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

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.