Repeated Carbon Monoxide Inhalation in Sports: A New Frontier or a Dangerous Gamble?

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Scandinavian Journal of Medicine & Science in Sports, 2024; 34:e70005
https://doi.org/10.1111/sms.70005
Scandinavian Journal of Medicine & Science in Sports
EDITORIAL
Repeated Carbon Monoxide Inhalation in Sports: A New
Frontier or a Dangerous Gamble?
BillySperlich1 | Hans- ChristerHolmberg2,3,4 | MarcosMartin- Rincon5 | ØyvindSkattebo6 | JamieF.Burr7 |
JosteinHallen6 | RobertC.Boushel4 | JoseA.L.Calbet4,5,6
1Integrative and Experimental Exercise Science and Training Science, Institute of Sport Sciences, University of Würzburg, Würzburg,
Germany | 2Department of Health, Education and Technology, Luleå University of Technology, Luleå, Sweden | 3Department of Physiology and
Pharmacology, Biomedicum C5, Karolinska Institutet, Stockholm, Sweden | 4School of Kinesiology, Faculty of Education, University of British Columbia,
Vancouver, British Columbia, Canada | 5Department of Physical Education, and Research Institute of Biomedical and Health Sciences (IUIBS), University
of las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain | 6Department of Physical Performance, Norwegian School of Sport Sciences, Oslo,
Norway | 7Department of Human Health & Nutritional Science, University of Guelph, Guelph, Ontario, Canada
Correspondence: Jose A. L. Calbet ( jose.calbet@ulpgc.es)
Received: 9 December 202 4 | Accepted: 10 December 2024
Funding: The authors received no specific funding for this work.
Over the past decade, carbon monoxide (CO) inhalation has gar-
nered significant interest in exercise science due to its potential
to enhance oxygen transport capacity and performance through
hypoxia induced erythropoiesis. Carbon monoxide binds to he-
moglobin (Hb) with an affinity 220–240 times greater than that
of oxygen (O₂), reducing the blood's oxygen- carrying capacity
and shifting the oxygen dissociation curve leftward. This mech-
anism may trigger compensatory erythropoiesis, leading to an
increase in hemoglobin mass (Hbmass), thereby theoretically
improving oxygen delivery and enhancing endurance perfor-
mance with chronic inhalation.
The potential risks of CO exposure have been recognized since
1857, when Claude Bernard demonstrated that CO impairs the
oxygen- carrying ability of hemoglobin, resulting in asphyxia.
Due to the slow dissociation of CO from hemoglobin, acciden-
tal over- administration can result in severe outcomes, includ-
ing permanent multiorgan damage or death. Carbon monoxide
is classified as a medical gas that requires stringent industrial
production, certification, and storage to avoid contamination
or the formation of toxic substances in gas cylinders. Although
low- dose CO administration is considered safe under medical
supervision, the long- term side effects of chronic CO inhalation
remain largely unexplored.
1 | Carbon Monoxide Effects Extend Beyond
Merely Binding to Hemoglobin
Carbon monoxide's effects extend beyond hemoglobin bind-
ing. Carbon monoxide can upregulate nuclear factor erythroid
2- related factor 2 (Nrf2), a transcription factor regulating over
250 genes involved in redox balance, mitochondrial biogene-
sis, metabolism, detoxification, cytoprotection, inflammation,
immunity, autophagy, cell differentiation, and xenobiotic me-
tabolism [1]. Inhalation of CO (200 ppm, 1 h/day for 5 days)
has been shown to induce significant changes in the human
vastus lateralis muscle [2], including increased protein expres-
sion of heme oxygenase- 1 (HO- 1) and elevated mRNA levels
of mitochondrial transcription factor A (Tfam), cytochrome c,
cytochrome oxidase subunit IV (COX IV), COX I, and NADH
dehydrogenase subunit 1 (NDI) [2]. Furthermore, CO inhala-
tion increased capillarization, mitochondrial density, citrate
synthase activity, myoglobin content, and GLUT4 protein lev-
els along with its sarcolemmal localization in human skeletal
muscle [2]. In a related study employing a similar protocol
(100 ppm, 1 h/day for 5 days), the same research group ob-
served elevated expression of HO- 1, superoxide dismutase 2,
and mRNA levels associated with proteins involved in mito-
chondrial fusion [3].
© 2024 J ohn Wiley & Sons A/S . Published by John W iley & Sons Ltd.

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2 | Studies on CO Inhalation—Impact on Hbmass,
VO₂Max, and Beyond
In 2019, a study of six well- trained male soccer players re-
ported that CO inhalation at a dose of 1 mL/kg body mass
for 2 min in O₂ (4 L) before treadmill training, performed five
times per week for 4 weeks, increased Hbmass by 3.7% and
VO₂max by 2.7% [4]. However, the control group, which un-
dertook similar training without CO inhalation, experienced
a comparable 2.8% increase in Hbmass, complicating any de-
finitive conclusions [4].
In a subsequent study, Schmidt etal. [5] administered CO to 11
moderately trained males at a daily dose of 1 mL/kg body mass
in the morning, followed by additional doses every 4 h to main-
tain carboxyhemoglobinaemia (COHb) levels between 4% and
8%. After 2 and 3 weeks, Hbmass increased by 3.3% and 4.8%,
respectively, though the observed 2.8% improvement in VO₂max
did not reach statistical significance. Notably, neither of these
studies assessed endurance performance directly.
More recently, Urianstad etal. [6] investigated 31 elite male cy-
clists (VO₂max: 73–75 mL/(kg.min)) in a study comparing three
groups: Live- High Train- High with CO inhalation, Live- High
Train- High at 2100 m above sea level, and Live- Low Train- Low.
The CO group inhaled the gas twice daily to achieve a COHb
concentration of ~10%. This group demonstrated a 5.8% increase
in Hbmass, while minimal or no changes were observed in the
other groups.
Collectively, these studies suggest that daily CO inhala-
tion over 2–3 weeks may increase Hbmass and, potentially,
VO₂max. The findings by Urianstad etal. [6] further indicate
that CO inhalation may amplify the erythropoietic response
to altitude exposure in athletes. Interestingly, athletes living
and training at altitude with CO supplementation showed
greater increases in Hbmass than those training at altitude
alone. However, improvements in VO₂max and performance
were similar in both altitude- trained groups, suggesting no
additional performance benefit from CO inhalation beyond
that observed with altitude training. This raises an important
question: why did the additional Hbmass from CO inhalation
not translate into enhanced performance in elite cyclists, who
are typically highly responsive to even minor increases in ox-
ygen delivery?
Athletes seeking to enhance Hbmass might consider com-
bining CO inhalation with hypoxic or heat training [7–10] to
further boost the erythropoietic response [6]. Additionally,
skeletal muscle adaptations to CO inhalation mimic some of
the responses to endurance training [2, 3]. However, whether
these effects occur in highly trained athletes remains un-
known. Although CO has vasodilatory effects [11] and may
protect against neurodegeneration [12] while conferring po-
tentially cardio- and neuroprotection against acute ischemia
[13–15] and suppressing pro- inflammatory cytokines while
promoting anti- inflammatory mediators [16], there are cur-
rently no FDA- approved clinical applications for CO as a
therapeutic agent. Thus, whether CO's anti- inflammatory and
antioxidant properties can be harnessed to aid athletic recov-
ery remains unclear.
3 | Health Risks of Carbon Monoxide
Supplementation
As mentioned, CO supplementation poses significant health
risks due to its high affinity for hemoglobin, which can poten-
tially lead to dangerous levels of COHb, hypoxic damage, and
even death. These risks are particularly concerning for athletes
who may attempt unsupervised use, which significantly in-
creases the likelihood of severe adverse effects. Additional risks
may arise if gas cylinders are contaminated or not certified for
medical use. Moreover, the chronic effects of CO exposure are
largely unknown. CO binds to myoglobin, neuroglobin, cytoglo-
bin, cytochrome c oxidase, monooxygenases (e.g., cytochrome
P- 450, nitric oxide synthase, dopamine β- hydroxylase), cys-
tathione β- synthase, and nicotinamide adenine dinucleotide
phosphate oxidase (NOX), among other enzymes, potentially
reducing or blocking their enzymatic activity or altering their
function. The impact of these effects on training adaptation and
overall health remains uncertain.
4 | Ethical Considerations and Competitive
Fairness
Beyond the health risks, CO supplementation raises ethical con-
cerns regarding fairness in competition. It can be argued that
repeated inhalation of carbon monoxide is a doping method that
may, in addition to enhancing limiting factors to endurance per-
formance, mask other doping procedures, such as autologous
blood transfusions and the misuse of erythropoiesis- stimulating
agents like erythropoietin (EPO) by altering biological passport
markers. This parallels the challenges of monitoring athletes
using altitude training, where fluctuating Hbmass compli-
cates the detection of EPO misuse or blood doping. The poten-
tial for CO to obscure key blood parameters warrants further
scrutiny, as it could allow athletes to evade detection of other
performance- enhancing drugs.
To qualify for the WADA prohibited list, a substance or method
must typically satisfy any two out of three criteria (https:// ww w.
wada- ama. org/ en/ prohi bited - list):
1. It has the potential to enhance or enhances sport
performance.
2. It represents an actua l or potential health ri sk to the athlete.
3. It violates the spirit of sports.
Repeated inhalation of CO satisfies all three and should be
banned. However, testing of hemoglobin mass by CO rebreath-
ing is essential for physiological assessment and should remain
allowable under controlled conditions. WADA's challenge is to
monitor, detect, and discourage its use.
5 | Conclusion
While CO may have some beneficial effects as a therapeutic
agent in specific medical contexts, the risks associated with
its use as a performance- enhancing supplement far outweigh
any potential benefits. The limited performance improvements
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observed, coupled with significant toxicity risks and ethical con-
cerns, render CO supplementation unsuitable for athletes. The
World Anti- Doping Agency (WADA) should express concern
and discourage the use of CO outside strictly controlled thera-
peutic applications.
Conflicts of Interest
There is no conf lict of interest to declare apart from using Carbon
Monoxide to measure blood volume in human research by most
co- authors.
Data Availability Statement
The authors have nothing to report.
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