The aim of this 16-week pilot randomized trial is to explore the potential benefit of the OTC supplement hydrogen water, for the symptoms of chronic fatigue syndrome (CFS). Methods: This 16-week home-based trial will compare two groups: (1) low dose hydrogen water (2-3 glasses/day) for all 16 weeks; and (2) low dose followed by high dose hydrogen water (up to 5 glasses/day). Condition (2) involves an initial 8 weeks of low dose H2 followed by 8 weeks of high dose H2 in order to test the premise that the higher dosage will be more effective with fewer adverse effects if preceded by several weeks of low dose H2. Outcomes measures will include online assessments of fatigue, physical function and stress. A salivary biomarker for oxidative stress, Uric Acid, will also be assessed.

Previous clinical studies (8-12 week intervention trials) have indicated that H2 enriched water reduces concentrations of markers of oxidative stress in patients with metabolic syndrome, improves lipid and glucose metabolism in patients with type 2 diabetes, improves mitochondrial dysfunction in patients with mitochondrial myopathies, and reduces inflammatory processes in patients with polymyositis/ dermatomyositis (Mizuno et al., 2017). In addition to its potential therapeutic properties, H2 water is portable, easily administered and safe to ingest (Nagata et al., 2013). Owing to its potential therapeutic efficacy and lack of adverse effects, H2 may show promise for clinical use in ME/CFS. Two CFS studies conducted in the PI's laboratory (Friedberg and Choi, 2022; Friedberg and Choi, under review) yielded mixed findings. The initial randomized controlled trial showed no benefit for H2 water, but the second study, a randomized trial of H2 and heart rhythm biofeedback that was of longer duration (60 days) with a lower dosage of H2 water found significant improvements in fatigue and physical function. The new proposed randomized trial will extend treatment to 120 days and test a standard dosage of H2 water for all 120 days in group1 in comparison to standard dosage for the initial 60 days followed by increased dosage for the remaining 60 days (Group 2). Group 2 is may show a greater treatment effect once subjects are acclimated to the lower initial dose. Thus, we are testing different dosing schedules to determine which may be more effective in CFS.

Inclusion Criteria:

- Patients aged 18-65 of both sexes; considered physically capable and willing to perform the study tasks.

• Meeting validated phone-screen eligibility for ME/CFS criteria.
• Patient has internet and computer.

Exclusion Criteria:

Cases of fatigue clearly attributable to self-report medical conditions such as untreated hypothyroidism, unstable diabetes mellitus, organ failure, chronic infections, and chronic inflammatory diseases, or AIDS.

__ Exclusionary psychiatric disorders include any psychosis, or alcohol/ substance abuse within two years prior to illness onset and any time afterward, and current or past depression with melancholic or psychotic features within 5 years prior to onset of ME/CFS or anytime afterward

• Pregnancy is an exclusion.
• Patients with BMI>35.
• Patients at significant risk of suicide or in need of urgent psychiatric treatment. As much as possible, appropriate medical and psychiatric referrals to facilities local to subjects will be provided.

The investigator is blinded to computer-generated condition assignment.