Melatonin: What and Why?

Melatonin is primarily used for sleep regulation and circadian rhythm disorders, with additional roles in neuroprotection, antioxidant activity, and potential adjunctive therapy in various medical conditions. It is generally well tolerated, but safety considerations include mild adverse effects and caution in specific populations.

Effects and Uses:

Melatonin is most established for improving sleep onset and treating circadian rhythm sleep-wake disorders, such as delayed sleep phase and jet lag. Meta-analyses and clinical guidelines show modest efficacy for sleep onset latency, with less impact on total sleep time or sleep maintenance.[1][2][3] Beyond sleep, melatonin exhibits antioxidant, anti-inflammatory, and immunomodulatory properties, and has been studied as adjunctive therapy in neurodegenerative diseases, cancer, metabolic disorders, and perioperative anxiety, though evidence in these areas is less robust and often preliminary.[4][5][6][7][8][3] Melatonin is also used in pediatric populations with neurodevelopmental disorders, but data on safety and efficacy in healthy children are limited.[2]

Safety Considerations:

Melatonin is generally regarded as safe, with most adverse events being mild and transient—such as daytime sleepiness, headache, dizziness, and vivid dreams or nightmares.[9][10][11][12] Systematic reviews and meta-analyses of both low and high doses (up to 10 mg or more) report no increase in serious adverse events or withdrawals due to adverse effects, though higher doses may increase the risk of mild side effects.[9][12] Rare but reported adverse effects include mood changes, gastrointestinal upset, blood pressure fluctuations, and impairment in glucose tolerance.[1][11] Caution is advised in children, adolescents, women of reproductive age, and patients with epilepsy or those taking warfarin, due to isolated case reports of exacerbation of underlying conditions or drug interactions.[1][9][10][11]

Long-term safety data are limited, and concerns remain about purity and dose consistency in over-the-counter preparations. United States Pharmacopeial Convention Verified formulations are recommended for reliability.[1] Most adverse effects resolve spontaneously or with discontinuation, but individualized dosing and monitoring are advised, especially for off-label or chronic use.[5][11]

Summary:

Melatonin is effective and safe for sleep onset and circadian rhythm disorders, with expanding but less conclusive evidence for other health conditions. Adverse effects are generally mild, but caution is warranted in specific populations and with long-term or high-dose use. Individualized protocols and careful monitoring are recommended, given variability in response and limited long-term data.[5][1][9][10][11][12][3]

References

1. Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. Auger RR, Burgess HJ, Emens JS, et al. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2015;11(10):1199-236. doi:10.5664/jcsm.5100.

2. Management of Insomnia. Morin CM, Buysse DJ. The New England Journal of Medicine. 2024;391(3):247-258. doi:10.1056/NEJMcp2305655.

3. Effects of Exogenous Melatonin Supplementation on Health Outcomes: An Umbrella Review of Meta-Analyses Based on Randomized Controlled Trials. Lim S, Park S, Koyanagi A, et al. Pharmacological Research. 2022;176:106052. doi:10.1016/j.phrs.2021.106052.

4. Is Melatonin the "Next Vitamin D"?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Minich DM, Henning M, Darley C, et al. Nutrients. 2022;14(19):3934. doi:10.3390/nu14193934.

5. Melatonin Supplementation: New Insights Into Health and Disease. Minari TP, Pisani LP. Sleep & Breathing = Schlaf & Atmung. 2025;29(2):169. doi:10.1007/s11325-025-03331-1.

6. Clinical Uses of Melatonin: Evaluation of Human Trials. Sánchez-Barceló EJ, Mediavilla MD, Tan DX, Reiter RJ. Current Medicinal Chemistry. 2010;17(19):2070-95. doi:10.2174/092986710791233689.

7. New Uses of Melatonin as a Drug; A Review. Pohanka M. Current Medicinal Chemistry. 2022;29(20):3622-3637. doi:10.2174/0929867329666220105115755.

8. Melatonin and Health: Insights of Melatonin Action, Biological Functions, and Associated Disorders. Ahmad SB, Ali A, Bilal M, et al. Cellular and Molecular Neurobiology. 2023;43(6):2437-2458. doi:10.1007/s10571-023-01324-w.

9. Adverse Events Associated With Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review. Besag FMC, Vasey MJ, Lao KSJ, Wong ICK. CNS Drugs. 2019;33(12):1167-1186. doi:10.1007/s40263-019-00680-w.

10. Investigating the Safety Profiles of Exogenous Melatonin and Associated Adverse Events: A Pharmacovigilance Study Using WHO-VigiBase. Ha M, Yoon D, Lee CY, et al. Journal of Pineal Research. 2024;76(2):e12949. doi:10.1111/jpi.12949.

11. Adverse Events Associated With Oral Administration of Melatonin: A Critical Systematic Review of Clinical Evidence. Foley HM, Steel AE. Complementary Therapies in Medicine. 2019;42:65-81. doi:10.1016/j.ctim.2018.11.003.

12. Safety of Higher Doses of Melatonin in Adults: A Systematic Review and Meta-Analysis. Menczel Schrire Z, Phillips CL, Chapman JL, et al. Journal of Pineal Research. 2022;72(2):e12782. doi:10.1111/jpi.12782.