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THE APPLICABILITY OF MOLECULAR HYDROGEN IN
THE TREATMENT OF NEURODEGENERATIVE DISEASES: A
BIBLIOGRAPHICAL REVIEW
Edis Rodrigues Junior1
Juliana Oliveira de Toledo2
Abstract: Introduction: This article discusses the growing research on the use of molecular hydrogen
(H2) in the treatment of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Amyotrophic
Lateral Sclerosis (ALS). H2 stands out for its antioxidant and anti-inammatory properties, which can
reduce oxidative stress and inammation in the brain, key factors in the progression of these diseases.
Objective: To review current studies on the applicability of molecular hydrogen as a neuroprotective
therapy, exploring its effects and possible benets in the treatment of neurodegenerative diseases.
Methodology: A literature review was carried out based on scientic articles published in the last
10 years in the PubMed, Scielo and ScienceDirect databases. Inclusion criteria included clinical
and preclinical studies investigating molecular hydrogen as a therapeutic agent. Discussion: Studies
indicate that H2 can act in the neutralization of free radicals, modulation of the cellular redox state and
reduction of inammation, which contributes to neuroprotection. Several administration methods are
analyzed, such as inhalation, H2-enriched water, and injections. Clinical trials suggest improvements
in cognitive function and reduction in the progression of neurodegenerative diseases, but research is
still needed to establish optimal doses and more detailed mechanisms of action. Conclusion: Molecular
hydrogen has great therapeutic potential for neurodegenerative diseases, being safe and low-cost.
However, more clinical studies are needed to validate its efcacy and dene treatment protocols.
1 CEP-HM Hydrogen Max Study and Research Center
2 AbmDF-Biomedical Association of the Federal District
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Keywords: Molecular hydrogen, neuroprotection, oxidative stress.
Introduction
In the last decade, research on therapies for neurodegenerative diseases, such as Alzheimer’s,
Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS), has expanded signicantly due to the increasing
prevalence of these diseases in the world population (FALCO, 2016). Although pharmacological
treatments exist, most have limited efcacy and adverse effects that are sometimes not tolerated by
patients, greatly reducing the cost-benet of treatment. Molecular hydrogen (H2), due to its antioxidant
and anti-inammatory properties, emerges as a promising alternative for complementary treatments.
(SARAMAGO, 2018).
Molecular hydrogen (H2) has emerged as a therapy with great potential in the treatment
of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Amyotrophic Lateral Sclerosis
(ALS). Its application in neurodegenerative conditions has been intensively studied, as H2 has
signicant antioxidant and anti-inammatory properties that can protect the brain from damage
caused by oxidative stress and chronic inammation — common and aggravating processes in many
of these diseases.
In terms of mechanism of action, it is a ammable, colorless, odorless, and water-insoluble
gas, which can easily cross cell membranes, including the blood-brain barrier, allowing its direct
arrival to brain tissue. (CAMPUS, 2018). One of the main ways of its action is the neutralization of
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free radicals, such as the hydroxyl radical and the superoxide anion, which are highly reactive and
toxic to neuronal cells.
In addition, H2can modulate the cellular redox state, increasing the expression of endogenous
antioxidants and improving the balance between the pro and antioxidant systems, which is essential
for the protection of neural cells. (BARBOSA, 2010)
In addition to antioxidant action, molecular hydrogen also exerts anti-inammatory effects by
reducing the release of pro-inammatory cytokines such as TNF-α and IL-6, which are often elevated
in neurodegenerative diseases. This helps decrease chronic brain inammation, which contributes to
the progressive death of neurons and cognitive decline. (CAPITA, 2024)
Methods of applying molecular hydrogen in therapies include its inhalation, oral administration
through H2-enriched water, and injections, depending on the clinical need and the desired degree
of absorption. Preclinical studies and trials early clinical ndings indicate that molecular hydrogen
administration may contribute to improved cognitive function, decreased motor symptoms, and slowed
the progression of neurodegenerative diseases, especially when integrated with other therapeutic
approaches. (FALCO, 2016)
Inhalation of H2 gas is the simplest and most widely used form. Inhaled H2 diffuses into the
alveoli of the lungs and is transported by blood throughout the body. On the other hand, the ingestion
of water dissolved in H2 (HW)* is considered safer and more convenient. Studies have shown that
drinking water saturated with H2 can prevent arteriosclerosis in animal models. However, the injection
of H2-dissolved saline (HS) is used in specic clinical settings and varies depending on the disease.
Studies so far suggest that the administration of H2 has signicant clinical potential for the
prevention, treatment, and mitigation of neurological disorders such as neurodegenerative diseases
and ischemic brain injuries. No adverse effects of H2 have been reported, and it is considered relatively
easy to use, cost-effective, and effective in daily medical practice. However, more research is still
needed to establish the optimal dose and route of administration for each disease, as well as elucidate
the mechanisms molecular effects that underpin the biological effects of H2. (IKETANI, 2017)
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This paper aims to review current studies on molecular hydrogen, addressing its therapeutic
properties and its applicability in neuroprotection.
Methodology
For the construction of this review, a search was carried out in the main scientic databases
(PubMed, Scielo, ScienceDirect) using the terms: “molecular hydrogen”, “neurodegenerative diseases”,
“Alzheimer’s”, “Parkinson’s”, “neuroprotection”. The inclusion criteria were clinical and preclinical
studies published in the last 10 years, which addressed molecular hydrogen as a therapeutic agent. We
excluded opinion articles and studies of poor methodological quality.
Discussion
The use of molecular hydrogen (H2) as a treatment for degenerative diseases such as
Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS) has attracted increasing attention
in scientic research due to its potential antioxidant and anti-inammatory properties. However, it is
important to note that despite initial promises, widespread implementation and clinical use are still in
the early stages. (TORRÃO, 2012)
According to SEO, the study investigated the effects of consuming hydrogen-rich water
(HW) compared to ordinary water (PW) on biological antioxidant potential (BAP) and markers of
oxidative damage in humans. The research is motivated by growing evidence that oxidative stress
It plays a crucial role in various diseases and molecular hydrogen may have antioxidant
properties.
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Conclusion
Consumption of hydrogen-rich water can increase biological antioxidant potential and reduce
oxidative damage in humans, especially in individuals aged 30 years and older. These results suggest
that hydrogen-rich water may be an effective intervention to improve antioxidant health.
Ingestion of 1.5 L of H2 water for 4 weeks reduced cell death and inammatory responses
by modulating the transcriptional networks of TLR-NFκB signaling. In addition, it may promote
biological antioxidant capacity in adults > 30 years older than in younger individuals. (YES, 2020)
Alzheimer’s and Parkinson’s
In the case of Alzheimer’s and Parkinson’s, several experimental and clinical studies have
explored H2 for its neuroprotective properties. Studies have suggested that H2 may help reduce
oxidative stress, a key factor in the progression of these diseases. H2 has shown potential in animal
model studies and in preliminary clinical trials. In the treatment of Alzheimer’s, some studies indicate
that H2 may have a protective effect on neurons, potentially helping to reduce inammation and
oxidation in the brain.
The mechanism of action of molecular hydrogen H2 is quite interesting and multifaceted,
acting mainly as an antioxidant, helping to neutralize free radicals in the body, which are unstable
molecules that can cause oxidative stress and cell damage. Specically, H2 has the ability to selectively
reduce the most toxic free radicals, such as hydroxyl radicals (•OH) and hydrogen peroxide (H2O2),
without affecting benecial free radicals that play important roles in physiological processes.
In addition to its antioxidant properties, H2 may also inuence several cell signaling
pathways. Studies suggest that it may regulate the expression of genes related to oxidative stress and
inammation, promoting a healthier cellular environment. For example, hydrogen gas inhalation has
shown positive effects in models of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s
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disease, possibly through the reduction of oxidative stress and modulation (JOHNSEN, 2023)
In the treatment of Parkinson’s, H2 has shown promise in reducing oxidative stress in
dopaminergic neurons, which are characteristically affected by Parkinson’s. Research shows that
H2 exerts neuroprotective effects, particularly in models of cerebral ischemia-reperfusion. The
administration of H2 was associated with reduced neuronal damage, due to its ability to inhibit the
production of ROS and reactive nitrogen species (RNS), preserving cellular integrity. (LI, 2020)
According to YORITAKA ET AL, 2013 a pilot study was a randomized, double-blind,
placebo-controlled clinical trial that evaluated the efcacy of water dissolved in molecular hydrogen
(H2) in Japanese patients with Parkinson’s disease (PD) medicated with levodopa. Participants were
18 patients, with a mean age of 62.7 years, 11 of whom were women. Participants were divided into
two groups: one group received 1,000 mL/day of H2 water and the other group received placebo water
for 48 weeks. The group that consumed H2 water showed a signicant improvement in the total scores
of the Unied Parkinson’s Disease Rating Scale (UPDRS), with a median of -21.0 and a mean of
-25.7±8.4. The placebo group showed worsening in the total UPDRS scores, with a median of 4.5 and
a mean of 4.1±9.2. The difference between the groups was statistically signicant (P<0.05).
H2 water intake was safe and well tolerated. There was a signicant improvement in total
UPDRS scores in the group that consumed H2 water, indicating a potential therapeutic benet for PD
patients.
The study participants were taking the following antiparkinsonian medications:
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None of the patients changed treatment with L-dopa or other antiparkinsonian drugs during
the study period.
The study suggests that longer trials with larger numbers of participants are needed to
conrm these ndings.
Amyotrophic Lateral Sclerosis (ALS)
In the context of ALS, some experimental studies suggest that H2 may help reduce neuronal
cell death, a mechanism that occurs in ALS, due to its ability to neutralize free radicals. However,
despite some initial trials being promising, the amount of clinical data and large-scale studies is still
small. (BARBOSA, 2010)
Although the exact mechanisms of action of molecular hydrogen are not completely understood,
its ability to cross the blood-brain barrier and reach the central nervous system is an important
differentiator. The modulation of oxidative stress and anti-inammatory activity suggest that H2 may
be benecial as an adjunct treatment in neurodegenerative diseases. However, the heterogeneity of the
studies, the variable dosages, and the different methodologies limit the comparability of the results,
highlighting the need for more robust clinical trials to conrm the effects in humans.
The results of the randomized controlled trial that looked at consuming 2 liters per day
of alkaline ionized water for 8 weeks showed a decrease in markers of oxidative stress, as well as
Drug Number of patients using the medication
Levodopa (L-dopa)
Dopamine agonists 7 patients in the placebo group and 5 in the H2 group
Anticholinergic agents 2 patients in each group
Selegiline 1 patient in the placebo group and 4 in the H2 group
Entacapona 2 patients in the placebo group and none in the H2 group
Amantadine 1 patient in each group
Zonisamide 1 patient in the placebo group and 5 in the H2 group
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improvements in participants’ quality of life and physical performance. However, it is essential to note
that the concentration of molecular hydrogen (H2) has not been reported, only the oxidation-reduction
potential (ORP), which is not a reliable indicator of dissolved H2 concentration. This means that it is
not possible to determine whether the positive results were actually attributed to the consumption of
water with a high concentration of H2 or if they were inuenced by other factors. (CHEN, 2021)
Furthermore, in another study that tested the effects of different pH levels on diabetic
patients, it was observed that only the group that consumed water with a high concentration of H2
showed signicant benets, while the group with a low concentration of H2, despite having an alkaline
pH, did not show positive results. This highlights the importance of measuring H2 concentration to
validate the biological effects of ERW and avoid misinterpretations of the data. Therefore, the results
suggest that the effectiveness of ERW is closely linked to the concentration of H2 present in the water
consumed. (LeBaron, 2022)
Conclusion
Molecular hydrogen presents a promising therapeutic prole for the treatment of
neurodegenerative diseases, offering the potential to improve the quality of life of patients and reduce
the progression of symptoms. However, more research is needed to establish administration protocols,
effective dosages, and understand the specic mechanisms of action in the central nervous system.
Thus, molecular hydrogen emerges as a complementary, safe, and low-cost treatment option that can
potentially improve quality of life and slow the progression of neurodegenerative diseases.
However, more research is needed to dene optimal dosages, treatment timing, and protocols
to ensure their efcacy and safety in different patient populations. However, larger, long-term clinical
trials are needed to conrm these ndings and determine whether it may be a viable treatment option.
However, the results are still inconclusive and more studies are needed to conrm the efcacy and
safety of H2 in these cases. In terms of statistics, the clinical use of H2 for the treatment of these
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diseases is still limited.
Most studies are in the preclinical investigation phase or small clinical trials, with few H2-
based therapies being ofcially approved by regulatory agencies in large markets, such as the FDA
(USA) or EMA (European Union). There are some alternative hydrogen-based therapies, such as H2
inhalers or hydrogenated water, but widespread use and clinical acceptance are still a long way off.
According to some scientic societies, such as the International Society for Molecular Hydrogen
Therapy (IHMS), although research is growing, H2 as a clinical treatment for neurodegenerative
diseases still needs more robust evidence to become an established practice.
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