study, higher blood carnitine levels corresponded to better clinical status. A 2-month study of 30 CFS subjects compared the drug amantadine (Symmetrel), an FDA-approved antiviral medication, with 1 g of L-carnitine three times daily; authors concluded that L-carnitine was better tolerated and produced significantly greater clinical improvement (Plioplys 1997). Another group of researchers treated CFS patients with either 2 g acetyl-L-carnitine, 2 g propionyl-L-carnitine, or 2 g of each (4 g total) daily; there were 30 subjects in each of the three groups. After 24 weeks of treatment, considerable improvements (as measured by the clinical global impression score) were experienced by 59%, 63%, and 37% of subjects in the acetyl-L-carnitine, propionyl-L-carnitine, and combined groups, respectively. In a preliminary open-label study, authors also reported greater improvement in a lower dose group (2 g) than a higher dose group (4 g) indicating increased efficacy for CFS with a 2 g dose. Acetyl-L-carnitine demonstrated a significant effect on mental fatigue and concentration whereas propionyl-L-carnitine showed most improvement in general and physical fatigue (Vermeulen 2004).
Carnitine may also be useful for other conditions that cause prolonged fatigue. A randomized controlled trial compared acetyl-L-carnitine to the drug amantadine for the treatment of chronic fatigue in individuals with multiple sclerosis. Patients who received 1 g acetyl-L-carnitine twice daily for 90 days experienceda significantly greater reduction in fatigue severity than those treated with 100 mg daily of amantadine (Tomassini 2004).
Roburin-rich French Oak Wood Extract
Roburins are constituents of oak wood; they belong to the class of phytochemicals known as ellagitannins (Natella 2014). Roburins have been consumed by humans for centuries in wine and spirits aged in oak barrels. Ellagitannins are a type of polyphenol, which are capable of modulating inflammatory responses within the body (Natella 2014; Piwowarski 2013). A roburin-rich French oak wood extract has been demonstrated to relieve a wide range of CFS symptoms (Belcaro 2014). It is believed to have this impact at least partially as a result of its ability to improve the functioning of ribosomes, a type of cellular machinery responsible for translating genetic information into usable proteins and peptides (Bhavsar 2010; Natella 2014). Thus, ribosomes are indispensable to every body function and organ system, and their dysregulation is implicated in the symptoms of CFS and chronic viral syndromes.
In an open-label trial that evaluated 85 patients with verified CFS, 45 received oak wood extract and 40 served as controls. After a thorough medical evaluation to exclude other causes of fatigue, subjects were followed up for at least six months. Researchers tracked the physical symptoms and mood of the CFS patients as well as measures of oxidative stress. At three and six months, the roburin-rich French oak wood extract group showed a significant decrease in oxidative stress as measured in whole blood, whereas there was no significant change in the control group (Belcaro 2014).
The oak wood-supplemented group experienced marked trends toward reductions in nearly every parameter of CFS symptom scores measured, especially after six months, whereas the control group experienced minimal improvement, or in some cases, worsening of symptoms at three and six months. Oak wood extract was shown to modestly improve sleep; memory or concentration; muscle and joint pain; headaches; and tender lymph nodes. Of the nine secondary symptoms evaluated, the control group experienced little change in symptoms, and in some cases, worsening of symptoms at three and six months, whereas the roburin extract-supplemented group had marked improvement in sensitivity to noise, food, medication, and chemicals; dizziness or lightheadedness; depression; mood swings; weight change; allergy symptoms; and visual symptoms (Belcaro 2014).
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