Dietary Supplementation for Fatigue Symptoms in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)-A Systematic Review

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmunological disorder with limited treatment options. Despite the widespread use of Dietary Supplements (DSs) among ME/CFS patients to alleviate fatigue and associated symptoms, evidence remains inconclusive. This systematic review aims to provide an updated synthesis of the efficacy of DS interventions and explore possible mechanisms underlying their therapeutic effects.

Methods: This systematic review was conducted according to PRISMA guidelines. Several databases (Ebsco Host, PubMed, Scopus, Google Scholar) were used for the systematic search, which was based on the broad search terms ME/CFS and DS with a focus on publications between 1994 and 2024. The primary outcome was fatigue, with additional considerations including psychological well-being, physical activity, and biochemical markers. Two independent researchers screened the studies for eligibility in a multi-stage process and assessed quality and bias using Cochrane’s risk of bias tools (RoB-2, ROBINS-I).

Results: Fourteen studies (N = 809) of heterogeneous designs were included, showing a high risk of bias, mostly due to missing data and selection bias. While some interventions (L-carnitine and guanidinoacetic acid, oxaloacetate, CoQ10-selenium combination, NADH and NADH-CoQ10 combination) showed significant reductions in fatigue, methodological limitations, like small sample sizes and missing data, prevent firm conclusions. Mixed results were reported for secondary outcomes like cognitive function and inflammatory markers. Six studies noted adverse effects, including nausea and insomnia.

Conclusions: Though some DSs showed potential in reducing fatigue in ME/CFS, methodological limitations and inconsistent results hinder definitive conclusions. Future research should improve diagnostic criteria and include more diverse populations.

Source: Dorczok MC, Mittmann G, Mossaheb N, Schrank B, Bartova L, Neumann M, Steiner-Hofbauer V. Dietary Supplementation for Fatigue Symptoms in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)-A Systematic Review. Nutrients. 2025 Jan 28;17(3):475. doi: 10.3390/nu17030475. PMID: 39940333; PMCID: PMC11819863. https://pmc.ncbi.nlm.nih.gov/articles/PMC11819863/ (Full text)

Language Matters: What Not to Say to Patients with Long COVID, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Other Complex Chronic Disorders

Abstract:

People with Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic disorders consistently report having difficulty obtaining effective and compassionate medical care and being disbelieved, judged, gaslighted, and even dismissed by healthcare professionals. We believe that these adversarial interactions and language are more likely to arise when healthcare professionals are confronting complex chronic illnesses without proper training, diagnostic biomarkers, or FDA-approved therapies.
These problematic conversations between practitioners and patients often involve specific words and phrases—termed the “never-words”—can leave patients in significant emotional distress and negatively impact the clinician–patient relationship and recovery. Seeking to prevent these destructive interactions, we review key literature on best practices for difficult clinical conversations and discuss the application of these practices for people with Long COVID, ME/CFS, dysautonomia, and other complex chronic disorders. We provide recommendations for alternative, preferred phrasing to the never-words, which can enhance therapeutic relationship and chronic illness patient care via compassionate, encouraging, and non-judgmental language.
Source: Smyth NJ, Blitshteyn S. Language Matters: What Not to Say to Patients with Long COVID, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Other Complex Chronic Disorders. International Journal of Environmental Research and Public Health. 2025; 22(2):275. https://doi.org/10.3390/ijerph22020275 https://www.mdpi.com/1660-4601/22/2/275 (Full text)

Mapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile and Vascular Dysfunction

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with no known underlying mechanisms, diagnostic tools, or treatments.  Multiple areas of dysfunction have been extensively studied, but rarely examined together. We recruited age- and sex-matched ME/CFS patients and healthy controls for a multi-modal study examining energy metabolism, immune profiles and plasma protein levels.

Elevated levels of adenosine monophosphate (AMP) were detected in both plasma and immune cells. Additionally, immune cells showed higher levels of adenosine diphosphate (ADP) and a reduced adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio.

These findings imply decreased ATP generation and the presence of energy stress within the immune cell population. Adaptive immune cell populations were skewed towards less mature effector subsets of CD4+, CD8+ and gd T cells, and proportions of CD1c+CD141-conventional DC type 2 (cDC2) and CD56lowCD16+ terminal natural killer (NK) cells were also reduced. Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Using Classification and Regression Tree (CART) modelling, we identified variables from each mode of investigation with strong predictive potential for ME/CFS. Together, this study provides new insights into the somatic symptoms and underlying biology of ME/CFS.

Source: Heng, Ruiwen Benjamin and Gunasegaran, Bavani and Krishnamurthy, Shivani and Bustamante, Sonia and Staats, Ananda and Chow, Sharron and Ahn, Seong Beom and Paul-Heng, Moumita and Maciver, Yolande and Smith, Kirsten and Tran, Denise Phuong and Howley, Peter P. and Bilgin, Ayse Aysin and Sharland, Alexandra and Schloeffel, Richard and Guillemin, Gilles J. and Administrator, Sneak Peek, Mapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile and Vascular Dysfunction. Available at SSRN: https://ssrn.com/abstract=5131664 or http://dx.doi.org/10.2139/ssrn.5131664  https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5131664 (Full text available as PDF file)

The Microbiota-Gut-Brain Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Narrative Review of an Emerging Field

Abstract:

The intricate relationship between gut microbiota and the brain has emerged as a pivotal area of research, particularly in understanding myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This complex condition is characterized by debilitating fatigue, cognitive dysfunction, and a wide array of systemic manifestations, posing significant challenges for diagnosis and treatment. Recent studies highlight the microbiota-gut-brain axis as a crucial pathway in ME/CFS pathophysiology, suggesting that alterations in gut microbial composition may impact immune responses, neurochemical signaling, and neuronal health.

This narrative review systematically explores English-language scholarly articles from January 1995 to January 2025, utilizing databases such as PubMed, Scopus, and Web of Science. The findings underscore the potential for targeted therapeutic interventions aimed at correcting gut dysbiosis. As research progresses, a deeper understanding of the microbiota-gut-brain connection could lead to innovative approaches for managing ME/CFS, ultimately enhancing the quality of life for affected individuals.

Source: El-Sehrawy AAMA, Ayoub II, Uthirapathy S, Ballal S, Gabble BC, Singh A, V K, Panigrahi R, Kamali M, Khosravi M. The Microbiota-Gut-Brain Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Narrative Review of an Emerging Field. Eur J Transl Myol. 2025 Feb 12. doi: 10.4081/ejtm.2025.13690. Epub ahead of print. PMID: 39937103. https://pubmed.ncbi.nlm.nih.gov/39937103/

Post-COVID-19 Small Fiber Neuropathy as a New Emerging Quality of Life-Threatening Disease: A Systematic Review

Abstract:

Post-acute sequelae of COVID-19 (PASC) syndrome is considered an emergent and diffuse multidisciplinary problem. Compelling evidence suggests that COVID-19 increases symptoms of pre-existent small fiber neuropathy (SFN) and might trigger de novo onset of SFN. In this systematic review, for the first time, we provide a comprehensive overview of the clinical and diagnostic features of PASC-SFN, including the accompanying disorders, disease evolution, and possible treatments, described in the recent literature.
Following infection, many patients reported a wide range of symptoms and complications, not self-limiting and independent from previous infection severity. SFN begins more frequently with distal limb burning pain and numbness, which accompany other dysautonomia, cognitive, visual, and osteoarticular disorders involving multiple organ systems. In an initial diagnostic suspicion, some tests might be useful as complementary examinations, such as nerve quantitative sensory testing, electromyography, and optic nerve tomography. Otherwise, definite diagnosis is reached with skin biopsy as the gold standard, along with corneal in vivo microscopy when ocular discomfort is present.
Being a long-term condition, multiple and dissimilar symptomatic and disease-modifying drugs were employed for the treatment of this condition with the achievement of partial results, including steroids, pregabalin, gabapentin, duloxetine, vitamins, homotaurine and phosphatidylserine, alpha lipoic acid, immunosuppressants, and intravenous immunoglobulin therapy. PASC-SFN is a complex emerging disease and extremely challenging for physicians. At present, the only feasible management of PASC-SFN is represented by a multidisciplinary tailored approach, with future definitive protocols for diagnosis and treatment deemed essential.
Source: Bandinelli F, Di Carlo M, Colantuono VA, Nozzoli F, Salaffi F, Chiocchetti B, Nucci E, Mastricci A, Gherardi E, Manetti M. Post-COVID-19 Small Fiber Neuropathy as a New Emerging Quality of Life-Threatening Disease: A Systematic Review. Microorganisms. 2025; 13(2):328. https://doi.org/10.3390/microorganisms13020328 https://www.mdpi.com/2076-2607/13/2/328 (Full text)

Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID

Abstract:

Background: Long-COVID is defined as the persistency or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. Common persistent symptoms are fatigue, sleep disturbances, post-exertional malaise (PEM), pain, and cognitive problems. Long-COVID is estimated to be present in about 65 million people. We aimed to explore clinical and biological factors that might contribute to Long-COVID.

Methods: Prospective longitudinal cohort study including patients infected with SARS-CoV-2 between March 2020 and March 2022. Patients were assessed between 4 and 12 months after infection at the COVID follow-up clinic at UZ Leuven. We performed a comprehensive clinical assessment (including questionnaires and the 6-min walking test) and biological measures (global DNA methylation, telomere length, mitochondrial DNA copy number, inflammatory cytokines, and serological markers such as C-reactive protein, D-dimer, troponin T).

Results: Of the 358 participants, 328 were hospitalised, of which 130 had severe symptoms requiring intensive care admission; 30 patients were ambulatory referrals. Based on their clinical presentation, we could identify 6 main clusters. One-hundred and twenty-seven patients (35.4%) belonged to at least one cluster. The bigger cluster included PEM, fatigue, sleep disturbances, and pain (n = 57). Troponin T and telomere shortening were the two main markers predicting Long-COVID and PEM-fatigue symptoms.

Conclusions: Long-COVID is not just one entity. Different clinical presentations can be identified. Cardiac involvement (as measured by troponin T levels) and telomere shortening might be a relevant risk factor for developing PEM-fatigue symptoms and deserve further exploring.

Source: Polli A, Godderis L, Martens DS, Patil MS, Hendrix J, Wyns A, Van Campenhout J, Richter E, Fanning L, Vandekerckhove O, Claeys E, Janssens W, Lorent N. Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID. BMC Med. 2025 Feb 4;23(1):60. doi: 10.1186/s12916-025-03881-x. PMID: 39901177; PMCID: PMC11792217. https://pmc.ncbi.nlm.nih.gov/articles/PMC11792217/ (Full text)

The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown aetiology characterised by symptoms of post-exertional malaise (PEM) and fatigue leading to substantial impairment in functioning. Other key symptoms include cognitive impairment and unrefreshing sleep, with many experiencing pain. To date there is no complete understanding of the triggering pathomechanisms of disease, and no quantitative biomarker available with sufficient sensitivity, specificity, and adoptability to provide conclusive diagnosis. Clinicians thus eliminate differential diagnoses, and rely on subjective, unspecific, and disputed clinical diagnostic criteria-a process that often takes years with patients being misdiagnosed and receiving inappropriate and sometimes detrimental care. Without a quantitative biomarker, trivialisation, scepticism, marginalisation, and misunderstanding of ME/CFS continues despite the significant disability for many. One in four individuals are bed-bound for long periods of time, others have difficulties maintaining a job/attending school, incurring individual income losses of thousands, while few participate in social activities.

Main body: Recent studies have reported promising quantifiable differences in the biochemical and electrophysiological properties of blood cells, which separate ME/CFS and non-ME/CFS participants with high sensitivities and specificities-demonstrating potential development of an accessible and relatively non-invasive diagnostic biomarker. This includes profiling immune cells using Raman spectroscopy, measuring the electrical impedance of blood samples during hyperosmotic challenge using a nano-electronic assay, use of metabolomic assays, and certain techniques which assess mitochondrial dysfunction. However, for clinical application, the specificity of these biomarkers to ME/CFS needs to be explored in more disease controls, and their practicality/logistics considered. Differences in cytokine profiles in ME/CFS are also well documented, but finding a consistent, stable, and replicable cytokine profile may not be possible. Increasing evidence demonstrates acetylcholine receptor and transient receptor potential ion channel dysfunction in ME/CFS, though how these findings could translate to a diagnostic biomarker are yet to be explored.

Conclusion: Different biochemical and electrophysiological properties which differentiate ME/CFS have been identified across studies, holding promise as potential blood-based quantitative diagnostic biomarkers for ME/CFS. However, further research is required to determine their specificity to ME/CFS and adoptability for clinical use.

Source: Clarke KSP, Kingdon CC, Hughes MP, Lacerda EM, Lewis R, Kruchek EJ, Dorey RA, Labeed FH. The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology. J Transl Med. 2025 Feb 4;23(1):149. doi: 10.1186/s12967-025-06146-6. PMID: 39905423.  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06146-6 (Full text)

Reactivated EBV, HHV6, HAdV in Sputum from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: Are autoAbs to IFN-I Impairing Antiviral Immunity?

Abstract:

An exhausted antiviral immune response is observed in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. In this study, potential mechanisms behind this exhaustion were investigated. First, the viral load of EBV, HAdV, human cytomegalovirus (HCMV), human herpesvirus 6 (HHV6), and SARS-CoV-2 was determined in sputum samples (n=29) derived from ME/CFS patients (n=13), healthy controls (n=10), elderly healthy controls (n=4), and immunosuppressed controls (n=2). Secondly, autoAbs to type I interferon (IFN-I) in sputum were analyzed to possibly explain impaired viral immunity.

We found that ME/CFS patients released EBV at a significantly higher level compared to controls (p=0.0256). HHV6 was present in ~50% of all participants at the same level. HAdV was detected in two cases with immunosuppression and severe ME/CFS, respectively. HCMV and SARS-CoV-2 were found only in immunosuppressed controls. Notably, anti-IFN-I autoAbs in ME/CFS and controls did not differ, except in severe ME/CFS with high levels.

We conclude that ME/CFS patients, compared to controls, have a significantly higher load of EBV. IFN-I autoAbs cannot explain IFN-I dysfunction, with the possible exception of severe cases showing elevated autoAbs, also reported in severe SARS-CoV-2. We forward that additional mechanisms, such as viral evasion of IFN-I effect, may be present in ME/CFS, which demands further studies.

Source: Hannestad, U., Allard, A., Nilsson, K., & Rosén, A. (2025). Reactivated EBV, HHV6, HAdV in Sputum from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: Are autoAbs to IFN-I Impairing Antiviral Immunity?. Preprints. https://doi.org/10.20944/preprints202502.0185.v1 https://www.preprints.org/manuscript/202502.0185/v1 (Full text available as PDF file)

Cerebral Blood Flow in Orthostatic Intolerance

Abstract:

Cerebral blood flow (CBF) is vital for delivering oxygen and nutrients to the brain. Many forms of orthostatic intolerance (OI) involve impaired regulation of CBF in the upright posture, which results in disabling symptoms that decrease quality of life. Because CBF is not easy to measure, rises in heart rate or drops in blood pressure are used as proxies for abnormal CBF. These result in diagnoses such as postural orthostatic tachycardia syndrome and orthostatic hypotension. However, in many other OI syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, heart rate and blood pressure are frequently normal despite significant drops in CBF. This often leads to the incorrect conclusion that there is nothing hemodynamically abnormal in these patients and thus no explanation or treatment is needed. There is a need to measure CBF, as orthostatic hypoperfusion is the shared pathophysiology for all forms of OI. In this review, we examine the literature studying CBF dysfunction in various syndromes with OI and evaluate methods of measuring CBF including transcranial Doppler ultrasound, extracranial cerebral blood flow ultrasound, near infrared spectroscopy, and wearable devices.

Source: Khan MS, Miller AJ, Ejaz A, Molinger J, Goyal P, MacLeod DB, Swavely A, Wilson E, Pergola M, Tandri H, Mills CF, Raj SR, Fudim M. Cerebral Blood Flow in Orthostatic Intolerance. J Am Heart Assoc. 2025 Feb 3:e036752. doi: 10.1161/JAHA.124.036752. Epub ahead of print. PMID: 39895557. https://www.ahajournals.org/doi/10.1161/JAHA.124.036752 (Full text)

Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods.
Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies.
A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma.
The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.
Source: Baraniuk JN. Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2025; 26(3):1282. https://doi.org/10.3390/ijms26031282 https://www.mdpi.com/1422-0067/26/3/1282 (Full text)