When was hydrogens therapeutic benefits first discovered ?

The earliest account of hydrogen gas having medicinal properties was in 1798, for things like inflammation. But, it didn’t become a popular topic among scientists until 2007, when an article about the benefits of hydrogen was published in the prestigious journal of Nature Medicine by Dr. Ohta’s group.

What are some of the key benefits to molecular hydrogen?

Hydrogen has now been demonstrated to have therapeutic effects in over 170 different human and animal disease models, and in essentially every organ of the human body. The main reason for this is because H2 helps attenuate excessive oxidative stress and inflammation, both of which are at the root of virtually every disease and pathology

SCIENTIFIC RECOGNITION OF HYDROGEN

How does hydrogen gas provide antioxidant, anti-inflammatory, and anti-aging effects?

Molecular hydrogen was 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 demonstrated that hydrogen gas administered via inhalation or drinking hydrogen water can attenuate markers of oxidative stress and improve antioxidant status. For example, in a small open label study of 20 patients with potential metabolic syndrome, subjects ingested 1.5-2 L of hydrogen water (≈0.6 mM) per day for 8 weeks [7].On average, besides improving cholesterol and glucose tolerance, the patients had a 43% decrease in the oxidative marker TBARS (thiobarbituric acid reactive substances) in the urine, and a 39% increase in the antioxidant enzyme superoxide dismutase. Similar benefits were also demonstrated in 16 healthy subjects in a randomized, double-blinded placebo controlled study. Drinking hydrogen water for 4 weeks decreased the oxidative marker malondialdehyde (MDA) by ≈26 %, p<0.001, increased superoxide dismutase, and the master antioxidant glutathione levels by 25.9% (p=0.003), and 10.1% (p=0.007), respectively.Besides demonstrating similar antioxidant effects, other animal and clinical studies also report decreased inflammation. For example, H2 can decrease and modify pro-inflammatory mediators/transcription factors (e.g. cytokines, C-reactive protein, TNF-a, NF-κB, NFAT, etc.).The exact mechanism(s) by which H2 attenuates oxidative stress are still under investigation. However, it has been demonstrated using miRNA interference, gene knockout studies, etc., that hydrogen can activate the Nrf2 pathway, which regulates the transcription of over 200 cytoprotective genes [13]. The activation of the Nrf2 pathway regulates phase ii enzymes involving detoxification (e.g., ABCG2, MRP3, MRP4, GST), antioxidation (e.g., NQO1, NQO2, HO-1), antiapoptotic (e.g., Bcl-2), and metabolic (e.g., G6PD, TKT, PPARγ) pathways. This may help explain why H2 can also exerts anti-diabetic and anti-obesity effects.

NEUROLOGICAL AND OTHER HEALTH BENEFITS

DR. SHIGEO OHTA, PHD

Some exciting neurological research on hydrogen is also showing promise. The Japanese government has approved H2 inhalation as an advanced medicine for the treatment of postcardiac arrest syndrome, which will also have neurological benefits. A small randomized controlled clinical study of 50 patients with cerebral infarction compared inhalation of hydrogen to the approved medical drug, edaravone. According to the MRI, and NIHSS scores for clinically quantifying stroke severity, these preliminary results suggest that hydrogen therapy was more effective than the approved medical drug. Simply drinking hydrogen water also appears to have good effects in ≈1-year randomized-placebo controlled trials of Parkinson’s, and mild cognitive impairments (n= 73) (particularly those of APOE4 genotype). A small double-blinded, placebo-controlled, cross over study also reported neurological benefits in healthy subjects. Drinking hydrogen water (600 mL/day) for 4 weeks resulted in decreased sympathetic nerve activation at rest, and improved mood and anxiety. This correlated well to an early animal study we performed where hydrogen therapy was effective at increasing resilience to acute and chronic stress by regulating the hypothalamic-pituitary-adrenal axis and the inflammatory responses to stress . We subsequently provided evidence in a study published in Frontier’s Journal of Behavioral Neuroscience, that oral ingestion of hydrogen water can reverse the autistic-like behaviors (e.g. impaired social behavior, memory impairment, inflammation TNF-α and IL-6, etc.) induced by maternal exposure to the toxin VPA in mice. However, the research on hydrogen is still in its infancy, and H2 therapy is not a panacea for every condition. For example, although many studies have found that hydrogen is beneficial to the brain in models of ischemia reperfusion, one study found that H2 inhalation was ineffective in a moderate to severe model of neonatal ischemia-reperfusion injury in rats.  Nevertheless, the preliminary data from animal and clinical studies continue to suggest that hydrogen may have significant implications in current medicine because it is safe, easy to administer, and has immediate clinical applications.

Although the primary targets or exact biochemical mechanisms of hydrogen are still not fully understood, the therapeutic effect in cells, tissues, animals, humans and even plants is becoming widely accepted due to the now over 500 peer-reviewed articles and the 1,600 researchers on the medical effects of hydrogen.

HYDROGEN AND IMMEDIATE MEDICAL APPLICATIONS

Hydrogen as a medical gas is also growing because it has immediate medical applications to help with many of the current health crises . Dixon and colleagues of Loma-Linda University reported that hydrogen has potential to help with the top 8/10 disease-causing fatalities as listed by the Centers of Disease Control . Dr. Banks, from the VA/U of Washington, reported that ingestion of hydrogen-rich water was protective against neurodegenerative changes induced by traumatic brain injury in mice. Their results show that hydrogen administration reduced brain edema, blocked pathological tau expression, and maintained ATP levels. This and other studies have profound effects for events where brain injury (e.g. concussion, chronic traumatic encephalopathy, etc.) is a common occurrence. Although many people report dramatic effects of hydrogen therapy, from rapid pain and inflammation relief to normalization of glucose and cholesterol levels, other people may not notice any immediate or observable benefits. Hydrogen is not considered a powerful drug, and as mentioned only helps bring the cell/organ back to homeostasis without causing major perturbations. Perhaps some of the reported dramatic effects can be attributed to the placebo effect or other things, although some researchers have noted that some people are more sensitive to hydrogen and experience greater effects.

HUMAN RESEARCH

.Although the research on hydrogen looks promising in the cell or animal models, more long-term clinical trials are required to confirm its efficacy in humans [70]. There are only a total of 40 human studies; few are in a double-blinded placebo controlled randomized fashion with sufficient subject numbers. A few of these clinical studies suggest that ingestion of hydrogen-rich water was beneficial for metabolic syndrome [71], diabetes [72], and hyperlipidemia [73, 74]. Another 1-year placebo-control clinical study suggested that hydrogen-rich water is beneficial for Parkinson’s disease [75], while other clinical studies suggest significant benefits for rheumatoid arthritis [24, 76], mitochondrial dysfunction [77], exercise performance [78], athletic recovery time [79], wound healing [80-82], reductions of oxidative stress from chronic hepatitis B [83], improvements to blood flow [84], and periodontitis [85], in dialysis [86, 87], and also the quality of life in patients receiving radiotherapy for tumors [88] and others [5].There have been an additional 15+ human studies completed with promising results, which are in the process of manuscript preparation and publication through the peer-reviewed process. More human studies are required to determine proper dosage, timing, method of administration, and for which diseases, and potentially genotypes, hydrogen is most effective [7]. Hydrogen is still in its infancy, and more data is required before we can scientifically claim any real benefit, but the preliminary data is intriguing. The research on disease models, mechanisms of action, and clinical studies are particularly relevant because the high safety profile of molecular hydrogen make it a superior choice [89].

SAFETY

Hydrogen is naturally produced by intestinal flora upon digestion of fibers [90]. A study from the University of Florida and the Forsythe Institute of Boston, Massachusetts confirmed that hydrogen produced from bacteria exerted therapeutic effects [91]. They found that reconstitution of intestinal microbiota with H2-producing E. coli, but not H2-deficient mutant E. coli, was protective against Concanvalin A-induced hepatitis. Other studies also show that bacterially produced hydrogen from acarbose administration is therapeutic [92]. Perhaps this helps explain why a large clinical trial from the Journal of American Medical Association (JAMA) found significant reductions in cardiovascular events by those taking the hydrogen-producing acarbose drug [92, 93]. These studies not only suggest the therapeutic action of molecular hydrogen, but also demonstrate its high safety profile. Hydrogen is very natural to our bodies, as we are exposed to it on a daily basis as a result of normal bacterial metabolism [1]. Additionally, hydrogen gas has also been used in deep sea diving since the 1940s to prevent decompression sickness [94, 95]. Hundreds of human studies for deep sea diving have shown inhalation of hydrogen gas, at orders of magnitude greater than what is needed for therapeutic use, is well-tolerated by the body with no chronic toxic effects [96]. In some people, however, it is reported that hydrogen may result in loose stools [97], and in rare cases with diabetics, hypoglycemia [77], which is controlled by reducing the level of insulin administered. The hundreds of studies on hydrogen from bacterial production, deep sea diving, and recent medical applications have not revealed any direct noxious side effects of hydrogen administration at biologically therapeutic levels. Such a high safety profile may be considered paradoxical because chemotherapeutic agents that exert biological effects should have both beneficial and noxious effects depending on dosage, timing, location, duration, etc. However, such noxious effects have yet to be reported for hydrogen. However, perhaps the noxious effects are so transient and mild that they are masked by the beneficial effects, or are even what mediate the beneficial effects via hormetic pathways.