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  • H2 Therapeutics


Molecular hydrogen (H2) has demonstrated therapeutic properties across numerous models. To date, the mechanism underlying the beneficial responses to H2 exposure remains elusive. The initial hypothesis that molecular hydrogen acts as a direct, selective antioxidant in vivo does not reconcile models where H2 has shown to increase oxidative stress, nor does it explain numerous other physiological changes that have been observed throughout the literature. Some researchers have proposed that H2 acts as a hormetic stress. This hypothesis does not reconcile H2 being non-toxic in nature, even at high doses. Hormetic stressors have contributed to evolutionary adaptations, with the absence of these stressors causing cellular dysfunction. H2 has played an intimate role in the evolution of our planets atmosphere, the evolution of mitochondria and of life on the planet. Endogenously produced H2 volumes vary dramatically between individuals and are expected to have varied through human evolution. Our cells have evolved to tolerate erratic and intermittent exposure to H2. Intermittent exogenous H2exposure yields results similar to various hormetic stressors. Continued research elucidating how H2 acts as an adaptive stressor, both through endogenous levels and exogenous supplementation, are highly warranted.
ISSN: 2320-5407 Int. J. Adv. Res. 8(11), 216-219
Journal Homepage:
Article DOI:10.21474/IJAR01/11998
Alex T. Tarnava1,2
1. Drink HRW.
2. Natural Wellness Now Health Products Inc Unit C 60 Braid St, New Westminster, BC, Canada.
Manuscript Info Abstract
……………………. ………………………………………………………………
Manuscript History
Received: 01 September 2020
Final Accepted: 05 October 2020
Published: Novem ber 2020
Key words:-
Molecular Hydrogen, Hormesis,
Mitochondria, Gaseous Signaling
Molecular hydrogen (H2) has demonstrated therapeutic properties
across numerous models. To date, the mechanism underlying the
beneficial responses to H2 exposure remains elusive. The initial
hypothesis that molecular hydrogen acts as a direct, selective
antioxidant in vivo does not reconcile models where H2 has shown to
increase oxidative stress, nor does it explain numerous other
physiological changes that have been observed throughout the
literature. Some researchers have proposed that H2 acts as a hormetic
stress. This hypothesis does not reconcile H2 being non-toxic in nature,
even at high doses. Hormetic stressors have contributed to evolutionary
adaptations, with the absence of these stressors causing cellular
dysfunction. H2 has played an intimate role in the evolution of our
planet’s atmosphere, the evolution of mitochondria and of life on the
planet. Endogenously produced H2 volumes vary dramatically between
individuals and are expected to have varied through human evolution.
Our cells have evolved to tolerate erratic and intermittent exposure to
H2. Intermittent exogenous H2 exposure yields results similar to various
hormetic stressors. Continued research elucidating how H2 acts as an
adaptive stressor, both through endogenous levels and exogenous
supplementation, are highly warranted.
Copy Right, IJAR, 2020,. All rights reserved.
The seminal article published in Nature Medicine in 2007 demonstrated potential therapeutic benefits of molecular
hydrogen (H2), attributing the results to direct scavenging of the hydroxyl radical (Ohsawa et al., 2007). This
attribution of mechanism of action does not resolve results demonstrating increases in oxidative stress (Hirayama et
al., 2019) or fully elucidate the significant observations in gene expression alteration (Nishiwaki et al, 2018). As
published results have broadened in therapeutic outcomes, researchers have been unable to determine the underlying
mechanisms, as it has long been believed that H2 is a physiologically inert, non-functional gas within our body
(Ohta, 2014). As research has progressed and empirical evidence has amassed, totalling an estimated 1500 unique
publications demonstrating its beneficial effects, with close to 100 of them having been conducted in humans, the
mechanisms by which H2 exerts its beneficial effects in the body continue to elude the research community
(Kawamura et al., 2020). Some researchers have hypothesized that when ingested H2 acts as a hormetic stress
(Murakami et al., 2017; Hirayama et al., 2019; LeBaron et al., 2019), but this hypothesis has not yet been reconciled
with what is known regarding the safety profile of H2, due to it being non-toxic in nature (LeBaron et al., 2019b).
Corresponding Author:- Alex T. Tarnava
Address:- Drink HRW.
ISSN: 2320-5407 Int. J. Adv. Res. 8(11), 216-219
Hormesis is typically defined as any intervention or process which exposes an organism to toxicity, producing a
biphasic response. Typically, exposure to low levels of a hormetic stressor yields a beneficial response, whereas
exposure to high levels produces a deleterious response. Conversely, exposure to H2 has typically demonstrated a
more beneficial response at higher doses. It is commonly accepted that correctly dosed hormetic stressors lead to
positive adaptations of the organism (Mattson, 2008). It has also been suggested that adaptive responses to hormetic
stressors have played a fundamental role in evolution (Mattson, 2009). In fact, the most commonly accepted forms
of hormesis to the human body, such as exercise (Radak et al., 2005), cold exposure (Le Bourg, 2007), heat
exposure (Rattan, 2005), fasting (Horne et al., 2015), caloric restriction (Masoro, 2007), radiation (Vaiserman, 2008)
and even ethanol (Parsons, 2001), all have been present throughout and can be explained by evolution, with the
likelihood that humans were exposed to variable levels of these stressors, often at high levels and in an erratic
manner, throughout the evolution of our species.
The role of H2 exposure as a beneficial form of hormesis can be reconciled when considering a different perspective
on how and why hormetic stressors positively impact cellular signalling (Calabrese, 2013). Since hormetic stressors
play both an adaptive role in our current physiology and have played a fundamental role in driving evolutionary
change, logic follows that we have evolved to anticipate and require adequate levels of stressors for our cellular
communication to operate harmoniously. This is corroborated by the known deleterious effects of the lack of
exercise-induced hormesis, defined as a sedentary lifestyle (Buford et al., 2010).
It is known that H2 has played an integral role in our evolution, with the “hydrogen hypothesis” being put forth to
explain the eukaryote origins of our mitochondria (Martin and Müller, 1998), which suggests that the first eukaryote
emerged from a symbiotic association between a hydrogen-dependent archaebacterium (the host) and eubacterium
(the symbiont) that was able to respire, but generated H2 as a waste product of anaerobic heterotrophic metabolism.
It is now commonly accepted that mitochondria and hydrogenosomes, which expel H2 as a waste product, share a
common evolutionary origin (Martin and Mentel, 2010). Moreover, it has been reported that the oldest water ever
discovered on our planet had measurable and significant levels of dissolved H2 gas (Lollar et al, 2014). Further, it is
recognized that H2 has played a pivotal role in our planet and atmosphere, with H2 escape leading to oxygenation
(Zahnle et al., 2018). It has also been known since the 1950s how critical H2 in the Earth’s atmosphere was for
promoting early life (Urey, 1952).
The human body produces up to 12L of hydrogen gas per day via bacterial breakdown of carbohydrates in the small
intestine (Ohno et al., 2012). It has recently been proposed that exercise-driven gut-microbial production of H2 gas is
a possible factor of metabolic health, (Ostojic, 2020) while inadequate endogenous H2 production may play a role in
development of Parkinson’s disease (Ostojic, 2018); moreover, it has been suggested that endogenously produced
H2 may serve in regulation of liver homeostasis (Zhang et al., 2020). In turn, exogenous supplementation with
hydrogen-rich water has been demonstrated to produce significant improvements in metabolic health (LeBaron et
al., 2020), protective effects against non-alcoholic fatty liver disease (Korovljev et al., 2019) and improvements in
symptoms of Parkinson’s disease (Yoritaka et al., 2013) in human pilot research. Furthermore, it is possible that
endogenous production of H2 varies widely across individuals, depending on factors such as diet, and has varied
widely throughout our species evolution and history. Due to the intermittent and erratic access to carbohydrates prior
to the Neolithic revolution, it is likely that endogenous hydrogen production throughout most of our evolution was
also intermittent, with high doses followed by periods of deprivation and absence. This could shed an evolutionary
explanation on why consumption of hydrogen water, and intermittent hydrogen inhalation, were shown to be
effective in a rodent model of Parkinson’s Disease, but continuous H2 gas inhalation and additional endogenous
production via lactulose were not (Ito et al., 2012).
If humans have evolved and adapted to anticipate intermittent exposure to hydrogen gas, leading to spikes and drops
in cellular concentrations, optimal cellular communication may depend on this erratic change. As specific,
intermittent, and constantly changing dietary protocols would likely come with low compliance, exogenous H2
supplementation may be the answer to address these potential evolutionary adaptations. Determining the extent of
the importance of H2, both endogenous and exogenous, on our physiology, particularly regarding stress adaptation,
warrants well constructed exploratory research.
Competing Interests:
The author is employed by, and has financial interest in, commercial entities involved in the development and
distribution of molecular hydrogen products intended for therapeutic benefits.
ISSN: 2320-5407 Int. J. Adv. Res. 8(11), 216-219
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... Molecular hydrogen therapy has emerged as a potential treatment option for numerous acute and chronic ailments due to its seeming ability to ameliorate the deleterious consequences of excess oxidative stress and inflammation [8,9]. Although the exact molecular mechanisms have yet to be elucidated, it has been proposed that molecular hydrogen may act in a similar fashion to hormetic stress [10], with its efficacy a potential result of evolutionary adaptation, as molecular hydrogen has played an integral role in our species, in fact all life, and our planet's, history [11]. Of note, other hormetic stressors such as cold exposure and heat exposure have been proposed, and are widely used, in treatment of MSK-Is and STIs [12]. ...
... Conversely, chronic cold exposure is associated with a higher rate of musculoskeletal disorders [13]. Molecular hydrogen therapy is believed to have a much higher safety profile than other known hormetic stressors, with no biphasic response determined to date, as higher dosages tend to produce more significant results [11]. As such, exploration of various protocols regarding dosing and duration of exposure is warranted. ...
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Background: Traditional treatments of soft tissue injuries (STIs) and some musculoskeletal injuries (MSK-Is) involves therapies such as the RICE protocol, which consists of rest, ice, compression and elevation for several days following acute trauma. Designed to improve comfort and reduce pain following traumatic injury, questions exist on the efficacy of RICE protocol; if it may in fact delay the rate of healing; and if it has any beneficial effect at all. Recently, a growing body of evidence has suggested molecular hydrogen therapy (H2) as a potential adjuvant, or first line treatment, for numerous MSK-Is, STIs, and afflictions affecting the skin, both through topical administration and oral consumption. Case report: The recovery of a middle-aged male who suffered an injury to the proximal phalanges of the 5th toe of the right foot while kickboxing. The participant received four 25-minute hydrogen-rich hydrotherapy sessions in a super saturated solution with an average concentration approaching 8mg/L, on days 1,3,5,7 following injury. Recovery noted a rapid reduction in pain and swelling, a dramatic improvement in range of motion and ability to bear weight, and an ability to conduct limited activities after first treatment, including walking and modified exercise (i.e., boxing). Conclusion: This case is yet another indication that high concentration hydrogen-rich hydrotherapy may be a helpful first line treatment in terms of reduction of pain and improvement in function following injury, in addition to the evidence suggesting benefit in reducing chronic indications caused by acute or chronic stress.
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Basic and clinical studies have shown that hydrogen (H2), the lightest gas in the air, has significant biological effects of anti-oxidation, anti-inflammation, and anti-apoptosis. The mammalian cells have no abilities to produce H2 due to lack of the expression of hydrogenase. The endogenous H2 in human body is mainly produced by anaerobic bacteria, such as Firmicutes and Bacteroides, in gut and other organs through the reversible oxidation reaction of 2 H+ + 2 e- ⇌ H2. Supplement of exogenous H2 can improve many kinds of liver injuries, modulate glucose and lipids metabolism in animal models or in human beings. Moreover, hepatic glycogen has strong ability to accumulate H2, thus, among the organs examined, liver has the highest concentration of H2 after supplement of exogenous H2 by various strategies in vivo. The inadequate production of endogenous H2 play essential roles in brain, heart, and liver disorders, while enhanced endogenous H2 production may improve hepatitis, hepatic ischemia and reperfusion injury, liver regeneration, and hepatic steatosis. Therefore, the endogenous H2 may play essential roles in maintaining liver homeostasis.
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Purpose: Metabolic syndrome is associated with several medical risk factors including dyslipidemia, hyperglycemia, and obesity, which has become a worldwide pandemic. The sequelae of this condition increase the risk of cardiovascular and neurological disease and increased mortality. Its pathophysiology is associated with redox dysregulation, excessive inflammation, and perturbation of cellular homeostasis. Molecular hydrogen (H2) may attenuate oxidative stress, improve cellular function, and reduce chronic inflammation. Pre-clinical and clinical studies have shown promising effects of H2-rich water (HRW) on specific features of metabolic syndrome, yet the effects of long-term, high-concentration HRW in this prevalent condition remain poorly addressed. Methods: We conducted a randomized, double-blinded, placebo-controlled trial in 60 subjects (30 men and 30 women) with metabolic syndrome. An initial observation period of one week was used to acquire baseline clinical data followed by randomization to either placebo or high-concentration HRW (> 5.5 millimoles of H2 per day) for 24 weeks. Results: Supplementation with high-concentration HRW significantly reduced blood cholesterol and glucose levels, attenuated serum hemoglobin A1c, and improved biomarkers of inflammation and redox homeostasis as compared to placebo (P < 0.05). Furthermore, H2 tended to promote a mild reduction in body mass index and waist-to-hip ratio. Conclusion: Our results give further credence that high-concentration HRW might have promising effects as a therapeutic modality for attenuating risk factors of metabolic syndrome.
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Molecular hydrogen (H2) is a colorless, tasteless, odorless, and minimal molecule with high flammability. Although H2 has been thought to be an inert gas in living bodies for many years, an animal study reported that inhalation of H2 gas decreased oxidative stress and suppressed brain injury caused by ischemia and reperfusion injury due to its antioxidant action. Since then, the antioxidant action of H2 has attracted considerable attention and many studies have reported on its benefits. Most studies have reported the effects of H2 on diseases such as cancer, diabetes, cerebral infarction, and Alzheimer’s disease. However, little is known regarding its effects on healthy subjects and exercise. Thus far, including our study, only 6 studies have explored the effect of H2 on exercise. H2 is the smallest molecule and therefore can easily penetrate the cellular membrane and rapidly diffuse into organelles. H2 is thought to be able to selectively reduce hydroxyl radicals and peroxynitrite and does not affect physiologically reactive species. H2 can be supplied to the body through multiple routes of administration, such as oral intake of H2 water and H2 bathing. Therefore, H2 may be a potential alternative strategy for conventional exogenous antioxidant interventions in sports science. The purpose of this review is to provide evidence regarding the effects of H2 intake on changes in physiological and biochemical parameters, centering on exercise-induced oxidative stress, for each intake method. Furthermore, this review highlights possible future directions in this area of research.
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Cardiovascular diseases are the most common causes of morbidity and mortality worldwide. Redox dysregulation and a dyshomeostasis of inflammation arise from, and result in, cellular aberrations and pathological conditions, which lead to cardiovascular diseases. Despite years of intensive research, there is still no safe and effective method for their prevention and treatment. Recently, molecular hydrogen has been investigated in preclinical and clinical studies on various diseases associated with oxidative and inflammatory stress such as radiation-induced heart disease, ischemia-reperfusion injury, myocardial and brain infarction, storage of the heart, heart transplantation, etc. Hydrogen is primarily administered via inhalation, drinking hydrogen-rich water, or injection of hydrogen-rich saline. It favorably modulates signal transduction and gene expression resulting in suppression of proinflammatory cytokines, excess ROS production, and in the activation of the Nrf2 antioxidant transcription factor. Although H 2 appears to be an important biological molecule with anti-oxidant, anti-inflammatory, and anti-apoptotic effects, the exact mechanisms of action remain elusive. There is no reported clinical toxicity; however, some data suggests that H 2 has a mild hormetic-like effect, which likely mediate some of its benefits. The mechanistic data, coupled with the pre-clinical and clinical studies, suggest that H 2 may be useful for ROS/inflammation-induced cardiotoxicity and other conditions.
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H2 has been clinically demonstrated to provide antioxidant and anti-inflammatory effects, which makes it an attractive agent in exercise medicine. Although exercise provides a multiplicity of benefits including decreased risk of disease, it can also have detrimental effects. For example, chronic high-intensity exercise in elite athletes, or sporadic bouts of exercise (i.e., noxious exercise) in untrained individuals, result in similar pathological factors such as inflammation, oxidation, and cellular damage that arise from and result in disease. Paradoxically, exercise-induced pro-inflammatory cytokines and reactive oxygen species largely mediate the benefits of exercise. Ingestion of conventional antioxidants and anti-inflammatories often impairs exercise-induced training adaptations. Disease and noxious forms of exercise promote redox dysregulation and chronic inflammation, changes that are mitigated by H2 administration. Beneficial exercise and H2 administration promote cytoprotective hormesis, mitochondrial biogenesis, ATP production, increased NAD+/NADH ratio, cytoprotective phase II enzymes, heat-shock proteins, sirtuins, etc. We review the biomedical effects of exercise and those of H2, and we propose that hydrogen may act as an exercise mimetic and redox adaptogen, potentiate the benefits from beneficial exercise, and reduce the harm from noxious exercise. However, more research is warranted to elucidate the potential ergogenic and therapeutic effects of H2 in exercise medicine.
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Hyposmia is one of the earliest and the most common symptoms in Parkinson’s disease (PD). The benefits of hydrogen water on motor deficits have been reported in animal PD models and PD patients, but the effects of hydrogen gas on PD patients have not been studied. We evaluated the effect of inhalation of hydrogen gas on olfactory function, non-motor symptoms, activities of daily living, and urinary 8-hydroxy-2′-deoxyguanine (8-OHdG) levels by a randomized, double-blinded, placebo-controlled, crossover trial with an 8-week washout period in 20 patients with PD. Patients inhaled either ~1.2–1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks. Inhalation of low dose hydrogen did not significantly influence the PD clinical parameters, but it did increase urinary 8-OHdG levels by 16%. This increase in 8-OHdG is markedly less than the over 300% increase in diabetes, and is more comparable to the increase after a bout of strenuous exercise. Although increased reactive oxygen species is often associated with toxicity and disease, they also play essential roles in mediating cytoprotective cellular adaptations in a process known as hormesis. Increases of oxidative stress by hydrogen have been previously reported, along with its ability to activate the Nrf2, NF-κB pathways, and heat shock responses. Although we did not observe any beneficial effect of hydrogen in our short trial, we propose that the increased 8-OHdG and other reported stress responses from hydrogen may indicate that its beneficial effects are partly or largely mediated by hormetic mechanisms. The study was approved by the ethics review committee of Nagoya University Graduate School of Medicine (approval number 2015-0295). The clinical trial was registered at the University Hospital Medical Information Network (identifier UMIN000019082).
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Atmospheric xenon is strongly mass fractionated, the result of a process that apparently continued through the Archean and perhaps beyond. Previous models that explain Xe fractionation by hydrodynamic hydrogen escape cannot gracefully explain how Xe escaped when Ar and Kr did not, nor allow Xe to escape in the Archean. Here we show that Xe is the only noble gas that can escape as an ion in a photo-ionized hydrogen wind, possible in the absence of a geomagnetic field or along polar magnetic field lines that open into interplanetary space. To quantify the hypothesis we construct new 1-D models of hydrodynamic diffusion-limited hydrogen escape from highly-irradiated CO2-H2-H atmospheres. The models reveal three minimum requirements for Xe escape: solar EUV irradiation needs to exceed that of the modern Sun; the total hydrogen mixing ratio in the atmosphere needs to exceed 1% (equiv. to CH4); and transport amongst the ions in the lower ionosphere needs to lift the Xe ions to the base of the outflowing hydrogen corona. The long duration of Xe escape implies that, if a constant process, Earth lost the hydrogen from at least one ocean of water, roughly evenly split between the Hadean and the Archean. However, to account for both Xe’s fractionation and also its depletion with respect to Kr and primordial 244Pu, Xe escape must have been limited to small apertures or short episodes, which suggests that Xe escape was restricted to polar windows by a geomagnetic field, or dominated by outbursts of high solar activity, or limited to transient episodes of abundant hydrogen, or a combination of these. Xenon escape stopped when the hydrogen (or methane) mixing ratio became too small, or EUV radiation from the aging Sun became too weak, or charge exchange between Xe+ and O2 rendered Xe neutral. In our model, Xe fractionation attests to an extended history of hydrogen escape and Earth oxidation preceding and ending with the Great Oxidation Event (GOE).
Background and aims: While non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide, its treatment remains elusive. Since metabolic impairment plays a major role in NAFLD pathogenesis, any pharmaceuticals, such as molecular hydrogen (H2), that advance lipid and glucose metabolism could be appropriate to tackle this complex condition. The aim of this study was to analyze the effects of 28-day hydrogen-rich water intake on liver fat deposition, body composition and lab chemistry profiles in overweight patients suffering from mild-to-moderate NAFLD. Methods: Twelve overweight outpatients with NAFLD (age 56.2 ± 10.0 years; body mass index 37.7 ± 5.3 kg/m2; 7 women and 5 men) voluntarily participated in this double-blind, placebo-controlled, crossover trial. All patients were allocated to receive either 1 L per day of hydrogen-rich water (HRW) or placebo water for 28 days. The study was registered at (ID NCT03625362). Results: Dual-echo MRI revealed that HRW significantly reduced liver fat accumulation in individual liver regions-of-interest at 28-day follow-up, as compared to placebo administration (P < 0.05). Baseline liver fat content was reduced from 284.0 ± 118.1 mM to 256.5 ± 108.3 mM after hydrogen treatment at 28-day follow-up (percent change 2.9%; 95% CI from 0.5 to 5.5). Serum aspartate transaminase levels dropped by 10.0% (95% CI; from -23.2 to 3.4) after hydrogen treatment at 28-day follow-up. No significant differences were observed between treatment groups in either weight or body composition among participants. Conclusions: Although preliminary, the results of this trial perhaps nominate HRW as an adjuvant treatment for mild-to-moderate NAFLD. These observations provide a rationale for further clinical trials to establish safety and efficacy of molecular hydrogen in NAFLD.
Dysbiosis of the gut flora accompanies Parkinson disease (PD), yet no specific cause-effect link has been identified so far. The gut microbiota produce molecular hydrogen (H2), a ubiquitous molecule recently recognized as a biologically active gas with antioxidant, antiapoptotic, anti-inflammatory, cytoprotective, and signaling properties. Here, we discuss an idea that an impaired production of endogenous H2by intestinal microbiota might play a role in PD pathogenesis, with supplemental H2debated as a possible therapy for this progressive neurodegenerative disease.