Physiological Reports. 2021;9:e14739. 
 
  | 1 of 9
https://doi.org/10.14814/phy2.14739
wileyonlinelibrary.com/journal/phy2
Received: 22 November 2020 | Revised: 7 January 2021 | Accepted: 11 January 2021
DOI: 10.14814/phy2.14739  
R E V I E W  A R T I C L E
The effect of L- arginine supplementation on maximal oxygen 
uptake: A systematic review and meta- analysis
Shahla Rezaei1,2 |   Maryam Gholamalizadeh3 |   Reza Tabrizi4 |   Peyman Nowrouzi- Sohrabi5 |   
Samira Rastgoo6 |   Saeid Doaei3
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original 
work is properly cited.
© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society
1Student Research Committee, 
Department of Clinical Nutrition, School 
of Nutrition and Food Sciences, Shiraz 
University of Medical Sciences, Shiraz, 
Iran
2Nutrition Research Center, School of 
Nutrition and Food Sciences, Shiraz 
University of Medical Sciences, Shiraz, 
Iran
3Student Research Committee, Cancer 
Research Center, Shahid Beheshti 
University of Medical Sciences, Tehran, 
Iran
4Non- Communicable Diseases Research 
Center, Fasa University of Medical 
Sciences, Fasa, Iran
5Department of Biochemistry, School of 
Medicine, Shiraz University of Medical 
Sciences, Shiraz, Iran
6Department of Clinical Nutrition and 
Dietetics, National Nutrition and Food 
Technology Research Institute Shahid 
Beheshti University of Medical Science, 
Tehran, Iran
Correspondence
Saeid Doaei, Student Research 
Committee, Cancer Research Center, 
Shahid Beheshti University of Medical 
Sciences, Tehran, Iran.
Email: sdoaee@yahoo.com
Funding information
Funding for this study was provided by 
the student research committee of Shahid 
Beheshti University of Medical Sciences, 
Tehran, Iran (code: 13172).
Abstract
Background: The efficacy and safety of L- arginine supplements and their effect on 
maximal oxygen uptake (VO2 max) remained unclear. This systematic review aimed 
to investigate the effect of L- arginine supplementation (LAS) on VO2 max in healthy 
people.
Methods: We searched PubMed, Scopus, Web of Science, Cochrane, Embase, 
ProQuest, and Ovid to identify all relevant literature investigating the effect of LAS 
on VO2 max. This meta- analysis was conducted via a random- effects model for the 
best estimation of desired outcomes and studies that meet the inclusion criteria were 
considered for the final analysis.
Results: The results of 11 randomized clinical trials indicated that LAS increased 
VO2 max compared to the control group. There was no significant heterogeneity 
in this meta- analysis. Subgroup analysis detected that arginine in the form of LAS 
significantly increased VO2 max compared to the other forms (weighted mean differ-
ence = 0.11 L min−1, I2 = 0.0%, p for heterogeneity = 0.485).
Conclusions: This meta- analysis indicated that supplementation with L- arginine 
could increase VO2 max in healthy people. Further studies are warranted to confirm 
this finding and to identify the underlying mechanisms.
K E Y W O R D S
L- arginine, maximal oxygen uptake, meta- analysis, VO2 max
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1 | INTRODUCTION
Cardiovascular endurance is one of the most important mea-
sures of overall health (Ruiz et al., 2006). A person's level 
of cardiovascular endurance helps predict ability to react 
to acute physical and mental stress (Gutin et al., 2005). For 
healthy individuals, higher cardiovascular endurance also can 
indicate an elevated level of physical fitness (Haghshenas 
et al., 2019). One of the best indicators for the athlete's car-
diovascular performance is the maximal oxygen uptake (VO2 
max) assessment (Campbell et al., 2006). A greater amount 
of oxygen consumed by the body is related to higher cardio-
vascular efficiency (Adams et al., 1995). Higher cardiovascu-
lar efficiency allows muscle to work at a higher intensity for 
a longer time period. The body can only exercise as long as 
oxygen is delivered to the muscle and waste products such as 
carbon dioxide are removed (Haghshenas et al., 2019). Many 
factors such as proteins could be associated with cardiovascu-
lar risk factors and other diseases (Doaei et al., 2018; Shidfar 
et al., 2018).
Amino acids are among the most common nutritional sup-
plements which are used by athletes to improve athletic per-
formance under aerobic and anaerobic conditions (Mashiko 
et al., 2004). L- arginine is one of the semi- essential amino 
acids that has positive effects on muscle metabolism (Preli 
et al., 2002). L- arginine may also have a key role in the car-
diac function of athletes. Arginine is a precursor of nitric 
oxide (NO) and NO causes vasodilatory effects, increased 
blood flow to the muscles, and increased release of cer-
tain hormones such as insulin and human growth hormone 
(Adams et al., 1995; Moazami et al., 2015). Oral L- arginine 
supplements improved coronary endothelium- dependent di-
lation (Melik et al., 2017).
L- arginine may have led to delayed fatigue by altering 
blood lactate concentration and metabolic indices of respi-
ration. It is frequently reported that using L- arginine supple-
ment may improve athletic performance in sports activities. 
(Yaman et al., 2010). Yaman et al. found that L- arginine sup-
plementation (LAS) significantly reduced blood pressure and 
increased VO2 max and may influence athletic performance 
capacity (Kalman et al., 2016).
However, the studies on the association between LAS 
and VO2 max reported contradictory results. Therefore, this 
systematic review and meta- analysis aimed to investigate the 
effect of LAS on VO2 max.
2 | METHODS AND MATHERIALS
2.1 | Literature search strategy
This systematic review and meta- analysis was performed 
in accordance with PRISMA (Preferred Reporting Items 
for Systematic Reviews and Meta- Analyses) guidelines 
(Liberati et al., 2009). The scientific databases includ-
ing PubMed, Scopus, Web of Science, Cochrane, Embase, 
ProQuest, and Ovid were reviewed to identify all relevant 
literature on the effects of LAS on VO2 max that were 
published by August 2020. The following search strat-
egy was used to finalize the first step of data gathering: 
(Arginine[Mesh] OR Arginine[tiab]) AND (VO2[tiab] OR 
"maximal aerobic"[tiab] OR "aerobic capacity"[tiab] OR 
"maximal O2"[tiab] OR "maximal O2 consumption"[tiab] 
OR "maximal O2 uptake"[tiab] OR "peak O2"[tiab] OR 
"maximal oxygen consumption"[tiab] OR "maximal oxygen 
uptake"[tiab] OR "peak oxygen uptake"[tiab] OR "maximal 
aerobic capacity"[tiab]).
To enhance the quality of the searches, hand search-
ing was performed to find all relevant articles using the 
references of the collected articles. The searches were 
limited to human studies and no language restriction was 
used in the search process. Two authors (Sh. R and P. N) 
independently screened the title and the abstracts of the 
included papers, performed data extraction, and carried 
out the quality assessments of the eligible studies. All dis-
agreements were resolved by consulting with a third author 
(R. T).
2.2 | Study selection
The following strategy was used to select the eligible pa-
pers for performing the meta- analysis: Randomized clini-
cal trials (parallel or cross- over) experiments, investigated 
the effect of LAS on VO2 max in healthy human subjects, 
individuals supplemented with arginine were compared 
to placebo- control individuals, arginine supplementation 
administered for at least 1 week, papers with enough in-
formation to measure the VO2 max, papers contained data 
for SD, SE, and CI parameters in the beginning and the 
end of the study for both of the intervention and control 
groups.
2.3 | Data extraction
All eligible randomized controlled trials were separately 
re- checked and the following data were extracted: the 
name of the first author, country, the number of individu-
als in the intervention and control groups, the form of 
supplemented arginine, arginine doses, duration of the 
study, type of the study, and the related data for further 
steps (Table 1). For each study, the value of mean and 
SD for VO2 max in the beginning and at the end of the 
study was extracted. The following formula was used to 
calculate the mean difference of SDs: 
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REZAEI Et Al.
TABLE 1 Participant and intervention characteristics of the studies included in the systematic review and meta- analysis
ID
Authors
Year
Country
Population
Age
Number of subjects 
in intervention/
control groups
Type of study
Type of Intervention
Control 
group
Duration 
of study
1
Camic et al.
2010
USA
College- aged male
22.1 ± 2.4
21/20
Randomized, double- blind, 
placebo, controlled, 
parallel design
3 g/day, LAS+300 mg of grape 
seed extract + 300 mg of 
polyethylene glycol
Placebo
28 days
2
Chen et al.
2010
USA
Male cyclists
ARG:57.6 ± 4.6 
PLA: 
60.6 ± 8.7
8/8
Two- arm prospectively 
randomized double- 
blinded and placebo- 
controlled trial
5.2 g/day, LAS + L- 
citrulline + 500 mg ascorbic 
acid, 400 IU vitamin E, 
400 μg folic acid, 300 mg L- 
taurine, and 10 mg alpha 
lipoic acid
Placebo
21 days
3
Muazzezzaneh 
et al.
2010
Iran
Healthy athletes
22.66 ± 1.46
14/13
Based on a single- blind 
placebo- controlled trial
5 g/day, LAS
Placebo
21 days
4
Sunderland 
et al.
2011
USA
Endurance- trained 
male cyclists
36.3 ± 7.9
9/9
Randomized, conducted in 
a double- blind manner
12 g/day, LAS
Placebo
28 days
5
Moazami et al.
2014
Iran
Female handballists
2.49 ± 22.15
8/8
Randomized clinical trial
3 g/day, LAS
Placebo
7 days
6
Zak et al.
2015
USA
Untrained men
22.0 ± 1.7
19/19
Double blinded, placebo- 
controlled, within 
subjects’ crossover 
design
3 g/day, LAS + 300 mg of 
grape seed extract (95% 
procyanidins), and 300 mg of 
polyethylene glycol
Placebo
7 days
7
Hosseini et al.
2015
Iran
Healthy futsal 
players
22.5 ± 1.39
10/10
Randomized control trial
4 g/day, LAS
Placebo
28 days
8
Pahlavani et al.
2017
Iran
Soccer players
20.85 ± 4.29
25/27
Double- blinded, 
randomized, placebo- 
controlled trial
2 g/day, LAS
Placebo
45 days
9
Dennis et al.
1991
France
Medical students, 
active in 
recreational 
activities
19– 26
15/15
Double- blind, cross- over 
study
5 g/day, AA
Placebo
10 days
10
Burtscher et al.
2005
Austria
Healthy athletes
22 ± 3
8/8
Double blind placebo- 
controlled trial
3 g/day, AA
Placebo
21 days
11
Campbel et al.
2005
USA
Resistance- trained 
healthy adult 
men
38.9 ± 5.8
20/15
Randomized, double- blind, 
controlled design
12 g/day, AAKG
Placebo
56 days
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REZAEI Et Al.
A correlation coefficient of 0.5 was used for R, esti-
mated between 0 and 1 values, respectively. Also, the for-
mula SD = SE ×
√
n (n = the number of individuals in each 
group) was used to measure SD in each article that reported 
SE instead of SD.
2.4 | Quality assessment
The quality assessment of the included papers in this meta- 
analysis was performed according to Cochrane criteria 
(Higgins, 2011). According to this guideline, any source of 
bias including selection bias, performance bias, detection 
bias, attrition bias, and reporting bias were judged for all in-
cluded studies (Figure 1).
2.5 | Statistical analysis
This meta- analysis was conducted using Stata version 11. 
Due to the population selection from different countries, a 
random- effects model was employed with a 95% confidence 
interval (CI) for the calculation of the pooled weighted 
mean difference (WMD). Analysis endpoints were calcu-
lated as the difference in mean between baseline and post- 
treatment (measure at the end of follow- up − measure at 
baseline); also, the SD of mean change was calculated by 
the pooled SD. The statistical heterogeneity between trials 
was calculated by p- value and using I2 statistic (p < 0.05 
and I2 > 50%). Publication bias was checked by the funnel 
plot, Begg's test (p = 0.815), and Egger's tests (p = 0.218; 
Figure 2).
SD =square root [(SD at baseline)2 +(SD at the end of study)2
−(2R×SD at baseline×SD at the end of study)] .
FIGURE 1 Summary of risk of bias: According to Cochrane 
criteria, any source of bias including selection bias, performance bias, 
detection bias, attrition bias, and reporting bias were judged for all 
included studies
FIGURE 2 
Publication bias was 
checked by the funnel plot, Begg's 
(p = 0.815) test, and Egger's (p = 0.218) 
tests. SE, standard error; WMD, weighted 
mean difference
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REZAEI Et Al.
3 | RESULTS
3.1 | Search results and study selection
The flow chart presented in Figure 3 describes the process 
of selection and the references retrieved in the database. A 
total number of 945 articles was identified in the first step of 
the literature search of electronic databases. After excluding 
duplicated studies (n = 617), irrelevant studies based on title 
and abstracts (n = 295), type of intervention (n = 1), type of 
outcomes (n = 5), and the required data (n = 4), 23 poten-
tially relevant articles were considered for full text review. 
After screening, 12 articles were excluded for the follow-
ing reasons: studies population, insufficient data reporting 
of outcome, and type of LAS. Finally, 11 studies were in-
cluded in the present meta- analysis (Burtscher et al., 2005; 
Camic et al., 2010; Campbell et al., 2006; Chen et al., 2010; 
Denis et al., 1991; Hosseini et al., 2015; Moazami et al., 
2015; Muazzezzaneh et al., 2010; Pahlavani et al., 2017; 
Sunderland et al., 2011; Zak et al., 2015).
3.2 | Quantitative data synthesis
Marginal 
significant 
increase 
in 
VO2 
max 
(WMD  =  0.07  L  min−1; 95% CI, 0.00– 0.13, p  =  0.047; 
I2 = 23.2%) was found after L-  arginine supplementation in 
comparison with the control group (Figure 4).
3.3 | Subgroup analysis
Subgroup analysis was performed based on the study dura-
tion (≥14 days), dosage of L- arginine (<5 g/day), and the 
type of arginine supplementation including LAS, arginine 
aspartate, arginine alpha- Ketoglutarate, and arginine in com-
bination with antioxidants to detect the source of heteroge-
neity. There was a significant increase in VO2 max in the 
subgroup analysis of trials with LAS (WMD = 0.11 L min−1, 
I2 = 0.0%, p for heterogeneity = 0.485; Table 2).
3.4 | Sensitivity analysis
The sensitivity analysis was performed using “one- study- 
removed” method to survey the impact of each study on the 
effect size. The results of sensitivity analysis identified the 
higher and lower pooled weight mean difference for VO2 
max (WMD  =  0.1  L  min−1; 95% CI 0.08, 0.13) after ex-
cluding the Burtscher et al. (2005) study and (WMD = 0.03 
L.min- 1; 95% CI 0.04, 0.1) after excluding Hosseini et al. 
(2015) study, respectively (Figure 5).
FIGURE 3 
Preferred Reporting Items 
for Systematic Review and Meta- Analyses 
flow diagram
Records idenﬁed through 
database searching 
(n =945) 
Eligibility 
Addional records idenﬁed by 
hand searching 
(n = 0)
Records aer duplicates removed 
(n = 617) 
Records screened 
(n = 328) 
Records excluded by tle 
and abstracts 
(n =295)
Full-text arcles assessed 
for eligibility 
(n = 33)
Full-text arcles excluded, 
with reasons 
(n = 10) 
Intervenon (1) 
( )
Studies included in 
qualitave synthesis 
(n = 23)
Studies included in 
quantave synthesis 
(meta-analysis) 
(n = 11)
Records excluded 
(n = 12 ) 
Populaon (2) 
Type of intervenon (2) 
Screening
Idenﬁcaon
Included
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REZAEI Et Al.
4 | DISCUSSION
This is the first meta- analysis that evaluates the effect of LAS on 
VO2 max in healthy human subjects. The results indicated that 
LAS resulted in a mean increase of 0.07 L min−1 for VO2 max 
compared with placebo (95% CI, 0.00– 0.13). No significant 
heterogeneity was detected in this meta- analysis. The subgroup 
analysis indicated that supplementation with L- arginine alone 
significantly increased VO2 max compared to the other types 
of arginine or combined with other metabolites or supplements.
Evidence suggest the relationship between LAS and im-
proved exercise performance. L- arginine is reported to have a 
key role in creatine synthesis as well as in increase endogenous 
growth hormone (Campbell et al., 2004). L- arginine is also 
the substrate for nitric oxide synthesis that plays a role in the 
autoregulation of blood flow, myocyte differentiation, respira-
tion, and glucose homeostasis in muscle (Stamler & Meissner, 
2001). Although some studies have shown a positive effect of 
LAS on exercise performance, the results of the trials which 
assessed the effect of LAS on VO2 max were inconsistent.
A positive effect of LAS on VO2 max was identified in 
the present meta- analysis. This finding is generally in line 
with some of the individual studies selected for this re-
view. Hosseini et al. (2015) reported that 4 g/day arginine 
FIGURE 4 Forest plot comparing the effects of L- Arg supplementation on VO2 max
Subgroup analysis for VO2 max
Subgroup
No. of 
trials
WMD (95% CI)
Test for the 
overall effect
Test for 
heterogeneity
I2 (%)
Duration of study (days)
>14 days
8
0.05 (−0.04, −0.13)
p = 0.261
p = 0.102
41.5
≤14 days
3
0.11 (−0.06, 0.28)
p = 0.188
p = 0.596
0.0
L- arginine dose (g/day)
<5
6
0.07 (−0.03, 0.17)
p = 0.186
p = 0.047
55.4
≥5
5
0.03 (−0.11, −0.16)
p = 0.704
p = 0.969
0.0
Type of L- arginine
LAS
5
0.11 (0.08, 0.14)
p = 0.000
p = 0.485
0.0
AA
2
−0.06 (−0.25, 0.12)
p = 0.506
p = 0.250
24.5
Other
4
0.01 (−0.14, 0.17)
p = 0.852
p = 0.956
0.0
Abbreviations: AA, arginine aspartate; AAKG, arginine alpha- Ketoglutarate; LAS, L- arginine 
supplementation.
TABLE 2 Subgroup analysis was 
performed based on the study duration, 
dosage of L- arginine, and the form of 
arginine supplementation
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REZAEI Et Al.
supplementation for 4  weeks could significantly increase 
VO2 max and subsequently improved sports performance 
in athletes. Another study conducted by Moazami et al. 
(2015) reported that VO2 max was significantly increased 
after a 7- day supplementation of L- arginine at the dose of 
21 g/day in female athletes. In addition, a placebo- controlled 
trial (Pahlavani et al., 2017) indicated that the oral supple-
mentation of L- arginine at the dose of 2 g/day for 45 days 
could increase VO2 max. Conversely, Burtscher et al. (2005) 
found that 3 weeks of L- arginine- L- aspartate supplementa-
tion at the dose of 3 g/day resulted in lower oxygen con-
sumption and reduced ventilation during submaximal cycle 
exercise. This may be explained by the difference in phys-
iological functions at a maximum level of effort compared 
with a submaximal (Larsen et al., 2007). It seems that nitric 
oxide derived from L- arginine through competitive inhi-
bition of oxygen use in the electron transport chain result 
in lower whole- body oxygen consumption at submaximal 
work (Burtscher et al., 2005; Larsen et al., 2007; Schweizer 
& Richter, 1994).
However, some studies did not observe any significant asso-
ciation between the intake of LAS and VO2 max (Abel et al., 
2005; Zak et al., 2015). These inconsistent results may be ex-
plained by the different test protocols applied, study duration, 
dosages of L- arginine, form of L- arginine supplement, and also 
the level of physical fitness. For example, oral supplementation 
of L- arginine was used in combination with various other me-
tabolites/salts in several studies that may cause synergistic or 
antagonistic effects (McConell, 2007). Furthermore, the train-
ing status of the subjects seems to be an important factor related 
to the positive effect of LAS. LAS could have lower positive 
effects in well- trained participants comparing with untrained 
people (Besco et al., 2012). Moreover, different L- arginine dos-
ages used in chronic and acute supplementation protocols could 
have different physiological mechanisms of action. A recent 
meta- analysis reported that the effective dose of LAS should 
be adjusted to 0.15 g/kg body weight taken 60– 90 min before 
exercise in the acute protocol or 10– 12 g LAS for 8 weeks in 
chronic protocol for improving both aerobic and anaerobic per-
formances (Viribay et al., 2020).
L- arginine can improve exercise performance by en-
hancing protein synthesis and reducing muscle fiber damage 
(Lomonosova et al., 2014). It is also the precursor of nitric oxide 
that is used to increase endurance and improvement in blood 
flow (Alvares et al., 2011; Moncada & Higgs, 1993).One of the 
possible mechanisms to describe the increase in VO2 max is 
the nitric oxide derived from L- arginine that results in vessel 
vasodilatation and flow, which, in turn, may positively influence 
coronary perfusion. An increase in NO production may enhance 
oxygen and nutrients delivery to the active muscles. Therefore, 
oxygen consumption increases dramatically in the active mus-
cles with a parallel increase in muscle blood flow. (Burgomaster 
et al., 2006; Nagaya et al., 2001; Stamler & Meissner, 2001).
The oral LAS also facilitates the phase II pulmonary VO2 
response. The proposed mechanism to explain this effect is an 
increase in L- arginine availability, with subsequent increases 
in certain tricarboxylic acid cycle intermediates which fi-
nally lead to enhance the oxidative metabolism (Koppo et al., 
2009). However, further studies are needed to understand the 
exact mechanisms of how L- arginine affects VO2 max in 
healthy human subjects.
Although this is the first meta- analysis that evaluates the 
effect of LAS on VO2 max in healthy human subjects, it has 
some limitations. There were some differences in the sup-
plementation protocols, doses, timing, and also form of L- 
arginine in the included trials which limited the extraction of 
strong conclusions.
5 | CONCLUSIONS
This meta- analysis indicated that LAS had a positive effect 
on increasing VO2 max. Future homogeneous and well- 
designed randomized clinical trials are needed to a deep un-
derstand of the effects of L- arginine on VO2 max in healthy 
human subjects.
FIGURE 5 
The sensitivity analysis 
was performed using the “one- study- 
removed” method to survey the impact of 
each study on the effect size
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REZAEI Et Al.
ETHICS APPROVAL AND CONSENT 
TO PARTICIPATE
This study has been approved by Local ethics review boards 
at Shahid Beheshti University of Medical Sciences.
CONSENT FOR PUBLICATION
Institutional consent forms were used in this study.
ACKNOWLEDGMENTS
This study was conducted at the Student research center of 
Shahid Beheshti University of Medical Sciences, Tehran, 
Iran (code 13172).
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
AUTHORS' CONTRIBUTIONS
Maryam Gholamalizadeh, Saeid Doaei, and Shahla Rezaei 
designed the study, and were involved in the data collec-
tion, analysis, and drafting of the manuscript. Reza Tabrizi, 
Peyman Nowrouzi- Sohrabi, and Samira Rastgoo were in-
volved in the design of the study, analysis of the data, and 
critically reviewed the manuscript. All authors read and ap-
proved the final manuscript.
DATA AVAILABILITY STATEMENT
Not applicable.
ORCID
Saeid Doaei 
 https://orcid.org/0000-0002-2532-7478 
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How to cite this article: Rezaei S, Gholamalizadeh 
M, Tabrizi R, Nowrouzi- Sohrabi P, Rastgoo S, Doaei 
S. The effect of L- arginine supplementation on 
maximal oxygen uptake: A systematic review and 
meta- analysis. Physiol Rep. 2021;9:e14739. https://
doi.org/10.14814/phy2.14739

The effect of L-arginine supplementation on maximal oxygen uptake: A systematic review and meta-analysis.
Rezaei, Shahla,Gholamalizadeh, Maryam,Tabrizi, Reza,Nowrouzi-Sohrabi, Peyman,Rastgoo, Samira,Doaei, Saeid