Medical Advice Disclaimer: The information provided in this blog post is for educational purposes only and is not intended to replace professional medical advice. Always consult with your healthcare provider before making any changes to your treatment plan.
In recent years, the medical community has been taking a closer look at the potential benefits of hydrogen gas, also known as H2. Studies have shown that when administered through inhalation or through the consumption of hydrogen-rich water, it may have therapeutic effects on the body. The interest in hydrogen therapy dates back to 1975, when researchers from Baylor University and Texas A&M published a study in the journal Science, demonstrating that hyperbaric hydrogen therapy was effective at reducing melanoma tumors in mice. However, it wasn’t until 2007 that scientists began to uncover the full extent of hydrogen’s potential therapeutic benefits. Through various studies and experiments, it has been found that hydrogen-rich water, also known as “H2 water” or “molecular hydrogen water”, can have positive effects on various health conditions. These findings suggest that hydrogen has immediate medical and clinical applications.
The Therapeutic Potential of Molecular Hydrogen (H2)
The use of hydrogen as a medical gas has been gaining significant attention from researchers, doctors, and physicians worldwide. In 2007, a study published in Nature Medicine showed that inhaling 2-4% hydrogen gas reduced cerebrospinal infarct volumes in a rat model of ischemia-reperfusion injury caused by middle cerebral artery occlusion. The results were even more effective than edaravone, a commonly used drug for cerebral infarction, without any toxic side effects. The study also found that dissolved hydrogen in the media of cultured cells, at biologically relevant concentrations, reduces the level of toxic hydroxyl radicals (*OH), but does not react with other physiologically important reactive oxygen species (e.g. superoxide, nitric oxide, hydrogen peroxide).
Despite being in its early stages, with around 1000 articles and 1,600 researchers, the research on hydrogen suggests that it has therapeutic potential in over 170 different human and animal disease models, and in essentially every organ of the human body. Hydrogen appears to provide these benefits by modulating signal transduction, protein phosphorylation, and gene expressions (See section Pharmacodynamics).
While the concept of therapeutic gaseous molecules isn’t new, hydrogen is unique in that it is a non-radical, non-reactive, non-polar, highly diffusible neutral gas, making it unlikely to have specific binding sites or interact with specificity on a specific receptor. However, from an evolutionary perspective, hydrogen’s role in the origins of the universe and the genesis of life suggest that it plays an important role in the evolution of eukaryotes.
Methods of Administration
There are several methods of administering molecular hydrogen, including inhalation, ingestion of solubilized hydrogen-rich solutions (e.g. water, flavored beverages, etc.), hydrogen-rich hemodialysis solution, intravenous injection of hydrogen-rich saline, topical administration of hydrogen-rich media (e.g. bath, shower, and creams), hyperbaric treatment, ingestion of hydrogen-producing material upon reaction with gastric acid, ingestion of non-digestible carbohydrates as prebiotic to hydrogen-producing intestinal bacteria, rectal insufflation, and other methods.
Inhalation of hydrogen gas is one common method of administration. A 2-4% hydrogen gas mixture is often used because it is below the flammability level. However, some studies use 66.7% H2 and 33.3% O2, which is nontoxic and effective, but flammable. Inhalation of hydrogen reaches a peak plasma level in about 30 min, and upon cessation of inhalation the return to baseline occurs in about 60 min.
Drinking Hydrogen Rich Water
Another method of administering hydrogen is by drinking hydrogen-rich water. The concentration/solubility of hydrogen in water at standard ambient temperature and pressure (SATP) is 0.8 mM or 1.6 ppm (1.6 mg/L). This concentration is easily achieved by many methods, such as simply bubbling hydrogen gas into water. The half-life of hydrogen-rich water is shorter than other gaseous drinks, but therapeutic levels can remain for a sufficient amount of time for easy consumption. Ingestion of hydrogen-rich water results in a peak rise in plasma and breath concentration in 5-15 min in a dose-dependent manner. The rise in breath hydrogen is an indication that hydrogen diffuses through the submucosa and enters systemic circulation where it is expelled out the lungs. This increase in blood and breath concentration returns to baseline in 45-90 min depending on the ingested dosage.
Understanding the Pharmacokinetics and Pharmacodynamics of Hydrogen Therapy
Hydrogen is a unique element that has a variety of therapeutic effects due to its special properties such as hydrophobicity, neutrality, size, and mass. It has the ability to easily penetrate biomembranes and reach subcellular compartments, which allows it to have a wide range of effects in the body.
There are several ways that hydrogen can be administered, including intravenous injection, inhalation, and drinking hydrogen-rich water. The pharmacokinetics of these methods are still being studied, but are dependent on dosage, route, and timing.
Unlocking the Secrets of Hydrogen’s Biological Effects: A Closer Look at Pharmacodynamics and Antioxidant-Like Effects
Despite a wealth of research confirming hydrogen’s impact on biological systems, the precise molecular mechanisms and primary targets remain a mystery. Initially, it was thought that hydrogen’s beneficial effects were due to its ability to neutralize harmful hydroxyl radicals. However, further studies have called this theory into question. For example, in a double-blinded placebo-controlled trial in rheumatoid arthritis, the positive effects of hydrogen continued to improve symptoms for four weeks after administration was halted. Additionally, pre-treatment with hydrogen has been shown to have significant benefits, even when the assault (e.g. toxin, radiation, injury, etc.) is administered long after all the hydrogen has dissipated out of the system.
Furthermore, the rate constants of hydrogen against hydroxyl radicals are relatively slow and the concentration of hydrogen at the cellular level is also quite low, making it unlikely that H2 could effectively compete with the other nucleophilic targets in the cell. Lastly, if the mechanism were primarily associated with scavenging of hydroxyl radicals, then we would see a greater effect from inhalation compared to drinking, but this is not always the case.
It is important to note that hydrogen is selective because it is a very weak antioxidant and does not neutralize important ROS or disturb important biological signaling molecules. A metabolic tracer study using deuterium gas has demonstrated that under physiological conditions, deuterium gas is oxidized, and the oxidation rate of hydrogen increases with an increasing amount of oxidative stress. However, the physiochemical mechanism for this may still not be direct radical scavenging. Research is ongoing to further understand the underlying mechanisms and primary targets of hydrogen’s effects on biological systems.
Understanding the NRF2 Pathway and Its Impact on Oxidative Stress
When it comes to fighting oxidative stress, hydrogen is unique among antioxidants. Unlike traditional antioxidants, hydrogen only reduces excessive oxidative stress when the cell is experiencing abnormally high levels that would be harmful. One mechanism that hydrogen uses to protect against oxidative damage is by activating the Nrf2-Keap1 system, which leads to the production of various cytoprotective proteins like glutathione, catalase, superoxide dismutase, glutathione peroxidase, and heme-1 oxygenase. In certain disease models, the benefits of hydrogen are negated by using Nrf2 gene knockouts, Nrf2 genetic silencing, or pharmacologically blocking the Nrf2 pathway. Importantly, hydrogen only activates the Nrf2 pathway when there is an assault, such as a toxin or injury, as opposed to constantly promoting it, which could be harmful.
Hydrogen also has the ability to modulate cells and reduce the formation of free radicals, such as by downregulating the NADPH oxidase system. These cell-modulating effects of hydrogen are responsible for mediating the anti-inflammatory, anti-allergy, and anti-obesity effects of hydrogen. Hydrogen has been shown to downregulate pro-inflammatory cytokines and attenuate the activation of various inflammatory mediators. Additionally, hydrogen has beneficial effects on obesity and metabolism by increasing the expression of various genes and proteins.
While the exact mechanism of how hydrogen modulates signal transduction, gene expression, and protein phosphorylation is still being investigated, recent research suggests that one of the mechanisms through which hydrogen accomplishes its various cell-modulating effects is by modifying lipid peroxidation in the cell membrane.