Chronic Fatigue Syndrome

Chronic Fatigue Syndrome

1 Overview

Summary and Quick Facts

  • Chronic fatigue syndrome (CFS) is a complicated condition characterized by profound fatigue that persists for more than six months. Between one and eight million people in the United States are believed to have CFS.
  • In this protocol you will learn about the complex nature of CFS and several factors that may contribute to its onset. You will also learn about the treatment approach typically taken by conventional physicians and how a more comprehensive, integrative approach may be necessary if CFS relief is to be achieved.
  • Once the diagnosis has been established, an effective treatment strategy must take into consideration the medical, nutritional, physical, psychological and social needs of each patient. Emerging research has led to the development of a number of novel treatment strategies that may benefit those with CFS.

Chronic fatigue syndrome (CFS) is a complicated condition characterized by profound fatigue that persists for more than six months. It is often accompanied by cognitive difficulties, muscle and joint pain, depression, poor sleep quality, or other nonspecific symptoms. Many people with CFS have difficulty working, attending school, exercising, and carrying out daily activities. Sadly, conventional physicians often overlook this condition, and as many as 80% of individuals suffering with CFS may not receive an accurate diagnosis.

However, studies show people with CFS may benefit from such integrative interventions as magnesium, L-carnitine, and roburin-rich French oak wood extract.

Causes and Risk Factors

A specific cause of CFS has not been conclusively demonstrated, but several factors may correlate with CFS incidence:

  • More common in women in early or middle adulthood, and in African, Hispanic, or Native American descent
  • Viruses such as human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV) may play a role in the development of CFS
  • Allergies, excessive inflammation, and mitochondrial dysfunction may also be involved

Diagnosis

  • There is no specific diagnostic test for CFS. A diagnosis of CFS first requires that other potential causes of fatigue be ruled out.
  • Diagnostic guidelines for CFS include chronic, unexplained fatigue for at least six months, which is of new onset, is not the result of ongoing exertion, is not substantially relieved by rest, and hinders occupational, social, or personal activities.
  • In addition, at least four of the following symptoms must be present 50% of the time for at least six months:
    • Unrefreshing sleep
    • Impaired memory or concentration
    • Sore throat
    • Tender lymph nodes in neck or armpit areas
    • Aching or stiff muscles
    • Multi-joint pain
    • Headache of new type, pattern, or severity
    • Post-exercise malaise or illness feeling which lasts more than 24 hours

Conventional Treatment

  • Cognitive behavioral therapy and graded exercise therapy are generally agreed to have the highest level of evidence for success in treating CFS.
  • Stimulant drugs such as methylphenidate (Ritalin, Concerta) or amphetamine/dextroamphetamine (Adderall) have been used to treat CFS.

Novel and Emerging Therapies

  • Drugs with antiviral and/or immunomodulating properties have been shown to improve energy and exercise tolerance.
  • DHEA supplementation in women who had CFS and low DHEA-S levels significantly improved fatigue, pain, memory, and sexual functioning.
  • Immune/stem cell mobilization therapy by granulocyte-colony stimulating factor (G-CSF) has been used successfully for CFS by a pioneering doctor.

Dietary and Lifestyle Considerations

  • Avoid exposure to tobacco smoke, toxic chemicals, and pollutants.
  • Detoxification regimens, such as sauna therapy, may be helpful for CFS.
  • Massage therapy and qigong may help improve fatigue.

Integrative Interventions

  • Magnesium: Magnesium is an essential mineral involved in hundreds of enzymatic reactions in humans. Its deficiency may be linked to chronic fatigue, and supplementation may improve symptoms of CFS.
  • B-vitamins: B vitamin-related enzyme activity has been found to be lower in patients with CFS, and women receiving a daily low potency multivitamin/mineral supplement containing B vitamins had significantly less fatigue, better sleep, and fewer and less intense headaches.
  • Adaptogenic herbs: 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 Rhodiola rosea, Panax ginseng, and ashwagandha.
  • L-carnitine: A study of CFS subjects compared the drug amantadine, an FDA-approved antiviral medication, with L-carnitine; authors concluded L-carnitine was better tolerated and produced significantly greater clinical improvement.
  • Roburin-rich French oak wood extract: In an open-label controlled trial that evaluated patients with CFS, roburin-rich French oak wood extract was demonstrated to relieve a wide range of CFS symptoms.

2 Introduction

Chronic fatigue syndrome (CFS) is a complicated condition characterized by profound fatigue that persists for more than six months. It is often accompanied by cognitive difficulties, muscle and joint pain, depression, poor sleep quality, or other nonspecific symptoms (Cella 2011; Jones 2011; Ciccone 2010). Between one and eight million people in the United States are believed to have CFS (Jason 2013; CDC 2012; Dinos 2009).

There is no clear cause of CFS, though numerous factors may contribute (Cairns 2005), including viral infections (Henderson 2014), nutritional deficiencies (Brown 2014), hormonal imbalance (Van Den Eede 2007; Aschbacher 2012), and immunological disturbances (Brown 2014). Concurrent psychological abnormalities have been observed among individuals with CFS, but the nature of the relationship remains unclear (Wessely 1996; Yoshiuchi 2007; Hickie 1990).

CFS can be a debilitating condition (Cairns 2005). Many people with CFS have difficulty working, attending school, exercising, and carrying out daily activities (Ross 2004; Anderson 1997; Taylor 2010). Sadly, conventional physicians often overlook this condition, and as many as 80% of individuals suffering with CFS may not receive an accurate diagnosis (Ward 1996; Griffith 2008; Nacul 2011). Worse yet, it has been estimated that achieving an accurate diagnosis of CFS may take as long as five years from the onset of symptoms (Brown 2014).

CFS is a multifactorial condition and requires complex management, which must begin with a rigorous clinical evaluation to rule out other possible causes of fatigue (Brown 2014; Teitelbaum 2001). Once the diagnosis has been established, an effective treatment strategy must take into consideration the medical, nutritional, physical, psychological, and social needs of each patient (Griffith 2008; Brown 2014). Unfortunately, the conventional medical establishment often fails to provide this kind of comprehensive care for individuals with CFS.

However, emerging research has led to the development of a number of novel treatment strategies that may benefit those with CFS. For instance, in one study, 15 individuals who met diagnostic criteria for CFS were treated with the antiviral drug valacyclovir (Valtrex) and 93% of them exhibited a positive response, suggesting that viral infection, and possibly post-viral alterations in the host’s immune system, may represent a piece of the CFS puzzle (Henderson 2014; Montoya 2013; Stringer 2013).

In addition, evidence suggests that individuals suffering with CFS may attain some benefit through the use of natural, integrative interventions including magnesium (Cox 1991), NADH (Santaella 2004; Forsyth 1999), L-carnitine (Plioplys 1997), D-ribose (Teitelbaum 2006), B vitamins (Maric 2014), omega-3 fatty acids (Behan 1990), melatonin (Van Heukelom 2006), and probiotics (Sullivan 2009). 

In this protocol you will learn about the complex nature of CFS and several factors that may contribute to its onset. You will also learn about the treatment approach typically taken by conventional physicians and how a more comprehensive, integrative approach may be necessary if CFS relief is to be achieved. You will read about several novel and emerging therapeutic strategies that may ease CFS symptoms, and a number of natural interventions that may benefit those affected by CFS. ​

3 Causes and Risk Factors

No reliable single cause or group of causes has been conclusively demonstrated for CFS. However, several studies have revealed various factors that correlate with CFS incidence.

Demographics

CFS affects all population groups, although it is more common in women. While early studies suggested that CFS mostly affects young, Caucasian, professional women, more recent research reveals it is more common among people of early or middle adulthood, and community studies have reported that it is somewhat more common in people of African, Hispanic, or Native American descent compared to those of European or Asian ancestry (Afari 2003; Dinos 2009).

CFS often occurs concurrently with other conditions that cause similar symptoms. Studies have reported that US Centers for Disease Control and Prevention (CDC) CFS criteria (see Diagnosis section) have been met by 88% of people with multiple chemical sensitivity (Ziem 1999), 20-70% of people with fibromyalgia (Afari 2003), and 15.7% of veterans in the US VA Gulf War Registry (Kipen 1999). Given the similarities between CFS and fibromyalgia, and their high degree of concurrence, studies on fibromyalgia are often viewed as potentially relevant to CFS, and integrative practitioners frequently apply similar approaches to the two conditions.

Viral Infections

Viral infection may cause prolonged fatigue during active infection, and some studies suggest that viruses such as human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) may play a role in the development of CFS (Morelli 2011; Bansal 2012; Klimas 2007; Montoya 2013). However, the exact mechanisms by which viral infection may trigger CFS are poorly understood. Some scientists have suggested that post-viral alterations in the host’s immune system may underlie CFS, but this theory is debated (Moss-Morris 2013; Hickie 2006). Chronic viral infections may alter white blood cell activity (such as triggering abnormalities in T cell function and decreasing activity of natural killer cells) and damage mitochondrial function (Klimas 2007; Bansal 2012).

Allergies and Food Sensitivities

Some evidence suggests that allergies may play a role in CFS (Bellanti 2005; Straus 1988); however, understanding the link between the two is complicated by the fact that not all CFS patients have allergies (Jones 2011). Similar to viral infections, it has been proposed that allergies may trigger immune abnormalities that lead to CFS (UMMC 2013). One study found that drug allergies were more frequently reported by people with CFS than healthy controls (Ferré Ybarz 2005). Additionally, certain measures of allergic reactions (ie, eosinophil activation) were increased in patients with CFS (Conti 1996).

Food sensitivities have also been considered as a potential cause or cofactor in CFS (Lind 2013; Trabal 2012; Berstad 2012). In one study, it was reported that 54% of a sample of CFS patients tried dietary modifications; of those, 73% reported reduced fatigue (Logan 2001). In an Australian study, 90% of CFS patients who eliminated wheat, milk, benzoates, nitrites, nitrates, and food colorings reported that the severity of their symptoms improved (Logan 2001; Emms 2001).

Inflammation

Many individuals with CFS show signs of excessive inflammation and increased levels of the pro-inflammatory factors interleukin-1, leptin, and tumor necrosis factor-alpha (TNF-α) (Bansal 2012; Maes 2012; Stringer 2013). A 2014 brain imaging study found that individuals with CFS had significantly more neuroinflammation in many areas of the brain compared to healthy controls (Nakatomi 2014). Evidence from an animal model suggests that induction of an activated, pro-inflammatory state in the resident immune cells of the central nervous system, microglial cells, may be involved in the heightened pain sensitivity observed in CFS (Yasui 2014). Animal models also demonstrated that fatigue arises when a stimulus induces activation of microglial cells and/or there is an increase in inflammatory chemicals within the brain (Harrington 2012).

Mitochondrial Dysfunction

Mitochondria are organelles within cells that are responsible for most of the cell’s supply of energy in the form of a chemical called adenosine triphosphate (ATP), which is used throughout the body (Myhill 2009). Research suggests dysfunction of mitochondria and mitochondrial enzymes may be associated with chronic fatigue and fibromyalgia. The proinflammatory cellular milieu seen in many individuals with CFS can impair mitochondrial functions and may reduce production of ATP in cells. An electron microscopy study of muscle biopsies from 50 CFS subjects reported that 80% had mitochondrial degeneration (Behan 1991).

Orthostatic Hypotension

Orthostatic hypotension is a syndrome comprised of low blood pressure, weakness, or faintness after moving from a lying or sitting position to a standing position (Lanier 2011). One study reported that 96% of subjects with CFS experienced orthostatic hypotension. Many of these subjects were on low-salt diets. Following treatment with a balanced diet and adequate amounts of liquid and salt, chronic fatigue was completely resolved in 39% of subjects. Some of these patients were also treated with the corticosteroid fludrocortisone (Florinef) to help increase blood pressure (Bou-Holaigah 1995). Studies in Australia and the UK, respectively, reported that 11% and 13% of those who met the CDC or Canadian CFS diagnostic criteria also met criteria for postural orthostatic hypotension (Reynolds 2014; Lewis 2013). Some researchers have suggested that measuring blood pressure at various postures may be a useful diagnostic tool for CFS (Frith 2012).​

4 Diagnosis

There is no specific diagnostic test for CFS, and it may be difficult to distinguish CFS from fatigue secondary to other health conditions. A diagnosis of CFS requires that other potential causes of fatigue be ruled out. Examples of such causes include:

  • obstructive sleep apnea (Norman 2008; Lieberman 2009)
  • depression (Skapinakis 2004)
  • hypothyroidism (Yancey 2012)
  • toxin exposures (Ziem 1999; Curtis 2004)
  • autoimmune diseases such as lupus or multiple sclerosis (Yancey 2012)
  • cancer (Yancey 2012)
  • traumatic brain injury (Mott 2012)
  • heart failure (King 2012)
  • anemia (Guralnik 2005; Jones 2011)
  • irritable bowel syndrome (Frissora 2005)
  • diabetes (Yancey 2012)
  • chronic or sub-acute infection (Jones 2011)
  • ongoing adverse reactions to medications (Jones 2011)

There are several diagnostic guidelines for CFS. A commonly used definition for CFS was developed at the US Centers for Disease Control and Prevention (CDC). These criteria include subjects who have experienced chronic, unexplained fatigue for at least six months, which is of new onset (ie, not a lifelong problem), is not the result of ongoing exertion, is not substantially relieved by rest, and hinders occupational, social, or personal activities. In addition, at least four of the following symptoms must be present 50% of the time for at least six months (Fukuda 1994; Jones 2011; Ferri 2014):

1) Unrefreshing sleep

5) Aching or stiff muscles

2) Impaired memory or concentration

6) Multi-joint pain

3) Sore throat

7) Headache of new type, pattern, or severity

4) Tender lymph nodes in neck or armpit areas

8) Post-exercise malaise or illness feeling which lasts more than 24 hours

Although there is no single diagnostic test for CFS, the following tests are used to help rule out other common causes of fatigue (Yancey 2012; Ferri 2014; Sawchuck 2013; Jones 2011):

  • basic blood chemistries and complete blood count (to check for anemia and other conditions)
  • thyroid hormone levels (to check for hypothyroidism)
  • blood sugar levels (to check for diabetes)
  • urinalysis (to check for kidney disease)
  • serum vitamin B12; serum and urinary methylmalonic acid (to check for vitamin B12 deficiency and insufficiency)

CFS is considered by some researchers to be the result of a chronic infection; however, testing for EBV, HHV-6, and Borrelia burgdorferi, which causes Lyme disease, are not routinely recommended. These tests can be considered on a case-by-case basis, depending on the patient's clinical presentation and history (Eymard 1993; Jones 2011). Other infections may be mistaken for CFS, so tests for tuberculosis; hepatitis A, B, and C; and HIV/AIDS should also be considered. Testing blood levels of 25-hydroxyvitamin D may be helpful as well, since vitamin D deficiency symptoms (ie, weakness, muscle pain) may sometimes overlap with CFS symptoms (Kennel 2010; Jones 2011). Psychological conditions, such as depression and substance abuse, should be ruled out as well (Jones 2011; Eymard 1993).

Sleep studies have been suggested for all CFS patients with symptoms suggestive of sleep disorders, as chronic sleep problems such as sleep apnea or insomnia can cause fatigue and be mistaken for CFS (Buchwald 1994; Neu 2014; Mariman 2013). A comprehensive discussion of several sleep disorders and methods of treating them is available in the Insomnia protocol.

Some researchers have suggested that sex hormone imbalances may contribute to CFS, especially in women, although the evidence is inconsistent (Harlow 1998; Boneva 2011). A full evaluation of hormonal status may be useful in understanding individual cases of CFS, with blood tests measuring levels of hormones such as DHEA-S, pregnenolone, estrogen, and testosterone. If levels are low, bioidentical hormone replacement may be a useful treatment or adjunct therapy. For more specific information on bioidentical hormone replacement and hormone testing, see the Female Hormone Restoration and Male Hormone Restoration protocols.​

5 Conventional Treatment

Cognitive Behavioral Therapy and Graded Exercise

Cognitive behavioral therapy and graded exercise therapy are generally agreed to have the highest level of evidence for success in treating CFS (Jones 2011; Moss-Morris 2013). Cognitive behavioral therapy involves systematically adjusting behavior and may encompass improved exercise, dietary, and sleep habits; relaxation; and getting support from others (Cox 2004). Graded exercise therapy involves initiating a low-intensity exercise program and slowly increasing the intensity over time (CDC 2013). Adaptive pacing therapy, which also may be useful in treating CFS, involves carefully controlling the amount of activity and exercise in accordance with tolerance (Cox 2004).

Although exercise can be quite helpful for individuals with CFS, exercise regimens must begin at a low level (such as walking a few blocks or bicycling a few miles) and gradually build up to longer and more intense exercise. Many people with CFS may experience worsened fatigue if they initially try to exercise or work at intensive levels without gradually building up stamina over time (Nijs 2008). One study randomly assigned 29 CFS subjects to a program of graded aerobic exercise and 30 CFS subjects to flexibility and relaxation exercises. The exercise group started with 5-15 minutes of slow walking with gradual increases in speed and duration; light swimming or bicycling were encouraged as alternative options to walking. The other group performed flexibility and relaxation exercises for 10 minutes a day, gradually increasing to 30 minutes. After 12 weeks of treatment, improvement occurred in both groups, though twice as many subjects in the exercise group (55%) rated themselves as “very much” or “much” better compared to the flexibility group (27%) (Fulcher 1997).

Stimulant Drugs

Stimulant drugs such as methylphenidate (Ritalin, Concerta) or amphetamine/dextroamphetamine (Adderall) have been used to treat CFS. In a randomized controlled trial on 60 CFS subjects, treatment with 10 mg methylphenidate twice daily resulted in significantly less fatigue and better concentration compared to placebo (Blockmans 2006). A study of 10 CFS subjects reported that fatigue was significantly reduced in 90% of subjects treated with 5 or 10 mg of Adderall twice daily for four weeks compared to 40% who improved in the placebo group (Olson 2003). Another study treated CFS subjects who had deficits in cognitive function with either lisdexamfetamine dimesylate (Vyvanse, 30-70 mg daily), an amphetamine stimulant that has been used to treat ADHD in children and adults (Hutson 2014), or placebo. After six weeks of treatment, the Vyvanse-treated subjects had significantly better emotional control and working memory as well as significantly less fatigue and generalized pain compared to subjects who received placebo (Young 2013). A study to evaluate the effects of daily low dose (5-10 mg) methylphenidate coupled with either a multifaceted nutritional supplement (containing vitamins, amino acids, and mitochondrial nutrients such as magnesium, coenzyme Q10 [CoQ10], and L-carnitine) or placebo is underway as of the time of this writing (Montoya 2014).

Stimulant drugs have a number of common adverse side effects including insomnia, loss of appetite, potential heart problems, as well as the potential for addiction and misuse (Chavez 2009; Reddy 2013). There is some evidence that such medications may alter normal brain function, including neurotransmission, and only limited information is available on the long-term effects of stimulant medication (Hyman 1996; Wang 2013; Vitiello 2001; Berman 2009).

Antidepressants

About 33-50% of CFS patients also experience depression (Morelli 2011). Selective serotonin reuptake inhibitor (SSRI) anti-depressant medications (such as fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil], and citalopram [Celexa]) are frequently prescribed to people with CFS. Some published studies have reported that antidepressant medications are of some help, although the topic has been the subject of little rigorous research. A double-blind study on 96 adults with CFS reported that six months of treatment with 20 mg fluoxetine was associated with significantly less depression but not significantly less fatigue compared with placebo (Wearden 1998). A small study of 16 CFS subjects reported that 10-20 mg of citalopram daily was associated with significantly less fatigue and depression after 12 weeks (Amsterdam 2008). ​

6 Novel and Emerging Therapies

Rintatolimod

Rintatolimod (Ampligen) is a drug with antiviral and immunomodulating properties. In a double-blind study, 234 subjects with severe CFS were treated with either 400 mg rintatolimod or placebo twice weekly. After 40 weeks of treatment, the rintatolimod-treated subjects had significantly higher exercise tolerance compared to subjects given placebo (Strayer 2012). An earlier study with 92 CFS subjects reported that after 24 weeks of rintatolimod treatment, subjects showed improved cognitive and physical performance, better functioning, and decreased symptoms compared to placebo (Strayer 1994). However, the US Food and Drug Administration (FDA) has stated that the data provided by these two trials was insufficient to allow approval of rintatolimod to go to market. More studies on the safety and efficacy of rintatolimod are needed (FDA 2013).

Valacyclovir

Valacyclovir (Valtrex) is an oral antiviral drug used to treat herpes virus infections. In one study, 27 CFS patients were treated with valacyclovir four times daily or placebo. After six months, the treatment group was judged to be more active, based on an estimate of energy expended in one day, compared to the placebo group (Lerner 2007). In another study, 15 children aged 8-18 years with treatment-resistant depression who met the CDC definition for CFS were treated with valacyclovir. After an average of over two years of treatment with 500-1000 mg twice daily, subjects experienced significant improvements in fatigue and vigor and markedly increased natural killer cell counts in their blood. Fourteen of fifteen study participants experienced a positive response after eight months of treatment. The author concluded “The study’s data support an intriguing hypothesis that a portion of treatment-resistant depression may in fact be undiagnosed CFS or other chronic viral infection” (Henderson 2014).

Valganciclovir

Valganciclovir (Valcyte), another oral antiviral medication, was the subject of an uncontrolled study in 61 CFS patients. Roughly half the subjects reported substantial improvement in physical and mental functioning, and their response was independent of initial viral infection severity tests (titers). Longer treatment yielded better results in this population (Watt 2012). A randomized controlled trial of valganciclovir treatment for six months was conducted in 30 CFS patients with elevated immunoglobulin G antibody titers against HHV-6 and EBV. Treatment produced significant improvements in mental fatigue, fatigue severity, and cognitive function. The improvement was noted within three months and was still present after an additional nine months (Montoya 2013).

Biofeedback

Brain-centered therapies such as biofeedback may be helpful for individuals with fibromyalgia and CFS (James 1996; Babu 2007; Boyer 2014). Biofeedback is a system in which several physiological parameters (such as brain waves and heart rate) are monitored with electrodes and computers while the patient receives visual and auditory feedback. The goal of biofeedback is to help the patient consciously control, at least to some degree, autonomous physiological functions. A case report of a CFS patient treated with an electroencephalography (EEG)-based biofeedback regimen indicated significant improvements in cognitive ability, functional skill level, and quality of life (James 1996). As mentioned earlier, 20-70% of people with fibromyalgia meet US CDC criteria for CFS, which makes the following study of interest regarding biofeedback therapy for CFS: six days of biofeedback training in a group of 15 fibromyalgia subjects was associated with significant reductions in tender points compared with 15 fibromyalgia subjects given a placebo treatment that imitated biofeedback but without therapeutic value (Babu 2007).  

Repetitive Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive treatment that involves passing an electromagnetic field through parts of the brain to modulate neural circuitry. rTMS has been successfully used for several conditions, including treatment-resistant depression, schizophrenia, and recovery in stroke patients (Hovington 2013; Hsu 2012). rTMS may also be helpful for those with fibromyalgia and CFS. One study compared rTMS treatment in 20 fibromyalgia patients to sham rTMS treatment (placebo). After 14 rTMS treatments, fatigue, pain, and stiffness were significantly reduced, and sleep significantly improved in the treatment but not the placebo group (Mhalla 2011). Although more studies are needed to evaluate the efficacy of rTMS in CFS, some researchers suggest this modality may be useful in conditions involving “unexplained” pain, such as CFS, as it may alter central pain processing (Nijs 2011).

Hormone Replacement Therapy

Deficiencies of testosterone and estrogen are common in aging adults, and low levels of these hormones are associated with fatigue (Stanworth 2008; Thornton 2013; Moller 2013; Schwartz 2011). In addition, dehydroepiandrosterone (DHEA) levels have been found to be significantly lower in individuals with CFS compared to healthy controls (Scott 1999; Kuratsune 1998).  

DHEA, a hormone produced mostly by the adrenal glands, declines with age to as little as 10-20% of the amount of a 30-year old by the 8th decade of life (Racchi 2003; Himmel 1999; Maggio 2013). DHEA is a precursor to several other hormones including testosterone and estrogens (Himmel 1999). DHEA has important antiviral, pro-immunity, and insulin-regulating effects (Torres 2012; Chang 2005; Mauriege 2003; Weiss 2011; Sawalha 2008; Himmel 1999). A study of 23 women who had CFS and levels of DHEA-S below 2 mcg/mL reported that six months of supplementation with 25 mg of oral DHEA daily was associated with significant improvements in fatigue, pain, memory, and concentration (Himmel 1999). A study that interviewed individuals with unexplained chronic fatigue reported that 11 of 17 subjects who self-treated with DHEA supplementation experienced positive results (Bentler 2005).

There is some evidence that CFS may be accompanied or partially caused by a dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis (Papadopoulos 2012). HPA axis hormone regulation abnormalities often seen in CFS include modest but clinically meaningful reductions in cortisol levels; changes in 24-hour cortisol patterns; and inadequate cortisol response to stimuli that should provoke cortisol release, known as enhanced negative feedback (Nijhof 2014; Papadopoulos 2012).

More information about the benefits of hormone replacement can be found in the Male Hormone Restoration and Female Hormone Restoration protocols, and a comprehensive discussion of strategies to manage stress and help balance the HPA axis is available in the Stress Management protocol.

Immune/Stem Cell Mobilization Therapy

There is an FDA-approved drug called granulocyte colony stimulating factor given to certain cancer patients that helps protect their immune system against the toxic effects of chemotherapy (NCI 2013).

Granulocyte colony stimulating factor induces the bone marrow to produce and release huge numbers of stem cells and immune cells into the circulation (Xu 2000; Ozguner 2014; Maharaj 1995).

A pioneering doctor wondered what would happen if granulocyte colony stimulating factorwere given to patients who suffered from diseases other than cancer. His hypothesis was that the mobilization of stem cells from one’s own bone marrow might have a systemic regenerative effect.

A before and after SPECT scan of the brain of a chronic fatigue syndrome patient showed remarkable restoration of cerebral blood flow and metabolic activity, along with marked clinical and symptomatic improvement.  

Below is a case history report of this chronic fatigue syndrome patient successfully treated with granulocyte colony stimulating factor:

The patient, identified as patient LS, began experiencing total body pain in 2010 and later received a diagnosis of fibromyalgia. In early 2013, she was diagnosed with heavy metal toxicity, gut dysbiosis, severe micronutrient deficiencies, food sensitivities, hormone imbalance, immune dysfunction, H. pylori infection, and chronic fatigue syndrome.

After undergoing extensive treatment (eg, opioid pain medication, IV nutrient therapy, hormone replacement therapy, etc.), patient LS continued to experience chronic pain in her head, neck, arms, and legs.

On 7/29/2013, patient LS began undergoing six weeks of treatment with a “stem cell mobilization protocol” in conjunction with an anti-inflammatory diet, stress management techniques, and nutritional supplementation.

Just two weeks after completing her treatment, patient LS noted relief of her total body and neck/back pain. She was able to significantly decrease her pain medication dosage and reported improved cognition.

A single-photon emission computed tomography (SPECT) scan of patient LS’s brain on 7/18/2013, before treatment, revealed reduced blood flow to parts of the brain or an ongoing neuroinflammatory process. The follow up SPECT scan on 9/12/2013, after treatment, revealed a significant improvement in blood flow to parts of the brain (BMSCTI 2014).

This doctor has now treated about 100 patients with various disorders including Parkinson’s, diabetes, and chronic fatigue syndrome. Clinical improvements in these diseased patients have ranged from good to astounding. Not only was their primary disorder responding to granulocyte colony stimulating factor, but they are reporting alleviation or elimination of other age-associated debilities like chronic pain, cognitive impairment and frailty (BMSCTI 2014).

These were not mere placebo effects, as clinical measurements of blood pressure, inflammation, gait, body composition, and cerebral perfusion markedly improved. Blood levels of glucose and lipids fell while HDL levels rose.

These are all indications of systemic age-reversal occurring in response to the mobilization and release of stem cells and healthy immune cells from the bone marrow of these patients.

A downside to this treatment is that drug expenses are quite high and not covered by most health insurance programs. To inquire about this program, contact the South Florida Bone Marrow/Stem Cell Transplant Institute at 561-752-5522. Their website is www.bmscti.org

7 Dietary and Lifestyle Considerations

Avoid Smoking and Chemical Exposures

People with CFS should avoid, as much as possible, exposure to tobacco smoke, toxic chemicals, and pollutants. Smoke contains many toxicants, including carbon monoxide and nicotine, which can cause fatigue, damage the nervous system, and increase risk of chronic pain (Balzan 1996; Shi 2010; Kirkpatrick 1987; Zvolensky 2009; Jay 2000). Exposure to cigarette smoke, even secondhand, is pro-inflammatory and suppresses or disorders immune response (Lugade 2014; Lee, Taneja 2012; Orosz 2007). In a large study of 984 fibromyalgia subjects of which 145 (14.7%) were tobacco users, the tobacco-using subgroup had significantly greater pain, joint stiffness, anxiety, depression, and fatigue compared to nonusers (Weingarten 2009).

Exposure to toxic compounds (including mercury, lead, petrochemical solvents, pesticides, and molds) has been linked to CFS-like symptoms (Brown 2014; Curtis 2004; Nacul 2009). Many people with chemical sensitivity also have severe chronic fatigue (Ziem 1999; Katerndahl 2012). Several studies have reported that a variety of generalized and multiple organ system symptoms have resolved in chemically sensitive subjects who reduce or eliminate toxicant exposure (Hillert 2013; Brown 2007; Yun 2013; Katerndahl 2012).

Heavy indoor exposure to molds has been linked to asthma, sinus problems, chronic fatigue, and significantly reduced levels of hormones essential for energy production such as growth hormone and thyroid hormones (Curtis 2004; Dennis 2009). In a study on 79 subjects with chronic fatigue, chronic sinusitis, and a history of mold exposure, 51% were deficient in growth hormone and 81% were deficient in the thyroid hormones T4 and/or T3. The subjects were then placed on a multifaceted treatment program including: cleanup of subject’s indoor environment to greatly reduce mold and moisture conditions that foster mold growth; saline nasal sprays; oral and nasal antibacterial and antifungal drugs; hormone replacement treatment with growth hormone, thyroid hormone, and other hormones as needed; and a broad range of nutritional supplements including vitamins, minerals, herbs, CoQ10 and L-carnitine. Following this treatment, sinusitis resolved in 93% of participants who achieved a normal indoor mold count; and fatigue improved in all 37 participants who received growth hormone and cortisol and/or thyroid hormone replacement based on a diagnosed deficiency in these hormones (Dennis 2009).

If possible, those with CFS should also live and work in well-ventilated buildings. Indoor levels of pollutants such as solvents, pesticides, and dust are generally higher in buildings that do not receive enough outdoor air ventilation, or in which the external air intake is improperly filtered or positioned. In a large study of 4106 office workers, symptoms of fatigue or difficulty concentrating were 38% less common in well-ventilated buildings (ie, ventilated with 100% outdoor air) compared to less well-ventilated buildings (Mendell 2008). Using an air purifier may also be advisable (Yun 2013).

Detoxification Regimens

Nutritional detoxification regimens may also be helpful for CFS. In a group of 111 patients with metal hypersensitivity and symptoms resembling CFS, removing mercury-containing dental amalgams was associated with major long-term health improvements in 76% of subjects (Stejskal 1999). A case series reported that treatment with oral vitamin C (ascorbate) and choline was associated with significant reduction in both fatigue and blood levels of organochlorine pesticides in four CFS subjects (Richardson 2000; Erkekoglu 2010; Mehedint 2013; Corbin 2012). Another case series of women with CFS reported that 35 days of once-daily thermal therapy (15 minutes of far-infrared dry sauna followed by 30 minutes resting in a very warm room) was associated with improvements in sleep, energy level, and concentration, as well as a reduction in depression (Masuda 2005). Sauna use may support detoxification, has sleep enhancing effects, and relieves muscular spasms related to muscle contraction and pain (Cecchini 2007; Crinnion 2007; Masuda 2005).

A review of detoxification strategies is available in the Metabolic Detoxification protocol.

Massage and Qigong

Alternative therapies such as massage and Qigong are often used by CFS patients. Qigong is a specialized form of gentle exercise that harmonizes breathing, posture, body movements, and mind in order to prevent and heal disease and improve quality of life (Dorcas 2003; Sun 2008; Alraek 2011). A small study of 20 CFS subjects reported that undergoing massage therapy twice weekly for five weeks was associated with significant reductions in pain and fatigue compared to placebo (which involved sham transcutaneous electrical nerve stimulation). Another study of 31 CFS cases reported that practicing Qigong and meditation for two hours weekly for 12 weeks was associated with significantly less fatigue and significantly greater work capacity compared with cases given no treatment (Alraek 2011).

Candida Treatment

Candida albicans (a yeast) is a common resident of the healthy human intestinal tract. However, overgrowth of Candida may cause health problems, including CFS-like symptoms, and may be involved in CFS in some individuals (Evengård 2007). One author reported on the treatment of 1100 CFS subjects with the oral anti-fungal drug ketoconazole (Nizoral) and a special diet that eliminated refined sugar, fruit juice, and alcohol. A favorable response was noted in 84% of CFS subjects after 3-12 months of treatment. Before treatment, 685 of these subjects were on disability, and after treatment, only 12 subjects were on disability (Cater 1995).

More information on fungal infections and Candida is available in the Fungal Infections (Candida) protocol.​

8 Integrative Interventions

Magnesium

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-Vitamins

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

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).

Vitamin C

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).

Vitamin D

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:

  1. Nutritional supplements. The treatment group received a daily multivitamin and mineral supplement; a magnesium and malic acid supplement; valerian; and 3-10 mg of melatonin at bedtime to improve sleep. Twenty-four subjects received additional iron and 30 received additional vitamin B12.
  2. Thyroid hormone replacement. Patients were treated with thyroid medication (18 with levothyroxine [Synthroid] and 15 with natural porcine thyroid [Armour]) if needed.
  3. Adrenal hormone replacement. Adrenal function was tested and subjects received treatment with oral hydrocortisone (Cortef) if needed (29 people).
  4. Fibromyalgia and depression treatment. To improve sleep, 29 subjects received anti-depressant drugs including sertraline, paroxetine, nefazodone (Serzone), and fluoxetine. In addition, the muscle relaxant cyclobenzaprine (Flexeril) was prescribed to 10 subjects with neuromuscular symptoms.
  5. Treatment of candida overgrowth. Thirty-five subjects were treated with nystatin and 27 with itraconazole (Sporanox).
  6. Steroid hormone replacement. Patients were tested for hormone levels and supplemented if indicated. Hormone replacement included DHEA (24 people), oxytocin (Pitocin) (15 people), testosterone (eg, Depo-Testosterone) (12 people), progesterone (eg, Prometrium) (9 patients), estradiol (Estrace) (7 people), and a mix of estrone, estradiol, and estriol (Tri-estrogen) (6 people).

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 Acids

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

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).

Probiotics

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

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:

  • Ginseng — Panax ginseng, a perennial herb native to Asia, is one of the most studied of all botanical medicines (Kiefer 2003; Kim, Son 2013; Jo 2011). It is reputed to have adaptogenic and fatigue-relieving qualities (Lee, Yoo 2012; Wang 2010). In a 2013 randomized controlled trial comparing a 1g or 2g daily dose of ginseng extract to placebo in a group of individuals with unexplained chronic fatigue, the 2g dose resulted in significantly less fatigue, better mental function, and less oxidative stress (Kim, Cho 2013).
  • RhodiolaRhodiola rosea is a small biennial herb that grows in cool climates around the world. It is one of the most promising adaptogenic herbs and in the past decade has rapidly grown in reputation. Rhodiola has been studied for its effect in non-CFS physical and mental fatigue, though with unclear results (Ishaque 2012). It has been suggested that rhodiolaextract may help improve cognitive function and attention in those with CFS (Panossian 2009; Lee 2009).
  • Ashwagandha — Withania somnifera has a long history of use in traditional Indian medicine (Ayurveda) as a “rejuvenator” and has come to be considered a useful and powerful adaptogen (Singh 2011). It has been studied for conditions affecting the central nervous system, including stress, drug addiction, and neurodegenerative diseases such as Parkinson’s and Alzheimer’s (Kulkarni 2008).

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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