Molecular Hydrogen – Clinical Studies

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Hydrogen: A Novel Option in Human Disease Treatment‘; Yang M, Dong Y, He Q, Zhu P, Zhuang Q, Shen J, Zhang X, Zhao M. Oxid Med Cell Longev. 2020 Sep 5;2020

H2 has shown anti-inflammatory and antioxidant ability in many clinical trials, and its application is recommended in the latest Chinese novel coronavirus pneumonia (NCP) treatment guidelines. Clinical experiments have revealed the surprising finding that H2 gas may protect the lungs and extrapulmonary organs from pathological stimuli in NCP patients. The potential mechanisms underlying the action of H2 gas are not clear. H2 gas may regulate the anti-inflammatory and antioxidant activity, mitochondrial energy metabolism, endoplasmic reticulum stress, the immune system, and cell death (apoptosis, autophagy, pyroptosis, ferroptosis, and the circadian clock, among others) and has therapeutic potential for many systemic diseases. This paper reviews the basic research and the latest clinical applications of H2 gas in multiorgan system diseases to establish strategies for the clinical treatment for various diseases.

Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles, Masatoshi Ichihara, Sayaka Sobue, Mikako Ito, Masafumi Ito, Masaaki Hirayama, and Kinji Ohno, Medical Gas Research volume 5, Article number: 12 (2015) 5:12 DOI 10.1186/s13618-015-0035-1

Therapeutic effects of molecular hydrogen for a wide range of disease models and human diseases have been investigated since 2007. A total of 321 original articles have been published from 2007 to June 2015. Most studies have been conducted in Japan, China, and the USA. About three-quarters of the articles show the effects in mice and rats. The number of clinical trials is increasing every year. In most diseases, the effect of hydrogen has been reported with hydrogen water or hydrogen gas, which was followed by confirmation of the effect with hydrogen-rich saline. 

Hydrogen Gas Therapy: From Preclinical Studies to Clinical Trials.; Sano M, Tamura T.; Curr Pharm Des. 2020 Dec 21. doi: Epub ahead of print. PMID: 33349213.

Summary: In this review, we have highlighted key findings from preclinical research and recent clinical studies demonstrating that H2 reduces the organ damage caused by ischemia-reperfusion. We have also outlined the critical role this effect plays in a variety of medical emergencies, including myocardial infarction, hemorrhagic shock, and out-of-hospital cardiac arrest, as well as in organ transplantation. H2 is compared with established treatments such as targeted temperature management, and we have also discussed its possible mechanisms of action, including the recently identified suppression of TNF-α-mediated endothelial glycocalyx degradation by inhaled H2. In addition, our new method that enables H2 gas to be easily transported to emergency settings and quickly injected into an organ preservation solution at the site of donor organ procurement has been described.

Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals; Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S.; Nat Med. 2007 Jun;13(6):688-94. doi: 10.1038/nm1577. Epub 2007 May 7. PMID: 17486089.

Conclusion: H2 is an easily administered, inexpensive, and well-tolerated agent that is highly effective for a wide range of conditions in emergency medicine, as well as for preserving donated organs.

Beneficial biological effects and the underlying mechanisms of molecular hydrogen – a comprehensive review of 321 original articles, Masatoshi Ichihara 1, Sayaka Sobue 1, Mikako Ito, Masafumi Ito, Masaaki Hirayama, Kinji Ohno; Med Gas Res; 2015 Oct 19;5:12. doi: 10.1186/s13618-015-0035-1. eCollection 2015.

Therapeutic effects of molecular hydrogen for a wide range of disease models and human diseases have been investigated since 2007. A total of 321 original articles have been published from 2007 to June 2015. Most studies have been conducted in Japan, China, and the USA. About three-quarters of the articles show the effects in mice and rats. The number of clinical trials is increasing every year. In most diseases, the effect of hydrogen has been reported with hydrogen water or hydrogen gas, which was followed by confirmation of the effect with hydrogen-rich saline. Hydrogen water is mostly given ad libitum. Hydrogen gas of less than 4 % is given by inhalation. The effects have been reported in essentially all organs covering 31 disease categories that can be subdivided into 166 disease models, human diseases, treatment-associated pathologies, and pathophysiological conditions of plants with a predominance of oxidative stress-mediated diseases and inflammatory diseases.

Molecular hydrogen: a preventive and therapeutic medical gas for various diseases; (2017) Ge, L., Yang, M., Yang, N. N., Yin, X. X., & Song, W. G. Oncotarget8(60), 102653–102673.

Since the 2007 discovery that molecular hydrogen (H2) has selective antioxidant properties, multiple studies have shown that H2 has beneficial effects in diverse animal models and human disease. This review discusses H2 biological effects and potential mechanisms of action in various diseases, including metabolic syndrome, organ injury, and cancer; describes effective H2 delivery approaches, and summarizes recent progress toward H2 applications in human medicine. We also discuss remaining questions in H2 therapy and conclude with an appeal for a greater role for H2 in the prevention and treatment of human ailments that are currently major global health burdens. This review makes a case for supporting hydrogen medicine in human disease prevention and therapy.

The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance Brandon J Dixon, Jiping Tang, John H Zhang; Med Gas Res: 2013 May

Studies on molecular hydrogen have evolved tremendously from its humble beginnings and have continued to change throughout the years. Hydrogen is extremely unique since it has the capability to act at the cellular level. Hydrogen is qualified to cross the blood-brain barrier, enter the mitochondria, and even has the ability to translocate to the nucleus under certain conditions. Once in these ideal locations of the cell, previous studies have shown that hydrogen exerts antioxidant, anti-apoptotic, anti-inflammatory, and cytoprotective properties that are beneficial to the cell. Hydrogen is most commonly applied as a gas, water, saline, and can be applied in a variety of other mediums. There are also few side effects involving hydrogen, thus making hydrogen a perfect medical gas candidate for the convention of novel therapeutic strategies against cardiovascular, cerebrovascular, cancer, metabolic, and respiratory diseases and disorders. Although hydrogen appears to be faultless at times, there still are several deficiencies or snares that need to be investigated by future studies. This review article seeks to delve and comprehensively analyze the research and experiments that allude to molecular hydrogen being a novel therapeutic treatment that medicine desperately needs.

Molecular Hydrogen as a Neuroprotective Agent.Iketani M, Ohsawa I.Curr Neuropharmacol. 2017;15(2):324-331. doi: 10.2174/1570159×14666160607205417.PMID: 27281176 Free PMC article. 

Oxidative stress and neuroinflammation cause many neurological disorders. Recently, it has been reported that molecularhydrogen (H2) functions as an antioxidant and anti-inflammatory agent. …

Molecular hydrogen: A potential radioprotective agent.Hu Q, Zhou Y, Wu S, Wu W, Deng Y, Shao A.Biomed Pharmacother. 2020 Oct;130:110589. doi: 10.1016/j.biopha.2020.110589. Epub 2020 Aug 4.PMID: 32763820 Free article. Review.

In recent years, many studies have shown that hydrogen has therapeutic and preventive effects on various diseases. …We also look into details of vitro and vivo studies for hydrogen‘s radioprotective effects, and clinical practices. We conclude that hydrogen …

A New Approach for the Prevention and Treatment of Cardiovascular Disorders. 
Molecular Hydrogen Significantly Reduces the Effects of Oxidative Stress.LeBaron TW, Kura B, Kalocayova B, Tribulova N, Slezak J.Molecules. 2019 May 31;24(11):2076. doi: 10.3390/molecules24112076.PMID: 31159153 Free PMC article.

 Despite years of intensive research, there is still no safe and effective method for their prevention and treatment. Recently, molecular hydrogen has been investigated in preclinical and clinical studies on various diseases associated with oxidative and inflammatory …

[Different types of molecular hydrogen donors and their pharmacokinetics in vivo].Liu BY, Qin SC.Sheng Li Xue Bao. 2019 Apr 25;71(2):371-377.PMID: 31008498 Free article. Review. 

Chinese.Molecularhydrogen (H(2)) has been shown to have diverse biomedical effects. As a small molecular gas, hydrogen can be diffused to the target without hindrance. …

Application of Molecular Hydrogen as a Novel Antioxidant in Sports Science.Kawamura T, Higashida K, Muraoka I.Oxid Med Cell Longev. 2020 Jan 14;2020:2328768. doi: 10.1155/2020/2328768. eCollection 2020.PMID: 32015786 Free PMC article. Review.

Molecularhydrogen (H(2)) is a colorless, tasteless, odorless, and minimal molecule with high flammability. …

Molecular hydrogen: potential in mitigating oxidative-stress-induced radiation injury (1).Kura B, Bagchi AK, Singal PK, Barancik M, LeBaron TW, Valachova K, Šoltés L, Slezák J.Can J Physiol Pharmacol. 2019 Apr;97(4):287-292. doi: 10.1139/cjpp-2018-0604. Epub 2018 Dec 13.PMID: 30543459 Review.

As a proof of principle, we also demonstrate that in rat hearts in vivo, administration of molecularhydrogen led to a significant increase in superoxide dismutase as well as pAKT, a cell survival signaling molecule. …We suggest that the beneficial effects of m …

Recent Advances in Studies of Molecular Hydrogen against Sepsis.Qiu P, Liu Y, Zhang J.Int J Biol Sci. 2019 May 11;15(6):1261-1275. doi: 10.7150/ijbs.30741. eCollection 2019.PMID: 31223285 Free PMC article. Review.

Molecularhydrogen exerts multiple biological effects involving anti-inflammation, anti-oxidation, anti-apoptosis, anti-shock, and autophagy regulation, which may attenuate the organ and barrier damage caused by sepsis. …This review focuses on the research progres …

Molecular Hydrogen, a Neglected Key Driver of Soil Biogeochemical Processes.Piché-Choquette S, Constant P.Appl Environ Microbiol. 2019 Mar 6;85(6):e02418-18. doi: 10.1128/AEM.02418-18. Print 2019 Mar 15.PMID: 30658976 Free PMC article. Review.

The atmosphere of the early Earth is hypothesized to have been rich in reducing gases such as hydrogen (H(2)). H(2) has been proposed as the first electron donor leading to ATP synthesis due to its ubiquity throughout the biosphere as well as its ability to easily diffuse …

Molecular Hydrogen Metabolism: a Widespread Trait of Pathogenic Bacteria and Protists.Benoit SL, Maier RJ, Sawers RG, Greening C.Microbiol Mol Biol Rev. 2020 Jan 29;84(1):e00092-19. doi: 10.1128/MMBR.00092-19. Print 2020 Feb 19.PMID: 31996394 Free PMC article. Review.

One widespread but often overlooked means of energy conservation is through the consumption or production of molecularhydrogen (H(2)). Here, we comprehensively review the distribution, biochemistry, and physiology of H(2) metabolism in pathogens. …

Molecular Hydrogen Protects Human Melanocytes from Oxidative Stress by Activating Nrf2 Signaling.Fang W, Tang L, Wang G, Lin J, Liao W, Pan W, Xu J.J Invest Dermatol. 2020 Nov;140(11):2230-2241.e9. doi: 10.1016/j.jid.2019.03.1165. Epub 2020 Mar 29.PMID: 32234461

Oxidative stress is proven to be critical for the initiation and progression of vitiligo. Molecularhydrogen (H(2)) possesses potent antioxidant activity and has been shown to protect against various oxidative stress-related diseases. …Correspondingly, H(2)        

Page 211CiteShare The Clinical Application of Hydrogen as a Medical Treatment.Iida A, Nosaka N, Yumoto T, Knaup E, Naito H, Nishiyama C, Yamakawa Y, Tsukahara K, Terado M, Sato K, Ugawa T, Nakao A.Acta Med Okayama. 2016 Oct;70(5):331-337. doi: 10.18926/AMO/54590.PMID: 27777424 Review.

In recent years, it has become evident that molecularhydrogen is a particularyl effective treatment for various disease models such as ischemia-reperfusion injury; as a result, research on hydrogenhas progressed rapidly. …Hydrogen‘s effectiveness i …

Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine.Ohta S.Pharmacol Ther. 2014 Oct;144(1):1-11. doi: 10.1016/j.pharmthera.2014.04.006. Epub 2014 Apr 24.PMID: 24769081 Review.

Molecularhydrogen (H2) has been accepted to be an inert and nonfunctional molecule in our body. …13CiteShare 

Therapeutic Efficacy of Molecular Hydrogen: A New Mechanistic Insight.Ishibashi T.Curr Pharm Des. 2019;25(9):946-955. doi: 10.2174/1381612825666190506123038.PMID: 31057105 Free PMC article. Review.BACKGROUND: 

Molecularhydrogen (H2) is now recognized as a therapeutic gas for the treatment of numerous diseases including neurodegenerative diseases, metabolic disorders, and inflammatory diseases. …

Recent advances in studies of molecular hydrogen in the treatment of pancreatitis.Li Y, Li G, Suo L, Zhang J.Life Sci. 2021 Jan 1;264:118641. doi: 10.1016/j.lfs.2020.118641. Epub 2020 Oct 24.PMID: 33148420 Review.

The inflammatory response, impaired autophagic flux, endoplasmic reticulum stress (ERS) and their interactions are involved in the development of pancreatitis. Molecularhydrogen (H(2)) is a novel antioxidant that possesses the features of selective scavenging of ox …

Molecular Hydrogen Therapy Ameliorates Organ Damage Induced by Sepsis.Zheng Y, Zhu D.Oxid Med Cell Longev. 2016;2016:5806057. doi: 10.1155/2016/5806057. Epub 2016 Jun 20.PMID: 27413421 Free PMC article. Review.

Since it was proposed in 2007, molecularhydrogen therapy has been widely concerned and researched. …Molecularhydrogen therapy is able to significantly reduce the release of inflammatory factors and oxidative stress injury. …16CiteShare 

Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation.Liu MY, Xie F, Zhang Y, Wang TT, Ma SN, Zhao PX, Zhang X, Lebaron TW, Yan XL, Ma XM.Stem Cell Res Ther. 2019 May 21;10(1):145. doi: 10.1186/s13287-019-1241-x.PMID: 31113492 Free PMC article.BACKGROUND:

Glioblastoma (GBM) is the most common type of primary malignant brain tumor. Molecularhydrogen has been considered a preventive and therapeutic medical gas in many diseases including cancer. …CONCLUSIONS: Together, these results indicated that mole …

Molecular hydrogen: current knowledge on mechanism in alleviating free radical damage and diseases.Tao G, Song G, Qin S.Acta Biochim Biophys Sin (Shanghai). 2019 Dec 13;51(12):1189-1197. doi: 10.1093/abbs/gmz121.PMID: 31738389

Ever since molecularhydrogen was first reported as a hydroxyl radical scavenger in 2007, the beneficial effect of hydrogen was documented in more than 170 disease models and human diseases including ischemia/reperfusion injury, metabolic syndrome, inflammati …

Molecular hydrogen in sports medicine: new therapeutic perspectives.Ostojic SM.Int J Sports Med. 2015 Apr;36(4):273-9. doi: 10.1055/s-0034-1395509. Epub 2014 Dec 19.PMID: 25525953 Review.

In the past 2 decades, molecularhydrogen emerged as a novel therapeutic agent, with antioxidant, anti-inflammatory and anti-apoptotic effects demonstrated in plethora of animal disease models and human studies. …This review will summarize recent research findings …

Molecular hydrogen regulates PTEN-AKT-mTOR signaling via ROS to alleviate peritoneal dialysis-related peritoneal fibrosis.Lu H, Chen W, Liu W, Si Y, Zhao T, Lai X, Kang Z, Sun X, Guo Z.FASEB J. 2020 Mar;34(3):4134-4146. doi: 10.1096/fj.201901981R. Epub 2020 Jan 12.PMID: 31930571

However, long-term peritoneal dialysis treatment causes peritoneal fibrosis. In recent years, the application potential of molecularhydrogen in the biomedicine has been well recognized. Molecularhydrogen selectively scavenges cytotoxic reactive oxyge …

Molecular hydrogen attenuates methamphetamine-induced behavioral sensitization and activation of ERK-deltaFosB signaling in the mouse nucleus accumbens.Wen D, Hui R, Liu Y, Luo Y, Wang J, Shen X, Xie B, Yu F, Cong B, Ma C.Prog Neuropsychopharmacol Biol Psychiatry. 2020 Mar 8;97:109781. doi: 10.1016/j.pnpbp.2019.109781. Epub 2019 Oct 17.PMID: 31629777

To this end, male C57BL/6 mice received METH (0.1, 0.5 and 1.0 mg/kg, i.p.) injections for 7 days followed by a METH challenge (0.1, 0.5 and 1.0 mg/kg, i.p.) after a 7-day transfer period. Molecularhydrogen, delivered through a hydrogen-rich saline (HRS) inj …

 Molecular hydrogen: An inert gas turns clinically effective.Ostojic SM.Ann Med. 2015 Jun;47(4):301-4. doi: 10.3109/07853890.2015.1034765. Epub 2015 May 4.PMID: 25936365 Review.

Molecularhydrogen (H2) appeared as an experimental agent in biomedicine approximately 40 years ago, yet the past 5 years seem to confirm its medicinal value in the clinical environment. …Clinical profiles of H2 provide evidence-based direction for practical appli …

Molecular hydrogen increases resilience to stress in mice.Gao Q, Song H, Wang XT, Liang Y, Xi YJ, Gao Y, Guo QJ, LeBaron T, Luo YX, Li SC, Yin X, Shi HS, Ma YX.Sci Rep. 2017 Aug 29;7(1):9625. doi: 10.1038/s41598-017-10362-6.PMID: 28852144 Free PMC article.

The inability to successfully adapt to stress produces pathological changes that can lead to depression. Molecularhydrogen has anti-oxidative and anti-inflammatory activities and neuroprotective effects. However, the potential role of molecularhydrogen …

Regulation of microRNAs by molecular hydrogen contributes to the prevention of radiation-induced damage in the rat myocardium.Kura B, Kalocayova B, LeBaron TW, Frimmel K, Buday J, Surovy J, Slezak J.Mol Cell Biochem. 2019 Jul;457(1-2):61-72. doi: 10.1007/s11010-019-03512-z. Epub 2019 Mar 4.PMID: 30830529

However, the impact of molecularhydrogen on the expression of miRNAs in the heart after irradiation has not been investigated. …We observed significant increase in miRNA-21 expression in the irradiated rat hearts. Molecularhydrogen lowered myocardi …

The preventive and therapeutic effects of molecular hydrogen in ocular diseases and injuries where oxidative stress is involved.Cejka C, Kubinova S, Cejkova J.Free Radic Res. 2019 Mar;53(3):237-247. doi: 10.1080/10715762.2019.1582770. Epub 2019 Mar 19.PMID: 30773939 Review.

To replace these weakened antioxidants, substances with effective antioxidant properties are needed in order to suppress oxidative stress and enable healing. Molecularhydrogen (H(2)) is very suitable for this purpose due to its unique properties. H(2) is the only a …

Targeting molecular hydrogen to mitochondria: barriers and gateways.Ostojic SM.Pharmacol Res. 2015 Apr;94:51-3. doi: 10.1016/j.phrs.2015.02.004. Epub 2015 Feb 24.PMID: 25720951 Review.

Although the administration of molecularhydrogen (H2, dihydrogen) has been recognized as an effective innovative therapeutic procedure in biomedicine, H2 cellular kinetics and utilization seems to be less understood. …

Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases.Ohno K, Ito M, Ichihara M, Ito M.Oxid Med Cell Longev. 2012;2012:353152. doi: 10.1155/2012/353152. Epub 2012 Jun 8.PMID: 22720117 Free PMC article. Review.Effects of molecularhydrogen on various diseases have been documented for 63 disease models and human diseases in the past four and a half years. …Further studies are required to elucidate molecular bases of prominent hydrogen effects and to determi …

Molecular hydrogen and radiation protection.Chuai Y, Qian L, Sun X, Cai J.Free Radic Res. 2012 Sep;46(9):1061-7. doi: 10.3109/10715762.2012.689429. Epub 2012 May 18.PMID: 22537465 Review.

Molecularhydrogen (dihydrogen, H(2)) acts as a therapeutic antioxidant by selectively reducing hydroxyl radicals (OH) and peroxynitrite (ONOO-). …

Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study (1).Mikami T, Tano K, Lee H, Lee H, Park J, Ohta F, LeBaron TW, Ohta S.Can J Physiol Pharmacol. 2019 Sep;97(9):857-862. doi: 10.1139/cjpp-2019-0059. Epub 2019 Jun 28.PMID: 31251888 

Clinical Trial.Acute physical exercise increases reactive oxygen species in skeletal muscle, leading to tissue damage and fatigue. Molecularhydrogen (H(2)) acts as a therapeutic antioxidant directly or indirectly by inducing antioxidative enzymes. …

Molecular hydrogen upregulates heat shock response and collagen biosynthesis, and downregulates cell cycles: meta-analyses of gene expression profiles.Nishiwaki H, Ito M, Negishi S, Sobue S, Ichihara M, Ohno K.Free Radic Res. 2018 Apr;52(4):434-445. doi: 10.1080/10715762.2018.1439166. Epub 2018 Mar 20.PMID: 29424253

Molecularhydrogen exerts its effect on multiple pathologies, including oxidative stress, inflammation, and apoptosis. However, its molecular mechanisms have not been fully elucidated. In order to explore the effects of molecularhydrogen, we me …

Oxidative Stress

What is Oxidative Stress? The movie. What IS Oxidative Stress? Simplistically speaking, oxidative stress is the result of normal cell functions. It’s the trash, and it’s created in every cell in our body. Molecular hydrogen “takes out the trash”. Watch the movie.