Review of Hydrogenated Water: Extra Healthy or a Hoax?: A Systematic 2 Review

Thank you for the opportunity to review this article. The article focuses on the therapeutic effects reported in studies on hydrogen gas obtained from ingesting water containing dissolved H2. These review articles are always helpful to bring more awareness to an emerging field of scientific research.

Below are some comments that can be used to improve the manuscript.

It is preferred to not use the word potent when referring to hydrogen’s antioxidant properties because it suggests that it can easily react with all radicals as a powerful reducing agent. It is a very weak reducing agent and so can only react with the strongest oxidants, which make it a selective antioxidant.

Introduction: Line 39: it is preferred to not use the term “hydrogenated water” because the chemical term hydrogenation indicates a chemical reaction between molecular hydrogen and another molecule. For example, the reduction of alkenes to form alkanes by hydrogen gas. H2 does not bond to the water molecule but is simply dissolved in the water. Thus, hydrogen water, hydrogen-rich water, hydrogen-infused water, etc. are more appropriate terms.

Line 40: please ensure that the 2 in H2 is subscript.

Materials and methods It is not clear why only 590 articles were found on PubMed, when there are at least 2000 publications including 140 human studies, two meta-analyses studies that are specifically on molecular hydrogen’s biological effects. Especially if searching for “molecular hydrogen” and “hydrogen gas”. Perhaps the term of “hydrogenated water” reduced the number of studies found on PubMed. Other systemic review also reported a higher number of studies. Perhaps more information on the exclusion criteria for the search engines could be provided as well as statement emphasizing that this was only on hydrogen water, which excluded the results on the therapeutic effects of hydrogen gas inhalation, injection of hydrogen-rich saline, etc.

Results Figure 2. This is a nice figure, but the spacing needs to be improved so that the words fit on the same line for the cardiovascular and management.

Section 3.1 It may be helpful to reference the systemic review and meta-analysis on hydrogen for exercise: https://doi.org/10.3389/fnut.2023.1094767

Section 3.2 Only a review article was cited in this section, but there are a number of clinical studies that show reductions in oxidative stress that could also be cited.

Section 3.3 More clinical studies could be cited in this section also. There are several more studies on metabolic syndrome that are even larger than the cited study, including another meta-analysis that could be cited.

Section 3.4 Similarly, there are additional human studies on hydrogen water that indicate possible benefits for COVID-19. More studies should be cited since they are readily available.

Section 3.5 There are also other studies on this topic that could be cited. Also, this section mentions the use of electrolyzed water as a source of hydrogen water (see also line 89 “water ionizers”). It may valuable to specify that this so called “electrolyzed-reduced water” produces H2 gas, and the H2 gas is exclusively responsible for any of the observed benefits, as has been recently reviewed.

Section 3.6. There are also many other studies that could be included as well, at least citing of a recent meta-analysis on the effects of hydrogen on cancer (PMID: 36708550).

Section 3.8 There are several other clinical studies on the effects of hydrogen water on NAFLD that could also be included.

Discussion Line 344: it is true that the mechanisms are not fully known, however, recent data shows that Fe-porphyrin to be a primary target of hydrogen, which may account for many of the therapeutic actions of hydrogen. It would be helpful to have a section discussion or summarizing some of these mechanisms. Perhaps re-organizing to include the discussion of the Nrf2 pathway along with other mechanisms. The discussion also contains studies hyperlipidemia that seem would belong in the earlier results sections.

Review 2.

Thank you for clarifying the exclusion criteria and how the terms were searched in PubMed. Section 3.3

Here is the meta-analysis on blood lipids that should be cite: DOI: 10.3390/ph16020142. The 24-week (n=60) randomized DBPC study on metabolic syndrome would also be helpful to include https://doi.org/10.2147/DMSO.S240122.

Discussion The reference you provided for the Fe-porphyrin, is mentioned in that reference, but the primary reference should be used: doi: 10.1007/s12274-022-4860-y