A cross-sectional report on the use of high doses of melatonin in humans.
High doses of melatonin in humans
Abstract
The administration of melatonin in chronobiotic doses (≤10 mg daily) is a common procedure in clinics. In addition, research in animals has led to greater awareness on the potentiality of melatonin as an antioxidant, immunological and mitochondrial regulator and anti-inflammatory compound. Doses allometrically derived from animal studies correspond to 75 to 112.5 mg daily range for a 75 kg human adult. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, we regularly use melatonin in this dose range to treat sleep disorders in aged patients to prevent age-related comorbidities. In an observational, analytical, retrospective, cross-sectional study of clinical history data from a closed population of patients taking melatonin in doses equal to or greater than 40 mg/day of melatonin for various sleep disorders, 80 patients (74.2 % female, mean age 74 years ± 9.26) were included. The indication of melatonin doses varied between 40 and 200 mg per day, with a mean of 76.56 mg ± 33.58 mg daily. The main reason for indication was complaints of disorders in falling asleep or maintaining sleep with melatonin doses varying depending on the comorbidities clinically detected. The 59 % of patients received treatment for more than 4 years. Laboratory variables related to liver function remain within the normal range after melatonin administration regardless of the dose employed. No relation was also found between melatonin dose and concomitant pharmacological treatment. The results advocate for the safe use of melatonin in higher doses than those commonly employed.
References
2. Kotagal S, Malow B, Spruyt K, Wang, G.; Bolaños Almeida CE, Tavera Saldaña LM, Blunden S, Narang I, Ipsiroglu OS, Bruni O et al. (2024) Melatonin use in managing insomnia in children with autism and other neurogenetic disorders - An assessment by the International Pediatric Sleep Association (IPSA). Sleep Med. 119: 222–228. doi:10.1016/J.SLEEP.2024.04.008.
3. Cardinali DP, Brown GM, Pandi-Perumal SR. (2022) Melatonin’s benefits and risks as a therapy for sleep disturbances in the elderly: current insights. Nat. Sci. Sleep 14: 1843–1855. doi:10.2147/NSS.S380465.
4. Reiter RJ, Sharma R, Chuffa LG. de A, Simko F, Dominguez-Rodriguez A. (2024) Mitochondrial melatonin: beneficial effects in protecting against heart failure. Life (Basel) 14:88. doi:10.3390/LIFE14010088.
5. Reiter RJ, Sharma R, Tan DX, Chuffa LG. de A, da Silva DGH, Slominski AT, Steinbrink K, Kleszczynski K (2024) Dual sources of melatonin and evidence for different primary functions. Front. Endocrinol. (Lausanne) 15:1414463. doi:10.3389/FENDO.2024.1414463.
6. Méndez N, Corvalan F, Halabi D, Ehrenfeld P, Maldonado R, Vergara K, Seron-Ferre M, Torres-Farfan C (2023) From gestational chronodisruption to noncommunicable diseases: pathophysiological mechanisms of programming of adult diseases, and the potential therapeutic role of melatonin. J. Pineal Res. 15: 12908. doi:10.1111/JPI.12908.
7. Ziaei S, Hasani M, Malekahmadi M, Daneshzad E, Kadkhodazadeh K, Heshmati J (2024) Effect of melatonin supplementation on cardiometabolic risk factors, oxidative stress and hormonal profile in PCOS patients: a systematic review and meta-analysis of randomized clinical trials. J. Ovarian Res. 17: 1–10. doi:10.1186/S13048-024-01450-Z/TABLES/2.
8. Reiter RJ, Sharma R, Tan DX, Huang G, de Almeida Chuffa LG, Anderson G (2023) Melatonin modulates tumor metabolism and mitigates metastasis. Expert. Rev. Endocrinol. Metab. 18: 321–336. doi:10.1080/17446651.2023.2237103.
9. Cardinali DP, Brown GM, Pandi-Perumal SR. (2022) Possible application of melatonin in long COVID. Biomolecules 12:1646. doi:10.3390/BIOM12111646.
10. Mohamed Taha A, Adel Abdelkader Saed S, Hossam-Eldin Moawad M, Abd El-Tawab Moawad W, Al-hejazi T, Mousa Y, Sharma R, Reiter RJ (2023) Safety and efficacy of melatonin as an adjuvant therapy in COVID-19 patients: systematic review and meta-analysis. Adv. Med. Sci. 68: 341–352. doi:10.1016/J.ADVMS.2023.09.007.
11. Valiensi SM, Folgueira A, Vera VA, González Cardozo A, Cardinali DP, Rugiero M. (2022) Pre-pandemic melatonin treatment for sleep disorders and COVID-19 infection. A retrospective cross-sectional study. Vertex. XXXIII:13–24. doi:10.53680/VERTEX.V33I155.132.
12. Reiter RJ, Sharma R, Simko F, Dominguez-Rodriguez A, Tesarik J, Neel RL, Slominski AT, Kleszczynski K, Martin-Gimenez VM, Manucha W et al. (2022) Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection. Cell Mol. Life Sci. 79:143. doi:10.1007/S00018-021-04102-3.
13. Bierzychudek L, Bierzychudek L. Prescripción off-label de medicamentos: definición y consideraciones ético-regulatorias en Argentina (2022) Rev. Bioet. Derecho. 2022: 165–191, doi:10.1344/RBD2022.55.36893.
14. Cardinali DP (2019) Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection? Melatonin Res. 2: 106–132. doi:10.32794/mr11250025.
15. Cardinali DP (2019) Melatonin: clinical perspectives in neurodegeneration. Front. Endocrinol. (Lausanne) 10: 480. doi:10.3389/fendo.2019.00480.
16. Cardinali DP (2019) Melatonin as a chronobiotic/cytoprotector: its role in healthy aging. Biol. Rhythm. Res. 50: 28-45. doi:10.1080/09291016.2018.1491200.
17. Cardinali DP (2020) High doses of melatonin as a potential therapeutic tool for the neurologic sequels of Covid-19 infection. Melatonin Res. 3: 311–317, doi:10.32794/mr11250064.
18. Cardinali DP (2024) Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved. J. Pineal Res. 76:12931. doi:10.1111/JPI.12931.
19. Pérez-Lloret S, Cardinali DP (2021) Melatonin as a chronobiotic and cytoprotective agent in Parkinson’s disease. Front. Pharmacol. 12: 650597. doi:10.3389/fphar.2021.650597.
20. Galley HF, Lowes DA, Allen L, Cameron G, Aucott LS, Webster NR (2014) Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis. J. Pineal Res. 56: 427–438. doi:10.1111/jpi.12134.
21. Zetner D, Andersen LPH, Rosenberg J (2016) Pharmacokinetics of alternative administration routes of melatonin: a systematic review. Drug Res. 66: 169–173. doi:10.1055/s-0035-1565083.
22. Boutin JA, Kennaway DJ, Jockers R. (2023) Melatonin: facts, extrapolations and clinical trials. Biomolecules 13: 943. doi:10.3390/BIOM13060943.
23. Benedict C (2022) Melatonin’s potential side effects: it may be in your genes. Mayo Clin. Proc. 97: 1401: doi:10.1016/j.mayocp.2022.05.011.
24. Pappolla MA, Matsubara E, Vidal R, Pacheco-Quinto J, Poeggeler B, Zagorski M, Sambamurti K (2018) Melatonin treatment enhances Aβ lymphatic clearance in a transgenic mouse model of amyloidosis. Curr. Alzheimer Res. 15: 637–642. doi:10.2174/1567205015666180411092551.
25. Reiter RJ, Sharma R, Cucielo MS, Tan DX, Rosales-Corral S, Gancitano G, de Almeida Chuffa LG (2023) Brain washing and neural health: role of age, sleep, and the cerebrospinal fluid melatonin rhythm. Cell Mol. Life Sci. 80: 88. doi:10.1007/s00018-023-04736-5.
26. Lelak K, Vohra V, Neuman MI, Toce MS, Sethuraman U (2022) Pediatric melatonin ingestions — United States, 2012–2021. MMWR Morb. Mortal. Wkly. Rep. 71: 725–729. doi:10.15585/MMWR.MM7122A1.
27. Imenshahidi M, Karimi G, Hosseinzadeh H (2020) Effects of melatonin on cardiovascular risk factors and metabolic syndrome: a comprehensive review. Naunyn. Schmiedebergs Arch. Pharmacol. 393: 521–536, doi:10.1007/S00210-020-01822-4.
28. Mohammadi-Sartang M, Ghorbani M, Mazloom Z (2018) Effects of melatonin supplementation on blood lipid concentrations: a systematic review and meta-analysis of randomized controlled trials. Clin. Nutr. 37: 1943–1954. doi:10.1016/J.CLNU.2017.11.003.
29. Yaghoobi A, Rezaee M, Hedayati N, Keshavarzmotamed A, Khalilzad M.A, Russel R, Asemi Z, Rajabi Moghadam H, Mafi A (2024) Insight into the cardioprotective effects of melatonin: shining a spotlight on intercellular Sirt signaling communication. Mol. Cell Biochem. doi:10.1007/S11010-024-05002-3.
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