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WIRKIJOWSKI, Jakub, WIRKIJOWSKA, Małgorzata, MĘDYK, Jolanta, PATAROCHA, Yauheniya, ROGULSKI, Michał,
ŚLUSARSKA, Aleksandra, BŁASIAK, Paulina, MIKOŁAJEC, Patryk, HUK, Ruslan and BILECKA, Barbara. Non-trivial uses of
melatonin: Its effects on sleep, jet lag, obesity, migraine, and gastrointestinal disorders. Journal of Education, Health and Sport.
2025;78:57497 eISSN 2391-8306.
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1
Non-trivial uses of melatonin: Its effects on sleep, jet lag, obesity, migraine, and
gastrointestinal disorders
Jakub Wirkijowski
Independent Public Clinical Hospital of Prof. W. Orlowski, Czerniakowska 231, 00-401,
Warsaw, Poland
https://orcid.org/0009-0007-9882-9341
k.wirkijowski0@gmail.com
Małgorzata Wirkijowska
Formmed Center for Treatment of Congenital Defects and Malformations,
ul. Warszawska 197D, Babice Nowe
https://orcid.org/0009-0003-5857-965X
wirkijowskam@gmail.com
2
Jolanta Mędyk
Wroclaw Medical University,
Wybrzeże L. Pasteura 1, 50-367 Wroclaw, Poland
https://orcid.org/0009-0008-3346-0827
lek.jolantamedyk@gmail.com
Yauheniya Patarocha
Independent Public Health Care Center in Garwolin
ul. Lubelska 50, Garwolin
https://orcid.org/0009-0007-0472-9789
eugeniapatarocha@gmail.com
Michał Rogulski
Independent Public Health Care Center in Garwolin
ul. Lubelska 50, Garwolin
https://orcid.org/0009-0004-7328-5016
michal.rogulski97@gmail.com
Aleksandra Ślusarska
Public Outpatient Medical Center in Strzelin,
ul. Mickiewicza 20 Strzelin
https://orcid.org/0009-0009-8208-1222
a.slusarska4@gmail.com
Paulina Błasiak
Independent Researcher
https://orcid.org/0000-0002-7967-1776
blasiak.paulina.alicja@gmail.com
Patryk Mikołajec
Hospital Saint Anne in Miechow,
ul. Szpitalna 3, Miechow
https://orcid.org/0009-0001-3300-0061
patrykmikolajec@gmail.com
3
Ruslan Huk
Independent Public Health Care Center in Garwolin,
ul. Lubelska 50, Garwolin
https://orcid.org/0009-0008-5756-9448
hukr1992@gmail.com
Barbara Bilecka
Jan Kochanowski University Collegium Medicum,
aleja IX Wieków Kielc 19A, Kielce
https://orcid.org/0009-0009-5611-2996
basiabilecka@gmail.com
ABSTRACT
Introduction and aim of the study: Melatonin consumption is steadily increasing. In this
literature review, the authors intended to introduce the latest scientific evidence on the influence
of the sleep hormone not only on the quality of time spent in bed and jet lag, but also to consider
possible other positive impacts. Its eventual effects on headaches, gastrointestinal complaints,
or obesity were analyzed.
Materials and methods: The authors searched the scientific literature utilizing search engines
such as Science Direct, Cochrane, PubMed, Google Scholar, and UpToDate. The literature
review focused on the association of melatonin with issues such as sleep, migraines, GERD,
IBS, and jet lag.
Results: Most of the articles reviewed in this study highlighted the positive effects of melatonin
supplementation on sleep problems and jet lag. Furthermore, many studies report that it likewise
has a beneficial impact on conditions not directly related to sleep, such as obesity, GERD, IBS,
or migraine. Nevertheless, the articles emphasize the need for further research to establish
treatment protocols and to select an optimal dose.
Keywords: melatonin, indoleamines, sleep, obesity, shift work, jet lag, safety, migraine, GERD,
IBS,
4
INTRODUCTION
Melatonin (N-acetyl-5-methoxytryptamine) is a versatile substance belonging to the
endogenous indoleamines. (1) It occurs endogenously in both animals and plants. The human
body obtains it from exogenous sources, i.e., diet, and produces it independently. Endogenous
production occurs from the amino acid tryptophan in the pineal gland and enterochromaffin
cells in the gut. Interestingly, 400 times more of it is in the intestines than in the pineal gland.
(2) Daily melatonin secretion in the pineal gland averages between 0.1 and 0.9 mg. (3,4) The
hormone has also been detected in the trachea, retina, lens, thyroid, cochlea, skin, brain, liver,
kidney, spleen, pancreas, thymus, and reproductive tissues, (3) as well as in all body fluids:
cerebrospinal fluid, saliva, feces, bile, amniotic fluid, urine, semen, synovial fluid, and breast
milk. (5–7)
Circadian generators in the brain regulate the concentration of this substance in the body
during the day. (8) This substance acts as a circadian rhythm indicator in the central nervous
system. (9) It is also attributed to the role of a darkness indicator, as its production is induced
by darkness sensed by the eye's retina. (4) Exposure to light reduces indoleamine production,
and this also applies to artificial light, which reduces melatonin levels and increases the risk of
disease. (3,4)
Due to the possible wide range of uses of melatonin, interest in its supplementation in
people with sleep disorders or in improving immunity, is very high. A study by Hartstein et. al
found that in 2022, as many as 19% of children and adolescents in the United States (US) are
taking these substances, when in 2017, the percentage was only 1.3%. (10) A study by Li et al.
among US adults showed an increase in melatonin intake from 0.4 percent in 1999- 2000 to 2.1
percent in 2017-2018. Trends were seen in both genders and across all age groups. There was
also an increase in the frequency of intake of this substance above 5mg/d. Results are presented
in graph 1. (11)
5
Graph 1
Incidence of general melatonin administration and administration at doses higher than 5 mg per
day in adults in the US. (11)
The amount of melatonin produced in humans changes with age. Infants do not produce
their melatonin until around 3 months of age, (12) and their natural source is breast milk. (13)
Subsequently, its levels in the body increase with puberty and reach a plateau at puberty,
followed by a gradual decline from the late twenties to the fifties. (14,15)
6
Graph 2
Fluctuations in melatonin levels with age. (14)
Studies have shown that calcification of the pineal gland, which has the highest
calcification rate among all organs and tissues of the human body, may also be responsible for
reducing hormone secretion, (7) disease, (16) diet, (4) medication, (17) lifestyle (17) and
exposure to bright light at night (18) may also have a significant impact on melatonin levels.
In their comprehensive review study, Minich et al. compared melatonin and its role in
the human body to vitamin D, as it is a highly interesting compound with broad applications
and pleiotropic activity. It has potent antioxidant activity and the ability to inhibit inflammation,
cross the blood-brain barrier, and interact with the gut microbiome, so it can have a significant
impact on the occurrence of systemic diseases. Disorders of its function can cause "darkness
deficiency”. (19)
In this review article, we will evaluate the existing evidence for the effects of melatonin
on directly related issues such as sleep disorders and jet lag and discuss this substance as a
potentially effective support for the treatment of obesity, migraine, and gastrointestinal
disorders. We will also consider the safety of the administration of this hormone.
7
METHODS
The authors searched the scientific literature utilizing search engines such as Science
Direct, Cochrane, PubMed, Google Scholar and UpToDate. The literature review focused on
the association of melatonin with issues such as sleep, migraines, Gastroesophageal reflux
disease (GERD), irritable bowel syndrome (IBS), and jet lag.
SLEEP
Gholami et al. conducted a meta-analysis based on The Pittsburgh Sleep Quality Index
and included 2642 articles, though 23 remained after exclusions. The study indicated that
melatonin supplementation significantly improved sleep quality, additionally showing positive
use in primary sleep disorders. (20) Another meta-analysis looked at the effect of melatonin on
sleep quality. The study showed that while the substance reduces the time to fall asleep and
improves sleep efficiency, but it showed no positive effect on patients with secondary sleep
disorders. (21) Timothy et al. conducted a Randomized trial of people with sleep disorders.
They demonstrated that low-dose exogenous melatonin (0.5 mg) significantly reduced the time
to fall asleep and improved patient’s subjective wellbeing.(22) In this meta-analysis,
researchers analyzed the effect of higher doses of melatonin and also showed bedtime
improvements in terms of falling asleep faster and sleep quality in individuals, who took
supplementation. (23) Moreover, the researchers, led by Jeanne F Duffy, decided to summarize
the magnitude of indoleamine on sleep in one study. They presented that low (0.3 mg) and
higher (5mg) doses improved sleep performance. However, it is worth noting that the positive
effects were only evident in the older population, whereas younger participants showed no
remarkable advantage. (24) What is more, researchers from the Royal Infirmary Edinburgh,
Ninewells Hospital, and the University of Surrey analyzed the action of this hormone in people
with visual impairment, during which they discovered that it is also able to regulate circadian
rhythms in this population. (25) The randomized controlled trial conducted at Hospital de Base
São José do Rio Preto and Hospital do Câncer de Barretos evaluated a total of 203 patients in
the intensive care unit. The researchers showed that melatonin positively affected the quality of
sleep-in individuals in that department, which increased the care possibilities of patients in
critical conditions. (26)
8
JET LAG AND SHIFT WORK
Current times allow long-distance travel by passenger aircraft. Long-distance flights
lead to jet lag, which can manifest in several non-specific symptoms, including gastrointestinal
distress, fatigue, headache, irritability, or loss of concentration. (27,28)
Moreover, a comparable situation exists for shift workers to a certain degree.(29)
Maintaining a regular circadian rhythm has an intrinsically positive influence on the
productivity and well-being of our functioning throughout the day. This guarantees the
maintenance of homeostasis in our body. (30) Interestingly, these destinations also have a
different impact on the human body. For example, manic episodes were more frequent in people
traveling from west to east, while the reverse direction of travel increases the risk of depression.
(31) In these instances, melatonin again becomes an instrument to help us. When supplemented,
it positively affects sleep cycles and speeds up the synchronization of diurnal rhythms disrupted
by travel or shift work. Consequently, an individual experiences a reduction in symptoms and
recovers from them faster. (8) Furthermore, supplementation with melatonin preparations is
likewise widespread in the application of athletes, who are prone to jet lag due to attending
international tournaments spread across the globe. In this study, researchers analyzed the
hormone intake in graduated decreasing doses, starting with a high concentration of 7-8 mg,
with positive effects observed. (32) On the other hand, in another study by Alfred J. Lewy et
al., the researchers looked at free-running athletes who took low doses of supplements of around
0.5 mg. They, too, declared a faster adaptation to the new time zone. Perhaps the fact that the
individuals were blind has a bearing on the fact that a lower dose of melatonin was
sufficient. (33)
According to the above-mentioned investigations, one may conclude that melatonin
contributes to faster recovery and implementation after jet lag. However, additional research is
needed to analyze and determine the most optimal dose of melatonin for supplementation.
GASTROINTESTINAL DISORDERS
Melatonin is also known to have favorable effects on different levels. These include the
gastrointestinal tract. Beginning in its initial region, the oral cavity, the hormone stimulates the
immune system, thus reducing inflammatory conditions such as periodontal disease and herpes.
In addition, it can also be used in patients with known oral cancer and in the case of xerostomia.
(34) Subsequently, numerous papers focusing on gastric complaints showed that melatonin
9
relieved symptoms. In a study that researchers in Iran conducted, 78 participants were recruited
from a selection of 163 individuals with GERD symptoms to investigate the influence of
sublingual 3 mg indolamine supplementation on perceived oesophageal complaints. Following
5 months, participants taking the hormone claimed significant improvement and a reduction in
pain. (35) Furthermore, an eight-week study conducted at Mansoura University showed that
daily supplementation with 3 mg of melatonin resulted in a comparable outcome to the use of
omeprazole. (36) Furthermore, the study by Konturek et al. highlighted the protective effect of
the oesophageal mucosa by reducing the reflux effect. They also highlighted the use of
Helicobacter pylori (H. pylori) in infections, gastric ulcers, and inflammatory bowel disease.
(37–39)
Finally, patients with intestinal complaints may also find relief when taking sleep
hormone supplementation. (40) In a meta-analysis by Si Nae Oh et al. where 30 trials were
analyzed, a reduction in the intensity of persistent pain among IBS patients was observed. (41)
Another study conducted at the Tehran University of Medical Sciences found that melatonin
reduced abdominal pain and additionally promoted defecation in patients diagnosed with IBS.
(42) A randomized, double-blind, placebo-controlled trial was conducted in 2023, which
included 136 patients with IBS. Over a period of eight weeks, 3 mg of melatonin was
administered on an empty stomach and 3 mg before bed, giving a daily dose of 6 mg. The results
showed that sleep hormone supplementation resulted in a significant reduction in
gastrointestinal complaints, including bloating and abdominal pain, as well as satisfaction with
bowel habits in IBS patients. (43)
MIGRAINE
Migraine is a chronic multifactorial disorder that is one of the most common
neurological problems encountered in clinical practice. Its prevalence is between 12 and 20%
of the population. (44) It manifests as paroxysmal, recurrent attacks of headache, which may
be accompanied by nausea, vomiting, drowsiness, and hypersensitivity to light and sound. (44)
Migraine patients report lower quality of life and indicate a disease-related social and economic
burden. (45,46) Treatment is mainly based on preventive measures. (47–49) Beta-blockers
without sympathomimetic activity, namely ethanol, metoprolol, and propranolol, are used as
first-line formulations. (50) In the second line, however, flunarizine, amitriptyline, and sodium
valproate are used. (48) It has been proven that the hypothalamus may be important in the
pathophysiology of this disorder. (51,52) In addition, studies show that three out of four patients
10
suffering from migraines also report problems with insomnia. (53,54) Therefore, melatonin as
a hypothalamic neuropeptide has gained interest as possibly effective in the treatment of
migraine. (55)
A 2022 meta-analysis conducted by Puliappadamb et al. demonstrated that taking
melatonin prophylactically at a dose of 2 to 3 mg reduces the severity and average duration of
a migraine attack and the amount of pain medication used compared to placebo. (56) Similar
results were provided by a meta-analysis by Tseng et al., which showed a positive effect of
taking 3 mg of melatonin before sleeping on the number and severity of attacks, with no side
effects. (47) As well as a study by Liampas et al. showed efficacy similar to amitriptyline,
sodium valproate or propranolol and better than pizotifen. (57) A randomized clinical trial
conducted by Mehramiri et al. in 2024, which included 60 migraine patients, showed that taking
melatonin at a dose of 3 mg, 1 hour before bedtime, for a period of 2 months, help to reduce the
frequency and duration of attacks and reduced the amount of analgesic medication taken,
compared to placebo. In this study, effects were seen for 4 months after the end of therapy. (58)
Similarly promising results were provided by earlier clinical trials conducted by Ali et al. (59),
Goncalves et al. (46) and Ebrahimi et al. (60) In the later mentioned study, melatonin as an
adjunct to treatment with nortriptyline and propranolol, lasting 8 weeks, resulted in reductions
in migraine attacks compared to placebo, comparable to valproate's effectiveness. (60) In
addition, in a study by Goncalves et al., the hormone had a beneficial effect on migraine
symptoms, demonstrating efficacy similar to amitriptyline, but importantly, while being better
tolerated than it. (46)
Several aspects underlie its effectiveness in treating migraine. It has been proven that
the relationship between pain and sleep is bi-directional, that is, both migraine attacks can
impair the quality of sleep, and sleep disturbances can negatively affect the severity of headache
attacks. (61) Therefore, it is speculated that treating a patient's existing sleep disorders and
insomnia may indirectly affect the alleviation of migraine symptoms. (53,62) Another aspect is
that melatonin also interacts with opioid, gamma-aminobutyric acid Gamma-aminobutyric acid
(GABA), adrenergic, serotonergic, and cholinergic receptors, as well as melatonergic (MT)
receptors, resulting in an antinociceptive role. (63,64) This hormone also has anti-inflammatory
properties (65) and has a decreasing effect on the production of vasoactive substances such as
calcitonin gene-related peptide (CGRP) and nitric oxide (NO), (66) It is significant, considering
that there is evidence that inflammation and neurogenic vasodilation are important in the
pathophysiology of migraine attacks. (65,67) In summary, the positive effects of melatonin on
migraine attacks may be multidirectional.
11
OBESITY
Obesity and overweight are common conditions, affecting more than two out of three
adults in the US (68) and in England, in 2017, these statistics reached 64%. (69) These numbers
are expected to increase in both countries in the future, resulting in huge healthcare expenditures
in this area. (70,71) Moreover, by 2050, the percentage of obese people will exceed 50%. (72)
There are many factors underlying this disease, such as excessive calorie intake, low physical
activity, sedentary lifestyle, and genetic factors. (73) The disease can also lead to the co-
morbidity of many other serious conditions, including diabetes, ischaemic heart disease, and
osteoarthritis.(74)
There is evidence that melatonin supplementation may help treat obesity. A 2021 meta-
analysis involving 16 studies and 1,065 patients found that patients taking doses of the hormone
< 8 mg had reduced body weight compared to those taking placebo. No beneficial effect on
BMI or waist circumference was proven. (75) Mostafavi et al., in another meta-analysis from
2017, did not confirm the weight-reducing impact of melatonin but hypothesized, based on the
study's results, that it may be a buffering factor for weight fluctuations. (76) Another study
conducted in 2019 also did not prove the effect of indolamine on anthropometric measurements
but found that it may be effective in improving lipid parameters and should be considered as a
preventive measure against cardiovascular disease. (77)
The mechanisms of indolamine's effect on weight loss are not fully understood.
Research indicates that this process may be influenced by various factors, such as modulation
of adipose tissue activity, impact on musculoskeletal metabolism, cardiovascular and lipid
profile, glucose homeostasis and insulin sensitivity, biochemical modulation of hepatic
parameters, and mitochondrial modulation. (78)
SAFETY
Generally, studies indicate that exogenous melatonin supplementation is safe. (79,80)
It has been confirmed that even high doses should not result in serious side effects in the short
term. Mild adverse effects such as dizziness, headache, nausea, and drowsiness may occur. (79)
Besag et al. conducted a study in 2019 that analyzed 37 randomized clinical trials in which
patients took doses ranging from 0.15 to 12 mg of the substance. Several mild-to-moderate side
effects were reported in the participants, such as daytime sleepiness (1.66%), headache (0.74%),
other sleep-related adverse events (0.74%), dizziness (0.74%) and hypothermia (0.62%). More
12
serious adverse events such as agitation, fatigue, mood swings, nightmares, skin irritation, and
palpitations were reported very rarely. (81) In a 12-month long-term study by Russcher et al.,
the hormone showed no serious side effects. (82) However, research suggests that exogenous
melatonin intake is not recommended for pregnant and breastfeeding women. (79,81)
CONCLUSION
Melatonin's role is crucial in regulating circadian rhythms, sleep-wake cycles, and all
sorts of neurohormonal processes. Hence, it could potentially be a valuable instrument that can
be administered as an additive to the treatment of conditions unrelated to sleep.
The literature review above discusses the value of melatonin supplementation in various
medical conditions. The scientific studies confirmed its benefits in improving sleep quality,
especially in people suffering from primary sleep disorders, jet lag, and shift
work. Furthermore, in addition to its impact on sleep, it demonstrates positive effects in treating
gastrointestinal conditions such as GERD and IBS, and chronic migraines and obesity offering
significant clinical potential. However, more detailed clinical studies are needed to establish
optimal doses and treatment protocols. Melatonin is generally well tolerated in terms of safety,
with mild side effects such as dizziness and daytime sleepiness reported infrequently.
In summary, melatonin appears to have pleiotropic effects, offering potential therapeutic
benefits beyond its initial association with sleep regulation. Additional research is required to
uncover its full benefits and establish more precise clinical guidelines for its use in various
conditions.
ABBREVIATIONS
GERD Gastroesophageal reflux disease
IBS Irritable bowel syndrome
US United States
GABA Gamma-aminobutyric acid
MT Melatonergic
CGRP Calcitonin gene-related peptide
NO Nitric oxide
13
DISCLOSURE
Author's contribution:
Conceptualization: Jakub Wirkijowski
Methodology: Yauheniya Patarocha, Jolanta Mędyk
Software: Michał Rogulski, Aleksandra Ślusarska
Check: Paulina Błasiak, Patryk Mikołajec
Formal analysis: Yauheniya Patarocha,
Investigation: Jolanta Mędyk, Ruslan Huk
Resources: Michał Rogulski, Barbara Bilecka
Data curation: Aleksandra Ślusarska, Paulina Błasiak
Writing - rough preparation: Jakub Wirkijowski, Małgorzata Wirkijowska,
Writing - review and editing: Patryk Mikołajec,
Visualization: Ruslan Huk, Jakub Wirkijowski
Supervision: Barbara Bilecka, Małgorzata Wirkijowska
Project administration: Małgorzata Wirkijowska
All authors have read and agreed with the published version of the manuscript.
Funding Statement: The study did not receive special funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflict of Interest Statement: There is no conflict of interest for the authors.
Acknowledgments: Not applicable.
14
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