Hydrogen for Neuroprotection?
When speaking with many hydrogen researchers and asking what they are most excited about regarding hydrogen therapy research, quite often the response is neurodegeneration. This is understandable since age-related neurological disorders, such as Parkinson’s disease (PD) and dementia, have a massive impact on the population; even though significant private and public research funds have pursued these challenges, there have been very few promising outcomes.
Hydrogen therapy research has found very strong results in preliminary rodent data, which is true for many molecules that have ultimately failed in humans, or in larger well-controlled human trials. Hydrogen has certainly shown to address many of the current targets of various neurological diseases, such as demonstrating the capability of reducing amyloid-beta cytotoxicity,¹ amyloid beta-driven inflammatory², and oxidative stress responses,³ blocking tau expression following traumatic brain injury⁴, as well as neuroinflammation, neuronal apoptosis and excessive oxidative stress in other non-amyloid beta driven rodent models.⁵⁶⁷
What makes hydrogen therapy particularly interesting is that in addition to showing a benefit in neurodegenerative conditions, it has shown significant promise in acute traumatic brain injuries, whether it be concussive or in relation to events such as a stroke. As I discuss in detail following the published case study using our hydrogen tablets for concussion recovery, traumatic brain injuries are strongly linked with a higher likelihood of developing neurodegenerative conditions. This gives rise to the hypothesis that hydrogen therapy could both aid in prevention, and treatment.
It’s easy for those who are not aware of the sharp decline in success rate when transitioning from rodent research to human research to get excited after seeing some of the early hydrogen therapy studies. Several studies have shown a benefit with hydrogen water and PD, for instance, with two rodents models using hydrogen water showing benefits⁸⁹ and a third comparative study showing that hydrogen water was the most effective, intermittent gas exposure still effective, and chronic gas exposure was not effective in a rodent model of PD.¹⁰ Mechanistically, one study suggested hydrogen water’s benefits in PD is attributable to increased excretion of ghrelin¹¹, while a subsequent paper found that the benefits of molecular hydrogen were independent of increased ghrelin excretion by using ghrelin knock-out mice.¹² Another hypothesis relies on recent work suggesting impairment of hydrogen gas createsing bacteria in the development of PD,¹³ to which the utilization of exogenous hydrogen has been discussed in this context in a published opinion paper.¹⁴ This could be a mechanistic avenue to explore in future research as hydrogen water has shown to positively impact the microbiota in both animal¹⁵¹⁶¹⁷¹⁸¹⁹ and human research.¹⁹
For Alzheimer’s disease and dementia, on top of two of the previously cited studies regarding amyloid beta, hydrogen water has shown to prevent stress-induced impairments caused by chronic physical restraint in a model designed to induce dementia, and has mitigated senescence driven cognitive decline, suggesting it may assist in age-related memory and cognitive decline. In other neurodegenerative diseases, a hydrogen-rich saline showed promise via attenuation of oxidative and nitrosative stress in a mouse model of ALS,²¹ and significantly improved outcomes in a rodent model of multiple sclerosis.²²
The strong early evidence in rodents and hypotheses on mechanisms of action in PD was met with early excitement in human research. The first study in humans following 17 participants for 48 weeks found significant benefits in improvements in the Unified Parkinson's Disease Rating Scale. Subsequent studies have been complete flops. However, there are caveats as to why they failed, allowing a glimmer of hope to remain. In an 8-week trial following 20 participants, hydrogen gas inhalation was ineffective.²³ As mentioned in regards to rodent research, hydrogen water was more effective than inhalation of hydrogen gas. In a large multicenter trial following 178 participants for 72 weeks, high-dose hydrogen water was no more effective than placebo,²⁴ with a massive caveat. The placebo water contained hydrogen gas, and both hydrogen water and placebo appeared to be very effective over the placebo group results in similar trials.
The dissolved hydrogen gas in the water reported as below the therapeutic threshold, but as noted at around the 45 min 30 second mark in a discussion between Tyler W. LeBaron and I, subsequent analysis of the placebo used in this study showed that the hydrogen concentration was greatly variable, some bottles delivering high doses known to be therapeutic. This means the placebo group was receiving the very intermittent high-dose of hydrogen water we know is effective. further, while for some issues, such as metabolic and response to acute stress, such as exercise, dose seems to be very important. For PD, where the hypotheses on mechanisms of action revolve more around gastric ghrelin secretion and improvements to our gut bacteria, this may not be the case and a lower dose may be as effective as a higher dose. these discrepancies need clarification, and fortunately, StonyBrook Medicine has registered a 52-week clinical trial (n=70) using our high-dose hydrogen creating tablets. Their trail incorporates a placebo control containing no ability to dissolve hydrogen.
Alzheimer's and Dementia
Studies looking at mild and advanced cognitive impairment have been disappointing when compared to rodent data, but overall much more positive than PD results. Unfortunately, for both trails, there are caveats and inconsistencies that greatly limit our ability to make strong conclusions from the published data. A single study in humans following 11 patients with advanced dementia for a period of between 4-7 months²⁵ showed strong results, however, the study was more of a case series than anything. These data, in comparison to weaker data from a study using a very low-dose of hydrogen water following 73 participants with mild cognitive impairment for 53 weeks (finding a significant result only in those carrying at least one APOE4 allele), led many marketers and consumers to speculate that hydrogen inhalation is more effective than hydrogen water for cognitive impairment. I detail the flaws in this rationale in my article “Why Hydrogen Concentration Matters Pt 1.”
Caveats and Confounding Variables Regarding the Inhalation Study:
From Why Hydrogen Concentration Matters Pt 1:
1)A more advanced disease state
2)Lithium carbonate was also administered alongside hydrogen, which in itself may have potential benefits in protection against Alzheimer's (although the body of evidence does not support this yet with mixed results).²⁶ The data clearly demonstrate that lithium on its own had no effect, while hydrogen inhalation on its own did. however, hydrogen has been shown to potentially lower the dosages of other drugs in the past.²⁷²⁸ Further, there was not washout period, and the study was more in line with observational case studies.
The inhalation study cites a concentration of 3% hydrogen gas for two one-hour sessions p/day, while not specifying a flow rate, but referencing another study using the same device.²⁹ This study, likewise, does not specify a flow rate, byt does state that it is delivered through a non-re-breating facemask. The average adult breathes in 5-8L p/minute at rest,³⁰³¹ so at 6.5 L p/minute, 3% hydrogen for 120 minutes p/day, participants were inhaling a total of 23.4 L of hydrogen gas. Reducing by a factor of 100* to consider impact between method,³² that is the equivalent of 234 mL of hydrogen dissolved in water a day, or 16.47 mg of H₂ in a direct comparison to water- a comparative dose of 45.74x more than what was used in the mild cognitive impairment study.
*The only published comparison shows that H₂ when dissolved in water has similar and perhaps even more prominent effect than inhaled gas at 1/100th the dose. This conversion is limited by a lack of data and a dearth of direct comparative studies and analysis. The exact conversion is likely different for different targets with comparative doses being affected by concentrations.
Caveats and confounding Variables in the Mild Cognitive Impairment Hydrogen Water Study
From Why Hydrogen Concentration Matters Pt 1:
"Participants were given 500mL of water with 1.2 ppm dissolved to consumer a day, and an average consumption estimated at just 300 mL p/participant. Going out on a leap and assuming that the 300 mL was consumed immediately before hydrogen dissipation lowered dissolved levels, the average participant consumed just 0.36 mh of hydrogen p/day. This is below the 0.5 mg with a max volume of 1 L p/day that the International Hydrogen Standards Association has declared the minimum observed therapeutic dose.
In a concurrent study conducted by the researchers utilizing mice, the animals experienced significant improvement in cognitive function and memory, decreased oxidative stress in the brain, DNA damage, recovery from neurodegeneration, and a significant increase in mean lifespan (but not maximal). The mice began drinking hydrogen water at either 1 month old, continuing until 18 months old, or starting at a later stage of 8 months and continuing to 18 months, to simulate a mid-age protocol.
The comparative dosage? The article suggests the mice were consuming super-saturated hydrogen water prepared at 0.4 mpa or 58 psi! If allowed to reach an equilibrium this would translate to roughly 6 ppm hydrogen water, given ad libitum, or a comparative dosage of 76.8 mg of H₂ compared to 0.36mg: A difference of 213x. Upon a closer look at another study using the same methods, the reported gas concentrations were at a minimum 1.2 ppm upwards of 1.6 ppm. With infrequent replacement of hydrogen water just twice a day (methods not specified), the scaled dosage with half-life would still be 2.52 - 3.36 mg in comparative conversion, or over 6.75 - 9x the comparative dosage the human participants received."
What we can take away is that after these studies, hydrogen therapy whether as hydrogen water or inhalation, still holds promise. The inhalation study was in a much more advanced disease state, with less controls, and an astronomically higher relative dosage. Cognitive impairment and Alzheimer's disease have been strongly linked to metabolic disorders, such as obesity, diabetes, and hypertension,³³ which hydrogen therapy has shown promising results, and indications are skewed towards a dose-dependent response. Future research on cognitive decline should explore the highest dosages and concentrations available and aim to seek better controls. These early human results are not shout from the rooftop exciting, but do warrant a deeper look and more research.
A small study showing the potential beneficial effects of hydrogen through saline³⁶ further demonstrating the safety of the treatment. Several years later, a controlled clinical trial following 50 patients was conducted on acute cerebral infraction using hydrogen inhalation.³⁷ Positive results and a high safety profile led to the registration of another clinical trial utilizing high dose hydrogen water produced by the open cup tablets and minocycline (an antibiotic) to be registered by StonyBrook Medicine, following 100 patients recovering from post-acute ischemic stroke.
Additionally, a case study was published on concussion recovery,³⁸ and an important study showing hydrogen water had significant benefits in newborn babies with hypoxic-ischemic encephalopathy,³⁹ meaning that the babies weren't getting enough oxygen or blood resulting in brain damage. Neither of these publications have been replicated, with nothing registered exploring either condition, and both warrant more attention.
Hydrogen therapy is not a proven medicine or treatment for any of the described states. Some of these data are not particularly promising, and indications that it is promising need a lot of future work. Most molecules fail when research advances to larger multicenter trials.This could be for many reasons, including inconsistency in methods in larger trials, or more likely, variables that were not controlled for in the smaller groups leading to positive results. We have seen this failure in hydrogen water and PD, although as described in detail, there are serious caveats and errors in that paper.
For cognitive decline, the evidence is neutral. Rodent data are very promising, human data are somewhat promising, and if that trend continues, larger scale trials are more likely to fail than succeed. That said, again, there are serious and caveats that need to be addressed before larger trials begin, more importantly, identifying an appropriate dose and duration.
Hydrogen therapy seems the most promising for acute events, which makes sense, and largely corresponds to last week's article regarding hydrogen and protecting from stress. That being sad, for all of these results, whether it is stroke, concussion recovery, or the infant model involving restricted oxygen and blood flow, the results need replication. They need larger, controlled d studies from teams not involved in the earlier research, in which, hopefully, there will be positive findings. Fortunately, we will have that in the coming years, at least regarding post stroke recovery.
Hydrogen therapy is exciting in a lot of areas and has a very high safety profile. By disregarding the weaknesses in some of the research and promoting it as a magical cure for all, we do the entire field of research a disservice. For some of these chronic disease states, it would be absolutely foolish to pursue hydrogen therapy as a standalone treatment, at least at this time. If your practitioner suggests it as such, get a second opinion. If your practitioner is suggesting hydrogen therapy in addition to an approved treatment, evaluate for yourself and weigh the costs against the limited benefits. It may help, but we don't know yet. It certainly is not a magic solution. For acute traumatic events, again, this is something that needs to be evaluated. The evidence is better, but preliminary. The safety profile is high. It may work, but it also may not. Weigh your options, but do not let anyone sway you into thinking it is proven and beyond refute. That said, in regards to these acute traumas, there really isn't anything that is proven to work and approved as a treatment - yet.