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Chronic FatigueChronic fatigue syndrome (CFS) is a complicated condition characterized by profound fatigue that persists for more than sixmonths. It is often accompanied by cognitive difficulties, muscle and joint pain, depression, poor sleep quality, or othernonspecific symptoms (Cella 2011; Jones 2011; Ciccone 2010). Between one and eight million people in the United Statesare 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 (Henderson2014), nutritional deficiencies (Brown 2014), hormonal imbalance (Van Den Eede 2007; Aschbacher 2012), andimmunological disturbances (Brown 2014). Concurrent psychological abnormalities have been observed among individualswith 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 oftenoverlook this condition, and as many as 80% of individuals suffering with CFS may not receive an accurate diagnosis (Ward1996; Griffith 2008; Nacul 2011). Worse yet, it has been estimated that achieving an accurate diagnosis of CFS may take aslong 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 torule out other possible causes of fatigue (Brown 2014; Teitelbaum 2001). Once the diagnosis has been established, aneffective treatment strategy must take into consideration the medical, nutritional, physical, psychological, and social needs ofeach patient (Griffith 2008; Brown 2014). Unfortunately, the conventional medical establishment often fails to provide thiskind 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 thosewith CFS. For instance, in one study, 15 individuals who met diagnostic criteria for CFS were treated with the antiviral drugvalacyclovir (Valtrex) and 93% of them exhibited a positive response, suggesting that viral infection, and possibly post-viralalterations in the hosts 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 (Plioplys1997), D-ribose (Teitelbaum 2006), B vitamins (Maric 2014), omega-3 fatty acids (Behan 1990), melatonin (Van Heukelom2006), 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 willalso 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 emergingtherapeutic strategies that may ease CFS symptoms, and a number of natural interventions that may benefit those affectedby CFS.

Causes and Risk FactorsNo reliable single cause or group of causes has been conclusively demonstrated for CFS. However, several studies haverevealed 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 mostlyaffects young, Caucasian, professional women, more recent research reveals it is more common among people of early ormiddle 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 Centersfor Disease Control and Prevention (CDC) CFS criteria (see Diagnosis section) have been met by 88% of people withmultiple chemical sensitivity (Ziem 1999), 20-70% of people with fibromyalgia (Afari 2003), and 15.7% of veterans in theUS VA Gulf War Registry (Kipen 1999). Given the similarities between CFS and fibromyalgia, and their high degree ofconcurrence, studies on fibromyalgia are often viewed as potentially relevant to CFS, and integrative practitioners frequentlyapply 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 humanherpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) may play a role in the development of CFS (Morelli 2011; Bansal2012; Klimas 2007; Montoya 2013). However, the exact mechanisms by which viral infection may trigger CFS are poorlyunderstood. Some scientists have suggested that post-viral alterations in the hosts immune system may underlie CFS, butthis theory is debated (Moss-Morris 2013; Hickie 2006). Chronic viral infections may alter white blood cell activity (such astriggering abnormalities in T cell function and decreasing activity of natural killer cells) and damage mitochondrial function(Klimas 2007; Bansal 2012).

Allergies and Food SensitivitiesSome evidence suggests that allergies may play a role in CFS (Bellanti 2005; Straus 1988); however, understanding the linkbetween the two is complicated by the fact that not all CFS patients have allergies (Jones 2011). Similar to viral infections, ithas been proposed that allergies may trigger immune abnormalities that lead to CFS (UMMC 2013). One study found thatdrug allergies were more frequently reported by people with CFS than healthy controls (Ferr 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% reportedreduced 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 factorsinterleukin-1, leptin, and tumor necrosis factor-alpha (TNF-) (Bansal 2012; Maes 2012; Stringer 2013). A 2014 brainimaging study found that individuals with CFS had significantly more neuroinflammation in many areas of the braincompared 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 theheightened pain sensitivity observed in CFS (Yasui 2014). Animal models also demonstrated that fatigue arises when astimulus 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 cells supply of energy in the form of a chemicalcalled adenosine triphosphate (ATP), which is used throughout the body (Myhill 2009). Research suggests dysfunction ofmitochondria and mitochondrial enzymes may be associated with chronic fatigue and fibromyalgia. The proinflammatorycellular milieu seen in many individuals with CFS can impair mitochondrial functions and may reduce production of ATP incells. An electron microscopy study of muscle biopsies from 50 CFS subjects reported that 80% had mitochondrialdegeneration (Behan 1991).

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

Diagnosis

There is no specific diagnostic test for CFS, and it may be difficult to distinguish CFS from fatigue secondary to other healthconditions. 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 forDisease Control and Prevention (CDC). These criteria include subjects who have experienced chronic, unexplained fatigue forat least six months, which is of new onset (ie, not a lifelong problem), is not the result of ongoing exertion, is notsubstantially relieved by rest, and hinders occupational, social, or personal activities. In addition, at least four of thefollowing 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 muscles2) Impaired memory or concentration 6) Multi-joint pain

3) Sore throat 7) Headache of new type, pattern, orseverity

4) Tender lymph nodes in neck or armpitareas

8) Post-exercise malaise or illness feelingwhich 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 offatigue (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 Borreliaburgdorferi, which causes Lyme disease, are not routinely recommended. These tests can be considered on a case-by-casebasis, depending on the patient's clinical presentation and history (Eymard 1993; Jones 2011). Other infections may bemistaken for CFS, so tests for tuberculosis; hepatitis A, B, and C; and HIV/AIDS should also be considered. Testing bloodlevels 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 andsubstance 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 sleepproblems such as sleep apnea or insomnia can cause fatigue and be mistaken for CFS (Buchwald 1994; Neu 2014; Mariman2013). A comprehensive discussion of several sleep disorders and methods of treating them is available in the Insomniaprotocol.

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

Conventional Treatment

Cognitive Behavioral Therapy and Graded ExerciseCognitive behavioral therapy and graded exercise therapy are generally agreed to have the highest level of evidence forsuccess in treating CFS (Jones 2011; Moss-Morris 2013). Cognitive behavioral therapy involves systematically adjustingbehavior and may encompass improved exercise, dietary, and sleep habits; relaxation; and getting support from others (Cox2004). Graded exercise therapy involves initiating a low-intensity exercise program and slowly increasing the intensity overtime (CDC 2013). Adaptive pacing therapy, which also may be useful in treating CFS, involves carefully controlling theamount 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 walkinga few blocks or bicycling a few miles) and gradually build up to longer and more intense exercise. Many people with CFSmay experience worsened fatigue if they initially try to exercise or work at intensive levels without gradually building upstamina 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 withgradual increases in speed and duration; they light swimming or bicycling. The other group performed flexibility andrelaxation exercises for 10 minutes a day, gradually increasing to 30 minutes. After 12 weeks of treatment, improvementoccurred in both groups, though twice as many subjects in the exercise group (55%) rated themselves as very much ormuch better compared to the flexibility group (27%) (Fulcher 1997).

Stimulant DrugsStimulant drugs such as methylphenidate (Ritalin, Concerta) or amphetamine/dextroamphetamine (Adderall) have been usedto treat CFS. In a randomized controlled trial on 60 CFS subjects, treatment with 10 mg methylphenidate twice dailyresulted in significantly less fatigue and better concentration compared to placebo (Blockmans 2006). A study of 10 CFSsubjects reported that fatigue was significantly reduced in 90% of subjects treated with 5 or 10 mg of Adderall twice dailyfor four weeks compared to 40% who improved in the placebo group (Olson 2003). Another study treated CFS subjectswho had deficits in cognitive function with either lisdexamfetamine dimesylate (Vyvanse, 30-70 mg daily), an amphetaminestimulant 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 lessfatigue and generalized pain compared to subjects who received placebo (Young 2013). A study to evaluate the effects ofdaily 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 isunderway 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 medicationsmay alter normal brain function, including neurotransmission, and only limited information is available on the long-termeffects 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]) arefrequently prescribed to people with CFS. Some published studies have reported that antidepressant medications are ofsome help, although the topic has been the subject of little rigorous research. A double-blind study on 96 adults with CFSreported that six months of treatment with 20 mg fluoxetine was associated with significantly less depression but notsignificantly less fatigue compared with placebo (Wearden 1998). A small study of 16 CFS subjects reported that 10-20 mgof citalopram daily was associated with significantly less fatigue and depression after 12 weeks (Amsterdam 2008).

Novel and Emerging Therapies

Rintatolimod

Rintatolimod (Ampligen) is a drug with antiviral and immunomodulating properties. In a double-blind study, 234 subjectswith severe CFS were treated with either 400 mg rintatolimod or placebo twice weekly. After 40 weeks of treatment, therintatolimod-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 improvedcognitive 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 wasinsufficient to allow approval of rintatolimod to go to market. More studies on the safety and efficacy of rintatolimod areneeded (FDA 2013).

Valacyclovir

Valacyclovir (Valtrex) is an oral antiviral drug used to treat herpes virus infections. In one study, 27 CFS patients weretreated 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, 15children aged 8-18 years with treatment-resistant depression who met the CDC definition for CFS were treated withvalacyclovir. After an average of over two years of treatment with 500-1000 mg twice daily, subjects experienced significantimprovements in fatigue and vigor and markedly increased natural killer cell counts in their blood. Fourteen of fifteen studyparticipants experienced a positive response after eight months of treatment. The author concluded The studys datasupport an intriguing hypothesis that a portion of treatment-resistant depression may in fact be undiagnosed CFS or otherchronic 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 wasindependent of initial viral infection severity tests (titers). Longer treatment yielded better results in this population (Watt2012). A randomized controlled trial of valganciclovir treatment for six months was conducted in 30 CFS patients withelevated immunoglobulin G antibody titers against HHV-6 and EBV. Treatment produced significant improvements in mentalfatigue, fatigue severity, and cognitive function. The improvement was noted within three months and was still present afteran additional nine months (Montoya 2013).

Biofeedback

Brain-centered therapies such as biofeedback may be helpful for individuals with fibromyalgia and CFS (James 1996; Babu2007; 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 ofbiofeedback is to help the patient consciously control, at least to some degree, autonomous physiological functions. A casereport of a CFS patient treated with an electroencephalography (EEG)-based biofeedback regimen indicated significantimprovements in cognitive ability, functional skill level, and quality of life (James 1996). As mentioned earlier, 20-70% ofpeople with fibromyalgia meet US CDC criteria for CFS, which makes the following study of interest regarding biofeedbacktherapy for CFS: six days of biofeedback training in a group of 15 fibromyalgia subjects was associated with significantreductions in tender points compared with 15 fibromyalgia subjects given a placebo treatment that imitated biofeedback butwithout therapeutic value (Babu 2007).

Repetitive Transcranial Magnetic StimulationRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive treatment that involves passing an electromagneticfield 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). rTMSmay also be helpful for those with fibromyalgia and CFS. One study compared rTMS treatment in 20 fibromyalgia patientsto sham rTMS treatment (placebo). After 14 rTMS treatments, fatigue, pain, and stiffness were significantly reduced, andsleep significantly improved in the treatment but not the placebo group (Mhalla 2011). Although more studies are needed toevaluate the efficacy of rTMS in CFS, some researchers suggest this modality may be useful in conditions involvingunexplained 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 withfatigue (Stanworth 2008; Thornton 2013; Moller 2013; Schwartz 2011). In addition, dehydroepiandrosterone (DHEA) levelshave been found to be significantly lower in individuals with CFS compared to healthy controls (Scott 1999; Kuratsune1998).

DHEA, a hormone produced mostly by the adrenal glands, declines with age to as little as 10-20% of the amount of a30-year old by the 8th decade of life (Racchi 2003; Himmel 1999; Maggio 2013). DHEA is a precursor to several otherhormones 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 23women who had CFS and levels of DHEA-S below 2 mcg/mL reported that six months of supplementation with 25 mg oforal 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 withDHEA 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 butclinically meaningful reductions in cortisol levels; changes in 24-hour cortisol patterns; and inadequate cortisol response tostimuli 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 FemaleHormone Restoration protocols, and a comprehensive discussion of strategies to manage stress and help balance the HPAaxis 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 helpsprotect 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 andimmune 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 whosuffered from diseases other than cancer. His hypothesis was that the mobilization of stem cells from ones own bonemarrow 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 cerebralblood 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 colonystimulating factor:

The patient, identified as patient LS, began experiencing total body pain in 2010 and later received a diagnosis offibromyalgia. 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 conjunctionwith 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 LSs 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 on9/12/2013, 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 Parkinsons, diabetes, and chronic fatiguesyndrome. Clinical improvements in these diseased patients have ranged from good to astounding. Not only was theirprimary disorder responding to granulocyte colony stimulating factor, but they are reporting alleviation or elimination ofother 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, andcerebral 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 andhealthy 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. Toinquire about this program, contact the South Florida Bone Marrow/Stem Cell Transplant Institute at 561-752-5522.Their website is www.bmscti.org

Dietary and Lifestyle Considerations

Avoid Smoking and Chemical ExposuresPeople with CFS should avoid, as much as possible, exposure to tobacco smoke, toxic chemicals, and pollutants. Smokecontains many toxicants, including carbon monoxide and nicotine, which can cause fatigue, damage the nervous system, andincrease risk of chronic pain (Balzan 1996; Shi 2010; Kirkpatrick 1987; Zvolensky 2009; Jay 2000). Exposure to cigarettesmoke, even secondhand, is pro-inflammatory and suppresses or disorders immune response (Lugade 2014; Lee, Taneja2012; Orosz 2007). In a large study of 984 fibromyalgia subjects of which 145 (14.7%) were tobacco users, thetobacco-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 toCFS-like symptoms (Brown 2014; Curtis 2004; Nacul 2009). Many people with chemical sensitivity also have severechronic fatigue (Ziem 1999; Katerndahl 2012). Several studies have reported that a variety of generalized and multiple organsystem 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 levelsof hormones essential for energy production such as growth hormone and thyroid hormones (Curtis 2004; Dennis 2009). In astudy on 79 subjects with chronic fatigue, chronic sinusitis, and a history of mold exposure, 51% were deficient in growthhormone and 81% were deficient in the thyroid hormones T4 and/or T3. The subjects were then placed on a multifacetedtreatment program including: cleanup of subjects indoor environment to greatly reduce mold and moisture conditions thatfoster mold growth; saline nasal sprays; oral and nasal antibacterial and antifungal drugs; hormone replacement treatmentwith growth hormone, thyroid hormone, and other hormones as needed; and a broad range of nutritional supplementsincluding vitamins, minerals, herbs, CoQ10 and L-carnitine. Following this treatment, sinusitis resolved in 93% ofparticipants who achieved a normal indoor mold count; and fatigue improved in all 37 participants who received growthhormone 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 assolvents, pesticides, and dust are generally higher in buildings that do not receive enough outdoor air ventilation, or in whichthe external air intake is improperly filtered or positioned. In a large study of 4106 office workers, symptoms of fatigue ordifficulty concentrating were 38% less common in well-ventilated buildings (ie, ventilated with 100% outdoor air) comparedto 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 andsymptoms resembling CFS, removing mercury-containing dental amalgams was associated with major long-term healthimprovements in 76% of subjects (Stejskal 1999). A case series reported that treatment with oral vitamin C (ascorbate) andcholine was associated with significant reduction in both fatigue and blood levels of organochlorine pesticides in four CFSsubjects (Richardson 2000; Erkekoglu 2010; Mehedint 2013; Corbin 2012). Another case series of women with CFSreported that 35 days of once-daily thermal therapy (15 minutes of far-infrared dry sauna followed by 30 minutes resting ina very warm room) was associated with improvements in sleep, energy level, and concentration, as well as a reduction indepression (Masuda 2005). Sauna use may support detoxification, has sleep enhancing effects, and relieves muscular spasmsrelated 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 QigongAlternative therapies such as massage and Qigong are often used by CFS patients. Qigong is a specialized form of gentleexercise that harmonizes breathing, posture, body movements, and mind in order to prevent and heal disease and improvequality of life (Dorcas 2003; Sun 2008; Alraek 2011). A small study of 20 CFS subjects reported that undergoing massagetherapy 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 practicingQigong and meditation for two hours weekly for 12 weeks was associated with significantly less fatigue and significantlygreater work capacity compared with cases given no treatment (Alraek 2011).

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

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

Integrative Interventions

Magnesium

Magnesium is an essential mineral involved in hundreds of enzymatic reactions in humans, and its deficiency may be linkedto 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 USRecommended 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. Onestudy reported that 20 adults with CFS had significantly lower red blood cell magnesium levels compared to 20 healthycontrols. In a follow-up placebo-controlled clinical trial, 15 CFS patients were randomly chosen to receive a weekly 1 gintramuscular injection of magnesium sulfate for six weeks. Members of the treatment group had significantly improvedenergy levels and less pain, were less emotionally reactive, and perceived significant overall improvement compared to thesubjects receiving placebo. Eighty percent of magnesium-treated subjects reported benefit from the treatment versus 18% ofcontrols (Cox 1991). Although not a CFS study, an uncontrolled trial of up to 600 mg magnesium and 2400 mg malic aciddaily 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 consideredunreliable, as they only show fairly severe deficiency, which has created confusion in some studies that test serummagnesium and conclude that magnesium status is adequate (Ismail 2010). While the perfect test for magnesium status hasnot 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 thecreation of new cells, repair of damaged ones, and normal function of the central nervous system (Woolf 2006; Reynolds2006). One study found significantly lower vitamin B1, B2, and B6-related enzyme activities in 12 CFS patients comparedwith 18 age- and gender-matched controls (Heap 1999). Another study reported that serum folate was abnormally low in 30of 60 CFS patients (Jacobson 1993). Yet another trial compared placebo to treatment with a daily low potencymultivitamin/mineral supplement containing B vitamins in 38 women aged 18-50 years who had CFS. Along with othernutrients, the supplement contained B vitamins in the following amounts: 4.2 mg B1, 4.8 mg B2, 6 mg B6, 54 mg niacin, 600mcg folate and 3 mcg B12. After two months, the women receiving the supplement had significantly less fatigue, bettersleep, and fewer and less intense headaches compared to women receiving placebo (Maric 2014). A multi-nutrientintravenous nutrition formula (ie, Myers cocktail) that includes B-vitamins, magnesium, and other nutrients has beenreported 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 zinclevels 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 3mg/kg bodyweight prevented an exercise-related decrease in thyroid hormone and testosterone. The author concluded thatthis result indicates supplemental zinc may improve performance (Kilic 2007). Another author, reviewing integrativetreatments for CFS, wrote that despite a lack of clinical trials of supplemental zinc for CFS, it is a worthwhile candidate forfurther investigation (Brown 2014).

Vitamin CWhile a number of studies have reported that supplemental vitamin C can improve immunity, reduce inflammation andoxidation damage, and improve blood vessel health, research examining vitamin C supplementation in CFS is sparse (Qian2001; Bryer 2006; Werbach 2000). A study of 25 disabled CFS patients reported that intravenous treatment with 15 g ofvitamin 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 thanhealthy controls (Berkovitz 2009) and far below optimal levels of 5080 ng/mL. It has also been found that, among peoplewith 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 theneed to perform additional studies with different methodological approaches to better understand this correlation (Witham2014). Vitamin D supplementation may benefit those affected by CFS; a small case series reported that fatigue was reducedin four adults with CFS who were treated with 5000-10000 IU of vitamin D plus minerals and trace elements daily (Hock2000). Other researchers have proposed that vitamin D may be a useful treatment for CFS by modulating inflammatorypathways thought to be involved in the condition, namely the NF-B pathway. Vitamin Ds active metabolite,1,25-dihydroxyvitamin D, represses activation of the NF-B pathway, which drives inflammation and whose chronicactivation has been implicated in CFS symptomatology (Hoeck 2011).

Omega-3 Fatty AcidsOmega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are abundant in marineoils such as fish and krill oil, effectively modulate inflammatory pathways in the body (Flock 2013). They are alsoimportant for supporting the integrity of cell membranes and can favorably impact blood lipid levels (Riediger 2009; Ginter2010).

In a study on 63 adults with postviral fatigue syndrome, subjects were treated daily with either a 4 g mixture of eveningprimrose oil and fish oil or 4 g of sunflower oil (placebo). The total daily dose in the evening primrose/fish oil group was 288mg of the omega-6 fatty acid gamma-linolenic acid (GLA) from evening primrose oil, 136 mg EPA, 88 mg DHA, and 80 mgvitamin E. At three months, 85% of the evening primrose/fish oil group reported significant improvement compared to only17% of the placebo group (Behan 1990). An uncontrolled study in four CFS patients found that 12 weeks of dailysupplementation 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, makingmultifaceted treatment more likely to produce noticeable and sustainable improvement (Teitelbaum 2001). Several publishedstudies 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-nutrientsupplement 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 fellby 33% (Ellithorpe 2003).

An earlier study of a multiple nutrient and drug intervention protocol in 72 adults with fibromyalgia randomly assigned 38subjects to receive treatment ; 96% of subjects also met CDC criteria for CFS. The reported average duration of CFSsymptoms, before entering the study, was 8.3 years. Chronic fatigue and fibromyalgia symptom outcomes were analyzedusing subject interviews and indexes of tender points and disability (Teitelbaum 2001).

The multi-faceted treatment program included:

Nutritional supplements. The treatment group received a daily multivitamin and mineral supplement; a magnesiumand malic acid supplement; valerian; and 3-10 mg of melatonin at bedtime to improve sleep. Twenty-four subjectsreceived additional iron and 30 received additional vitamin B12.

1.

Thyroid hormone replacement. Patients were treated with thyroid medication (18 with levothyroxine [Synthroid]and 15 with natural porcine thyroid [Armour]) if needed.

2.

Adrenal hormone replacement. Adrenal function was tested and subjects received treatment with oralhydrocortisone (Cortef) if needed (29 people).

3.

Fibromyalgia and depression treatment. To improve sleep, 29 subjects received anti-depressant drugs includingsertraline, paroxetine, nefazodone (Serzone), and fluoxetine. In addition, the muscle relaxant cyclobenzaprine (Flexeril)was prescribed to 10 subjects with neuromuscular symptoms.

4.

Treatment of candida overgrowth. Thirty-five subjects were treated with nystatin and 27 with itraconazole(Sporanox).

5.

Steroid hormone replacement. Patients were tested for hormone levels and supplemented if indicated. Hormonereplacement included DHEA (24 people), oxytocin (Pitocin) (15 people), testosterone (eg, Depo-Testosterone) (12people), progesterone (eg, Prometrium) (9 patients), estradiol (Estrace) (7 people), and a mix of estrone, estradiol, andestriol (Tri-estrogen) (6 people).

6.

At the end of the trial, the treatment group had significantly fewer symptoms of fibromyalgia and chronic fatigue andsignificantly 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 placebosubjects (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 followingamino 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 prescribedbased 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 FlavonoidsDark chocolate is made from cocoa beans, which contain a wide range of phytochemicals (such as polyphenols and otherflavonoids) 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-richdark chocolate three times daily. After eight weeks of treatment, fatigue, depression, and anxiety scores all declinedsignificantly. Then, following a two-week period of no treatment, participants were given another preparation of 15 g oflow-polyphenol, simulated chocolate three times daily. During this time, their condition deteriorated significantly. Thesimulated chocolate had other differences besides the lower polyphenol content; it contained whole milk powder (activetreatment contained none) and almost twice the percentage of sugar and more than twice the percentage of carbohydrate asthe active treatment. Chocolate has been shown to increase neurotransmitters (eg, serotonin), and an imbalance ofneurotransmitters 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 thesleep-wake cycle and is an efficient antioxidant (Cipolla-Neto 2014; Romero 2014). An analysis of 14 published studiesrevealed that melatonin taken shortly before bedtime significantly reduced sleep latency (time to fall asleep) in persons withdelayed sleep phase syndrome, or difficulty falling asleep (Buscemi 2005). One promising study gives reason to suspect thatmelatonin 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 astandardized assessment of fatigue, concentration, and activity all significantly improved. Excessive fatigue was eliminatedentirely in eight of the subjects during treatment (Van Heukelom 2006). Individuals with Parkinsons disease often developchronic and unremitting fatigue that meets the diagnostic criteria for CFS. In a study on 30 Parkinsons patients with CFSsymptoms, treatment with melatonin led to a significant reduction in fatigue and anxiety scores on standardized assessmentsas 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 symptomsof CFS. A controlled trial in 29 healthy adults aged 60-81 years reported that daily consumption of 100 g of a fermentedmilk drink containing live Lactobacillus helveticus for three weeks significantly improved sleep compared to a placebobeverage that contained no probiotics (Yamamura 2009). A study of 15 subjects who met the CDC criteria for CFS reportedthat treatment with 20 billion colony forming units (CFUs) of Lactobacillus paracasei, Lactobacillus acidophilus,andBifidobacterium lactis bacteria twice daily for 30 days reduced CFS-related symptoms in 40% of subjects (Sullivan 2009). Ina placebo-controlled pilot study of probiotics for CFS, 39 adults were given a probiotic mixture containing eight billion liveLactobacillus 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 cells genetic material), aswell as many compounds involved in energy production (such as CoA, ATP, NADH, and FADH). A pilot study analyzed36 subjects with CFS and/or fibromyalgia who took 5 g of D-ribose three times daily. After an average of 25 days oftreatment, subjects reported experiencing significantly less fatigue and improved overall well-being, better sleep, increasedmental 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 bodys overall resistance tomental and physical stress. Although the precise mechanisms are unclear, there is evidence that they may influence the HPAaxis and several biochemical pathways involved in the bodys stress response (Panossian 2009).

Adaptogenic herbs are of particular interest in CFS due to their reputation for boosting energy as well as their possibleeffects on the HPA axis and on supporting healthy immune system function. Some adaptogens considered promising for CFSinclude:

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, Yoo2012; Wang 2010). In a 2013 randomized controlled trial comparing a 1g or 2g daily dose of ginseng extract to placeboin a group of individuals with unexplained chronic fatigue, the 2g dose resulted in significantly less fatigue, bettermental function, and less oxidative stress (Kim, Cho 2013).Rhodiola Rhodiola rosea is a small biennial herb that grows in cool climates around the world. It is one of the mostpromising adaptogenic herbs and in the past decade has rapidly grown in reputation. Rhodiola has been studied for itseffect in non-CFS physical and mental fatigue, though with unclear results (Ishaque 2012). It has been suggested thatrhodiolaextract 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 arejuvenator and has come to be considered a useful and powerful adaptogen (Singh 2011). It has been studied forconditions affecting the central nervous system, including stress, drug addiction, and neurodegenerative diseases suchas Parkinsons and Alzheimers (Kulkarni 2008).

Additional information on adaptogens can be found in the Stress Management protocol.

Nutrients to Support Mitochondrial FunctionThe mitochondria are the energy powerhouses of cells; they generate chemical energy in the form of ATP, which is used tofuel cellular reactions throughout the body. Thus, supporting mitochondrial function may be beneficial in conditionsinvolving 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 manyenergy-producing reactions within the body. In an open-label trial, 20 individuals with CFS were randomized to treatment asfollows: 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 asignificantly greater reduction in mean CFS symptom score (Santaella 2004). Another study of 26 subjects who met CDCcriteria for CFS reported that 31% responded favorably to four weeks of daily supplementation with 10 mg NADHcompared 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 productionof ATP within mitochondria (Maes 2009). CoQ10 is found in meat and synthesized in small quantities in the body, thoughin healthy individuals it is abundant in the mitochondria (Molyneux 2008). A study of 58 people with CFS reported that upto 45% had blood CoQ10 levels below normal (ie, below 0.49 g/mL), while none of the 22 healthy controls had bloodCoQ10 levels below this level. CFS subjects with very low CoQ10 levels (ie, below 0.39 g/mL) had significantly moreproblems 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 subjectswho received 100 mg CoQ10 three times daily for 40 days compared to 10 placebo-treated fibromyalgia subjects (Cordero,Alcocer-Gmez, de Miguel 2013). Other researchers have reported that CoQ10 supplementation reduced production ofpro-inflammatory interleukins IL-1 and IL-18 in subjects with fibromyalgia (Cordero, Alcocer-Gmez, Culic 2013).

L-carnitine. L-carnitine is an amino acid derivative that plays two important roles in energy production. First, L-carnitineand its derivatives acetyl-L-carnitine and propionyl-L-carnitine transport fatty acids into the mitochondria where they areoxidized for energy. Second, L-carnitine also upregulates several enzymes involved in energy production (Scioli 2014; Kudoh2014; Huertas 1992; Mingorance 2011; Mazzio 2003; Kuratsune 1994). Some evidence suggests that L-carnitine may beuseful for people with CFS or other conditions characterized by fatigue. Two studies reported significantly lower bloodcarnitine 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 drugamantadine (Symmetrel), an FDA-approved antiviral medication, with 1 g of L-carnitine three times daily; authors concludedthat L-carnitine was better tolerated and produced significantly greater clinical improvement (Plioplys 1997). Another groupof 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 (asmeasured 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 alsoreported greater improvement in a lower dose group (2 g) than a higher dose group (4 g) indicating increased efficacy for CFSwith 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 comparedacetyl-L-carnitine to the drug amantadine for the treatment of chronic fatigue in individuals with multiple sclerosis. Patientswho received 1 g acetyl-L-carnitine twice daily for 90 days experienceda significantly greater reduction in fatigue severitythan those treated with 100 mg daily of amantadine (Tomassini 2004).

Roburin-rich French Oak Wood ExtractRoburins 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 ofpolyphenol, which are capable of modulating inflammatory responses within the body (Natella 2014; Piwowarski 2013). Aroburin-rich French oak wood extract has been demonstrated to relieve a wide range of CFS symptoms (Belcaro 2014). It isbelieved to have this impact at least partially as a result of its ability to improve the functioning of ribosomes, a type ofcellular machinery responsible for translating genetic information into usable proteins and peptides (Bhavsar 2010; Natella2014). Thus, ribosomes are indispensable to every body function and organ system, and their dysregulation is implicated inthe 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 threeand six months, the roburin-rich French oak wood extract group showed a significant decrease in oxidative stress as measuredin 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 CFSsymptom scores measured, especially after six months, whereas the control group experienced minimal improvement, or insome 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 symptomsevaluated, the control group experienced little change in symptoms, and in some cases, worsening of symptoms at three andsix 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; andvisual symptoms (Belcaro 2014).

Life Extension SuggestionsMagnesium: 500 1500 mg dailyCoenzyme Q10 (CoQ10) (as ubiquinol): 100 200 mg dailyDHEA (Dehydroepiandrosterone): 15 75 mg daily (depending on blood test results)L-Carnitine (as Acetyl L-Carnitine, Acetyl L-Carnitine Arginate and Propionyl L-Carnitine): 2100 mg dailyVitamin B1 (thiamine): 100 mg dailyVitamin B2 (riboflavin): 50 100 mg dailyVitamin B3 (niacin): 500 1000 mg dailyVitamin B6 (pyridoxine): 250 mg dailyFolate (as L-Methylfolate): 1000 mcg dailyVitamin B12 (as methylcobalamin): 1 8 mg daily, sometimes up to 40 mg dailyVitamin D: 5000 8000 IU daily; depending upon blood levels of 25-OH-vitamin DNADH: 5 mg dailyVitamin C: 500-1000 mg dailyZinc: 50 mg dailyProbiotics (including Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus paracasei): 15 billion colonyforming units (CFUs) dailyMelatonin: 0.3 5 mg 30 to 60 minutes before bedtimeRibose: 5100 mg dailyFish Oil (with olive polyphenols and sesame lignans): 1400 mg EPA and 1000 mg DHA dailyGamma-linolenic acid (GLA): 299 1495 mg dailyPanax ginseng: 250 1000 mg daily

Rhodiola rosea: 250 mg dailyAshwagandha extract (std. to 8% withanolide glycoside conjugates [10 mg] and 32% oligosaccharides [40 mg]): 250mg dailyDark Chocolate: 45 g of a polyphenol-rich dark chocolate daily5-HTP (5-Hydroxytryptophan): 50 200 mg dailyFrench oak wood extract: 200 mg daily

In addition, the following blood tests may provide helpful information:

Chronic Fatigue ProfileChemistry Panel & Complete Blood Count (CBC)Thyroid Panel (including TSH, T4, and T3)UrinalysisVitamin D, 25-HydroxyCytomegalovirus (CMV) AntibodiesHepatitis Panel (A, B, C), AcuteEstrogens, TotalPregnenoloneDehydroepiandrosterone Sulfate (DHEA-S)Testosterone (Free with Total)Serum Vitamin B12, Serum and Urine Methylmalonic Acid

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or otherqualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle changeintended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician orother qualified health care professional. Pregnant women in particular should seek the advice of a physician before using anyprotocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified.Product labels may contain important safety information and the most recent product information provided by the productmanufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National,state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes therisk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage topersons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of theinformation contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens canguarantee health benefits. The publisher has not performed independent verification of the data contained herein, andexpressly disclaim responsibility for any error in literature.

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