Effects of daytime ingestion of melatonin on heart rate response during prolonged exercise

Abstract

The current study sought to investigate the effect of melatonin consumption on cardiovascular response during submaximal exercise in healthy men. For this purpose, eight students (age: 21.8 ± 0.9) were asked to run for 45 minutes at submaximal intensity after melatonin-(6 mg) or placebo-ingestion, in a randomized and counterbalanced order. Heart rate (HR) and rectal temperature ( T re ) evolution during exercise were measured. Blood samples were drawn twice (before and immediately after exercise) for the determination of triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-c), lactate, protein, and superoxide dismutase concentrations. The results showed that melatonin may disturb thermoregulatory control by exerting an effect on HR at 10 min of exercise, reducing HR by 6.6% (9 bpm; P < 0.001), and this effect decreased to 3.6% at the end of exercise ( P < 0.01). Melatonin has no effect on triglycerides total cholesterol, HDL-c, lactate, and protein at rest and post-exercise. Although melatonin administration did not present a risk for cardiovascular function in healthy men, melatonin at high doses could decrease superoxide dismutase concentrations owing to the alteration of redox balance. These findings suggest that a high concentration of antioxidants does not enhance cardiovascular performance and may impair thermoregulatory control during prolonged exercise.

Full text

ARTICLE
Effects of daytime ingestion of melatonin on heart rate response
during prolonged exercise
Amine Souissi
1,2,*
, Ismail Dergaa
3,4
, Sarah Musa
4
, Helmi Ben Saad
1,2
, and Nizar Souissi
3
1
University of Sousse, Farhat Hached Hospital, Research Laboratory “Heart Failure, LR12SP09”, Sousse, Tunisia
2
Université de Sousse, Faculté de médecine de Sousse, Laboratoire de physiologie et explorations fonctionnelles, Sousse, Tunisia
3
Physical Activity, Sport and Health, UR18JS01, National Observatory of Sport, Tunis, Tunisia
4
Primary Health Care Corporation (PHCC), Preventative Health Department–Wellness, Doha, Qatar
Received 22 July 2021, Accepted 1 November 2021
Abstract -- The current study sought to investigate the effect of melatonin consumption on cardiovascular
response during submaximal exercise in healthy men. For this purpose, eight students (age: 21.8 ±0.9) were
asked to run for 45 minutes at submaximal intensity after melatonin-(6 mg) or placebo-ingestion, in a
randomized and counterbalanced order. Heart rate (HR) and rectal temperature (T
re
) evolution during exercise
were measured. Blood samples were drawn twice (before and immediately after exercise) for the determination
of triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-c), lactate, protein, and superoxide
dismutase concentrations. The results showed that melatonin may disturb thermoregulatory control by
exerting an effect on HR at 10 min of exercise, reducing HR by 6.6% (9 bpm; P<0.001), and this effect decreased
to 3.6% at the end of exercise (P<0.01). Melatonin has no effect on triglycerides total cholesterol, HDL-c,
lactate, and protein at rest and post-exercise. Although melatonin administration did not present a risk for
cardiovascular function in healthy men, melatonin at high doses could decrease superoxide dismutase
concentrations owing to the alteration of redox balance. These findings suggest that a high concentration of
antioxidants does not enhance cardiovascular performance and may impair thermoregulatory control during
prolonged exercise.
Keywords: catecholamine, endurance exercise, free radicals, nitric oxide, pro-oxidants
Résumé --L’ingestion de mélatonine améliore-t-il la réponse cardiovasculaire lors de l’exercice
sous-maximal ? L’objectif de la présente étude était d’évaluer l’effet de la consommation de la mélatonine sur
la réponse cardiovasculaire lors d’un exercice sous-maximal. Huit étudiants en éducation physique ont été
appelés à courir pendant 45 minutes à une intensité sous-maximale après avoir ingérer 6-mg de mélatonine ou de
placebo, dans un ordre randomisé. La fréquence cardiaque (FC) et la température rectale (T
re
) au cours de
l’exercice étaient mesurées. Des échantillons de sang étaient prélevés pour analyser les taux de triglycérides, de
cholestérol total, de cholestérol des lipoprotéines de haute densité (HDL-c), de lactate, de protéines et de
superoxyde dismutase (SOD). Les résultats ont révélé que la mélatonine n’a aucun effet sur les triglycérides, le
cholestérol total, le HDL-c, le lactate et les protéines au repos et après l’effort. Cependant, elle peut affecter
légèrement la SOD et le contrôle thermorégulateur lors de l’exercice en exerçant un effet sur la FC à 10 min,
réduisant la FC de 6,6 % (9 bpm ; p<0,001). Cet effet a diminué à 3,6 % à la findel’exercice (P<0,01). Ainsi une
concentration élevée d’antioxydants (mélatonine) n’améliore pas la performance cardiovasculaire, par ailleurs,
elle peut altérer le contrôle thermorégulateur pendant l’exercice.
Mots clés : catécholamines, exercice d’endurance, radicaux libres, oxyde nitrique, pro-oxydants
*Corresponding author: amine.swissi@gmail.com
Movement & Sport Sciences - Science & Motricité 2022, 115,25–32
©ACAPS, 2022
https://doi.org/10.1051/sm/2021020
Science Motricité
Movement Sport Sciences
Available online at:
www.mov-sport-sciences.org

1 Introduction
Melatonin (N-acetyl-5 methoxytryptamine) is mainly
secreted in the pineal gland and plays an important role in
the regulation of circadian rhythms, contributing to the
temporal organization of human behavior and physiology
(Escames et al., 2012). Indeed, it has been reported that
melatonin administration reduced heart rate (HR) and
blood pressure in humans at rest, implying that melatonin
increases cardiac vagal tone in awake men in the supine
position (Escames et al., 2012). However, it is unclear how
melatonin affects the HR response to exercise. One study
reported no significant difference in HR during intermit-
tent activity between both the melatonin and the placebo
groups (Atkinson et al., 2005a), while another highlighted
a significant “slight”decrease in HR of 6 to 9 bpm
(Atkinson, Jones, Edwards, & Waterhouse, 2005b).
Melatonin lowers HR by suppressing sympathetic tone
(Viswanathan, Hissa, & George, 1986;Wang et al., 1999)
and decreasing catecholamine levels (Laflamme, Wu,
Foucart, & de Champlain, 1998).Melatonin was noted to
be safe and effective in protecting the infected heart
from reactive oxygen species, regardless of the cause
(Dominguez-Rodriguez & Abreu-Gonzalez, 2010;
Dominguez-Rodriguez, Abreu-Gonzalez, Piccolo,
Galasso, & Reiter, 2016;Dominguez-Rodriguez,
Abreu-Gonzalez, & Reiter, 2012). Adults’pro- and
antioxidant mechanisms are both upregulated in response
to acute exercise (Avloniti et al., 2017). Superoxide
dismutase (SOD), an antioxidant free-radical chain-
breaking enzyme, catalyzes the dismutation of superoxide
into oxygen and hydrogen peroxide and it may accelerate
healing after oxidative damage (Halliwell & Gutteridge,
2015). In aerobic organisms, SOD is an essential antioxi-
dant defense mechanism that may be impacted by greater
body temperature (Öztürk & Gümüslü, 2004). In the case
of acute oxidative stress, SOD may play a role in biological
response. Endogenous melatonin levels have been shown
to have a positive relationship with antioxidant capacity
(Benot et al., 1999). Although it appears to be a reasonable
idea to use melatonin to boost serum antioxidant activities
and protect the heart from free radicals during exercise,
there have been a few reports of adverse effect of
melatonin, such as down-regulation of nitric oxide
synthase (NOS) (Geary, Duckles, & Krause, 1998;
Okatani, Wakatsuki, Watanabe, Taniguchi, & Fukaya,
2001;Pozo, Reiter, Calvo, & Guerrero, 1994;Silva et al.,
2007;Tamura, Silva, & Markus, 2006). Indeed, a low
concentration of free radicals appears to be effective in the
regulation of hyperaemia during physical exercise in
perfectly functioning hearts (Trinity, Broxterman, &
Richardson, 2016). There is a scarcity of data on the effects
of antioxidants on healthy hearts in normal redox balance.
The aims of this research were to look into the effect of
melatonin on the evolution of HR during submaximal
exercise in healthy men, as well as to determine if melatonin
could be used to improve cardiovascular function.
2 Population and methods
2.1 Participants
Eight healthy physical education students volun-
teered to take part in the study [age: 21.8 ±0.9 years;
BMI: 21.0 ±0.8 kg/m
2
]. All participants were non-
smokers, have abstained from exercising and consuming
alcohol or caffeine-containing beverages for at least
24 hours prior to the assessments. Participants were
chosen based on their chronotype using Horne and
Ostberg’s questionnaire (Horne & Östberg, 1976). The
study was approved also by the Farhat HACHED ethical
committee, Sousse, Tunisia (FH/1609021). The study
protocol was in accordance with current national laws
and regulations. After receiving both a verbal and
written explanation of the experimental protocol, as well
as its potential risks and benefits, the participants gave
their written informed consent.
2.2 Study design
The participants were requested to visit the research
laboratory three times (Fig. 1). On the very first visit,
the participants completed the VAMEVAL test to
determine their maximum aerobic speed (MAS). Partic-
ipants were asked to complete the two visits of the
protocol in a randomized and counterbalanced order on
the second and third occasions (placebo or melatonin).
All the three visits were performed indoors at a relative
humidity of 60% ±3% and a temperature of 23 °C±0.1 °C
and at the same time of the day (i.e., between 8.00 and
10.35 A.M.) to minimize the effects of diurnal variations in
the measured variables (Souissi, Yousfi, Souissi, Haddad, &
Driss, 2020).
2.3 Experimental protocol
Participants sat in a supine position, then each
participant had a rectal thermistor implanted (inserted
10 cm beyond the anal sphincter). At 09:00 A.M., the
participants ingested whether the 6-mg of quick-release
vegetable melatonin (Jamieson Laboratories Toronto,
Montreal, Canada) or placebo capsule with 500 mL of
water before resting for 40 minutes in the supine
position. The HR and rectal temperature (T
re
)were
continuously recorded using a HR monitor (Polar
RS800, Finland) and a rectal probe (Universal
YSI400, China), respectively. Then, a blood sample
was taken from the right antecubital vein. At 09:50 A.
M. participants ran for 45 minutes at a submaximal
intensity fixed at 60% of their MAS on a treadmill
(Finnlo, Germany). HR and T
re
were measured
simultaneously, and data were selected every five
minutes. At the end of the exercise, blood samples
were taken from the left antecubital vein, triglycerides,
cholesterol, HDL-c, lactate, SOD and protein concen-
trations were measured.
26 A. Souissi et al.: Mov Sport Sci/Sci Mot 2022, 115,25–32

Figure 1. Flowchart of the study’s methodology.
A. Souissi et al.: Mov Sport Sci/Sci Mot 2022, 115,25–32 27

2.4 Blood variables analysis
Biochemical assays were carried out at the Laboratory
of the Hospital of Children in Tunis (Tunisia), using
standard methods and the COBAS 6000. As per
Beauchamp and Fridovich (1971), SOD concentrations
was measured spectrophotometrically by monitoring the
inhibition of photochemical reduction of nitro blue
tetrazolium (NBT) at 560 nm.
2.5 Statistical analyses
The data were presented as the mean and standard
deviation (±SD). The Kolmogorov-Smirnov test for
normality indicated that all data-sets were normally
distributed. The data were analyzed using repeated
measures analysis of variance (ANOVA). The Bonferro-
ni’s test was used to determine significant differences.
Effect sizes were calculated as partial eta-squared (h
p2
)to
determine the practical significance of the results.
Magnitudes of effect sizes were classified as trivial (0–
0.19), small (0.20–0.49), medium (0.50–0.79), and large
(≥0.80) (Cohen, 1992). An independent samples t-test was
performed for T
re
and HR to compare the difference
between conditions. The level of significance was prede-
termined to be P<0.05 for all statistical analyses. The
Statistical Software Version 10.0 for Windows (StatSoft,
Maisons-Alfort, France) was used for data analysis.
3 Results
All the participants undergoing submaximal exercise
successfully completed the exercise. None of the partic-
ipants achieved a thermal steady state during exercise and
the mean lactate values for both conditions were less than
2.50 mmol/L.
The changes in HR during the rest period and exercise
under both conditions are presented in Figure 2A. HR was
significantly higher at the end of exercise under the
placebo condition (P<0.01). HR increased progressively
during exercise, but it did not reach its maximum in the
two conditions. At 10 minutes, we observed the most
important difference between the two conditions
(Fig. 3A). HR increased considerably during exercise
from 5 to 10 minutes, only under the placebo condition. In
brief, the results show that melatonin exerts an effect on
HR at 10 minutes of exercise, reducing HR by 6.6%
(9 bpm; P<0.001), and this effect decreased to 3.6% at the
end of exercise (6 bpm; P<0.01).
The changes in T
re
during the rest period and exercise
under both conditions are presented in Figure 2B. The
results showed that melatonin has hypothermic effect only
at rest. The Student’st-test revealed that the total
increase of T
re
during exercise was more important in
melatonin condition compared to placebo condition
(P<0.01) (Fig. 3B).
No significant (condition exercise) interaction was
obtained for triglycerides [F=1.6; P= 0.24; h
p2
= 0.9]. A
significant exercise effect was indicated for the triglycerides
[F= 50.6; P= 0.0001; h
p2
= 0.8]. No significant (condition
exercise) interaction was obtained for cholesterol [F=4;
P= 0.08; h
p2
= 0.3]. A significant exercise effect was
indicated for the cholesterol [F= 7.9; P= 0.02; h
p2
= 0.5].
No significant (condition exercise) interaction was
obtained for HDL-C [F= 0.06; P= 0.8; h
p2
= 0.009]
(Tab. 1).
No significant (condition exercise) interaction was
obtained for protein [F=&#9617 P= 0.33; h
p2
= 0.1]. A
significant condition was obtained for SOD [F= 9.8;
P= 0.01; h
p2
= 0.58]. Post-hoc analysis revealed that
SOD was significantly higher under placebo than melato-
nin condition at rest (P<0.01) (Tab. 1).
4 Discussion
In agreement with Marrin, Drust, Gregson, &
Atkinson (2013) who confirmed that melatonin decreased
the body temperature at rest. However, melatonin has no
hypothermic effect during exercise. In agreement with the
results of Brandenberger, Ingalls, Rupp, & Doyle (2018)
and McLellan, Smith, Gannon, & Zamecnik (2000), which
indicated that melatonin has no hypothermic effect during
submaximal exercise. The main finding of the present
study revealed that melatonin reduced HR by 6.6% after
Table 1. The pre- and post-exercise results of biochemical variables for both conditions (n= 8 healthy men).
Parameters Unit Placebo Melatonin Global effect
0
min
45
min
0
min
45
min
Condition Exercise Interaction
Triglycerides mmol/L 0.76 ±0.2 0.96 ±0.2 0.74 ±0.3 1.08 ±0.3
*
NS *** NS
Cholesterol mmol/L 3.18 ±0.7 3.51 ±0.6
*
3.12 ±0.6 3.2 ±0.6 NS
*
NS
HDL-C mmol/L 1.1 ±0.3 1.16 ±0.3 1.12 ±0.3 1.17 ±0.3 NS NS NS
Lactate mmol/L 1.8 ±0.3 2 ±0.5 1.7 ±0.4 1.8 ±0.4 NS NS NS
Protein mg/mL 29.2 ±1.7 29.7 ±2.1 30.5 ±1.5 30 ±2.1 NS NS NS
SOD U/g protein 663 ±98 576 ±78 467 ±78
x
571 ±43
*
NS **
Data were mean ±SD; NS: non-significant (P>0.05).
*
Significant different from corresponding pre-exercise value (P<0.05).
**
Significant different from corresponding pre-exercise value (P<0.01).
***
Significant different from corresponding pre-exercise value (P<0.001).
x
Significant difference from the placebo condition (P<0.05).
28 A. Souissi et al.: Mov Sport Sci/Sci Mot 2022, 115,25–32

10 minutes of exercise, and this effect fades to 3.6% at the
end of the exercise. To the best of the author’s knowledge,
this is the first study that looked at the impact of a single
high dose of melatonin on the HR response to continuous,
submaximal exercise.
The findings of the present study are in agreement with
Atkinson et al. (2005b) who reported that melatonin may
reduce HR by 6 to 9 bpm. The authors suggested that
melatonin lowers HR by suppressing sympathetic tone
(Viswanathan et al., 1986;Wang et al., 1999) and
decreasing catecholamine levels (Laflamme et al., 1998).
It has been shown that melatonin administration (in a dose
of 1-mg) greatly influences artery blood flow, decreases
blood pressure, and blunts noradrenergic activation in
young, healthy subjects (Cagnacci et al., 1997). However,
it was reported that 2.5-mg of melatonin did not influence
HR during intermittent exercise (Atkinson et al., 2005a).
This contradiction might be due to the difference in
methodology (protocol, intensity, and duration). The
current results showed that melatonin reduced rectal
Figure 2. Changes in physiological parameters during the test (n= 8 men). A 6-mg of melatonin or a placebo capsule was ingested just
before the rest period. (A) Changes in heart rate during the rest period and exercise at 23 °C and 60% relative humidity. (B) Changes in
rectal temperature during the rest period and exercise at 23 °C and 60% relative humidity. Significant differences between placebo
condition and melatonin condition are indicated by a dashed line in the diagrams (P<0.05). Data in (A and B) were analyzed with
Student’st-test. The values are presented as the mean ±SD.
Figure 3. Heart rate response at 10 min of exercise and total temperature elevation during exercise in placebo and melatonin
conditions (n= 8 men). (A) Heart rate recorded at 10 min after melatonin or placebo ingestion. (B) The total increase of rectal
temperature during exercise after melatonin or placebo ingestion. Data in (A and B) were analyzed with Student’st-test. *Significant
difference between melatonin and placebo (P<0.05). The values are presented as the mean and ±SD.
A. Souissi et al.: Mov Sport Sci/Sci Mot 2022, 115,25–32 29

temperature only at rest. The present study confirms that
melatonin has no hypothermic effect during exercise
(Brandenberger et al., 2018;McLellan et al., 2000).
Therefore, we wonder why melatonin has an hypothermic
effect only at rest. The effect of melatonin on cardiovas-
cular response during exercise could explain perhaps the
absence of hypothermic effect. In fact, it is well known that
the increase in HR induced an elevation in cardiac output
to enhance thermoregulatory control and heat dissipation
by increasing skin blood flow (Johnson & Proppe, 2010;
Taylor, Johnson, O’Leary, & Park, 1984;Souissi, Haddad,
Dergaa, Saad, & Chamari, 2021). Indeed, the HR increase
during exercise could be related to exercise induced-
vasodilation (Horiuchi & Fukuoka, 2019;Rowell, 1974;
Souissi et al., 2021). Since the results of the present study
indicated an important increase of HR at 10 minutes in the
placebo condition associated with appropriate thermoreg-
ulatory response, one could speculate that the HR raise at
10 minutes is partially due to the involvement of free
radical (nitric oxide) to the active vasodilator response.
Furthermore, previous findings revealed that performing
10-minutes submaximal exercise increases circulating
nitric oxide levels (Franco, Doria, & Mattiucci, 2001;
Rowell, 1974). It is possible that the rise in HR at
10 minutes, which is usually accompanied by an increase in
skin blood flow and cardiac output (Rowell, 1974), is
connected to the effects of nitric oxide-induced vasodila-
tion. It would be possible to suggest that melatonin may
exert antioxidants and anti-adrenergic effects at
10 minutes of exercise reducing the extent of HR elevation
and limiting the ability of thermoregulatory control. On
the other hand, we highlight that the important effect of
melatonin exerted on heart rate at 10 minutes could be
simply due to the fact that the half-life of melatonin is
40–60 minutes and the time required to reach the
maximum concentration of the drug in the blood after
oral administration is ≈41 minutes (Andersen et al., 2016).
The present results revealed different findings from our
hypothesis. A high dose of antioxidant has no beneficial
effect in healthy men at rest and could decrease SOD
concentration. In agreement with previous studies dem-
onstrating that high-dose of antioxidants may have pro-
oxidant activities by disrupting the redox balance (Kruk,
Aboul-Enein, & Duchnik, 2021;Trinity et al., 2016). The
present study is also in agreement with several inves-
tigations observing an alteration of blood flow (vascular
control) during dynamic exercise in healthy young adults
following the inhibition of free radical accumulation/
production with oral antioxidant administration (Donato,
Uberoi, Bailey, Walter Wray, & Richardson, 2010;
Richardson et al., 2007). Moreover, a large dose of
melatonin provided during the day (at bedtime) can
cause mild narcotic effects, drowsiness, and other side
effects, so it is not advised (Hardeland, Coto-Montes, &
Poeggeler, 2003). When taken during the day, melatonin
can disrupt the internal time system, resulting in an
elevation of oxidative stress (Hardeland et al., 2003). The
present results revealed, however, that melatonin did not
affect triglycerides, HDL-C, and cholesterol levels.
In short, this study supports the research results that
suggest that the dose of antioxidants must be carefully
selected and based on expert knowledge (Meagher &
Rader, 2001). The current finding could enable physicians,
coaches, and practitioners to take action (by using
antioxidants) in order to comply with the humans’bodies
needs in order to enhance cardiovascular function during
exercise or other stressful situations.
Amongst the limitations of the present study are:
–the post-exercise analytical values were expressed
without a correction for plasma volume changes:
–the assessed blood parameters were limited, further
research is needed to measure catecholamine and free
radical concentrations to assess the effect of exogenous
melatonin on cardiovascular response during submaxi-
mal exercise:
–the study was conducted exclusively in men students
with a small sample size; replication studies on a larger
number of participants is warranted.
Additionally, the thermoregulatory outcome measures
were limited to rectal temperature.
5 Conclusions
Acute melatonin administration (50 min prior to the
start of exercise) did not enhance cardiovascular
function during prolonged exercise in healthy men.
Melatonin supplementation at high doses caused brady-
cardia during exercise and may have a negative impact
on cardiovascular function and thermoregulatory control
by lowering free radicals (by exerting antioxidants
effects) and catecholamine production. Based on previ-
ous studies, the authors of the present study believe that
the key to improving cardiovascular function during
exercise is to restore or maintain an "optimal" redox
balance. Interestingly, the present study showed that the
significant increase in HR during the first 5–10 minutes
of submaximal exercise is a cardiovascular response that
may be partly due to free radicals’role in thermoregula-
tory control.
Acknowledgments. The authors would like to thank the
students who assisted in the project, as well as each of the
subjects for their selfless participation.
Conflicts of interest
The authors declare that they have no conflicts of
interest in relation to this article.
Authors’contributions
Dr. Amine Souissi contributed to the conception,
management of the study and original draft.
Professor Helmi Ben Saad contributed to the concep-
tion, management of the study, writing, review and
editing.
30 A. Souissi et al.: Mov Sport Sci/Sci Mot 2022, 115,25–32

Dr. Ismail Dergaa analyzed the data and contributed
to the preparation (writing) of the manuscript.
Professor Nizar Souissi contributed to the writing,
review and editing.
Dr. Sarah Musa added the flowchart of the study’s
methodology.
All authors read and approved the final version of the
manuscript.
Abbreviations
ANOVA analysis of variance
HR heart rate
MAS maximum aerobic speed
NBT nitro blue tetrazolium
NOS nitric oxide synthase
SD standard deviation
SOD superoxide dismutase
T
re
srectal temperature
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Cite this article as: Souissi A, Dergaa I, Musa S, Ben Saad H, & Souissi N (2022) Effects of daytime ingestion of melatonin on heart
rate response during prolonged exercise. Mov Sport Sci/Sci Mot, 115,25–32
32 A. Souissi et al.: Mov Sport Sci/Sci Mot 2022, 115,25–32