After much debate and consideration, IHSA suggests that the minimal amount of hydrogen should be established as a dose per day in a maximal volume of solution. The standard has been determined to provide at least 0.5 mg of H₂ by ingesting a maximal volume of 1 L of product water, or 500 mL of specialty beverages.

It is understood that more research is needed to fully know the minimum effective dose (MED) and the minimum effective concentration (MEC) of H₂ at the cellular level. Ideally, the dose would be given in mg/kg of body weight with an optimal time factor based on its half-life and pharmacokinetics/pharmacodynamics. However, this is more challenging with H₂ because, unlike conventional pharmacological agents, H₂ does not have a single/specific receptor/target or organ function. The MED/MEC will likely vary based on factors such as age, body weight, disease, genetics, intestinal bacteria, diet, etc. The IHSA recommendation is simply a standard based on the current cell, animal, and human clinical studies. This standard is subject to change based on additional biomedical research. The following discussion provides the rationale and justification for the standards set forth by IHSA.

Unlike conventional drugs, it is logical that humans may require a similar equivalent dose of H₂ as do rodents, because there are no receptors to bind H₂ as there are for drugs. The IHSA standard of a minimum of a 0.5 mg dose per liter of water is supported by the lower-dose studies in animals and humans. For example, in a mouse model of Parkinson’s disease, Fujita, K. et al (2009) reported that a concentration of 0.08 mg/L, but not 0.04 mg/L was effective. Interestingly, mice (C57BL/6J) drinking 0.08 mg/L would provide a dose of H₂ per day which is somewhat comparable to a human ingesting about 0.5 mg of H₂ per day (0.08 mg/L * 0.0045 L/0.03 kg = 0.012 mg/kg. 45-75kg = 0.5-0.9 mg H₂). Similarly, a 0.04 mg/L would equate to about 0.27 mg to 0.45 mg H₂ per day in humans. These doses are in line with two human studies that suggest that 0.5 mg, but not 0.25 mg per day is effective.

In one human study (Ito, M. et al. 2011), subjects ingested 0.25 mg/day by drinking 0.5 L of 0.5 mg/L H₂ water. At this low dose, there were no observed benefits. The researchers suggested that if they either a) consumed the same amount of water at a higher concentration, or b) consumed a higher volume of water at a similar concentration, then they would have noticed a benefit. Indeed, the preliminary data (open-label trial) in the same article, used 1 L of water (0.5 mg H2 per day), and significant benefits were observed (only 0.5 L were consumed in the placebo-controlled trial because patients struggled to consume 1 L per day). However, another explanation could be the longer duration of the open-label study, which lasted 12 weeks instead of only 8 weeks. Another human study provided 0.5 mg H₂per day by ingestion 1 L of 0.5 mg/L, and noted significant benefits (Song G. et al. 2013).

Dose instead of concentration

Setting a specific concentration (e.g. 0.8 mg/L) does not take into consideration the actual dose delivered due to the potential for varying ingested volumes. For example, a higher dose of hydrogen can be ingested by drinking 1 liter of 0.5 mg/L, than could be ingested by drinking a 250mL container of 1 mg/L H₂ water (i.e. 0.5 mg vs. 0.25 mg). Therefore, the IHSA standard is based on dose (mass), and not concentration (mass per unit volume).

Volume

Although one can reach 0.5 mg of H₂ by ingesting a large volume of low concentration H₂-water (e.g. 5 L of 0.1 mg/L), this is problematic because 1) some have difficulty drinking high volumes of water, or may be required by a physician to limit fluid intake; 2) it is possible that ingesting H₂ in this manner may not result in equivalent therapeutic effects as would ingesting 0.5 mg all at once. This may be because the cellular concentration may not reach the “unknown” minimal required concentration (e.g. 5-10 mM). Additionally, the therapeutic effects of H₂ are not only dependent upon the dose/cellular concentration but also on the frequency/exposure time.  For example, continuous inhalation of H₂, or administration of non-digestible carbohydrates (e.g. lactulose), would provide a dose of H₂orders of magnitude greater than that from drinking hydrogen water. However, only drinking hydrogen water, and not continuous hydrogen inhalation or lactulose administration was effective in an animal model of Parkinson’s disease (Ito, M. et al. 2012).  This further illustrates the need for more scientific research to elucidate the optimal doses, timing, and methods of administration. Based on the above human studies and current guidelines for ingesting water, we have set the maximal volume as 1 L per day for water and 500 mL per day for specialty beverages (e.g. juice, carbonated drinks, teas, etc.).