Molecular hydrogen therapy in musculoskeletal conditions: An evidence-based review and critical analysis

Table 3 Overview of hydrogen therapy studies in chronic musculoskeletal pain

Ref.	Year	Condition	Study type	Participants/model (number, species)	Intervention (method, dose, duration)	Key outcomes (measured)	Observed effects/significance	Main conclusions	Limitations
Kawaguchi et al[31]	2014	Neuropathic Pain	Preclinical animal model	Rats (sciatic nerve injury model)	HRW ingestion (free access); also, during induction phase (day 0-4)	Mechanical allodynia, thermal hyperalgesia, oxidative stress markers (4-HNE, 8-OHdG) in spinal cord/DRG	HRW relieved allodynia and hyperalgesia; reduced oxidative stress in spinal cord/DRG. Effects observed even with short-term induction phase treatment	HRW may be beneficial for neuropathic pain	Preclinical (animal model); direct translation to humans needs validation
Ho et al[35]	2025	FM	Scoping review (preclinical and small-scale clinical)	Human FM patients, preclinical models	Redox-modulating therapies (include molecular hydrogen)	Pain, fatigue, sleep, oxidative stress markers (MDA, 4-HNE), mitochondrial dysfunction	Suggests potential benefits of molecular hydrogen; addresses oxidative stress and mitochondrial dysfunction	Human trial evidence is limited; standardized treatment protocols lacking
Hirano et al[32]	2022	FM	Review/conceptual	FM patients	Hydrogen inhalers (daily 30 minutes - 1 hour)	Pain reduction (hyperalgesia), fatigue improvement, anxiolytic effect, mitochondrial protection	Hydrogen offers innovative approach for FM by neutralizing free radicals, reducing oxidative stress, modulating inflammation, and protecting mitochondria	Research still in early stages; further research needed (protocols, subgroups, long-term effects)
Friedberg et al[44]	2025	Chronic fatigue syndrome (similar to FM)	Pilot randomized trial	13 participants (54% female, 46% male)	HRW + HRV-B	C19YRS-m, COMPASS-31, RMSSD, WHODAS, pain, fatigue, sleep, cognitive performance, inflammatory state	HRW has therapeutic antioxidant properties, beneficial in mitigating oxidative stress-induced damage via anti-inflammatory/anti-apoptotic pathways. Significant improvements in various patient profiles	Pilot study; small sample size (n = 13); primary focus on HRV-B; mechanisms need full explanation
Fernández-Serrano et al[45]	2022	Panic disorder (with body pain)	Randomized, placebo-controlled clinical trial	Women with panic disorder	Psychological treatment + 1.5 L hydrogenated water for 3 months. Control: Psychological treatment + placebo	Severity of anxiety/depression, pro-inflammatory cytokine levels, cortisol awakening response, general health, body pain	Treatment group not significantly better overall, but further reduction in pro-inflammatory cytokine scores; improved body pain and physical health	Focus on panic disorder, not primary MSK pain; limited direct applicability to MSK pain syndromes

FM: Fibromyalgia; HRW: Hydrogen-rich water; HRV-B: Human rhinovirus B; 4-HNE: 4-Hydroxynonenal; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; DRG: Dorsal root ganglion; MDA: Malondialdehyde; C19YRS-m: Modified coronavirus disease 2019 Yorkshire Rehabilitation Scale; COMPASS-31: Composite Autonomic Symptom Score 31; RMSSD: Root mean square of successive difference; WHODAS: World Health Organization Disability Assessment Schedule; MSK: Musculoskeletal.