Caffeine Increases Exercise Performance,

Maximal Oxygen Uptake, and Oxygen Deficit in

Elite Male Endurance Athletes
HANS KRISTIAN STADHEIM1, TRINE STENSRUD1, SØREN BRAGE2, and JØRGEN JENSEN1
1
Department of Physical Performance, Norwegian School of Sport Sciences, Ullevål Stadion, NORWAY; and 2MRC
Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Sciences, Cambridge Biomedical
Campus, England, UNITED KINGDOM

ABSTRACT
STADHEIM, H. K., T. STENSRUD, S. BRAGE, and J. JENSEN. Caffeine Increases Exercise Performance, Maximal Oxygen Uptake, and
Oxygen Deficit in Elite Male Endurance Athletes. Med. Sci. Sports Exerc., Vol. 53, No. 11, pp. 2264-2273, 2021. Caffeine increases endur-
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ance performance, but the physiological mechanisms improving high-intensity endurance capacity are not well characterized. Purpose: The
aims of the present study were to test the hypothesis that caffeine increases maximal oxygen uptake (V̇O2max) and to characterize the physi-
ological mechanisms underpinning improved high-intensity endurance capacity. Methods: Twenty-three elite endurance-trained male athletes
were tested twice with and twice without caffeine (four tests) in a randomized, double-blinded, and placebo-controlled study with crossover
design. Caffeine (4.5 mg·kg−1) or placebo was consumed 45 min before standardized warm-up. Time to exhaustion during an incremental test
(running 10.5° incline, start speed 10.0 km·h−1, and 0.5 km·h−1 increase in speed every 30 s) determined performance. Oxygen uptake was mea-
sured continuously to determine V̇O2max and O2 deficit was calculated. Results: Caffeine increased time to exhaustion from 355 ± 41 to 375 ± 41 s
(Δ19.4 ± 16.5 s; P < 0.001). Importantly, caffeine increased V̇O2max from 75.8 ± 5.6 to 76.7 ± 6.0 mL·kg−1·min−1 (Δ 0.9 ± 1.7 mL·kg−1·min−1;
P < 0.003). Caffeine increased maximal heart rate (HRpeak) and ventilation (VEpeak). Caffeine increased O2 deficit from 63.1 ± 18.2 to
69.5 ± 17.5 mL·kg−1 (P < 0.02) and blood lactate compared with placebo. The increase in time to exhaustion after caffeine ingestion was reduced
to 11.7 s after adjustment for the increase in V̇O2max. Caffeine did not significantly increase V̇O2max after adjustment for VEpeak and HRpeak.
Adjustment for O2 deficit and lactate explained 6.2 s of the caffeine-induced increase in time to exhaustion. The increase in V̇O2max, VE, HR,
O2 deficit, and lactate explained 63% of the increased performance after caffeine intake. Conclusion: Caffeine increased V̇O2max in elite ath-
letes, which contributed to improvement in high-intensity endurance performance. Increases in O2 deficit and lactate also contributed to the
caffeine-induced improvement in endurance performance. Key Words: EXERCISE PERFORMANCE, OXYGEN CONSUMPTION,
HEART RATE, OXYGEN DEFICIT AND LACTATE

C
affeine ingestion improves endurance performance of workload after caffeine ingestion also elevates cardiac output
both short and longer duration (1–5), and whether the (Qc) and increases oxygen uptake (8,9,13,15–18). It seems
performance is measured as time to exhaustion (1,6) likely that caffeine improves performance, at least partly, via
or time trial (2,7,8). Importantly, caffeine reduces RPE at inhibition of adenosine receptors (4,19). However, adenosine
standard loads (9,10). Caffeine also increases anaerobic capacity receptors are expressed in most tissues including brain, heart,
and power (11,12), and lactate accumulation is higher after muscles, blood vessels, and lungs (20). Therefore, caffeine-
maximal effort exercise such as during time trials or time-to- induced inhibition of adenosine receptors can theoretically
exhaustion exercise (2,4,9,13). affect several physiological mechanisms contributing to improved
The higher performance at time trials after caffeine intake endurance performance.
requires higher power production and is associated with higher Maximal oxygen uptake (V̇O2max) represents the integrated
heart rate (HR) and ventilation (VE) (2–4,9,14). The higher capacity of the pulmonary, cardiovascular, and muscle systems
to take up, transport, and use oxygen (21–23), and V̇O2max is
a major determinant of endurance capacity. Although test
Address for correspondence: Jørgen Jensen, Ph.D., Department of Physical
Performance, Norwegian School of Sport Sciences, Ullevål Stadion, Norway; protocols for reaching V̇O2max have been a topic of controversy
E-mail: [Link]@[Link]. since introduced in the 1920s (24,25), there is broad agreement
Submitted for publication December 2020. that V̇O2max determines endurance capacity. It is generally
Accepted for publication May 2021. accepted that V̇O 2max is reached during an incremental
0195-9131/21/5311-2264/0 protocol of 4–8 min duration after warm-up (23,26–29).
MEDICINE & SCIENCE IN SPORTS & EXERCISE® Importantly, the same protocol can also be used to test
Copyright © 2021 by the American College of Sports Medicine performance and measure maximal ventilation (VEpeak),
DOI: 10.1249/MSS.0000000000002704 maximal heart rate (HRpeak), and O2 deficit (23).

2264

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 Maximal oxygen uptake seems under most circumstances written consent to participate in the study after being informed
to be limited by the capacity to transport oxygen to the work- of the purposes of the study and risks involved. The study
ing muscles (21,24,30). At sea level, Qc and blood volume (or was reviewed by the Regional Ethics Commit (REK sør-øst
total hemoglobin mass) restrict V̇O2max in most people (30). B; 2011/2554), concluding that approval from REK was not re-
Indirectly, this is also supported by the fact that elite endurance quired to perform the study as described. The study was con-
athletes have high Qc and total hemoglobin mass (30–32). ducted according to the Declaration of Helsinki. Physical
However, there are indications that arterial O2 desaturation characteristics (mean ± SD) of the participants were as fol-
occurs in elite athletes during maximal aerobic exercise supporting lows: age, 24.0 ± 1.0 yr; height, 182.1 ± 1.3 cm; weight,
a pulmonary limitation of maximal oxygen uptake (21,33–37). 73.0 ± 1.6 kg; and V̇O2max running, 75.9 ± 5.8 mL·kg−1·min−1
In support of this idea, it has been shown that breathing O2 at the pretest. Inclusion criteria were that all subjects were
enriched air (26% vs 21% O2), prevented O2 desaturation, and male, with a V̇O2max above 65 mL·kg−1·min−1, and training
increased V̇O2max in highly endurance-trained athletes (36). competitively to qualify for national or international endur-
Caffeine increases VEmax and HR (17), which raises the ance competitions the upcoming season.
possibility that caffeine may also increase maximal oxygen Experimental procedures. The study was conducted
uptake in elite athletes. using a randomized, double-blinded, placebo-controlled crossover
Recently, we observed that professional cross-country skiers design. Before the main V̇O2max performance testing started, each
obtained higher maximal oxygen uptake during a 10-min participant performed a pretest for familiarization with the testing

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double-poling time trial after intake of caffeine compared with procedure and to verify that all subjects had V̇O2max above
maximal oxygen uptake during an incremental test without caf- 65 mL·kg−1·min−1. A schematic overview of the study is shown
feine intake (9). The higher maximal oxygen uptake after in Figure 1. The study had one dropout because of illness.
caffeine ingestion was associated with both higher VEmax and Pretest. During the pretest, all subjects performed a stan-
HRmax (9). However, caffeine is not believed to increase dardized incremental treadmill test consisting of four work-
maximal oxygen uptake (3,17). Furthermore, maximal oxygen loads at 7, 8, 9, and 10 km·h−1 with each lasting 5 min. All
uptake during double poling was found to be ~10% lower than workloads were performed with 10.5° uphill incline on the
during running (9). Therefore, it remains unknown whether treadmill (Woodway, Weil am Rein, Germany), and a 1-min
caffeine increases maximal oxygen uptake. break was given between each workload. Oxygen uptake at
The present study was designed to test the hypothesis that caf- the four workloads were then used to estimate the individual
feine increases V̇O2max in elite endurance athletes during running. oxygen cost for calculation of O2 deficit during the V̇O2max
The incremental protocol used to determine maximal oxygen up- performance tests as previously described by Medbø et al.
take was also used to assess time to exhaustion (performance). (38). Linear regression was also used to calculate individual
VEpeak, HRpeak, O2 deficit, and blood lactate, in addition to speeds equal to 55%, 60%, 65%, and 70% of V̇O2max performed
V̇O2max, were determined to assess their influence over any ob- as a standardized warm-up (incremental test) before each main
served caffeine-induced improvement in endurance performance. V̇O2max performance test. When the standardized warm-up was
finished, all subjects walked 5 min at 5 km·h−1, before starting
MATERIALS AND METHODS the pre-V·O2max test. Starting velocity during all testing was
Subjects. Twenty-three healthy male endurance-trained 10 km·h−1 with an uphill incline of 10.5° on the treadmill. The
athletes (cross-country skiing, running, and triathlon) gave their V̇O2max performance tests was performed as an incremental test

FIGURE 1—Experimental design. A, Top line shows pretests and main testing during the 3 wk used to complete the V̇O2max test for one subject. B, The
bottom figure shows the test procedure for all V̇O2max performance tests. Before the V̇O2max test, subjects performed a standardized warm-up (incremental
test) consisting of four intensities all lasting 5 min.

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 where velocity was increased by 0.5 km·h−1 every 30 s until as the subjects’ O2 deficit. In the present study, O2 deficit was
subjects were unable to maintain the speed and stepped/jumped not adjusted for the contribution of the body’s oxygen stores
off the treadmill. The highest HR and VE during the test were to the energy supply.
defined as HRpeak and VEpeak. The criteria for having reached Measurement of V̇O2 and VE. Oxygen consumption
V̇O2max during all testing were as follows: 1) voluntary and RER were measured with an Oxycon Pro metabolic sys-
exhaustion; 2) oxygen consumption plateaued, meaning tem (Jaeger, Hochberg, Germany). Before each test, the Oxy-
V̇O2 increased less than 1 mL·kg−1·min−1 when there were gen Pro was calibrated with a gas mixture composed of O2 and
consecutive increases in treadmill speed of 0.5 km·h−1; 3) CO2 (14.93% O2 and 5.99% CO2) and normal air (20.90% O2
RER > 1.10; and 4) blood lactate >7.0 mM. The V̇O2max was and 0.04% CO2). Volume was calibrated manually using a
calculated as the average of the two highest 30-s measurements. pump containing 3 L of volume (Calibration Syringe, Series
V̇O2max performance tests. To test the effect of caffeine 5530; Hans Rudolph Inc., Kansas City, MO). During all test-
on V̇O2max, each subject completed four tests over a 2-wk pe- ing, expired air was collected using a mouth V2-mask (Hans
riod. During both weeks, one test was performed with caffeine Rudolph Inc.) in combination with a nose clip and directed
and the other with placebo in a randomized order. Before all into a mixing chamber (Oxycon Pro) and analyzed with a tur-
main tests, resting HR and lung function (described below) bine (Triple V volume transducer). Both the hose and the
were measured at arrival and 30 min after consuming either V2-mask were tested for leakage before each individual test.
placebo or caffeine. After finishing lung function testing, sub- HR was measured using an HR monitor (Polar RS 800, Kempele,
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jects were given a 10-min break before starting the standard- Finland), where the error of measurement as stated by the
ized warm-up. The warm-up consisted of four workloads company is ±1%.
(55%, 60%, 65%, and 70% of V̇O2max) each lasting 5 min, Lung function. Spirometry was measured by maximum
with a 1-min break in between when blood glucose and lactate expiratory flow volume loops according to guidelines from
were measured. All workloads of the warm-up were performed the European Respiratory Society (40) and recorded as forced
with a 10.5° uphill incline on the treadmill (Woodway). During expiratory volume in the first second (FEV1), forced vital
each workload HR, V̇O2 and RER were measured as means capacity (FVC), and forced expiratory flow in 50% of FVC
between 3 and 4.5 min of each workload. Subjective RPE (FEF50). Lung function measurements were performed using
was evaluated according to the Borg scale (6 to 20) (39). a MasterScreen Pneumo Jaeger® (Würzburg, Germany), and
After the warm-up, a 5-min break was used for blood sampling reference values used are according to Quanjer et al. (41).
(presample) for determining lactate and glucose, recording Fractional exhaled nitric oxide. Fractional exhaled ni-
HR, and providing final instructions to the subjects. The goal tric oxide (FENO) was measured by the single breath online
for each subject was to run for as long as possible during each technique according to American Thoracic Society/European
V̇O2max performance test. Performance was measured as time Respiratory Society guidelines (40). The subject was in a
to exhaustion. Participants did not receive information regarding seated position and instructed to breathe quietly. To avoid
time, velocity, or physiological measurements during the tests. potential contamination from ambient NO, the subjects inhaled
The criteria for reaching V̇O2max was as described above for the NO-free air close to total lung capacity, immediately followed
pretest. Encouragement was given during all tests from the test by a full exhalation for at least 6 s at a constant flow of
leader, who was blinded to treatment to eliminate any bias. 50 mL·s−1. The constant flow rate was maintained with the
Maximal oxygen uptake was measured in milliliters per minute. aid of a visual feedback system. The expiratory pressure was
Elite athletes are normally weight stable, and therefore the same kept between 5 and 20 mm Hg to close the soft palate and to
weight was used at the four tests for calculation of V̇O2max in eliminate nasal NO. FENO measurements were assessed before
milliliters per kilogram per minute. After finishing the V̇O2max pulmonary function tests and were recorded as a mean value
performance tests, the subjects were given a 5-min break before from three successive reproducible plateaus. A chemiluminescence
taking postexercise measurements of lung function and filling analyzer, EcoMedics CLD 88 Exhalyzer® (Eco Medics AG,
out questionnaires. Duerten, Switzerland) (measurement range of 0.1–5000 parts
Measurement and calculation of O2 deficit. During per billion, was used and calibrated daily with a certified
the standardized incremental tests, V̇O2 was measured between concentration of NO.
2.5 and 4.5 min of each 5-min work period, and the mean was Pretesting information. All subjects were informed to
determined as a subject’s oxygen cost for the velocity. Oxygen only perform light training for the 48 h preceding each V̇O2max
uptake at the four velocities tested (7, 8, 9, and 10 km·h−1) dur- performance test. To minimize variation in preexercise glyco-
ing the submaximal exercise was used to construct a linear re- gen stores, diet and exercise diaries were used to standardize
gression estimate of oxygen cost for the different running food intake and training for each subject. Subjects were asked
velocities used during the V̇O2max performance tests as previ- to prepare for the tests as they prepared for competitions. They
ously described by Medbø et al. (38). The collection of expired were instructed to follow the same training and diet regime be-
air started 15 s before starting the V̇O2max performance tests fore each test and to refrain from caffeine the last 24 h before
and was continued until subjects reached task failure (when each test day. Seven out of the 23 subjects in the study had a
they stepped off the treadmill). The difference in estimated high intake of caffeine products on a daily basis (>150 mg).
oxygen cost and measured oxygen uptake was then calculated On each of the four main test days, subjects arrived at the

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laboratory at the same time (±15 min) of the day for each of performance could be explained by changes in V̇O2max, HRmax,
their tests. The first two tests were performed with a washout VEmax, O2 deficit, or blood lactate by sequentially adjusting for
period of 3 d between them. Before test three, a washout pe- each of these variables. Similarly, we examined to what extent
riod of 4 d was imposed, and subjects performed test three the caffeine effect on V̇O2max could be explained by HRmax,
and four the following week on the same weekdays as tests VEmax, O2 deficit, and blood lactate.
1 and 2.
Blood analyses. Capillary blood samples for measure-
RESULTS
ments of glucose and lactate were taken from the fingertip after
skin puncture using a Saft-T-Pro Plus (Accu-Check, Mannheim, Caffeine improved time-to-voluntary exhaustion (perfor-
Germany). For measurement of blood lactate, blood samples mance) in both testing weeks (Table 1). In the first week,
were collected into a 50-μL capillary tube, and 20 μL was pi- caffeine increased time to exhaustion by 18 s (355 ± 41 vs
petted into the YSI 1500 SPORT analyzer (Yellow Springs In- 373 ± 40 s, P < 0.001) compared with placebo, and in the
struments Life Sciences, Yellow Springs, OH). The analyzer second week by 21 s (355 ± 44 vs 376 ± 45 s, P < 0.001). The
was calibrated with a 5.0-mM lactate stock solution before average effect was 19.4 s (5.45%; P < 0.001; Fig. 2A; Table 1).
each test. Values between 4.95 and 5.05 mM were accepted. Time to exhaustion was highly reproducible, with no statistical dif-
Capillary blood glucose was measured with a HemoCue ferences between the two placebo trials (P = 0.78) or the two
Glucose 201+ analyzer (HemoCue Glucose 201+, Ängelholm, caffeine trials (P = 0.74). The intraclass correlation coefficient

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Sweden) as previously described (42) (ICC) values for time to exhaustion were 0.94 and 0.90 in pla-
Caffeine and placebo intake. Caffeine (Coffeinum; cebo and caffeine trials, respectively.
Oslo Apotekerproduksjon, Oslo, Norway) was dissolved in a Caffeine ingestion also increased mean maximal oxygen
cordial concentrate (Fun Light) at 3 mg·mL−1 concentration uptake from 75.8 ± 5.6 to 76.7 ± 6.0 mL·kg−1·min−1
at the Norwegian School of Sports Sciences. Ingestion of caf- (0.9 mL·kg−1·min−1; 1.2%; P < 0.003) compared with placebo
feine (4.5 mg·kg−1) or placebo (Fun Light without additions; (Table 1; Fig. 2B). The ICC values for V̇O2max were >0.95 for
indistinguishable from caffeine) occurred 45 min before the both conditions. The O2 kinetics were similar between caffeine
standardized warm-up. Therefore, the V̇O2max performance test and placebo except when comparing the last minute where
started 75 min after caffeine ingestion. higher V̇O2max was reached with caffeine (Fig. 3). The higher
Questionnaires. Questionnaires were used to evaluate V̇O2max after caffeine ingestion contributed to the longer run-
motivation and “current fitness” using a scale from 1 to 100 ning time during the performance test because statistical ad-
(9). Sleep habits were evaluated by asking approximate sleep justment for V̇O2max reduced the caffeine-induced effect on
duration (h) the 24 h before each test. In addition, for each running time from 19.4 s to 15.4 s (21% attenuation).
trial, subjects were asked what product they believed they HR and VE developed similarly during the performance
had received 30 min after ingestion and again before leaving tests with and without caffeine (Fig. 3). However, higher max-
the laboratory. imal HR and VE values were reached during the last minute of
Statistical analysis. All data are presented as means ± SD. the test after caffeine ingestion compared with placebo.
A two-way repeated-measures ANOVA was used to examine Specifically, HRpeak increased from 191 ± 8 to 193 ± 9 bpm
differences in HR, lactate, V̇O2, glucose, and RPE during two (P < 0.001), and VEpeak increased from 187.8 ± 17.8 to
submaximal workloads between the two treatments. If treat- 192.2 ± 15.3 L·min−1 (P < 0.001) after caffeine ingestion com-
ment differences were observed, a paired t-test was used to test pared with placebo (Table 1). The caffeine-induced increase in
differences at workloads. In exploratory analyses, multiple lin- V̇O2max was attenuated by 0.7 mL·kg−1·min−1 (P < 0.001) after
ear regression was used to disentangle if any caffeine effect on adjustment for the increase in HRpeak. When V̇O2max was

TABLE 1. Exercise response to maximal performance tests after placebo or caffeine consumption.
Placebo Placebo Caffeine Placebo Caffeine
Pretest Test 1 Test 2 Test 1 Test 2 Mean Mean P % Dif
Time (s) 5:59 ± 00:49 5:55 ± 0:41 5:55 ± 0:44 6:13 ± 0:40* 6:16 ± 0:45* 5:55 ± 0:42 6:15 ± 0:43* <0.01 5.6
V̇O2max (mL·kg−1·min−1) 75.9 ± 6.2 76.0 ± 5.9 75.7 ± 5.7 76.7 ± 6.0* 76.8 ± 6.4* 75.8 ± 5.6 76.8 ± 6.2* <0.019 1.2
V̇O2max (mL·min−1) 5540 ± 717 5551 ± 673 5527 ± 667 5592 ± 652* 5607 ± 642* 5539 ± 674 5602 ± 646* <0.019 1.2
ΣO2 deficit (mL·kg−1) No data 64.9 ± 16.6 65.3 ± 18.9 69.9 ± 20.2 71.2 ± 17.8 65.1 ± 17.8 70.5 ± 19.1* <0.02 8.3
VEpeak (L·min−1) 193.8 ± 17.0 189.3 ± 18.4 185.8 ± 18.3 193.2 ± 17.6* 191.2 ± 14.8* 187.3 ± 17.8 192.0 ± 15.3* <0.001 2.3
BFpeak (breaths per minute) 59 ± 8 58 ± 9 58 ± 9 60 ± 9 59 ± 7 58 ± 9 60 ± 7 <0.07 3.4
RER (V̇CO2/V̇O2) 1.10 ± 0.04 1.10 ± 0.23 1.11 ± 0.22 1.11 ± 0.24 1.11 ± 0.23 1.11 ± 0.04 1.11 ± 0.04 <0.78 0.4
HFpeak (bpm) 192 ± 9 192 ± 6 191 ± 8 194 ± 8* 193 ± 7* 191 ± 8 193 ± 9* <0.01 1.1
HF pre (bpm) No data 113 ± 12 109 ± 9 113 ± 15 113 ± 13 111 ± 12 113 ± 14 <0.11 1.8
Lactate pre (mM) No data 0.86 ± 0.28 0.79 ± 0.27 1.12 ± 0.21* 1.06 ± 0.33* 0.82 ± 0.26 1.09 ± 0.31* <0.01 32.9
Lactate post (mM) 8.34 ± 1.33 7.90 ± 1.05 8.00 ± 1.13 8.21 ± 1.14* 8.65 ± 0.94* 7.94 ± 1.06 8.54 ± 1.02* <0.01 7.0
Glucose pre (mM) No data 5.2 ± 0.5 5.1 ± 0.4 5.3 ± 0.5 5.3 ± 0.5 5.1 ± 0.4 5.3 ± 0.8 <0.61 2.0
Glucose post (mM) No data 7.4 ± 0.8 7.2 ± 0.9 7.8 ± 0.7* 8.0 ± 0.9* 7.3 ± 0.9 7.9 ± 1.1* <0.01 8.2
Values are listed as means ± SD. HF pre, lactate pre and glucose pre were measured before the start of the performance test and 5 min after the incremental test.
*Significantly different from placebo (P < 0.05).

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FIGURE 2—Effect of caffeine on time to exhaustion, maximal oxygen uptake, and oxygen deficit. A, Individual and mean time to exhaustion at the per-
formance test. Duration, V̇O2max, and O2 deficit obtained during the V̇O2max performance tests after placebo (open symbols) or caffeine (filled symbols).
B, Percent change in running duration, V̇O2max, and O2 deficit after caffeine consumption compared with placebo for each subject. Values are listed as
means ± SD. *Significant different from placebo trials (P < 0.05).

adjusted for VEpeak, the effect of caffeine on V̇O2max decreased and blood lactate increased progressively from the first to
by about 50% and was no longer significant (P = 0.11). Despite the last of the four workloads (Table 2). HR and V̇O2 at sub-
a higher VEpeak after caffeine ingestion, breathing frequency maximal loads were similar after placebo and caffeine
(BF) was not significantly elevated when V̇O2max was achieved (treatment effect: P = 0.077 for means of the two tests),
(60 ± 7 vs 59 ± 9 breaths per minute; Table 1). When running whereas VE and lactate were higher after caffeine than pla-
duration was adjusted for V̇O2max, VEpeak, and HRpeak, there cebo ingestion (P < 0.001), but no significant interaction
was still 11.7 s (P < 0.001) an improvement in time to exhaus- was observed. RPE was lower after caffeine ingestion com-
tion after caffeine ingestion (40% attenuation). pared with placebo (treatment effect: P < 0.029; Table 2)
The accumulated oxygen deficit during the performance with post hoc analyses showing lower RPE at the two highest
test increased from 63.1 ± 18.2 mL·kg−1 in placebo to workloads after caffeine.
69.5 ± 17.5 mL·kg−1 with caffeine ingestion (P < 0.02; Table 1; The lung function measurements FEV1, FVC, FEF50, and
Fig. 2C). The ICC values for measurements of O2 deficit were FENO performed at arrival, 30 min after placebo or caffeine in-
0.61 and 0.64 for placebo and caffeine trials, respectively. Blood gestion, and post-V̇O2max performance tests were not different
lactate values were higher with caffeine compared with placebo between treatments (Table 3).
(8.54 ± 1.02 vs 7.94 mM ± 1.06; P < 0.001; Table 1). Calcula- Based on the questionnaire, there were no differences be-
tions showed that the anaerobic processes (O2 deficit) covered tween caffeine and placebo trials regarding self-reported “cur-
14.7% ± 3.1% and 15.0% ± 2.7% of total O2 cost in placebo rent fitness” and motivation. Before the performance tests,
and caffeine trials. When time to exhaustion was adjusted for subjects reported motivation of 77 ± 14, 79 ± 16 (placebo),
both O2 deficit and lactate concentration, the effect of caffeine and 76 ± 14, 76 ± 14 (caffeine) before tests (75 = high/very
was reduced from 19.4 to 13.2 s (P < 0.001). With additional ad- high), and 79 ± 17, 82 ± 12 (placebo), and 79 ± 14, 81 ± 14
justment for V̇O2max, the effect of caffeine on time to exhaustion (caffeine) after the performance tests. Ratings pretest “current
was reduced to 8.0 s (59% attenuation), but still significant fitness” were 62 ± 11, 62 ± 13 (PLA), and 61 ± 13, 63 ± 12
(P < 0.001). With further adjustment for VEpeak and HRpeak, (caffeine) (65 = high) before, and 62 ± 11, 65 ± 14 (placebo),
the caffeine effect on performance was further reduced to 7.1 s and 67 ± 15, 79 ± 14 (caffeine) after the performance tests.
(63% attenuation), but remained significant (P = 0.003). Plasma Furthermore, the subjects were unable to sense which product
glucose levels after the performance tests were higher in caffeine they received during the different trials, with 50% answering
compared with placebo trials (7.9 ± 1.1 vs 7.3 ± 0.9 mM; “uncertain” to the question. Of the subjects who answered that
P < 0.001). The highest RER during the performance test they thought they knew the treatment (caffeine or placebo), about
was independent of test conditions (Table 1). 50% guessed wrong both pre- and posttesting independent of
During the submaximal incremental testing, repeated-measures treatment ingestion. Hours of sleep, training, intake of food,
ANOVA showed that oxygen uptake, HR, VE, BF, RPE, and liquid intake before tests also did not differ, confirming that

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subjects had followed instructions regarding training, food, liquid, analyses showed that both parameters contributed to the in-
and caffeine consumption for the 48 h before each test. crease in V̇O2max. The increase in V̇O2max was small
(1.2%) but explained about 4 s (~20%) of the improved
performance (run time to exhaustion). Accumulated O2
DISCUSSION
deficit and lactate during the performance test was also
We confirmed the primary hypothesis that caffeine increases higher after intake of caffeine. Overall, these mechanisms
maximal oxygen uptake in elite endurance athletes. Caffeine accounted for 63% of the caffeine-mediated improvement
also increased HRpeak and VEmax, and the exploratory statistical in performance.

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FIGURE 3—A, The 30-s measurements for V̇O2, HR, VE, BF, and RER during placebo (open symbols) and caffeine (filled symbols) V̇O2max performance
tests. B, The last 120 s for each individual shown as mean for the group for V̇O2, HR, VE, BF, and RER. Values are listed as means ± SD. *Significant dif-
ferent from placebo trials (P < 0.05).

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 TABLE 2. Exercise response during submaximal incremental testing (standardized warm-up) after placebo or caffeine consumption.
Workload Percent of V̇O2max
55% 60% 65% 70%
Placebo Caffeine Placebo Caffeine Placebo Caffeine Placebo Caffeine
V̇O2 (mL·kg−1·min−1) 40.5 ± 3.4 41.0 ± 3.3 44.8 ± 3.7 45.1 ± 3.8 49.3 ± 4.2 49.6 ± 4.1 53.5 ± 4.7 53.7 ± 4.2
HR (bpm) 131 ± 8 129 ± 9 141 ± 9 140 ± 9 151 ± 9 151 ± 9 160 ± 9 160 ± 9
Lactate (mM)** 1.00 ± 0.20 1.20 ± 0.25* 0.91 ± 0.35 1.1 ± 0.30* 1.06 ± 0.40 1.28 ± 0.40* 1.43 ± 0.43 1.67 ± 0.46*
Borg (6–20)** 8.8 ± 1.2 8.6 ± 1.3 10.2 ± 1.1 10.0 ± 1.3 11.8 ± 1.1 11.5 ± 1.0* 13.3 ± 1.1 12.9 ± 1.1*
VE (L·min−1)** 70.4 ± 3.2 74.3 ± 3.5* 79.8 ± 3.3 84.0 ± 3.5* 89.2 ± 3.6 92.9 ± 3.9* 98.6 ± 4.0 101.9 ± 4.0*
BF (breaths per minute) 28 ± 6 28 ± 6 32 ± 7 31 ± 6 34 ± 7 34 ± 7 36 ± 8 36 ± 8
Values are listed as means ± SD.
*Significant difference between placebo and caffeine (P < 0.05).
**Treatment effect of caffeine (P < 0.05).

Recently, we observed that caffeine intake induced higher (21,24). In agreement with other studies, HRpeak was 2 bpm
oxygen uptake during a 10-min time trial compared with maxi- higher during the caffeine trials (2), which would increase Qc,
mal oxygen uptake during an incremental test without caffeine assuming stroke volume was maintained (24). Statistical analyses
in professional cross-country skiers (9). The present study suggest that the increased HRpeak explained 0.2 mL·kg−1·min−1
was designed to test the hypothesis that caffeine increases (22%) of the caffeine-induced increase in V̇O2max. The heart
V̇O2max in elite endurance athletes during running. The expresses all four isoform of adenosine receptors (45), which
BASIC SCIENCES

finding that caffeine increased V̇O2max from 75.8 ± 5.6 to are blocked by caffeine, and adenosine is used to treat
76.7 ± 6.0 mL·kg−1·min−1 (1.2%) confirms our hypothesis. supraventricular tachycardia (46). However, the role of
Caffeine is normally not believed to increase maximal oxygen adenosine receptors on HR is not completely clear (47). In the
uptake (3,17,43), and the small increase in V̇O2max observed present study, caffeine did not influence HR at submaximal
in this randomized placebo-controlled crossover study may loads as expected (2,10). Intake of caffeine normally increases
therefore be questioned despite it being highly significant plasma concentrations of adrenaline and noradrenaline during
(P value of 0.003). However, several facts support that the maximal exercise (2,9), and stronger adrenergic stimulation
increase is real. First, the 23 participants were tested twice may explain the higher HR after caffeine intake.
with and twice without caffeine intake during two consecutive Elite endurance athletes often develop hypoxemia during
weeks under standardized training and diet days before all tests, maximal exercise (37,48,49). In the present study, several
and the effect was reproducible. Second, the participants participants had V̇O2max higher than 80 mL·kg−1·min−1, and
were elite endurance athletes of national and international subjects with higher V̇O2max have a greater oxygen desaturation
level (five participants are medalists in Olympic or U23 upon reaching V̇O2max than less trained subjects (49). Several
World Championship) accustomed to intense efforts, and the studies have found that reduced O2 saturation can limit maximal
ICC for V̇O2max was >0.95 with and without caffeine. Third, oxygen consumption for highly trained athletes because of
more than 20% of the increase in running performance after arterial desaturation (33–35,37,48). The limitation of O2
caffeine intake was explained by the increase in VO2mas saturation in elite endurance athletes is also supported by
according to our statistical analyses. Fourth, more than 50% the fact that mild hyperoxia (26% O2) increases V̇O2max in
of the increase in V̇O2max could be explained by likely highly endurance-trained subjects but not in moderately trained
physiological mechanisms. Finally, the finding is also supported subjects (36). The higher VEpeak after caffeine, with similar BF
by our previous study showing higher maximal oxygen uptake as the placebo trial, improves conditions for O2 saturation.
during a 10-min double poling time trial after intake of caffeine However, caffeine has previously been reported to increase
compared with V̇O2max during an incremental test without VEpeak during maximal exercise, without improving V̇O2max
caffeine (9), and recent studies reporting that caffeine increases (34,48). The increased VE may also increase the expiration
V̇O2max in moderately trained males (44) and mice (19). of CO2, and we have previously found that plasma bicarbonate
The classical view is that V̇O2max is determined by the deliv- at exhaustion is lower after intake of caffeine compared with
ery of oxygen to the active muscles and, therefore, maximal placebo (18). However, the higher VE could also be driven
Qc (HR  stroke volume) during running in healthy subjects by higher central command.

TABLE 3. Lung function at arrival, 30 min after caffeine/placebo ingestion, and after V̇ O2max performance tests.
Arrival 30 min after Placebo/Caffeine Ingestion Post-V̇O2max Performance Test
Placebo Caffeine P Placebo Caffeine P Placebo Caffeine P
FENO (ppb) 27.9 ± 25.1 26.0 ± 27.1 0.222 29.0 ± 26.9 27.1 ± 30.1 0.449 21.0 ± 17.8 20.4 ± 20.1 0.557
FEV1 (L) 5.00 ± 0.54 5.04 ± 0.58 0.191 4.98 ± 0.60 5.04 ± 0.66 0.146 5.15 ± 0.53 5.18 ± 0.69 0.311
FVC (L) 6.05 ± 0.64 6.06 ± 0.69 0.732 6.20 ± 0.83 6.05 ± 0.67 0.127 6.05 ± 0.67 6.03 ± 0.73 0.68
FEF50 (L·s−1) 5.94 ± 1.39 5.90 ± 1.38 0.665 5.94 ± 1.42 5.88 ± 1.34 0.448 6.26 ± 1.46 6.34 ± 1.50 0.187
Values are listed as means ± SD.
*Significantly different from sea level (P < 0.05).
ppb, part per billion.

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 Bronchioles express adenosine receptors, and adenosine and discomfort. However, it has been reported that caffeine
contributes to physiological and pathophysiological regulation intake reduces interstitial potassium during high-intensity
of bronchoconstriction (50,51). In the present study, caffeine exercise (56) and improved potassium handling may improve
increased VEpeak as well as VE during submaximal intensities. performance (57). This effect of caffeine could be indirectly
The caffeine-induced increase in VE at submaximal intensities is on muscles or via elevated adrenaline concentration. In the
well documented (2,10) and could result from bronchodilation. present study, statistical adjustments for O2 deficit and lactate
In the present study, however, caffeine did not improve FEV1, reduced the caffeine-mediated improvement in performance
FVC, or expiratory flow at 50% of FVC (FEF50), although it from 19.4 to 13.2 s (~30%; P < 0.001). Therefore, these
has been reported that caffeine causes a small increase in results show that higher O2 deficit and lactate are contributing
FEV1 (52). Interestingly, our statistical analyses supported the physiological factors to the improved running duration during
notion that the increased VE after intake of caffeine contributed the V̇O2max performance test.
to the higher V̇O2max. Adjustment for the higher VE after Caffeine has well-defined effects at the molecular level, and
caffeine intake reduced the caffeine-induced increase in caffeine is an adenosine receptor antagonist, inhibits phospho-
V̇O2max by 50%, and the effect of caffeine on V̇O2max was no diesterase, inhibits PI-3 kinase, inhibits glycogen phosphory-
longer significant (P = 0.11), suggesting VE per se is an lase a, and stimulates Ca2+ release from sarcoplasmic reticulum
important pathway by which V̇O2max is increased by caffeine at high concentrations (20,58,59). Data from our previous
in elite endurance athletes. studies suggest that plasma caffeine concentration was ~30 μM

BASIC SCIENCES
The incremental performance test was designed to optimally (9), and this concentration inhibits most adenosine receptors
measure V̇O2max and lasted 355 s (5 min 55 s) during the placebo (20). However, this knowledge may be of limited importance
trial. Caffeine improved running duration by 19.4 s (5.5%) during for understanding the physiological effects of caffeine on
the performance test in agreement with previous studies (2,7,9). performance as adenosine receptors are expressed broadly
When time to exhaustion was adjusted for caffeine-mediated throughout the human body. A consistent finding is that caffeine
increase in V̇O2max, VEpeak, and HRpeak, running duration was reduces RPE, which will allow higher work capacity. The
reduced from 19.4 to 11.7 s (P < 0.001). These data suggest mechanisms are unclear, but blocking adenosine receptors
that improved aerobic power explained nearly 40% of the reduces pain (60,61). The reduced pain sensation may increase
increased performance after intake of caffeine. effort and performance, which again will drive higher HR.
The remaining improvements after caffeine compared with However, caffeine also improves VE (10,33), which will reduce
placebo might be anaerobic processes because exercise economy hypoxemia and therefore increase performance.
is not influenced by caffeine (Table 1). It is well documented that Caffeine influences a number of tissues and physiological
plasma lactate is higher at exhaustion after intake of caffeine processes, which collectively improves performance. Our data
(2,9). Although plasma lactate is the by-product from anaerobic show that caffeine appears to increase both aerobic and anaer-
glycolysis and an indirect measure of anaerobic work, the obic capacity during the ~6-min time-to-exhaustion test. Sta-
higher lactate with caffeine intake supports larger anaerobic tistical analyses with sequential adjustment suggest that the
contribution. In the present study, O2 deficit was higher in higher aerobic capacity contributed an additional 7 s, whereas
caffeine than in placebo (69.5 ± 17.5 vs 63.1 ± 18.2 mL⋅kg−1). anaerobic processes contributed and additional 6 s of the 19.4-s
The magnitude of O2 deficit agrees with previous studies improvement in performance. Interestingly, adjustment for the
(38), and anaerobic processes accounted for ~15% of the increases in V̇O2max, VE, HR, O2 deficit, and lactate reduced
energy cost during the V̇O2max time-to-exhaustion performance the improvement in performance (running time) to 7 s. There-
test. Caffeine increases anaerobic work capacity during fore, we are able to explain ~63% of the effect via plausible
Wingate tests and tests up to 6–7 min (11,53–55). Performance physiological mechanisms for the caffeine-mediated increase
has also been reported higher after caffeine intake during in performance during the ~6-min performance test.
4-km cycling time trials, in which anaerobic processes highly The strength of the present study is that the performance
contribute (53,55). Doherty (13) reported that caffeine increased protocol was designed to test maximal oxygen uptake and
maximal accumulated oxygen deficit by 11% in highly trained the tests with and without caffeine were performed twice. It
male athletes when running until exhaustion at ~125% of is also a strength that the study was performed in highly
V̇O2max. These results are very comparable with the results endurance-trained subjects accustomed to exhaustive exercise.
in the present study where 10% increase in O2 deficit was Another strength is that the effects of caffeine on both aerobic
observed. Although aerobic energy production contributed to and anaerobic capacities were examined. However, one limita-
most of the energy requirement in the present study, there is tion of the study is that we did not directly measure Qc and O2
no doubt that accumulated oxygen deficit and lactate were saturation in arterial blood because we suggested that these
key physiological components in delaying development of two mechanisms contribute to the performance enhancing ef-
fatigue at the end of the incremental test. fect of caffeine. However, measurements of maximal Qc dur-
The mechanisms by which caffeine increases anaerobic ca- ing maximal exercise are challenging. It would also have been
pacity are not clear. It is well documented that caffeine reduces interesting to measure blood levels of CO2 and bicarbonate to
RPE at submaximal load (4,9,10), and a common explanation investigate if the increased VE reduced CO2. However, the in-
is that caffeine increases performance simply by reducing pain crease in V̇O2max was only 1.2%, which makes it difficult to

CAFFEINE INCREASES MAXIMAL OXYGEN UPTAKE Medicine & Science in Sports & Exercise® 2271

Copyright © 2021 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
 determine the mechanisms by which caffeine increases maxi- collectively contributes to significant improvement in high-
mal oxygen uptake. intensity endurance performance.
In conclusion, the present study shows for the first time that The authors thank Astrid Bolling for skillful technical assistance and
caffeine increases V̇O2max in elite athletes, which contributed the participants for their effort. The authors declare no conflicts of inter-
significantly to improving time to exhaustion during a high- est. The data are presented clearly, honestly, and without fabrication,
falsification, or inappropriate data manipulation. The results presented
intensity performance test. Our data suggest that increased do not constitute endorsement by the American College of Sports
VE and HRpeak contribute to the higher V̇O2max. Caffeine also Medicine. H. K. Stadheim declares no conflicts of interests. T. Stensrud
increased O2 deficit and lactate at exhaustion, which contrib- declares no conflicts of interests. S. Brage declares no conflicts of in-
terests, and J. Jensen declares no conflicts of interests. Disclosure of
uted to improved performance. The present study shows that funding received for this work from any of the following organizations:
caffeine improves several physiological mechanisms, which Research Councils UK (RCUK).

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