HEALTH SAFETY OF MOLECULAR HYDROGEN

“Have you ever wondered how the simplest and smallest element in the known universe could lead to “a brighter, more intellectual, and healthier way of living?” (1)

No researcher has expressed the wonderment of molecular hydrogen (H2) as a therapeutic gas more accurately than Dixon and Zhang (2016).

Physical & Chemical Properties

  • Hydrogen is the first element on the periodic table, with atomic number 1 – the smallest element in the known universe.
  • Hydrogen gas is colorless, odorless and tasteless.
  • Hydrogen gas is not flammable, unless the temperature exceeds 527oC and the concentration in air exceeds 4 % in volume.
  • When dissolved in water, hydrogen gas has a rating of 0/0/0 for health/flammability/instability on the Hazardous Material Information System in the United States.
  • Hydrogen gas has low water solubility, with the saturation concentration at normal conditions being around 1.6 ppm (1.6 mg H2 per liter).

Current Status of Research

In 1975, Dole et al. reported the possible application of hyperbaric hydrogen therapy in the treatment of cancer (2). More than 20 years later, Shirahata et al. (1997) reported a possibility of molecular hydrogen acting as a scavenger of reactive oxygen species (3). Another decade past, Ohsawa et al. (2007) reported in a prestigious medical journal, Nature Medicine, that molecular hydrogen might act as a selective antioxidant (4). Specifically, they suggested that molecular hydrogen might neutralize hydroxyl radical, the most reactive of all reactive oxygen species (ROS), as well as peroxynitrite, the most reactive of all reactive nitrogen species (RNS).

Since the landmark article of Ohsawa et al. (2007), more than 500 original and review articles on the potential therapeutic benefits of molecular hydrogen have been published in medical journals (5). These articles cover more than 60 disease models and include more than 40 clinical studies. Taken altogether, they suggest that molecular hydrogen has antioxidant and anti-inflammatory properties.

Number of publications on H2 biological effects in various organ system diseases between 2007 and 2017 (Ge et al., 2017) (5)

Number of publications on H2 biological effects in various organ system diseases between 2007 and 2017 (Ge et al., 2017) (5)

However, further studies are required for evaluating the potential therapeutic benefits of molecular hydrogen. Perhaps, the most important fact at this stage of research is that no adverse effect has been found in the use of molecular hydrogen in the human.

Health Safety

We examined the clinical studies to date and found no adverse effect in the use of molecular hydrogen. This can be attributed to several observations and facts.Selective Antioxidant

Molecular hydrogen is inert and, as mentioned above, is unlikely to react with ROS and RNS with low reactivity, which play an important role in physiological functions as signalling molecules.Short Residence Time

Owing to its small size, molecular hydrogen can quickly enter the blood stream and diffuses into organs, tissues, cells and part of the body where most of antioxidants fail to reach. Similarly, molecular hydrogen is expelled in the breath as quickly as it enters the body (10, 11, 12). In case of the study by Shimouchi et al. (2009), molecular hydrogen taken orally appeared in the breath within 15 minutes and the concentration of molecular hydrogen in the breath returned to the basal level within 60 minutes. Unlike common drugs, the liver and the kidney are not involved in the metabolization of molecular hydrogen.Use in Deep Diving

Hydrogen gas has safely been used in deep diving. The first report dates back to 1945 – by the Swedish engineer, Arne Zetterstrom. It was a mixture of oxygen and hydrogen gases, known as Hydrox. In late 1960’s, the United States Navy and the Compagnie Maritime d’Expertises of France also started testing the use of high-concentration hydrogen gas (up to 49%) in dives as deep as 700 m (6).Endogenous Intestinal Gas

The health safety of molecular hydrogen has been discussed based on facts that the human gastrointestinal tract harbours trillions of microbes, namely the gut microbiota, and that molecular hydrogen is amongst the common biological gases produced by the gut microbiota – other common gasses being oxygen, nitrogen, carbon dioxide, methane and hydrogen. This is a long-accepted fact and constitutes the principle of the breath hydrogen test – a test to determine small intestinal bacterial overgrowth (7,8,9).

Ruling by Regulatory Bodies

US FDA

US Food & Drug Administration issued the “generally regarded as safe” or GRAS ruling to hydrogen water products. This ruling applies to a chemical substance, which is considered safe by experts as a food additive and is exempted from the food additive tolerance requirements of the US Food, Drug, and Cosmetic Act. Japan, South Korea and China permit the sales of hydrogen water products in their markets on a similar basis to GRAS ruling.Japanese Ministry of Health, Labor and Welfare

In December 2016, Japanese Ministry of Health, Labor and Welfare added hydrogen gas inhalation to the Advanced Medicine List (B-68: Hydrogen gas inhalation therapy). The decision is followed by the multi-institutional, randomized, double-blind, placebo-controlled study, which evaluates the effect of 2 % hydrogen gas in the inhalation gas (2 % H2) on the survival and neurological functions of patients resuscitated from cardiac arrest.

Conclusion

More than 500 original and review articles on the potential therapeutic benefits of molecular hydrogen have been published in medical journals. Taken altogether, they suggest that molecular hydrogen has antioxidant and anti-inflammatory properties. However, further studies are required for evaluating the potential therapeutic benefits of molecular hydrogen. Perhaps, the most important fact at this stage of research is that no adverse effect has been found in the use of molecular hydrogen in the human.

References

  1. Dixon, B.J. & Zhang, J.H., 2016. An innovative collection in hydrogen molecular biology and medicine research. Medical Gas Research, 6: 55-56.
  2. Dole, M. et al., 1975. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science, 190: 152-154.
  3. Shirahata, S. et al., 1997. Electrolyzed-reduced water scavenges active oxygen species and protects DNA from oxidative damage. Biochemical and Biophysical Research Communications. 234: 269-274.
  4. Ohsawa, M. et al., 2007. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature Medicine, 13: 688-694.
  5. Ge, L. et al., 2017. Molecular hydrogen a preventive and therapeutic medical gas for various diseases. Oncotarget, 8: 102653-102673.
  6. Abraini, J.H. et al., 1994. Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture. Journal of Applied Physiology, American Physiological Society, 76: 1113-1118.
  7. Newcomer, A.D. et al., 1975. Prospective comparison of indirect methods for detecting lactase deficiency. New England Journal of Medicine, 293: 1232-1236.
  8. Metz, G. et al., 1976. Breath-hydrogen test for small-intestinal bacterial colonisation. Lancet, 1: 668-669.
  9. Rhodes, J.M. et al., 1979. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scandinavian Journal of Gastroenterology, 14:333-336.
  10. Shimouchi, A. et al., 2009. Breath hydrogen produced by ingestion of commercial hydrogen water and milk. Biomarker Insights, 4: 27-32.
  11. Ono, H. et al., 2012. A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Medical Gas Research, 2: 21.
  12. Ono, H. et al., 2012. Hydrogen (H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Medical Gas Research, 2: 14.

List of Clinical Studies

  1. Aoki, K., et al., 2012. Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes. Medical Gas Research, 2: 12.
  2. Azuma, T. et al., 2015. Drinking hydrogen-rich water has additive effects on non-surgical periodontal treatment of improving periodontitis: A pilot study. Antioxidants, 4: 513-522.
  3. Da Ponte, A., et al., 2018. Effects of hydrogen rich water on prolonged intermittent exercise. Journal of Sports Medicine and Physical Fitness, 58: 612-621.
  4. Hirayama, M. et al., 2018. Inhalation of hydrogen gas elevates urinary 9-hydroxy-2’-deoxyguanine in Parkinson’s disease. Medical Gas Research, 8: 144-149.
  5. Ishibashi, T. et al., 2012. Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patient with rheumatoid arthritis: an open-label pilot study. Medical Gas Research, 2: 27.
  6. Ishibashi, T. et al., 2014. Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: A randomized, double-blind, placebo-controlled pilot study. International Immunopharmacology, 21: 468-473.
  7. Ishibashi, T. et al., 2015. Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Molecular Medicine Reports, 12: 2757-2764.
  8. Ito, M., et al., 2011. Open-label trial and randomized, double-blind, placebo-controlled crossover trial of hydrogen enriched water for mitochondrial and inflammatory myopathies. Medical Gas Research, 1: 24.
  9. Kajiyama, S. et al., 2008. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutrition Research, 28: 137-143.
  10. Kang, K.M. et al., 2011. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Medical Gas Research, 1: 11.
  11. Kato, S. et al., 2012. Hydrogen-rich electrolyzed warm water represses wrinkle formation against UVA ray together with type-I collagen production and oxidative-stress diminishment in fibroblasts and cell-injury prevention in keratinocytes. Journal of Photochemistry and Photobiology B, 106: 24-33.
  12. Kawamura, T. et al., 2018. Involvement of neutrophil dynamics and function in exercise-induced muscle damage and delayed-onset muscle soreness: Effect of hydrogen bath. Antioxidants, 7: E127.
  13. Korovljev, D. et al., 2018. Molecular hydrogen affects body composition, metabolic profiles, and mitochondrial function in middle-aged overweight women. Irish Journal of Medical Science, 187: 85-89.
  14. Korovljev, D. et al., 2018. Hydrogen inhalation positively affects cardiometabolic risk factors in men and women aged 65 years or older: a preliminary report. European Geriatric Medicine, 9: 729-730.
  15. LeBaron, T.W. et al., 2019. Acute supplementation with molecular hydrogen benefits submaximal exercise indices. Randomized, double-blinded, placebo-controlled crossover pilot study. Journal of Lifestyle Medicine, 9: 36-43.
  16. Li, Q. et al., 2013. Hydrogen water intake via tube-feeding for patients with pressure ulcer and its reconstructive effects on normal human skin cells in vitro. Medical Gas Research, 3: 20.
  17. Maeda, K. et al., 2016. Improvement of the fraction of human mercaptalbumin on hemodialysis treatment using hydrogen-dissolved hemodialysis fluid: a prospective observational study. Renal Replacement Therapy, 2: 42-49.
  18. Matsumoto, S. et al., 2013. Effect of supplementation with hydrogen-rich water in patients with interstitial cystitis / painful bladder syndrome. Urology, 81: 226-230.
  19. Mizuno, K. et al., 2018. Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life. Medical Gas Research, 7: 247-255.
  20. Nagatani, K. et al., 2013. Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies. Medical Gas Research, 3: 13.
  21. Nakao, A. et al., 2010. Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome – an open label pilot study. Journal of Clinical Biochemistry and nutrition, 46: 140-149.
  22. Nakayama, M. et al., 2010. A novel bioactive haemodialysis system using dissolved dihydrogen (H-2) produced by water electrolysis: a clinical trial. Nephrology Dialysis Transplantation, 25: 3026-3033.
  23. Nakayama, M. et al., 2017. Possible clinical effects of molecular hydrogen (H2) delivery during hemodialysis in chronic dialysis patients: Interim analysis in a 12-month observation. PLoS One, 12: e0184535.
  24. Nakayama, M. et al., 2018. Novel haemodialysis (HD) treatment employing molecular hydrogen (H2)-enriched dialysis solution improves prognosis of chronic dialysis patients: A prospective observation study. Scientific Reports, 8: 245.
  25. Nishimaki, K. et al., 2017. Effects of molecular hydrogen assessed by an animal and a randomized clinical study on mild cognitive impairment. Current Alzheimer Research, In Press.
  26. Ono, H. et al., 2012a. A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Medical Gas Research, 2: 21.
  27. Ono, H. et al., 2012b. Hydrogen (H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Medical Gas Research, 2: 14.
  28. Ono, H. et al., 2017. Hydrogen gas inhalation treatment in acute cerebral infarction: A randomized controlled clinical study on safety and neuroprotection. Journal of Stroke and Cerebrovascular Diseases, 26: 2587-2594.
  29. Ostojic, S.M. and Stojanovic, M.D., 2014. Hydrogen-rich water affected blood alkalinity in physically active men. Research in Sports Medicine, 22: 49-60.
  30. Ostojic, S.M. et al., 2014. Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries. Journal of Postgraduate Medicine, 126: 188-196.
  31. Da Ponte, A. et al., 2018. Effect of hydrogen rich water on prolonged intermittent exercise. Journal of Sports Medicine and Physical Fitness, 58: 612-621.
  32. Qian, L.R. and Shen, J.L., 2016. Successful treatment with hydrogen rich water in a case of ghronic graft-versus-host-disease. Medical Gas Research, 6: 177-179.
  33. Sakai, T. et al., 2014. Consumption of water containing over 3.5 mg of dissolved hydrogen could improve vascular endothelial function. Vascular Health and Risk Management: 10: 591-597.
  34. Shimouchi, A. et al., 2009. Breath hydrogen produced by ingestion of commercial hydrogen water and milk. Biomarker Insights, 4: 27-32.
  35. Song, G. et al., 2013. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome. Journal of Lipid Research, 54: 1884-1893.
  36. Song, G. et al., 2015. Hydrogen activates ATP binding cassette transporter a1-dependent efflux ex vivo and improves high-density lipoprotein function in patients with hypercholesterolemia: a double-blinded, randomized, and placebo-controlled trial. Journal of Clinical Endocrinology and Metabolism, 100: 27624-2733.
  37. Tamura, T. et al., 2016. Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome – first-in-human pilot study. Circulation Journal, 80: 1870-1873.
  38. Tanaka, Y. et al., 2018. Electrolytically generated hydrogen warm water cleanses the keratin—plug-clogged hair-pores and promotes the capillary bloodstreams, more markedly than normal warm water does. Medical Gas Research, 8: 12-18.
  39. Terawaki, H. et al., 2013. Transperitoneal administration of dissolved hydrogen for peritoneal dialysis patients: a novel approach to suppress oxidative stress in the peritoneal cavity. Medical Gas Research, 3: 14.
  40. Terawaki, H. et al., 2014. Effect of a hydrogen (H2)-enriched solution on the albumin redox of hemodialysis patients. Hemodialysis International., 18: 459-466.
  41. Xia, C. et al., 2013. Effect of hydrogen-rich water on oxidative stress, liver function and viral load in patients with chronic hepatitis B. Clinical and Translational Science, 6: 372-375.
  42. Yoritaka, A. et al., 2013. Pilot study of H2 therapy in Parkinson’s disease: A randomized double-blind placebo-controlled trial. Movement Disorders, 28: 836-839.
  43. Yang, Q. et al., 2017. Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy. Molecular and Clinical Oncology, 7: 891-896.
  44. Zhu, Q. et al., 2018. Positive effects of hydrogen-water bathing in patients of psoriasis and parapsoriasis en plaques. Scientific Reports, 8: 8051.

Important Notice: The statement in this article is not reviewed by regulatory bodies in any country.

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