Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop
Abstract
BACKGROUND: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a debilitating multisystem condition affecting more than 1 million adults in the United States. PURPOSE: To determine benefits and harms of treatments for adults with ME/CFS and identify future research needs. DATA SOURCES: MEDLINE, PsycINFO, and Cochrane databases (January 1988 to September 2014); clinical trial registries; reference lists; and manufacturer information. STUDY SELECTION: English-language randomized trials of the effectiveness and adverse effects of ME/CFS treatments. DATA EXTRACTION: Data on participants, study design, analysis, follow-up, and results were extracted and confirmed. Study quality was dual-rated by using prespecified criteria; discrepancies were resolved through consensus. DATA SYNTHESIS: Among 35 treatment trials enrolling participants primarily meeting the 1994 Centers for Disease Control and Prevention and Oxford case definitions of CFS, the immune modulator rintatolimod improved some measures of exercise performance compared with placebo in 2 trials (low strength of evidence). Trials of galantamine, hydrocortisone, IgG, valganciclovir, isoprinosine, fluoxetine, and various complementary medicines were inconclusive (insufficient evidence). Counseling therapies and graded exercise therapy compared with no treatment, relaxation, or support improved fatigue, function, global improvement, and work impairment in some trials; counseling therapies also improved quality of life (low to moderate strength of evidence). Harms were rarely reported across studies (insufficient evidence). LIMITATION: Trials were heterogeneous and were limited by size, number, duration, applicability, and methodological quality. CONCLUSION: Trials of rintatolimod, counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for other treatments and harms is insufficient. More definitive studies comparing participants meeting different case definitions, including ME, and providing subgroup analysis are needed to fill research gaps.
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Systematic reviews have shown low strength of evidence for the effectiveness of complementary therapies, CBT, counseling and behavioral therapies, and graded exercise therapy for improvement of fatigue, physical functioning, sleep, and quality of life in patients with ME/CFS.
“Systematic reviews have shown low strength of evidence for the effectiveness of different complementary therapies [19], cognitive-behavioral therapy (CBT), counseling and behavioral therapies [14,22], and graded exercise therapy [23] for improvement of fatigue, physical functioning, sleep, and quality of life in patients with ME/CFS.”
From Systematic review of mind‐body interventions to treat myalgic encephalomyelitis/chronic fatigue syndrome (2021) · cites this paper as [19]
There is no cure for ME/CFS nor any FDA or Health Canada approved medication to treat it.
“There is no cure for ME/CFS nor any FDA or Health Canada approved medication to treat it [14,19], therefore the focus tends to be on managing and minimizing the symptoms and improving quality of life.”
From Systematic review of mind‐body interventions to treat myalgic encephalomyelitis/chronic fatigue syndrome (2021) · cites this paper as [19]
The Oxford criteria may fail to exclude individuals with other fatiguing conditions.
“It has long been suspected that the Oxford criteria may therefore fail to exclude individuals with other fatiguing conditions [14,19].”
From Systematic review of mind‐body interventions to treat myalgic encephalomyelitis/chronic fatigue syndrome (2021) · cites this paper as [19]
Although some studies indicate an effect by counseling and CBT, results remain inconsistent.
“Although some studies indicate an effect by counseling and CBT, results remain inconsistent [19] spurring interest in third-wave cognitive therapies like ACT [20].”
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“In some trials, counseling and behavior therapies improved fatigue (8, 38, 39, 41, 43, 46, 48, 62), physical function (Figure 1) (38, 40, 41, 43, 44, 48), quality of life (42, 45), work impairment (38, 48), and the clinical global impression of change scale (38, 48, 59) (low to moderate strength of evidence).”
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“One trial met criteria for good quality (31, 33), 5 for fair quality (29, 32, 34, 35), and 1 for poor quality (30).”
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“These included GET involving an exercise plan with structured incremental increases in exercise over time (23, 48, 50, 52, 53), qigong exercise (49, 51), and home orthostatic training (54).”
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“In some trials, counseling and behavior therapies improved fatigue (8, 38, 39, 41, 43, 46, 48, 62), physical function (Figure 1) (38, 40, 41, 43, 44, 48), quality of life (42, 45), work impairment (38, 48), and the clinical global impression of change scale (38, 48, 59) (low to moderate strength of evidence).”
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“These therapies were compared with usual care, wait-list control, no treatment, relaxation techniques, adaptive pacing (avoiding activities demanding >70% of a participant's perceived energy), anaerobic therapy that promoted gradual return of pleasurable activities (40, 47, 63, 64), graded exercise therapy (GET) (48),…”
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“The trials were too heterogeneous to allow us to determine whether one type of counseling intervention was more effective than another, and a small trial comparing faceto-face versus telephone CBT indicated no differences between these therapeutic approaches (37).”
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“001), but there were no statistically significant differences in serious deterioration measured by a composite score (48, 65).”
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“Characteristics of Responders and Nonresponders Four trials suggested that younger patients with less impairment, who are less focused on symptoms, adherent to cognitive therapy programs, and avoid over- and underexertion (that is, they stay within their energy envelope) are more likely to improve in some measures of…”
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“In some trials, counseling and behavior therapies improved fatigue (8, 38, 39, 41, 43, 46, 48, 62), physical function (Figure 1) (38, 40, 41, 43, 44, 48), quality of life (42, 45), work impairment (38, 48), and the clinical global impression of change scale (38, 48, 59) (low to moderate strength of evidence).”
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Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
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“One trial met criteria for good quality (31, 33), 5 for fair quality (29, 32, 34, 35), and 1 for poor quality (30).”
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“Some trials were primarily intended to measure intermediate outcomes, such as natural killer cell–mediated cytotoxicity (25), and most were underpowered for the health outcomes relevant to this systematic review.”
BackgroundInfluentialProvision of social support to individuals with chronic fatigue syndrome
Jason, L. A., Roesner, N., Porter, N. S., Parenti, B., Mortensen, J., & Hoyt, L. T. (2009) · Journal of Clinical Psychology · doi:10.1002/jclp.20648 · Cited by 28 · cited 5× · see citing works
“Five trials met criteria for good quality (44–48), 6 for fair quality (36–38, 40, 41, 43), and 3 for poor quality (8, 39, 42).”
BackgroundInfluentialDietary intervention in chronic fatigue syndrome
Hobday, R. A., Thomas, S., O’Donovan, A., Murphy, M., & Pinching, A. J. (2008) · Journal of Human Nutrition and Dietetics · doi:10.1111/j.1365-277x.2008.00857.x · Cited by 25 · cited 3× · see citing works
“One trial met criteria for good quality (31, 33), 5 for fair quality (29, 32, 34, 35), and 1 for poor quality (30).”
BackgroundHlavaty, L. E., Brown, M. M., & Jason, L. A. (2011) · Rehabilitation Psychology · doi:10.1037/a0024118 · Cited by 24 · cited 1× · see citing works
“Characteristics of Responders and Nonresponders Four trials suggested that younger patients with less impairment, who are less focused on symptoms, adherent to cognitive therapy programs, and avoid over- and underexertion (that is, they stay within their energy envelope) are more likely to improve in some measures of…”
BackgroundDepressive symptoms and pragmatic rehabilitation for chronic fatigue syndrome
Wearden, A. J., Dunn, G., Dowrick, C. F., & Morriss, R. K. (2012) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.111.107474 · Cited by 24 · cited 3× · see citing works
“Characteristics of Responders and Nonresponders Four trials suggested that younger patients with less impairment, who are less focused on symptoms, adherent to cognitive therapy programs, and avoid over- and underexertion (that is, they stay within their energy envelope) are more likely to improve in some measures of…”
BackgroundMeirleir, K. L. D., Bateman, L., Darragh, A., & Carruthers, B. M. (2012) · Cited by 23 · see citing works
The Effect of Acclydine in Chronic Fatigue Syndrome: A Randomized Controlled Trial
The, G. K. H., Bleijenberg, G., & van der Meer, J. W. M. (2007) · PLoS Clinical Trials · doi:10.1371/journal.pctr.0020019 · Cited by 22 · cited 3× · see citing works
“One trial met criteria for good quality (31, 33), 5 for fair quality (29, 32, 34, 35), and 1 for poor quality (30).”
BackgroundModerators of the treatment response to guided self-instruction for chronic fatigue syndrome
Tummers, M., Knoop, H., van Dam, A., & Bleijenberg, G. (2013) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2013.01.007 · Cited by 21 · see citing works
Sutcliffe, K., Gray, J., Tan, M. P., Pairman, J., Wilton, K., Parry, S. W., & Newton, J. L. (2009) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2009.02225.x · Cited by 19 · cited 4× · see citing works
“These included GET involving an exercise plan with structured incremental increases in exercise over time (23, 48, 50, 52, 53), qigong exercise (49, 51), and home orthostatic training (54).”
BackgroundMethodInfluentialRedefining the Chronic Fatigue Syndrome
Ganiats, T. G. (2015) · Annals of Internal Medicine · doi:10.7326/m15-0357 · Cited by 17 · cited 1× · see citing works
“The Institute of Medicine recently released new diagnostic criteria for CFS that require the presence of postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance (7, 72).”
Wearden, A. J., Riste, L., Dowrick, C. F., Chew-Graham, C. A., Bentall, R. P., Morriss, R. K., Peters, S., Dunn, G., Richardson, G. A., Lovell, K., et al. (2010) · Research Explorer (The University of Manchester) · Cited by 13 · see citing works
Effect of Galantamine Hydrobromide in Chronic Fatigue Syndrome
Blacker, C. V. R., Greenwood, D. T., Wesnes, K. A., Wilson, R. J., Woodward, C., Howe, I., & Ali, T. (2004) · JAMA · doi:10.1001/jama.292.10.1195 · cited 4×
“Galantamine was associated with higher rates of withdrawal and attrition than was placebo, demonstrating a dose-dependent relationship; the highest rates were seen at doses of 15 mg or more per day (26).”
BackgroundInfluential
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Sorted by citations
Immune-related adverse events with immune checkpoint blockade: a comprehensive review
Michot, J. M., Bigenwald, C., Champiat, S., Collins, M., Carbonnel, F., Postel-Vinay, S., Berdelou, A., Varga, A., Bahleda, R., Hollebecque, A., et al. (2016) · European Journal of Cancer · doi:10.1016/j.ejca.2015.11.016 · Cited by 2,127 · see citing works
“Abnormal fatigue could correspond to form of chronic fatigue syndrome, in this setting one possible remedy is exercise therapy [30].”
BackgroundLim, E., Ahn, Y., Jang, E.-S., Lee, S., Lee, S., & Son, C. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02269-0 · Cited by 489 · see citing works
“These studies may be promising; however, no therapeutics that can cure CFS/ME or objective diagnostic methods are available yet [13].”
BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review
Rivera, M. C., Mastronardi, C. A., Silva, C., Arcos‐Burgos, M., & Lidbury, B. A. (2019) · Diagnostics · doi:10.3390/diagnostics9030091 · Cited by 316 · see citing works
“Complementary and alternative medicine Nutritional supplements, Acetyl-l-carnitine, Essential fatty acids, Magnesium, Vitamins, Coenzyme Q10 plus Nutritional supplements may improve ME/CFS-related physical and mental fatigue in patients with specific nutritional deficiencies [215].”
BackgroundTLR Agonists as Vaccine Adjuvants Targeting Cancer and Infectious Diseases
Luchner, M., Reinke, S., & Milicic, A. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020142 · Cited by 287 · see citing works
“In patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), treatment with the poly-IC12U drug rintatolimod led to an improvement in exercise tolerance and showed dose-sparing effects in a Phase III clinical trial in 2012 [23].”
BackgroundInfluentialKomaroff, A. L., & Lipkin, W. I. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.06.002 · Cited by 266 · see citing works
“Moreover, controlled studies of the antidepressant fluoxetine in people with ME/CFS have demonstrated no benefit [32].”
The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 Infection
Moghimi, N., Napoli, M. D., Biller, J., Siegler, J. E., Shekhar, R., McCullough, L. D., Harkins, M. S., Hong, E., Alaouieh, D., Mansueto, G., et al. (2021) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-021-01130-1 · Cited by 195 · see citing works
Karshikoff, B., Sundelin, T., & Lasselin, J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00021 · Cited by 180 · see citing works
“One of the key symptoms is “postexertional fatigue” (64), which, interestingly, appears to be somewhat unique for this patient group (65).”
BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview
Deumer, U.-S., Varesi, A., Floris, V., Savioli, G., Mantovani, E., López-Carrasco, P., Rosati, G. M., Prasad, S., & Ricevuti, G. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10204786 · Cited by 153 · see citing works
“Although different meta-analysis and clinical trials have shown robust evidence in favor of cognitive-behavioral therapy (CBT) and graded exercise therapy (GET) [8–17], more research should be carried out to find advanced therapeutic approaches [6,18].”
BackgroundCastro‐Marrero, J., Sáez‐Francàs, N., Santillo, D., & Alegre, J. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13702 · Cited by 142 · see citing works
“Drugs such as isoprinosine and rintatolimod have been used in experimental studies of the illness but have not been approved for marketing for any condition in the USA (Smith et al., 2015).”
BackgroundMethodInfluentialESCMID rapid guidelines for assessment and management of long COVID
Yelin, D., Moschopoulos, C. D., Margalit, I., Gkrania‐Klotsas, E., Landi, F., Stahl, J. ‐., & Yahav, D. (2022) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2022.02.018 · Cited by 145 · see citing works
The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)
König, R. S., Albrich, W. C., Kahlert, C. R., Bahr, L. S., Löber, U., Vernazza, P., Scheibenbogen, C., & Forslund, S. K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.628741 · Cited by 123 · see citing works
Wormgoor, M. E. A., & Rodenburg, S. C. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-020-02683-4 · Cited by 117 · see citing works
“However, several previous systematic reviews mentioned some uncertainty as to whether findings in studies with Oxford or Fukuda criteria are applicable to ME/CFS patients diagnosed with criteria requiring PEM [33, 35, 37, 44].”
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease
Arron, H. E., Marsh, B. D., Khan, M. A., Jaeger, B., Kell, D., & Pretorius, E. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1386607 · Cited by 111 · see citing works
Importance of fatigue and its measurement in chronic liver disease
Gerber, L. H., Weinstein, A. A., Mehta, R., & Younossi, Z. M. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i28.3669 · Cited by 90 · see citing works
Chronic fatigue syndrome: progress and possibilities
Sandler, C. X., & Lloyd, A. R. (2020) · The Medical Journal of Australia · doi:10.5694/mja2.50553 · Cited by 74 · see citing works
Zhang, Z.-T., Du, X.-M., Ma, X., Zong, Y., Chen, J., Yu, C., Liu, Y.-G., Chen, Y., Zhao, L.-J., & Lu, G. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0539-1 · Cited by 72 · see citing works
Geraghty, K., Hann, M., & Kurtev, S. (2017) · Journal of Health Psychology · doi:10.1177/1359105317726152 · Cited by 72 · see citing works
Geraghty, K., & Blease, C. R. (2018) · Disability and Rehabilitation · doi:10.1080/09638288.2018.1481149 · Cited by 68 · see citing works
“While another systematic review found inconsistent evidence of modest benefit using CBT versus control treatments and more consistent evidence of benefit using GET [95], it was noted that some trials used broad entry criteria (i.”
ResultMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from?
Toogood, P. L., Clauw, D. J., Phadke, S., & Hoffman, D. L. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105465 · Cited by 68 · see citing works
Updated Clinical Practice Guidelines for the Diagnosis and Management of Long COVID
Seo, J.-W., Kim, S. E., Kim, Y., Kim, E. J., Kim, T., Kim, T., Lee, S. H., Lee, E. J., Lee, J., Seo, Y. B., et al. (2024) · Infection and Chemotherapy · doi:10.3947/ic.2024.0024 · Cited by 70 · see citing works
“Some studies have suggested potential benefits of taking rintatolimod, as well as counseling and graded exercise therapy; however, the evidence is limited [117, 118].”
BackgroundPreliminary Guidelines for the Clinical Evaluation and Management of Long COVID
Kim, Y., Kim, S. E., Kim, T., Yun, K. W., Lee, S. H., Lee, E. J., Seo, J.-W., Jung, Y. H., & Chong, Y. P. (2022) · Infection and Chemotherapy · doi:10.3947/ic.2022.0141 · Cited by 65 · see citing works
“Although some studies have suggested the benefit of rintatolimod, counseling therapy, and step-bystep exercise therapy [114, 115], these studies have limitations in using different fatigue interventions and evaluation methods for the outcome.”
MethodHaider, S., Janowski, A. J., Lesnak, J. B., Hayashi, K., Dailey, D. L., Chimenti, R. L., Frey‐Law, L., Sluka, K. A., & Berardi, G. (2022) · Pain · doi:10.1097/j.pain.0000000000002711 · Cited by 54 · see citing works
The ‘cognitive behavioural model’ of chronic fatigue syndrome: Critique of a flawed model
Geraghty, K., Jason, L. A., Sunnquist, M., Tuller, D., Blease, C., & Adeniji, C. (2019) · Health Psychology Open · doi:10.1177/2055102919838907 · Cited by 56 · see citing works
“A wide range of treatments have been tested on ME/CFS patients, ranging from drug therapies, mainly antidepressants and immunological modulators, to non-pharmacological therapies, predominantly psycho-behavioural therapies (Smith et al., 2015).”
Do graded activity therapies cause harm in chronic fatigue syndrome?
Kindlon, T. (2017) · Journal of Health Psychology · doi:10.1177/1359105317697323 · Cited by 47 · see citing works
“This was a significant improvement over previous trials of CBT and GET, where the reporting of harms has been described as poor (Chambers et al., 2006; Marques et al., 2015; Price et al., 2008; Smith et al., 2015).”
ResultCytokine Inhibition in Patients With Chronic Fatigue Syndrome
Roerink, M. E., Bredie, S. J. H., Heijnen, M., Dinarello, C. A., Knoop, H., & van der Meer, J. W. M. (2017) · Annals of Internal Medicine · doi:10.7326/m16-2391 · Cited by 44 · see citing works
“The only effective treatments are cognitive behavioral therapy and graded exercise therapy (3–5), although a substantial proportion of patients do not improve with these treatments (6).”
BackgroundAcupuncture for chronic fatigue syndrome: a systematic review and meta-analysis
Zhang, Q., Gong, J., Dong, H., Xu, S., Wang, W., & Huang, G.-Y. (2019) · Acupuncture in Medicine · doi:10.1136/acupmed-2017-011582 · Cited by 43 · see citing works
“Acupuncture in Medicine, 37(4) Fi rs t au th or (y ea r) D ia gn os is Pa rt ic ip an ts In te rv en tio ns O ut co m e”
BackgroundInfluentialVink, M., & Vink-Niese, F. (2019) · Diagnostics · doi:10.3390/diagnostics9040124 · Cited by 45 · see citing works
“Systematic reviews by Cairns and Hotopf (2005), Castro-Marrero et al. (2017), Chambers et al. (2006), Malouff et al. (2007), Smith et al. (2015) and Whiting et al. (2001) [10,106,107,178–180], a systematic review and meta-analysis by Marques et al. (2015) [181] and a meta-analysis by Castell et al.…”
BackgroundJoseph, P., Pari, R., Miller, S., Warren, A., Stovall, M. C., Squires, J., Chang, C.-J., Xiao, W., Waxman, A. B., & Systrom, D. M. (2022) · CHEST Journal · doi:10.1016/j.chest.2022.04.146 · Cited by 44 · see citing works
Cabanas, H., Muraki, K., Eaton-Fitch, N., Staines, D., & Marshall‐Gradisnik, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.687806 · Cited by 40 · see citing works
Patient-reported treatment outcomes in ME/CFS and long COVID
Eckey, M., Li, P., Morrison, B., Bergquist, J., Davis, R. W., & Xiao, W. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2426874122 · Cited by 35 · see citing works
Revolutionizing medicine with toll-like receptors: A path to strengthening cellular immunity
Malik, J. A., Kaur, G., & Agrewala, J. N. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.127252 · Cited by 34 · see citing works
Metselaar, P. I., Mendoza‐Maldonado, L., Yim, A. Y. F. L., Abarkan, I., Henneman, P., Velde, A. A. T., Schönhuth, A., Bosch, J. A., Kraneveld, A. D., & Lopez‐Rincon, A. (2021) · Scientific Reports · doi:10.1038/s41598-021-83660-9 · Cited by 33 · see citing works
Kavyani, B., Lidbury, B. A., Schloeffel, R., Fisher, P. R., Missailidis, D., Annesley, S. J., Dehhaghi, M., Heng, B., & Guillemin, G. J. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04380-5 · Cited by 32 · see citing works
“FMT is the infusion of liquid filtrate faeces from a healthy donor into the gut of a recipient to target microbiota-gut-brain axis [31].”
BackgroundWhite, P. D., Abbey, S. E., Angus, B., Ball, H. A., Buchwald, D., Burness, C. E., Carson, A. J., Chalder, T., Clauw, D. J., Coebergh, J. A., et al. (2023) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2022-330463 · Cited by 35 · see citing works
“Smith, 2015 50 21 ‘Trials of rintatolimod, counselling therapies and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for other treatments and harms is insufficient.’”
BackgroundLarkin, D. T., & Martin, C. R. (2017) · Neurophysiologie Clinique · doi:10.1016/j.neucli.2017.01.012 · Cited by 32 · see citing works
“As a consequence of diagnostic challenges and because patients often present with a multitude of symptoms, treatment approaches have been broad and included immunologic, pharmacologic, behavioral treatment and complementary and alternative medicines [57].”
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Real Illness
Komaroff, A. L. (2015) · Annals of Internal Medicine · doi:10.7326/m15-0647 · Cited by 31 · see citing works
“The AHRQ-commissioned review of treatment trials, published in this issue (2), finds that counseling therapies and graded exercise therapy might help improve fatigue and function in some, but not all, patients; that not all trials show a benefit for the average patient; and that neither treatment is curative.”
Khanpour Ardestani, S., Karkhaneh, M., Stein, E., Punja, S., Junqueira, D. R., Kuzmyn, T., Pearson, M., Smith, L., Olson, K., & Vohra, S. (2021) · Medicina · doi:10.3390/medicina57070652 · Cited by 30 · see citing works
“It has long been suspected that the Oxford criteria may therefore fail to exclude individuals with other fatiguing conditions [14,19].”
BackgroundInfluentialAcceptance & Commitment Therapy for ME/CFS (Chronic Fatigue Syndrome) – A feasibility study
Jonsjö, M. A., Wicksell, R. K., Holmström, L., Andreasson, A., & Olsson, G. L. (2019) · Journal of Contextual Behavioral Science · doi:10.1016/j.jcbs.2019.02.008 · Cited by 27 · see citing works
Göebel, A. (2016) · Autoimmunity Reviews · doi:10.1016/j.autrev.2016.02.011 · Cited by 28 · see citing works
Kuut, T. A., Buffart, L. M., Braamse, A. M. J., Csorba, I., Bleijenberg, G., Nieuwkerk, P., Moss-Morris, R., Müller, F., & Knoop, H. (2024) · Psychological Medicine · doi:10.1017/s0033291723003148 · Cited by 27 · see citing works
“…2022; Malouff, Thorsteinsson, Rooke, Bhullar, & Schutte, 2008; Marques, De Gucht, Gouveia, Leal, & Maes, 2015; Price, Mitchell, Tidy, & Hunot, 2008; Smith et al., 2015) and one systematic review (Ingman, Smakowski, Goldsmith, & Chalder, 2022), although one meta-analysis revised its decision to…”
Chronic fatigue syndrome in the emergency department
Timbol, C. R., & Baraniuk, J. N. (2019) · Open Access Emergency Medicine · doi:10.2147/oaem.s176843 · Cited by 24 · see citing works
Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome
Pietrangelo, T., Fulle, S., Coscia, F., Gigliotti, P. V., & Fanò, G. (2018) · European Journal of Translational Myology · doi:10.4081/ejtm.2018.7688 · Cited by 22 · see citing works
Dai, L., Liu, Z., Zhou, W., Zhang, L., Miao, M., Wang, L., Hua, H., Wang, B., & Ji, G. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155636 · Cited by 23 · see citing works
Almenar‐Pérez, E., Sánchez-Fito, T., Ovejero, T., Nathanson, L., & Oltra, E. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11030126 · Cited by 22 · see citing works
“as reference papers to evaluate common drug-based ME/CFS therapies [46,47].”
Are ME/CFS Patient Organizations “Militant”?
Blease, C., & Geraghty, K. (2018) · Journal of Bioethical Inquiry · doi:10.1007/s11673-018-9866-5 · Cited by 23 · see citing works
Jonsjö, M. A., Wicksell, R. K., Holmström, L., Andréasson, A., Bilevičiūtė-Ljungar, I., & Olsson, G. (2017) · Fatigue Biomedicine Health & Behavior · doi:10.1080/21641846.2017.1287546 · Cited by 19 · see citing works
“The evidence for any effective medical treatment of the condition is weak, despite numerous studies [4].”
BackgroundPediatric chronic fatigue syndrome: current perspectives
Crawley, E. M. (2018) · Pediatric Health Medicine and Therapeutics · doi:10.2147/phmt.s126253 · Cited by 21 · see citing works
Robbins, R. C., Helmer, D. A., Monahan, P., Hunt, S. C., McAndrew, L. M., Nazario, M., Brown, W. J., Chao, W., Navarro, A., & Sall, J. (2022) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2022.01.031 · Cited by 20 · see citing works
“Finally, a systematic review found that after exclusion of an outlier, there was evidence that cognitive-behavioral therapy improved physical functioning in ME/CFS compared with control.(15) This finding was supported by 2 subsequent clinical trials for ME/CFS that found evidence for cognitive-behavioral therapy’s imp…”
ResultCognitive remediation training improves performance in patients with chronic fatigue syndrome
McBride, R., Horsfield, S., Sandler, C. X., Cassar, J., Casson, S. M., Cvejic, E., Vollmer-Conna, U. S., & Lloyd, A. R. (2017) · Psychiatry Research · doi:10.1016/j.psychres.2017.08.035 · Cited by 20 · see citing works
“Both the CBT/GET and the CET groups also displayed improvement on the self-report symptoms relating to fatigue and to physical and social function status, consistent with previous research (Larun et al., 2015; Sandler et al., 2016; Smith et al., 2015).”
Sun, Y., Zhang, Z., Qiao, Q., Zou, Y., Wang, L., Wang, T., Lou, B., Li, G., Xu, M., Wang, Y., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05710-w · Cited by 19 · see citing works
Kronisk utmattelsessyndrom/myalgisk encefalopati – sykdomsmekanismer, diagnostikk og behandling
Wyller, V. B., Reme, S. E., & Mollnes, T. E. (2015) · Tidsskrift for Den norske legeforening · doi:10.4045/tidsskr.15.1180 · Cited by 18 · see citing works
“With the possible exception of the immunomodulatory drug rintatolimod, a recent systematic review failed to show efficacy of any pharmaceutical therapies for chronic fatigue syndrome/myalgic encephalomyelitis, be it immunoglobulins, hydrocortisone, selective serotonin reuptake inhibitors or antiviral agents (38).”
BackgroundZhang, Y., Jin, F., Wei, X., Jin, Q., Xie, J., Pan, Y., & Shen, W. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.958005 · Cited by 18 · see citing works
Baklund, I. H., Dammen, T., Moum, T. Å., Kristiansen, W., Sosa, D. D., Castro‐Marrero, J., Helland, I. B., & Strand, E. B. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10143105 · Cited by 18 · see citing works
“No cure or specific treatment exists, nor are there any specific biomarkers [10,11].”
BackgroundSubjective insomnia is associated with low sleep efficiency and fatigue in middle-aged women
Hirose, A., Terauchi, M., Akiyoshi, M., Owa, Y., Kato, K., & Kubota, T. (2016) · Climacteric · doi:10.1080/13697137.2016.1186160 · Cited by 18 · see citing works
Frontera, J. A., Guekht, A. B., Allegri, R., Ashraf, M., Baykan, B. B., Crivelli, L., Easton, A., García‐Azorín, D., Helbok, R., Joshi, J., et al. (2023) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2023.120827 · Cited by 17 · see citing works
Categorical interoception and the role of threat
Zacharioudakis, N., Vlemincx, E., & den Bergh, O. V. (2019) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2019.12.009 · Cited by 17 · see citing works
Zhang, Y., & Wang, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1373748 · Cited by 17 · see citing works
Le syndrome de fatigue chronique : une nouvelle maladie ?
de Korwin, J.-D., Chiche, L., Banovic, I., Ghali, A., Delliaux, S., Authier, F., Cozon, G. J. N., Hatron, P., Fornasieri, I., & Morinet, F. (2016) · La Revue de Médecine Interne · doi:10.1016/j.revmed.2016.05.003 · Cited by 16 · see citing works
El-Mokadem, J. F. K., DiMarco, K., Kelley, T. M., & Duffield, L. (2020) · Spirituality in Clinical Practice · doi:10.1037/scp0000232 · Cited by 14 · see citing works
Bijlsma, N., & Cohen, M. M. (2018) · Environmental Health and Preventive Medicine · doi:10.1186/s12199-018-0709-0 · Cited by 14 · see citing works
Ahmed, A., Mewes, J. C., & Vrijhoef, H. J. (2019) · Journal of Health Psychology · doi:10.1177/1359105319847261 · Cited by 14 · see citing works
“In light of the debate around the scientific rigour of studies on therapies for ME/CFS, existing reviews assessing the effectiveness of these therapies (e.g. Larun et al., 2017; Smith et al., 2015) need to be updated, given the main methodological concerns raised more recently.”
BackgroundSchmid, S. R., Uecker, C., Fröhlich, A., & Langhorst, J. (2024) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-024-01792-1 · Cited by 13 · see citing works
“According to Smith and colleagues [8] CFS is furthermore defined as a severely debilitating, multisystem disorder that is also characterized by neurological and cognitive changes, motor dysfunction, altered immune response, autonomic responses, persistent deterioration after exertion, and memory or…”
Sapra, A., & Bhandari, P. (2021) · StatPearls · Cited by 13 · see citing works
A reexamination of the cognitive behavioral model of chronic fatigue syndrome
Sunnquist, M., & Jason, L. A. (2018) · Journal of Clinical Psychology · doi:10.1002/jclp.22593 · Cited by 12 · see citing works
Vink, M. (2016) · Journal of Neurology and Neurobiology · doi:10.16966/2379-7150.124 · Cited by 12 · see citing works
“This is in stark contrast to the PACE trial authors’ response to a National Institutes of Health treatment review of ME/CFS [89], in which the PACE trial authors stated, “It is important not to overemphasise the harms associated with an effective treatment when there are so few others available” [90].”
Mansoubi, M., Richards, T., Ainsworth-Wells, M., Fleming, R., Leveridge, P., Shepherd, C., & Dawes, H. (2025) · BMJ Open · doi:10.1136/bmjopen-2024-094658 · Cited by 10 · see citing works
Espejo, J., Garcia-Escudero, M., & Oltra, E. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092673 · Cited by 10 · see citing works
“A more promising option for the treatment of CFS/ME is provided by the CTs using the Toll-like Receptor TLR-3 agonist rintatolimod (Poly I:C(12)U), which activates interferon-induced proteins, showing medically significant improvement in some cohorts of participating patients [22,27].”
MethodLi, Y., Yang, J., Chau, C. I., Shi, J., Chen, X., Hu, H., & Ung, C. O. L. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1266803 · Cited by 9 · see citing works
Noble, S., Bonner, C., Hersch, J. K., Jansen, J., McGeechan, K., & McCaffery, K. J. (2018) · Patient Education and Counseling · doi:10.1016/j.pec.2018.10.011 · Cited by 9 · see citing works
McPhee, G., Baldwin, A., Kindlon, T., & Hughes, B. M. (2019) · Journal of Health Psychology · doi:10.1177/1359105319854532 · Cited by 9 · see citing works
Self-Reported Fatigue Predicts Incident Stroke in a General Population
Barlas, G., Luben, R., Neal, S. R., Wareham, N. J., Khaw, K., & Myint, P. K. (2020) · Stroke · doi:10.1161/strokeaha.119.027163 · Cited by 9 · see citing works
“through deprescribing culprit drugs or prescribing drugs such as antidepressants, is likely to be less widely applicable.(41,43) At”
BackgroundPerry, S. E., & Santhouse, A. M. (2016) · Medicine · doi:10.1016/j.mpmed.2016.09.015 · Cited by 9 · see citing works
Mindfulness training for chronic fatigue syndrome: A pilot study
Sollie, K., Næss, E. T., Solhaug, I., & Thimm, J. C. (2017) · Health Psychology Report · doi:10.5114/hpr.2017.65469 · Cited by 8 · see citing works
“However, the effects of pharmacological treatments are small, and the findings about psychological interventions are inconsistent (Smith et al., 2015).”
BackgroundSomatoforme Störungen – somatoforme Belastungsstörung und verwandte Störungen
Kapfhammer, H. (2017) · Springer eBooks · doi:10.1007/978-3-662-49295-6_74 · Cited by 8 · see citing works
Fauske, L., Bruland, Ø. S., Dahl, A. A., Myklebostad, A., & Rème, S. E. (2021) · Cancers · doi:10.3390/cancers13164076 · Cited by 8 · see citing works
“In terms of tackling chronic fatigue among the general population, cognitive behaviour therapy (CBT) has been documented to offer certain benefits, albeit with only small to moderate effect sizes [3,4].”
BackgroundBack to the Future? Immunoglobulin Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Brownlie, H., & Speight, N. (2021) · Healthcare · doi:10.3390/healthcare9111546 · Cited by 8 · see citing works
“Firstly, the assessed results of the four trials, historically summarised as “mixed” [25], “inconclusive” [26,76], and/or “insufficient” [76].”
ResultMartín, A. D. V., Salazar, A. D., Pérez, I. M. M., & Pérez, S. E. M. (2025) · International journal of exercise science · doi:10.70252/daya4589 · Cited by 7 · see citing works
“5,6 CFS exhibits significant clinical overlap with fibromyalgia, with a global prevalence estimate ranging from 0.5% to 2%, affecting over 17 million individuals worldwide.”
InfluentialDifferences in Symptoms among Black and White Patients with ME/CFS
Jason, L. A., & Torres, C. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11226708 · Cited by 7 · see citing works
“In the literature, patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been described as being mostly white, upper-class women, but these samples were primarily recruited from clinical and hospital-based settings [4,5].”
BackgroundEriksen, W. (2017) · Medical Hypotheses · doi:10.1016/j.mehy.2017.02.011 · Cited by 6 · see citing works
Comhaire, F. H., & Deslypère, J. P. (2019) · Medical Hypotheses · doi:10.1016/j.mehy.2019.109444 · Cited by 6 · see citing works
Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
White, P. D., Clauw, D. J., van der Meer, J. W. M., Moss-Morris, R. E., & Taylor, R. R. (2015) · Annals of Internal Medicine · doi:10.7326/l15-5171 · Cited by 6 · see citing works
Falaguera-Vera, F. J., Garcia-Escudero, M., Bonastre-Férez, J., Zacarés, M., & Oltra, E. (2020) · Preprints.org · doi:10.20944/preprints202009.0264.v1 · Cited by 5 · see citing works
Chronic fatigue syndrome: what is it and how to treat?
Moylan, S., Eyre, H. A., & Berk, M. (2015) · The Lancet Psychiatry · doi:10.1016/s2215-0366(15)00475-7 · Cited by 5 · see citing works
Chronic Fatigue Syndrome, Functional Mitochondriopathy, and Enterohepatic Dysfunction.
Bland, J. S. (2017) · Europe PMC (PubMed Central) · Cited by 5 · see citing works
Sleep Disturbances in General Medical Disorders
Chokroverty, S. (2017) · Springer eBooks · doi:10.1007/978-1-4939-6578-6_47 · Cited by 5 · see citing works
Unexpected findings and promoting monocausal claims, a cautionary tale
Copeland, S. M. (2016) · Journal of Evaluation in Clinical Practice · doi:10.1111/jep.12584 · Cited by 4 · see citing works
Meng, H., & Friedberg, F. (2017) · Fatigue Biomedicine Health & Behavior · doi:10.1080/21641846.2017.1343171 · Cited by 4 · see citing works
“have indicated mixed results with great heterogeneity with respect to the beneficial effect of CBT [9,10].”
ResultFalaguera-Vera, F. J., Garcia-Escudero, M., Bonastre-Férez, J., Zacarés, M., & Oltra, E. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17218044 · Cited by 4 · see citing works
McDonald, S., Tan, S. X., Banu, S., van Driel, M., McGree, J. M., Mitchell, G. K., & Nikles, J. (2021) · Patient · doi:10.1007/s40271-021-00540-0 · Cited by 4 · see citing works
Antimicrobial therapies for chronic pain (part 2): the prevention and treatment of chronic pain
Wang, E. J., Dolomisiewicz, E., Karri, J. V., Tontisirin, N., & Cohen, S. P. (2023) · The Korean journal of pain · doi:10.3344/kjp.23130 · Cited by 4 · see citing works
Review: Exercise therapy reduces fatigue in chronic fatigue syndrome
Denman, A. M. (2016) · Annals of Internal Medicine · doi:10.7326/acpjc-2016-164-10-055 · Cited by 4 · see citing works
Twisk, F. (2018) · Diagnostics · doi:10.3390/diagnostics8020034 · Cited by 4 · see citing works
“The Dutch Health Council did not conduct a review of the research into ME (and CFS), but based their findings and definition of “ME/CFS” on four reviews by others: (1) the IOM report [9], which reviewed CFS [5] studies only and proposed new criteria; (2) a systemic review of diagnostic criteria commissioned by the US…”
The efficacy and safety of moxibustion for chronic fatigue syndrome
Xue, K., Wang, Y., Wang, X., Chen, P.-N., Xiao, C., Fu, J., & Cui, J. (2021) · Medicine · doi:10.1097/md.0000000000025742 · Cited by 3 · see citing works
The effects of traditional Chinese manual therapy (Tuina) for chronic fatigue syndrome
Ren, J., He, T., Zhou, X., Wu, Z., & Kong, L. (2021) · Medicine · doi:10.1097/md.0000000000027700 · Cited by 3 · see citing works
“In order to reduce the severity of symptoms and improve functional status, treatments are mainly based on the clinical symptoms of patients with CFS since the cause of CFS has not been clearly defined.([10,11]) Although patients with CFS can choose to take drugs to relieve fatigue, the trial shows that except for poor…”
Wang, B., Zhang, X., Lu, P., Sun, P., & He, T. (2025) · JMIR Research Protocols · doi:10.2196/65958 · Cited by 3 · see citing works
“However, the efficacy of these treatments remains controversial [16].”
Yang, B., Wang, T., Xiong, K., Ding, X., Zhang, M., Chen, H., Huang, M. X., & Wu, X. (2025) · Acupuncture and Herbal Medicine · doi:10.1097/hm9.0000000000000180 · Cited by 3 · see citing works
Khakban, I., Jain, S., Gallab, J., Dharmaraj, B. G., Zhou, F., Lokker, C., Abdelkader, W., Zeraatkar, D., & Busse, J. W. (2025) · Journal of Medical Internet Research · doi:10.2196/65087 · Cited by 2 · see citing works
“First, although current evidence supports exercise therapy [77] and CBT [78] for the management of ME/CFS, some patients find these approaches unacceptable.”
Young, J. L., Powell, R. N., Powell, A., Welling, L. L. M., Granata, L. E., & Saal, J. (2025) · Journal of Psychopharmacology · doi:10.1177/02698811251368371 · Cited by 2 · see citing works
“These include mild pain relievers, COX-2 inhibitors, non-steroidal anti-inflammatory drugs, antidepressants, and immune modulators (Castro-Marrero et al., 2017; Graves et al., 2024; Smith et al., 2015).”
Perry, S. E. (2020) · Medicine · doi:10.1016/j.mpmed.2020.09.007 · Cited by 2 · see citing works
Rødevand, L. N. (2017) · Scandinavian Psychologist · doi:10.15714/scandpsychol.4.e1 · Cited by 2 · see citing works
- Authors
- Smith, M. E. B., Haney, E., McDonagh, M., Pappas, M., Daeges, M., Wasson, N., Fu, R., & Nelson, H. D.
- Affiliations
- Oregon Health & Science University (US)
- Venue
- Annals of Internal Medicine
- Publisher
- American College of Physicians
- Published
- 2015-06-16
- Volume
- 162
- Issue
- 12
- Pages
- 841-850
- ISSN
- 0003-4819 (ISSN-L)
- 1539-3704
- OpenAlex
- W1601664045
- Cited by
- 142
- References
- 68
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 9 · 2023: 7 · 2022: 12 · 2021: 18 · 2020: 10 · 2019: 14 · 2018: 10 · 2017: 18 · 2016: 17 · 2015: 12
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (290201200014I)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- chronic fatigue syndrome, treatment effectiveness, treatment harms, immunomodulators, graded exercise therapy, counseling, complementary therapy, galantamine, cortisol, isoprinosine, valganciclovir, fluoxetine, fatigue, quality of life, case definition
- MeSH terms
- Adult, Complementary Therapies, Antiviral Agents, Counseling, Encephalomyelitis, Exercise Therapy, Humans, Immunologic Factors, Poly I-C, Poly U, Quality of Life, Fatigue Syndrome, Chronic, Cognitive Behavioral Therapy, Myalgia
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