Short-term H2 inhalation improves running performance and torso strength in healthy adults

Abstract

In this randomized, double-blind, placebo-controlled, crossover pilot trial, we evaluated the effects of 7-day H2 inhalation on exercise performance outcomes and serum hormonal and inflammation profiles in a cohort of young men and women. All participants (age 22.9 ± 1.5 years; body mass index 23.4 ± 2.5 kg m-2; 10 women and 10 men) were allocated to receive either gaseous hydrogen (4%) or placebo (room air) by 20-min once-per-day inhalation for 7 days, with a wash-out period of 7 days to prevent the residual effects of interventions across study periods. The primary treatment outcome was the change in running time-to-exhaustion in the incremental maximal test from baseline to day 7. Additionally, assessment of other exercise performance endpoints and clinical chemistry biomarkers was performed at baseline and at 7 days after each intervention. The trial was registered at ClinicalTrials.gov (ID NCT03846141). Breathing 4% hydrogen for 20 min per day resulted in increased peak running velocity (by up to 4.2%) as compared to air inhalation (P = 0.05). Hydrogen inhalation resulted in a notable drop in serum insulin-like growth factor 1 (IGF-1) by 48.2 ng/mL at follow-up (95% confidence interval [CI]: from -186.7 to 89.3) (P < 0.05), while IGF-1 levels were elevated by 59.3 ng/mL after placebo intervention (95% CI; from -110.7 to 229.5) (P < 0.05). Inhalational hydrogen appears to show ergogenic properties in healthy men and women. Gaseous H2 should be further evaluated for its efficacy and safety in an athletic environment.

Full text

Biology of Sport, Vol. 36 No4, 2019 333
Hydrogen inhalation and exercise performance
INTRODUCTION
The use of medical gasses has been recently described as an emerg-
ing exotic strategy in the exercise physiology and sports medicine
community[1], with a few unconventional medical gasses (such as
NO, Xe, O3) put forward as performance-enhancing agents. Among
others, molecular hydrogen (H2) appears as an innovative compound
that might be applicable among athletes. Usually administered in
the form of a dietary supplement, either as hydrogen-rich water or
hydrogen-producing tablets, H2appears to positively affect exercise
capacity in both animal studies[2–4] and human trials[5–8]. This
might be due to its antioxidant and anti-inammatory properties[9]
that perhaps reduce exercise-induced inammation and oxidative
stress or through alteration of anabolic hormones production by sig-
nal modulation[10,11]. For instance, Aoki and co-workers[5] re-
ported that hydration with 1.5 L/day of hydrogen-rich wa-
ter(0.92–1.02mM of hydrogen) signicantly reduced blood lactate
levels and improved exercise-induced decline of muscle function in
male soccer players. Buffering capacity of hydrogen-rich wa-
ter(1.1 mM) during exercise-induced acidosis has also been
Short-term H2 inhalation improves running performance and
torso strength in healthy adults
AUTHORS: Dejan Javorac1, Valdemar Stajer1, Laszlo Ratgeber2, Jozsef Betlehem2, Sergej
Ostojic1,2
1 University of Novi Sad, Faculty of Sport and Physical Education, Novi Sad, Serbia
2 University of Pécs, Faculty of Health Sciences, Pécs, Hungary
ABSTRACT: In this randomized, double-blind, placebo-controlled, crossover pilot trial, we evaluated the
effects of 7-day H2 inhalation on exercise performance outcomes and serum hormonal and inammation proles
in a cohort of young men and women. All participants (age 22.9 ± 1.5years; body mass index 23.4 ±2.5kgm-2;
10women and 10 men) were allocated to receive either gaseous hydrogen (4%) or placebo (room air) by
20-min once-per-day inhalation for 7days, with a wash-out period of 7days to prevent the residual effects of
interventions across study periods. The primary treatment outcome was the change in running time-to-exhaustion
in the incremental maximal test from baseline to day 7. Additionally, assessment of other exercise performance
endpoints and clinical chemistry biomarkers was performed at baseline and at 7days after each intervention.
The trial was registered at ClinicalTrials.gov (ID NCT03846141). Breathing 4% hydrogen for 20 min per day
resulted in increased peak running velocity (by up to 4.2%) as compared to air inhalation (
P
= 0.05). Hydrogen
inhalation resulted in a notable drop in serum insulin-like growth factor1(IGF-1) by 48.2ng/mL at follow-up
(95% condence interval[CI]: from -186.7 to 89.3) (
P
< 0.05), while IGF-1 levels were elevated by 59.3ng/mL
after placebo intervention (95% CI; from -110.7 to 229.5) (
P
< 0.05). Inhalational hydrogen appears to show
ergogenic properties in healthy men and women. Gaseous H2 should be further evaluated for its efcacy and
safety in an athletic environment.
CITATION: Javorac D, Stajer V, Rátgéber L et al. Short-term H2 inhalation improves running per formance and
torso strength in healthy adults. Biol Sport. 2019;36(4):333
–
339.
Received: 2019-06-22; Reviewed: 2019-08-30; Re-submitted: 2019-09-07; Accepted: 2019-10-05; Published: 2019-10-31.
Original Paper
DOI: https://doi.org/10.5114/biolsport.2019.88756
Key words:
Hydrogen
Running to exhaustion
Insulin
IGF-1
Ergogenic
Corresponding author:
Sergej M. Ostojic
ORCID ID: http://orcid.org/
0000-0002-7270-2541
Applied Bioenergetics Lab
Faculty of Sport and Physical
Education
University of Novi Sad
Lovcenska 16,
Novi Sad 21000, Serbia
Phone: (++381)-21-450-188
Fax: (++381)-21-450-199
E-mail: sergej.ostojic@chess.edu.rs
Abbreviations
ANOVA Analysis of variance
CI Condence interval
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
FGF21 Fibroblast growth factor 21
H2 Molecular hydrogen
IGF-1 Insulin-like growth factor 1
MVIS Maximal voluntary isometric strength
VO2max Maximal oxygen uptake

334
Sergej M. Ostojic et al.
health check. Participants were asked to maintain their usual diets
and physical activity levels during the study.
Experimental intervention
All participants were allocated to receive either gaseous hydrogen
(4%) or placebo (room air) by 20-min once-per-day inhalation for
7days, with a wash-out period of 7days to prevent the residual
effects of interventions across study periods. The concentration of
H2 used and the duration of an inhalational session (20min) were
chosen as a method that gave a favourable effect in a previous human
study[15]. Previous studies suggested that continuous inhalation of
H2gas requires ~ 10 min to reach equilibrium in the tissue and
blood[16]. Gaseous hydrogen was provided via a gas mask by bio-
logical gas supplying apparatus (MIZ Company Ltd, Kanagawa, Ja-
pan), with the H2 ow rate approximately constant (~ 45mL/min)
and diluted by ambient air. Day-to-day H2 inhalation was supervised
by the study investigators throughout the trial. Placebo gas was
identical in appearance to hydrogen. The inhalation was administered
at the same time of day (08:00–09:00), ~ 60min before breakfast,
with all participants receiving the intervention simultaneously using
multiple machines. The primary treatment outcome was the change
in running time-to-exhaustion in the incremental test (see below)
from baseline to day 7. Additionally, assessment of other exercise
performance endpoints and clinical chemistry biomarkers was per-
formed at baseline and at 7days after each intervention (Figure 1).
Study design
The study was conducted in the FSPE Applied Bioenergetics Labora-
tory at the University of Novi Sad from February 2018 to April 2018,
with the trial registered at ClinicalTrials.gov (ID NCT03846141).
Laboratory assessments were carried out between 08:00 and 12:00
after an overnight fast and no exhaustive exercise over the previous
24h. Before testing exercise performance outcomes, participants
rst provided a blood sample at rest from a median cubital vein into
demonstrated after both continuous[6] and progressive running-to-
exhaustion exercise [7]. In addition, two weeks of hydrogen-rich
water intake (2L per day, 0.45 mM of free hydrogen) helped to
maintain peak power output in repetitive sprints to exhaustion over
30minutes in male cyclists [8]. Although the above preliminary
studies provided initial evidence about the performance-enhancing
capacity of hydrogen-rich water, it remains an open question wheth-
er the favourable effects originate from H2itself or perhaps from
magnesium, a conventional source of hydrogen in hydrogen-rich
water. Specically, the apparent buffering capacity of hydrogen-rich
water might be due to various pH buffers (e.g. bicarbonate, metallic
magnesium) found in liquid hydrogen products used previously[6,7]
rather than to H2gas, which is known not to inuence pH. Applying
pure hydrogen gas, instead of magnesium-based hydrogen formula-
tions, might, therefore, help to better reveal the authentic ergogenic
potential of H2. Moreover, using inhalation as a parenteral route of
H2 administration could emphasize the systemic action of hydrogen,
including the possible impact on insulin and ghrelin secretion[10].
Drinking hydrogen-rich water appears to alter plasma glucose and
insulin levels, an effect likely mediated by enhanced expression of
broblast growth factor 21 (FGF21), a metabolic hormone that im-
proves insulin sensitivity and glucose clearance[10]. The possible
augmented insulin response driven by hydrogen inhalation might
promote energy utilization and performance during exercise[12],
thus fostering H2 as an insulin secretion stimulator in an athletic
environment. Furthermore, recent evidence suggests that H2 has
therapeutic value for diseases that involve inammation[13,14],
thus raising the possibility of its use in the athletic environment by
counterbalancing biomarkers of exercise-induced inammation and
damage (e.g. creatine kinase, myoglobin, ferritin, C-reactive protein).
In this randomized controlled preliminary trial, we evaluated the
effects of 7-day H2 inhalation on exercise performance outcomes and
serum hormonal and inammation proles in a cohort of young ac-
tive men and women. We hypothesized that gaseous H2 would im-
prove cardiorespiratory and muscular performance, and stimulate
insulin secretion, along with attenuation of the inammatory response.
This appears to be the rst clinical study where H2 inhalation was
used for athletic performance.
MATERIALS AND METHODS
Participants
Twenty healthy, physically active young volunteers (age
22.9±1.5years; body mass index 23.4 ± 2.5kg/m2; 10women
and 10men) signed informed consent to voluntarily participate in
this randomized, double-blind, placebo-controlled, crossover pilot
trial, with all procedures approved by the local Institutional Review
Board at the University of Novi Sad in accordance with the Declara-
tion of Helsinki. All participants had no history of H2 supplementation
(or other performance-enhancing dietary supplements or drugs)
within the 4weeks before the study commenced, and no acute or
chronic disorders and diseases, as evaluated by the pre-participation
FIG. 1. Study protocol. Vertical arrows indicate sampling intervals
for primary and secondary outcomes.

Biology of Sport, Vol. 36 No4, 2019
335
Hydrogen inhalation and exercise performance
an evacuated test tube while seated. The venous blood was
immediately centrifuged within the next 10min at 3000g, with
serum separated and analyzed for ghrelin and insulin-like growth
factor1(IGF-1) using commercial ELISA kits on an automated ana-
lyzer (ChemWell 2910, AWARENESS Technology Inc., Palm City,
FL). Insulin and ferritin were analyzed using chemiluminescence
immunoassays (ADVIA Centaur XP, Siemens Healthcare GmbH, Er-
langen, Germany). Myoglobin was analyzed with solid-phase enzyme
immunoassay (AIA-360, Tosoh Bioscience, San Francisco, CA), while
serum creatine kinase (CK) and C-reactive protein (CRP) were mea-
sured by standard enzymatic methods with an automatic analyzer
(Hitachi 912, Tokyo, Japan). Erythrocyte sedimentation rate (ESR)
was measured with the reference Westergren technique. Blood lac-
tates were measured by the enzymatic-colorimetric method (Accu-
Trend, Hoffmann-La Roche Ltd., Basel, Switzerland). After blood
chemistry analyses, participants performed a series of different ex-
ercise tests. First, maximal voluntary isometric strength (MVIS) of
forearm muscles was evaluated with a hydraulic hand dynamometer
(Jamar J00105, Lafayette Instrument Company, Lafayette, IN), and
MVIS of torso and leg muscles with a Back-Leg-Chest dynamometer
(Baseline 12-0403, Fabrication Enterprises Inc., White Plains, NY).
Second, muscular endurance in the upper body was assessed through
the gender-specic YMCA Bench Press Test[17]. Finally, cardiore-
spiratory endurance was evaluated by a maximal incremental running
test on an institutional treadmill (3-min warm-up walk at 6km/h
followed by running at 8km/h with a progressive workload increment
rate of 1.5 km/h every 60s until exhaustion). Gas exchange data
were collected throughout the test using a breath-by-breath meta-
bolic system (Quark CPET, COSMED, Rome, Italy). The test was
nished when participants were too physically tired to continue run-
ning, and additional criteria for the maximal test were met (e.g. rise
in oxygen uptake satised a plateau representing less than 2mL/kg/min
to the next level, respiratory exchange ratio ≥ 1.10 and peak heart
rate ≥ 95% of age-predicted maximal heart rate). Participants were
also instructed to report on adverse effects of H2intervention through
an open-ended questionnaire for self-assessment of side effects dur-
ing the study. All participants were familiarized with testing procedures
and were assessed on the same day with the tests performed in the
same order.
Statistical analyses
The appropriate sample size (n = 20) was calculated using power
analysis (effect size 0.3, alpha error probability 0.05, power 0.80)
for the primary treatment outcome (G-Power 3, Heinrich Heine Uni-
versity Düsseldorf, Germany). Two-way mixed model analysis of vari-
ance (ANOVA) with repeated measures was used to establish wheth-
er any significant differences existed between participants’
responses over time of intervention (0vs. 7days). When non-homo-
geneous variances were identied, values were compared using Fried-
man’s 2-way ANOVA by ranks. Identication and removal of outliers
were conducted according to the interquartile range method. The
signicance level was set at P ≤ 0.05.
RESULTS
All participants completed the study, with no men or women report-
ing any adverse events of molecular hydrogen or placebo inhalation.
No signicant differences were found in most biomarkers’ responses
between two interventions (P > 0.05), except for serum IGF-1, CRP,
and ferritin (Table 1). Hydrogen inhalation resulted in a notable drop
in serum IGF-1 for 48.2ng/mL at follow-up (95% confidence
TABLE 1. Changes in biochemical markers during the study. Values are mean ± SD.
Baseline At 7 days
Placebo H2
Insulin (IU/mL) 5.3 ± 1.6 4.6 ± 1.6 4.7 ± 1.5
Ghrelin (ng/mL) 9.1 ± 4.3 15.7 ± 4.8 13.4 ± 5.0
IGF-1 (ng/mL) 513.1 ± 235.3 572.5 ± 293.1 464.9 ± 192.2 *
Creatine kinase (U/L) 214.0 ± 125.8 229.5 ± 125.1 220.4 ± 130.7
Myoglobin (ng/mL) 36.6 ± 12.8 42.1 ± 15.1 41.3 ± 15.5
C-reactive protein (mg/L) 1.4 ± 0.8 0.7 ± 0.6 0.4 ± 0.5 *
Ferritin (µg/L) 31.8 ± 19.7 26.2 ± 22.0 25.4 ± 19.2 *
ESR (mm/1 h) 4.6 ± 3.0 4.1 ± 2.3 4.4 ± 2.5
Lactate (mmol/L) 2.0 ± 0.7 1.8 ± 0.4 1.9 ± 0.5
Abbreviations: IGF-1– insulin-like growth factor 1, ESR– erythrocyte sedimentation rate.
* indicates a signicant difference (P ≤ 0.05) for time vs. trial interaction between placebo and H2 intervention.

336
Sergej M. Ostojic et al.
compared to placebo (6.4µg/L vs. 5.6µg/L; P ≤ 0.05). Breathing
H2 was superior to placebo to increase peak running velocity during
a maximal incremental running test (by up to 4.2%), also to attenu-
ate a drop in MVIS of torso muscles at 7-day follow-up (Figure 2).
No inter-group differences were observed in terms of handgrip and
leg MVIS, muscular endurance during repetitive bench press exercise,
interval[CI]: from -186.7 to 89.3), while IGF-1 levels were elevat-
ed by 59.3ng/mL after placebo intervention (95% CI; from -110.7
to 229.5). Baseline CRP levels were decreased by 1.0mg/L (95%CI;
0.6–1.4) and by 0.7mg/L (95% CI; 0.3–1.2) after hydrogen and
placebo inhalation at 7-day follow up, respectively. Hydrogen also
induced a more powerful drop in serum ferritin at follow-up, as
FIG. 3. Individual changes in primary treatment outcome (running time-to-exhaustion) between trials.
FIG. 2. Changes in exercise performance outcomes at baseline vs. follow-up (7 days). Values are presented as mean percentage
changes, with error bars representing SD. Asterisk (*) indicates a signicant difference between trials at P ≤ 0.05. MVIS– maximal
voluntary isometric strength, VO2max– maximal oxygen uptake.

Biology of Sport, Vol. 36 No4, 2019
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Hydrogen inhalation and exercise performance
or running time-to-exhaustion and maximal oxygen consumption.
Individual changes in the primary outcome (running time-to-exhaus-
tion) between trials are presented in Figure 3, with 12 out of 20par-
ticipants (60%) having performed better (or less inferior) after H2
inhalation. Nevertheless, an effect size analysis for the primary out-
come measure change revealed a small effect size for time vs. inter-
vention interaction (95% CI; from 71 to 183s after H2 intervention,
and from 66 to 174s after placebo intervention, η2= 0.002). Also,
resting blood pressure and heart rate remained unaffected by either
intervention (not presented here).
DISCUSSION
This rst-in-humans randomized controlled pilot trial provided pre-
liminary evidence that short-term hydrogen inhalation is superior to
placebo (room air) in improving exercise performance in healthy men
and women, with ergogenic effects of hydrogen accompanied by
notable changes in selected hormonal and inammatory biomarkers
at follow-up. However, inhalational H2demonstrated no signicant
effect on insulin and ghrelin secretion. In addition, hydrogen inhala-
tion caused no adverse events during our trial, implying low risk of
this route of H2administration for a short-term experimental period.
Hydrogen administration as a performance-enhancing intervention
in humans dates back to 2012. A Japanese group was rst to dem-
onstrate that H2 dispensed before exercise during 7days reduced
blood lactate levels and improved the exercise-induced decline of
muscle function in male soccer players subjected to strenuous exer-
cise[5]. Peak torque and muscle activity throughout 100repetitions
of maximal isokinetic knee extension appear to be less attenuated
after hydrogen intervention, as compared to placebo. Similar results
were found in a recent study[8], with 2-week hydrogen intake main-
taining peak power output during repetitive sprints to exhaustion in
trained male cyclists. Our study conrmed the above results, with
inhalational hydrogen increasing peak running velocity during exhaus-
tive exercise and attenuating the drop in maximal isometric strength
of the upper body muscles. Although this level of enhancement for
peak running velocity (4.2%) could be considered trivial, it might be
relevant for competing athletes, particularly due to the fact that the
effects were noted after such short-term administration. A combina-
tion of a nominal increase in time-to-exhaustion and notable improve-
ment of maximal running speed after inhaling H2 (although VO2max
tended to drop at follow-up) perhaps suggests better anaerobic ca-
pacity at the end of exercise. Hence, H2inhalation might be a suitable
performance-enhancing strategy for sporting activities characterized
by a high anaerobic contribution, including middle- and long-distance
events, team games or martial arts. While previous studies used
magnesium-based hydrogen[18], with magnesium possibly contrib-
uting to the ergogenic properties of the formulation by itself, the
present study conrmed benecial effects of pure hydrogen gas perse.
Although the exact mechanism of H2action remains to be eluci-
dated, the acute ergogenic effects of hydrogen might be due to its
strong antioxidative power and buffering capacity that could coun-
terbalance exercise-induced changes in metabolism[19]. Further-
more, hydrogen appears to stimulate many signalling pathways and
expression of genes that alter mitochondrial bioenergetics and hor-
mone secretion[20,21], which in turn might have a steady effect
on exercise performance. In the present study, we demonstrated an
effect of hydrogen on insulin-like growth factor-1, an anabolic hormone
that acts as a primary mediator of the effects of growth hormone.
Serum IGF-1 appeared to drop by ~ 10% after 7-day hydrogen in-
halation while serum IGF-1 remained high after placebo intervention,
implying a possible down-regulation link between exogenous H2 and
the anabolic response. This disagrees with a recent paper that re-
ported an up-regulating effect of hydrogen-rich water on the growth
hormone-IGF-1 axis, with an effect mediated by ghrelin, a peptide
hormone produced predominantly in the gut[22]. We found no no-
table differences in serum ghrelin response after hydrogen gas or
placebo in our pilot trial. This suggests that inhalational and oral
hydrogen might have different effects on the ghrelin-growth-hormone-
IGF-1 axis, with ghrelin-mediated effects perhaps playing a minor or
irrelevant role during short-term hydrogen inhalation. A drop in IGF-1
driven by hydrogen inhalation could be benecial among athletes,
particularly those who strive for lower body mass, since a decreased
level of IGF-1 seems to be associated with reduced weight and fat
mass in an active population[23]. H2inhalation might, therefore,
be recognized as a novel short-term strategy to manage weight, yet
more studies are needed to conrm this presumption. We also found
that H2 inhalation reduces levels of serum ferritin and CRP, both
non-specic biomarkers of inammation. This corroborates previous
ndings from animal and human studies about anti-inammatory
effects of H2[24,25], with hydrogen gas possibly exerting a regula-
tory role in the release of pro- and anti-inammatory cytokines me-
diated by haem oxygenase-1 expression and activation[26]. In the
context of the athletic environment, which is often characterized by
low-grade systemic inammation[27], inhalational hydrogen thus
may contribute to the more favourable internal milieu and perhaps
act as a protective compound[28] and an alternative to non-steroi-
dal anti-inammatory agents. On the other hand, regular exercise
induces inammation to promote repair, remodelling and signalling
in the body, with this hormetic response considered benecial to
achieve abiding muscle overcompensation and adaptation[29]. In
the present study, we found that non-specic biomarkers of inam-
mation were reduced after short-term H2 inhalation, yet whether
hydrogen affects long-term hormesis remains unknown at the mo-
ment. A recent study[30] proposed that H2 may act as an exercise
mimetic and redox adaptogen, potentiating the benets from regular
exercise (accompanied by low-grade inammation), and reducing
the adverse effects of harmful exercise (high-grade inammation).
Although our pilot study provided early evidence about the ben-
ecial effects of short-term hydrogen inhalation for athletic perfor-
mance, several limitations must be considered when the study nd-
ings are interpreted. We recruited only physically active young healthy
volunteers; it remains unknown how breathing H2 affects elite and

338
Sergej M. Ostojic et al.
CONCLUSIONS
In conclusion, breathing 4% gaseous hydrogen for 20min/day for
7days resulted in increased peak running velocity and attenuated
the drop in maximal isometric strength of trunk muscles in a cohort
of healthy, physically active young men and women. This was ac-
companied by hydrogen-driven changes in serum levels of insulin-like
growth hormone-1, ferritin and C-reactive protein at follow-up, as
compared to room air inhalation. Inhalational hydrogen should be
further evaluated for its efcacy and safety in an athletic environment.
Funding
Study was supported by the Serbian Ministry of Education, Science
and Technological Development (# 175037), the Provincial Secre-
tariat for Higher Education and Scientic Research (# 114-451-710),
and the Faculty of Sport and Physical Education.
Declaration of interest
The authors report no conicts of interest associated with this man-
uscript.
sub-elite athletes or the active population of advanced age. Here,
we evaluated both men and women, yet the small sample size lim-
ited subgroup analyses that might reveal possible gender-specic
effects of gaseous hydrogen. Even though we asked participants to
maintain their usual diets and physical activity levels during the
study, a lack of strict control of subject compliance with dietary and
exercise regime calls into question a possible role of these confound-
ing variables for changes in study outcomes. The short duration of
H2 treatment perhaps restricted the scope of our trial to acute re-
sponses while long-term intervention might reveal alternative or op-
posing effects of inhalational hydrogen. With a limited number of
clinical tests employed, a course of hydrogen action could not be
reliably determined. Therefore, more studies are highly warranted to
identify the exact mechanism underlying the ergogenic effects of
inhalational hydrogen, using randomized-controlled design for long-
term and well-powered trials that include advanced physiological,
metabolic and genomic proling. Also, legislative advocacy is need-
ed to address regulatory issues related to this route of H2 administra-
tion. While the World Anti-Doping Agency forbids the use of spe-
cic medical gases (such as argon and xenon)[1], it permits the use
of inhalational oxygen, while other therapeutic gases (including mo-
lecular hydrogen) are currently not controlled.
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