Here is a translation of an article from the website of the INSTITUTE OF MOLECULAR HYDROGEN. It presents data on the therapeutic effects of hydrogen gas on human health, based on the large number of clinical studies on patients over the last 10 years. At the end we have put a link to the original article on the Institute's website. The bracketed figures you will encounter as you read indicate the official papers/reports in which the benefits of molecular hydrogen have been demonstrated. You will find a list of these papers/reports at the end of the original text.
Hydrogen - the fuel of alternative medicine.
(Also published on the Foundation for Alternative and Integrative Medicine website, September 2018.)
Hydrogen gas (H2) has been lauded for its use as "green energy," as an alternative fuel, but biomedical research over the past decade has shown that it also has therapeutic biological benefits. The 1000+ pre-clinical and clinical studies done report that hydrogen has antioxidant, anti-inflammatory, anti-allergic, anti-obesity and anti-aging effects [1, 2]. This is rather surprising from a biochemistry point of view, since hydrogen gas, a natural fermentation derived product from the gut microbiota, was previously considered "biologically inert" .
What exactly is molecular hydrogen (H2)?
Molecular hydrogen is simply two hydrogen atoms bonded together forming hydrogen gas. It has the chemical structure H-H with the simple chemical formula "H2". Although in nature hydrogen atoms are often found bonded to other atoms, such as oxygen to form water (H2O) or carbon to form methane (CH4), for therapeutic purposes hydrogen gas (H2) is specifically used by the molecule. Furthermore, to avoid confusion, it is also important to distinguish between pH and H2; they are completely different. The term pH refers to the concentration of positively charged hydrogen ions (H+) in solution, which is completely different from H2 gas. In fact, molecular hydrogen has no effect on pH and is irrelevant to alkaline water. Furthermore, when H2 gas dissolves in water, it does not change the water chemistry/properties (e.g. it does not form H4O), it is just H2 gas dissolving in water.
How is molecular hydrogen taken up?
In clinical studies, we typically administer molecular hydrogen by inhalation, ingestion of water that contains the dissolved H2 gas (i.e., hydrogen water), bath with hydrogen water for skin inflammations, intravenous administration of hydrogen saline, and even hyperbaric hydrogen chambers .
What are the main benefits of molecular hydrogen?
Hydrogen has been shown to have therapeutic effects in over 170 different disease models in humans and animals, and in every organ of the human body . The main reason for this is that H2 assists in reducing excessive oxidative stress and inflammation, which are at the root of virtually every disease and pathology [1, 2].
How does hydrogen gas provide antioxidant, anti-inflammatory, and anti-aging effects?
The benefits of molecular hydrogen (H2) were first reported in Nature Medicine  to protect the brain during ischemia/reperfusion injury and to selectively reduce cytotoxic oxygen radicals . Many animal and clinical studies have subsequently shown that hydrogen gas administered by inhaling or drinking hydrogen water reduces markers of oxidative stress and improves antioxidant status. For example, in a small open-label study of 20 patients with potential metabolic syndrome, subjects drank 1.5-2 liters of hydrogen water (≈0.6 mM) per day for 8 weeks . In addition to improved cholesterol and glucose tolerance, patients had a 43% reduction in the oxidative marker TBARS (thiobarbituric acid reactive substances) in urine and a 39% increase in the antioxidant enzyme superoxide dismutase . Similar benefits were also demonstrated in 16 healthy subjects in a randomized, double-blind placebo-controlled trial . Drinking hydrogen water for 4 weeks reduced the oxidative marker malondialdehyde (MDA) by ≈26%, p < 0.001, increased superoxide dismutase and levels of the major antioxidant glutathione by 25.9% (p = 0.003) and 10.1% (p = 0.007), respectively .
In addition to the antioxidant effects, other clinical studies have also reported reduced inflammation . For example, H2 reduces and modifies proinflammatory mediators/transcription factors (e.g., cytokines, C-reactive protein, TNF-a, NF-kB, NFAT, etc.)  [1, 2, 5, 9, 11 ].
The exact mechanism by which H2 reduces oxidative stress is still under investigation. But using miRNA interference, genetic knockout studies, it has been shown that hydrogen can activate the Nrf2 pathway [5, 12], which regulates the transcription of over 200 cytoprotective genes . Nrf2 pathway activation regulates enzymatic phases including detoxification, antioxidation, antiapoptotic, and metabolic pathways . This explains why Nrf2 also exerts antidiabetic and anti-obesity effects [15, 16].
Benefits of autophagy
Animal and cell studies have shown beneficial effects of molecular hydrogen on gene expression and signal transduction. The benefits of autophagy and mitophagy (self-cannibalization mechanisms to remove damaged/dysfunctional cells and mitochondria) have also been investigated. Hydrogen therapy in rodents activates autophagic pathways, increased autophagosomes, autolysosomes [17, 18] and mitophagy mediated by PINK1/Parkin signaling pathway .
Neurological and other health benefits
Exciting studies have been done on the action of hydrogen in neurological disease, which are very promising. The Japanese government has approved H2 inhalation as an advanced drug for the treatment of post-cardiac infarction syndrome to produce neurological benefits . A small randomized controlled clinical trial of 50 cerebral infarction patients  compared hydrogen inhalation with the approved medical drug "edaravone". According to MRI and NIHSS results for clinical determination of stroke severity, these results indicated that hydrogen therapy was more effective than the approved medical drug . Drinking hydrogen water also had good effects in ≈1-year randomized placebo-controlled trials of Parkinson's  and mild cognitive impairment (n = 73) (especially those of the APOE4 genotype) . A small double-blind placebo-controlled study also reported neurological benefits in healthy subjects. Drinking hydrogen water (600 mL/day) for 4 weeks resulted in reduced sympathetic nerve activation, improved mood, and decreased feelings of anxiety . This is directly related to an early animal study we did where hydrogen therapy was effective in increasing resistance to acute and chronic stress by regulating the hypothalamic-pituitary-adrenal axis and inflammatory responses to stress . We subsequently provided evidence in a study published in Frontier's Journal of Behavioral Neuroscience that oral hydrogen ingestion can reverse autistic behaviors (e.g., impaired social behavior, memory impairment, TNF-α and IL-6 inflammation, etc.).
However, hydrogen research is still in its infancy and H2 therapy is not a panacea for every condition. However, data from animal and human clinical studies continue to show that hydrogen has significant applications in modern medicine because it is safe, easy to administer, and has immediate clinical results [1, 2].
How can physicians and patients access molecular hydrogen?
There are a growing number of hydrogen products that are widely available on the market. These include hydrogen inhalation devices, ready-to-drink hydrogen beverages, hydrogen water devices, hydrogen production tablets, etc. If consumers wish to take H2, we advise them to check whether the products actually contain/produce hydrogen gas and have consistent effective performance, as many products do not reach the H2 saturation levels we use in our research, or do not meet the description made by the companies offering them.
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