

Citation: Huffman, R.P.;
Van Guilder, G.P. The Effect of
Acetaminophen on Running
Economy and Performance in
Collegiate Distance Runners. Int. J.
Environ. Res. Public Health 2022, 19,
2927. https://doi.org/10.3390/
ijerph19052927
Academic Editor: Jooyoung Kim
Received: 25 January 2022
Accepted: 27 February 2022
Published: 2 March 2022
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International  Journal  of
Environmental Research
and Public Health
Article
The Effect of Acetaminophen on Running Economy and
Performance in Collegiate Distance Runners
Riley P. Huffman
and Gary P. Van Guilder *
Department of Recreation, Exercise & Sport Science, Western Colorado University, Gunnison, CO 81230, USA;
riley.huffman@western.edu
* Correspondence: gvanguilder@western.edu; Tel.: +1-970-943-7133
Abstract: Acetaminophen (ACT) may decrease perception of pain during exercise, which could allow
runners to improve running economy (RE) and performance. The aim of this study was to determine
the effects of ACT on RE and 3 km time trial (TT) performance in collegiate distance runners.
A randomized, double blind, crossover study was employed in which 11 track athletes (9M/2F;
age: 18.8 ± 0.6 years; VO2 max: 60.6 ± 7.7 mL/kg/min) completed three intervention sessions.
Participants ingested either nothing (baseline, BSL), three gelatin capsules (placebo, PLA), or three
500 mg ACT caplets (ACT). One hour after ingestion, participants completed a graded exercise test
consisting of 4 × 5 min steady-state stages at ~55–75% of VO2 max followed by a 3 km TT. There
was no inﬂuence of ACT on RE in any stage. Similarly, ACT did not favorably modify 3 km TT
performance [mean ± SD: BSL = 613 ± 71 s; PLA = 617 ± 70 s; ACT = 618 ± 70 s; p = 0.076]. The
results indicate that ACT does not improve RE or TT performance in collegiate runners at the 3 km
distance. Those wanting to utilize ACT for performance must understand that ACT’s beneﬁts have
yet to be signiﬁcant amongst well-trained runners. Future studies should examine the effects of
ACT on well-trained runners over longer trial distances and under more controlled conditions with
appropriate medical oversight.
Keywords: endurance; time trial; perceived exertion; pain reliever
1. Introduction
During high intensity efforts runners experience a great deal of pain [1]. This pain
can be a result of muscle fatigue, tissue damage, or aggravation of previous injury [1]. In
elite races, where all runners are well-trained with comparable aerobic capacities, pain
management is often the primary factor for determining success [2]. Taking pain-relieving
medications, which are not banned by the governing body of the sport, and which are safe
to ingest for healthy individuals with no allergies to their ingredients or contraindications
to the medication, has been investigated as a way to enhance exercise performance. Ac-
etaminophen (ACT), also known as paracetamol, is an over-the-counter pain reliever and
fever reducer. ACT can alter acute and chronic responses to exercise by increasing pain
threshold and demanding a greater amount of a stimulus before pain is felt [3].
The use of analgesics is extremely prevalent among runners [4]. In a study of 806
runners conducted by Rosenbloom et al., researchers found that 87.8% of subjects had
utilized analgesics within the last year [4]. Over 200 of the subjects in the study reported
the use of non-steroidal anti-inﬂammatory drugs (NSAIDs) directly prior to a race event.
The top three reasons for use before a race are: (1) to reduce inﬂammation/swelling (58%),
(2) to increase pain tolerance (42.7%), and (3) to continue running through an injury
(42.7%) [4]. As the use of NSAIDs and analgesics in running is highly prevalent for
these three primary reasons, it is important for runners that wish to utilize these drugs to
understand how the drug they choose to use acts on the body and the risks associated with
each drug.
Int. J. Environ. Res. Public Health 2022, 19, 2927. https://doi.org/10.3390/ijerph19052927
https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2022, 19, 2927
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ACT is considered to be a selective cyclooxygenase-2 (COX-2) inhibitor [5]. Being a
selective COX-2 inhibitor, ACT lacks the antiplatelet and detrimental effects on gastroin-
testinal mucosa of COX-1 inhibition, making it safer on the gastrointestinal tract than
other drugs that are not selective inhibitors. Most NSAIDs, such as ibuprofen, are not
selective inhibitors and therefore contain a risk of intestinal damage. Unlike NSAIDs, ACT
is almost unanimously considered to have no anti-inﬂammatory activity and does not
produce gastrointestinal damage or untoward cardiorenal effects [6]. Indeed, a major ad-
verse effect of NSAIDs is their known tendency to cause gastrointestinal (GI) complications,
such as mucosal ulceration, bleeding, perforation, and the formation of diaphragm-like
strictures [7]. In a study analyzing the aggravation of exercise-induced intestinal injury by
ibuprofen in athletes, Van Wijck et al. examined four scenarios around ibuprofen and exer-
cise (800 mg ibuprofen before cycling, cycling without ibuprofen, 800 mg ibuprofen at rest,
and rest without ibuprofen intake). They found that ibuprofen consumption and cycling
resulted in increased plasma intestinal fatty acid binding protein (I-FABP) levels, reﬂecting
small intestinal injury. These levels were higher after cycling with ibuprofen than after
cycling without ibuprofen, rest with ibuprofen, or rest without ibuprofen. Additionally,
small intestinal permeability increased, especially after cycling with ibuprofen, reﬂecting
loss of gut barrier integrity. They concluded that ibuprofen aggravates exercise-induced
small intestinal injury and induces gut barrier dysfunction in healthy individuals [7]. This
phenomenon does not occur with ACT due to the different mechanisms of action of ACT
compared to ibuprofen and other NSAIDs [5]. These studies demonstrate that those wish-
ing to utilize drugs prior to races in order to increase pain tolerance are at an increased
risk of adverse health effects when choosing NSAIDs, such as ibuprofen, as opposed to an
analgesic drug, such as ACT [7]. They also demonstrate that ACT should not be used to
treat inﬂammation or swelling, as ACT does not have an anti-inﬂammatory effect [5,6].
ACT is a safe drug at appropriate doses [6]. The amount of 7.5 g in adults is widely
considered as the lowest acute dose capable of causing toxicity [6]. All studies examining
ACT and its effect on performance utilize doses ranging from 0.5 g to 1.5 g [3,8–14], well
under the threshold for the potential of toxicity. There have been no reports of acute
toxicity in healthy adults ingesting a single dose of ACT below 125 mg/kg [6]. Unlike
ibuprofen or other NSAIDs, ACT has only a small peripheral effect and acts primarily
on the central nervous system [6]. Even so, the risks of ACT should be fully outlined for
coaches and athletes to consider. As with many drugs, ACT can have very harmful effects,
speciﬁcally to the liver, if taken above prescribed doses. Unfortunately, ACT overdose is
responsible for more acute liver failure cases in the US and UK than all other etiologies
combined [15]. The most common reason ACT ingestion results in death by overdose is
its use in suicide attempts. Suicide attempts are a frequent cause of exposure to a single,
high overdose of ACT [15]. Regrettably, unintentional overdose can occur as a result of
combining multiple over-the-counter drugs, such as sleep-aids and cold medications, that
may all have components of ACT [15]. Nevertheless, extensive literature reviews suggest
that even susceptible people are unlikely to suffer adverse effects from therapeutic doses
of ACT [15]. Additionally, there is an antidote against ACT-induced liver injury, the drug,
N-acetylcysteine (NAC). NAC acts through facilitating scavenging of a reactive metabolite
during the metabolism phase and is most effective when administered within 8 h of the
overdose. This allows ACT-induced liver injury and liver failure to have a relatively high
survival rate. As ACT is one of the most common over-the-counter drugs and because the
vast majority of those who take ACT do not come close to taking over-therapeutic dosages
of it, it is one of the safest over-the-counter drugs available [15].
Several studies have demonstrated signiﬁcant endurance performance improvements
among participants in ACT conditions compared to placebo conditions during both cy-
cling and running. These improvements have been contributed to improved ability to
tolerate pain as a result of prolonged exercise or a decreased perception of perceived
pain or exertion during exercise. For example, the cycling studies by Delextrat et al. [8],
Foster et al. [9], Mauger et al. [10], Mauger et al. [11], and Morgan et al. [12] have demon-
Int. J. Environ. Res. Public Health 2022, 19, 2927
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strated that ingestion of ACT before a cycling bout improved performance through an
increased average or peak power output or a decreased time to complete a speciﬁed dis-
tance [8–12]. Some researchers concluded that these improvements in performance were a
result of the participants’ improved ability to tolerate pain during cycling [8–10]. Despite
the many studies completed on cycling performance and ACT, there have been few studies
conducted to examine the effects of ACT ingestion on running performance. In the only
study examining running endurance performance and ACT ingestion, Dagli et al. [3] found
that after taking ACT, recreationally active runners were able to improve 3 km time trial
performance by 1.9% compared to placebo [3]. However, this study was conducted using
exclusively male participants and was performed on a treadmill, which is not as speciﬁc to
distance running compared to the running over ground that is characteristic of National
Collegiate Athletic Association (NCAA) track and cross-country runners. Indeed, there are
no well-controlled randomized studies investigating the potential exercise performance
effects of ACT on well-trained, elite level male and female distance runners. Additionally,
there have not been any studies examining the effects of ACT on running economy (RE).
RE is determined by the steady state oxygen consumption for a standard speed [16–18].
An athlete with improved RE consumes less oxygen for a given steady state running
speed [19], thus improving their performance by expending less energy throughout a
race [19]. Over the course of a race, runners experience increasing amounts of fatigue, which
contributes to reduced mechanical efﬁciency and poor economy of motion [1]. For instance,
Meardon et al. [1] found that stride time became less consistent over the course of a 5 km
time trial while examining stride time variability, indicating that during prolonged running
there was an increased need for gate adjustments due to increasing fatigue [1].
Based on the evidence to date in a multitude of studies, ACT has been demonstrated
to improve cycling performance [8–12]. Yet, the only study examining the effects of ACT
ingestion on endurance running performance used recreationally active runners and did
not examine its effect on RE [3]. Therefore, the purpose of this randomized, double blind,
crossover experiment was to determine the effects of ACT on RE and a 3 km time trial
performance in well-trained NCAA collegiate distance runners. It was hypothesized that
ACT would improve RE and 3 km time trial performance through a reduction in perceived
pain during running.
2. Materials and Methods
2.1. Experimental Approach
In this randomized, double blind, crossover experiment, participants reported to the
High Altitude Exercise Physiology Laboratory on ﬁve separate occasions (see Figure 1). The
experiment was randomized by order; the research assistant randomly assigned each par-
ticipant’s ﬁrst condition as either a baseline condition (BSL), only water ingestion, placebo
condition (PLA), water and placebo ingestion, or ACT condition (ACT), water and ACT
ingestion. The random assignment was accomplished using a random number generator,
which selected a number at random between one and three. Participants proceeded to
complete each session based on their starting condition. For example, if a participant was
randomly assigned ACT as their ﬁrst condition, their condition order would be ACT then
BSL then PLA. The ﬁrst session for all participants consisted of completing questionnaires,
informed consent, and a treadmill running familiarization. This session lasted 30–45 min
and was followed by the next session two days later. In the second session, lasting about
an hour, anthropomorphic measurements and determination of VO2 max were completed.
In the third, fourth, and ﬁfth sessions, each occurring one week apart and commencing on
the same day of the week at the same time of day, subjects were assigned to ingest either
eight ounces of water to serve as their baseline (BSL), eight ounces of water paired with
three empty red gelatin capsules which served as a placebo (PLA), or eight ounces of water
paired with three 500 mg capsules of ACT (1.5 g) (ACT). Following ingestion, participants
waited 60 min and then completed a 20-min RE assessment on a treadmill, which also
served as a warm-up for their 3 km time trial on the indoor track.
Int. J. Environ. Res. Public Health 2022, 19, 2927
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Figure 1. Experimental ﬂowchart. (BSL = baseline) (PLA = placebo) (ACT = acetaminophen)
(RE = running economy) (TT = Time Trial).
2.2. Subjects
Eleven total participants (9 men and 2 women) were recruited to participate in the
study. Participants were well-trained distance runners on the NCAA division II cross-
country team at Western Colorado University (WCU). Participants were considered well-
trained based on VO2 max and were in the 99th percentile for VO2 max in their age and
sex-group based on ﬁtness guidelines [20]. Participants completed the study during the
middle of the indoor track season. They typically performed two workouts per week and
four low intensity runs per week in addition to the experimental trials. One workout
would consist of four to ten intervals of 400 to 1000 m with one to three minutes of jogging
between repetitions. The other workout would be a continuous run of 20–35 min at 80–90%
of VO2 max. Men in the study ran between 80 and 120 km/wk. Women in the study
ran between 56 and 96 km/wk. Men and women runners trained at an average running
velocity of 14.0 km/h and 12.5 km/h, respectively. Participants were excluded from the
study if they were found to be allergic to, or had previous complications with, the drug
ACT, if they were heavy alcohol users, or if they had had any liver complications in the past.
Participants were also excluded from the study if they were not classiﬁed as low risk for
heart disease based on the American College of Sports Medicine risk algorithm. Exclusion
criteria were assessed with the physical activity readiness questionnaire (PAR-Q) [21] and a
medical history questionnaire, which included questions regarding over-the-counter drug
use and alcohol use. All measurements of participants were conducted in the High Altitude
Performance Laboratory at WCU, except for the 3 km time trial, which was performed on
the indoor track in the WCU Mountaineer Fieldhouse. All subjects provided written and
verbal informed consent prior to participating in the study. This study was approved by
the Institutional Review Board at WCU [HRC2020-01-01-R12].
2.3. Procedures
2.3.1. Familiarization and Lead-In
Following completion of the informed consent and other screening questionnaires,
participants underwent a lead-in period to familiarize them with the VO2 max protocol
and treadmill RE assessments. The familiarization session was a way for participants to
gain an understanding of how to run on a treadmill with open-circuit indirect calorimetry
and to get a sense of the rating of the perceived exertion (RPE) scale. In this session the
participant did not run to volitional exhaustion. This allowed them to return to the lab
within 48 h for the genuine VO2 max assessment without the possibility of fatigue.
For this familiarization session participants were ﬁtted with a mask attached to falconia
tubing, which was attached to the metabolic cart (Parvo Medics TrueOne® 2400, Sandy City,
UT, USA) to collect expired gases. Participants were also ﬁtted with a chest strap (Polar,
Lake Success, NY, USA) to monitor heart rate throughout the test. Participants ran for 10 to
Int. J. Environ. Res. Public Health 2022, 19, 2927
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12 min at increasing speeds on the treadmill (Trackmaster, Newton, KS, USA). This session
was paced in a way that participants would reach an RPE of about 7 within 10–12 min,
giving them an understanding of the perception of effort they would feel throughout the
genuine VO2 max assessment and later RE assessments. At the conclusion of the session,
participants completed a low intensity cool-down at a self-selected pace for at least ﬁve
minutes and were dismissed from the lab. The entirety of the screening and familiarization
session lasted 30–45 min.
2.3.2. Anthropomorphic Measurements
While wearing only running attire, the participant removed their shoes and stood on a
scale (Tanita, Arlington Heights, IL, USA) to be weighed in kilograms (kg). A measuring
stick built into the scale was used to measure the participant’s height in centimeters (cm).
Body mass index (BMI) was later calculated from these measurements using the formula
BMI = weight (kg)/height (m)2. Body fat percentage was assessed using an Omron HBF-300
handheld body composition analyzer (Omron, Bannockburn, IL, USA).
2.3.3. Maximal Oxygen Consumption
Following anthropomorphic measurements, participants completed a self-selected
10-min dynamic warm-up consisting of stretches and other exercises on the indoor track in
the WCU Mountaineer Fieldhouse. The same warm-up routine was performed for each
participant prior to the RE test and time trial. This allowed the participant to prepare to
perform as they would in a typical training session or race.
VO2 max was determined using open-circuit spirometry combined with indirect
calorimetry (Parvo Medics TrueOne® 2400, Sandy City, UT, USA) in response to incre-
mental treadmill running (Trackmaster, Newton, KS, USA). Flow and gas calibrations
were performed prior to each test using standard operating procedures provided by the
manufacturer. Participants were ﬁtted with a mask attached to falconia tubing, which was
attached to the metabolic cart to collect expired gases. They were also ﬁtted with a chest
strap (Polar, Lake Success, NY) to monitor heart rate throughout the test. The treadmill was
set to an initial incline of one percent grade, as one percent grade most accurately reﬂects
the energetic cost of outdoor running [22,23].
Male participants completed a 3-min warm up at 12 km/h at a 1% grade. There-
after, the treadmill velocity was increased 0.8 km/h every minute until velocity reached
19.2 km/h; at this point, the velocity remained constant and grade of the treadmill was in-
creased 2% every minute of the test until the participant reached volitional fatigue. Female
participants followed a similar pattern. They completed a 3-min warm up at 10.5 km/h
at a 1% grade. Thereafter, treadmill velocity was increased 0.8 km/h every minute until
velocity reached 17.7 km/h. At this point the velocity remained constant and grade of the
treadmill was increased 2% every minute of the test until the participant reached volitional
fatigue. Heart rate and RPE were recorded at the end of each minute throughout the test.
Participants were provided verbal encouragement throughout the test until exhaustion.
VO2 data were smoothed with a 15-s moving average. VO2 max was denoted as the highest
15 s moving average obtained during the last minute of exercise with no further increase in
VO2. All tests were terminated by volitional exhaustion. A true VO2 max was conﬁrmed
based on a plateau in VO2 deﬁned by a change of <150 mL/min despite a change in
workload and an RER greater than 1.10.
2.3.4. Intervention Sessions
Each of the three intervention sessions took place on the same day of the week,
beginning at the same time of day, exactly one week apart for each participant. Participants
were instructed to avoid caffeine for four hours prior to all interventions and tests. They
were also instructed to maintain similar diet and sleep habits on the days prior to testing
and on the days of testing. Each session began with the participant meeting with the
research assistant who would administer one of the three interventions. The participant
Int. J. Environ. Res. Public Health 2022, 19, 2927
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received either a baseline of 8 ounces of water paired with nothing, three placebo capsules
paired with 8 ounces of water, or 1.5 g ACT in the form of three 500 mg capsules paired
with 8 ounces of water. The order of the intervention was randomized and was blinded
to the participant and the primary investigators. Following ingestion, the participant was
instructed to relax and perform a non-stressful activity, such as reading or listening to music
for 50 min. Thereafter, participants completed their individualized 10-min dynamic warm
up routine, and then transitioned to the RE test. This timeframe was chosen because peak
plasma concentration of ACT occurs approximately 45–60 min after oral administration [6].
2.3.5. Running Economy
Each participant was ﬁtted with a heart rate monitor and a mask connected to a tube
leading to the metabolic cart in the same fashion as the familiarization and VO2 max tests.
The RE test consisted of four and ﬁve-minute stages at increasing running velocities. The
intensity of each stage was kept relatively low as RE at lower speeds has been demonstrated
to be more strongly correlated with performance [16]. The duration of ﬁve minutes for
each stage was selected, as it takes approximately four to ﬁve minutes to reach steady
state oxygen consumption [24]. The total duration of 20 min was selected because the
participants in the study consistently warm-up for workouts and race for 20 min and the
RE portion of the assessment served as a warm-up for the subsequent 3 km time trial
performance measure. Heart rate, oxygen consumption, and RPE were recorded during
the last minute of each stage. Male participants ran each stage at 10.5 km/h, 11.2 km/h,
12.0 km/h, and 12.9 km/h (174.4 m/min, 187.8 m/min, 201.2 m/min, and 214.6 m/min).
Female participants ran each stage at 9.7 km/h, 10.5 km/h, 11.2 km/h, and 12.0 km/h
(160.9 m/min, 174.4 m/min, 187.8 m/min, and 201.2 m/min). The intensity of these
stages ranged from approximately 55% to 75% of VO2 max throughout the duration of
the test. RE was expressed in two ways. First, as the oxygen cost required to run 1 km
of horizontal distance (mL/kg/km) and second, as the caloric unit cost—the energy in
kilocalories required to run 1 km of horizontal distance (kcal/kg/km). This unit has been
demonstrated to be more sensitive to changes in relative velocity compared with oxygen
cost [25]. Caloric unit cost was calculated by dividing the steady-state energy expenditure
cost (kcal/min) obtained during the last four 15-s moving averages of each stage by body
mass (kg), divided by running velocity (m/min) and multiplied by 1000 (1000 m/km), as
done in a previous RE study [24].
2.3.6. Track Time Trial
Following the RE test, participants were given 15 minutes to use the restroom, change
shoes if desired, and perform any additional warm up stretches or exercises as they nor-
mally would prior to a race. This routine was again kept constant for each individual
participant. Exactly 15 min following the conclusion of the RE test, the participants began
the 3 km time trial on the indoor track at the Mountaineer Fieldhouse.
Participants were instructed to complete ﬁfteen laps on the 200 m track in the inner-
most lane as quickly as possible, as they would in a race. Researchers recorded the duration
of each lap split. At the completion of the time trial, the total run duration, heart rate,
and oxygen saturation were recorded. The participant’s heart rate and oxygen saturation
(SpO2) were measured by a ﬁngertip pulse oximeter (American Diagnostic Corporation,
Hauppauge, NY, USA). The participant then performed a low intensity cool down of their
choosing and subsequently completed a four-question survey regarding their perception of
effort and difﬁculty during the time trial. The questions on the survey were answered on a
1–10 scale with 1 being lowest and 10 highest. The questions were: (1) How would you rate
your level of effort over the course of the time trial? (2) How would you rate the exercise
difﬁculty of the entire time trial? (3) How would you rate your level of performance based
on your current ﬁtness level during the time trial? (4) How would you rate your average
level of perceived exertion over the time trial? Following the completion of the survey,
Int. J. Environ. Res. Public Health 2022, 19, 2927
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the participant was dismissed for the day. Each remaining intervention was separated by
exactly one week and repeated at the same time of day in the randomly determined order.
2.3.7. Statistical Analysis
Descriptive characteristics of the participants are presented as means and standard
deviations. With the exception of the 3 km time trial, all data met assumptions of normality.
Therefore, the nonparametric Friedman’s test was used to determine treatment differences
in the 3 km time trial, and data are reported with median and interquartile range as
appropriate. A 3 × 4 (trial × exercise stage) analysis of variance for repeated measures
with Bonferroni adjustment for pairwise multiple comparisons was used for treatment
differences in submaximal exercise variables (i.e., VO2 and heart rate) and RE between the
four treadmill stages. A three-way analysis of variance with repeated measures was used to
determine differences in post time trial heart rate and oxygen saturation. A Friedman’s test
was used to determine differences in RPE and the four-question self-evaluation form. These
data were therefore displayed accordingly as median and interquartile range. All other
continuous data that met assumptions of normality were reported as mean ± standard
deviation. Level of statistical signiﬁcance was set at p < 0.05 and SPSS version 27 (IBM-SPSS,
Boston, MA, USA) was used to perform these statistical analyses.
3. Results
Table 1 shows subject characteristics. Runners were normal weight based on body
mass index and presented with VO2 max values at or above the 99th percentile for age and
sex [20]. Each participant continued normal track training during the study: the average
mileage for the men was 103 km/wk; the average mileage for the women was 76 km/wk.
Table 1. Descriptive characteristics of participants.
Characteristic (Units)
All Participants
(n = 11)
Men
(n = 9)
Women
(n = 2)
Age (years)
18.8 ± 0.6
18.7 ± 0.5
19.5 ± 0.7
Height (cm)
171.1 ± 6.9
173.7 ± 4.2
159.5 ± 2.1
Weight (kg)
58.6 ± 5.3
59.7 ± 5.1
53.8 ± 2.9
BMI (kg/m2)
20.0 ± 1.1
19.8 ± 0.8
21.2 ± 1.7
BF%
9.7 ± 5.1
7.6 ± 1.0
19.5 ± 4.2
ABS VO2 max (L/min)
3.6 ± 0.6
3.8 ± 0.4
2.6 ± 0.3
REL VO2 max (mL/kg/min)
60.6 ± 7.7
63.3 ± 5.3
48.4 ± 2.2
Weekly training distance (km/wk)
98.1 ± 16.7
103.0 ± 9.9
76.0 ± 28.3
Abbreviations: cm (centimeters), kg (kilograms), kg/m2 (kilogram/meter2), BF% (body fat %) ABS (absolute),
L/min (liters/minute), REL (relative), mL/kg/min (milliliters/kilogram/minute), and km/wk (kilometers
per week).
3.1. Time and Splits
Figure 2 shows the 3 km time trial performance for the interventions. There were
no signiﬁcant differences in the time to complete the time trial among the interventions.
Performance times observed in the present study were within 2–5% of what the participants
actually performed in a competitive 3 km race in the weeks following the study. Mean
performance time between the three conditions were within ﬁve s (p = 0.076). Similarly, no
signiﬁcant differences were found in any of the 1 km split times between BSL, PLA, and
ACT groups (p = 0.406, 0.234, and 0.811, respectively). Mean values for the ﬁrst, second,
and third split times from start to 1 km, 1 km to 2 km, and 2 km to 3 km were all within
three seconds between BSL, PLA, and ACT conditions.
Int. J. Environ. Res. Public Health 2022, 19, 2927
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Figure 2. Box and whisker plot for 3 km time trial times in s for baseline, placebo, and ACT conditions.
The box is the interquartile range, the horizontal line is the median, the cross (
 
within three seconds between BSL, PLA, and ACT conditions. 
 
Figure 2. Box and whisker plot for 3 km time trial times in s for baseline, placebo, and ACT condi-
tions. The box is the interquartile range, the horizontal line is the median, the cross (✛) is the mean, 
and the error bars are the minimum and maximum. ACT; acetaminophen. 
3.2. Running Economy 
The RE exercise intensities for stage 1, 2, 3, and 4 corresponded to approximately 
60%, 66%, 71%, and 74% of V̇O2 max, respectively. All subjects achieved steady-state 
oxygen consumption in each stage. As shown in Figure 3, there were no significant dif-
ferences between BSL, PLA, and ACT conditions in RE expressed as mL/kg/km in any of 
the four stages. For example, the average RE across stage 4 for BSL was 207.4 mL/kg/km, 
compared with 208.6 mL/kg/km for PLA and 208.5 mL/kg/km for ACT (p = 0.886; Figure 
3). Likewise, when expressed as kcal/kg/km, RE was also similar among the conditions. 
For example, the average RE across stage 4 for BSL was 1.009 kcal/kg/km, compared with 
1.015 kcal/kg/km for PLA and 1.016 kcal/kg/km for ACT (p = 0.857; Figure 4). 
) is the mean, and the
error bars are the minimum and maximum. ACT; acetaminophen.
3.2. Running Economy
The RE exercise intensities for stage 1, 2, 3, and 4 corresponded to approximately
60%, 66%, 71%, and 74% of VO2 max, respectively. All subjects achieved steady-state
oxygen consumption in each stage. As shown in Figure 3, there were no signiﬁcant
differences between BSL, PLA, and ACT conditions in RE expressed as mL/kg/km
in any of the four stages.
For example, the average RE across stage 4 for BSL was
207.4 mL/kg/km, compared with 208.6 mL/kg/km for PLA and 208.5 mL/kg/km for ACT
(p = 0.886; Figure 3). Likewise, when expressed as kcal/kg/km, RE was also similar among
the conditions. For example, the average RE across stage 4 for BSL was 1.009 kcal/kg/km,
compared with 1.015 kcal/kg/km for PLA and 1.016 kcal/kg/km for ACT (p = 0.857;
Figure 4).
Figure 3. Box and whisker plots for RE expressed as mL/kg/km for baseline, placebo, and ACT
conditions for (A) Stage 1: 60% of VO2 max, (B) Stage 2: 66% of VO2 max, (C) Stage 3: 71% of VO2
max, and (D) 74% of VO2 max. The box is the interquartile range, the horizontal line is the median,
the cross (
8 of 15 
, kg (kilograms), kg/m2 (kilogram/meter2), BF% (body fat %) ABS 
), REL (relative), mL/kg/min (milliliters/kilogram/minute), and 
m time trial performance for the interventions. There were no 
e time to complete the time trial among the interventions. 
 in the present study were within 2–5% of what the partici-
a competitive 3 km race in the weeks following the study. 
ween the three conditions were within five s (p = 0.076). Sim-
nces were found in any of the 1 km split times between BSL, 
406, 0.234, and 0.811, respectively). Mean values for the first, 
from start to 1 km, 1 km to 2 km, and 2 km to 3 km were all 
n BSL, PLA, and ACT conditions. 
 
for 3 km time trial times in s for baseline, placebo, and ACT condi-
e range, the horizontal line is the median, the cross (✛) is the mean, 
mum and maximum. ACT; acetaminophen. 
ties for stage 1, 2, 3, and 4 corresponded to approximately 
f V̇O max respectively All subjects achieved steady state
) is the mean, and the error bars are the minimum and maximum. ACT; acetaminophen.
Int. J. Environ. Res. Public Health 2022, 19, 2927
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Figure 4. RE expressed as kcal/kg/km for baseline, placebo, and ACT conditions for (A) Stage 1:
60% of VO2 max, (B) Stage 2: 66% of VO2 max, (C) Stage 3: 71% of VO2 max, and (D) 74% of VO2
max. ACT; acetaminophen.
3.3. Heart Rate, Oxygen Consumption, and Saturation
Table 2 shows the sub-maximal heart rate and oxygen consumption during the RE tests,
and the post time trial oxygen saturation and heart rate. Sub-maximal oxygen consumption
was similar between BSL, PLA, and ACT at each of the four RE stages (p = 0.529, 0.148,
0.234, and 0.159, respectively) as was heart rate (bpm) throughout the four RE stages
(p = 0.518, 0.135, 0.071, and 0.176, respectively). Post time trial oxygen saturation (p = 0.913) and
post time trial heart rate (p = 0.846) were not different between BSL, PLA, and ACT conditions.
Table 2.
Oxygen consumption and heart rate between baseline (BSL), placebo (PLA), and ac-
etaminophen (ACT) conditions.
Stage
Speed (m/min)
(Male, Female)
BSL
(M ± SD)
PLA
(M ± SD)
ACT
(M ± SD)
p-Value
Oxygen Consumption (mL/kg/min)
1
174.4, 160.9
36.0 ± 2.6
35.9 ± 3.6
35.0 ± 2.8
0.529
2
187.8, 174.4
38.3 ± 2.8
38.3 ± 3.7
38.9 ± 2.4
0.148
3
201.2, 187.8
41.2 ± 3.5
41.6 ± 3.5
41.8 ± 2.2
0.234
4
214.6, 201.2
44.0 ± 2.7
44.2 ± 3.9
44.2 ± 2.5
0.159
Heart Rate (bpm)
1
174.4, 160.9
134 ± 11
139 ± 8
136 ± 9
0.518
2
187.8, 174.4
143 ± 10
150 ± 9
147 ± 9
0.135
3
201.2, 187.8
149 ± 8
155 ± 8
154 ± 8
0.071
4
214.6, 201.2
158 ± 8
162 ± 9
160 ± 8
0.176
Post TT Oxygen Saturation (%)
N/A
(Post 3 km TT)
87.6 ± 2.8
87.6 ± 3.0
87.4 ± 3.1
0.913
Post TT Heart Rate (bpm)
N/A
(Post 3 km TT)
176.7 ± 6.4
174.1 ± 11.3
175.7 ± 6.2
0.846
M ± SD, (mean ± standard deviation); mL/kg/min, (milliliters/kilogram/minute); m/min, (meters/minute);
bpm, (beats per minute); TT, (time trial); km, (kilometer); BSL, baseline; PLA, placebo; ACT, acetaminophen.
Int. J. Environ. Res. Public Health 2022, 19, 2927
10 of 14
3.4. RPE and Questionnaire Responses
As shown in Table 3, there were no signiﬁcant differences in RPE during each RE stage
between the three conditions. In addition, no signiﬁcant differences were found in any of
the post 3 km time trial questionnaire responses between the three conditions.
Table 3. Rating of perceived exertion (RPE) (1 = very low RPE, 10 = very high RPE) during RE stages
and post TT perception of effort and difﬁculty responses between BSL, PLA, and ACT trials.
Stage/Question
Speed (m/min)
(Male, Female)
BSL
Med (25th, 75th)
PLA
Med (25th, 75th)
ACT
Med (25th, 75th)
p-Value
RPE during RE Stages
1
174.4, 160.9
1 (1, 2)
1 (1, 2)
1 (1, 2)
0.273
2
187.8, 174.4
2 (1, 2.5)
2 (2, 2.5)
2 (1, 3)
0.957
3
201.2, 187.8
2.5 (1.5, 3)
3 (2, 3)
2 (2, 4)
0.519
4
214.6, 201.2
3 (1.5, 5)
3 (2, 5)
2 (2, 5)
0.922
Responses to Questionnaire
Q1
Effort level
9 (8, 9)
9 (8, 9.5)
9 (9, 9)
0.091
Q2
Exercise difﬁculty
8.5 (8, 9)
9 (8, 10)
9 (8, 9)
0.656
Q3
Performance level
8 (8, 9)
8 (7, 9)
8 (7.5, 9)
0.368
Q4
Perceived exertion
8 (7, 9)
8 (8, 9)
9 (8, 9)
0.140
Abbreviations: TT (time trial); BSL, baseline; PLA, placebo; ACT, acetaminophen; Med 25th, 75th (median
(25th percentile, 75th percentile)); m/min (meters/minute); Q, (question).
4. Discussion
In contrast to our hypothesis, the primary ﬁndings of this randomized, double-blind
crossover trial indicate that supplementation with ACT does not improve RE or 3 km time
trial performance in NCAA competitive cross-country athletes. Baseline RE expressed as
mL/kg/km and kcal/kg/km were within 1% of the placebo and ACT conditions for all
stages of the incremental exercise test. Additionally, there was no noticeable difference in
the time to complete the 3 km time trial, as well as with 1 km splits with ACT. Collectively,
given similar steady-state oxygen consumption, heart rate, minute ventilation, respiratory
exchange ratio, and gross energy cost during incremental treadmill running between
conditions, ACT supplementation does not favorably modify exercise economy or 3 km
time trial performance.
ACT’s primary mechanism of action for pain relief is on the serotonergic descending
pain pathway [26]. ACT inhibits prostaglandin (PG) synthesis from arachidonic acid in
human skeletal muscle; as a result, PGs regulate adaptations to muscular exercise [26].
An analgesic drug, such as ACT, can alter the acute and chronic responses to exercise by
elevating the pain threshold and requiring a greater amount of pain before it is felt [3]. As
exercise-induced pain is a contributor to volitional exhaustion or changes in pacing during
exercise [2], a reduction in perceived pain should increase the athlete’s performance [2,3].
RE has been demonstrated to account for a signiﬁcant amount of the variation observed
in race performance amongst elite level runners [16]. RE is dependent on a variety of factors,
including efﬁciency of form [27] and both central and peripheral fatigue [1,28,29]. Due to the
inﬂuence of RE to be affected by central fatigue and its correlation with performance in elite
runners, it was hypothesized that ACT, which has a direct effect on central fatigue [26,30],
would improve RE in competitive athletes. The results of this study demonstrate that RE
was similar across BSL, PLA, and ACT conditions for all RE stages, both as measured in
mL/kg/km and in kcal/kg/km.
Our ﬁndings are in contrast to those by Dagli et al. [3], who reported a 1.9% (14 s)
improvement in the 3 km time trial performance. It is important to note the crucial
study design and sample differences between the present study and those by Dagli and
colleagues. While Dagli et al. studied recreationally active male runners with an av-
erage VO2 max of 55.67 ± 5.35 mL/kg/min, measured at sea level [3], we speciﬁcally
recruited in-competition NCAA elite male and female athletes with an average VO2 max of
Int. J. Environ. Res. Public Health 2022, 19, 2927
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60.6 ± 7.7 mL/kg/min, measured at 7700 feet, which had already undergone substantial
endurance training. Indeed, the participants in our study completed the 3 km distance
two minutes faster on average than participants in the study by Dagli et al. [3], despite
completing the trials at 7700 feet as opposed to sea level. Notably, the average post exercise
oxygen saturation levels in the present study are quite low, as shown in Table 2. This
difference in completion time and duration of effort may be a critical reason as to why the
present study did not demonstrate appreciable differences in performance with ACT.
Of the previous studies examining endurance performance, the majority of studies
that found statistically signiﬁcant differences in performance between ACT and control
conditions required exercise times of at least 20 min. For example, Mauger et al. [10] found
a 30 s improvement between ACT and control in a 10-mile cycle time trial, which lasted
on average 26.25 min for the ACT condition and 26.75 min for the control condition [10].
Mauger et al. [11] found a four-minute difference between ACT and control conditions
in a cycle test to exhaustion in the heat in which subjects in the ACT condition were able
to cycle for 22.7 min compared to only 18.8 min in the control condition [11]. Foster et al.
found a 19 watt improvement in average power between ACT and control conditions in a
repeated Wingate study with a total exercise time of 20 min when active recovery cycling
was included [9]. Delextrat et al. found a 24-watt improvement in peak power [8] in a
similar study design as Foster et al. [9]. All of these studies used a randomized double-
blind crossover design [8–11]. Only two previously conducted studies investigated the
effects of ACT on exercise bouts involving an exercise duration less than 20 min [3,12].
Both of these studies were also randomized double blind crossover studies with an ACT
condition and a placebo condition. These two studies reported signiﬁcant performance
beneﬁts of ACT compared with control conditions. However, it should be emphasized
that both studies demonstrated marginal, albeit signiﬁcant, improvements with ACT. First,
the study by Dagli et al. [3] reported a small difference of 1.9% with ACT. Second, the
study by Morgan et al. [12] also demonstrated a small, 5-watt difference in average power
over a 3-min maximum cycle test, which was a 1.4% difference compared with control
conditions [12].
ACT has been demonstrated to decrease participants’ RPE during running bouts of
similar or increased intensities [3,13]. We did not demonstrate any signiﬁcant differences
in RPE between treatment conditions. Likewise, we did not demonstrate any signiﬁcant
differences in the perception of effort and difﬁculty questionnaire among trials. The median
reported value for all four of the post time trial questions on the questionnaire were within
1 point of each other on the 1–10 scale across the three treatment conditions. This dis-
plays that the participants did not perceive a signiﬁcant difference in effort, difﬁculty,
performance, or exertion between the three conditions.
A limitation of this study was the small sample size (11) and unequal distribution of
male (9) and female (2) participants. Although all statistical tests were performed while
examining only one sex at a time and results were the same as when all participants
were examined together, a more balanced quantity of male and female participants is
recommended for future studies. Another limitation of the present study was the training
schedule of participants was not controlled from week to week. Although participants
completed similar weekly training volumes throughout the study, the exact workouts of
the participants varied from week to week and thus may have resulted in the participants
feeling more or less fatigued from each week’s workouts between the three trials. However,
the variability between training loads should not have had a signiﬁcant effect on the total
outcome of the study, due to the randomization of the order each participant undertook.
Future studies can minimize the potential for this phenomenon by scheduling data collec-
tion during the off-season, where the participants are less likely to be doing high intensity
training over the study duration. Furthermore, the duration between trials may not need
to be an entire week, as well-trained runners typically have the ability to recover from
hard efforts faster than recreationally active runners. For example, it has been suggested
that “aerobic ﬁtness enhances recovery from high intensity intermittent exercise through
Int. J. Environ. Res. Public Health 2022, 19, 2927
12 of 14
enhanced aerobic contribution, increased post-exercise VO2, and possibly by increased
lactate removal and increased PCr restoration, which has been linked to improved power
recovery” [31,32]. Therefore, in studies involving well-trained participants, the required
time between trials may only be 48–72 h as opposed to studies with recreationally active
participants who require more time between trials to fully recover.
Another variable that future research studies involving well-trained participants
should examine is the trial distance. The present study examined the effectiveness of ACT
over a relatively short time trial distance of 3 km. On average, participants completed this
distance in just over ten minutes. ACT has been demonstrated to be effective in improv-
ing performance amongst well-trained participants over longer durations. For example,
Mauger and colleagues examined ACT’s inﬂuence on performance over a ten-mile cycle
time trial in 13 trained male cyclists [10]. They found that ACT signiﬁcantly improved
performance by 30 s over the course of the ten-mile trial. As this study was examining a
distance that took over 26 min to complete, it is possible that ACT’s effectiveness increases
as the required trial duration increases, especially in studies involving well-trained par-
ticipants. Future studies on well-trained runners should investigate the effectiveness of
ACT over distances of at least 8 km, which would require an average duration of effort of
at least 26 min, as in the study by Mauger et al. [10].
5. Conclusions
The results of the present study indicate no performance beneﬁt of ACT on RE or a
3 km time trial performance among NCAA competitive collegiate distance runners. These
results are in contrast to some [3,8–12], but not all [13,14] studies investigating the potential
for ACT to improve exercise performance. To our knowledge, as this is the ﬁrst study
to examine the effects of ACT on well-trained collegiate distance runners, it appears that
ACT has a more signiﬁcant effect on performance for recreationally active runners than
well-trained runners [3]. It remains to be found whether ACT is beneﬁcial for well-trained
runners at distances other than 3 km or under more controlled experimental circumstances,
such as with a higher number of participants and a more favorable proportion of male and
female participants. Finally, it should be emphasized that ingestion of ACT is for medical
purposes only. It is not recommended for athletes to use ACT for exercise performance
without a medical indication. Moreover, prior review of relevant medical history by
the athletes’ healthcare team, and physician approval before an athlete uses ACT, is the
best practice.
Author Contributions: This work is the result of collaboration among R.P.H. and G.P.V.G. Both
authors have equally contributed, reviewed, and improved the manuscript. Conceptualization,
R.P.H., G.P.V.G.; Methodology, R.P.H., G.P.V.G.; Formal Analysis, R.P.H., G.P.V.G.; Investigation,
R.P.H., G.P.V.G.; Data Curation, R.P.H., G.P.V.G.; Writing—Original Draft Preparation, R.P.H., G.P.V.G.;
Writing—Review and Editing, R.P.H., G.P.V.G.; Visualization, R.P.H., G.P.V.G.; Supervision, G.P.V.G.;
Project Administration, R.P.H., G.P.V.G. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki and was approved by the Institutional Review Board of Western Colorado University
(HRC2020-01-01-R12).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Some or all data and models that support the ﬁndings of this study are
available from the corresponding author upon reasonable request.
Acknowledgments: The authors would like to thank the research assistant, Jonathan Specht, who
was able to begin every experimental session by administering the treatment for each participant.
They also thank Coach Jennifer Michel for allowing the utilization of her athletes as participants for
this project. Finally, they thank all the student athletes who volunteered their time and energy to
Int. J. Environ. Res. Public Health 2022, 19, 2927
13 of 14
participate in this study. This study would not have been possible without the tremendous amount
of effort they put into each session. We are very grateful for their willingness to arrive on time to
each meeting, follow all instructions, and participate to their fullest capacity for the entirety of the
study. Thank you to everyone who helped to make this research project possible.
Conﬂicts of Interest: The authors declare no conﬂict of interest.
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The Effect of Acetaminophen on Running Economy and Performance in Collegiate Distance Runners.
Huffman, Riley P,Van Guilder, Gary P