CBT and graded exercise therapy studies have proven that ME/CFS and long COVID are physical diseases, yet no one is aware of that

Introduction:

The cognitive behavioral model (CBmodel) (Surawy et al., ; Vercoulen et al., ) has dominated the world of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) since the 1990s. According to this model, a belief in an organic illness, known as dysfunctional beliefs, stops ME/CFS patients engaging in normal activities, resulting in avoidance behavior and deconditioning. The deconditioning then leads to further avoidance behavior and more deconditioning. According to the CBmodel, symptoms of ME/CFS are caused by deconditioning and not by an underlying illness.

Cognitive behavioral therapy with graded activity (CBTplus) and graded exercise therapy (GET) were designed to reverse the dysfunctional beliefs, the avoidance behavior and the deconditioning and lead to recovery. However, an extensive review of the literature found that CBTplus and GET do not restore the ability to work (Vink and Vink-Niese, ). Additionally, there are now many papers documenting complex disruptions to the body’s physiology in ME/CFS, particularly involving immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in the cellular energy production and the gene expression (Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, ; Liu et al., ; Missailidis et al., ).

Source: Vink M, Vink-Niese A. CBT and graded exercise therapy studies have proven that ME/CFS and long COVID are physical diseases, yet no one is aware of that. Front Hum Neurosci. 2025 Jan 29;19:1495050. doi: 10.3389/fnhum.2025.1495050. PMID: 39944089; PMCID: PMC11814198. https://pmc.ncbi.nlm.nih.gov/articles/PMC11814198/ (Full text)

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)

Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome

Abstract:

Background: Etiology remains elusive for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and no treatment exists. Antivirals had no efficacy in randomized clinical trials (RCT) for Epstein-Barr Virus and HHV-6. Enteroviruses (EV) have been implicated, but no antivirals are available. Many patients who received SARS–CoV-2-specific antiviral drugs for acute Covid-19 (COV19) infection experienced significant improvement of prior ME/CFS symptoms. This study summarizes their responses to antivirals for SARS-Cov-2.
Methods: Neutralizing Antibody (NA) for Coxsackievirus B (CVB)1-6 and Echovirus 6, 7, 9, 11, 30 were done by ARUP lab. Enterovirus Protein (EVP) of Peripheral Blood Leukocytes (PBL) was determined by Western Blot. ME/CFS patients fulfilled Canadian consensus criteria, and had either elevated NA for enteroviruses and/or positive EVP in PBL. ME/CFS patients hospitalized for acute COV19 infection and patients without COV19, were given 5-10 days of IV Remdesivir (Rem) +/- immune modulators. Controls: 20 ME/CFS patients seen concurrently without Remdesivir treatment. Other ME/CFS patients (non-COV19) were given Nirmaltrelvir/Ritonavir (PAX) daily for 10 days +/- one repeat. The energy index (EI) was monitored by the patients before, during and after treatment. Significant improvement was defined as > 30%.
Results: 15/20 (75%) ME/CFS patients – 10/12 hospitalized, 5/8 non-COV19 patients – responded to IV Rem 2-6 weeks after infusions; remission lasted 6-8 weeks to 6-9 months before relapse. Of Controls: 2/20 had mild improvement (< 0.001, X 2 ).

104/200 (52%) of PAX-treated ME/CFS patients improved, often within 2-3 days; all relapsed within days to weeks after treatment. 66%, 33% and 44% of CVB4+, CVB3+, non-CVB3,4+ patients responded to treatment, respectively. EVP decreased and increased with clinical response and relapse.

Conclusion: Rem and PAX demonstrated clinical efficacy in ME/CFS patients with chronic enterovirus infections. Placebo-controlled RCT will be needed to clarify the role of antivirals in ME/CFS.
Source: John K Chia, David Wang, P-2363. Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome, Open Forum Infectious Diseases, Volume 12, Issue Supplement_1, February 2025, ofae631.2514, https://doi.org/10.1093/ofid/ofae631.2514 https://academic.oup.com/ofid/article/12/Supplement_1/ofae631.2514/7988721?login=false 

Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS

Abstract:

Autoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments.

We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients’ blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1β, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients.

30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.

Source: Anft M, Wiemers L, Rosiewicz KS, Doevelaar A, Skrzypczyk S, Kurek J, Kaliszczyk S, Seidel M, Stervbo U, Seibert FS, Westhoff TH, Babel N. Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS. Mol Ther. 2025 Jan 9:S1525-0016(25)00011-5. doi: 10.1016/j.ymthe.2025.01.007. Epub ahead of print. PMID: 39797400. https://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(25)00011-5.pdf (Full text) https://pubmed.ncbi.nlm.nih.gov/39797400/ (Abstract)

Clinical Remission After Therapeutic Apheresis in a Patient Suffering from Long Term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Case Report

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multifactorial illness characterized by profound fatigue persisting for more than six months, post-exertional malaise, cognitive impairments, and a range of systemic symptoms. Until now, no accepted causal treatment regimens have been available; therapeutic options include different approaches, such as alleviation of symptoms and promotion of energy conservation.

In this study, we report the case of a 49-year-old female presented to our center suffering from ME/CFS for more than 15 years, characterised by a strong energy loss and neurological and systemic symptoms; previous therapies remained unsuccessful. Therefore, we decided to perform double-filtration apheresis.

After comprehensive laboratory evaluation, including investigation of persistent viral infections, the patient was treated eight times with double-filtration apheresis within a period of 2 years, which resulted in a remarkable sustained clinical remission and significant improvement in her quality of life. Therefore, we conclude that double-filtration apheresis could be an effective therapeutic tool for the treatment of ME/CFS.

Source: Burgard H. Clinical Remission After Therapeutic Apheresis in a Patient Suffering from Long Term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Case Report. Int Med Case Rep J. 2024 Dec 6;17:997-1002. doi: 10.2147/IMCRJ.S476044. PMID: 39660109; PMCID: PMC11629661. https://pmc.ncbi.nlm.nih.gov/articles/PMC11629661/ (Full text)

Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment

Abstract:

Chronic Inflammatory Response Syndrome (CIRS) is an acquired medical condition characterized by innate immune dysregulation following respiratory exposure to water-damaged buildings (WDB). This chronic syndrome involves a range of symptoms that simultaneously affecting multiple organ systems. The purpose of this literature review was to search the published literature for successful treatments for chronic inflammatory response syndrome, an under-recognized, underdiagnosed, multisymptom multisystem illness that can affect up to 25% of the population, thus representing a silent epidemic.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a common misdiagnosis for CIRS, is an entity that has broader awareness within the medical community despite the absence of a defined etiology, biomarkers or a treatment protocol that reverses the underlying conditions. Therefore, the search also included treatments for ME/CFS and sick building syndrome (SBS). Thirteen articles referenced treatment for CIRS, and 22 articles referenced treatment for CFS.

The only treatment with documented clinical efficacy was the Shoemaker Protocol, which was described in 11 of the 13 articles. This treatment protocol exhibits superior outcomes compared with the treatment protocols for ME/CFS.

Source: Dooley M, Vukelic A, Jim L. Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment. Ann Med Surg (Lond). 2024 Nov 8;86(12):7248-7254. doi: 10.1097/MS9.0000000000002718. PMID: 39649915; PMCID: PMC11623837. https://pmc.ncbi.nlm.nih.gov/articles/PMC11623837/ (Full text)

Patient-Reported Treatment Outcomes in ME/CFS and Long COVID

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID are persistent multi-system illnesses affecting many patients. With no known effective FDA-approved treatments for either condition, patient-reported outcomes of treatments are invaluable for guiding management strategies in patient care and generating new avenues for research. Here, we present the results of an ME/CFS and Long COVID treatment survey with responses from 3,925 patients.

We assessed the experiences of these patients with more than 150 treatments, as well as their demographics, symptoms, and comorbidities. Patients with each condition who participated in the study shared similar symptom profiles, including all the core symptoms of ME/CFS, e.g., 89.7% of ME/CFS and 79.4% of Long COVID reported post-exertional malaise (PEM). Treatments with the greatest perceived benefits were identified, which had varied effects on different core symptoms.

In addition, treatment responses were significantly correlated (R² = 0.68) between the two patient groups. Patient subgroups with distinct profiles of symptoms and comorbidities showed varied responses to treatments, e.g., a POTS-dominant cluster benefiting from autonomic modulators and a cognitive-dysfunction cluster from CNS stimulants.

This study underscores the symptomatic and therapeutic similarities between ME/CFS and Long COVID and highlights the commonalities and nuanced complexities of infection-associated chronic diseases and related conditions. Insights from patient-reported experiences, in the absence of approved treatments, provide urgently needed real-world evidence for targeted therapies in patient care and for developing future clinical trials.

Source: Martha EckeyPeng LiBraxton MorrisonRonald W DavisWenzhong Xiao. Patient-Reported Treatment Outcomes in ME/CFS and Long COVID.

Confirmed: The Conclusion by NICE that CBT is not an Effective Treatment for ME/CFS; Re-Analysis of a Systematic Review

Abstract:

In this article, we analyzed the systematic review by Kuut et al. into the efficacy of cognitive behavioral therapy (CBT) for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease that predominantly affects women, and the eight trials
in it. We found many issues with the studies in the review, but also with the review itself.

For example, the systematic review by Kuut et al. included a researcher who was involved in seven of the eight studies in their review, and another one who was involved in five of them. Moreover, at least one of them was involved in every study in the review. On top of that, the three professors who were involved in the systematic review, have all built their career on the CB model and the reversibility of ME/CFS through CBT and GET and two of the systematic reviewers have a potential financial conflict of interest. Yet they failed to inform the readers about these conflicts of interest. Conducting a review in this manner and not informing the readers, undermines the credibility of a systematic review and its conclusion.

Regarding outcome differences between treatment and control group, it’s highly likely that the combination of non-blinded
trials, subjective outcomes and poorly chosen control groups, alone or together with response shift bias and/or patients filling in questionnaires in a manner to please the investigators, allegiance bias, small study effect bias and other forms of bias,
produced the appearance of positive effects, despite the lack of any substantial benefit to the patients, leading to the erroneous inference of efficacy in its absence. That CBT is not an effective treatment is highlighted by the fact that patients remained
severely disabled after treatment with it.

The absence of objective improvement as shown by the actometer, employment status and objective cognitive measures, confirms the inefficacy of CBT for ME/CFS. The systematic review did not report on safety but research by the Oxford Brookes University shows that CBT, which contains an element of graded exercise therapy, is harmful for many patients. Finally, our reanalysis highlights the fact that researchers should not mark their own homework.

Source: Vink M, Vink-Niese A. Confirmed: The Conclusion by NICE that CBT is not an Effective Treatment for ME/CFS; Re-Analysis of a Systematic Review. SciBase Neurol. 2024; 2(3): 1022. https://www.scibasejournals.org/neurology/1022.pdf (Full text)

Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID

Highlights:

  • Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are enigmatic diseases sharing many characteristics.
  • The most debilitating aspects of these diseases are cognitive dysfunction, ‘brain fog’, and exercise intolerance, ‘post-exertional malaise’.
  • There is no cure for these diseases; treatment is palliative only.
  • Mitochondrial dysfunction with endoplasmic reticulum (ER) stress occurs in both diseases.
  • Salubrinal inhibits the phosphatase that dephosphorylates phospho-eukaryotic initiation factor-2α (peIF2α), a protective protein for cells undergoing ER stress when phosphorylated.
  • Salubrinal reduces the formation of Wiskott–Aldrich syndrome protein family member 3 (WASF3), a protein that causes mitochondrial dysfunction that is overexpressed in a cohort of ME/CFS patients.
  • Salubrinal reduces WASF3 expression, restoring mitochondrial function in fibroblasts of a patient with ME/CFS.

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating condition with no cure that shares commonality with long-COVID.

This review examines current understanding of long-COVID symptoms, characteristics of the affected population, the connection with ME/CFS, and the potential for salubrinal, an agent known for its influence on cellular stress pathways, to mitigate these disorders.

It also describes the historical development and mechanism of action of salubrinal, to mitigate endoplasmic reticulum (ER)/cellular stress responses, that could potentially contribute to symptom improvement in both ME/CFS and long-COVID patients.

Further research and clinical trials are warranted to advance our understanding of the potential role of salubrinal in improving the quality of life for individuals with long-COVID-related ME/CFS symptoms as well as ME/CFS patients.

Source: Aseel Warrayat, Ayah Ali, Joulin Waked, Darcy Tocci, Robert C. Speth. Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID. Trends in Molecular Medicine, 2024. ISSN 1471-4914, https://doi.org/10.1016/j.molmed.2024.10.001. https://www.sciencedirect.com/science/article/abs/pii/S1471491424002685

Six-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic medical condition with no specific pharmacological treatment. Creatine, a nutrient essential for maintaining energy homeostasis in the cells, is a candidate for interventions in ME/CFS.

Methods: Fourteen participants with ME/CFS received supplementation with 16 g creatine monohydrate for 6 weeks. Before starting creatine and on the last day of treatment, participants underwent brain magnetic resonance spectroscopy (MRS) scanning of the pregenual anterior cingulate cortex (pgACC) and dorsolateral prefrontal cortex (DLPFC), followed by symptom, cognition, and hand-grip strength assessments.

Results: Eleven participants completed the study. Creatine treatment increased creatine concentration in both the pgACC and DLPFC (p = 0.004 and 0.012, respectively), decreased fatigue and reaction time (RT) on congruent and incongruent trials of the Stroop test (p = 0.036 and 0.014, respectively), and increased hand-grip strength (p = 0.0004). There was a positive correlation between increases in pgACC creatine and changes in RT on Stroop congruent and incongruent trials (p = 0.048 and p = 0.022, respectively). Creatine was well tolerated, and none of the participants stopped treatment.

Conclusion: Creatine supplementation over six weeks in ME/CFS patients increased brain creatine and improved fatigue and some aspects of cognition. Despite its methodological limitations, this study encourages placebo-controlled investigations of creatine treatment in ME/CFS.

Source: Godlewska BR, Sylvester AL, Emir UE, Sharpley AL, Clarke WT, Martens MAG, Cowen PJ. Six-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla. Nutrients. 2024 Sep 30;16(19):3308. doi: 10.3390/nu16193308. PMID: 39408275. https://www.mdpi.com/2072-6643/16/19/3308 (Full text)