Therapeutic benefits of melatonin beyond sleep regulation: a comprehensive review
DOI:
https://doi.org/10.18203/2319-2003.ijbcp20262884Keywords:
Melatonin, Circadian rhythm, Antioxidant, Immunomodulation, Neuroprotection, Anti-inflammatory, Therapeutic applications, PharmacologyAbstract
Melatonin is an endogenous indoleamine primarily synthesized by the pineal gland and is best known for its role in regulating the sleep–wake cycle and circadian rhythm. However, accumulating evidence suggests that melatonin exerts a wide range of biological actions beyond sleep regulation. It displays antioxidant, anti-inflammatory, and immunomodulatory properties, and has been investigated for potential benefits in neurological, cardiovascular, metabolic, respiratory, gastrointestinal, hepatic, renal, reproductive, oncological, and aging-related disorders. In addition, melatonin may influence gene regulation, mitochondrial function, appetite control, energy homeostasis, and thermoregulation, highlighting its pleiotropic therapeutic profile. Preclinical and clinical studies have also explored novel formulations, including sustained-release systems and nanotechnology-based delivery approaches, to improve its bioavailability and therapeutic utility. Although melatonin is generally considered safe and well tolerated, clinical evidence remains heterogeneous, and variations in dose, formulation, and treatment duration continue to limit standardization. Therefore, larger randomized controlled trials are needed to clarify its efficacy, optimize dosing strategies, and define its long-term safety across different disease settings. Overall, melatonin represents a promising multifaceted therapeutic agent with expanding clinical relevance beyond its traditional use in sleep medicine.
References
Ahmad SB, Ali A, Bilal M, Rashid SM, Wani AB, Bhat RR, et al. Melatonin and Health: Insights of Melatonin Action, Biological Functions, and Associated Disorders. Cell Mol Neurobiol. 2023;43(6):2437-58.
Masters A, Pandi-Perumal SR, Seixas A, Girardin JL, McFarlane SI. Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment. Brain Disord Ther. 2014;4(1):1000151.
Galano A, Tan DX, Reiter RJ. Melatonin: A Versatile Protector against Oxidative DNA Damage. Molecules. 2018;23(3):530.
Repova K, Baka T, Krajcirovicova K, Stanko P, Aziriova S, Reiter RJ, Simko F. Melatonin as a Potential Approach to Anxiety Treatment. Int J Mol Sci. 2022;23(24):16187.
Tuft C, Matar E, Menczel Schrire Z, Grunstein RR, Yee BJ, Hoyos CM. Current Insights into the Risks of Using Melatonin as a Treatment for Sleep Disorders in Older Adults. Clin Interv Aging. 2023;18:49-59.
Mannino G, Pernici C, Serio G, Gentile C, Bertea CM. Melatonin and Phytomelatonin: Chemistry, Biosynthesis, Metabolism, Distribution and Bioactivity in Plants and Animals-An Overview. Int J Mol Sci. 2021;22(18):9996.
Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015;71(8):901-9.
Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol. 2016;56:361-83.
Waly NE, Hallworth R. Circadian Pattern of Melatonin MT1 and MT2 Receptor Localization in the Rat Suprachiasmatic Nucleus. J Circadian Rhythms. 2015;13:1.
Xie X, Ding D, Bai D, Zhu Y, Sun W, Sun Y, et al. Melatonin biosynthesis pathways in nature and its production in engineered microorganisms. Synth Syst Biotechnol. 2022;7(1):544-53.
Carley DW, Farabi SS. Physiology of Sleep. Diabetes Spectr. 2016;29(1):5-9.
Steele TA, St Louis EK, Videnovic A, Auger RR. Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease. Neurotherapeutics. 2021;18(1):53-74.
Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018;175(16):3190-9.
Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, Zagrean AM. Melatonin's Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules. 2020;10(9):1211.
Lee JG, Woo YS, Park SW, Seog DH, Seo MK, Bahk WM. The Neuroprotective Effects of Melatonin: Possible Role in the Pathophysiology of Neuropsychiatric Disease. Brain Sci. 2019;9(10):285.
Domínguez-Rodríguez A, Abreu-González P, Báez-Ferrer N, Reiter RJ, Avanzas P, Hernández-Vaquero D. Melatonin and Cardioprotection in Humans: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Cardiovasc Med. 2021;8:635083.
Talib WH, Alsayed AR, Abuawad A, Daoud S, Mahmod AI. Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities. Molecules. 2021;26(9):2506.
Srinivasan V, Maestroni GJ, Cardinali DP, Esquifino AI, Perumal SR, Miller SC. Melatonin, immune function and aging. Immun Ageing. 2005;2:17.
Cho JH, Bhutani S, Kim CH, Irwin MR. Anti-inflammatory effects of melatonin: A systematic review and meta-analysis of clinical trials. Brain Behav Immun. 2021;93:245-53.
Wajid F, Poolacherla R, Mim FK, Bangash A, Rutkofsky IH. Therapeutic potential of melatonin as a chronobiotic and cytoprotective agent in diabetes mellitus. J Diabetes Metab Disord. 2020;19(2):1797-825.
Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol. 2011;17(34):3888-98.
Mathes AM. Hepatoprotective actions of melatonin: possible mediation by melatonin receptors. World J Gastroenterol. 2010;16(48):6087-97.
Cheng MC, Wu TH, Huang LT, Tain YL. Renoprotective effects of melatonin in young spontaneously hypertensive rats with L-NAME. Pediatr Neonatol. 2014;55(3):189-95.
Reiter RJ, Rosales-Corral SA, Manchester LC, Tan DX. Peripheral reproductive organ health and melatonin: ready for prime time. Int J Mol Sci. 2013;14(4):7231-72.
Maria S, Samsonraj RM, Munmun F, Glas J, Silvestros M, Kotlarczyk MP, et al. Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: Implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. J Pineal Res. 2018;64(3):10.
Moon E, Kim K, Partonen T, Linnaranta O. Role of Melatonin in the Management of Sleep and Circadian Disorders in the Context of Psychiatric Illness. Curr Psychiatry Rep. 2022;24(11):623-34.
Martín Giménez VM, de Las Heras N, Lahera V, Tresguerres JAF, Reiter RJ, Manucha W. Melatonin as an Anti-Aging Therapy for Age-Related Cardiovascular and Neurodegenerative Diseases. Front Aging Neurosci. 2022;14:888292.
Xie S, Fan W, He H, Huang F. Role of Melatonin in the Regulation of Pain. J Pain Res. 2020;13:331-43.
Li L, Gang X, Wang J, Gong X. Role of melatonin in respiratory diseases (Review). Exp Ther Med. 2022;23(4):271.
Wang C, Wang L, Wang X, Cao Z. Beneficial Effects of Melatonin on Periodontitis Management: Far More Than Oral Cavity. Int J Mol Sci. 2022;23(23):14541.
Monayo SM, Liu X. The Prospective Application of Melatonin in Treating Epigenetic Dysfunctional Diseases. Front Pharmacol. 2022;13:867500
Nogueira LFR, Marqueze EC. Effects of melatonin supplementation on eating habits and appetite-regulating hormones: a systematic review of randomized controlled clinical and preclinical trials. Chronobiol Int. 2021;38(8):1089-102.
Refinetti R. Circadian rhythmicity of body temperature and metabolism. Temperature (Austin). 2020;7(4):321-62.
Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61(3):253-78.
Rondanelli M, Faliva MA, Perna S, Antoniello N. Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks. Aging Clin Exp Res. 2013;25(5):499-510.
Hardeland R. Melatonin and inflammation-Story of a double-edged blade. J Pineal Res. 2018;65(4):e12525.
Zhang Z, Xue P, Bendlin BB, Zetterberg H, De Felice F, Tan X, Benedict C. Melatonin: A potential nighttime guardian against Alzheimer's. Mol Psychiatry. 2025;30(1):237-250.
Wichniak A, Kania A, Siemiński M, Cubała WJ. Melatonin as a Potential Adjuvant Treatment for COVID-19 beyond Sleep Disorders. Int J Mol Sci. 2021;22(16):8623.
Guardiola-Lemaître B. Toxicology of melatonin. J Biol Rhythms. 1997;12(6):697-706.
Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C. Melatonin: Pharmacology, Functions and Therapeutic Benefits. Curr Neuropharmacol. 2017;15(3):434-43.
Thanawala S, Abiraamasundari R, Shah R. Comparative Pharmacokinetics of Sustained-Release versus Immediate-Release Melatonin Capsules in Fasting Healthy Adults: A Randomized, Open-Label, Cross-Over Study. Pharmaceutics. 2024;16(10):1248.
Mirza-Aghazadeh-Attari M, Mihanfar A, Yousefi B, Majidinia M. Nanotechnology-based advances in the efficient delivery of melatonin. Cancer Cell Int. 2022;22(1):43
Stanford SC. Recent developments in research of melatonin and its potential therapeutic applications. Br J Pharmacol. 2018;175(16):3187-9.
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