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image of Exogenous Melatonin as a Sleep-promoting Agent beyond its Chronobiotic Properties: A Scoping Review of its Effects on Key Sleep-wake Neurotransmitters

Abstract

Introduction

Exogenous melatonin (exo-MLT) is a sleep-promoting agent that modulates key sleep-wake neurotransmitters.

Methods

This scoping review analyzed 623 studies retrieved from PubMed/MEDLINE and ISI/Web of Science, applying PRISMA methodology to ensure rigorous inclusion criteria. After screening, 58 original research papers were analyzed for exo-MLT's effects on gamma-aminobutyric acid (GABA), serotonin, dopamine, glutamine, norepinephrine, epinephrine, orexin, acetylcholine, adenosine, glycine, galanin, and histamine.

Results

We identified 20 studies on the GABAergic system, showing that exo-MLT enhances GABA activity through different mechanisms, promoting non-REM sleep and reducing stress-related hyperarousal. On serotonin, 16 studies revealed limited and variable effects depending on the dose and physiological conditions. Total 13 dopamine studies suggested that exo-MLT does not alter physiological dopamine turnover, restoring dopaminergic balance in pathological states. On the glutamatergic system, seven studies showed a compensatory role of exo-MLT on glutamate excitotoxicity. Six studies on norepinephrine highlighted exo-MLT's ability to regulate sympathetic activity. The orexinergic system was the focus of five studies, indicating exo-MLT's inhibitory action on orexinergic neurons, enhancing sleep quality and consolidation. Five studies investigated exo-MLT on the cholinergic system, revealing an enhancing effect on acetylcholine activity in physiological and pathophysiological conditions. Lastly, four studies exploring adenosine and glycine were inconclusive of the exo-MLT effect, while we could not find any data on histamine and galanin.

Discussion

This review underscores exo-MLT's mechanisms beyond circadian regulation, offering therapeutic promise in sleep disorders associated with other neuropsychiatric conditions.

Conclusion

Exo-MLT’s interactions provide insights into its safety and non-addictive characteristics, supporting its integration into personalized sleep medicine.

© 2025 Bentham Science Publishers
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2025-07-22
2025-09-18

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Exogenous Melatonin as a Sleep-promoting Agent beyond its Chronobiotic Properties: A Scoping Review of its Effects on Key Sleep-wake Neurotransmitters
Bentham Science Publishers ; https://doi.org/10.2174/011570159X379708250702084616
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  • Article Type:     Review Article
Keywords: sleep ; Melatonin ; sleep-wake neurotransmitters ; scoping review ; sleep disorders

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