Clinical Trials (Interventional)
1 LIFT Trial (Low-Dose Naltrexone and Pyridostigmine)
Principal Investigator:: David Systrom, MD
Institution:: Brigham and Women’s Hospital, Harvard Medical School, United States
Contact/URL:: https://solvecfs.org/exploring-current-me-cfs-and-long-covid-clinical-trials-on-national-clinical-trials-day/
Funder:: Solve ME/CFS Initiative (Ramsay Research Grant)
Status:: Recruiting
Phase:: Clinical trial (interventional)
Cohort:: ME/CFS patients (specific \(n\) to be confirmed)
Mechanism/Focus:: Tests whether low-dose naltrexone (LDN) and pyridostigmine reduce symptoms and improve quality of life. LDN targets neuroinflammation via glial cell modulation; pyridostigmine is an acetylcholinesterase inhibitor used for autonomic dysfunction.
Primary Outcomes:: Symptom severity; quality of life measures
Estimated Completion:: Not yet announced
Timeline:: Recruitment ongoing as of 2026
Publication Medium:: Not yet announced
Document Relevance:: Ch. 16 (supplements and nutraceuticals), Ch. 10 (cardiovascular/autonomic), Ch. 17 (lifestyle interventions)
The LIFT trial addresses two of the most widely used off-label treatments in ME/CFS clinical practice. LDN has accumulated substantial anecdotal and preliminary evidence (Chapter 16) but lacks rigorous RCT data in ME/CFS specifically. Pyridostigmine targets the preload failure mechanism identified in invasive cardiopulmonary exercise testing by Systrom’s own group (Chapter 10). A positive result could provide the first high-quality evidence base for two treatments already in widespread empirical use.
2 UAB LDN Dose-Finding Study
Principal Investigator:: Jarred Younger, PhD
Institution:: University of Alabama at Birmingham, United States
Contact/URL:: https://clinicaltrials.gov/study/NCT07285473
Registry ID:: NCT07285473
Funder:: Institutional
Status:: Recruiting (remote/decentralised, US-wide)
Phase:: Dose-finding study
Cohort:: Adults with ME/CFS (specific \(n\) TBD)
Mechanism/Focus:: Dose-finding study for low-dose naltrexone in ME/CFS. Distinct from the LIFT trial (which combines LDN with pyridostigmine, Section Clinical Trials (Interventional)) and the RECOVER paediatric LDN trial (Section Large-Scale Federally Funded Programmes): this study focuses on determining optimal adult LDN dosing specifically for ME/CFS. Remote design enables broad US enrolment.
Primary Outcomes:: Dose-response for symptom reduction; safety and tolerability
Estimated Completion:: Not yet announced
Timeline:: Recruitment ongoing as of 2026
Publication Medium:: Not yet announced
Document Relevance:: Ch. 16 (supplements—LDN), Ch. 7 (immune dysfunction—microglial hypothesis)
Younger’s laboratory has prior immunology work on LDN in ME/CFS (NCT02965768). While the LIFT trial tests LDN in combination, this study isolates LDN’s independent effect and seeks to establish the optimal dose—a fundamental gap in the current evidence base. Most clinicians prescribe 1.5–4.5 mg empirically; systematic dose-finding data could substantially improve clinical practice.
3 Low-Dose Rapamycin in ME/CFS and Long Covid
Principal Investigator:: Multi-site collaboration
Institution:: Simmaron Research Institute, Bateman Horne Center, CDC, and Mayo Clinic, United States
Contact/URL:: https://batemanhornecenter.org/promising-clinical-trials/
Funder:: Multi-institutional
Status:: Active
Phase:: Clinical trial (interventional)
Cohort:: ME/CFS and Long Covid patients (specific \(n\) TBD)
Mechanism/Focus:: Rapamycin (sirolimus) is an mTOR inhibitor with immunomodulatory and anti-inflammatory properties. Targets mTOR pathway dysregulation implicated in ME/CFS immune and metabolic abnormalities.
Primary Outcomes:: Symptom improvement; immune marker changes; safety and tolerability
Estimated Completion:: Not yet announced
Timeline:: Study active as of 2025–2026
Publication Medium:: Not yet announced
Document Relevance:: Ch. 7 (immune dysfunction), Ch. 6 (energy metabolism), Ch. 19 (integrative approaches)
The rapamycin trial is notable for its multi-institutional design (Simmaron, Bateman Horne, CDC, Mayo Clinic), which lends credibility and ensures phenotyping rigour. mTOR pathway dysregulation has been reported in ME/CFS (Chapter 7) and connects immune activation to metabolic dysfunction (Chapter 6). This trial directly tests a mechanistic hypothesis rather than treating symptoms empirically, making it particularly informative regardless of outcome.
4 Lumbrokinase for ME/CFS and Long Covid
Principal Investigator:: David Putrino, PhD
Institution:: Abilities Research Center, Mount Sinai Icahn School of Medicine, United States
Contact/URL:: https://solvecfs.org/exploring-current-me-cfs-and-long-covid-clinical-trials-on-national-clinical-trials-day/
Funder:: Institutional
Status:: Recruiting
Phase:: Clinical trial (interventional)
Cohort:: Adults with Long Covid, post-treatment Lyme disease syndrome, and ME/CFS
Mechanism/Focus:: Lumbrokinase is a fibrinolytic enzyme targeting microclot pathology. The microclot hypothesis proposes that persistent fibrin amyloid microclots impair microcirculation, contributing to tissue hypoxia and fatigue.
Primary Outcomes:: Fibrinolytic markers; symptom scores; exercise tolerance
Estimated Completion:: Not yet announced
Timeline:: Recruitment ongoing as of 2026
Publication Medium:: Not yet announced
Document Relevance:: Ch. 10 (cardiovascular dysfunction), Ch. 19 (integrative approaches)
The microclot hypothesis has generated significant interest since 2021 but lacks interventional trial data. This study directly tests whether fibrinolytic treatment improves outcomes, providing a causal test of the hypothesis. The inclusion of three post-infectious conditions (Long Covid, post-Lyme, ME/CFS) mirrors the Rosetta Stone Study’s cross-disease approach, potentially revealing whether microclot pathology is a shared mechanism.
5 Hydrogen Water for ME/CFS
Principal Investigator:: Fred Friedberg, PhD
Institution:: Stony Brook University School of Medicine, United States
Contact/URL:: https://solvecfs.org/exploring-current-me-cfs-and-long-covid-clinical-trials-on-national-clinical-trials-day/
Funder:: Solve ME/CFS Initiative
Status:: Recruiting
Phase:: Clinical trial, dosing study
Cohort:: ME/CFS patients (specific \(n\) TBD)
Mechanism/Focus:: Hydrogen-rich water as an antioxidant intervention. Molecular hydrogen (\(\text{H}_2\)) selectively scavenges hydroxyl radicals and may reduce oxidative stress and neuroinflammation.
Primary Outcomes:: Fatigue severity; stress markers; physical function
Estimated Completion:: Not yet announced
Timeline:: Recruitment ongoing as of 2026
Publication Medium:: Not yet announced
Document Relevance:: Ch. 6 (energy metabolism—oxidative stress), Ch. 16 (supplements and nutraceuticals)
This dosing study addresses a practical gap: even if hydrogen water has antioxidant benefits, optimal dosing for ME/CFS has not been established. The oxidative stress hypothesis in ME/CFS (Chapter 6) provides a mechanistic rationale, though the evidence base for molecular hydrogen in any chronic condition remains preliminary. Results will be most informative if they include objective oxidative stress biomarkers alongside subjective symptom measures.
6 RESTORE-ME: Oxaloacetate for ME/CFS Fatigue
Principal Investigator:: Alan Cash, PhD
Institution:: Terra Biological LLC, United States (multi-site RCT)
Contact/URL:: https://clinicaltrials.gov/study/NCT05273372
Registry ID:: NCT05273372
Funder:: Terra Biological LLC (industry)
Status:: Results published (November 2024)
Phase:: Phase II, randomised, double-blind, placebo-controlled
Cohort:: 82 ME/CFS patients (2,000mg oxaloacetate vs control daily for 3 months)
Mechanism/Focus:: Oxaloacetate (OAA) is a mitochondrial metabolite that supports the citric acid cycle and NAD+/NADH ratio. Targets metabolic dysfunction by supplementing a key TCA cycle intermediate.
Primary Outcomes:: Fatigue reduced \(>\) 25% from baseline in OAA group (\(p=0.0039\) vs control); cognitive improvement at day 60 (\(p=0.034\)); modest increase in uptime at day 30
Estimated Completion:: Completed
Timeline:: RCT completed 2024; results published November 2024 in Frontiers in Neurology; cognitive follow-up published 2025
Publication Medium:: Frontiers in Neurology (open access)
Document Relevance:: Ch. 6 (energy metabolism—TCA cycle), Ch. 16 (supplements and nutraceuticals)
RESTORE-ME is one of very few completed RCTs showing statistically significant fatigue reduction in ME/CFS. The mechanistic rationale is direct: oxaloacetate is an obligate TCA cycle intermediate, and ME/CFS metabolomic studies have consistently identified TCA cycle disruption (Chapter 6). The 25% fatigue reduction is clinically meaningful, though the modest sample size (\(n=82\)) and industry sponsorship warrant independent replication. The cognitive improvement findings strengthen the case that metabolic support can address both physical and cognitive symptoms.
7 Stellate Ganglion Block for ME/CFS
Principal Investigator:: Deborah Duricka, PhD; Lipeng Liu, MD
Institution:: Multi-site, United States
Contact/URL:: https://doi.org/10.1080/21641846.2025.2455876
Funder:: Solve ME/CFS Initiative (Ramsay Research Grant)
Status:: Pilot study published (February 2025); larger trials needed
Phase:: Prospective cohort pilot (\(n=10\))
Cohort:: 10 patients meeting both WHO Long Covid and IOM ME/CFS criteria
Mechanism/Focus:: Sequential bilateral stellate ganglion blocks (local anaesthetic injection near the cervical sympathetic chain) administered over 3 consecutive weeks. Hypothesised to “reset” sympathetic/parasympathetic balance of the autonomic nervous system, increasing regional blood flow and reducing sympathetic hyperactivation.
Primary Outcomes:: Significant improvements in cognition, physical and social functioning, vitality; reduced orthostatic intolerance and POTS symptoms. Cortisol levels did not change.
Estimated Completion:: Pilot completed; larger RCT recommended
Timeline:: Pilot published February 2025; larger trial planning stage
Publication Medium:: Fatigue: Biomedicine, Health & Behavior (2025)
Document Relevance:: Ch. 10 (cardiovascular/autonomic dysfunction), Ch. 8 (neurological dysfunction), Ch. 19 (integrative approaches)
The stellate ganglion block is a well-established procedure in pain medicine repurposed for autonomic dysfunction. The pilot results are notable for improvement across both autonomic (OI, POTS) and cognitive domains, suggesting a shared upstream mechanism. The “autonomic reset” hypothesis aligns with evidence of sympathetic hyperactivation in ME/CFS (Chapter 10). The very small sample (\(n=10\)) limits conclusions, but the effect sizes and the procedure’s established safety profile justify a larger sham-controlled RCT.
8 Transcutaneous Vagus Nerve Stimulation (tVNS) for Long Covid/ME/CFS
Principal Investigator:: Multiple investigators (several parallel studies)
Institution:: Multi-site (US and European studies)
Contact/URL:: https://clinicaltrials.gov/study/NCT06585254
Registry ID:: NCT06585254 (US dosing study); additional European trials ongoing
Funder:: Multiple (Solve ME/CFS Initiative, institutional)
Status:: Recruiting (multiple trials)
Phase:: Interventional (parameter optimisation and efficacy)
Cohort:: Long Covid and ME/CFS patients fulfilling CFS criteria; prior studies \(n=10\)–25 per trial
Mechanism/Focus:: Non-invasive auricular stimulation of the vagus nerve to activate the cholinergic anti-inflammatory pathway (CAP). Targets neuroinflammation, autonomic imbalance, and systemic inflammation. Prior pilot studies showed improvements in cognition, anxiety, depression, sleep, and autonomic scores (COMPASS-31).
Primary Outcomes:: Optimal stimulation parameters; health-related quality of life; fatigue severity; autonomic function
Estimated Completion:: Varies by trial; results expected 2026–2027
Timeline:: Multiple pilot studies published 2024–2025; current trials optimising parameters and assessing efficacy in larger cohorts
Publication Medium:: Frontiers in Neurology, PLOS ONE, and others (prior studies published open access)
Document Relevance:: Ch. 8 (neurological dysfunction), Ch. 10 (autonomic dysfunction), Ch. 7 (immune dysfunction—inflammation)
Vagus nerve stimulation represents a compelling intersection of neurology and immunology: the cholinergic anti-inflammatory pathway provides a mechanism through which neural stimulation can modulate systemic inflammation. The consistency of improvements across multiple small pilot studies (cognition, autonomic function, sleep) is encouraging, though no large RCT has yet been completed. The non-invasive nature, low side-effect profile, and consumer device availability (e.g., Nurosym) make tVNS a practical intervention if efficacy is confirmed. The current parameter-optimisation trials are a necessary step before definitive efficacy studies.
9 Masitinib for Severe Mast Cell Activation Syndrome
Principal Investigator:: Multiple investigators
Institution:: AB Science (sponsor), multi-site
Contact/URL:: https://clinicaltrials.gov/study/NCT05449444
Registry ID:: NCT05449444
Funder:: AB Science (industry)
Status:: Phase 2 (active)
Phase:: Phase 2 clinical trial
Cohort:: Patients with severe mast cell activation syndrome (MCAS)
Mechanism/Focus:: Masitinib is a tyrosine kinase inhibitor that targets mast cell activity directly, unlike antihistamines that only address downstream mediator release. MCAS is identified in an estimated 50% of ME/CFS patients by some specialists.
Primary Outcomes:: MCAS symptom severity; safety and tolerability
Estimated Completion:: Not yet announced
Timeline:: Trial active as of 2025–2026
Publication Medium:: Not yet announced
Document Relevance:: Ch. 7 (immune dysfunction—mast cells), Ch. 19 (integrative approaches)
Mast cell activation has emerged as a significant comorbidity in ME/CFS subsets, with some clinicians reporting MCAS in up to half of their ME/CFS patients. A 2026 cromolyn sodium case series from Dutch and Johns Hopkins investigators showed improvement in ME/CFS-related symptoms alongside MCAS management. Masitinib’s upstream mechanism (direct tyrosine kinase inhibition rather than antihistamine blockade) could provide more complete mast cell stabilisation. If effective, this trial could open a treatment pathway for the MCAS subset of ME/CFS patients who respond poorly to conventional antihistamine regimens.
10 Cornell NAC–Glutathione Brain Study
Principal Investigator:: Dikoma Shungu, PhD
Institution:: Weill Cornell Medical College, United States
Contact/URL:: https://clinicaltrials.gov/study/NCT04542161
Registry ID:: NCT04542161
Funder:: NINDS (National Institute of Neurological Disorders and Stroke)
Status:: Recruiting (Phase 2)
Phase:: Phase 2, double-blind, placebo-controlled, randomised
Cohort:: 60 participants (20 per arm: 0 mg / 900 mg / 3600 mg daily NAC), ages 21–60, baseline brain GSH at or below predefined cutoff, primary ME/CFS diagnosis
Mechanism/Focus:: Tests N-acetylcysteine (NAC) as a glutathione (GSH) precursor to restore cortical GSH reserves depleted by oxidative stress. Uses magnetic resonance spectroscopy (MRS) to measure brain GSH levels as a direct target engagement biomarker. Three-arm dose-response design.
Primary Outcomes:: Brain GSH levels (MRS); plasma oxidative stress markers
Estimated Completion:: \(\sim\) 2026
Timeline:: Recruitment ongoing
Publication Medium:: Not yet announced
Document Relevance:: Ch. 6 (energy metabolism—oxidative stress), Ch. 22 (mechanistic studies)
This trial is notable for using MRS as both a mechanistic measurement and treatment-response biomarker in a single tool. If NAC restores brain GSH levels and correlates with symptom improvement, it would establish oxidative stress as a druggable target in ME/CFS and validate a non-invasive brain biomarker for treatment monitoring. The three-arm dose-response design addresses the fundamental question of whether standard supplement doses (900 mg) achieve meaningful CNS penetration.
11 NSU Directed Probiotics for ME/CFS
Principal Investigator:: Nancy Klimas, MD
Institution:: Nova Southeastern University, Institute for Neuro-Immune Medicine, United States
Contact/URL:: https://clinicaltrials.gov/study/NCT06211062
Registry ID:: NCT06211062
Funder:: Institutional
Status:: Recruiting (Phase 2)
Phase:: Phase 2, randomised, placebo-controlled
Cohort:: 100 participants (25 per arm \(\\times\) 4 arms: ME/CFS with/without IBS \(\\times\) active/placebo), ages 45–70, Canadian Consensus Criteria
Mechanism/Focus:: Tests i3.1 probiotic (Floradapt Intensive GI) to reduce GI inflammation, normalise gut–brain axis, and reset microbiome. Four-arm design allows interaction analysis between IBS comorbidity and treatment response.
Primary Outcomes:: GI inflammation markers; IBS severity score; ME/CFS global function; assessed at 8 and 12 weeks
Estimated Completion:: \(\sim\) 2026
Timeline:: Recruitment ongoing
Publication Medium:: Not yet announced
Document Relevance:: Ch. 11 (gut microbiome—primary), Ch. 7 (immune dysfunction—gut–immune axis)
This is the first ME/CFS-specific probiotic RCT with IBS stratification. The Klimas group’s neuro-immune medicine expertise and the four-arm design (separating ME/CFS-only from ME/CFS+IBS) could determine whether gut-targeted interventions benefit all ME/CFS patients or specifically those with GI comorbidity—a distinction with direct clinical implications for the microbiome hypothesis discussed in Chapter 11.
12 ADDRESS-LC (Bezisterim for Long Covid Neurocognition)
Principal Investigator:: Multi-site (BioVie Inc.)
Institution:: Multi-centre, United States (DoD-funded)
Contact/URL:: https://clinicaltrials.gov/study/NCT06847191
Registry ID:: NCT06847191
Funder:: Department of Defense (US)
Status:: Recruiting (first patient enrolled May 2025)
Phase:: Phase 2, multi-centre, double-blind, RCT
Cohort:: 200 adults with Long Covid, enriched for cognitive impairment and fatigue, symptoms \(\geq\) 3 months
Mechanism/Focus:: Bezisterim (NE3107) is an orally bioavailable, blood–brain barrier-permeable insulin sensitiser and selective NF-\(\kappa\)B/ERK modulator. Blocks TNF-\(\alpha\) and neuroinflammation without global immunosuppression. Targets the neuroinflammation hypothesis for brain fog. Same drug being explored in Alzheimer’s and Parkinson’s.
Primary Outcomes:: Cogstate Cognition battery (cognitive performance); secondary: fatigue
Estimated Completion:: Data expected H1 2026
Timeline:: 84-day treatment period
Publication Medium:: Not yet announced
Document Relevance:: Ch. 7 (immune dysfunction—neuroinflammation), Ch. 22 (mechanistic studies—Long Covid overlap)
ADDRESS-LC is notable for targeting neuroinflammation via a mechanism distinct from LDN: selective NF-\(\kappa\)B modulation rather than glial cell modulation. The blood–brain barrier permeability and dual insulin-sensitising/anti-inflammatory action address two pathophysiological axes simultaneously. Cross-disease application (Alzheimer’s, Parkinson’s, Long Covid) could accelerate regulatory pathways and provide comparative data on shared neuroinflammatory mechanisms.
13 LC-REVITALIZE (Upadacitinib + Pirfenidone)
Principal Investigator:: Douglas Fraser, MD PhD
Institution:: Western University, London, Ontario, Canada; Schmidt Initiative for Long COVID (SILC); multi-national
Contact/URL:: https://clinicaltrials.gov/study/NCT06928272
Registry ID:: NCT06928272
Funder:: Schmidt Initiative for Long COVID (SILC)
Status:: Recruiting (Phase 3)
Phase:: Phase 3, double-blind, placebo-controlled, multi-arm platform
Cohort:: \(\sim\) 348 adults with Long Covid (prior confirmed SARS-CoV-2, symptoms \(\geq\) 3 months); sites in Brazil, Canada, Italy, Uganda, USA, Zambia
Mechanism/Focus:: Repurposed drug platform trial. Upadacitinib (JAK1 inhibitor, approved for rheumatoid arthritis) and pirfenidone (anti-fibrotic, approved for lung disease) identified via AI proteomics screen of 5,400 blood proteins from 1,028 participants.
Primary Outcomes:: Five symptom domains: fatigue, breathlessness, cognition, musculoskeletal pain, circulation
Estimated Completion:: \(\sim\) 2027
Timeline:: Recruitment ongoing across 6 countries
Publication Medium:: Not yet announced
Document Relevance:: Ch. 7 (immune dysfunction—JAK pathway), Ch. 13 (integrative models), Ch. 22 (mechanistic studies—Long Covid overlap)
LC-REVITALIZE is the first Long Covid treatment trial to use AI-driven proteomics for drug selection, screening 5,400 proteins to identify candidate interventions. The JAK1 inhibitor arm complements the RECOVER-TLC baricitinib trial (Section Large-Scale Federally Funded Programmes), testing a more selective JAK inhibitor. The multi-national platform design across six countries enables geographic and genetic diversity rarely achieved in ME/CFS-adjacent trials. If positive, the AI proteomics drug-selection methodology could be applied directly to ME/CFS cohorts.
15 CHIIME (Chronic Infections and Inflammation in ME/CFS)
Principal Investigator:: UCSF / PolyBio Research Foundation network (LIINC collaborative); Dr. John Chia (Enterovirus Medical Research Center) as key partner
Institution:: University of California San Francisco, United States
Contact/URL:: https://clinicaltrials.gov/study/NCT07227441
Registry ID:: NCT07227441
Funder:: PolyBio Research Foundation
Status:: Recruiting (start date January 2026)
Phase:: Observational, prospective, longitudinal
Cohort:: ME/CFS patients with pre-2019 onset only (excludes Long Covid onset to avoid confounding)
Mechanism/Focus:: Investigates viral persistence (particularly enterovirus tissue persistence in gut, muscle, brain), T-cell neuroinflammation, and longitudinal biological signatures. Gut tissue collected from a subset via biopsy to search for enterovirus RNA/protein. Uses whole-body PET imaging and single-nuclei RNA sequencing.
Primary Outcomes:: Longitudinal biomarker trajectories; enterovirus persistence confirmation; neuroimmune phenotyping
Estimated Completion:: September 2030
Timeline:: Multi-year longitudinal follow-up
Publication Medium:: Not yet announced
Document Relevance:: Ch. 7 (immune dysfunction—viral persistence), Ch. 11 (gut microbiome), Ch. 13 (integrative models), Ch. 22 (mechanistic studies)
CHIIME represents a paradigm shift from serology-based viral persistence research to direct tissue-level detection. By collecting gut, muscle, and CNS-adjacent tissue, this study can directly test whether enterovirus RNA and protein persist in tissues of ME/CFS patients—moving beyond the indirect evidence that has characterised viral persistence research for decades. The pre-2019 onset criterion ensures that findings apply to classical ME/CFS rather than post-COVID presentations, addressing a critical gap in the field.