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Hydrogen: An Intriguing Agent to Address Autoimmunity

hydrogen for autoimmunity

With its well-documented action as an antioxidant and anti-inflammatory, it is not surprising that hydrogen (H2) has been studied as treatment for autoimmunity and related diseases. The power of H2 as an antioxidant is somewhat more prominent in a highly stressed state,[1,2] which commonly exists in diseases of autoimmunity.[3] In addition to reducing the highly damaging hydroxyl radical (OH) and peroxynitrite (ONOO-),[4] numerous studies have shown that H2 reduces overproduction of oxidants like nitric oxide (NO) and hydrogen peroxide (H2O2).[5] H2 also decreases levels of proinflammatory cytokines generated in response to stressors such as lipopolysaccharide stimulation or ischemia/reperfusion injury, including interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNFα).[6-9] As each of these signaling molecules plays a role in the cycle of immune activation, inflammation, and oxidative stress, breaking the cycle with a therapy such as H2 that addresses each of these imbalances may greatly improve the symptoms and severity of autoimmune disease.

The first publication investigating the impact of H2 on autoimmune disease was an open-label pilot study in patients with rheumatoid arthritis (RA).[10] As levels of the OH radical have been shown in RA to be associated with a higher level of disease activity and the damage that is seen,[11] it is highly plausible that H2, an excellent OH scavenger, would be of benefit.

Of the 20 patients in this pilot study, five of them had early RA (duration of less than 12 months), and four of these individuals were not on any medication. The other participants were either on methotrexate or abatacept, a combination of these, or no medication, often abandoned due to side effects. Participants were instructed to consume 530 mL of H2-rich water (containing 4 to 5 ppm of H2) daily for four weeks, followed by a four-week washout, and then another four weeks of H2 water consumption.

hydrogen for autoimmunity

During each period of treatment with the H2-rich water, RA disease activity scores, based on assessment of 28 joints (DAS28), improved. In the first four weeks, scores decreased in 18 of the 20 patients. By the end of the study, the average DAS28 score for participants had decreased from the baseline of 3.83 to 2.26, and the five patients having early RA all achieved remission (defined for the purpose of this study as a DAS28 < 2.3, although a cutoff value of 2.6 is often used[12]), with four of them becoming symptom-free.

One particularly interesting finding in this study was that the DAS28 score continued to improve during the four-week washout period, suggesting that the H2 treatment continued to have residual effects. Urinary 8-hydroxy-deoxyguanosine (8-OHdG) levels, a marker of DNA oxidative damage,[13] also improved not only during treatment but during the washout phase as well, remaining below the baseline through the end of the study. It has been suggested that longer-term effects such as these are due to the impact of H2 on cellular signal transduction, protein activity, and genetic transcription, as its direct antioxidant effects would be limited to its time in circulation.[14]

Prolonged benefits with hydrogen treatment were also seen in a follow-on randomized, double-blind, placebo-controlled study in RA patients that were treated for five days with 500 mL of intravenous, H2-enhanced saline.[15] In this study, the DAS28 score in the H2-treated group decreased from the baseline of 5.18 to 4.02 immediately after the five days of infusions and to 3.74 by four weeks while there was no change in the score of the placebo group. Additionally, the level of IL-6 and matrix metalloproteinase-3, markers of inflammation and joint damage,[16] decreased significantly in the H2-treated group while they increased in the placebo group.

Impressive results also have been seen in individuals with treatment-resistant psoriasis.[17] Higher levels of oxidative stress and a lower antioxidant status have also been shown to exist in this population,[18] which suggests H2 may be of benefit. Of the 41 patients in the treatment group, 21 were resistant to topical corticosteroid and calcipotriol ointments, 10 were resistant to UVB phototherapy, seven were resistant to systemic retinoids, and three were resistant to methotrexate.

Participants were instructed to bathe in H2 water (prepared using nanobubble technology to dissolve hydrogen gas at a level of 1 ppm in the water) or the placebo bath for 10 to 15 minutes every three days for eight weeks. At the completion of the study, an improvement of 75% or more in the Psoriasis Area Severity Index score was seen in 10 of 41 of patients, while only one of 34 patients in the control group had the same level of improvement. Substantial improvements in pruritis, as assessed by the visual analog scale scores, were also seen in the H2 treated patients. Additionally, six of the patients were able to either reduce or discontinue their medication use. Images accompanying this publication further attest to these remarkable results.

Although a whole-body bath may not be practical for most, soaking a portion of the body that is affected with psoriasis lesions in H2-rich water is not tremendously difficult and worthy of consideration. A publication of three psoriasis case studies using a variety of different H2 administration techniques (inhalation, intravenous, and taken orally in water) also reported improvements in skin lesions and arthritis symptoms regardless of the route of intervention.[19]

The positive outcomes of these studies, as well as animal models of multiple sclerosis,[20,21] clearly show that H2 has great potential in the setting of autoimmune disease. The improvements or sustained benefits seen post-intervention for a prolonged period also are particularly exciting, as this would minimize cost and the burden of taking a daily supplement. Without a doubt, many exciting applications for H2 as a therapy will be seen in years to come.

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. Ohta S. Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications. Methods Enzymol. 2015;555:289-317.
  2. Nagata K, et al. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology. 2009 Jan;34(2):501-8.
  3. Khojah HM, et al. Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants. Free Radic Biol Med. 2016 Aug;97:285-291.
  4. Matei N, et al. Emerging mechanisms and novel applications of hydrogen gas therapy. Med Gas Res. 2018 Sep 25;8(3):98-102.
  5. 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).
  6. 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.
  7. 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.
  8. 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.
  9. Zheng X, et al. Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res. 2009 May;43(5):478-84.
  10. Ishibashi T, et al. Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Med Gas Res. 2012 Oct 2;2(1):27.
  11. Khojah HM, et al. Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants. Free Radic Biol Med. 2016 Aug;97:285-291.
  12. Mäkinen H, et al. Definitions of remission for rheumatoid arthritis and review of selected clinical cohorts and randomised clinical trials for the rate of remission. Clin Exp Rheumatol. 2006 Nov-Dec;24(6 Suppl 43):S-22-8.
  13. Wu LL, et al. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta. 2004 Jan;339(1-2):1-9.
  14. 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.
  15. 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.
  16. Yamanaka H, et al. Serum matrix metalloproteinase 3 as a predictor of the degree of joint destruction during the six months after measurement, in patients with early rheumatoid arthritis. Arthritis Rheum. 2000 Apr;43(4):852-8.
  17. 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.
  18. Kadam DP, et al. Role of oxidative stress in various stages of psoriasis. Indian J Clin Biochem. 2010 Oct;25(4):388-92.
  19. Ishibashi T, et al. Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Mol Med Rep. 2015 Aug;12(2):2757-64.
  20. Zhao M, et al. Hydrogen-rich water improves neurological functional recovery in experimental autoimmune encephalomyelitis mice. J Neuroimmunol. 2016 May 15;294:6-13.
  21. Liu Y, et al. Hydrogen-Rich Saline Ameliorates Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice Via the Nrf2-ARE Signaling Pathway. Inflammation. 2019 Apr;42(2):586-597.


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