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Brown—Chronic Fatigue Syndrome ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1 29
Chronic Fatigue Syndrome: A Personalized
Integrative Medicine Approach
Benjamin I. Brown, ND
REVIEW ARTICLE
ABSTRACT
Chronic fatigue syndrome/myalgic encephalomyelitis
(CFS/ME) is a relatively common illness, yet despite con-
siderable investigation, current treatments have modest
benets, and the prognosis remains poor. Because
CFS/ME is a heterogeneous disorder with diverse etio-
logical factors and pathological features, a patient-cen-
tered integrative framework based on modiable physio-
logical and environmental factors may oer hope for more
eective management and better clinical outcomes. An
individualized approach may also help target interven-
tions for subgroups most likely to respond to specic
treatments. is review summarizes a number of avenues
for integrative management, including dietary modica-
tion, functional nutritional deciencies, physical tness,
psychological and physical stress, environmental toxicity,
gastrointestinal disturbances, immunological aberrations,
inammation, oxidative stress, and mitochondrial dys-
function. A personalized, integrative approach to
CFS/ME deserves further consideration as a template for
patient management and future research. (Altern er
Health Med. 2014;20(1):29-40.)
Benjamin I. Brown, ND, is a lecturer at the UK College of
Nutrition and Health (BCNH) in London, England.
Corresponding author: Benjamin I. Brown, ND
E-mail address: BenBrown@bcnh.co.uk
Chronic unexplained fatigue is a very common clinical
complaint. In primary care settings, an estimated
24% of patients report fatigue as a signicant prob-
lem, and population estimates for chronic fatigue syndrome/
myalgic encephalomyelitis (CFS/ME) range from 1.85% to
11.3%.1 Despite the high prevalence of CFS/ME and consid-
erable research on the disease, the amount of time required
to diagnose it remains long, and its prognosis continues to be
poor. Diagnosis takes an average of 5 years from initiation of
symptoms to identication of the syndrome, with total
recovery rates between 0% and 37% and rates of improve-
ment between 6% and 63%.2 e poor prognosis for CFS/ME
in part may be due to its heterogeneous nature, and like
many chronic diseases, it has a number of etiological and
functional disturbances that contribute to the disease’s course
and symptoms.
Although the exact cause of CFS/ME is unknown, sev-
eral underlying and sometimes characteristic states of physi-
ological dysfunction have been identied; in particular,
abnormalities of the immune and central nervous systems
have been found.3 ese nding have led some researchers to
suggest that looking for the cause of CFS/ME is a self-defeat-
ing exercise; they suggest that focusing on rehabilitation and
improvement of functional status is more important.4 is
notion leads to the possibility of creating an integrative man-
agement approach that is grounded in the hypothesis that
CFS/ME is the manifestation of a complex state of physio-
logical dysfunction unique to an individual.5
Integrative medicine involves the application of a
patient-centered, individualized approach to disease man-
agement that incorporates the best available treatment
options, including conventional and evidence-based com-
plementary and alternative medicine.6 To this end, the prac-
titioner may evaluate physiological function during assess-
ment, while treatments typically may incorporate environ-
mental, lifestyle, mind-body, dietary, and nutraceutical
interventions. e aim of this review is to explore modiable
environmental and physiological factors that may play a role
in CFS/ME and to discuss the current evidence for corre-
sponding treatments from an integrative perspective.
CLINICAL ASSESSMENT AND DEFINITION
e current method of diagnosis of CFS/ME is based on
exclusion of alternative explanations for fatigue, and no
accepted, standard investigative tests exist that can conrm
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Brown—Chronic Fatigue Syndrome
30 ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1
therapies are available.18 Clinical improvements, however, are
modest, with some 40% to 50% of patients reporting improve-
ments in fatigue aer treatment with CBT or GET versus
20% to 30% in usual care. Furthermore, the generalizability
of ndings from randomized, controlled trials to real-world
clinical settings is contentious, and long-term treatment out-
comes are uncertain.19
e eects of GET and CBT on disability and quality of
life are discouraging. At 12 months, health-related quality of
life was not shown to improve with CBT and GET versus
usual care; in fact, physical function and scores for bodily
pain were worse in the intervention group.20 One study
examined the impact of interventions, including GET and
CBT, on disability, as indicated primarily by the ability to
work.21 It concluded that no currently available intervention
was able to restore functional status (ie, the ability to work).
e apparent limitations of current treatments, coupled
with the diverse etiopathogenesis of CFS/ME, has led some
investigators to suggest that an individually tailored approach
to treatment, which takes into account a patient’s unique
pathological features and employs corresponding evidence-
based treatments, may be a more rational approach to patient
management.19
A number of modiable physiological and environmen-
tal factors have been investigated as contributors to CFS/ME.
ese factors include dietary and nutritional factors, physical
tness, psychological and physical stress, various environ-
mental pollutants, gastrointestinal disturbances, chronic
infection, inammation and oxidative stress, and mitochon-
drial dysfunction (Figure 1).
In this review, the author explores each of these catego-
ries sequentially, briey discussing supportive evidence for
their contribution to CFS/ME and then investigating poten-
tial treatments, including behavioral, mind-body, dietary,
lifestyle, and nutraceutical interventions.
DIETARY AND GENERAL NUTRITIONAL
CONSIDERATIONS
Although diet is known to be a potent modier of sev-
eral chronic diseases, investigations of diet in CFS/ME are
lacking. One investigation found no relationship between
current dietary habits—including intake of alcohol, fat,
bers, fruit, and vegetables—and fatigue severity or func-
tional impairments in individuals with CFS/ME.22 Although
individuals with CFS/ME tended to lead healthier lifestyles
compared to the general population, in one study, 70% had
unhealthy fat, fruit, and vegetable intake, and 95% had
unhealthy ber intake.22
It is plausible to suggest that dietary intervention could
improve functional status in CFS/ME, considering that a
healthy dietary pattern such as a traditional Mediterranean-
style diet could counter functional impairments, such as low-
grade inammation and oxidative stress, and improve men-
tal vigor, mood, and physical tness.23-27 Some evidence that
supports this hypothesis comes from a dietary intervention
with high-polyphenol dark chocolate. In this study, eating
or refute a diagnosis.7 e most commonly accepted symp-
tom criterion is the 1994 case denition for CFS/ME from
the Centers for Disease Control and Prevention (CDC).8
According to this denition, an individual must satisfy 2
criteria to be diagnosed with CFS. e individual (1) must
have self-reported, persistent or relapsing fatigue for at least 6
consecutive months, and other medical conditions for which
manifestation includes fatigue must be excluded by clinical
diagnosis and (2) must have 4 or more of the following symp-
toms concurrently: postexertional malaise, impaired memory
or concentration, unrefreshing sleep, muscle pain, multijoint
pain without redness or swelling, tender cervical or axillary
lymph nodes, sore throat, or headache—that must have per-
sisted or recurred during 6 or more consecutive months of
illness and must not have predated the fatigue.
Scientists have also noted that children may dier in
presentation from adults with CFS/ME, displaying symp-
toms such as sadness, hyperactivity (initial phase), episodic
tension headaches, abdominal pain, tachycardia, and ortho-
static hypotension. Notably CFS/ME in children may be
mistaken for laziness or school phobia.9
Routine clinical investigations are recommended by the
UK National Institute of Clinical Excellence to exclude medi-
cal causes of chronic fatigue, and additional serology should
be done to exclude bacterial and/or viral involvement if the
individual’s history suggests the possibility of a recent infec-
tion.10
Individuals with CFS/ME should also be evaluated for
psychiatric illnesses, as symptoms of depression and psycho-
logical stress are commonly associated with the condition.11
Although depressive disorder may be an important diagnos-
tic exclusion, a number of important features can indicate a
concomitant presentation of CFS/ME with depression.
Dierential symptoms of CFS/ME with depression com-
pared to primary depression include the following: (1) indi-
viduals with CFS/ME lack feelings of anhedonia (inability to
experience pleasure, guilt, and decreased motivation that is
classically seen in individuals with depression); (2) individu-
als experience several CFS/ME symptoms, including pro-
longed fatigue aer physical exertion, night sweats, sore
throats, and swollen lymph nodes, which are not commonly
found in depression; (3) fatigue is the principal feature of
CFS/ME but does not assume equal prominence in depres-
sion; and (4) illness onset with CFS/ME is oen sudden,
occurring over a few hours or days, whereas primary depres-
sion generally shows a more gradual onset.12,13
Most important, CFS/ME shares many symptomatic
features with other functional somatic syndromes, including
irritable bowel syndrome (IBS), bromyalgia (FM), multiple
chemical sensitivity, headaches, and temporomandibular
joint dysfunction.14 Overlap between CFS/ME and FM is
particularly common, with approximately 20% to 75% of
individuals with CFS/ME meeting the criteria for FM.15-17
Currently recommended treatments for CFS/ME
include cognitive behavior therapy (CBT) and graded exer-
cise therapy (GET), and no suggested pharmacological
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Brown—Chronic Fatigue Syndrome ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1 31
dark chocolate for 8 weeks—15 grams, 3 times per day—sig-
nicantly reduced fatigue, increased physical activity, and
reduced anxiety and depression in CFS/ME suerers.28
Phytonutrient-dense, polyphenol-rich foods are thought to
be a major reason for the benecial eects of a traditional
Mediterranean-style diet.29
Food sensitivities may play a role in chronic unexplained
fatigue. One investigation reportedly found that the elimina-
tion of wheat, milk, benzoates, nitrites, nitrates, food additives,
and food colorings resulted in a signicant improvement in
CFS/ME symptoms of fatigue, recurrent fever, sore throat,
muscle pain, headache, joint pain, cognitive dysfunction, and
IBS.30 In addition, celiac disease is commonly associated with
fatigue, which improves on a gluten-free diet; however the
possibility of a relationship between CFS/ME and gluten sen-
sitivity has not been investigated.31
Functional Nutritional Deciencies
Functional nutrition is a paradigm grounded in the
notion that unique imbalances in nutritional status can give
rise to changes in physiological function that may ultimately
inuence the expression of disease.32 e functional-nutri-
tion model is a patient-centered approach that is concerned
with identifying nutritional imbalances unique to an indi-
vidual and correcting them through diet and/or nutritional
supplementation to restore healthy physiological function. A
number of functional nutritional deciencies have been
identied in CFS/ME. While nutrient interventions are likely
to have small eect sizes and considerable variations in treat-
ment response in studies, it is important to consider that
they may still oer benet to the individual, and they have an
excellent safety prole.33
Vitamin D. A retrospective survey of serum levels of
25-hydroxyvitamin D (25[OH]D) in individuals with
CFS/ME found that vitamin D levels were signicantly lower
compared to the general population, with a mean of 44.4
nmol/L (optimal levels
>
75 nmol/L).34 Researchers have
hypothesized that vitamin D deciency may contribute to
CFS/ME though association with increased oxidative stress,
inammation, and subsequent generation of fatigue symp-
toms.35 In a series of case reports, the treatment of CFS/ME
with vitamin D was reported to result in a modest clinical
improvement in some individuals.36 No controlled clinical
trials of vitamin D in CFS/ME have occurred.
Because symptoms of severe vitamin D deciency may
include fatigue, depression, weakness, and muscle pain, peo-
ple with vitamin D deciency may oen be misdiagnosed as
having FM or CFS.37 In one report, 93% of adults and chil-
dren presenting with nonspecic muscle pain were vitamin
D decient.38 Another study found that 58% of participants
with musculoskeletal pain, headache, and fatigue were vita-
min D decient.39 Individuals with nonspecic skeletomus-
cular pain should have their serum 25(OH)D assessed
because of the wide-ranging health benets of treating vita-
min D deciency.40
Long-chain Polyunsaturated Fatty Acids. It has been
hypothesized that a functional impairment of fatty-acid
metabolism may in part explain functional changes in the
central nervous system as well as clinical symptoms for indi-
viduals with CFS/ME. Central to this hypothesis is the
Figure 1. Modiable Physiological and Environmental Factors
Psychological/Physical Stress
Central nervous system dysfunction.
Low cortisol output.
Environmental Toxicity
Increased body burden of
environmental pollutants.
Immune Dysfunction
Decreased resistance to pathogens.
Chronic viral infection.
Gastrointestinal Involvement
Bacterial imbalance (dysbiosis). Intestinal permeability.
Low-grade metabolic endotoxemia.
Inammation/Oxidative Stress
Systemic elevations in oxidative stress.
Chronic low-grade inammation.
Nutritional Considerations
Low nutrient density. Food sensitivities.
Functional nutritional deciencies.
Physical Fitness
Exercise intolerance.
Decreased conditioning
Mitochondrial Dysfunction
Impaired cellular energy production.
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Brown—Chronic Fatigue Syndrome
32 ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1
mitter synthesis and production of adenosine triphosphate
(ATP) might contribute to CFS/ME, an exploratory open
label study was conducted.59 CFS/ME participants had their
fasting levels of plasma amino acid measured and were then
prescribed 15-gram mixtures of free-form amino acids based
on their test results. e treatment duration was 3 months.
Of the 20 participants who completed the study, 90% experi-
enced at least a 25% improvement in symptoms, with 75%
having reported a 50% to 100% improvement. is promis-
ing study suggests a need for further research on the poten-
tial of personalized amino acid therapy.
Carnitine. e amino acid carnitine plays a crucial role
in mitochondrial energy production, and both functional
deciencies and the eects of dietary supplementation have
been investigated. In one study, the plasma carnitine status of
participants with CFS/ME was found to be 30% to 40% lower
in certain forms of carnitine than controls, with a signicant
correlation between carnitine concentrations and clinical
symptoms.60
A randomized, controlled trial of carnitine (3000 mg/d)
in individuals with CFS/ME demonstrated a signicant
clinical improvement in symptoms, especially between the
fourth and eighth week of treatment.61 Comparing acetyl-L-
carnitine (2000 mg/d), propionyl-L-carnitine (2000/d), or a
combined treatment (2000 mg of each/d), an open label
study found benecial eects on symptoms such as fatigue,
pain, and cognitive function from all treatments.62
Zinc. Serum zinc has been found to be signicantly lower
in individuals with CFS/ME versus healthy controls, and low
levels of zinc have been associated with an increase in symp-
tom severity and measures of immunological dysfunction.63
Based on the correlation between low serum zinc and increased
clinical symptom severity, the study’s investigators suggested
that some participants with CFS/ME should be considered for
treatment with zinc supplements. Although no clinical trials of
zinc in CSF/ME have occurred, clinical evidence suggests that
zinc supplementation may inuence fatigue, immune func-
tion, mood, inammation, and oxidative stress.64-67
PHYSICAL FITNESS
A characteristic feature of CFS/ME is worsening of
symptoms aer increased daily physical activity or modest
amounts of exercise.68,69 Individuals with CFS/ME are also
known to have a lower, peak, isometric muscle strength and
perform less physical activity during daily life.70 Compared
to healthy controls, individuals with CFS/ME tend to have a
relatively lengthened and accentuated, oxidative stress
response to physical activity that is linked to the develop-
ment of postexertional symptom exacerbation.71 Elevations
in the proinammatory, cytokine tumor necrosis factor-α
(TNF-α) at 2 time points—3 hours and 3 days aer exer-
cise—have also been observed.72
To improve physical tness gradually and reduce symp-
toms, GET has been proposed as a treatment for CFS/ME
and appears to be moderately eective when delivered by
highly experienced therapists. A systematic review of GET
notion that viral infection associated with CFS/ME may
impair the biosynthetic pathway for long-chain polyunsatu-
rated fatty acids (PUFAs) that in turn could have important
consequences for the structure and function of the central
nervous system.41
e ndings of a randomized, controlled clinical trial
lend support to this hypothesis.42 e researchers observed
that treatment with the fatty acids γ-linolenic acid (GLA),
eicosapentaenoic acid (EPA), and docosahexaenoic acid
(DHA) improved the symptoms of CFS/ME. A second clini-
cal trial, however, failed to conrm these results.43
In a series of case reports, treatment with high potency
EPA and GLA resulted in clinical improvement for CFS/ME
suerers.44 And in a separate case report, high-resolution,
structural scans using magnetic resonance imaging (MRI)
revealed that treatment was accompanied by improvements in
brain structure—a reduction in lateral ventricular volume.45
B Vitamins. Functional deciencies of the vitamins
pyridoxine, riboavin, and thiamine in individuals with
CFS/ME have been reported.46 And evidence of low levels of
serum folate and elevated levels of homocysteine in cerebro-
spinal uid—a functional marker of folate or vitamin B12
deciency—have also been documented.47,48
Studies of clinical interventions with B vitamins have
been mixed. Two randomized, controlled trials have com-
pared treatment with nicotinamide adenine dinucleotide
(NADH), the active form of niacin, to treatment with a pla-
cebo or to psychological therapy. One randomized clinical
trial showed statistically signicant eects for NADH (10 mg)
on symptom scores aer 1 month of treatment, when com-
pared with a placebo.49 A second clinical trial also reported
signicant positive eects for NADH (5-10 mg) in the rst
month of treatment and a continued but modest trend toward
improvement aer 3 months.50 Treatment with a multivitamin
and minerals was found to improve symptoms of functional
fatigue while another study of a multivitamin in CFS/ME suf-
ferers demonstrated no benet.51,52 A study of a folate and
vitamin B12 also reported no evidence of benet.53
Magnesium. Low magnesium status has been described
in CFS/ME and FM suerers in some but not all studies, and
the contribution of low magnesium status to the pathogen-
esis of chronic fatigue remains controversial.54,55 It has been
suggested, however, that subclinical magnesium deciency
could be dicult to detect and could be linked to the devel-
opment of CFS/ME via contribution to a pro-oxidant, low-
grade inammatory state.56
Some empirical evidence suggests that magnesium
supplementation may be helpful to individuals with CFS/
ME. In a case control study, intravenous treatment with
magnesium was found to improve energy levels and emo-
tional state and to reduce pain.57 And an isolated case report
described an individual with severe CFS/ME who experi-
enced signicant clinical improvement aer intravenous
magnesium therapy.58
Amino Acids. Based on the hypothesis that a functional
deciency in various amino acids required for neurotrans-
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Brown—Chronic Fatigue Syndrome ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1 33
suggested that some individuals might benet from exercise
therapy.73 A more recent review of GET, which examined 12
studies, concluded that consistent evidence of benet exists,
although the level of benet was not quantiable.74
Nevertheless the role of GET has been criticized based on
marginal benets versus usual care, and opponents suggest
that exercise may exacerbate an underlying pathological
state of inammatory and oxidative stress, resulting in symp-
tom exacerbation and patients’ dissatisfaction.75
Overall, the eects of GET appear to be modest and may
have adverse eects.76 erefore, GET may not always be
appropriate, and the underlying inammation and oxidative
stress may need to be addressed rst. If commencing exercise
therapy, a self-paced approach may minimize risk of adverse
eects (ie, advise patients not to increase physical activity if
they are well and to reduce or stop exercise if unwell).77
PSYCHOLOGICAL AND PHYSICAL STRESS
Stress Management
e role of stress and the functional dynamics of the
hypothalamic-pituitary-adrenal (HPA) axis in the
development, maintenance, and treatment of CFS/ME have
attracted considerable research. Dysfunction of the HPA axis
is one of the most consistent ndings in CFS/ME, with
evidence suggesting an inuence on functional status and
treatment response.78
A review of the current evidence concluded that the
most generalizable characteristic of the HPA axis dysfunction
across CFS/ME suerers is a modest reduction in cortisol
levels in some individuals.79 Underlying, low cortisol levels
are changes in HPA axis dynamics, including an attenuated,
diurnal variation of cortisol; enhanced negative feedback to
the HPA axis; and blunted HPA axis responsiveness.
In some cases, the development of CFS/ME may be
preceded by adverse life events and neuroendocrine
dysfunction.80 However, it seems that HPA axis dysfunction
typically develops aer the onset of CFS/ME, at which point
it plays an important role in the maintenance of symptoms
and in the disease’s course.79 It has been proposed that the
cause of HPA axis dysfunction is multifactorial and involves
a variety of factors, including physical inactivity, diet, sleep
disturbance, chronic psychological stress, mental health, and
the phase of the CFS/ME itself.81
Cognitive Behavioral erapy
One intervention that may improve some individuals’
ability to cope with the illness and modestly improve clinical
symptoms is cognitive behavioral therapy (CBT).82 A clinical
trial of CBT found a 16% increase in total cortisol output
aer 6 months of therapy, making it one of the few interven-
tions shown to improve cortisol levels in individuals with
CFS/ME.83 It is worth noting, however, that some individuals
with CFS/ME report feeling worse aer CBT, which may be
due in part to decits in clinical administration or to side
eects from graded exercise usually incorporated in CBT
treatment.84
Mind-Body Medicine
Mind-body therapies may help reduce stress and
improve HPA axis function. ree meditation interventions
for CFS/ME have found a reduction in symptoms and/or an
increase in physical functioning.85 And fatigue symptoms
and mental functioning improved compared to controls in a
randomized, controlled trial of qigong exercise.86
Low-dose Hydrocortisone
Because low cortisol is a common feature of CFS/ME,
some studies have explored the eects of low-dose hydrocor-
tisone administration, although this treatment is not recom-
mended.87 While low-dose hydrocortisone is generally well-
tolerated and can reduce fatigue in the short term, studies of
clinical interventions have suggested that treatment sup-
presses adrenal glucocorticoid responsiveness, which limits
the usefulness of this therapy.88,89
Herbal Adaptogens
Herbal medicines with evidence for improving
physiological adaption to stress are referred to as adaptogens.90
An isolated case report suggested that treatment with the
herbal medicine licorice (Glycyrrhiza glabra) could improve
symptoms of CFS/ME.91 e researcher hypothesized that
this eect was due to the ability of glycyrrhetic acid, an active
metabolite in licorice, to inhibit the enzymatic breakdown of
cortisol. Evidence suggests that licorice can increase cortisol
availability; however, it has not been studied in individuals
with CFS/ME.92
e herbal medicine Rhodiola rosea has demonstrated
an antifatigue eect in a number of clinical studies.93 In
individuals with stress-related burnout, R rosea was found to
improve mood, fatigue, and HPA axis function, although
investigations related to CFS/ME are lacking.94
A clinical study of Siberian ginseng (Eleutherococcus
senticosus) failed to nd overall evidence of benet in
participants with chronic fatigue; however, a subgroup
analysis did suggest a modest benet in participants with
less-severe fatigue.95
ENVIRONMENTAL POLLUTANTS
A number of reports have linked toxins—including pes-
ticides and insecticides, mercury, lead, nickel, and ciguatera
poisoning—to CFS/ME or chronic, fatigue-like symptoms.96
Cadmium and tobacco smoke have also been hypothesized
to play a role.97,98 Because these reports are limited by several
factors, such as variable exposure and outcome measure-
ments, small sample sizes, and unreliable CFS/ME deni-
tions, they provide only weak evidence of an association;
however, further research in this area appears warranted.
In an illustrative study, serum organophosphates in
CFS/ME participants were found to be higher than in con-
trol participants and comparable CFS/ME participants with
a known chemical exposure.99 is nding suggests a possi-
ble role for low-level bioaccumulation of persistent organic
pollutants in the development of CFS/ME. Another report
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Brown—Chronic Fatigue Syndrome
34 ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1
found that a small group of individuals who had developed
CFS/ME aer toxic exposure (ciguatera poisoning or expo-
sure to solvents) had disturbances of hypothalamic function
similar to matched CFS/ME controls. Moreover, the group
with toxic exposure had more severe dysfunction of the
immune system.100
Nutritional Detoxication
Various methods are available to enhance detoxication.
A number of foods and nutrients have been shown to reduce
absorption and/or enhance the excretion of various toxi-
cants, while avoidance of environmental and food sources of
toxins may minimize exposure.101 Nutritional detoxication
incorporates dietary change and the use of nutrients to sup-
port endogenous detoxication pathways and has been
shown to enhance hepatic metabolism and improve subjec-
tive symptoms of fatigue.102-105
A detoxication program using ascorbic acid and
choline for individuals with CFS/ME reported that symptoms
improved as blood levels of pesticides decreased.106 And a
group of individuals with mercury toxicity and severe
fatigue, but not established CFS/ME, reportedly experienced
excellent improvements aer specialized dental-amalgam
removal (a source of mercury exposure) and a detoxication
program incorporating oral dimercapto-succinic acid
(DMSA), chlorella, and additional nutrient and antioxidant
support.107 Interestingly, infrared sauna therapy, which might
support diaphoretic elimination of persistent organic pollut-
ants, may also benet CFS/ME.108,109
GASTROINTESTINAL DISTURBANCES
Gastrointestinal dysfunction is very common in
CFS/ME and may contribute to the pathogenesis of the
disease.110 A number of changes in gastrointestinal function
have been identied in CFS/ME, including alterations in the
gut microbiota (dysbiosis), increased gastrointestinal perme-
ability, and altered mucosal immunity. e gastrointestinal
system has also been considered a source of systemic, low-
grade inammation and oxidative stress in CFS/ME.111
In particular, dysbiosis, increased intestinal permeability,
and subsequent low-grade metabolic endotoxemia, or leaky
gut, have been suggested to play a role in CFS/ME
pathogenesis.112,113 Low levels of Bidobacterium, high levels of
Enterococcus and Streptococcus, and small intestinal bacterial
overgrowth (SIBO) have been identied and may inuence
systemic CFS/ME pathology.114,115 And compared to healthy
controls, the prevalence and median values for serum antibod-
ies against the lipopolysaccharide (endotoxin) were found to
be signicantly greater in participants with CFS/ME and were
signicantly correlated to symptom severity.116
Nutritional Management of Leaky Gut
Circulating endotoxin has been shown to be highly
responsive to dietary change, with a healthy dietary pattern
able to reduce circulating endotoxin by 31% within 1
month.117 One study examined the eects of a clinical
intervention aimed at reducing intestinal permeability and
circulating endotoxin in CFS/ME. Dietary change and
treatment with anti-inammatory and antioxidative nutri-
ents—such as glutamine, N-acetylcysteine, and zinc—over
10 to 14 months signicantly reduced antibody responses to
endotoxin, with over 50% of participants showing signi-
cant clinical improvement or remission.118
Probiotics
Experimental evidence suggests that administration of
probiotic bacteria may attenuate the underlying pathology of
CFS/ME, namely systemic inammation and oxidative
stress.119 Probiotic bacteria have also been demonstrated to
inuence HPA-axis function and mood in humans, which
may be of particular relevance to CFS/ME suerers.120
A clinical intervention with a strain of Lactobacillus casei
Shirota in participants with CFS/ME was found to increase gut
Lactobacillus and Bidobacterium and to decrease anxiety
symptoms signicantly aer 8 weeks of treatment, as com-
pared to controls.121 And another clinical trial of a probiotic
(Lactobacillus paracasei sp. paracasei F19, Lactobacillus aci-
dophilus NCFB 1748, and Bidobacterium lactis Bb12) in
CFS/ME found a signicant improvement in neurocognitive
function and a trend toward improvement in general symp-
toms and quality of life in some individuals.122
CHRONIC INFECTION
e development of CFS/ME is frequently reported to
occur aer infectious-like illness characterized by symptoms
such as myalgia, fever, adenopathy, and respiratory issues,
and/or gastrointestinal disturbances. Several viruses and
some bacteria have been implicated, although the evidence
for a specic infectious cause of CFS/ME is mixed. Immune
dysfunction has also been reported; in particular, impaired
T- and B-cell memory and altered natural killer (NK) cell
activity may decrease resistance to viral pathogens. It is
likely that an interplay between decreased immunological
resistance and chronic viral infection plays a role in main-
taining CFS/ME symptoms.123
Many of the pathogens linked to CFS/ME are able to
produce a persistent, oen lifelong, infection and, therefore,
may be a cause of continued immunological involvement.
Several have also been shown to be neuropathogens directly
or indirectly aecting the central nervous system, which may
in part explain the pathological features and clinical symp-
toms of CFS/ME.124 Further, experimental evidence suggests
that viral infection may be exacerbated by chronic stress.125
A number of immunological therapies have been
explored, with mixed evidence of benet. For example, intra-
venous immunoglobulin therapy was found to be ineective,
while α-interferon treatment improved quality of life only in
individuals with low NK cell function.126,127 In contrast, long-
term treatment with the antiviral drug valacyclovir led to
decreased serum antibodies to Epstein-Barr virus (EBV) and
a signicant clinical improvement in a subgroup of individu-
als with CFS/ME with persistent EBV infection.128
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Brown—Chronic Fatigue Syndrome ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1 35
Immunonutrition and Herbal Medicine
Nutritional interventions—for example, vitamin C, zinc,
and essential fatty acids—have been proposed to play a role
in CFS/ME management due to their potential to improve
immunological function and/or act as antiviral agents;
however, human clinical investigations are lacking.56 Of
particular note, low PUFAs and zinc status have been
observed in individuals with CFS/ME and correlated with
decreased immune function.129,130 Both zinc and PUFAs have
well documented immunomodulatory activity.131,132
An exploratory study of the herbal medicines Echinacea
and Panax ginseng found that they were able to stimulate cel-
lular immune function in the isolated serum of participants
with CFS/ME.133 Considering the well-established immune
modulating and antiviral eects of Echinacea, investigation
in CFS/ME suerers with evidence of chronic viral infection
appears warranted.134
INFLAMMATION AND OXIDATIVE STRESS
Inammation and oxidative stress have been proposed
as fundamental pathological features of CFS/ME, and several
independent investigations have found evidence of distinct
elevations in chronic, low-grade inammation and oxidative
stress in CFS/ME suerers compared to healthy controls.135-137
For example, one study found signicantly increased levels
of C-reactive protein (CRP) and 8-iso-prostaglandin F2α iso-
prostanes in participants with CFS/ME versus healthy partici-
pants.138 In another investigation, peroxide concentrations
were signicantly higher in participants with CFS/ME and
distinctly dierentiated participants with CFS/ME from healthy
controls.139 And some evidence suggests that elevations in oxi-
dative stress correlate directly with symptom severity.140
e elevation in inammation and oxidative stress
underlying CFS/ME has been proposed to place individuals
at risk for other chronic diseases associated with these
pathological sequelae; in particular, heart disease may be a
risk.141 Cardiovascular risk factors are higher in CFS/ME
suerers, and a lower life expectancy has been reported in
individuals with CFS/ME, with heart failure a major cause of
mortality.142,143
Antioxidant and Anti-inammatory Nutrition
Because oxidative stress may play an important role in
disease pathogenesis and can be reduced by dietary change
and nutritional supplementation, such interventions have
been proposed for the management of CFS/ME but so far are
not well-investigated.144 Additionally the interpretation of
nutritional antioxidant interventions is limited by the fact
that an antioxidative function is typically only one of many
diverse and unique biological eects of various nutritional
substances. Nonetheless some experimental evidence in
models of CFS/ME has indicated that certain natural
antioxidants may result in reductions in oxidative stress that
correlate with symptom improvement.145 For example, both
green tea extract and curcumin have been shown to reduce
oxidative stress and fatigue.146,147
e dietary supplement coenzyme Q10 (CoQ10) is an
essential cofactor in mitochondrial energy metabolism and a
strong antioxidant with indications of potential benet in
CFS/ME. CoQ10 is produced endogenously; however, a num-
ber of studies have indicated a functional deciency of CoQ10
in individuals with CFS/ME and FM that may be related to
clinical symptoms, increased oxidative stress, and compro-
mised mitochondrial energy metabolism.148-151 Although
CoQ10 supplementation has not yet been studied in CFS/ME,
a number of clinical reports concerning individuals with FM
have suggested CoQ10 treatment can improve symptoms, such
as muscle pain, sleep, alertness, headache, and fatigue while
decreasing oxidative stress and increasing the formation of
new mitochondria (mitochondrial biogenesis).152-154
Inammation can also be mitigated by nutrition. For
example, the traditional Mediterranean dietary pattern has
been shown to reduce chronic, low-grade inammation and
may hypothetically be of benet in CFS/ME.155 A number of
dietary supplements have demonstrated anti-inammatory
eects in human clinical studies, including PUFAs and
magnesium, which, as previously discussed, may have
particular relevance to CFS/ME suerers.156,157
MITOCHONDRIAL DYSFUNCTION
A number of independent investigators have suggested
that mitochondrial dysfunction may be central to the
pathology of CFS/ME.158-161 Using a test that measures the
availability of ATP and the eciency of oxidative phosphor-
ylation in mitochondria, it was found that all tested individu-
als with CFS/ME had evidence of mitochondrial dysfunc-
tion, as compared to controls, and this dysfunction was cor-
related with the severity of the illness.162 is nding is sup-
ported by other studies indicating the involvement of mito-
chondrial dysfunction.163-166
Evidence of CoQ10 deciency in CFS/ME provides
further support for mitochondrial involvement, as CoQ10
status has been proposed as a measure of mitochondrial
function.167 CoQ10 deciency has been shown to decrease
expression of proteins involved in mitochondrial energy
metabolism, reduce mitochondrial membrane potential,
increase production of reactive oxygen species, and result in
the degradation of dysfunctional CoQ10-decient mitochon-
dria.168
Mitochondrial Nutrition
Mitochondrial nutrients have been dened as nutri-
tional compounds that (1) enter the cells and mitochondria
following exogenous administration, (2) protect the mito-
chondria from oxidative damage, and (3) improve mito-
chondrial function.169 A number of important eects have
been ascribed to various mitochondrial nutrients, including
the ability to reduce oxidative stress, enhance energy metab-
olism, and increase mitochondrial biogenesis.170
e clinical eects of a number of nutrients discussed
above may be due in part to improvements in mitochondrial
function. For example, high doses of B vitamins can stimu-
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36 ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1
Table 1. Functional Pathology Assessment Methods Relevant to CFS/ME
Area of
Investigation Functional Assessments Discussion
Diet and
nutritional
status
• Nutritional/functional
deciencies:
− Vitamin D
− Fatty acids
− Magnesium
− Zinc
− Carnitine
− B vitamins
• Gluten sensitivity/celiac disease
• Food sensitivity prole (IgG)
• Identication of nutritional deciencies could
individualize treatment.
• e possibility of celiac disease can be explored with IgA
antitissue transglutaminase antibodies.171
• IgG testing can be used to structure an elimination
diet.172
HPA axis
dysfunction
• Salivary cortisol/DHEA
(waking, diurnal)
• Salivary cortisol is a sensitive measure of dynamic HPA
axis activity and diurnal and/or waking cortisol and can
be used assesses cortisol output.173-175
Environmental
toxicity
• Provoked urinary excretion
challenge
• Serum, persistent organic
pollutants
• Available testing methods may underestimate total body
burden of environmental pollutants; however, provoked
urinary excretion challenge for toxic metals and serum
persistent organic pollutants are clinically useful.176,177
Gastrointestinal
function
• Comprehensive stool
microbiology
• SIBO
• Intestinal permeability
(lactulose/mannitol)
• Assessment of gut ecology and small intestinal bacterial
overgrowth can help identify dysbiosis.178,179
• Because endotoxin is not easily measured in a clinical
setting, the lactulose mannitol test may act as an
indicator of leaky gut and elevated blood endotoxin.180
Chronic viral
infection
• Chronic viral disease evaluation
(eg, Epstein-Barr virus, herpes
virus, cytomegalovirus)
• If infection is a suspected disease trigger a viral disease
evaluation should be undertaken.10
Oxidative stress • Biomarkers of oxidative stress
(eg, F2-isoprostanes)
• F2-isoprostanes in blood or urine are widely regarded a
reliable reference marker for oxidative stress.181
Inammation • hs-CRP • hs-CRP is a sensitive marker of low-grade inammation
and could also be used to assess associated
cardiovascular disease risk.182
Mitochondrial
function
• Urinary organic acids
• Serum CoQ10
• Urinary organic acids may help identify impaired
mitochondrial energy production and functional
deciencies in mitochondrial nutrients.183
• Serum CoQ10 is a proposed biomarker of mitochondrial
dysfunction.143
Abbreviations: IgG = immunoglobulin G; SIBO = small intestinal bacterial overgrowth; DHEA = dehydroepiandrosterone;
HPA = hypothalamic-pituitary-adrenal; hs-CRP = high sensitivity C-reactive protein (hs-CRP); CoQ10 = coenzyme Q10.
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Brown—Chronic Fatigue Syndrome ALTERNATIVE THERAPIES, JAN/FEB 2014 VOL. 20, 1 37
late defective coenzymes; magnesium is a cofactor in ATP
metabolism; and acetyl-L-carnitine is responsible for the
transport of acetyl-CoA into the mitochondria during fatty
acid oxidation.184-186 An open-label study with D-ribose, a
structural component of intermediate metabolites required
for mitochondrial energy metabolism, found signicant
improvements in energy, well-being, sleep, and mental clar-
ity and decreased pain in a group of participants with
CFS/ME and FM aer 3 weeks.187 And investigation of a
nutritional formulation designed to support mitochondrial
function—containing vitamins, minerals, amino acids, plant
extracts, phospholipids, and fatty acids—reported a 43%
reduction in fatigue in individuals with CFS/ME and FM
aer 8 weeks of treatment.188
Preliminary ndings from a clinical audit of CFS/ME
individuals who showed evidence of mitochondrial dysfunc-
tion and who had received an integrative treatment plan, sug-
gested that this approach may result in important improve-
ments in clinical symptoms and mitochondrial function.189
is plan frequently included the mitochondrial nutrients
D-ribose, magnesium, acetyl-L-carnitine, and CoQ10.
DISCUSSION
e possible causes, disordered physiology, and clinical
presentations of CFS/ME vary between individuals. For
example not all individuals may have vitamin D deciency,
low diurnal cortisol, or active EBV infection. An integrative
management approach could help identify an individual’s
unique state of dysfunction and personalize treatment.
Clinical assessment might therefore use investigative
methods that help delineate functional status (ie, functional
pathology); see Table 1.
e assessment of the unique functional status of an
individual may help identify treatments that are more likely
to elicit a clinical response. Personalization of treatments
may be particularly relevant to nutritional interventions
where background nutritional status may inuence
therapeutic eect. is comprehensive approach could be
very useful in the clinical practice to get symptom relief for
one unique individual at a time.
Relevant to future CFS/ME research, this approach is
evidently dierent from clinical trials that evaluate single
interventions across broad groups of participants.
Methodology would need to be developed that takes into
account subgroups of participants, individualized
assessments, and tailored treatment plans.
Finally, an integrative management model may increase
the cost and commitment to treatment; however, it is likely
to produce better outcomes by addressing the fundamental
pathological features as well as environmental, lifestyle, and
behavioral factors that contribute to the maintenance of the
disease.
CONCLUSION
Currently accepted treatments for CFS/ME have modest
clinical benets and for most patients the disease prognosis
remains poor. Because CFS/ME is a heterogeneous disorder
with diverse etiological factors and pathological features, a
patient-centered integrative framework based on modiable
physiological and environmental factors may oer hope for
more eective management and better clinical outcomes. An
individualized approach to patient management may also
help identify patient subgroups that are more likely to
respond favorably to specic treatments. A personalized,
integrative approach to CFS/ME deserves further
consideration as a template for patient management and
future research.
ACKNOWLEDGEMENTS
e author received no grants or other nancial support for this review.
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