In this double-blind, placebo-controlled trial with 45 ME/CFS patients, participants received either 60 mg of pyridostigmine or placebo between two invasive cardiopulmonary exercise tests. Pyridostigmine significantly improved peak VO2, cardiac output, and right atrial pressure, while all these parameters declined in the placebo group – potentially signaling the onset of post-exertional malaise (PEM). The findings support the hypothesis that treatable neurovascular dysregulation – likely mediated via the autonomic nervous system – underlies exercise intolerance in ME/CFS.

This study is of the highest relevance for ME/CFS: it provides, for the first time in an RCT design, objective evidence that neurovascular dysregulation and reduced cardiac output biologically underlie exercise intolerance in ME/CFS. At the same time, pyridostigmine – an already approved drug (acetylcholinesterase inhibitor, known from treatment of myasthenia gravis and POTS) – offers a concrete therapeutic approach for symptom relief. The decline in cardiac output in the placebo group also provides the first measurable physiological signal for the onset of PEM.

In this randomized, double-blind, placebo-controlled trial involving 151 ME/CFS patients, rituximab – an antibody that depletes B-cells of the immune system – was administered over 12 months. The response rate was actually lower in the rituximab group (26%) than in the placebo group (35%), and there were no significant differences in fatigue or function scores. The study thus refutes earlier smaller Phase 2 trials that had suggested benefit.

This study is of central importance for ME/CFS research: it directly tests the hypothesis that autoantibodies produced by B-cells cause the disease. The negative result strongly challenges this hypothesis and redirects research away from B-cell depletion as a therapeutic approach. The high placebo response rate (35%) is also scientifically noteworthy and underscores the importance of controlled trial designs. The study is methodologically robust and sets an important negative benchmark for future intervention trials.

This review analyzes the growing body of evidence linking mitochondrial dysfunction to low-grade systemic inflammation in ME/CFS, fibromyalgia, and Long COVID. It critically evaluates the effectiveness of Coenzyme Q10 (CoQ10), an essential component of the mitochondrial respiratory chain, in alleviating fatigue and pain symptoms. Given the current absence of FDA-approved therapies for PVFS, CoQ10 supplementation is discussed as a promising novel therapeutic approach.

This paper is directly relevant to ME/CFS and PVFS as it explicitly addresses mitochondrial dysfunction as a central pathomechanism in ME/CFS, fibromyalgia, and Long COVID. The linkage to post-exertional fatigue, pain, and neurological symptoms aligns with the core presentation of these conditions. Particularly valuable is the evaluation of Coenzyme Q10 as a concrete, already-available supplement with drug repurposing potential, specifically targeting impaired mitochondrial ATP synthesis and oxidative stress – two of the best-documented mechanisms in ME/CFS.

This clinical review establishes salt and hydration as the cornerstone of dysautonomia treatment. Recommendations include 2–3 litres of fluid daily and 3–5g of additional sodium. Oral Rehydration Solutions (ORS) with an optimised sodium-glucose ratio are particularly effective as glucose stimulates active sodium transport in the gut. Intravenous isotonic saline shows rapid effect in acute POTS episodes. Beyond sodium, potassium (muscle contraction, vascular tone), magnesium (neuromuscular function) and chloride (osmotic balance) play complementary roles.

A large proportion of ME/CFS patients suffer from POTS or orthostatic intolerance – caused by reduced blood volume. Salt and ORS are inexpensive, immediately available and well tolerated. ORS works within hours for many patients. Patrick Ussher explicitly describes ORS as a "gamechanger" in his experience report on this site.

Researchers found that both ME/CFS and Long COVID patients show elevated autoantibodies against beta-adrenergic and muscarinic receptors. Extracorporeal apheresis using a specialized filter significantly reduced these antibodies, resulting in marked symptom improvement in CFS patients. The authors propose that this so-called neuropheresis could represent a promising therapeutic option for post-COVID-19 patients as well.

This paper is highly relevant for ME/CFS and Long COVID as it identifies a shared biological feature – autoantibodies against adrenergic receptors – in both conditions and describes apheresis as a potential treatment. It supports the autoimmune hypothesis of ME/CFS and opens a concrete therapeutic avenue that may also apply to Long COVID.

The study examined the effects of combined CoQ10/NADH supplementation on fatigue, sleep, and quality of life in ME/CFS patients. The treatment group showed significant improvements in cognitive fatigue (FIS-40, p < 0.001), overall fatigue score (p = 0.022), and health-related quality of life (SF-36, p < 0.05). Sleep duration and sleep efficiency also improved significantly over time, suggesting a potential benefit of these mitochondrially active supplements.

CoQ10 and NADH are key components of mitochondrial energy production (ATP synthesis) and act as antioxidants. Since mitochondrial dysfunction and oxidative stress are considered core mechanisms in ME/CFS, this well-designed RCT provides direct clinical evidence for a causally grounded therapeutic approach. The significant improvement in cognitive fatigue and quality of life is immediately relevant to patients, and the study further supports the biological hypothesis of the disease.

A post-hoc analysis of a Phase III trial found that rintatolimod, a selective TLR3 agonist, achieved significantly better outcomes in ME/CFS patients with a symptom duration of 2–8 years compared to those with shorter or longer illness. 51.2% of treated patients in this target group improved their exercise tolerance by at least 25%, accompanied by clinically meaningful quality of life enhancements. The authors note that these findings may also be relevant for Long COVID patients experiencing persistent fatigue and cognitive impairment.

Rintatolimod acts via the TLR3 signaling pathway to modulate innate immune responses – a mechanism discussed in ME/CFS in the context of viral persistence and chronic immune dysregulation. Identifying a therapeutic window (2–8 years of disease duration) for optimal treatment response is clinically highly relevant and could improve patient selection for future trials. The connection to Long COVID makes these findings especially timely.

91 participants with ME/CFS following SARS-CoV-2 infection (PASC) or following vaccination (PVS) and vitamin D deficiency were treated over 12 weeks with either comprehensive vitamin D therapy (supplementation, dietary counseling, sunlight, exercise) or vitamin D supplements alone. The intervention group showed a significantly greater reduction in symptoms (-6.7 vs. -1.2 symptoms) and a significantly greater increase in serum vitamin D levels. Notably, 16 out of 46 participants in the intervention group no longer met the diagnostic criteria for ME/CFS, compared to only 1 person in the control group.

This study is one of the first randomized controlled trials to investigate a therapeutic approach specifically for ME/CFS following COVID-19 and vaccination. It provides evidence that vitamin D deficiency could be a relevant, modifiable factor in a subset of those affected. However, it should be noted that the study only included individuals with confirmed vitamin D deficiency, the intervention combined several components, and the study design (open-label) is susceptible to expectation effects – the results are therefore not transferable to all individuals with ME/CFS.

In this placebo-controlled trial with 65 ME/CFS patients, 35 participants received a daily combination of beta-glucan (250 mg), vitamin D3, vitamin B6, and zinc for 36 weeks. Cognitive fatigue, measured with the FIS-40 score, improved significantly in the treatment group compared to baseline (p = 0.0338). Other symptoms such as physical fatigue, sleep quality, and anxiety/depression showed no statistically significant improvement.

Beta-glucans are known immune modulators that can influence inflammatory processes – a central mechanism in ME/CFS. This study is directly relevant as an RCT that first demonstrates beta-glucan can improve cognitive fatigue (brain fog) in ME/CFS patients. Despite the small sample size and limited effects on other symptoms, it provides an important pointer for immunometabolic interventions. The interaction of beta-glucan with the immune system and gut microbiome could provide insights into the pathomechanisms of ME/CFS.

This systematic review analyzed nine intervention studies on nutraceuticals targeting mitochondrial dysfunction in ME/CFS. Six out of nine studies reported improvements in fatigue levels. However, the authors conclude that evidence is still insufficient and better-designed studies are needed to clarify both the role of mitochondria in ME/CFS and the therapeutic potential of mitochondrial-modifying agents.

Mitochondrial dysfunction is one of the central biological hypotheses explaining ME/CFS symptoms, particularly post-exertional fatigue and energy deficits. This review consolidates existing evidence on interventions such as CoQ10, L-carnitine, NADH and similar substances directly targeting this mechanism, providing guidance for patients and impulses for future research.

This narrative review analyzes studies from 1995 to 2025 on the role of the gut microbiome in ME/CFS, finding that changes in microbiome diversity and composition are associated with systemic inflammation and cognitive and physical impairments. Potential therapeutic approaches discussed include probiotics, prebiotics, specific diets, supplements, fecal microbiota transplantation, and pharmacological interventions. The authors emphasize the need for standardized diagnostics and longitudinal studies to develop personalized treatment strategies.

This review is directly relevant to ME/CFS as it synthesizes evidence on gut microbiome dysbiosis – a recognized pathophysiological mechanism – and evaluates multiple therapeutic strategies targeting the gut-brain axis. It provides a structured overview of intervention options that could improve symptom management and quality of life, while also identifying critical research gaps that need to be addressed for clinical translation.

In this randomized, double-blind, placebo-controlled trial with 26 post-COVID ME/CFS patients, a synbiotic containing four bacterial strains, fructooligosaccharides, and zinc was administered for 3 months. The synbiotic significantly outperformed placebo in reducing post-exertional malaise (PEM) and increasing choline and creatine levels in specific brain regions, indicating improved cerebral metabolism. General fatigue decreased in both groups, but the PEM reduction was clinically meaningful only in the synbiotic group.

This study is directly relevant to ME/CFS as it addresses post-exertional malaise (PEM) as a primary endpoint and demonstrates significant improvement through gut microbiome modulation. It also provides objective biomarker data (brain MRS: choline, creatine) as potential treatment-effect indicators. The microbiome modulation approach aligns with known dysbiosis findings in ME/CFS and Long COVID, offering a well-tolerated, cost-effective therapeutic strategy.

VLCADD prevents the conversion of long-chain fatty acids into energy at cellular level, causing severe mitochondrial dysfunction and ATP recycling impairment. Treatment has two components: first, MCT C8 oil (medium-chain fatty acids that can be metabolised even in VLCADD) gradually increased to 120ml daily split across three meals; second, near-complete elimination of long-chain dietary fats (very lean meats, tuna, fruit, vegetables and carbohydrates). Improvement felt within 48 hours, sustained over 29 months confirmed (as of March 2026). Additionally the patient had an active EBV infection causing POTS symptoms which was successfully treated with Valtrex. Diagnostic pathway: M1+M2 mitochondrial function test (AONM, ~£350, self-order) → acylcarnitine profile → confirmation at NHS Rare Mitochondrial Disorders Service London.

VLCADD is one of the few identified treatable causes of ME/CFS with documented full remission. Important: this is a single case report – the majority of ME/CFS patients do not have VLCADD. But since fatty acid oxidation disorders are almost never screened for in adults, a subset of patients may have a similar undetected metabolic disorder. The diagnostic pathway can be self-initiated via AONM without a doctor referral. Additional notes from comments: reactive hypoglycaemia and unexplained kidney problems over years may be early signs of VLCADD. Patients who respond poorly to ketogenic diets should consider this mechanism particularly.

In this 12-week open-label study with 33 ME/CFS patients, (-)-OSU6162 was administered in escalating doses (15–45 mg twice daily). 28 patients completed the study, and the drug was well tolerated. Clinical scales showed improvements in fatigue, depression and health-related quality of life, although an increase in serum prolactin was observed.

(-)-OSU6162 is a monoaminergic stabilizer acting on dopaminergic and serotonergic systems – systems known to be dysfunctional in ME/CFS and linked to fatigue, cognitive impairment and autonomic dysfunction. The drug stabilizes rather than stimulates, distinguishing it from classical stimulants. Improvements across multiple validated scales in an ME/CFS patient cohort are promising, although controlled trials are still lacking.

In this randomized, double-blind, placebo-controlled phase 4 trial, 38 ME/CFS patients received either solriamfetol (75–150 mg) or placebo for 8 weeks. At week 8, the treatment group showed significant improvement in fatigue severity (FSI) and executive functioning, particularly metacognition. The drug was well tolerated, with sleep disturbances and headaches as the most common adverse events.

ME/CFS currently has no approved disease-specific therapies. Solriamfetol as a dual norepinephrine-dopamine reuptake inhibitor could address the known autonomic dysfunction and neurocognitive impairments (brain fog) in ME/CFS. This study provides initial controlled evidence for a pharmacological approach improving both fatigue and cognitive symptoms – two of the core complaints in ME/CFS.

Salubrinal is a substance known for modulating stress responses in the so-called endoplasmic reticulum (ER) of the cell – a cellular component responsible, among other things, for protein folding. The authors argue that disrupted ER stress pathways could be a common mechanism in ME/CFS and Long COVID, and that salubrinal could thereby alleviate symptoms of both conditions. Since this is a purely review-based work without any own study data, clinical evidence is still lacking.

The paper demonstrates a biologically plausible connection between cellular stress and ME/CFS or Long COVID, and proposes a concrete pharmacological approach with salubrinal. This is relevant because ER stress is increasingly being discussed as part of the pathophysiology of ME/CFS – however, no clinical studies on salubrinal in humans have been conducted to date, which greatly limits the significance of the findings.

In ME/CFS, standard blood values for B12 and folate may appear normal while a functional deficiency exists at the cellular level. Relevant markers include Holo-Transcobalamin (active B12), methylmalonic acid (MMA) and homocysteine. Additionally, folate receptor autoantibodies (FRAA) can block folate transport into the brain – with inflammatory and mitochondrial consequences. The MTHFR gene mutation further impairs the conversion of B12 and folate into their active forms in affected patients.

Enlarged and misshapen red blood cells have been described in ME/CFS patients – a classic sign of B12 deficiency (pernicious anaemia). EBV-triggered ME/CFS cases show elevated FRAA rates in studies. High-dose B12 injections and biologically active folate forms (methylfolate or folinic acid in FRAA-positive cases) could improve cellular and neurological availability – folinic acid, unlike folic acid, can cross the blood-brain barrier.

The review article examines how metformin can intervene in the disrupted metabolic pathways in ME/CFS and Long COVID – including mitochondrial dysfunction, elevated inflammatory markers, disrupted gut flora, and impaired blood circulation. Metformin inhibits certain complexes of the respiratory chain (I and IV), which relieves the overburdened complex V and reduces the formation of harmful free radicals. Furthermore, metformin could improve energy metabolism via mTOR signaling pathways and exert anti-inflammatory as well as neuroprotective effects.

Metformin is a well-established, well-tolerated, and inexpensive medication that has been in use for decades and is now being discussed as a possible candidate for ME/CFS and Long COVID. Since both conditions currently have no approved therapies, the identification of repurposable agents with known safety profiles is of great practical importance. The article provides a systematic assessment of why metformin may be mechanistically relevant – even though clinical evidence from randomized trials is still largely lacking.