Hydrogen as a Therapeutic Gas: The Science Behind the Bubble

Hydrogen as a Therapeutic Gas

Hydrogen may simultaneously be one of the most basic and broadly applicable therapies that exists. Having one proton and one electron, hydrogen is the simplest element—if assessed only by these characteristics. Much like the halogens (substances like fluorine, iodine, and bromine), hydrogen naturally forms a bond with another hydrogen atom in order to fill its outer electron shell, resulting in a diatomic, neutral, stable molecule of hydrogen—which we write scientifically as H2.

The earliest therapeutic application of H2 gas dates back to the 1940s, when it was used for the prevention of decompression sickness in divers.[1,2] In 1975, hyperbaric H2 had a surge of interest when research showed that H2-treated mice experienced significant regression of squamous cell carcinoma.[3] However, such a therapy was not incredibly practical due to the flammability of H2 gas when present at more than 4% in air, and thus research did not progress substantially.

In 2007, landmark research was published in Nature Medicine, showing benefits with H2 in forms that were practical clinically: via inhalation at a concentration of less than 4%, and as a dissolved gas in a cellular nutrient solution.[4] In animals, the inhalation of H2 substantially decreased damage to the brain after ischemia/reperfusion injury, and in stressed cells, the dissolved H2 gas reduced the amount of hydroxyl radicals (OH) generated in both the cytoplasm and the nucleus. Additionally, H2 was shown to protect the DNA from oxidation and cellular lipid membranes from peroxidation, ultimately preventing cellular death in a dose-dependent fashion.

In this publication and others that followed soon after, it was shown that H2 actually is highly effective because it is a weak reducing agent rather than a strong reducing agent.[4,5] Thus, it reacts primarily with highly reactive and toxic oxidants (such as OH and peroxynitrite [ONOO-]), leaving weaker (and biologically necessary) oxidants like nitric oxide (NO) and hydrogen peroxide (H2O2) present. H2 additionally has been shown to modulate cellular signal transduction, protein activity, and genetic transcription by activating the nuclear factor erythroid 2-related factor (Nrf2)–antioxidant response element (ARE) pathway, [6] leading to a biological response that persists far longer than the time that H2 is present in the body.[7]

Ergo, the antioxidant principles and other effects of H2 have a broad effect on physiology. And, this translates to a diverse spectrum of potential benefits—so many, in fact, that in the last two decades, there have been over 1000 scientific studies [9] reflecting over 170 different human and animal disease conditions or models.[9]

Mechanism of Action

Because of its size,neutral charge, stability, and nonpolarity, H2 readily passes into all cellular compartments and biological tissues, rapidly appearing in the expired air from the lungs. [10] After consumption of H2-rich water, the H2 concentration of the breath and plasma has been shown to be dose dependent, peaking between five to 15 minutes, and returning to baseline roughly 45 to 90 minutes later, depending on the ingested dosage. However, its biological effects are not limited to the time it remains in circulation, evidenced by numerous scientific studies.[7,11,12]

The power of H2 as an antioxidant is somewhat more prominent in a highly stressed state.[13] Under normal, unstressed conditions, the body always experiences some aspects of oxidative stress, which enables our very existence: biologically necessary oxidants like NO and H2O2 trigger cellular signaling pathways, the immune response, and vasodilation.[14] However, when the body is put into a highly stressed state (which exists in most chronic diseases or during treatment for a condition like cancer), the threshold above which these and other oxidants can be beneficial is exceeded. It is above this threshold when many of the benefits of H2 may be best realized, as it reduces production of excessive amounts of these important oxidants.[15]

In addition to neutralizing OH and ONOO- radicals and reducing excessive NO and H2O2 production, H2 activates the Nrf2/ARE pathway, turning on the transcription of antioxidant elements, detoxification enzymes, and proteins required for glutathione synthesis and recycling.[5,16,17,18] These effects of H2 are eliminated in various Nrf2 knockout or pathway-blocking models.[19] In vitro, the impact of treatment with H2 on Nrf2-related antioxidant protection has been shown to extend up to eight hours after H2 is no longer detectible in the cellular medium.[12]

Numerous animal models utilizing lipopolysaccharide (LPS)-induced inflammation or ischemia/reperfusion injury have demonstrated mechanisms via which H2 may be protective.[20,21,22,23] Generally, treatment with H2 has been shown to reduce numerous cytokines and other inflammatory mediators that LPS or ischemia/reperfusion normally triggers, decreasing cellular damage and subsequent tissue or organ injury. Treatment with H2 has been shown to decrease levels of numerous proinflammatory cytokines, including interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor alpha (TNFα).[24,25] In ischemia/reperfusion injury, protective effects have been demonstrated in the liver,[26] kidneys,[27] heart,[28] brain,[29] lungs,[30] intestines,[31] and even the testes.[32] Positive findings from these and other studies have led to substantial research investigating the use of H2 to improve survival of tissue grafts and organ transplants.[33]

In addition to the antioxidant and anti-inflammatory effects, H2 acts as a signaling molecule and mediates activation of c-Jun N-terminal kinase (JNK),[34] a regulator of apoptosis and the cell response to stress;[35] nuclear factor-kappa B (NF-κB),[36] a regulator of genes that control the immune system response, inflammation, and processes that lead to cancer;[37] vascular endothelial growth factor (VEGF)–induced angiogenesis;[38] and numerous other signaling pathways;[39] each of which may contribute to effects seen with H2 treatment in a diverse array of pathologies.

Sources of Hydrogen for Therapeutic Application

In human studies, H2 has been administered as an inhaled gas,[40] dissolved in water for oral delivery or topical application,[41,42] and delivered in saline intravenously.[43] The amount of H2 delivered is quite variable, and depends in part upon the method via which it is produced. Various commercial ionizing machines are available that produce H2-rich water,[44] and at most, they are able to saturate the water with H2, providing 1.6 ppm or 1.6 mg/L. This compares to the H2 concentration of tap water, which is a mere 8.7 × 10-7 ppm.[45]

In many studies, H2 is produced by the reaction of a metallic magnesium stick or tablet with water: Mg + 2H2O → H2 (g) + Mg(OH)2.[46,47] The release of H2 can easily be seen by bubbles that form in the water. By using additional agents such as malic and tartaric acid to neutralize the magnesium hydroxide and catalyze the reaction rate, it is possible to supersaturate the water with H2, achieving a concentration of nearly 10 ppm.[48] The half-life of H2 in saturated water (often termed H2-rich water) is approximately two hours; however, in a supersaturated solution, H2 will leave the solution much more rapidly (similar to air leaving a highly pressured bike tire) until the saturation concentration is reached, and then dissipates at the typical rate (t1/2 = 2 hours) until equilibrium is achieved with the environment.

H2-rich wateris not pH-altered water (although it may have an altered pH due to other reasons) and carries no claims of containing microclustered or organized water molecules (a means by which ionization or other homeopathic and energetic applications are often asserted to alter the form of water).[49] Although the hydrogen ion (H+) is responsible for changing the pH of water, H2 is a neutral molecule that does not alter the pH of water. As alkaline ionized water (much different from water that is simply alkaline) is produced by the removal of H+ ions, it will not only be alkaline but also contains H2. Studies suggest the presence of H2 may be the reason beneficial effects have been seen with consumption of alkaline ionized water,[50,51] other than general benefits that increased water consumption delivers.

Safety

Because H2 is produced to some extent by the bacteria present in the digestive tract (although amounts are variable),[52] our bodies are routinely exposed to it. Numerous studies using considerably higher doses than H2-rich water provides have shown that H2 has a very high safety profile and is not cytotoxic, even at very high concentrations.[53,54,55] Because excess H2 is rapidly expired via respiration, overdosing is not possible. That said, based on the mechanisms and studies thus far, one should not anticipate that higher doses will result in an improved therapeutic response. In one isolated setting, hypoglycemic episodes were reported in an insulin-dependent patient with mitochondrial myopathy and were resolved by reducing the insulin dose.[56] Other than this, a side effect that can occur is loose stools or increased bowel movement frequency. Human studies with H2-rich water have not been performed in pediatric or pregnant populations; however, animal studies in these groups have shown protective effects against disease and toxin exposure,[57,58,59] including to the fetus in utero.[60,61] Safety concerns with flammability do not exist with H2-rich water because the amount of H2 in saturated or even supersaturated water is far below the flammability threshold.

The information contained herein is only a backdrop for future posts in which we will take a closer look at the clinical research that exists using H2 as a therapy. Stay tuned for upcoming posts in which we look at the research behind H2 in settings including autoimmune disease, cancer, neurodegenerative disease, metabolic syndrome, and for performance enhancement.


Dr. Carrie Decker, ND graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Dr. Decker sees patients remotely, with a focus on gastrointestinal disease, mood imbalances, eating disorders, autoimmune disease, and chronic fatigue. Prior to becoming a naturopathic physician, Dr. Decker was an engineer, and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectively.  Dr. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr. Decker supports Allergy Research Group as a member of their education and product development team.
  1. Bjurstedt H, Severin G. The Prevention of Decompression Sickness and Nitrogen Narcosis by the Use of Hydrogen as a Substitute for Nitrogen (The Arne ZetterstrÖm Method for Deep-Sea Diving). The Military Surgeon (United States). 1948 Aug 1;103(2):107-16.
  2. Dougherty JJ. Use of H2 as an inert gas during diving: pulmonary function during H2-O2 breathing at 7.06 ATA. Aviation, space, and environmental medicine. 1976 Jun;47(6):618-26.
  3. Dole M, et al. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. 1975 Oct 10;190(4210):152-4.
  4. Ohsawa I, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007 Jun;13(6):688-94.
  5. Matei N, et al. Emerging mechanisms and novel applications of hydrogen gas therapy. Med Gas Res. 2018 Sep 25;8(3):98-102.
  6. Yu J, et al. Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic cholangiocytes by activating Nrf2 expression. Toxicol Lett. 2015 Nov 4;238(3):11-9.
  7. Ishibashi T, et al. Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double-blind, placebo-controlled pilot study. Int Immunopharmacol. 2014 Aug;21(2):468-73.
  8. Qian L, et al. Medical Application of Hydrogen in Hematological Diseases. Oxid Med Cell Longev. 2019 Nov 28;2019:3917393.
  9. Ichihara M, et al. Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles. Med Gas Res. 2015 Oct 19;5:12.
  10. Qian L, et al. Methods of Hydrogen Application. In: Sun X, Ohta S, Nakao S, eds. Hydrogen Molecular Biology and Medicine. Dordrecht, Netherlands: Springer; 2015.
  11. Gu H, et al. Pretreatment with hydrogen-rich saline reduces the damage caused by glycerol-induced rhabdomyolysis and acute kidney injury in rats. J Surg Res. 2014 May 1;188(1):243-9.
  12. Hara F, et al. Molecular Hydrogen Alleviates Cellular Senescence in Endothelial Cells. Circ J. 2016 Aug 25;80(9):2037-46.
  13. Ohta S. Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications. Methods Enzymol. 2015;555:289-317.
  14. Mattson MP. Hormesis defined. Ageing Res Rev. 2008 Jan;7(1):1-7.
  15. Sakai T, et al. Hydrogen Indirectly Suppresses Increases in Hydrogen Peroxide in Cytoplasmic Hydroxyl Radical-Induced Cells and Suppresses Cellular Senescence. Int J Mol Sci. 2019 Jan 21;20(2).
  16. Buendia I, et al. Nrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol Ther. 2016 Jan;157:84-104.
  17. Diao M, et al. Hydrogen Gas Inhalation Attenuates Seawater Instillation-Induced Acute Lung Injury via the Nrf2 Pathway in Rabbits. Inflammation. 2016 Dec;39(6):2029-39.
  18. Kawamura T, et al. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol. 2013 May 15;304(10):L646-56.
  19. Xie K, et al. Nrf2 is critical in the protective role of hydrogen gas against murine polymicrobial sepsis. Brit J Anaesthesia. 2012;108(3):538-9.
  20. Itoh T, et al. Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages. Biochem Biophys Res Commun. 2011 Jul 22;411(1):143-9.
  21. Xie K, et al. Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis. Shock. 2012 May;37(5):548-55.
  22. Ren JD, et al. Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species. Biochim Biophys Acta. 2016 Jan;1863(1):50-5.
  23. Qiu X, et al. Hydrogen inhalation ameliorates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol. 2011 Dec;11(12):2130-7.
  24. Zheng X, et al. Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res. 2009 May;43(5):478-84.
  25. Liu Q, et al. Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver Int. 2010 Aug;30(7):958-68.
  26. Fukuda K, et al. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun. 2007 Sep 28;361(3):670-4.
  27. Wang F, et al. Hydrogen-rich saline protects against renal ischemia/reperfusion injury in rats. J Surg Res. 2011 May 15;167(2):e339-44.
  28. Zhang Y, et al. Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. Int J Cardiol. 2011 Apr 1;148(1):91-5.
  29. Cai J, et al. Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res. 2009 Feb 23;1256:129-37.
  30. Kawamura T, et al. Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats. Transplantation. 2010 Dec 27;90(12):1344-51.
  31. Eryilmaz S, et al. The effects of hydrogen-rich saline solution on intestinal anastomosis performed after intestinal ischemia reperfusion injury. J Pediatr Surg. 2019 Aug 13.
  32. Lee JW, et al. Inhaled hydrogen gas therapy for prevention of testicular ischemia/reperfusion injury in rats. J Pediatr Surg. 2012 Apr;47(4):736-42.
  33. Yuan L, Shen J. Hydrogen, a potential safeguard for graft-versus-host disease and graft ischemia-reperfusion injury? Clinics (Sao Paulo). 2016 Sep;71(9):544-9.
  34. Tao B, et al. Hydrogen-Rich Saline Attenuates Lipopolysaccharide-Induced Heart Dysfunction by Restoring Fatty Acid Oxidation in Rats by Mitigating C-Jun N-Terminal Kinase Activation. Shock. 2015 Dec;44(6):593-600.
  35. Chen YR, Tan TH. The c-Jun N-terminal kinase pathway and apoptotic signaling (review). Int J Oncol. 2000 Apr;16(4):651-62.
  36. Xin HG, et al. Consumption of hydrogen-rich water alleviates renal injury in spontaneous hypertensive rats. Mol Cell Biochem. 2014 Jul;392(1-2):117-24.
  37. Mitchell S, et al. Signaling via the NFκB system. Wiley Interdiscip Rev Syst Biol Med. 2016 May;8(3):227-41.
  38. Lee PC, et al. Concomitant inhibition of oxidative stress and angiogenesis by chronic hydrogen-rich saline and N-acetylcysteine treatments improves systemic, splanchnic and hepatic hemodynamics of cirrhotic rats. Hepatol Res. 2015 May;45(5):578-88.
  39. Liu GD, et al. Molecular hydrogen regulates the expression of miR-9, miR-21 and miR-199 in LPS-activated retinal microglia cells. Int J Ophthalmol. 2013 Jun 18;6(3):280-5.
  40. Ono H, et al. Hydrogen gas inhalation treatment in acute cerebral infarction: a randomized controlled clinical study on safety and neuroprotection. J Stroke Cerebrovasc Dis. 2017 Nov;26(11):2587-94.
  41. Zhu Q, et al. Positive effects of hydrogen-water bathing in patients of psoriasis and parapsoriasis en plaques. Sci Rep. 2018 May 23;8(1):8051.
  42. Kajiyama S, et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 2008 Mar;28(3):137-43.
  43. Ishibashi T, et al. Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double-blind, placebo-controlled pilot study. Int Immunopharmacol. 2014 Aug;21(2):468-73.
  44. Henry M, Chambron J. Physico-chemical, biological and therapeutic characteristics of electrolyzed reduced alkaline water (ERAW). Water. 2013 Dec;5(4):2094-115.
  45. Molecular Hydrogen Institute. Concentration and Solubility of H2 [Internet]. Molecular Hydrogen Institute [cited 2019 May 6]. Available from: http://www.molecularhydrogeninstitute.com/concentration-and-solubility-of-h2
  46. Kang KM, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res. 2011 Jun 7;1(1):11.
  47. Korovljev D, et al. Hydrogen-rich water reduces liver fat accumulation and improves liver enzyme profiles in patients with non-alcoholic fatty liver disease: a randomized controlled pilot trial. Clin Res Hepatol Gastroenterol. 2019 Apr 11.
  48. LeBaron TW, et al. Acute Supplementation with Molecular Hydrogen Benefits Submaximal Exercise Indices. Randomized, Double-Blinded, Placebo-Controlled Crossover Pilot Study. J Lifestyle Med. 2019 Jan;9(1):36-43.
  49. Hiraoka A, et al. Studies on the Physicochemical Properties and Existence of Water Products (as Drinks) Advertised as Having Smaller Cluster Sizes of H2O Molecules than Those of Regular Water. J Health Sci. 2010;56(6):717-20.
  50. Shirahata S, et al. Advanced research on the health benefit of reduced water. Trends Food Sci Tech. 2012 Feb 1;23(2):124-31.
  51. Ignacio RM, et al. Clinical effect and mechanism of alkaline reduced water. J Food Drug Analysis. 2012 Apr 1;20(Suppl 1):394-7.
  52. Eastwood MA, et al. The physiological effect of dietary fiber: an update. Annu Rev Nutr. 1992;12:19-35.
  53. Friess SL, et al. Toxicology of hydrogen-containing diving environments. I. Antagonism of acute CO2 effects in the rat by elevated partial pressures of H2 gas. Toxicol Appl Pharmacol. 1978 Dec;46(3):717-25.
  54. Nagatani K, et al. Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies. Med Gas Res. 2013 Jun 25;3:13.
  55. Abraini JH, et al. Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture. J Appl Physiol. 1985;76:1113-8.
  56. Ito M, et al. Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Med Gas Res. 2011 Oct 3;1(1):24.
  57. Yang X, et al. Protective effects of hydrogen-rich saline in preeclampsia rat model. Placenta. 2011 Sep;32(9):681-6.
  58. Muramatsu Y, et al. Hydrogen-rich water ameliorates bronchopulmonary dysplasia (BPD) in newborn rats. Pediatr Pulmonol. 2016 Sep;51(9):928-35.
  59. Zheng W, et al. Hydrogen-Rich Water and Lactulose Protect Against Growth Suppression and Oxidative Stress in Female Piglets Fed Fusarium Toxins Contaminated Diets. Toxins (Basel). 2018 Jun 4;10(6).
  60. Hattori Y, et al. Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury. Free Radic Res. 2015;49(8):1026-37.
  61. Nakano T, et al. Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury. J Clin Biochem Nutr. 2015 Nov;57(3):178-82.