Chronic fatigue syndrome (CFS) is a complicated condition characterized in part by profound fatigue that persists for more than six months. Other features can include 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. The illness follows a variable course and is associated with significant quality of life issues.

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

What are Causes and Risk Factors for CFS?

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
• Viruses such as human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV) may play a role in the development of CFS
• Oxidative stress, excessive inflammation, mitochondrial dysfunction, and autoimmunity may also be involved

How is CFS Diagnosed?

• There is no specific diagnostic test for CFS. A diagnosis of CFS first requires that other potential causes of fatigue be ruled out.
• Diagnostic criteria 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.
• Two additional symptoms must also be present: unrefreshing sleep and post-exertional malaise (worsening of symptoms after mental or physical exertion).
• Impaired memory or concentration and/or worsening of symptoms on standing up or sitting upright (orthostatic intolerance) is also necessary for a diagnosis of CFS.

How is CFS Treated?

• No single treatment has shown strong or consistent success for CFS. The most important consideration is that treatment be customized to the individual and evaluated and administered on a case-by-case basis.
• While a wide range of drugs have been studied and used for CFS, none have provided consistently satisfactory results, and for many the side effects outweigh the benefits. However, stimulant drugs and drugs with antiviral and/or immunomodulating properties have been shown to improve symptoms of CFS.
• Mind-body therapies, like cognitive behavioral therapy and biofeedback, are important symptom-controlling interventions associated with overall functional improvement.
• Exercise-based therapies are a double-edged sword and need to be carefully tailored to individual energy budget and physical activity threshold to prevent debilitating malaise.

What Novel and Emerging Therapies Appear Promising for CFS?

• DHEA replacement therapy in women who had CFS and low DHEA-S levels significantly improved fatigue, pain, memory, and sexual functioning.
• Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain simulation technique, may be a useful therapeutic approach for helping manage symptoms of CFS.

What Dietary and Lifestyle Considerations May Benefit CFS?

• Avoid exposure to tobacco smoke, toxic chemicals, and pollutants.
• Massage therapy, yoga, and Qigong may help improve fatigue.
• Gut flora manipulation has the potential to improve symptoms in CFS.

What Nutrients May Benefit CFS?

• 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.
• L-carnitine: A study of CFS subjects compared the FDA-approved antiviral drug amantadine with L-carnitine; authors concluded L-carnitine was better tolerated and produced significantly greater clinical improvement.
• D-ribose: Ribose is critical to the synthesis of important biological compounds as well as many compounds involved in cellular energy production and transfer, and low levels of ATP generation are considered one possible underlying mechanism for fatigue upon minimal exertion in CFS.
• Probiotics: Several studies have found that probiotic bacteria such as Lactobacillus and Bifidobacterium may decrease 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.

Chronic fatigue syndrome (CFS) is a complex condition characterized by fatigue that is often severe, persists for more than six months, is not relieved by rest, and is made worse by activity or exertion. Patients with CFS do not feel refreshed by sleep. Cognitive difficulties and/or dizziness or lightheadedness are also features of CFS.^1-3 Muscle aches and pain are common in CFS. Depression and anxiety also frequently occur, and are generally believed to be consequences, rather than causes, of the condition.⁴ Due to multiple sets of diagnostic criteria and a lack of agreement on its definition, it is difficult to estimate the true prevalence of CFS. A 2015 report by the National Academy of Medicine suggested that between 836,000 and 2.5 million people in United States have CFS.²

There is no single known cause of CFS, though numerous factors may contribute, including infections, particularly viral; nutritional deficiencies; hormonal dysregulation; and immunological disturbances.^5,6

CFS can be a debilitating condition. Many people with CFS have difficulty working, attending school, exercising, and carrying out daily activities.^7-9 Sadly, conventional physicians often overlook this condition, and as many as 80% of individuals suffering with CFS may not receive an accurate diagnosis.¹⁰ The lack of agreed upon diagnostic criteria or definition, coupled with a dearth of biomarkers or diagnostic tests compounds the challenge,¹¹ and it has been estimated that achieving an accurate diagnosis of CFS may take as long as five years from symptom onset.^4,12

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. 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.^5,11

Emerging research has identified several novel treatment strategies that may benefit those with CFS. For instance, one randomized controlled trial conducted at Stanford found clinical benefit with the antiviral drug valganciclovir (Valcyte) in a subset of CFS patients.¹³ This suggests viral infection, and possibly post-viral alterations in the host’s immune system, may represent a piece of the CFS puzzle.

In addition, individuals suffering with CFS may attain some benefit through the use of natural, integrative interventions including French oak extract,¹⁴ the co-enzymes nicotinamide adenine dinucleotide (NADH) and NAD+, L-carnitine, magnesium, D-ribose, B vitamins, omega-3 fatty acids, melatonin, and probiotics.^11,15

Demographics

The prevalence of CFS varies widely depending on populations studied and case definitions applied.¹⁸ A meta-analysis of studies using the most-cited CDC-1994/Fukuda case definition estimated the worldwide prevalence of CFS in the range of 0.1‒6.4%.¹⁹

CFS affects all population groups, although it has been estimated to be 1.5 to 2-fold more common in women than men.¹⁸ While early studies suggest CFS mostly affects young, Caucasian, professional women, more recent research reveals it is more common among people of early or middle adulthood. Although it is typically under-reported due to socio-economic factors and different healthcare-seeking behavior, a meta-analysis concluded the odds of CFS are nearly three times as high in African and Native Americans compared with white Americans.²⁰ A study of Gulf War veterans health by the U.S. Department of Veterans Affairs (VA) found those who had been deployed had dramatically greater odds of CFS than those who had not.²¹

CFS often occurs concurrently with other conditions that cause similar symptoms. Common conditions that may overlap to varying degrees with CFS include fibromyalgia, allergies and chemical sensitivities, anxiety and depression, and irritable bowel syndrome.²² Given the concurrence and similarities between CFS, fibromyalgia, and allergies and chemical sensitivities, studies on these conditions are often viewed as potentially relevant to CFS, and integrative practitioners frequently apply similar approaches to the three conditions.

Prognosis

CFS is a heterogeneous disorder; it generally presents with a diverse set of symptoms of varying onset and severity, sometimes with no identifiable triggers.^23,24 The course of the illness varies widely, with some patients returning to full function, some never returning to pre-illness levels of function, and many requiring adjustments in daily activities to remain improved or symptom-free.²⁵ A 2005 systematic review concluded that full recovery from CFS is rare, but symptomatic improvement does occur.¹² Similarly, an observational study in 150 subjects meeting the 1994 Fukuda diagnostic criteria found that the onset and course of the condition do indeed vary greatly.²⁴ Nevertheless, the following characteristics have been reported across multiple studies:

• Many patients can identify precipitating events or a specific time the illness began, prior to which they were subjectively healthy.
• The illness tends to follow a fluctuating pattern and symptoms tend to wax and wane with periods of temporary remission.
• Individuals rarely, if ever, return to previously normal levels of functionality.
• The presence of psychiatric illness and more fatigue at the time of diagnosis are predictors of poorer outcome.
• Some symptoms tend to resolve over time while others do not.
• Most commonly, physical symptoms resolve early in the course of the illness whereas cognitive symptoms, like lack of concentration, generally tend to linger.

CFS has not been shown to increase risk of death, as reported by a retrospective UK study which looked at mortality rates in CFS patients and failed to find increased all-cause mortality in the 2,147 cases studied.²⁶

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

Viral Infections

Viral infection may cause prolonged fatigue during active infection, and some studies suggest viruses such as human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) may play a role in the development of CFS.^27,28 The potential association between retroviruses and CFS has been studied, although this is an area of some controversy and a robust link between any specific retroviral infection and CFS onset has yet to be established.^4,29

A similar association between viral infections and disabling fatigue has been described by patients who have recovered from infectious mononucleosis and Dengue fever.^30,31 A subset of patients with these infections develop a constellation of symptoms, which bears resemblance to CFS and persist for months to years after recovery from the acute infection. This illness has been termed post-viral fatigue syndrome.³⁴ This association has been one of the leading arguments, in addition to finding antiviral antibodies, for viral infections being possible etiological triggers for the development of full-blown CFS.⁴

The mechanisms by which viral infection may trigger CFS are poorly understood; there are many theories, but none have been proven. Some scientists suggest post-viral alterations in the host’s immune system may underlie CFS, but this theory is debated.^35-37 Chronic viral infections may alter white blood cell activity (such as triggering abnormalities in T-cell function and decreasing activity of natural killer [NK] cells)^38,39 and impair mitochondrial function.⁴⁰

Bacterial Infections

Similarities have also been noted between CFS and sequelae of certain bacterial infections, notably Lyme disease and Q-fever (query fever), particularly with regard to persistent pain, cognitive difficulties, and fatigue.^4,41,42 However, the relationship between any bacterial infection and subsequent onset of CFS remains unclear.

Allergies

“Atopy” refers to a form of allergy resulting from an exaggerated response by the IgE antibody type and is the basis for several common allergic disorders such as asthma, eczema, and seasonal allergies.

An early literature review proposed that allergy may play a role in the risk of CFS.⁴³ One small study found that while there was no significant difference in overall allergy occurrence, drug allergies were more frequently reported by people with CFS than healthy controls.⁴⁴ Another study found measures of allergic tendency (mast cell activation) were increased in patients with CFS.⁴⁵

To investigate the link between immune dysfunction and CFS, early studies examined the history of allergy in CFS patients. A 1991 paper reported that a group of children with CFS had a strong history of atopy,⁴⁶ while a 1987 randomized controlled trial of acyclovir in CFS found 50% of subjects were positive for a skin allergy test, all of whom also had a positive history of atopy.⁴⁷ However, the link between allergies and CFS is uncertain, as not all CFS patients have allergies.

Food Sensitivities

Food sensitivities, perceived or otherwise, have also been considered as a potential contributor to general fatigue.^48,49 Sensitivities or intolerances to different foods are distinct from food allergies—they may not necessarily be due to immune system abnormalities and are often unexplained.

In one small randomized controlled trial, 52 subjects with CFS were randomized to either a low-sugar low-yeast (LSLY) diet or general “healthy eating” plan. The LSLY diet did not improve fatigue scores or overall quality of life compared with the general healthy eating pattern.⁵⁰ However, given the well-documented role of excess sugar intake in contributing to metabolic dysregulation,⁵¹ larger, more rigorous trials are needed to determine whether reducing intake of processed carbohydrates and sugar can improve symptoms among people with CFS or related conditions.

Immune Dysregulation and Inflammation

An array of pro-inflammatory cytokines have been elevated in patients with CFS, including interleukin-1 and tumor necrosis factor-alpha (TNF-α).^4,52 One study found that increased levels of pro-inflammatory mediators correlated with CFS symptom severity.⁵³ A small 2014 brain imaging study found individuals with CFS had significantly more neuroinflammation in many areas of the brain compared with healthy controls. Furthermore, inflammation in different brain regions correlated with depression and cognitive impairment scores.⁵⁴ Evidence from an animal model suggests 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.⁵⁵ Animal models also demonstrate that fatigue arises when a stimulus induces activation of microglial cells and/or there is an increase in inflammatory chemicals within the brain.⁵⁶ A literature review on the mechanisms underlying depression and CFS concluded that neuroinflammation and activated microglia play a key role in both conditions, and present an important therapeutic target.⁵⁷

Autoimmunity

Autoantibodies are antibodies directed against the individual’s own tissues and cells. Autoantibodies directed against some HPA hormone receptors have been reported in a series of patients with CFS, suggesting these might be a contributing factor to the development of the condition. In addition, clinical trials of treatment modalities that deplete B cells, and thus reduce autoantibody production, have shown clinical benefit in CFS, supporting the role of autoimmunity in CFS pathogenesis.⁵⁸

Mitochondrial Dysfunction

Mitochondria are organelles within cells that are responsible for generating most of the cell’s energy supply, which they contribute in the form of small energy packets called adenosine triphosphate (ATP). Dysfunction of mitochondria and mitochondrial enzymes may be associated with chronic fatigue and fibromyalgia.⁵⁹ The pro-inflammatory state discussed earlier that is seen in many individuals with CFS can impair mitochondrial function, leading to reduced ATP generation, which could explain the easy fatiguability after exertion.⁶⁰ An early electron microscopy study of muscle biopsies from 50 people with what was then called post-viral fatigue syndrome reported that 80% had mitochondrial degeneration.⁶¹ It has been posited that oxidative and inflammatory stress may explain mitochondrial dysfunction in CFS.⁶²

Endocrine Dysfunction

Several endocrine abnormalities have been described in CFS, but their cause is unclear. One of the endocrine abnormalities investigated in CFS is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. An early study identified HPA axis dysfunction resulting in reduced glucocorticoid levels in CFS patients relative to controls, and a 2017 study found an altered cortisol secretion rhythm.^63,64 The relationship between HPA axis function and CFS continues to be an area of active research, with the relationship between neuroinflammation and hypothalamic inflammation being explored as a possible causal link.^65-67

Abnormal levels of the hormone insulin-like growth factor (IGF-1), which plays a role in normal growth and development, have been observed in CFS.⁶⁸ However, such changes in endocrine function are not specific to CFS, as similar abnormalities are observed in patients with fibromyalgia,⁶⁹ other mood disorders,⁶⁹ and even in healthy individuals following altered sleep patterns.⁷⁰

A study that mapped endocrine-immune interactions in 88 women found that levels of several hormones (including sex hormones) and immunological factors may be suggestive of CFS.⁷¹ More research is needed to explore the interactions between hormonal and immunological signalling networks in the context of CFS.

Orthostatic Intolerance

Orthostatic intolerance denotes the inability to tolerate prolonged upright posture or the transition to upright posture from sitting or lying. One of the most common manifestations of this intolerance is orthostatic hypotension, in which transitioning from a lying or sitting position to a standing position causes low blood pressure, weakness, or faintness.⁷² Orthostatic hypotension results from inadequate blood flow to the brain due to autonomic nervous system dysfunction.⁷³ One early study reported a high prevalence of orthostatic hypotension in a small sample of subjects with CFS.⁷⁴ Many of these subjects were on low-salt diets. Following treatment for orthostatic hypotension, which included the corticosteroid fludrocortisone (Florinef) and increased dietary salt intake to help increase blood pressure, chronic fatigue was completely resolved in 39% of subjects.

Studies in Australia and the UK reported 11% and 13%, respectively, of those who met the U.S. CDC or Canadian CFS diagnostic criteria also met criteria for orthostatic hypotension.^75,76 Objective reductions in blood flow to the brain after being tilted, measured using Doppler imaging, were reported in 26% of CFS patients in one study compared with 7% in healthy controls.⁷⁷ Some researchers have suggested that measuring blood pressure at various postures may be a useful diagnostic tool for CFS, but more research is needed to clarify the link between CFS and postural blood pressure variability.⁷⁸

An impairment of the body’s ability to properly modulate blood pressure (ie, autonomic dysregulation) most commonly manifests as orthostatic hypotension, but a study in CFS patients has also reported symptoms of dizziness and lightheadedness while lying down. The researchers proposed that these two symptoms may also inform the clinical evaluation of CFS.⁷⁹

Sleep Disruption

Poor sleep is common among people with CFS. In fact, it is one of three required symptoms for a formal CFS diagnosis and has been proposed as a possible contributing factor. Sleep quality directly correlates with CFS such that the worse the quality of sleep, the more frequent and severe the symptoms of CFS.⁸⁰ Polysomnographic studies in CFS patients have shown significant sleep disruption when compared with healthy people. After excluding underlying sleep disorders and fibromyalgia, findings of overnight sleep studies showed CFS patients had less total and uninterrupted sleep time, efficiency, and spent less time in rapid eye movement (REM) sleep compared with controls.⁸¹

Genetic Susceptibility

Some evidence suggests genetics may contribute to CFS risk. Genome-wide studies identified some patterns of gene variations in individuals with CFS. Reported genetic variations most commonly are found in the following systems: HPA axis, contributing to endocrine dysregulation; white blood cells, contributing to immunologic dysfunction; and central nervous system neurotransmitters, contributing to behavioural disturbances.^82,83 Multiple studies reported similar associations, leading to the conclusion that no single biologic cause accounts for all CFS, but that a range of different physical and emotional stressors could contribute to the illness in susceptible individuals.⁴

However, not all genome studies have reported significant associations.⁸⁴ If a genetic basis of CFS can be more firmly established, therapies targeting specific genetic abnormalities, or altered cellular processes driven by these abnormalities, could be explored in future research.

Psychiatric Disorders

There is little known about the nature of the association of CFS with anxiety and depression, despite these psychiatric illnesses being consistently reported in CFS patients.^85,86 While many symptoms of clinical depression are shared with CFS (eg, low mood, sleep disturbance, fatigue), they often vary qualitatively and a clinical distinction between CFS and depression can usually be made through diagnostic criteria.⁸⁷ In addition to associations often observed between psychiatric disorders and CFS, two studies found certain central nervous system abnormalities were present in both depressive disorders and CFS.^57,88 However, neither the co-occurrence nor shared biological characteristics answer the question of whether depression or anxiety are a consequence of living with CFS, co-exist as symptoms, or even as etiological risk factors.

There is no specific diagnostic test for CFS, and it may be difficult to distinguish CFS from fatigue secondary to other health conditions. The problem is further compounded by the several case definitions used, leading to a wide variation in the detection and accurate reporting of the condition’s prevalence.⁸⁹

Several diagnostic criteria exist for CFS and disparities in care practices for diagnosis and treatment of CFS across different countries have been reported.⁹⁰ Among the most commonly used diagnostic criteria are the Fukuda criteria (1994),⁹¹ Canadian Consensus Criteria (CCC 2003),⁹² International Consensus Criteria (ICC 2011),⁹³ and Oxford criteria (1991).⁹⁴ Following an extensive review of evidence on CFS, the National Academy of Medicine proposed a new set of diagnostic criteria in 2015.^2,95

All criteria mentioned here apply to individuals who have experienced new onset fatigue and sleep disturbance for at least six months, not explained by another active medical conditions, leading to significant impairment of day-to-day activities. It is, therefore, essential for health care practitioners to elicit a thorough medical history, conduct a detailed physical exam, and perform a targeted lab work-up to rule out other disorders that could cause similar symptoms.²

Laboratory Work-up

There is no single diagnostic test or treatment biomarker for CFS.⁹⁶ The following baseline tests are frequently used to help rule out other common causes of fatigue:

• 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)

Additional testing may reveal imbalances or deficiencies that should be addressed:

• Vitamin D, coenzyme Q10, and magnesium levels
• Hormone levels: cortisol, DHEA, pregnenolone, estrogens, testosterone
• Fatty acid profile

Ancillary Investigations

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.¹⁰² Other infections may be mistaken for CFS, so testing for tuberculosis; hepatitis A, B, and C; and HIV/AIDS may also be considered. Testing blood levels of 25-hydroxyvitamin D may help as well since symptoms of vitamin D deficiency (eg, weakness, muscle pain) may sometimes overlap with CFS symptoms.¹⁰⁷ Psychological conditions, such as depression and substance abuse, should be ruled out as well.¹⁰²

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.^108,109 A comprehensive discussion of several sleep disorders and methods of treating them is available in the Insomnia protocol.

Some researchers have suggested sex hormone imbalances may contribute to CFS, especially in women, although evidence is inconsistent.^110,111 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(s), and testosterone. If levels are low, bioidentical hormone replacement may be a useful adjunct therapy, although hormone replacement therapy as a specific treatment for CFS has not been evaluated. For more specific information on bioidentical hormone replacement and hormone testing, see the Female Hormone Restoration and Male Hormone Restoration protocols.

Because of the unclear etiology and complexity of CFS, its management is supportive rather than curative, and standard treatments are generally directed at alleviating symptoms. Unfortunately, no therapy, either single or combination, has proven reliably effective. Thus, treatment must be tailored to each individual, and may consist of trial-and-error with different therapies, including drugs, diet, behavioral, novel/emerging, and integrative interventions.

Pharmacological Approaches

Stimulant drugs. Stimulant drugs such as methylphenidate (Ritalin, Concerta) or amphetamine/dextroamphetamine (Adderall) have been used to treat CFS. In a randomized controlled crossover trial on 60 CFS subjects, four weeks of treatment with 10 mg methylphenidate twice daily followed by placebo, or the reverse order, resulted in significantly less fatigue and better concentration compared with baseline and with placebo. The effects were clinically significant in 17% of patients for fatigue and 22% for concentration.¹¹² A randomized controlled trial in 20 CFS subjects reported that fatigue was significantly reduced in 9 of 10 subjects treated with 5 or 10 mg Adderall twice daily for four weeks compared with 4 of 10 subjects who improved in the placebo group.¹¹³ Another randomized trial treated 26 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,¹¹⁴ or placebo. After six weeks of treatment, the Vyvanse group had significantly better emotional control and working memory as well as significantly less fatigue and generalized pain compared with placebo.¹¹⁵

A 2018 paper reported on a phase 2, randomized, double-blind, placebo-controlled, multi-center trial evaluating the effects of a daily dose of an experimental treatment—a combination of low-dose (5‒10 mg) methylphenidate with a micronutrient cocktail (containing vitamins, amino acids, minerals, and others) for mitochondrial support.¹¹⁶ Compared with placebo, the treatment group tended toward reduction in fatigue and concentration disturbance symptoms after 12 weeks of treatment. Participants with more severe baseline symptoms, and with both fatigue and pain symptoms, experienced the greatest treatment response. There was no statistically significant difference in adverse events between the two groups.

Stimulant drugs have a number of common adverse side effects including insomnia, loss of appetite, potential cardiovascular effects, as well as the potential for addiction and misuse.^117,118 Only limited information is available on long-term effects of stimulant medication.¹¹⁹

Antidepressants. Anxiety and depression can be features of CFS, and appropriate pharmacological treatment is an option for these symptoms. They can also co-occur with CFS. In this setting, treatment of the mood disorder is indicated. Selective serotonin reuptake inhibitor (SSRI) antidepressant medications as well as other classes such as monoamine oxidase inhibitors (MAOIs) may be appropriate in these circumstances. Antidepressant medications cannot, however, be considered a direct treatment for CFS, as studies have produced conflicting results.³

A small open-label trial in 16 patients with both major depressive disorder and CFS reported that 10‒20 mg citalopram (Celexa) daily was associated with significantly less fatigue and depression after 12 weeks.¹²⁰ This suggests depression may worsen CFS symptoms, though more rigorous study is needed to confirm this hypothesis.

Antiviral Drug Therapy

Valganciclovir. Valganciclovir is an oral medication that is converted in the body to the antiviral guanosine analog ganciclovir. It is widely used for treating cytomegalovirus infections in immunocompromised individuals.¹²¹ Valganciclovir was the subject of a retrospective chart review in 61 CFS patients, roughly half of whom were responders (ie, experienced at least 30% improvement in physical and/or cognitive functioning), with 19 reporting improvement in physical function and 26 reporting improvement in mental functioning; their responses were independent of initial viral infection severity tests (titers). Longer treatment yielded better results in this population.¹²² In a group of 12 patients with high antibody titers for EBV and HHV-6, central nervous system dysfunction, fatigue and depressive symptoms, an open-label trial of valganciclovir for six months showed near resolution of symptoms in 75% of subjects.¹²³

In a randomized controlled trial, 30 CFS patients with elevated immunoglobulin G (IgG) antibody titers against HHV-6 and EBV (IgG antibodies indicate past exposure but not necessarily present, active infection) were received either valganciclovir or placebo for six months. Treatment with valganciclovir produced significant improvements in mental fatigue, fatigue severity, and cognitive function. The improvement was noted within three months and still present after an additional nine months.¹³

Immune Modulator: Rituximab

As B cells, a type of white blood cell, are implicated in the development of autoimmunity, drugs that modulate B-cell function may have potential use in treating CFS. One such drug is rituximab (Rituxan), an antibody that triggers cell death in B cells.¹²⁴ The first published investigation of its efficacy came in a case series of three CFS patients in 2009, all of whom responded well.¹²⁵ The researchers followed up the case series with a randomized controlled trial published in 2011.¹²⁶ The data showed a delayed (2‒7 months after initial treatment) response in improvement of symptoms, especially fatigue scores. A later open-label trial by the same group showed clinical improvement in 64% of patients after receiving two antibody infusions, two weeks apart followed by maintenance infusions for up to 15 months. From among those who responded to treatment, 61% remained in sustained remission at 3-year follow-up.¹²⁷ However, the same group of researchers reported negative findings in 151 CFS patients in a phase 3, multi-center, randomized, placebo-controlled trial, with no difference in response rates between patients and controls over 24 months. There was a high rate of significant adverse effects in the rituximab group. This failure in a large, rigorous controlled trial suggests rituximab for CFS is of questionable benefit.¹²⁸

Behavioral Approaches

Mind-body-based therapies such as biofeedback, cognitive behavioral therapy, and graded exercise training may help some individuals with fibromyalgia and CFS.^129,130 However, the effectiveness and utility of some of these approaches has been questioned, and more research is needed to help clarify which therapies are best for which patients. For instance, graded exercise therapy may exacerbate post-exertional malaise in some people with CFS, so a tailored approach is important.

Biofeedback. Biofeedback is a technique used to control some automatic bodily functions, like heart rate. During biofeedback, several physiological parameters (eg, brain waves and heart rate) are monitored and the patient receives real-time feedback. The goal of the feedback 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.¹³¹ A study in 28 women with CFS reported that fatigue and depression improved significantly in response to heart rate variability biofeedback therapy, while graded exercise therapy improved physical quality of life. Both interventions were judged to have reduced general fatigue.¹³²

A study applying biofeedback therapy in 15 fibromyalgia patients found six days of biofeedback training resulted in physical and psychological improvement compared with sham (placebo) biofeedback.¹²⁹ Given the overlap of these two conditions, this study can be considered suggestive of a similar possible benefit for CFS.

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) involves a series of counseling sessions aimed at altering unhelpful thoughts and behaviors. Fatigue, a cardinal clinical feature of CFS, is a reason for generally reduced physical activity in these patients and can lead to a progressive decline in overall activity state. While not a psychological illness in itself, it has been proposed that CBT can reduce fatigue, along with other symptoms of the illness, by providing coping strategies to counter the activity avoidance behaviour.^34,133 A review, which evaluated long-term outcomes in 511 CFS patients who underwent CBT at various stages of their illness, predicted that better physical functioning at follow-up (up to 10 years) was associated with a higher sense of control over fatigue. Furthermore, the study concluded that augmenting sense of control through CBT and starting treatment sooner after diagnosing CFS could positively influence long-term outcome.¹³⁴ A systematic literature review concluded CBT is more effective than usual care in attenuating fatigue and may be more effective at reducing fatigue-related symptoms compared with other psychological approaches. However, the review did not find consistent evidence of sustained response at follow-up.¹³⁵

Exercise. Self-pacing and graded exercise therapy (GET) are some of the exercise-based interventions often discussed as treatments for CFS. Self-pacing is essentially pushing oneself to increasing levels of activity as allowed by individual energy levels. GET, on the other hand, is structured, usually administered with a therapist, and includes exercise designed to increase physical activity through gradual increasing of exercise tolerance levels. There is much ongoing debate around the utility of exercise in improving CFS symptoms, especially fatigue, with some evidence and some patient advocacy groups suggesting it may have a negative impact.^130,136 Post-exertional malaise (PEM) is a cardinal feature of CFS, and thus the concept of an “energy envelope” or “energy budget” has been popularized to describe how patients need to learn to plan activity and rest so as not to exceed their limits.¹³⁷ Respecting these limits may be essential to successful application of GET, and is one reason self-pacing may be preferable.¹³⁸ A practical guideline for any exercise-based intervention for CFS is individualization to the patient’s energy levels by establishing a baseline activity threshold at the outset with subsequent regular periodic reassessments. In such an intervention, the patient consciously stays within their “budget” or “envelope” to prevent PEM and gradually and incrementally increase their activity tolerance capacity. This tailored approach is supported by data from observational studies.^136,139

Recently, a systematic review of eight randomized controlled trials involving 1,518 patients evaluated exercise in CFS. Exercise was considered an “active” intervention in this analysis and was compared with “passive” interventions such as drug therapies. The duration of exercise therapy ranged from 12 to 26 weeks at varying levels of intensity (walking, swimming, cycling, etc.). The authors concluded that exercise probably has a positive effect on fatigue, at the end of treatment, and may improve sleep at the end of treatment and long-term in CFS.¹⁴⁰

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 signaling. Although rTMS has been studied for several conditions, including major depression, schizophrenia, recovery in stroke, and CFS,^144-146 the number of subjects in these studies was small. A case series in seven patients who underwent a 3-day course of rTMS reported that most of the patients experienced an improvement in fatigue.¹⁴⁶ Another trial used rTMS in 22 patients with CFS, divided into two groups—severe and mild—and noted significant improvement in fatigue symptoms in both groups.¹⁴⁷

In a study of 30 fibromyalgia patients comparing rTMS treatment to sham treatment, pain intensity was significantly reduced from day 5 to week 25 and long-term improvement in fatigue and sleep were noted in the treatment group.¹⁴⁸ Similar results in pain improvement and quality of life were observed in another fibromyalgia study with treatment and placebo arms, using high frequency rTMS.¹⁴⁹ Although more studies are needed to evaluate the efficacy of rTMS in CFS, it has been suggested this modality may be useful in conditions involving multiple types of difficult-to-treat pain.¹⁵⁰

Treatment of Candida Infection

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. A study found a higher number of C. albicans in fecal samples of CFS subjects during acute CFS symptom exacerbation compared with the remission phase when symptoms were less pronounced.¹⁵¹ A positive response of a large number of patients with CFS to an oral antifungal agent and a diet for intestinal candidiasis has also been described.¹⁵² The observational and uncontrolled nature of these studies make more rigorous study of the relationship between candida overgrowth and CFS necessary.

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

Hormone Replacement Therapy

Declining levels of sex hormones (eg, testosterone and estrogen) are common with aging, and low levels of these hormones are associated with fatigue.¹⁵³ In addition, levels of dehydroepiandrosterone (DHEA) and its sulfated form (ie, DHEA-S) have been found to be significantly lower in individuals with CFS compared with healthy controls.^154,155

DHEA, a hormone produced mostly by the adrenal glands and the most abundant circulating steroid hormone in the body, is reported to have immune-modulating effects.^156,157 It is also a precursor to several other hormones including testosterone and estrogens, and together with its derivative DHEA-S, important for maintaining healthy neuronal function in the brain.¹⁵⁸ DHEA levels decline by age 80 to as little as 10‒20% of those typical around age 30.¹⁵⁹

Because DHEA-S has a longer half-life, its blood levels are easier to measure to evaluate adrenal gland function. A 6-month uncontrolled trial in 23 women with CFS, and DHEA-S levels below 2 mcg/dL, reported that six months of supplementation with 25 mg oral DHEA daily was associated with significant improvements in fatigue, pain, memory, and anxiety.¹⁶⁰ A study in which researchers interviewed individuals with unexplained chronic fatigue revealed that 11 of 17 subjects who self-treated with DHEA supplementation experienced positive results in self-reported fatigue scores.¹⁶¹

There is some evidence that CFS may be accompanied or partially caused by a dysfunction in the HPA axis.^162,163 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.^162,164

More information about 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.

Other Antivirals

Rintatolimod. Rintatolimod (Ampligen) is a drug with antiviral and immunomodulating properties. It has been approved in some countries for the treatment of CFS, although not in the United States as of early 2021.³ In a randomized controlled trial, 234 subjects with severe CFS were treated with either 400 mg intravenous rintatolimod or placebo twice weekly. After 40 weeks, the treatment group had significantly higher exercise tolerance compared with placebo, as well as reduced use of symptom-relief medication.¹⁶⁵ A later reexamination of the data from this trial revealed that exercise tolerance improved by 18.3% in the rintatolimod group versus 4.6% deterioration for placebo.¹⁶⁶ An earlier study by the same research group in 92 CFS subjects reported that after 24 weeks of rintatolimod treatment, subjects showed improved cognitive and physical performance, better functioning, and decreased symptoms compared with placebo.¹⁶⁷

Despite these trials showing statistically significant improvements in the primary endpoints (fatigue, exercise tolerance, and cognition) with a favorable safety profile, the drug has not received FDA approval. However, rintatolimod has long-standing FDA orphan drug status for use in CFS,¹⁶⁸ and research is ongoing that may lead to expanded use in the future if results are positive.¹⁶⁹

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 alter the function of the nervous system and may increase risk of chronic pain.^170,171 Exposure to cigarette smoke, even secondhand, is pro-inflammatory and suppresses or disorders immune response.¹⁷² A large multi-center prospective study of 9,209 non-demented patients found higher cigarette exposure correlated with significantly higher rates of cognitive decline.¹⁷³ Other studies have linked tobacco smoke exposure with greater symptom burden in CFS or related conditions (ie, fibromyalgia).^174,175

Exposure to toxic compounds (including heavy metals, petrochemical solvents, pesticides, and molds) has been associated with CFS.^176,177 Some individuals with reported chemical sensitivities also have severe chronic fatigue. In some cases, CFS symptoms have resolved in chemically sensitive individuals when they reduced or eliminated their toxicant exposure.¹⁷⁸

Heavy indoor exposure to molds has been linked to asthma, sinus problems, chronic fatigue, and significantly reduced levels of hormones essential for energy production (eg, growth hormone and thyroid hormones).¹⁷⁹ In a study on 79 subjects with fatigue, chronic sinusitis, and a history of mold exposure, 51% were identified as being 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 that included: cleanup of subjects’ indoor environment to greatly reduce mold and moisture conditions that foster mold growth; saline nasal irrigation; oral and nasal antifungal drugs; hormone replacement treatment with growth hormone, thyroid hormone, and other hormones to restore physiologic levels; and a broad range of nutritional supplements. Following treatment, sinusitis resolved in 93% of participants who achieved a normal indoor mold count; and fatigue improved in all 37 participants who were treated with growth hormone and cortisol and/or thyroid hormone.¹⁸⁰

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 with poor ventilation. In a study of 100 large office buildings, office workers experiencing fatigue or difficulty concentrating were less likely to work in well-ventilated buildings or buildings with well-maintained ventilation systems compared with less well-ventilated or well-maintained buildings.¹⁸¹

Detoxification Regimens

“Detoxification” refers to the process of removing toxins from the body to promote health. While the body naturally detoxes itself and the liver and kidneys are quite effective at filtering and/or eliminating harmful substances, some people may undertake various methods (eg, diet, therapies, or regimens) to improve or address difficult-to-treat conditions like CFS. Rigorous scientific study has not yet firmly established the clinical utility of these methods. A critical review of “detox diets” concluded that none have been the subject of randomized controlled trials.¹⁸²

In a group of 111 patients with metal hypersensitivity and symptoms resembling CFS, removing mercury-containing dental amalgams was associated with long-term health improvements in 76% of subjects.¹⁸³ 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.¹⁸⁴

Sauna therapy has been investigated in the context of CFS. Sauna use may support detoxification, enhance sleep, and relieve pain.¹⁸⁵ In a case series of two women with CFS, 35 days of once-daily sauna therapy (15 minutes of far-infrared dry sauna followed by 30 minutes resting under a blanket) was associated with improvements in sleep, energy level, and concentration, as well as a reduction in depression.¹⁸⁶

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

Massage

There is little robust evidence supporting the use of massage as complementary therapy in CFS.¹⁸⁷ A small study of 20 people with “chronic fatigue immunodeficiency syndrome” reported that undergoing 30 minutes of massage therapy twice weekly for five weeks was associated with significant reduction in pain, fatigue, depression, and anxiety compared with an inert comparison treatment consisting of sham transcutaneous electrical nerve stimulation.¹⁸⁸ Another trial compared two different types of massage in 182 adult subjects with CFS. When asked to rate the therapeutic effect, the 91 subjects that received a type of traditional Chinese medical massage reported an overall better outcome compared with the 91 controls who received a conventional massage.¹⁸⁹

Yoga and Qiqong

Yoga has been studied as a therapeutic modality in a variety of illnesses, including multiple sclerosis, chronic kidney disease requiring hemodialysis, and cancer to help with pain and fatigue.^190-192 Japanese researchers carried out three randomized trials in CFS patients to investigate the effect of regular isometric yoga exercises, in seated and lying positions, undertaken for 2‒6 months alongside their standard medical regimes.^193-195 They reported significant reduction in fatigue and pain through subjective, self-reported measures. The researchers also reported reduced levels of certain blood biomarkers of inflammation (eg, TNF-α) and improved levels of the stress-related biomarkers cortisol and DHEA-S as possible underlying mechanisms to the beneficial effects of yoga.^196,197

Qigong is a specialized form of gentle exercise that harmonizes breathing, posture, body movements, and mind. Some limited evidence suggests Qigong may reduce fatigue and improve quality of life.^187,198 A study of 137 people with CFS reported practicing Qigong daily for four months was associated with significantly less fatigue and depressive symptoms in the intervention group versus control.¹⁹⁹

Gut Microbiota Manipulation

Gastrointestinal symptoms are common in CFS, which is often accompanied by a diagnosis of irritable bowel syndrome.²² In a study comparing the gut microbiota of CFS patients and controls, scientists found a less diverse and abundant gut flora in those with CFS.²⁰⁰ Data supporting this link between gut microbiome and CFS have led to investigations into new therapies aimed at restoring the diversity and balance of the gut microbiome.²⁰⁰

The most familiar methods for influencing microorganism populations in the digestive tract are the use of probiotics, probiotic foods, prebiotics, and synbiotics, which combine probiotics and prebiotics in one preparation. Another means of restoring the bowel flora is fecal microbiota transplantation (FMT). FMT is a recognized treatment for recurrent Clostridium difficile infection, a rare but dangerous complication of antibiotics. Other applications of FMT are being actively investigated. The process involves transplanting a liquid preparation of the stool of a healthy person into the colon of a sick person, after it has been screened and matched to the recipient.²⁰¹

A small retrospective study reported on the treatment of 42 individuals with CFS, half of whom received FMT and half who received standard integrative nutritional therapy. The study authors reported their subjective clinical impression of the response to therapy in both groups, concluding that the FMT group had significantly greater clinical benefit than the control group.²⁰² This study lacked objective assessments and thus provides only preliminary information on the application of FMT to CFS.

“Bacteriotherapy” is a more general term for the use of harmless bacteria to supplant pathogens in the body, and FMT has been considered one form of bacteriotherapy.^203,204 A retrospective study in 60 CFS patients, 52 of whom had concurrent IBS, examined the results of a course of bacteriotherapy, in this case infusing the patients’ colons with a blend of 13 normal bacterial inhabitants of the human gut flora. The researchers reported a 70% initial response rate and 58% sustained response.²⁰⁵

Roburin-rich French Oak Wood Extract

Roburins, which are constituents of oak wood, belong to the class of phytochemicals known as ellagitannins (a type of polyphenol).²⁰⁶ Roburins have been consumed by humans for centuries in wine and spirits aged in oak barrels. Ellagitannins are capable of modulating inflammatory responses within the body.^206,207 Up to 300 mg oak wood extract, taken daily in capsules, has been shown to improve mental focus, energy levels, and athletic performance in healthy adults.^208,209 Recently reported findings from a randomized, double-blind, placebo-controlled pilot study in 66 women who had undergone hysterectomy showed improved self-reported convalescence outcomes in response to four weeks of oak wood extract supplementation.²¹⁰

French oak wood extract is believed to have this effect 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.²⁰⁶ Ribosomal dysregulation is also implicated in symptoms of CFS and chronic viral syndromes.²¹¹

In an open-label trial that evaluated 85 patients with 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 for at least six months. Researchers tracked physical symptoms and mood of the CFS patients as well as measures of oxidative stress. At three and six months, the treatment group showed a significant decrease in oxidative stress, as measured in whole blood, versus no significant change in the control group.²¹² The oak wood-supplemented group experienced marked trends toward reductions in most 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 statistically significant improvement in sensitivity to noise, food, medication, and chemicals; dizziness or lightheadedness; depression; mood swings; weight change; allergy symptoms; and visual symptoms.

Mitochondrial-Targeted Support

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.^213,214

Nicotinamide adenine dinucleotide (NAD). NAD, a critical co-factor in myriad physiological processes, is made in the body from niacin (vitamin B3). Among its essential roles are involvement in numerous energy-producing reactions.²¹⁵ In a randomized open-label trial of 20 individuals with CFS, 12 subjects received 5 mg oral NADH (a type of NAD) daily, escalating to 10 mg if no symptomatic improvements were noted, and eight subjects received an integrative program that included psychotherapy. After three months, the NADH group had a significantly greater reduction in mean CFS symptom score, though later measurements found the treatments were comparable.²¹⁶ 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 with 8% given placebo.²¹⁷ One randomized controlled trial combined NADH with coenzyme Q10 (CoQ10) as both support mitochondrial function and are clinically promising in CFS. In this trial, 73 women with CFS diagnoses received either 200 mg CoQ10 plus 20 mg NADH or placebo daily for eight weeks. Baseline measurements were taken before supplementation and again at the end of week eight. Supplementation resulted in significantly higher levels of ATP production than placebo as well as significant improvement in levels of fatigue as reported through an assessment questionnaire.

NADH is the reduced form of NAD+, and the two are regularly interconverted as part of the electron transport chain in indispensable energy-producing cellular processes. Besides its role in ATP generation, NAD+ is essential to sirtuins, specialized proteins that guard against DNA damage and may help mitigate age-related decline.²¹⁸ This process is dependent on a healthy supply of NAD+.²¹⁹ Unfortunately, NAD+ levels decline with age.²¹⁸ The good news is compounds like nicotinamide riboside can boost NAD+ levels.²²⁰

Coenzyme Q10 (CoQ10). CoQ10 is a crucial factor in the process by which mitochondria produce the cellular energy currency, ATP.²²¹ CoQ10 is found in meat and synthesized in small quantities in the body, although in healthy individuals it is abundant in the mitochondria.²²² A study of 58 people with CFS reported that up to 45% had blood CoQ10 levels below normal, while none of the 22 healthy controls had levels below this level. CFS subjects with extremely low CoQ10 levels had significantly more problems with fatigue, concentration, and memory compared with CFS subjects with higher levels.²²¹ CoQ10 alone and in combination with NADH has been shown to reduce fatigue and improve exercise tolerance in fibromyalgia and CFS.^223,224 A randomized controlled trial in people with fibromyalgia 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 with 10 placebo-treated fibromyalgia subjects.²²⁵

L-carnitine. L-carnitine is an amino acid derivative that plays an important role in energy production by aiding the transport of fatty acids into the mitochondria where they are oxidized for energy. It has several other important roles in energy and cellular metabolism.^226,227 Two studies reported significantly lower blood carnitine and acylcarnitine in CFS patients compared with controls.^228,229 In the second study, higher blood carnitine levels corresponded to better clinical status. A 2-month study of 30 CFS subjects compared the antiviral drug for influenza A, amantadine (Symmetrel), with L-carnitine. Amantadine was poorly tolerated and did not result in any significant improvement. L-carnitine supplementation was well tolerated and resulted in significant improvement in 12 of 18 measured clinical parameters, with the greatest improvement in the second month of treatment.²³⁰ Another group of researchers treated 90 CFS patients (30 in each group) with either 2 grams acetyl-L-carnitine, 2 grams propionyl-L-carnitine, or 2 grams of each (4 grams total) daily in an open-label trial. After 24 weeks of treatment, considerable improvements (as measured by 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. Acetyl-L-carnitine demonstrated a significant effect on mental fatigue and concentration whereas propionyl-L-carnitine showed most improvement in general and physical fatigue.²³¹

Acetyl-L-carnitine was also part of the previously mentioned trial for CFS that used both a nutraceutical targeting mitochondrial function and low-dose methylphenidate. In that study, the test group showed significant better clinical response in fatigue and pain compared with placebo.¹¹⁶

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 36 individuals with multiple sclerosis. Patients who received 1 gram of acetyl-L-carnitine twice daily for 90 days experienced a significantly greater reduction in fatigue severity than those treated with 100 mg amantadine twice daily.²³² ​​​

Ribose

Ribose is a carbohydrate critical to the synthesis of important biological compounds such as RNA and DNA (the cell’s genetic material), as well as many compounds involved in cellular energy production and transfer (such as CoA, ATP, NADH, and FADH).²³³ A pilot study analyzed 36 subjects with CFS and/or fibromyalgia who took 5 grams 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 an improved pain threshold.²³⁴

Low levels of ATP generation are considered one possible underlying mechanism for fatigue upon minimal exertion in CFS. A similar pattern of ATP depletion is observed in exercise physiology after intense bouts of exercise, and D-ribose has been shown to enhance ATP recovery in that setting. In a crossover double-blind study, 26 healthy subjects (mean age 28 years) were given 10 grams loading doses of D-ribose for two days before exercise followed by 10 grams daily supplementation which was accompanied by 60 minutes of intense training for three days. The control group was given the modified glucose sugar, dextrose.²³⁵ After D-ribose supplementation, subjects showed increased power output and reduced perceived exertion compared to no observed benefit with control intervention.

With this understanding of the link between enhanced restoration of energy levels and D-ribose supplementation, beneficial effects of D-ribose in the context of CFS warrant further investigation.

Probiotics

Gastrointestinal symptoms are a common occurrence in CFS, and gastrointestinal barrier dysfunction is a possible mechanism for immune dysregulation in CFS. A diverse and balanced gut flora is essential to a healthy gut barrier, but a lack of biodiversity and imbalance in the gut flora has been reported in CFS patients.²⁰⁰ This provides a sound rationale for the use of probiotics in CFS.

Several studies have found that probiotic bacteria such as Lactobacillus and Bifidobacterium may decrease symptoms of CFS. An Italian study reported a progressive improvement in fatigue and significant reduction in inflammatory biomarkers in 13 CFS patients after being treated for eight weeks with various combination probiotics that included Bifidobacteria and Lactobacilli.²³⁶ A controlled trial in 29 healthy adults aged 60‒81 years reported daily consumption of 100 grams of a fermented milk drink containing live L. helveticus for three weeks significantly improved sleep compared with a placebo beverage that contained no probiotics.²³⁷ A study of 15 subjects who met the 1994 CDC criteria for CFS reported treatment with L. paracasei, L. acidophilus, and B. lactis bacteria twice daily for 30 days reduced CFS-related neurocognitive symptoms in 40% of subjects.²³⁸ In a placebo-controlled pilot study of probiotics for CFS, 39 adults were given a probiotic mixture containing 8 billion live L. casei bacteria three times daily for two months. Treatment significantly reduced anxiety compared with placebo.²³⁹ However, a few more recent systematic reviews assert that evidence for benefit from probiotics in the context of CFS is limited and not of rigorous methodological quality.^240,241 Therefore, larger controlled trials of probiotics in people with CFS are needed.

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 (B9) and B12 (eg, methylcobalamin), are important for the creation of new cells, repair of damaged cells, and normal function of the central nervous system.^242,243

One study found significantly lower vitamin B1, B2, and particularly B6-related enzyme activities in 12 CFS patients compared with 18 age- and gender-matched controls.²⁴⁴ Another study reported serum folate was abnormally low in 30 of 60 CFS patients.²⁴⁵ 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 folic acid, 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 with women receiving placebo.²⁴⁶ A multi-nutrient intravenous nutrition formula popularly known as “Myer’s cocktail” that includes B vitamins, magnesium, and other nutrients has been reported to help CFS patients.²⁴⁷

A 2019 study looked at the efficacy of high-dose vitamin B12 administered as nasal drop in CFS patients. Treatment was 5,000 mcg of hydroxycobalamin twice per week. Two-thirds of those who received the nasal drops responded to treatment, showing significant improvement in physical activity and fatigue levels, along with dramatically increased serum levels of B12.²⁴⁸ The non-responders in this study, on the other hand, showed minimal improvement in fatigue and activity level, and even in levels of B12, after treatment.

Melatonin

Melatonin, a natural hormone produced by the pineal gland in the brain, regulates the sleep-wake cycle and is an efficient antioxidant.²⁴⁹ An analysis of 14 published studies revealed melatonin taken shortly before bedtime significantly reduced sleep latency (time to fall asleep) in persons with delayed sleep phase syndrome, or difficulty falling asleep.²⁵⁰ 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.²⁵¹ Individuals with Parkinson disease often develop chronic and unremitting fatigue that meets the diagnostic criteria for CFS. In a study on 30 Parkinson patients with CFS symptoms, treatment with melatonin led to a significant reduction in fatigue and anxiety scores on standardized Parkinson assessments as well as improvements in quality of life; sleep quality also improved following melatonin treatment.²⁵² On the basis of evidence available as of mid-2020, it would be appropriate to conduct larger, randomized, controlled trials of melatonin supplementation in CFS patients.

Curcumin

Turmeric is a spice rich in the polyphenol curcumin, long hailed as a potent antioxidant and anti-inflammatory agent.²⁵³ An open-label Dutch study looked at the benefit of curcumin supplementation in 44 CFS patients.²⁵⁴ The subjects were given curcumin phytosome complexed with choline daily for eight weeks and were asked to fill out a CFS symptom inventory questionnaire before the start of intervention and at the end. Subjects reported significant reductions in scores of fatigue, sleep disturbance, and pain.

It is known that curcumin in its pure form has poor bioavailability, meaning only a small proportion of the molecule is absorbed, and much of what is absorbed is metabolized and transformed to other forms. ²⁵⁵ Scientists may have found a solution to dramatically improve curcumin’s bioavailability by combining it with a compound called “galactomannan” found in fenugreek.²⁵⁶ This formulation, called curcumagalactomannoside, was studied in a randomized double-blind crossover trial in 50 healthy human subjects.²⁵⁷ Results showed the new, conjugated formula allowed for active free curcumin to reach 45 times greater levels in blood compared to unconjugated, pure curcumin. Since then, more studies using this formulation have been performed including a randomized controlled trial to test the efficacy in 60 subjects with occupational stress-related anxiety and fatigue,²⁵⁶ of which 20 received the curcumagalactomannoside formula at a dose of 500 mg twice per day. Using a quality-of-life metric, the investigators reported significant improvements in anxiety, stress, and fatigue levels.

Magnesium

Magnesium is an essential mineral involved in hundreds of enzymatic reactions in humans, and its deficiency may be linked to chronic fatigue.²⁵⁸ Inadequate magnesium intake is a common and often underestimated problem.²⁵⁹ For example, a data analysis from the National Health and Nutrition Examination Survey (NHANES) of 2013‒2016 found 49% of Americans of all ages ingest less magnesium from food and beverages than their estimated average requirements, which are 420 mg and 320 mg daily for men and women over age 30, respectively.²⁶⁰

Some, but not all, studies reported supplemental magnesium is helpful for people with CFS or fibromyalgia. To test the utility of magnesium in CFS, researchers in a single study first reported that 20 adults with CFS had significantly lower red blood cell magnesium levels compared with 20 healthy controls, and followed it up in a placebo-controlled clinical trial in which 32 CFS patients were randomly chosen to receive either an intramuscular injection of 1 gram magnesium sulfate (15 patients) or placebo (17 patients) weekly for six weeks.¹⁴ The treatment group had significantly improved energy levels and less pain, were less emotionally reactive, and perceived significant overall improvement compared with placebo. Eighty percent of magnesium-treated subjects reported benefit from the treatment versus 18% of controls. Although not a CFS study, an uncontrolled trial of up to 600 mg magnesium and 2,400 mg malic acid daily in 24 fibromyalgia subjects reported significant declines in pain and tenderness.²⁶¹

Magnesium levels can be measured in a variety of ways. These include red blood cell magnesium, serum magnesium, and sometimes 24-hour urine magnesium. The traditional test for magnesium is subject to misinterpretation, as the standard normal range includes suboptimal levels and subclinical magnesium deficiency.^262,263 This has created confusion in some studies that test serum magnesium and conclude that magnesium status is adequate. Both red blood cell and serum magnesium must be interpreted properly, with a correct understanding of true optimal and subclinical deficiency levels.

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, modulate inflammatory pathways in the body. They are also important for supporting the integrity of cell membranes and can favorably impact blood lipid levels.²⁶⁴

A low omega-3 level in the body is associated with a pro-inflammatory state and increased cardiovascular risk. A 2018 cross-sectional study of 31 CFS patients in Spain found low levels of DHA and EPA in the vast majority of participants.²⁶⁵ These findings corroborate earlier, similar findings of low omega-3 levels in people with CFS.²⁶⁶

In a study on 63 adults with post-viral fatigue syndrome, subjects were treated daily with either a 4-gram per day dosage of a mixture of omega-6 fatty acids and fish oil or matching placebo. At three months, 85% of the treatment group reported significant improvement compared with 17% of the placebo group.²⁶⁷ An uncontrolled study in four subjects with CFS found 12 weeks of daily supplementation with a high EPA formula resulted in symptomatic improvement in all subjects.²⁶⁸

Vitamin D

Vitamin D, which is both a vitamin and hormone, plays a critical role in immune, musculoskeletal, cardiovascular, and endocrine function.²⁶⁹ Given its myriad roles in the body, it is not surprising vitamin D has been implicated in CFS.

One study of 221 people with CFS demonstrated average vitamin D blood levels less than 18 ng/mL—significantly lower than controls.²⁷⁰ Another study in 41 people with CFS found vitamin D levels correlated inversely with some biomarkers of cardiovascular risk, inflammation, and oxidative stress, including TNF-α, isoprostanes, and brachial diastolic blood pressure.²⁷¹ In this study, subjects’ vitamin D levels were similarly low, also with a median level of only 18 ng/mL.

Other researchers have suggested vitamin D may be useful in ameliorating CFS by modulating inflammatory pathways thought to be involved in the condition, namely the nuclear factor kappa B (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.²⁷²

Cocoa

Chocolate is made from cocoa beans, which contain a wide range of phytochemicals (eg, 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 grams polyphenol-rich dark chocolate three times daily. After eight weeks of treatment, fatigue, depression, and anxiety scores declined significantly. Then, following a 2-week period of no treatment, participants were given another preparation of 15 grams of low-polyphenol, simulated dark chocolate three times daily. During this time, their condition deteriorated significantly. The simulated dark 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.²⁷³ Compounds in chocolate may interact with various receptors in the brain,²⁷⁴ and an imbalance of neurotransmitters has been suggested in CFS subjects.²⁷⁵ The researchers hypothesized that by modulating neurotransmitters, polyphenol-rich chocolate reduced symptoms of CFS.²⁷³ More studies on high phenolic foods and diets should be carried out to confirm these findings in CFS.

Vitamin C

Oxidative stress, particularly after exertion, may contribute to chronic fatigue. In a study that included 38 CFS patients and five healthy controls, levels of reduced ascorbic acid (the form of vitamin C available in the body as an antioxidant) were lower in the 20 CFS patients with a history of severe acute infection (peritonitis, pneumonia, acute respiratory distress syndrome, or encephalomyelitis) than in controls. This study also found that, after a maximal exercise cycling test, a marker of oxidative stress (TBARS) was elevated in CFS patients with a history of high-level sport practice or severe acute infection relative to control subjects.²⁷⁶ In another study, the ratio of reduced ascorbic acid to TBARS was lower in those with CFS than in healthy subjects.²⁷⁷ Ascorbic acid oxidation was found in other research to be almost three-fold higher in participants with CFS compared with healthy individuals after the same intensity of exercise.²⁷⁸ Taken together, these findings suggest some CFS patients may have an increased demand for vitamin C, especially during exertion.

Vitamin C may be beneficial in CFS patients with EBV infection. A clinical report based on data from 218 patients with EBV infection, of whom 110 had CFS, found higher vitamin C levels were correlated with lower EBV antibody levels, and treatment with intravenous vitamin C, at doses of 7.5–50 grams per session, resulted in dramatic reductions in EBV antibody levels. Furthermore, those who received five or more treatments with intravenous vitamin C had significantly greater and faster reductions in EBV antibody levels than others who did not receive any intravenous vitamin C.²⁷⁹ Unfortunately, the study did not report on changes in levels of fatigue.

Phosphatidylcholine and Choline

Phosphatidylcholine is a major component of cell membranes, assists in fat metabolism, and is a source of the essential nutrient choline, which itself is a precursor for the methyl donor betaine and neurotransmitter acetylcholine.^280,281 Blood levels of phosphatidylcholine have been found to be lower in patients with CFS compared with healthy controls.^282,283 It has been proposed that supplementing with phosphatidylcholine and other cell membrane components plus antioxidants can enhance repair of membrane phospholipids damaged by oxidative stress and improve cellular and mitochondrial function in people with CFS.^284,285 One open-label trial found 15 subjects with moderate-to-severe chronic fatigue exhibited better mitochondrial function and reduced fatigue after four to eight weeks of treatment with a supplement containing a proprietary combination of membrane lipids, probiotic bacteria, and a variety of nutrients.²⁸⁵ In another open-label trial in 58 participants with chronic fatigue (30 of whom had CFS), treatment with the same supplement, along with other supplements providing vitamin E, NADH, coenzyme Q10, calcium, phosphorus, magnesium, alpha-ketoglutarate, L-tyrosine, L-carnitine, L-tartrate, and pantethine (a vitamin B5-related nutrient), led to a greater than 30% reduction in scores on tests of fatigue after eight weeks.²⁸⁶

In addition to improving cellular and mitochondrial function, choline may help CFS patients by supporting methylation and clearance of toxins.⁵ A combination of choline and vitamin C was reported to improve symptoms in four patients diagnosed with CFS who were found to have high levels of organophosphates (pesticide environmental toxins). Reductions in organophosphate levels occurred in tandem with symptom improvement.²⁸⁷