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The Massachusetts ME/CFS & FM Association, a 501(c)3 founded in 1985, exists to meet the needs of patients with ME (Myalgic Encephalomyelitis), CFS (Chronic Fatigue Syndrome) or FM (Fibromyalgia), their families and loved ones. The Massachusetts ME/CFS & FM Association works to educate health-care providers and the general public regarding these severely-disabling physical illnesses. We also support patients and their families and advocate for more effective treatment and research.

Research articles

Research Advances in Chronic Fatigue Syndrome: Impact on Treatment

Compiled by R. Sanderson

Reviewed and  edited by K. Casanova

Editor's Note, 2015: Dr. Klimas is now the Director of the Institute for Neuro Immune Medicine at Nova Southeastern University, professor of medicine, and chair of the Department of Clinical Immunology at NSU’s College of Osteopathic Medicine.  She is no longer President of IACFS/ME. She won the Annual Provost’s Research and Scholarship Award at Nova in 2015 and the 2014 Perpich Award from the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) for distinguished community service. She also was featured as a “Woman to Watch” on WFOR CBS 4.

On Sunday, April 30, 2006, Dr. Klimas presented a lecture titled, “Research Advances in Chronic Fatigue Syndrome: Impact on Treatment,” at the Connecticut CFIDS & FM Association’s Spring Conference.

Dr. Nancy Klimas is Professor of Medicine at the University of Miami and the Director of Research for the Clinical AIDS/HIV Research at the Miami Veterans Affairs Medical Center. She has been a leader in the field of ME/CFS research, is a founding editor of the Journal of Chronic Fatigue Syndrome [no longer published as of 2009] and is the current President of the International Association for CFS/ME (IACFS/ME). 

As much as everyone looks forward to hearing Dr. Klimas speak, such an event is never long enough. She always has a great deal of information to share with her audience, and it can be very hard to keep up with her. Therefore, please note that a lot of data was incorporated directly from a copy of her PowerPoint presentation (which includes complete information on the articles cited), along with elaborations made by Dr. Klimas on specific topics. In this way, we hope to provide you with as much information as is possible on recent research advances.

Since CFS was the term used in the lecture, this name is used throughout this summary.

Dr. Klimas began her presentation with a brief review of issues that continue to affect our patient population: including the clinical case definition for CFS (Canadian Consensus Panel Clinical Case Definition for CFS/ME vs. the CDC 1994 criteria); CFS epidemiology and the high percentage of undiagnosed CFS cases; and the economic impact of CFS on productivity.

She emphasized how these issues, along with the trivializing name, have negatively impacted treatment. Klimas acknowledged that many physician attitudes show a negative bias towards CFS due to its name. A survey of 811 GPs revealed that 44% did not feel confident making the diagnosis [of CFS], and 41% did not feel confident in treating it. Physicians had reported they would likely have more confidence in the diagnosis if they had a friend or family member with CFS. The doctors also reported that education that emphasizes acceptance of CFS as a real entity would improve their confidence in treatment. (Source: Bowen J et al, Family Pract April 1 (2005)).

She provided an update regarding recent research advances and publications (2003 through early 2006) using her well-known model as a basis.


Model for CFS pathogenesis

Genetic Predisposition

Triggering event/ infection

Mediators (Immune, endocrine, neuroendocrine, psychosocial)

Health Outcome/ Persistence

Genetic Predisposition

Dr. Klimas went over some of HLA DR haplotypes identified in an earlier study of CFS patients that revealed these patients were at a 4 to 6-fold increased relative risk for haplotypes DR4, DR3, and DQ3 (Keller et al, 1992). Klimas explained that gene array data can separate patients into subgroups by their patterns of gene dysregulation in both immune and HPA gene clusters.

Technological progress has made it possible to analyze genes to a greater depth than we are presently able to medically understand what the data mean. Klimas further noted individuals with CFS cannot be lumped together, as they are part of subgroups and therefore should be treated differentially.

Triggering event/infection

A brief review was done of prior studies that demonstrated an association between onset of CFS and an acute viral-like illness in 60-80% of patients (Komaroff and Buchwald). Furthermore, a percentage of patients remained sick after acute viral infections, such as EBV, Q fever or Ross River Virus (according to Australian and UK research). One of the newer theories of great interest to Dr. Klimas is the possibility that only fragments of viruses (like EBV) could “trash” [i.e., dysregulate] a patient’s system.

Ronald Glaser et al.1 have found evidence that regulatory peptides encoded by EBV are expressed in CFS despite the absence of replicating virus. These peptides are known to modulate immune function by inducing pro-inflammatory and Type-2 cytokines.

A. Martin Lerner2 and his group have found evidence of a two subgroups of CFS patients with incomplete viral multiplication (CMV viral “fragments” and EBV antigen.)

[The remainder of this discussion of Lerner’s recent paper (see citation below) departs from what Dr. Klimas presented in her lecture. We reviewed Lerner’s paper and we present some of his more interesting findings in the next three paragraphs. Then we return to Dr. Klimas' lecture.]

At the same time, Lerner has found abnormal oscillating cardiac T-waves (by 24 Holter monitor) in a significant percentage of CFS patients (as opposed to controls). A smaller percentage of patients had Abnormal Cardiac Wall Motion.

Lerner suggests that the findings of incomplete viral multiplication and cardiac anomalies may be causally linked in subsets of CFS patients. The link may be direct in terms of viral damage or mediated by immune system activity. He stresses that further research must be done in this area. He also notes that “one preliminary trial of antiviral therapy (valacyclovir) in a cohort of CFS patients with single virus Epstein-Barr Virus (EBV) persistent infection is promising.”

However, Lerner also notes that the other subset of patients with CMV incomplete viral multiplication did not respond to the antiviral. He says this makes sense because the antiviral is known to have anti-EBV effects, “but does not have significant anti-HCMV activity…”

Lerner, interestingly for CFS patients, also discusses Gunther Stent’s theory regarding: “Premature scientific discovery. Premature scientific discoveries are met by the scientific community with resistance and ridicule.” [Here Lerner is saying that much of the pioneering CFS research remains in the “premature scientific discovery” category.]

Dr. Klimas indicated HHV-6 is another prevalent virus in individuals with CFS. It has been detected in 22% - 54% of patients in cross-sectional studies (Ablashi, Krueger, and Knox) and in 79% of CFS patients in longitudinal studies (HHV-6 PCR assay, Knox). Dr. Klimas emphasized that the only reliable lab for patient HHV-6 testing is the Wisconsin Viral Research Group in Milwaukee, WI. This is the laboratory in which Dr. Konstance Knox has done extensive research on the virus. However, Klimas cautioned HHV-6 does not respond to traditional antivirals, but requires aggressive treatment with very potent agents administered through IVs.

1. Glaser R et al, “Stress-associated Changes in the Steady-State Expression of Latent Epstein–Barr virus: Implications for Chronic Fatigue Syndrome and Cancer,” Brain, Behavior and Immunity 19 (2) (2005): 91-103.

2. Lerner AM et al, "Prevalence of Abnormal Cardiac Wall Motion in the Cardiomyopathy Associated with Incomplete Multiplication of Epstein-Barr Virus and/or Cytomegalovirus in Patients with Chronic Fatigue Syndrome," In Vivo Jul-Aug; 18(4) (2004): 417-24.


Mediators (immune, endocrine, neuroendocrine, psychosocial)

An Immune Cascade chart was used to illustrate how various immune response processes are activated in response to an infection. Basically, the helper T-cell function in individuals with CFS no longer remains balanced; instead, it shifts to a TH-2 pattern, which in turn, triggers pro-inflammatory cytokines.

More recent endocrinology studies show evidence of reduced cortisol output (by the adrenals) via several mechanisms, such as heightened negative feedback, heightened receptor function and impaired ACTH and cortisol responses to challenge. Research data also supports DHEA functional abnormality, abnormal serotonin function, and IL-6 increase associated with low cortisol. (The low cortisol is mediated by a hypothalamic dysregulation of Cortisol Releasing Hormone.) In spite of these findings, Dr. Klimas stated that cortisol treatment, especially long-term, is not being recommended. The following two studies address this issue:

Cleare AJ, “The Neuroendocrinology of Chronic Fatigue Syndrome,” Endocrine Reviews 24 (2) (2003): 236-252.

Papanicolaou DA et al (representing a large US panel), “Neuroendocrine Aspects of Chronic Fatigue Syndrome," Neuroimmunomodulation 11(2) (2004): 65-74.

Some of the latest research on Autonomic Nervous System abnormalities in CFS (as shown on the chart for ANS) and other sources, are as follows:

  • Haemodynamic Instability Score taken during tilt table testing predicts CFS with 90% sensitivity. 1
  • Heart rate variability as a predictor of CFS. 2
  • Gastric emptying delayed in 23 out of 32 CFS subjects. 3

1. Naschitz J, The Head-up Tilt Test with Haemodynamic Instability Score in Diagnosing Chronic Fatigue Syndrome,” QJM 96(2) (2003): 133-42.

2. Yamamoto et al, “A Measure of Heart Rate Variability Is Sensitive to Orthostatic Challenge in Women with Chronic Fatigue Syndrome,” Experimental Biology and Medicine 228 (2003):167-174.

3. Burnet R, “Gastric Emptying is Slow in Chronic Fatigue Syndrome,” BMC Gastroenterology 4 (2004): 32.


Sleep physiology

H. Modolfsky’s early studies have documented a variety of circadian sleep disturbances in CFS patients, such as altered diurnal patterns in cortisol, prolactin, and NK cell function, as well as alpha wave intrusion on sleep EEG, and a reduced state of stage III and IV sleep. A more recent study by Nathanial Watson has shown a higher percentage of REM sleep in CFS twins (Twin Study of 22 discordant twins 1). This finding suggests an element of sleep-state dysregulation.

Dr. Klimas mentioned there are several new Stage IV sleep inducer medications being used. The strongest of these is Xyrem (a form of gamma hydroxybutyrate (GHB))—a beneficial drug in treatment of narcolepsy; but it is also known for its illegal use as a date-rape drug. Currently, it is only available through enrollment in a special program (not through retail pharmacies) and is so potent, it must be taken when already in bed.

Remeron is a medication—actually, this is an antidepressant that promotes stage III and IV sleep—that Klimas has prescribed, often in ¼ doses. She recommended that individuals with sleep problems consult with sleep doctors and pointed out these physicians are in two specialties: pulmonology and neurology. It is also important to choose a doctor who will provide continuing care after the initial evaluation.

1. Watson et al, “Comparison of Subjective and Objective Measures of Insomnia in Monozygotic Twins Discordant for Chronic Fatigue Syndrome,” Sleep May 1; 26(3) (2003): 324-8.


Muscle

Though research findings pertaining to muscle function/ disturbances, including those of the heart, were not discussed in any great detail. A summary of these findings is included for your information:

  • An oxidative stress study measuring protein carbonyls suggested higher levels of protein oxidation in CFS subjects as opposed to controls 1.
  • Exercise testing in 189 CFS subjects resulted in clinically significant subgroups with 50% of subjects showing moderate to severe functional impairment. An unexpected blunting of Heart Rate and Blood Pressure responses was noted. 2
  • Sarcoplasmic reticulum defect: conduction and calcium transport abnormalities. 3
  • Cardiac muscle—cardiac output found related to illness severity and the predicted exercise-induced relapse 4.
  • Subset of CFS patients with IgM-EBV or CMV-Antibody found to be at risk for cardiac motility abnormalities and occasionally true cardiomyopathy 5.
  • Raises the issue of incomplete viral replication activating immune responses as suggested by Glaser et al 6.

[Again, for a moment we depart from Klimas’ lecture. Our review of Glaser’s paper sheds somewhat more light on Klimas’ note on his research. Glaser’s team for a number of years has studied the workings of EBV and its effects in a variety of illnesses. In CFS, Glaser found strong indications that constituent components or expressions of the latent virus may by themselves account for immune dysregulation and symptoms in subgroups of CFS patients. The same process may occur for other viruses, including CMV and HHV-6.]

1. Smirnova IV, “Elevated Levels of Protein Carbonyls in Sera of Chronic Fatigue Syndrome patients,” Mol Cell Biochem Jun 248(1-2) (2003): 93-5.

2. Vanness JM et al, "Subclassifying Chronic Fatigue Syndrome through Exercise Testing." Med Sci Sports Exerc. Jun 35(6) (2003): 908-913.

3. Fulle S et al, “Modification of the Functional Capacity of Sarcoplasmic Reticulum Membranes in Patients Suffering from Chronic Fatigue Syndrome,” Neuromuscular Disorders 13 (2003): 479–484.

4. Peckerman A et al, "Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome," Am J Med Sci. Aug 326(2) (2003): 55-60.

5. Lerner AM et al, "Prevalence of Abnormal Cardiac Wall motion in the Cardiomyopathy Associated with Incomplete Multiplication of Epstein-Barr Virus and/or Cytomegalovirus in Patients with Chronic Fatigue Syndrome," In Vivo 18( 4) (2004): 417-424.

6. Glaser R et al, “Stress-associated Changes in the Steady-state Expression of Latent Epstein–Barr virus: Implications for Chronic Fatigue Syndrome and Cancer,” Brain Behavior and Immunity 19 (2) (2005): 91-103.


New studies on the brain—important research findings published over the last 12 months

  • After a fatigue-inducing mental task, imaging studies showed decreased brain responsiveness to auditory stimulation (study of 6 male CFS patients and 7 male healthy controls carried out by researchers in Japan). 1
  • Decreased absolute cortical blood flow in the brain (25 CFS patients, 7 controls). When stratified for psychiatric disorders, CFS subjects with psychiatric disorders had decreased blood flow in one region only (left cerebral artery) in contrast to CFS subjects without any psychiatric disorders who had reduced flow in both the right and left middle cerebral arteries. Therefore, those patients having CFS only (devoid of psychopathology) had the largest reduction in flow. 2
  • Using more brain physiology to process tasks—A study using BOLD fMRI done in NJ (see the brief summary below). 3
  • Reduced grey matter in the brain was linked to reduced activity (study done in the Netherlands of 2 groups of 15 females each, one group was younger than the other). 4

Briefly digressing from Dr. Klimas’ lecture, information has been included about the specific findings of the New Jersey study (the 3rd one listed just above) by the researcher herself, Grudin Lange, PhD at one of the afternoon workshops. Lange’s study group, that also included Drs. DeLuca and Natelson (Univ. of Medicine & Dentistry of NJ), looked at mental concentration in CFS patients.

Using a particular type of imaging technique—Blood Oxygen Level Dependent (BOLD) functional MRI, they measured differences in blood flow in the brains of CFS patients compared to controls, especially when challenged with complex auditory processing while doing a simple task. This study shows that people with CFS have to exert more effort to process the same data as healthy controls and provides “evidence of increased neural resource allocation when processing more complex auditory information.”

This conclusion was taken from the study.

Dr. Klimas remarked Japan has become very active in CFS research and that more money is being spent on CFS research there than in the US].

1. Tanaka M et al, “Reduced Responsiveness is an Essential Feature of Chronic Fatigue Syndrome: a fMRI Study,” BMC Neurol Feb 22; 6 (2006): 9.

2. Yoshiuchi K, “Patients with Chronic Fatigue Syndrome have Reduced Absolute Cortical Blood Flow.” Clin Physiol Funct Imaging Mar 26(2) (2006): 83-6.

3. Lange G et al, "Objective Evidence of Cognitive Complaints in Chronic Fatigue Syndrome: a BOLD fMRI Study of Verbal Working Memory," Neuroimage Jun 26(2) (2005):5 13-24.

4. De Lange FP et al, "Gray Matter Volume Reduction in the Chronic Fatigue Syndrome," Neuroimage Jul 1; 26(3)(2005): 777-81.


Microarray technology and genes

In microarray testing, samples are arranged in a grid-like order, within a defined area, on glass microscope slides. This technology allows a huge number of genes to be surveyed at one time.

Samples appear as series of spots (that represent genes) which undergo a binding process and produce signals relating to the gene still present from the samples. It is the intensity of these spots (like an on/off type of mechanism) that provide the data—so for example, the intensity of one spot (CFS) can be compared to the intensity of the corresponding spot (control).

Agents are used to display the data in certain colors like red and green to help facilitate analysis. In one sample chart, Dr. Klimas pointed out how the red pattern was showing downregulated mitochondrial function, while the green one was showing upregulated cytokines.

In that particular study, gene expression helped to demonstrate a difference between sudden and gradual onset of illness. The importance of this technology is that it will help to identify specific gene markers associated with CFS and ultimately lead to better treatments.

Gene research has provided meaningful information about CFS (again, as taken from Dr. Klimas’ presentation chart):

A CDC study of 20,000 genes studied the activity of 26 genes—activity that could accurately predict which of 6 categories of chronic fatigue a patient had on the basis of symptoms and other clinical tests.

  • Most of these genes are involved in immune system regulation, the adrenal gland, and the brain’s hypothalamus and pituitary glands.
  • Studies of hormones and immune factors confirm these findings.
  • Kerr’s study revealed differential expression of 35 genes in 25 patients as compared with 25 controls. The differential expression in patients suggested T-cell activation and disturbances of neuronal and mitochrondrial function.

Other studies have pinpointed 5 specific genes that correlate with an apparent susceptibility to chronic fatigue—more specifically with levels of serotonin and glutamate affected.

Speaking of the recent CDC study, Dr. Klimas felt newspapers had misreported the study findings and the role of stress. She stated there is a “huge difference” between stress as implied in these articles (assuming she meant how one might psychologically cope under pressure) and one’s stress response.

In the latter, there are biological defense mechanisms called into action, which involve everything from the autonomic nervous system, the cardiovascular system, the neuroendocrine axis, and the immune system. These systems react automatically to stressors.

Such stressors would include environmental triggers, infections, or disruptions caused by illness. Klimas also announced that on or around June 1st, the CDC is supposed to release another press release. She is optimistic this may have something to do with upcoming treatments.


Management of CFS

Time had run out by the time we got to this part of the presentation. Nearly a dozen charts summarized a variety of interventions, which were broken down into 4 major categories (pathogenisis directed): immune modulatory approaches, HPA-axis interventions, neurally mediated hypotension (NMH) treatment, and sleep. Since many of these were not discussed in detail, most have been left off because their use, benefit or status is uncertain. (A number of therapies are in various phases of study.)

Overall, Dr. Klimas indicated that sleep should be one of the first problems to be treated. Earlier, she talked about the Stage III and IV sleep inducers. She also mentioned Doxepin as another helpful medication for sleep.

On her chart, it is noted that short acting hypnotics should be avoided (as they can “trap” a person in light alpha wave sleep).

Melatonin and Ritalin were also noted as still being studied for effectiveness in CFS, but the response/results to these appear to be rather poor. (In one study of 60 CFS patients, placebo-controlled, using 10 mg. BID of Ritalin, only 17% of subjects reported decreased fatigue with 22% showing improvement in concentration.)

The following information on immune modulatory treatments comes not from her lecture, but directly from Klimas’ PowerPoint notes. The text of the notes is as follows: “Ampligen, a immune modulator and antiviral (Phase 3 recently completed); Allergic immunotherapy to dow-regulate allergic drive; Future immunomodulators (trials underway): Isoprinosine, thalidomide, anti-TNF-alpha monoclonal Ab.”

Dr. Klimas’s PowerPoint notes (not mentioned in lecture) also state, under HPA-axis interventions—“Growth hormone study – was in Phase 1 (Antwerp study).”

Dr. Klimas mentioned a drug that is being used in Japan called Neurotropin is used to treat reflex sympathetic dystrophy and other painful conditions. Neurotropin is a “non-protein extract of cutaneous tissue from rabbits inoculated with vaccinia virus.” There is some indication it may be helpful with CFS. However, the drug has not undergone clinical therapeutic testing in the United States.” (Source: Clinical Trials – NIH site).

A survey was been done at the University of Iowa to determine things that patients have tried and found to be helpful. (Bentler SE, J Clin Psychiatry May 66(5) (2005): 625-32). A few supplements: Co-Q10, DHEA and ginseng were found to be helpful.

[Ed. Note: Treatment with DHEA can have very serious side effects and must be managed and monitored by a competent physician. Dr. Klimas has stated she is against such treatment. Also, there is some literature that of 3 types of ginseng, only one is helpful to CFS patients, while the other two types may worsen symptoms.]

Vitamins predicted improvement. Yoga seemed to be the most helpful form of exercise and treatment. However, the subjects in this study were described as having “unexplained chronic fatigue of unknown etiology for at least 6 months”—hence participants may or may not have had CFS.

Another study at the Univ. of Georgia (Black CD and McCully KK, Dynamic Medicine Oct 28; 4 (2008): 10) examined how people with CFS were initially able to meet target goals in a prescribed daily walking program (for 4 to 10 days), but then these individuals developed exercise intolerance and worsening of symptoms.

Dr. Klimas feels exercise is beneficial, but it is usually is best tolerated in short intervals (even 5 minutes at a time) with many rest breaks in between.

Dr. Klimas’ PowerPoint presentation (not presented in lecture) also noted certain dangers of nutritional interventions including: “Licorice root—potassium deficiencies [that can affect the heart]; ‘supplements’ that are actually hormones [including DHEA]; ‘supplements’ that have iffy contents—eg., St. John’s Wort, melatonin; products that make unsubstantiated claims; Under and overhydration.”

[Ed. note: either of these states can be very serious. Having enough water is important, but drinking too much water can harm essential physiological systems and processes.]

Everyone should really exercise caution about taking supplements without a full appreciation of their side effects or interactions with current medications.

So, what we can take away from this latest presentation is that there have been ongoing studies to help better understand ME/CFS. The breadth and depth of biologically-based ME/CFS research is expanding. There is some promise of more effective therapies—targeted to specific physiological systems—becoming available. Researchers conducting gene expression studies also hold out hope that their research may yield effective therapies.

 

Supplements

Important notice: Please note that the information on Treatment provided here has been compiled by patients for patients, and represents a summary of what patients may have experienced in working with their individual health care providers. The information in this website is not a substitute for professional medical advice. Please consult with your physician or other healthcare provider in matters pertaining to your medical care. See our full Medical Disclaimer.

Health Care Providers: Please see the information on pp. 25-26 in the 2014 ME/CFS: A Clinician's Primer.

Vitamin and supplement production has become big business and many people spend a lot of money on these without having a reasonably good understanding about their effects (especially how one might interact with another and with pharmaceuticals), potency, and even their personal need for some of these.

It is essential to keep in mind that although dietary supplements are promoted as "natural" alternatives, they will still contain many potent compounds that trigger various biochemical reactions or changes in the body. After all, the reasons for using supplements are to use some as substitutes for standard medications, or to make up for what one's body may be severely lacking.

Check for additives, fillers and waxy coatings and realize that not all vitamins/supplements are extracted from "natural" food sources. Also, check for other ingredients in snacks and "enhanced" beverages, as these may contain stimulating herbs in vaguely stated amounts.

Consumers must beware of exaggerated claims or testimonials and promises of miracle cures. On a positive note, a number of vitamin and dietary supplement manufacturers do submit their products for quality assurance review by United States Pharmacopeia (USP) and NSF International (formerly National Sanitation Foundation). These are independent public health and safety organizations, and products for which ingredients and manufacturing processes were reviewed by them for consistency, safety and quality will display USP or NSF certified symbols.

Herbal extracts will often display the term "standardized" which means the levels of key ingredients are supposed to be uniform from one batch to another, but this does not necessarily mean better or stronger, nor does it take into account other substances used to manufacture them.

Many people routinely start their day with a multi-vitamin. These come in a large variety of forms, combinations and potencies. Recommended daily allowances (RDAs) were instituted well over 40 years ago, which were set at levels to ward off severe deficiencies and are now considered to be too low to achieve optimal effects.

In contrast, some formulas contain excessively high and potentially dangerous levels. More is not always better, especially in the case of fat soluble (A, D, E and K) vitamins because they are stored in the liver and fatty tissues. There is also a risk in isolating and taking certain vitamins by themselves for they may trigger an imbalance or deplete other nutrients.Therefore, balance and synergy of vitamins and minerals are two other important considerations.

One leading school of thought is that the most beneficial form of vitamins are those made from concentrated whole foods because the co-existing structures and properties of each will be retained and work together (in a more synergistic way). Most proponents of dietary supplements will agree these should never be used to replace food or a healthy diet.

Formulas with added iron should not be used, unless specifically directed by one's doctor, as iron can be quite harmful when not needed.

Clinicians who work closely with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM) patients are turning to specific supplements or herbs to correct deficiencies and make use of their therapeutic properties. We have incorporated recommendations or opinions by some of the leading specialists in the field, such as Drs. Charles Lapp, Jacob Teitelbaum, Nancy Klimas and Roland Staud, on the top one dozen or so supplements used in the management of ME/CFS and FM. 

Other credible sources (such as the Physician's Desk Reference for Nutritional Supplements) were referenced and data included from multiple sources on these and a few other products in order to provide enough basic information so individuals can make informed decisions.

It is strongly urged that people consult with a qualified healthcare professional.


Sleep aids

Melatonin

This is a hormone produced by the pineal gland in the brain and used by the body to regulate sleep/wake cycles. (It is at its highest level at night). It is considered to be fairly safe and has been found to be beneficial in far lower amounts than what most formulas contain. One ME/CFS and FM specialist recommends using only about 0.3 mg and not the standard 3.0 mg dose. Several precautions need to be taken with melatonin in those with cardiovascular risks, as it can affect blood pressure and trigger abnormal heart rhythm. It should be avoided by those taking blood-thinners. At higher levels it can also raise blood-sugar levels, aggravate Crohn's disease symptoms, and disrupt other hormones (which can lead to a change in menstrual patterns, for instance).

Valerian root

The rootstock portion of this plant (grown in North America and Europe) is dried and has been used as a mild sedative and sleep aid for hundreds of years. It is unique in that it will usually have a calming effect, but if someone is very fatigued, it can actually have a stimulating effect. Valerian root has been studied for treatment of anxiety and shown to have good results at 100 mg given 3 times per day for a 6-month period. The average dose for sleep will be 180 - 360 mg, depending on each individual's reaction. No clear benefit has been noticed at higher doses and therefore, the daily dose should not exceed 600 mg. Lemon balm is a member of the mint family and is known for its calming effect on anxiety and digestion. It is often combined with valerian in sleep formulas, to enhance the relaxing effect.

Sleep formulas

There are an overwhelming number of sleep formulas, many specifically marketed for ME/CFS or FM. These contain a wide variety of ingredients, most often herbs such as valerian, lemon balm, chamomile, passionflower and hops. Some formulas will also include amino acids, minerals, and Chinese herbs. Therefore, making a choice can become difficult. The best approach would be to work with a naturopathic doctor or holistic practitioner who is well informed about the medicinal use of these herbal preparations. Otherwise, consider preparations with the fewest active ingredients and use herbs which are familiar to you.

Calcium and magnesium are often used at night to help relax muscles and promote sleep. These minerals offer a wide range of other benefits further described under those for improved energy. Since magnesium is an electrolyte which influences heartbeat and potassium levels (which also affect heartbeat), it is wise to only supplement with magnesium or potassium with regular checks by a doctor of serum blood levels of both minerals.


Improve energy, strength and/or mitochondrial function

Calcium

The advantages of calcium are many, such as maintaining healthy bones and teeth, healthy muscle tone and function, cardiac function, and nerve transmission. Calcium should not be taken in greater amounts than 500 mg at a time in order to maximize absorption, and it should be taken with meals. Too much calcium could lead to kidney stones. The average daily dose of calcium is 1000-1200 mg daily. Since magnesium works closely with calcium, the suggested ratio is 2:1, calcium to magnesium. Recent research has shown that calcium works best when Vitamin D levels in the blood are adequate.

Magnesium 

This mineral is of particular importance in ME/CFS and FM because of its involvement in numerous biological and metabolic functions. Magnesium affects the production of cellu­lar energy, stability of cells, nerve conduction and muscle contraction. It helps transport oxygen to muscles, which in turn, strengthens but also relaxes muscles. Furthermore, there is a link between magnesium and functioning of the immune system. An activated immune system uses magnesium and zinc at rapid rates.

Studies have shown that ME/CFS patients in particular have lower levels of intracellular magnesium than healthy controls. The typical magnesium test only measures serum levels of magnesium and while serum levels can be normal, intracellular levels can be low at the same time. Magnesium deficiency can cause low potassium. Other signs of magnesium deficiency are fatigue and muscle cramps. There is some evidence that magnesium has anti­osteoporotic activity. It definitely has anti­arrhythmic activity. Magnesium may have anti­hypertensive, glucose-regulatory and bron­chodilatory activity and possible anti-migraine activity. Since magnesium is an electrolyte which influences heartbeat and potassium levels (which also affect heartbeat), it is wise to only supplement with magnesium or potassium with regular checks by a doctor of serum blood levels of both minerals.

Magnesium is contraindicated in those with kidney failure and certain types of heart problems. It should not be taken two-to-four hours before or after certain medications such as bisphospho­nate, a quinolone or a tetracycline, as magnesium can interfere with their absorption. The standard recommended dose for healthy people is 100-300 mg per day. But it is often used in higher amounts of 500-750 mg for ME/CFS and FM while frequently combined with malic acid. In view of magnesium's effect on so many functions and other medical conditions, it would be advisable for one's doctor to determine the appropriate dose for each individual.

Malic acid

Malic acid is a natural compound found in fruits, sometimes called fruit acid, which is involved in the Krebs cycle and mitochondrial creation of energy. The Krebs cycle (citric acid cycle) is part of a metabolic pathway involved in the chemical conversion of carbohydrates, fats and proteins into carbon dioxide and water to generate a form of usable energy. Other relevant reactions in the pathway include those in glycolysis and pyruvate oxidation before the citric acid cycle, and oxidative phosphorylation after it. Malic acid has been found to improve energy in ME/CFS as well as reduce pain and stiffness in FM. There are no known contraindications or precautions. A typical dose would be 1200-2400 mg daily with 300 to 600 mg daily magnesium.

Since magnesium is an electrolyte which influences heartbeat and potassium levels (which also affect heartbeat), it is wise to only supplement with magnesium or potassium with regular checks by a doctor of serum blood levels of both minerals.

Vitamin B-12

Vitamin B-12 is a water-soluble vitamin found naturally in animal foods, fish, and dairy products. It is vital to red blood cell formation, absorption of foods, metabolic regulation, growth, and protection of nerve cells and function. Deficiency often presents as chronic fatigue, digestive disorders, pernicious anemia, various memory, mood or neurologic problems. B-12 deficiency may also be present in some individuals who consume a very limited vegan-type diet. Long-term use of proton pump inhibitor medications which reduce stomach acid (like those controlling GERD) may also interfere with the absorption of B-12.

Therapeutic treatment with this vitamin is often delivered as hydroxocobalamin injections and for ME/CFS and FM, at higher and more frequent doses than usual because of the amount needed to notice improvement. Not only does B-12 help to promote energy and overall better function, but also it works at a deeper level to reduce nitric oxide and peroxynitrite levels regarded by some researchers to be the main culprit in causing the ME/CFS process.

It is generally not found to be toxic or problematic in the majority of people, unless they are sensitive to the compounds that make up the vitamin, an ingredient in the injection material and/or have an unusual optic neuropathy. Vitamin B-12 injections, when used for ME/CFS, are often started at a high-dose of approximately 3000 mcg, several times per week, for 15 doses and then it is tapered down. Sublingual B-12 is the preferred oral form, from 1000 up to 5000 mcg day.

Vitamin D

This vitamin has received a lot of attention over recent years because low levels have been detected in many people, but this can be a fairly tricky vitamin to use. Vitamin D deficiency, in particular, is often associated with bone loss and multiple sclerosis, but also with persistent musculoskeletal pain.

There are two types of Vitamin DD-2 is derived from plant sources, and D-3 from animal sources and through the skin when exposed to ultraviolet-B (UVB) rays from the sun. Obtaining adequate Vitamin D from sunlight on a regular basis depends on geographic location, weather, and pollution and is adversely influenced by the current common use of sunscreen. It has been shown that the bodies of people in New England make inadequate amounts of Vitamin D most of the year. Those on certain medications or with autoimmune-driven conditions usually need to avoid direct sunlight, and their levels of Vitamin D can be low as a result.

Vitamin D helps to increase calcium and phosphorous absorption which, in turn, helps to strengthen bones and muscles. It is also commonly thought this vitamin helps to protect people against certain diseases while more recent research (on autoimmunity) has found routine supplementation might actually make some diseases worse by how it affects gene expression at the microbiologic level. It has definitely been established that Vitamin D helps the immune system fight certain viral and bacterial infections. Therefore, there is conflicting data on whether Vitamin D is beneficial or more harmful in certain situations.

Vitamin D-3 has become the preferred type because it is found to work better. Some doctors recommend Vitamin D-3 at about 1000 IU daily, but only for a set period of time, just to build up reserve levels. (It is important to remember this is a fat-soluble vitamin and stored in fatty tissues, so it has the potential of becoming toxic if levels get too high.) The daily dose would then be reduced to about 800 IU/ day and increased again only when patients are found to be deficient. It should be taken with calcium. In view of the emerging controversy on Vitamin D supplementation, patients should get their levels checked and then be advised and monitored by their own physicians regarding the best dose for their needs.

Coenzyme Q-10

Usually referred to as simply CoQ-10 (also called ubiquinone), it is a vitamin-like substance which has notable cardioprotective, cytoprotective and neuroprotective activities. It is vital for the energy generating process at the cellular level in the mitochondrial electron transport chain. CoQ-10 is well regarded and used by physicians to treat various metabolic and neurologic diseases, cardiovascular conditions and diabetes. There are no contraindications, but general side effects may include stomach upset, nausea and headaches.

Individuals with certain illnesses may need to have their medications adjusted or be more closely monitored such as those with type-2 diabetes (CoQ-10 lowers blood sugar levels), those on anticoagulant drugs, and those using statin drugs (which decrease CoQ-10 serum levels). Some beta-blockersmay block CoQ-10 dependent enzymes. The average daily dose recommended by ME/CFS and FM clinicians is 100-200 mg. However, mitochondrial specialists who see ME/CFS patients recommend the same dosage as used for mitochondrial disease patients—300-400 mg twice a day. 

Acetyl-L-Carnitine

Acetyl-L-carnitine is one of several forms of carnitine. Carnitine has the chemical structure similar to an amino acid and is involved in fatty acid transport across mitochondrial membranes, which increases the use of fat as an energy source. Acetyl-L-carnitine may have neuroprotective, cytoprotective, antioxidant and anti-apoptotic activity. (Anti-apoptotic activity means it inter­feres with abnormal cellular suicide, which is a documented problem in ME/CFS). Mitochondrial membrane potential improves with acetyl-L-carnitine, which improves the functioning of mitochondria. People with seizure disorders should only use it under medical supervision. Adverse reactions are infrequent and are mild gastrointesti­nal symptoms such as nausea, vomiting, abdom­inal cramps and diarrhea. Antiseizure medications (valproic acid), nucleoside analogues, a type of antiviral treatment (didanosine, zalcitabine and stavudine), and pivalic acid-con­taining antibiotics may lead to secondary L-car­nitine deficiency and the need for acetyl-L-carnitine. Dosage may be 500-2000 mg daily in divided doses.

Nicotinamide adenine dinucleotide (NADH)

This is an active coenzyme form of Vitamin B-3 and necessary for energy production. NADH is located both in the mitochondria and cytosol of cells. (The cytosol is the cytoplasm or interior of the cell omitting the mitochondria.) It depends on the essential nutrient nicotinamide (a form of niacin) for its synthesis. The Physician's Desk Reference for Nutritional Supplements notes that mitochondrial membranes are impervious to NADH. However, NADH in the cytosol can still be used in cellular energy production in certain cells—mainly heart and liver cells. A small study was done on its benefits for ME/CFS and the dosage used in the trial was 10 mg daily, taken in the morning, about 45 minutes before eating. Clinicians who have used it since then find that if it is going to work, then about 30% will notice an improvement in 3 months, while 50% will show improvement in 6-12 months.

Dehydroepiandrosterone (DHEA)

DHEA is a steroid hormone produced by the adrenal glands and is converted to other hormones such as estrogen and testosterone. DHEA levels start to decrease with age and are found to be prematurely lower in people with ME/CFS and FM. A few specialists do prescribe this supplement to their patients; however, more are opposed to its use because of a strong potential to cause breast and ovarian cancer as well as prostate cancer.

The Physicians' Desk Reference (PDR) emphasizes that DHEA and its metabolite DHEA-S should not be used unless ordered by a doctor for documented abnormally low levels of DHEA. Canada and the UK have banned its sale over-the-counter.


More resources

Complementary and Mainstream Treatment Approaches by Dr. Jeanne Hubbuch

Review of Nutritional Supplements Used for ME/CFS/FM

About Fibromyalgia

What is Fibromyalgia (FM)?

Fibromyalgia means “soft tissue and muscle pain.” The soft tissues are the tendons or ligaments. FM is a chronic pain syndrome often associated with ME/CFS, and sometimes confused with it. The pain can be severe enough to interfere with routine daily activities. It migrates, can be achy, burning, throbbing, shooting, or stabbing, and is worse in areas used most, such as the neck or back. FM may be associated with “tender points” which are painful when pressure is applied to them. Individuals often say they awaken feeling as if they hadn’t slept. A sudden onset of profound fatigue can occur during or following exertion. Many other symptoms are common to fibromyalgia, including stiffness on waking, memory and concentration problems, excessive sensitivity of the senses, headaches, Temporomandibular Joint Syndrome (TMJ), irritable bowel, and bladder and muscle spasm.


Who gets FM?

Medical research indicates that over 6 million people in the US have FM, and that 80-90% of them are women. On the other hand, there is an estimate that about 1 million people in the U.S. suffer from ME/CFS. However, about 80% of those with ME/CFS also suffer from FM—or about 800,000. Thus most people with ME/CFS also have FM, but most people with FM don’t have ME/CFS.


How is FM diagnosed?

The 1990 American College of Rheumatologists diagnostic criteria are:

1) Widespread pain for at least 3 months.

2) Pain in all four quadrants of the body: right side, left side, above and below the waist.

3) Pain in at least 11 of 18 specified tender points when they are pressed. These 18 sites cluster around the neck, shoulder, chest, hip, knee, and elbow regions.

No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities.

Please note: In May 2010, the American College of Rheumatology (ACR) released new criteria for the clinical diagnosis of Fibromyalgia (FM). However not all health care providers are using these new criteria, so it is good for patients to be familiar with both. The new criteria recommend that the tender point examination be replaced with a combination of a widespread pain index (WPI) and severity scale of symptoms (SS). 

Using these new criteria, a diagnosis of Fibromyalgia will be made on the following basis:

The values and ranges allowed for the WPI and the SS scales should meet one of the combinations: WPI >7 AND SS >5 or WPI 3–6 AND SS >9.
Symptoms have persisted at this level for the past 3 months.
Patient does not have any other disorder or cause to explain the pain.

Read more about the diagnosis of FM.


Are FM and ME/CFS the same illness?

Research authorities vary in viewpoint as to the relation of FM and ME/CFS, but the best research to date indicates that the two illnesses, while often associated, are different and separable—both in nature of causation and in their pathophysiologies (effects on processes in the body.)

Medically, FM is classified as a rheumatological illness, and FM is most commonly diagnosed and treated by rheumatologists. ME/CFS historically comes more under the rubric of internal medicine or infectious disease. This difference occurs because ME/CFS very often presents with viral-like or infectious symptoms, which do not occur as often in FM. The primary symptom complexes in FM are 1) pain; 2) sleep disturbance; 3) fatigue and exhaustion. Viral and other infectious-type symptoms aremuch less frequent.

However, because of the similarities of many of the ME/CFS and FM symptoms, including the fact that many patients can have both, differential diagnosis can be a problem. It is very important that the two illnesses be diagnosed correctly because treatments for each are somewhat different.

A person with ME/CFS who is diagnosed with FM and treated accordingly may run into severe problems; and a person with FM who is incorrectly diagnosed with ME/CFS may also be treated improperly and lose the benefits of helpful treatments.

The fact that the two illnesses are the province of separate specialties can also lead to diagnostic problems. As a rheumatologist is trained in rheumatological illnesses, there are occurrences of ME/CFS being diagnosed as FM when the physician is not well-versed in ME/CFS diagnosis. And an infectious disease specialist may be prone to misdiagnosing FM as ME/CFS.

Therefore, when there is doubt about which illness a patient has, she or he should become familiar with the differences between the two illnesses and seek a physician who knows how to diagnose both illnesses.


Who treats FM?

Medically, FM is classified as a rheumatological illness, and FM is most commonly diagnosed and treated by rheumatologists.

How is FM treated?

There is presently no cure for FM. Treatment is aimed at reducing pain and improving sleep.

Most often prescribed medications include anti-inflammatories, tricyclics, and pain medications.

Lifestyle measures to lessen stress, balance exercise and rest, and the avoidance of factors that aggravate symptoms are helpful.

Many individuals have also benefited from incorporating nutritional approaches, physical or occupational therapy, counseling, and peer support groups as part of their treatment.

Recently three medications, Cymbalta, Lyrica, and Savella, have been approved for use in the treatment of FM.

Read more about the treatment of FM. For information about Cymbala, Lyrica and Savella, read an article about a German study comparing them.


Where can I find out more about FM?

There is a great deal of excellent research and clinical information about fibromyalgia. Please refer to other sections of this website, as well as to other Fibromyalgia websites listed below.

Fibromyalgia, like ME/CFS, continues to remain a somewhat controversial illness, and a number of doctors continue to believe that it causally is linked with psychiatric illness. However, like ME/CFS, extensive research has been done that demonstrates clear physiological dysregulation and abnormalities in FM patients. Obviously, as with any other chronic illness, a person with FM can develop secondary depression or anxiety.

More resources

Social Security Ruling for Evaluation of Fibromyalgia (eff. July 2012)

A study of 1555 FM Patients provides valuable insight

Clinical Guides for Fibromyalgia

Chronic Pain Control

Complementary and Mainstream Treatment Approaches

Comprehensive Treatment of Fibromyalgia

Drugs that can cause fibromyalgia by Dr. Byron Hyde

Insights about FM and Chronic Pain

New Study Finds That Pain Levels in Patients With Fibromyalgia Are Linked to Resting Brain Connectivity

Pharmacological Therapies Approved for FM

Presentation on Fibromyalgia by Dr. Byron Hyde

Review of Nutritional Supplements Used for ME/CFS/FM

Subcategories

Notice about names

The Massachusetts ME/CFS & FM Association would like to clarify the use of the various acronyms for Chronic Fatigue Syndrome (CFS), Chronic Fatigue & Immune Dysfunction Syndrome (CFIDS) and  Myalgic Encephalomyelitis (ME) on this site. When we generate our own articles on the illness, we will refer to it as ME/CFS, the term now generally used in the United States. When we are reporting on someone else’s report, we will use the term they use. The National Institutes of Health (NIH) and other federal agencies, including the CDC, are currently using ME/CFS. 

Massachusetts ME/CFS & FM Association changed its name in July, 2018, to reflect this consensus.