Category: Treatment

Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are complex multisystem conditions with significant functional disability. Many patients experience symptoms of orthostatic intolerance, which can be captured in some cases as Orthostatic Hypotension (OH) or Postural orthostatic Tachycardia Syndrome (PoTS) on objective testing. Conservative treatments are recommended for first-line symptom management, but there is a lack of efficacy evidence. This study aims to assess the feasibility of an 8-week clinically supervised, personalised Dysautonomia Management Protocol (DMP) in a cohort of ME/CFS and LC patients with subjective and objective evidence of orthostatic intolerance (dysautonomia).

Methods: ME/CFS and LC patients with objective dysautonomia on the 10 min active Lean Test (LT) were recruited to an 8-week DMP, with interventions introduced cumulatively every two weeks. Interventions included increasing daily fluid intake to 3 litres and salt intake to 10 g, pacing to avoid crashes and calf activation. Baseline and weekly data collection included the LT, Composite Autonomic Symptom Score questionnaire (COMPASS-31) and Yorkshire Rehabilitation Scale (YRS).

Results: Sixteen participants completed the 8-week program, five discontinued during the program, and one was withdrawn following a severe crash. The COMPASS-31 improved by 7.7 points from week 1 to week 8 (p = 0.045), with a medium Cohen’s d effect size of 0.55. For the same period, there was a non-significant (p = 0.16) improvement in the YRS symptom severity score by 2 points. Comparing the final two weeks of the program with the first two weeks, mean heart rate during the LT decreased by 4.8 beats per minute (p = 0.032), with a medium Cohen’s d effect size of 0.44. Adherence to the interventions was highly variable, with none of the patients able to fully employ all four recommendations.

Conclusions: The results suggest that targeted conservative interventions could influence autonomic function and symptom reduction. However, the magnitude of change was limited, and statistical significance might not necessarily relate to a clinically significant improvement in symptoms.

Source: Barr J, Marsden L, Dassanayake T, Almutairi N, McKeever V, Gaber T, Tarrant R, Godfrey B, Witton S, Sivan M. Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID. J Clin Med. 2026 Mar 25;15(7):2510. doi: 10.3390/jcm15072510. PMID: 41976810. https://www.mdpi.com/2077-0383/15/7/2510 (Full text)

Molecular hydrogen as a treatment for ME/CFS: a mini-review of clinical evidence and mechanistic rationale

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction, yet it currently lacks FDA-approved treatments. Molecular hydrogen (H2), administered primarily as hydrogen-rich water (HRW), has emerged as a potential therapeutic candidate due to its selective antioxidant effects, anti-inflammatory activity, and support of mitochondrial and cellular homeostasis. These mechanisms align with several biological abnormalities implicated in ME/CFS, including oxidative stress, chronic inflammation, and impaired energy metabolism. This narrative mini-review summarizes mechanistic evidence relevant to ME/CFS and evaluates three developmental clinical studies of HRW in this population.

Although early trials are small and methodologically limited, moderate-dose HRW consumed over extended durations has demonstrated feasibility and preliminary benefits in reducing fatigue and improving physical function, with generally mild side effects. Overlapping findings in Long COVID further suggest potential applicability across related post-viral fatigue conditions. Key limitations include small sample sizes, reliance on self-report outcomes, and the absence of objective biomarkers.

Future research should prioritize larger, rigorously controlled trials incorporating remote biometric and biochemical assessments to clarify mechanisms of action and identify responsive subgroups. Overall, molecular hydrogen represents a promising, low-burden adjunctive therapy warranting further investigation in ME/CFS.

Source:Friedberg F and LeBaron TW (2026) Molecular hydrogen as a treatment for ME/CFS: a mini-review of clinical evidence and mechanistic rationale. Front. Med. 13:1760210. doi: 10.3389/fmed.2026.1760210 https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2026.1760210/full (Full text)

A Continuous Oral Regimen of High-Dose Cromolyn Sodium Is Effective for Some Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients With Mast Cell Activation Syndrome

Abstract:

Our clinical experience in the last four years using oral cromolyn in patients with mast cell activation syndrome (MCAS) suggests that a continuous oral regimen of high-dose cromolyn may enhance compliance with the medication. The five patients described in this retrospective case series were given instructions to take oral cromolyn using a continuous dosing regimen, placing the entire day’s dose in an opaque bottle that is then filled with water, and sipping the solution throughout the day. If a conventional maximum dose of eight vials daily (800 mg) was tolerated but ineffective after a week, the patients were instructed to increase to 1600-2400 mg daily until reaching an optimal effect.

We report that a cromolyn dose of 1600-2400 mg daily, administered using the continuous oral dosing regimen during the day, was effective in controlling signs and symptoms of mast cell activation. All five patients benefitted from a dose of cromolyn that is higher than usual and customary recommendations, but within the safety guidelines of the original Food and Drug Administration (FDA) application. The continuous oral regimen has some theoretical advantages over four discrete doses per day, though further study is needed.

Source: Christoforou ME, van Campen LC, Visser FC, Lee CK, Lemmon SL, Rowe PC, Azola AM. A Continuous Oral Regimen of High-Dose Cromolyn Sodium Is Effective for Some Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients With Mast Cell Activation Syndrome. Cureus. 2026 Jan 22;18(1):e102064. doi: 10.7759/cureus.102064. PMID: 41728426; PMCID: PMC12924640. https://pmc.ncbi.nlm.nih.gov/articles/PMC12924640/ (Full text)

Use and Perceived Helpfulness of Different Intervention Strategies in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Depression

Abstract:

Background: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or depression both frequently report debilitating exhaustion, yet the two conditions differ in their etiological and diagnostic clarity, and clinical management. This study aimed to examine differences in the use and perceived helpfulness of a broad range of conventional treatments and complementary interventions, including nutritional approaches, between patients with ME/CFS and depression.

Methods: A cross-sectional online survey was conducted in 2024. A total of 819 participants self-identified as having either ME/CFS (n = 576) or depression (n = 243). Participants (80% female) reported their use and perceived helpfulness of 52 treatments and interventions, encompassing behavioral therapies, medications, and dietary supplements. Group differences were examined using multivariate analyses of variance and covariance (MANOVA/MANCOVA). Open-ended responses were analyzed descriptively using thematic grouping and frequency counts.

Results: Participants with depression most commonly reported the use of psychotherapy (M = 2.49, SD = 1.00) and antidepressant medication (M = 2.44, SD = 2.30), and they rated fewer interventions as helpful compared to participants with ME/CFS. In contrast, participants with ME/CFS reported a significantly broader engagement with diverse intervention modalities, particularly pacing (M = 2.73, SD = 0.80) and dietary supplements (M = 2.43, SD = 1.09), and perceived many of them as helpful. Group differences remained significant after controlling for age, gender, and whether treatment was medically recommended. Supplements targeting energy metabolism (e.g., CoQ10, NADH) were especially favored among ME/CFS participants.

Conclusions: Findings suggest that participants with ME/CFS tend to adopt an exploratory and expansive intervention approach, potentially reflecting the lack of standardized guidelines and limited effectiveness of available treatment options. Participants with depression, in contrast, appeared to follow more guideline-concordant, evidence-based treatment pathways. Taken together, the findings point to a need for further development and evaluation of empirically supported, patient-centered treatment and intervention strategies for ME/CFS and suggest differences in clinical care structures between ME/CFS and depression.

Source: Dorczok MC, Mossaheb N, Mittmann G, Thomas MF, Bartova L, Schrank B, Steiner-Hofbauer V. Use and Perceived Helpfulness of Different Intervention Strategies in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Depression. J Clin Med. 2026 Jan 20;15(2):849. doi: 10.3390/jcm15020849. PMID: 41598786. https://www.mdpi.com/2077-0383/15/2/849 (Full text)

Multi-Strain Probiotic Improves Tryptophan Metabolism and Symptoms in Chronic Fatigue Syndrome Patients with Co-Occurring Irritable Bowel Syndrome: An Open-Label Pilot Study

Simple Summary:

Chronic Fatigue Syndrome (CFS) is a debilitating condition often accompanied by gut health issues, but effective treatments are scarce. Recent research suggests that an imbalance in gut bacteria (dysbiosis) may contribute to CFS symptoms by producing harmful substances that affect the nervous system. We investigated whether a specific multi-strain probiotic (CDS22-formula) could improve symptoms in women with CFS and co-occurring IBS. Over 12 weeks, patients took a high-dose probiotic supplement. We monitored their fatigue levels and analyzed urine samples to track changes in tryptophan metabolism—a key pathway linking the gut to the brain. The results showed that the probiotic intervention was associated with an improved gut bacteria profile. Importantly, this coincided with a reduction in neurotoxic metabolites and a significant decrease in fatigue severity. Our findings suggest that targeting the gut microbiome can be a valuable strategy for managing chronic fatigue, potentially by modulating the production of metabolites that affect brain function.
Abstract:

Background/Objectives: Gut dysbiosis in Chronic Fatigue Syndrome (CFS) drives low-grade inflammation and shifts tryptophan metabolism toward neurotoxic pathways. The causal link between bacterial translocation, kynurenine pathway dysregulation, and symptom severity remains under-defined. We evaluated the impact of a high-concentration multi-strain probiotic on the “gut-kynurenine axis” and clinical status in CFS patients with co-morbid IBS-U and confirmed dysbiosis.
Methods: Forty female patients with confirmed dysbiosis (GA-map™ Dysbiosis Index > 2) received the CDS22 formula (450 billion CFU/day) for 12 weeks. We compared urinary tryptophan metabolite profiles (LC-MS/MS), gut dysbiosis markers (3-indoxyl sulfate), and fatigue severity (FSS) against 40 age-matched healthy controls.
Results: Baseline analysis revealed profound metabolic perturbations: elevated bacterial proteolytic markers (3-IS), substrate depletion (low tryptophan), and a neurotoxic signature (high quinolinic acid [QA], low kynurenic acid [KYNA]). Following the intervention, fatigue scores declined by 40.3%, with 97.5% of patients reaching the remission threshold (FSS < 36). Biochemically, 3-IS levels decreased to the range observed in healthy controls and attenuated xanthurenic acid levels. Although absolute QA concentrations remained elevated compared to controls, the neuroprotective KYNA/QA ratio increased significantly (+45%). Increased systemic tryptophan availability correlated directly with clinical symptom reduction (Spearman’s rho = −0.36, p = 0.024).
Conclusions: The CDS22 formulation was associated with a restoration of intestinal eubiosis and functional tryptophan partitioning. Clinical remission coincides with a metabolic shift favoring neuroprotection (increased KYNA/QA ratio), validating the gut–kynurenine axis as a modifiable therapeutic target. Peripheral metabolic improvement relative to the healthy baseline appeared sufficient for symptom relief in this specific phenotype, despite incomplete clearance of neurotoxic metabolites.
Source:

Testing the Feasibility of a Self-Help Intervention That Includes Lymphatic Drainage to Reduce Fatigue-Related Symptoms Among Patients with Long COVID in General Practice: Experiences from Our Randomized Controlled Trial (RCT)

Abstract:

Introduction: Long COVID-related fatigue affects a large number of people across the world, with increasing numbers of people experiencing long-term disability as a consequence. We tested the feasibility of a self-help version of a manual osteopathic approach initially developed for people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to treat people with long COVID-related fatigue.

Methods: Our feasibility study assessed recruitment into a 1:1 randomized controlled trial (RCT) to receive (i) self-help intervention (self-massage, mobility, flexibility, and breathing exercises, and alternating cold and warm packs to the top of the spine) or (ii) wait-list control group. Follow-up was assessed by online surveys at 3 and 6 months (indicating retention). Verbal feedback was obtained from participants.

Results: Of the 138 eligible survey participants, 126 (90.6%) agreed to participate in two RCTs, achieving the required sample size of 100. Follow-up rates of 79.3% and 59.4% were achieved at 3 and 6 months, respectively. Improvements in Chalder Fatigue Questionnaire (CFQ) scores were observed in both groups between 0 and 3 months (- 4.6 and – 2.9, respectively), to a greater degree in the intervention group (p = 0.01). Feedback showed a cohort keen to engage with the intervention, although some found the intervention onerous at times.

Conclusions: We have reported the results of a feasibility study examining a potentially beneficial intervention for people with long COVID. There were indications of benefit in a patient group with often intractable symptoms. Based on this feasibility study, we believe that the low-cost self-help intervention in isolation could help support fatigue reduction in some people. This has implications for the treatment of both long COVID and ME/CFS.

Source: Riste L, Perrin R, Mulholland T, Hann M, McDonald O, Heald A. Testing the Feasibility of a Self-Help Intervention That Includes Lymphatic Drainage to Reduce Fatigue-Related Symptoms Among Patients with Long COVID in General Practice: Experiences from Our Randomized Controlled Trial (RCT). Infect Dis Ther. 2025 Dec 24. doi: 10.1007/s40121-025-01287-z. Epub ahead of print. PMID: 41442105. https://link.springer.com/article/10.1007/s40121-025-01287-z (Full text)

Effects of recumbent isometric yoga on the daily functioning level of patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, controlled trial

Abstract:

Background: Although seated isometric yoga has been shown to reduce the fatigue and pain of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), some patients who are for the most part bedridden have difficulty practicing it. Many patients with this disease also suffer from fibromyalgia (FM). We developed a recumbent isometric yoga program for patients who were for the most part bedridden, including patients with comorbid FM. The aim of this study was to investigate the effect of this recumbent isometric yoga intervention with such patients.

Methods: This was a randomized, controlled trial of 48 adult patients (7 male, 41 female, age 20-70 years) with ME/CFS without satisfactory improvement after ≥ 3 months of conventional therapy. They were divided randomly into a yoga group (n = 24) and a control group (n = 24). The yoga group received conventional therapy with recumbent isometric yoga practice for ~ 12 weeks (25-min sessions with a yoga instructor at hospital visits and daily in-home sessions). The control group received conventional therapy alone. The effect of recumbent isometric yoga on the level of functioning was assessed by measuring Performance Status (PS). Fatigue was assessed with self-rated questionnaires, including the Chalder Fatigue Scale (FS) and Profile of Mood States (POMS). Adverse events and benefits were recorded for the yoga group.

Results: After the intervention period, the PS score of the yoga group was significantly lower than that of the control group (P < 0.001), suggesting an improvement in functioning level. The Chalder FS score decreased in both groups, but the decrease was greater in the yoga group than in the control group (P < 0.01). Subgroup analysis showed that the Chalder FS score was reduced significantly only in the yoga group in patients with severe disease (P < 0.001) and those with comorbid FM (P < 0.01), although the PS scores did not differ significantly. In the yoga group, a single practice session with a yoga instructor significantly reduced fatigue and increased vigor in patients with severe disease and patients with comorbid FM. Patients reported no serious adverse effects and many benefits of recumbent isometric yoga, including improvements in physical symptoms and brain fog, enhanced awareness of their limits to activities that cause post-exertional malaise, and promotion of behavioral changes to live better within their limits.

Conclusions: Recumbent isometric yoga is an effective adjunctive therapy for patients with ME/CFS, including those for the most part bedridden and those who have FM.

Trial registration: University Hospital Medical Information Network (UMIN CTR) UMIN000023472 (Registered Aug. 4, 2016) and UMIN000030051 (Registered Nov. 20, 2017).

Source: Oka T, Lkhagvasuren B, Yamada Y. Effects of recumbent isometric yoga on the daily functioning level of patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, controlled trial. Biopsychosoc Med. 2025 Oct 10;19(1):19. doi: 10.1186/s13030-025-00339-7. PMID: 41074089; PMCID: PMC12512564. https://pmc.ncbi.nlm.nih.gov/articles/PMC12512564/ (Full text)

Relationships between fatigue, cognitive function, and upright activity in a randomized trial of oxaloacetate for myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition characterized by fatigue, cognitive impairment, and reduced physical function. Oxaloacetate (OAA), a metabolic compound with potential mitochondrial and neuroprotective effects, has shown promise in reducing fatigue symptoms in ME/CFS. However, the interrelationships between fatigue, cognitive performance, and physical activity and their responsiveness to treatment remain poorly understood in ME/CFS.

Methods: This 90-day randomized, double-blind, controlled trial evaluated the effects of 2,000 mg/day OAA or a control of 2,000 mg rice flour in 82 adults with ME/CFS. Self-reported fatigue (Chalder Fatigue Questionnaire), cognitive function (DANA Brain Vital), and upright activity time (UP Time) were assessed at baseline and three follow-up visits. Linear mixed-effects models examined associations between fatigue severity and cognitive/physical function, with treatment group interactions. Responder status at the last visit (Visit 4) was classified based on ≥15% fatigue reduction and/or ≥10% cognitive improvement.

Results: The OAA group showed greater cognitive improvement over time, with a significant between-group difference at Visit 3, 60 days into the trial, (p = 0.034) and trends at other visits. Higher fatigue was significantly associated with reduced cognitive gains in the OAA group (β = −0.34, p < 0.0001), but not in controls. UP Time increased modestly in the OAA group, reaching significance at Visit 2, day 30 (p = 0.044), though fatigue was not a strong predictor of UP Time in either group. At Visit 4, day 90, Global and Fatigue Only Responders were more frequent in the OAA group, while Cognitive Only Responders were more frequent in controls, though group differences did not reach statistical significance (p = 0.10).

Conclusion: OAA supplementation was associated with improved cognitive performance and small improvement in UP Time in ME/CFS participants receiving OAA. Fatigue–cognition coupling was particularly strong in OAA-treated participants, suggesting a potentially targetable phenotype. These findings underscore the importance of multidimensional outcome measures in ME/CFS clinical trials and support the need for more research and trials of metabolic interventions in ME/CFS.

Source: Vernon Suzanne D. , Rond Candace , Sun Yifei , Roundy Shad , Bell Jennifer , Rond Bella , Kaufman David L. , Cash Alan B. , Yellman Brayden , Bateman Lucinda. Relationships between fatigue, cognitive function, and upright activity in a randomized trial of oxaloacetate for myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Neurology, Volume 16 – 2025. DOI=10.3389/fneur.2025.1691147 ISSN=1664-2295 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1691147/full (Full text)

Specialised care for severely affected ME/CFS patients

Abstract:

Introduction: A specialised care unit for severely and very severely ill ME/CFS patients opened in 2021. The results from the first 3 years are reported.

Methods: People with ME/CFS who were diagnosed according to the Canadian Consensus Criteria, who are aged 18 or above with severe or very severe ME/CFS according to the UK NICE guidelines, are eligible to stay at Røysumtunet. The study design is a retrospective review of medical records.

Results: Between June 2021 and June 2024, 24 ME/CFS patients, 20 women and 4 men with a confirmed diagnosis of ME, were admitted to the unit for stays of at least 3 months. Seventeen were very severely affected and 7 were severely affected. Ages ranged from 18 to 68 years, with mean (SD) 37.5 (12.8) years. Seven patients showed significant improvement (p < 0.01), and five others showed some improvement. In total 50% improved (p < 0.01). Patients who improved were borderline significantly younger than those who did not, with a mean age of 30.3 (SD 12.6) years compared to 39.8 (SD 11.8) years (p = 0.06). The mean duration of disease was 2.3 (1.3) years for those who improved versus 6.7 (3.9) years for those who did not improve (p < 0.05).

Conclusion: This is the first report of a specialised care unit for the most severely ill ME/CFS patients. Fifty per cent of patients showed significant or partial improvement. The mechanisms behind these improvements are discussed but require further exploration in future studies.

Source: Saugstad, O. D., Sollie, M. G., Torp, H. A., & Storla, D. G. (2025). Specialised care for severely affected ME/CFS patients. Fatigue: Biomedicine, Health &amp; Behavior, 1–13. https://doi.org/10.1080/21641846.2025.2565101 https://www.tandfonline.com/doi/full/10.1080/21641846.2025.2565101 (Full text)

Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies

Abstract:

Although Gulf War Illness (GWI), fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID have distinct origins, in this article we have reviewed evidence that these disorders comprise a group of so-called low-energy associated disorders with overlapping common symptoms underlying pathology.

In particular, evidence for mitochondrial dysfunction, oxidative stress, inflammation, immune dysregulation, neuroendocrine dysfunction, disrupted brain-gut-microbiome axis, apoptosis/ferroptosis and telomere shortening as common features in the pathogenesis of these disorders has been identified.

Given the role of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, as an antioxidant, antiinflammatory and antiapoptotic and antiferroptotic agent, there is a rationale for supplementary CoQ10 in the management of these disorders. The reported benefits of supplementary CoQ10 administration in GWI, FM, ME/CFS and long COVID have been reviewed; the potential benefit of supplementary CoQ10 in reducing telomere shortening and improving the efficiency of stem cell transfer relevant has also been identified as promising therapeutic strategies in these disorders.

This review advances beyond previous systematic reviews and consensus statements on overlapping similar symptoms and underlying biological pathomechanisms in these complex disorders.

Source: Mantle D, Domingo JC, Golomb BA, Castro-Marrero J. Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies. Int J Mol Sci. 2025 Sep 17;26(18):9044. doi: 10.3390/ijms26189044. PMID: 41009608. https://www.mdpi.com/1422-0067/26/18/9044 (Full text)