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

Table 1 Clinical evidence of hydrogen therapy in osteoarthritis

Ref.	Year	Study design	Participants (number, characteristics, KL grade)	Intervention (method, dose, duration)	Primary outcome (WOMAC score, significance)	Secondary outcomes (inflammation, functional tests, QoL, significance)	Main conclusions (initial vs sustained effects)	Limitations
Wang et al[24]	2025	Open-label, blinded-endpoint, randomized controlled trial	121 elderly KOA patients (average age 812 years, 80.2% female; KL grade 2 or grade 3; KOA duration ≥ 6 months)	H2-O2 inhalation (2.0 L/minute H2, 1.0 L/minute O2) for 60 minute/day over 2 weeks, adjunctive to 12-week HBE program; control: HBE only	WOMAC total score: (1) Group H improved -22.9 from baseline (P < 0.001); (2) Group C improved -19.4 from baseline (P < 0.001); (3) Between-group difference at week-12: -5.2 (P = 0.140), not clinically significant (MCID = 9); and (4) Peak MD at week-2: -8.0 (P = 0.024)	(1) Inflammation (hs-CRP, NLR, PLR, LMR): No significant between-group differences at week-12 (P > 0.4); (2) Functional tests (CST, TUG): No significant between-group differences at week-12 (P > 0.1). Both groups improved from baseline; (3) QoL (SF-36): No significant between-group differences at week-12. Both groups improved from baseline; and (4) Adverse events: Low incidence, no significant difference	H2-O2 inhalation alleviated KOA symptoms and enhanced functional activity during initial 2 weeks. No sustained effects observed at 12 weeks	Open-label design (bias risk); self-reported adherence; no analysis of plasma inflammatory markers; control group did not receive O2 inhalation; limited generalizability (CCRC population)

KL: Kellgren-Lawrence; KOA: Knee osteoarthritis; HBE: Home-based exercise; WOMAC: Western Ontario and McMaster Universities Arthritis Index; MCID: Minimum clinically important difference; MD: Mean difference; QoL: Quality of life; hs-CRP: High-sensitivity C-reactive protein; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; CST: Chair stand test; TUG: Timed up and go test; SF-36: Short Form 36 Health Survey Questionnaire; CCRC: Continuing care retirement community.

Table 2 Clinical trials investigating hydrogen therapy in rheumatoid arthritis

Ref.	Year	Study design	Participants (number, conditions, characteristics)	Intervention (method, dose, duration)	Primary outcomes (measured)	Secondary outcomes (measured)	Statistical significance	Main conclusions	Limitations
Ishibashi et al[39]	2012	Small pilot study, open-label, no placebo control	20 RA patients	Hydrogen-rich water (duration 4 weeks)	Disease activity, oxidative stress markers	Significant decrease in disease activity and oxidative stress markers		Suggests potential benefits but requires further validation	Open-label, small sample size, lack of placebo control
Ishibashi et al[18]	2014	Randomized, double-blind, placebo-controlled pilot study	24 RA patients	Intravenous infusion of 500 mL of 1 ppm H2-saline daily for 5 days	DAS28	IL-6, TNF-α, MMP-3, urinary 8-OHdG	DAS28: Significant decrease in H2 group (P < 0.05); IL-6: Significant decrease in H2 group (P < 0.05); MMP-3: Significant decrease in H2 group (P < 0.05); 8-OHdG: Significant decrease in H2 group (P < 0.05); TNF-α: No remarkable change	H2 infusion safely and effectively reduced RA disease activity	Small sample size (n = 24); short duration (5-day infusion, 4-week follow-up); generalizability limited
Shen et al[38]	2022	Clinical trial (NCT05196295)	15 autoimmune patients (14 RA, 1 SLE; average age 54 years, 80% female)	Oral hydrogen-rich coral calcium: Low (1 capsule/day), medium (3 capsules/day), high (6 capsules/day) for 1 month	Safety (adverse effects)	DAS28, BFI-T, CRP, ESR, CBC, urinary biomarkers	Safety: No adverse effects reported; DAS28: Significant decrease overall (P = 0.02), pronounced in high dose (P = 0.01); BFI-T: Significant decrease overall (P = 0.0002), pronounced in high/medium doses; CRP/ESR: Trend of decrease, not statistically significant; WBC: Neutrophils: Significant decrease; monocytes: Significant increase	No adverse effects; potential therapeutic effects addressed for future studies	Small sample size (n = 15); short duration (1 month); no separate RA treatment control group; need for more calcium biomarkers; need for longer studies (≥3 months)

RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; DAS28: Disease Activity Score 28; IL: Interleukin; TNF: Tumor necrosis factor; MMP-3: Matrix metalloproteinase-3; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; BFI-T: Brief Fatigue Inventory-Taiwan; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; CBC: Complete blood count; WBC: White blood count.

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.

Table 4 Preclinical and clinical findings on hydrogen therapy in tendinopathies and soft tissue injuries

Ref.	Year	Condition	Study type	Participants/model (number, species)	Intervention (method, dose, duration)	Key outcomes (measured)	Observed effects/significance	Main conclusions	Limitations
Meng et al[46]	2019	Tendon adhesion (post-repair)	Preclinical animal model	36 Sprague Dawley rats (tendon repair model)	Hydrogen water vs normal saline post-operative	Tendon adhesion, oxidative stress markers (MDA, 8-OHdG), antioxidant enzymes (SOD, GSH), Nrf2 pathway expression	HS group showed reduced tendon adhesion, lower MDA/8-OHdG, higher SOD/GSH. Associated with Nrf2 activation	Hydrogen water can reduce tendon adhesion and inhibit excessive inflammatory response, possibly via Nrf2 pathway	Preclinical (animal model); direct translation to humans needs validation
Sládečková et al[22]	2024	Muscle injury recovery	Review/conceptual	Athletes	Hydrogen therapy (drinking, bathing, inhaling)	Anti-oxidation, anti-inflammation, improved recovery from injury	Hydrogen therapy shows potential for muscle recovery by reducing oxidative stress and inflammation	Conceptual/review; lacks specific clinical trial data in these snippets
Ostojic[3]	2016	Soft tissue injuries (sports-related)	Small-scale pilot clinical study	36 young men with sports-related soft tissue injuries	Oral and topical H2 for 14 days, as complementary treatment	Joint flexibility, plasma viscosity, C-reactive protein, IL-6, pain scores, limb swelling	Faster return to normal joint flexibility; augmented plasma viscosity decrease. Other inflammation markers and clinical outcomes not consistently significant	Provides early support for H2 in soft tissue injuries, but limited efficacy on general inflammation markers	Small sample size; short duration; pilot nature; inconsistent reporting of all outcomes
Agyeman-Prempeh et al[47]	2025	Tendinopathy (general preclinical)	Scoping review	Various animal models (in vitro & in vivo)	Various AT treatments (general)	Tendon properties (load, stiffness, fiber structure, collagen), inflammation	Promising preclinical outcomes (improved biomechanical, histological, biochemical properties)	Poor face validity of animal models; heterogeneity in AT induction; low quality/high risk of bias in included studies; translation to clinical practice lags

AT: Achilles tendon; MDA: Malondialdehyde; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; SOD: Superoxide dismutase; GSH: Glutathione; Nrf2: Nuclear factor erythroid 2-related factor 2; IL: Interleukin.

Table 5 Common hydrogen delivery methods and research dosages

Delivery method	Typical research dosages/concentrations	Administration duration	Targeted systems/conditions	Prospective	Disadvantages
hydrogen-rich water ingestion	0.9 ppm H2 (1260 mL/day - 2520 mL/day)	3 days to 4 weeks	Muscle recovery; RA; neuropathic pain; muscle atrophy	Accessible; convenient for daily/Long-term use; systemic effects	H2 can escape from containers; variability in commercial products
	4-5 ppm H2 (530 mL/day)	1 month
	> 1.5 mmol/L H2 (average 15 mL/day in mice)	Up to 12 weeks
	Proposed therapeutic dose: 80 mL H2 gas (6.6 mg/3.3 mmol) per day
Hydrogen gas inhalation	< 4 % H2 in air; 2.0 L/minute H2 + 1.0 L/minute O2 for 60 minutes	60 min/day over 2 weeks single sessions	Respiratory; cardiovascular; KOA; fibromyalgia; acute conditions (stroke)	Rapid systemic delivery; precise dosing with devices	Requires specialized equipment (inhaler/generator); risk if O2 is insufficient or H2 is contaminated
H2-saturated saline injection	1 ppm H2-saline (500 mL)	Daily for 5 days	RA; acute conditions (ischemic stroke)	Direct and rapid systemic delivery; bypasses GI tract	Invasive; requires medical professional administration
Topical application	Not specified (part of combined treatment)	Not specified (part of combined treatment)	Soft tissue injuries	Localized effect; potentially fewer systemic side effects	Limited systemic absorption; variable penetration
Oral tablets/capsules	Hydrogen-rich coral calcium: 170-1020 mg/day	1 month	Autoimmune diseases (RA, SLE)	Convenient; easy to administer	Absorption variability; potential for other ingredients (e.g., calcium)

RA: Rheumatoid arthritis; KOA: Knee osteoarthritis; SLE: Systemic lupus erythematosus; GI: Gastrointestinal.

Table 6 Safety profile and reported adverse events of hydrogen therapy

Safety status	Observed adverse events (type, frequency, severity)	Associated delivery method	Context/condition of study	Important safety considerations
GRAS by FDA	No toxic side effects reported in many clinical trials	All methods (HRW, inhalation, injection, topical)	General clinical use, ischemic stroke, various conditions	Ensure adequate oxygen during inhalation; avoid contaminated H2; consult healthcare provider for high/extended doses
No contraindications shown when taken as directed	Headaches (2/121, 1.7%); nasal cavity dryness (1/121, 0.8%); no significant difference vs control	H2-O2 inhalation	Knee osteoarthritis	Proper device use; avoid excessive water intake
No adverse effects/toxicity observed	None reported (qualitative improvements in energy, sleep, defecation noted)	Oral hydrogen-rich coral calcium	Autoimmune diseases (RA, SLE)	Monitor for potential effects of other components (e.g., calcium) in combined supplements
No adverse effects reported	None reported	H2-saline infusion	RA, ischemic stroke	Ensure sterile preparation and professional administration for injections
No substantially negative effect	None reported (as defined by MCID)	Hydrogen-rich water	exercise-induced muscle damage in athletes	Adherence to recommended dosages

GRAS: Generally recognized as safe; FDA: Food and Drug Administration; MCID: Minimum clinically important difference; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus.