Optimal dosages for melatonin supplementation therapy in older adults: A systematic review of current literature
Abstract
Background Melatonin is a hormone that regulates circadian rhythm, and its levels decline with age. As melatonin levels decrease, older adults are prone to develop disorders related to an altered circadian rhythm. The effective dose of melatonin supplementation in these disorders remains unclear.Objectives Our objective was to define the optimal dosage of exogenous melatonin administration in disorders related to altered melatonin levels in older adults aged 55 years and above by determining the dose-response effect of exogenous administered melatonin on endogenous levels.Methods We conducted a systematic review through PubMed/MEDLINE and Embase, both from 1980 until November 2013. Included articles studied the effect of exogenous melatonin administration on endogenous melatonin levels in either serum, urine, or saliva in humans aged 55 years and above.Results We included 16 articles, nine of which were randomized controlled trials (RCTs). The mean age varied from 55.3 to 77.6 years. Melatonin dosage varied from 0.1 mg to 50 mg/kg and was administered orally in all studies. Pre- and post-intervention levels revealed a significant elevation of the post-intervention melatonin levels in a dose-dependent fashion. The maximum concentrations measured in serum and urine were all elevated compared with placebo, and a higher elevation in older adults than in younger adults was demonstrated. Even though there were no differences between times to reach maximum concentration in serum and urine, melatonin levels with higher doses were maintained longer above a certain threshold than were lower doses.Conclusion In older adults, we advise the use of the lowest possible dose of immediate-release formulation melatonin to best mimic the normal physiological circadian rhythm of melatonin and to avoid prolonged, supra-physiological blood levels.
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Controlled-release melatonin formulations have been discouraged in older adults due to the possibility of prolonged melatonin levels and unknown implications.
“Controlled-release formulations have been discouraged in older adults due to the possibility of prolonged melatonin levels and unknown implications thereof [273].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [273]
Cites
Brzezinski, A. (1997) · New England Journal of Medicine · doi:10.1056/nejm199701163360306 · Cited by 1,549 · see citing works
Dollins, A. B., Zhdanova, I. V., Wurtman, R. J., Lynch, H. J., & Deng, M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.5.1824 · Cited by 578 · see citing works
Alterations in Nocturnal Serum Melatonin Levels In Humans With Growth and Aging*
Waldhauser, F., Weiszenbacher, G., Tatzer, E., Gisinger, B., Waldhauser, M., SCHEMPER, M., & Frisch, H. (1988) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-66-3-648 · Cited by 407 · see citing works
Lewy, A. J., Bauer, V. K., Ahmed, S., Thomas, K. H., Cutler, N. L., Singer, C. M., Moffit, M. T., & Sack, R. L. (1998) · Chronobiology International · doi:10.3109/07420529808998671 · Cited by 360 · see citing works
Sleep disorders and melatonin rhythms in elderly people
Haimov, I., Laudon, M., Zisapel, N., Souroujon, M. C., Nof, D., Shlitner, A., Herer, P., Tzischinsky, O., & Lavie, P. (1994) · BMJ · doi:10.1136/bmj.309.6948.167 · Cited by 315 · see citing works
Melatonin treatment for age-related insomnia
Zhdanova, I. V., Wurtman, R. J., Regan, M. M., Taylor, J. A., Shi, J. P., & Leclair, O. U. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.10.7901 · Cited by 308 · see citing works
Melatonin decreases delirium in elderly patients: A randomized, placebo‐controlled trial
Alaama, T. Y., Brymer, C. D., Gutmanis, I., Woolmore-Goodwin, S., Esbaugh, J., & Dasgupta, M. (2010) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2582 · Cited by 291 · see citing works
Bourne, R. S., MILLS, G. H., & Minelli, C. (2008) · Critical Care · doi:10.1186/cc6871 · Cited by 266 · see citing works
Daily Rhythm in Human Urinary Melatonin
Lynch, H. J., Wurtman, R. J., Moskowitz, M. A., Archer, M. C., & Ho, M. H. (1975) · Science · doi:10.1126/science.1167425 · Cited by 263 · see citing works
Asayama, K., Yamadera, H., Ito, T., Suzuki, H., Kudo, Y., & Endo, S. (2003) · Journal of Nippon Medical School · doi:10.1272/jnms.70.334 · Cited by 242 · see citing works
Zhdanova, I. V., Wurtman, R. J., Morabito, C., Piotrovska, V. R., & Lynch, H. J. (1996) · SLEEP · doi:10.1093/sleep/19.5.423 · Cited by 224 · see citing works
Nagtegaal, J. E., KERKHOF, G. A., Smits, M. G., Swart, & van der Meer, Y. G. (1998) · Journal of Sleep Research · doi:10.1046/j.1365-2869.1998.00102.x · Cited by 221 · see citing works
Human Phase Response Curves to Three Days of Daily Melatonin: 0.5 mg <i>Versus</i> 3.0 mg
Burgess, H. J., Revell, V. L., Molina, T. A., & Eastman, C. I. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2590 · Cited by 221 · see citing works
Hughes, R. J., Sack, R. L., & Lewy, A. J. (1998) · SLEEP · doi:10.1093/sleep/21.1.52 · Cited by 202 · see citing works
Sultan, S. S. A. (2010) · Saudi Journal of Anaesthesia · doi:10.4103/1658-354x.71132 · Cited by 190 · see citing works
Plasma concentrations of melatonin in man following oral absorption of different preparations.
Aldhous, M. E., Franey, C. S., Wright, J., & Arendt, J. (1985) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1985.tb02679.x · Cited by 179 · see citing works
A three pulse phase response curve to three milligrams of melatonin in humans
Burgess, H. J., Revell, V. L., & Eastman, C. I. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.143180 · Cited by 176 · see citing works
Melatonin Is Able to Influence Its Secretion in Humans: Description of a Phase-Response Curve
Zaidan, R., Geoffriau, M., Brun, J., Taillard, J., Bureau, C., Chazot, G., & Claustrat, B. (2008) · Neuroendocrinology · doi:10.1159/000126726 · Cited by 170 · see citing works
Léger, D., Laudon, M., & Zisapel, N. (2004) · The American Journal of Medicine · doi:10.1016/j.amjmed.2003.07.017 · Cited by 157 · see citing works
Postoperative delirium and melatonin levels in elderly patients
Shigeta, H., Yasui, A., Nimura, Y., Machida, N., Kageyama, M.-O., Miura, M., MENJO, M., & Ikeda, K. (2001) · The American Journal of Surgery · doi:10.1016/s0002-9610(01)00761-9 · Cited by 155 · see citing works
Some Effects of Melatonin and the Control of its Secretion in Humans
Arendt, J., Bojkowski, C. J., Folkard, S., Franey, C. S., Marks, V., Minors, D. S., Waterhouse, J. M., Wever, R. A., Wildgruber, C. M., & Wright, J. (1985) · Novartis Foundation symposium · doi:10.1002/9780470720981.ch16 · Cited by 131 · see citing works
Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection
Mallo, C., Zaidan, R., Galy, G., Vermeulen, E., Brun, J., Chazot, G., & Claustrat, B. (1990) · European Journal of Clinical Pharmacology · doi:10.1007/bf00315035 · Cited by 121 · see citing works
Effect of pharmacological daytime doses of melatonin on human mood and performance
Dollins, A. B., Lynch, H. J., Wurtman, R. J., Deng, M., Kischka, K. U., Gleason, R. E., & Lieberman, H. R. (1993) · Psychopharmacology · doi:10.1007/bf02244899 · Cited by 120 · see citing works
de Jonghe, A., Korevaar, J., van Munster, B. V., & de Rooij, S. (2010) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2454 · Cited by 119 · see citing works
Bioavailability of melatonin in humans after day-time administration of D7 melatonin
Fourtillan, J. B., Brisson, A. M., Gobin, P., Ingrand, I., Decourt, J., & Girault, J. (2000) · Biopharmaceutics & Drug Disposition · doi:10.1002/1099-081x(200001)21:1 · Cited by 119 · see citing works
The use of high‐dose melatonin in liver resection is safe: first clinical experience
Nickkholgh, A., Schneider, H., Sobirey, M., Venetz, W. P., Hinz, U., Pelzl, L. H., Gotthardt, D. N., Čekauskas, A., Manikas, M., Mikalauskas, S., et al. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00854.x · Cited by 110 · see citing works
Plasma Melatonin Rhythms In Young and Older Humans During Sleep, Sleep Deprivation, and Wake
Zeitzer, J. M., Duffy, J. F., Lockley, S. W., Dijk, D., & Czeisler, C. A. (2007) · SLEEP · doi:10.1093/sleep/30.11.1437 · Cited by 110 · see citing works
Gooneratne, N. S., Edwards, A. Y. Z., Zhou, C., Cuellar, N. G., Grandner, M. A., & Barrett, J. S. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00958.x · Cited by 108 · see citing works
Pharmacokinetics of orally administered melatonin in critically ill patients
Mistraletti, G., Sabbatini, G., Taverna, M., Figini, M. A., Umbrello, M., Magni, P., Ruscica, M., Dozio, E., Esposti, R., Demartini, G., et al. (2010) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2009.00737.x · Cited by 108 · see citing works
Endogenous Melatonin Levels and the Fate of Exogenous Melatonin: Age Effects
Zhdanova, I. V., Wurtman, R. J., Balcioglu, A., Kartashov, A. I., & Lynch, H. J. (1998) · The Journals of Gerontology Series A · doi:10.1093/gerona/53a.4.b293 · Cited by 107 · see citing works
Lewy, A. J., Emens, J. S., Sack, R. L., Hasler, B. P., & Bernert, R. A. (2002) · Chronobiology International · doi:10.1081/cbi-120004546 · Cited by 99 · see citing works
Loss of response to melatonin treatment is associated with slow melatonin metabolism
Braam, W., Van Geijlswijk, I., Keijzer, H., Smits, M. G., Didden, R., & Curfs, L. M. G. (2010) · Journal of Intellectual Disability Research · doi:10.1111/j.1365-2788.2010.01283.x · Cited by 94 · see citing works
Lewy, A. J., & Sack, R. L. (1997) · Journal of Biological Rhythms · doi:10.1177/074873049701200614 · Cited by 92 · see citing works
Ibrahim, M. G., Bellomo, R., Hart, G. K., Norman, T. R., Goldsmith, D., Bates, S., & Egi, M. (2006) · Critical Care and Resuscitation · doi:10.1016/s1441-2772(23)02086-0 · Cited by 90 · see citing works
Kędziora–Kornatowska, K., Szewczyk‐Golec, K., Kozakiewicz, M., Pawluk, H., Czuczejko, J., Kornatowski, T., Bartosz, G., & Kędziora, J. (2009) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2009.00666.x · Cited by 87 · see citing works
Greenblatt, D. J., Harmatz, J. S., & Karim, A. (2007) · The Journal of Clinical Pharmacology · doi:10.1177/0091270006298602 · Cited by 64 · see citing works
Cognitive Effects of Exogenous Melatonin Administration in Elderly Persons: A Pilot Study
Peck, J. S. (2004) · American Journal of Geriatric Psychiatry · doi:10.1176/appi.ajgp.12.4.432 · Cited by 63 · see citing works
Antioxidative effects of melatonin administration in elderly primary essential hypertension patients
Kędziora–Kornatowska, K., Szewczyk‐Golec, K., Czuczejko, J., Pawluk, H., de Lumen, K. V. M., Kozakiewicz, M., Bartosz, G., & Kędziora, J. (2008) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2008.00592.x · Cited by 60 · see citing works
Mallo, C., Zaidan, R., Faure, A., Brun, J., Chazot, G., & Claustrat, B. (1988) · European Journal of Endocrinology · doi:10.1530/acta.0.1190474 · Cited by 56 · see citing works
Zisapel, N., Lemoine, Garfinkel, D., Laudon, M., & Nir (2011) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s23036 · Cited by 54 · see citing works
Dawson, D. E., Rogers, N. L., van den Heuvel, C. J., Kennaway, D. J., & Lushington, K. (1998) · Journal of Biological Rhythms · doi:10.1177/074873098129000354 · Cited by 53 · see citing works
Effects of Melatonin and Rilmazafone on Nocturia in the Elderly
Sugaya, K., Nishijima, S., Miyazato, M., Kadekawa, K., & Ogawa, Y. (2007) · Journal of International Medical Research · doi:10.1177/147323000703500513 · Cited by 37 · see citing works
Melatonin Pharmacokinetics in Premenopausal and Postmenopausal Healthy Female Volunteers
Markantonis, S. L., Tsakalozou, E., Paraskeva, A., Staikou, ., & Fassoulaki, A. (2007) · The Journal of Clinical Pharmacology · doi:10.1177/0091270007311112 · Cited by 31 · see citing works
Effects of daytime melatonin infusion in young adults
van den Heuvel, C. J., Kennaway, D. J., & Dawson, D. E. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.1.e19 · Cited by 21 · see citing works
Lushington, K., Dawson, D. E., Kennaway, D. J., & Lack, L. C. (1999) · Psychopharmacology · doi:10.1007/s002130051150 · Cited by 13 · see citing works
Feasibility and Functionality of OROS® Melatonin in Healthy Subjects
Shah, J. A., Langmuir, V. K., & Gupta, S. K. (1999) · The Journal of Clinical Pharmacology · doi:10.1177/00912709922008218 · Cited by 10 · see citing works
de Lumen, K. V. M., Kędziora–Kornatowska, K., Czuczejko, J., Szewczyk‐Golec, K., Pawluk, H., Motyl, J., Kornatowski, T., & Kȩdziora, J. (2008) · PubMed · Cited by 5 · see citing works
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Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders
Auld, F., Maschauer, E. L., Morrison, I., Skene, D. J., & Riha, R. L. (2016) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2016.06.005 · Cited by 402 · see citing works
Review of Safety and Efficacy of Sleep Medicines in Older Adults
Schroeck, J. L., Ford, J., Conway, E. L., Kurtzhalts, K. E., Gee, M. E., Vollmer, K. A., & Mergenhagen, K. A. (2016) · Clinical Therapeutics · doi:10.1016/j.clinthera.2016.09.010 · Cited by 374 · see citing works
Inflammaging: Implications in Sarcopenia
Antuña, E., Cachán-Vega, C., Bermejo-Millo, J. C., Potes, Y., Caballero, B., Vega-Naredo, I., Coto-Montes, A., & García-González, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315039 · Cited by 199 · see citing works
Adrenal Aging and Its Implications on Stress Responsiveness in Humans
Yiallouris, A., Tsioutis, C., Agapidaki, E., Zafeiri, M., Agouridis, A. P., Ntourakis, D., & Johnson, E. O. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00054 · Cited by 190 · see citing works
Minich, D. M., Henning, M., Darley, C., Fahoum, M., Schuler, C. B., & Frame, J. (2022) · Nutrients · doi:10.3390/nu14193934 · Cited by 176 · see citing works
de Jonghe, A., Munster, B. C. V., Goslings, J. C., Kloen, P., van Rees, C., Wolvius, R., van Velde, R., Levi, M. M., de Haan, R. J., & de Rooij, S. E. (2014) · Canadian Medical Association Journal · doi:10.1503/cmaj.140495 · Cited by 174 · see citing works
Rios, P. D. L., Cardoso, R., Morra, D. E., Nincic, V., Goodarzi, Z., Farah, B., Harricharan, S., Morin, C. M., Leech, J. A., Straus, S. E., et al. (2019) · Systematic Reviews · doi:10.1186/s13643-019-1163-9 · Cited by 141 · see citing works
Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19
Reiter, R. J., Abreu-González, P., Marik, P. E., & Domínguez‐Rodríguez, A. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00226 · Cited by 105 · see citing works
Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action
Posadzki, P., Bajpai, R. C., Kyaw, B. M., Roberts, N., Brzezinski, A., Christopoulos, G. I., Divakar, U., Bajpai, S., Soljak, M., Dunleavy, G., et al. (2018) · BMC Medicine · doi:10.1186/s12916-017-1000-8 · Cited by 101 · see citing works
Sleep Disturbances in the Elderly
Zdanys, K. F., & Steffens, D. C. (2015) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2015.07.010 · Cited by 91 · see citing works
“The current recommendation for treatment of sleep disorders in the elderly with melatonin is to use the lowest possible dose of the immediate-release formulation so as to approximate normal physiologic pattern.(132)”
MethodExogenous Melatonin for Delirium Prevention: a Meta-analysis of Randomized Controlled Trials
Chen, S., Shi, L., Liang, F., Xu, L., Doycheva, D. M., Wu, Q., & Zhang, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9350-8 · Cited by 87 · see citing works
“5 mg per day), which might influence the effect of melatonin because the high dose of exogenous melatonin supplementation might disturb the endogenous melatonin secretion [50].”
BackgroundSleep as a Therapeutic Target in the Aging Brain
Bah, T. M., Goodman, J. R., & Iliff, J. J. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00769-6 · Cited by 75 · see citing works
Tuft, C., Matar, E., Schrire, Z. M., Grunstein, R. R., Yee, B. J., & Hoyos, C. M. (2023) · Clinical Interventions in Aging · doi:10.2147/cia.s361519 · Cited by 72 · see citing works
“Peak concentrations after oral administration have been reported as substantially higher in older adults, up to 240% greater than in adults under the age of 45 years.(42,49) Other studies have found lower peak serum concentrations but approximately 50% higher mean concentrations with a greater variability in those age…”
BackgroundRedox Biology of Melatonin: Discriminating Between Circadian and Noncircadian Functions
Hardeland, R. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0275 · Cited by 69 · see citing works
“…has been used or tested preclinically and clinically for many different purposes, such as correction of circadian malfunction (12, 50, 57, 246, 272), sleep improvement (26, 233, 238, 303), mood disorders (23, 146, 241, 243, 271), prevention of metabolic syndrome and related pathologies (28,…”
Ye, L., & Richards, K. C. (2017) · Sleep Medicine Clinics · doi:10.1016/j.jsmc.2017.09.011 · Cited by 64 · see citing works
Benefits and adverse events of melatonin use in the elderly (Review)
Anghel, L., Baroiu, L., Popazu, C., Pătraș, D., Fotea, S., Nechifor, A., Ciubară, A., Nechita, L., Mușat, C. L., Ștefanopol, I. A., et al. (2022) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2022.11142 · Cited by 60 · see citing works
“Lerner and colleagues in 1958 and was initially thought to change the skin color of frogs, and thus was considered to be associated with human skin disorders, such as vitiligo (1).”
BackgroundSanabria, F. C., Bruno, S., Crippa, A., Frumento, P., Scarselli, M., Skene, D. J., & Faraguna, U. (2024) · Journal of Pineal Research · doi:10.1111/jpi.12985 · Cited by 62 · see citing works
“Nonetheless, we acknowledge that the lowest effective dose of exo ‐ MEL is recommended to minimize other side effects [21, 68].”
Han, Y., Wu, J., Qin, Z., Fu, W., Zhao, B.-C., Li, X., Wang, W., Sha, T., Sun, M., Li, J., et al. (2020) · Journal of Pineal Research · doi:10.1111/jpi.12644 · Cited by 52 · see citing works
Pivonello, C., Negri, M., Patalano, R., Amatrudo, F., Montò, T., Liccardi, A., Graziadio, C., Muscogiuri, G., Pivonello, R., & Colao, A. (2021) · Obesity Reviews · doi:10.1111/obr.13390 · Cited by 46 · see citing works
“3 mg 1 h before bedtime up to a maximum of 1 or 2 mg melatonin to best mimic its normal physiological levels.(104) Interestingly, subjects with obesity (five men and 10 women) supplemented with a high dose (10 mg/day) of melatonin and subjected to caloric restriction for 30 days showed significant weight loss,”
BackgroundMelatonin in the treatment of fibromyalgia symptoms: A systematic review
Hemati, K., Kadijani, A. A., Sayehmiri, F., Mehrzadi, S., Zabihiyeganeh, M., Hosseinzadeh, A., & Mirzaei, A. (2019) · Complementary Therapies in Clinical Practice · doi:10.1016/j.ctcp.2019.101072 · Cited by 40 · see citing works
Lee, E. K., Poon, P., Yu, C., Lee, V. W., Chung, V. C., & Wong, S. Y. (2022) · The Journal of Clinical Hypertension · doi:10.1111/jch.14482 · Cited by 38 · see citing works
Perspectives on the Management of Vascular Depression
Taylor, W. D., Schultz, S. K., Panaite, V., & Steffens, D. C. (2018) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2018.18050568 · Cited by 37 · see citing works
“A systematic review of the literature that synthesized sixteen studies of the use of melatonin in older adults noted that low doses are recommended, no more than 1 – 2 mg of immediate-release melatonin is optimal and should be administered approximately one hour prior to bedtime for disturbed sleep in this population…”
BackgroundGila-Díaz, A., Carrillo, G. H., Cañas, S., de Pipaón, M. S., Martínez-Orgado, J. A., Rodríguez‐Rodríguez, P., de Pablo, Á. L. L., Martin-Cabrejas, M. A., Ramiro‐Cortijo, D., & Arribas, S. M. (2020) · Nutrients · doi:10.3390/nu12092569 · Cited by 35 · see citing works
“Melatonin levels in plasma are known to decline with age [51] and plasma concentrations match those found in BM [38].”
BackgroundDessap, A. M., Ricard, J.-D., Contou, D., Desnos, C., Decavèle, M., Sonneville, R., Vivier, E., Terzi, N., Callahan, J.-C., Jochmans, S., et al. (2025) · Intensive Care Medicine · doi:10.1007/s00134-025-08002-z · Cited by 31 · see citing works
“First, we investigated only two dose regimens of melatonin; an even lower dose could theoretically be of interest to better mimic the normal physiological circadian rhythm of melatonin [28], as the 0.3 mg nightly dose did not achieve the optimal pharmacologic profile in half of the cases.”
InfluentialCheng, D. C., Ganner, J. L., Gordon, C. J., Phillips, C. L., Grunstein, R. R., & Comas, M. (2021) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2021.101491 · Cited by 32 · see citing works
White, B., Snyder, H. S., & Patel, M. A. V. B. (2021) · Journal of pharmacy and practice · doi:10.1177/08971900211017857 · Cited by 27 · see citing works
“Advanced age and higher melatonin doses (>10 mg) may increase the risk of adverse CNS effects; therefore, elderly patients may benefit from lower doses.(34) Dependence has not been reported with melatonin use and serious side effects were not observed in 1 large systematic review.”
BackgroundThe enigma of vascular depression in old age: a critical update
Jellinger, K. A. (2022) · Journal of Neural Transmission · doi:10.1007/s00702-022-02521-5 · Cited by 27 · see citing works
“Melatonin supplementation (2–5 mg/ day) may be useful to reduce sleep impairment, administered approximately on hour before bedtime (Alghamdi 2018; Vural et al. 2014).”
Chibaatar, E., Le, K., Abdoulaye, I. A., Wu, S., & Guo, Y. (2020) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01699-1 · Cited by 23 · see citing works
Chen, I., Yang, C.-P., Lin, S.-H., Lai, C.-M., & Wong, C. (2020) · Antioxidants · doi:10.3390/antiox9090780 · Cited by 21 · see citing works
Tian, Y., Gong, Z., Zhao, R., & Zhu, Y. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4820 · Cited by 21 · see citing works
Iwan, P., Stępniak, J., & Karbownik‐Lewińska, M. (2021) · Life · doi:10.3390/life11060592 · Cited by 21 · see citing works
“The melatonin level declines gradually over the life-span, which may cause disorders related to an altered circadian rhythm, such as sleeping disorders, delirium or disorders of cognitive functioning, especially characteristic for the elderly [58].”
BackgroundMelatonin supplementation: new insights into health and disease
Minari, T. P., & Pisani, L. P. (2025) · Sleep And Breathing · doi:10.1007/s11325-025-03331-1 · Cited by 20 · see citing works
“The study involved 32 female SLE patients who were randomly assigned to receive either melatonin or cognitive performance in patients with these conditions [38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48].”
InfluentialMelatonin in Alzheimer’s Disease: Literature Review and Therapeutic Trials
Steinbach, M. J., & Denburg, N. L. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230760 · Cited by 20 · see citing works
Ghaleh, H. E. G., Hosseini, A., Aghamollaei, H., Fasihi‐Ramandi, M., Alishiri, G. H., Saeedi‐Boroujeni, A., Hassanpour, K., Mahmoudian‐Sani, M., & Farnoosh, G. (2021) · Zeitschrift für Naturforschung C · doi:10.1515/znc-2021-0101 · Cited by 19 · see citing works
Traumatic Brain Injury, Sleep, and Melatonin—Intrinsic Changes with Therapeutic Potential
Bell, A., Hewins, B., Bishop, C., Fortin, A. H., Wang, J., Creamer, J. L., Collen, J. F., & Werner, J. K. (2023) · Clocks & Sleep · doi:10.3390/clockssleep5020016 · Cited by 19 · see citing works
“Common dosing regimens for insomnia may range from 1 to 5 mg [141] but can be as low as 200 mcg and as high as 50 mg [142], typically taken a few hours prior to bedtime due to its rapid absorption and half-life between 20–50 min.”
BackgroundMelatonin attenuates inflammatory bone loss by alleviating mitophagy and lactate production
Lin, Z., Gu, Y., Liu, Y.-S., Chen, Z.-L., Fang, S., Wang, Z., Liu, Z., Lin, Q., Hu, Y., Jiang, N., et al. (2025) · Apoptosis · doi:10.1007/s10495-025-02096-y · Cited by 19 · see citing works
Melatonin promotes hair regeneration by modulating the Wnt/β ‐catenin signalling pathway
Niu, Y., Li, Y., Gao, C., Li, W., Li, L., Wang, H., Shen, W., & Ge, W. (2024) · Cell Proliferation · doi:10.1111/cpr.13656 · Cited by 16 · see citing works
“…hair regeneration in the depilation mouse model and the fact that MLT concentrations in human serum have been demonstrated to decrease with age, 56,57 it is therefore plausible that the aging-induced decrease in serum MLT levels may be responsible for the failure of hair regeneration in the…”
BackgroundHow does healthy aging impact on the circadian clock?
Popa‐Wagner, A., Buga, A.-M., Dumitraşcu, D. I., Uzoni, A., Thome, J., & Coogan, A. N. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-015-1424-2 · Cited by 16 · see citing works
“An optimal regime for the use of exogenous melatonin, or melatoninergic agonists, to counter such effects in old age has yet to be formulated and thoroughly investigated (Vural et al. 2014).”
BackgroundShin, H. W., Kwak, J. S., Choi, Y. J., Kim, J. W., You, H. S., Shin, H. J., & Jang, Y. (2024) · Journal of International Medical Research · doi:10.1177/03000605241239854 · Cited by 15 · see citing works
“52 In our study, the perioperative use of melatonin and melatonin agonists decreased POD without severe adverse events, particularly at higher melatonin doses, during the early postoperative period, and in cardiopulmonary surgeries.”
BackgroundMelatonin Alleviates Neuronal Damage After Intracerebral Hemorrhage in Hyperglycemic Rats
Liang, F., Wang, J., Zhu, X., Wang, Z., Zheng, J., Sun, Z., Xu, S., Zhang, J., Zhou, J., & Shi, L. (2020) · Drug Design Development and Therapy · doi:10.2147/dddt.s257333 · Cited by 15 · see citing works
The role of melatonin in sarcopenia: Advances and application prospects
Jin, H., Xie, W., Hu, P., Tang, K., Wang, X., Wu, Y., He, M., Yu, D., & Li, Y. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111319 · Cited by 15 · see citing works
Programmed cell death and melatonin: A comprehensive review
Rafiyan, M., Reiter, R. J., Manesh, S. M. R., Asemi, R., Sharifi, M., Mohammadi, S., Mansournia, M. A., & Asemi, Z. (2024) · Functional & Integrative Genomics · doi:10.1007/s10142-024-01454-4 · Cited by 14 · see citing works
“Generally, for sleep onset and sleep disorders doses could range from 0.5 to 10 mg. but the effective dose for induction of other health benefits should be investigated (Suhner et al. 1998; Burgess et al. 2010; Vural et al. 2014; Andersen et al. 2016 ).”
InfluentialShift Workers at Risk for Metabolic Syndrome
Kulkarni, K., Schow, M., & Shubrook, J. H. (2020) · Journal of Osteopathic Medicine · doi:10.7556/jaoa.2020.020 · Cited by 15 · see citing works
Quality of life for older patients with cancer: a review of the evidence supporting melatonin use
Ginzac, A., Dubois, S., Hager, M.-O., Kwiatkowski, F., Passildas, J., Biau, J., Abrial, C., Mouret‐Reynier, M., Thivat, É., & Durando, X. (2020) · Aging Clinical and Experimental Research · doi:10.1007/s40520-020-01532-0 · Cited by 14 · see citing works
Nutritional Supplements for Healthy Aging: A Critical Analysis Review
Kaufman, M. W., DeParis, S., Oppezzo, M., Mah, C. D., Roche, M. D., Frehlich, L., & Fredericson, M. (2024) · American Journal of Lifestyle Medicine · doi:10.1177/15598276241244725 · Cited by 14 · see citing works
Morley, J. E. (2015) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2015.05.001 · Cited by 13 · see citing works
Should Melatonin Be Used as a Sleeping Aid for Elderly People?
Papillon‐Ferland, L., & Mallet, L. (2019) · The Canadian Journal of Hospital Pharmacy · doi:10.4212/cjhp.v72i4.2920 · Cited by 13 · see citing works
Potential and Possible Therapeutic Effects of Melatonin on SARS-CoV-2 Infection
Shchetinin, E., Батурин, В. А., Arushanyan, E., Bolatchiev, A., & Bobryshev, D. (2022) · Antioxidants · doi:10.3390/antiox11010140 · Cited by 13 · see citing works
Ang, M. J., Kang, S., & Moon, C. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24708 · Cited by 13 · see citing works
Martínez, M. R., Aguilar, E. G., Martín‐Vílchez, S., García, J. G., Bueno, S. L., Camargo-Mamani, P., Mejía-Abril, G. P., García-Castro, L., de Miguel‐Cáceres, A., Saz-Leal, P., et al. (2022) · Drugs in R&D · doi:10.1007/s40268-022-00394-3 · Cited by 12 · see citing works
“Thus, this type of prolonged-release melatonin might be mimicking the physiological melatonin secretion curve [2].”
BackgroundInsomnia in Children Affected by Autism Spectrum Disorder: The Role of Melatonin in Treatment
Bruni, O., Biggio, G., Malorgio, E., & Nobili, L. (2024) · Sleep Medicine · doi:10.1016/j.sleep.2024.05.046 · Cited by 11 · see citing works
Milanowski, J., Kozerawski, K., Falęcka, W., Dudek, D., Lisewska, B., Lisewski, P., Nuszkiewicz, J., Wesołowski, R., Wojtasik, J., Mila-Kierzenkowska, C., et al. (2023) · Metabolites · doi:10.3390/metabo13050668 · Cited by 11 · see citing works
“Melatonin production is suppressed by light, which reduces the level of this compound during the day [53].”
BackgroundChojnacki, C. J., Mędrek-Socha, M., Konrad, P., Chojnacki, J., & Błońska, A. (2020) · BMC Women s Health · doi:10.1186/s12905-020-01117-z · Cited by 11 · see citing works
“In order to control sleep, the most frequently recommended dose was 1 mg to 5 mg at night, while most treatments of alimentary tract disease [30–35] or climacteric disorders in women were based on doses of 3 mg or 5 mg per day [39, 40].”
BackgroundMelatonin as an adjunctive therapy in cardiovascular disease management
Luo, Z., Tang, Y., & Zhou, L. (2024) · Science Progress · doi:10.1177/00368504241299993 · Cited by 10 · see citing works
Current Treatments to Counter Sleep Dysfunction as a Pathogenic Stimulus of Fibromyalgia
Choy, E. (2016) · Pain Management · doi:10.2217/pmt-2016-0009 · Cited by 9 · see citing works
Melatonin Prescription in Children and Adolescents in Relation to Body Weight and Age
Kimland, E. E., Dahlén, E., Martikainen, J., Célind, J., & Kindblom, J. M. (2023) · Pharmaceuticals · doi:10.3390/ph16030396 · Cited by 8 · see citing works
“However, the dosing in that study displayed a large variation [33], indicating that several individual factors may be of importance for dosing of melatonin, such as pronounced inter-individual differences in melatonin production [34], endogenous melatonin production sensitivity to ambient light [35,36], timing of inta…”
BackgroundCarlos, R. M., Matias, C. N., Cavaca, M. L., Cardoso, S., Santos, D. A., Giro, R., Vaz, J. R., Pereira, P. M. D. C. C., Vicente, F., Leonardo-Mendonça, R. C., et al. (2024) · Chronobiology International · doi:10.1080/07420528.2024.2353225 · Cited by 7 · see citing works
“This mineral is directly involved in the metabolism of several neurotransmitters, with its deficiency inducing Central Nervous System hyperexcitability (Vural et al. 2014) which is closely linked with sleep disorders.”
BackgroundFusi, J., Scarfò, G., Silvestro, R., & Franzoni, F. (2025) · Nutrients · doi:10.3390/nu17111779 · Cited by 9 · see citing works
“Vural et al. (2014) investigated optimal melatonin supplement dosages in elderly subjects (0.1 mg to 50 mg/kg) [72].”
InfluentialBhaskar, R., Narayanan, K. B., Singh, D. K. K., & Han, S. S. (2025) · Current Alzheimer Research · doi:10.2174/0115672050381989250626071304 · Cited by 6 · see citing works
Leung, L. Y. L., Tam, H. L., Asiamah, N., & Ho, J. K.-M. (2025) · Alzheimer s Research & Therapy · doi:10.1186/s13195-025-01881-w · Cited by 6 · see citing works
“However, it is suggested to start with a lower dosage of 1–2 mg daily [38] and avoid exceeding 10 mg daily, as a higher dosage is associated with a higher rate of adverse effects [14].”
Melatonin inhibits muscular-mucosal stretch-sensitive bladder afferents via the MT2 receptors
Ramsay, S. D., & Zagorodnyuk, V. P. (2022) · Scientific Reports · doi:10.1038/s41598-022-22705-z · Cited by 6 · see citing works
Fritsch, M. A., & Shelton, P. S. (2017) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2017.01.003 · Cited by 6 · see citing works
Fritsch, M. A., & Shelton, P. S. (2019) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2019.01.010 · Cited by 5 · see citing works
Moyad, M. A. (2015) · Springer eBooks · doi:10.1007/978-3-319-23422-9_7 · Cited by 5 · see citing works
Liu, Y.-J., Swaab, D. F., & Zhou, J.-N. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-323-90918-1.00001-0 · Cited by 4 · see citing works
Melatonin and blood pressure: a narrative review
Serhiyenko, O., Sehin, V. B., Kuznets, V., & Сергієнко, В. О. (2024) · INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine) · doi:10.22141/2224-0721.20.3.2024.1393 · Cited by 4 · see citing works
Possible effects of melatonin on reperfusion injury following coronary artery bypass graft surgery.
طلاساز, آ. ح. ح., Dianatkhah, M., Ghaeli, P., Salehiomran, A., & Dianatkhah, M. (2022) · PubMed Central · doi:10.48305/arya.v18i0.2208 · Cited by 4 · see citing works
Genetic and biological factors in sleep
Gentry, N. W., Ptáček, L. J., & Fu, Y. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-815501-1.00001-6 · Cited by 4 · see citing works
Kelleher, A. B., O’Donovan, M. R., O’Doherty, D., Lavery, R., Lehane, E. A., & Saab, M. M. (2025) · PLoS ONE · doi:10.1371/journal.pone.0332031 · Cited by 3 · see citing works
“A systematic review by Vural et al. [70] advised using the lowest dose of melatonin possible in older patients to avoid prolonged, supra-physiological blood levels.”
Khatami, S., Faghihi, M., Sheibani, M., Hosseinzadeh, A., Jamaldini, S. H., & Mehrzadi, S. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-12222-x · Cited by 2 · see citing works
Dietary Supplements for Insomnia
Ring, M. R., Marchlewski, A., & Kaplan, J. (2017) · Current Sleep Medicine Reports · doi:10.1007/s40675-017-0091-2 · Cited by 2 · see citing works
Dündar, G., Günaydın, Ö., Yazıcı, G., Kurtulan, O., Öğüş, E., & Şahin, İ. (2022) · Auris Nasus Larynx · doi:10.1016/j.anl.2022.08.003 · Cited by 2 · see citing works
Features of using prolonged-release melatonin in patients with type 2 diabetes
Кравчун, П. П., Дунаєва, І., & Кравчун, Н. А. (2023) · INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine) · doi:10.22141/2224-0721.19.2.2023.1260 · Cited by 2 · see citing works
Possible protective effects of the Bmal1 gene and melatonin on the prognosis of apical periodontitis
Küçük, M., Aksoy, U., & Şehirli, A. Ö. (2022) · Medical Hypotheses · doi:10.1016/j.mehy.2022.110806 · Cited by 1 · see citing works
Therapeutic and pharmacological potential of melatonin
Hussain, K., Ara, T., & Koul, A. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13814-0.00010-7 · Cited by 1 · see citing works
Grigoraş, M., Grigoras, R. M., Anghelescu, D. V., Iacobescu, G. L., Popa, M. I. G., & Matei, V. P. (2018) · Romanian Journal of Psychiatry & Psychotherapy · doi:10.37897/rjpp.2018.3.3 · Cited by 1 · see citing works
Meghji, Z., Hategan, A., Maclean, M., & Amoako-Tuffour, A. (2024) · Springer eBooks · doi:10.1007/978-3-031-47802-4_24 · Cited by 1 · see citing works
Chronobiology and Chronotherapeutics: Resetting the Biologic Clock
Horowitz, S. (2015) · Alternative and Complementary Therapies · doi:10.1089/act.2015.29008.sh · Cited by 1 · see citing works
“44 Melatonin dosages varied from 0.1 mg to 50 mg/kg.”
InfluentialNew Galenic Formulations of Melatonin
García‐García, P., Lopez-Munoz, F. J., & Álamo, C. (2016) · Springer eBooks · doi:10.1007/978-81-322-2803-5_15 · Cited by 1 · see citing works
Stenveld, F., Bosman, S., Munster, B. C. V., Beishuizen, S. J. E., Hempenius, L., van der Velde, N., Smidt, N., & de Rooij, S. E. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-025514 · Cited by 1 · see citing works
“The dosage of 1 mg melatonin is chosen based on a recent systematic review, to best mimic the normal physiological circadian rhythm of melatonin by avoiding prolonged supra-physiological blood levels in case of higher dosages.(35) The dosage of 10 mg temazepam is the recommend dose for older patients.”
MethodPippa, Ν., & Demetzos, C. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.91155 · Cited by 1 · see citing works
The features of optimal nonhormonal therapy of vegetative disorders among women with postmenopause
Konkov, D. G., Taran, O. A., Rud, V. O., & Кливак, В. В. (2022) · Reproductive Endocrinology · doi:10.18370/2309-4117.2022.65.90-96 · Cited by 1 · see citing works
Sleep-Wake Disorders in Late Life
Meghji, Z., Hategan, A., & Amoako-Tuffour, A. (2017) · Springer eBooks · doi:10.1007/978-3-319-67555-8_24
Low doses of melatonin may be best for older adults with insomnia
Corvese, R. (2018) · Pharmacy Today · doi:10.1016/j.ptdy.2018.10.008
Anti-Cancer Effect of Melatonin with Radioprotective/Radiosensitive Property
Cihan, Y. B. (2020) · Klinicka onkologie · doi:10.14735/amko2020150
“150 Klin Onkol 2020; 33(2): 150– 151 SHORT COMMUNICATIONS”
EFFECT OF PSQI SCORE ON ADMINISTRATION MELATONIN IN PERIMENOPAUSE WOMEN
Vebrian, H. R., Siregar, M. F. G., Adenin, I., Sihite, H., Ardiansyah, E., Dina, S., & Eyanoer, P. C. (2020) · International Journal of Current Pharmaceutical Research · doi:10.22159/ijcpr.2020v12i4.39097
“5 mg for phase changes, doses that increase plasma melatonin levels during the day to the normal nocturnal range observed in young adults) [11].”
BackgroundButkevych, Т. А., Полова, Ж. М., & Savchenko, S. (2023) · Ukrainian Scientific Medical Youth Journal · doi:10.32345/usmyj.2(139).2023.105-112
“…insomnia (Cardinali et al., 2012, Xie et al., 2017, Palagini et al., 2021, Schroder et al., 2021, Marupuru et al., 2022, Tuft et al., 2023)� Literature data recommends a wide range of melatonin doses (from 0.5 mg to 10 mg) and it’s taking 1 hour before sleep (Vural et al., 2014, Tuft et al., 2023).”
BackgroundInfluentialKeloğlan, S., Şahin, L., Annaç, E. E., & Tiraşçi, N. (2025) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.1007/s44411-025-00203-8
“Due to the decrease in melatonin levels with age [60], melatonin alone in old rats may not have the improved effect on SI stress that it does in adult rats.”
Shikarkhane, P. A., Rupapara, R., Sangalli, L., & Thomas, D. C. (2026) · Medical Clinics of North America · doi:10.1016/j.mcna.2026.01.006
de Almeida, L., Lins, A., Eiró‐Quirino, L., de Souza, L. V., Hamoy, M. K. O., Hartcoff, P. F. P., Brito, M. V. D. S., Barbosa, G. B., Reis, T. D. S., & Hamoy, M. (2026) · ACS Omega · doi:10.1021/acsomega.6c00727
Ozel, F., Sapmaz, T., Kuraş, S., Topkaraoğlu, S., & Kutlucan, K. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154341
- Authors
- Vural, E. M. S., van Munster, B. C., & de Rooij, S. E.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Vural, Esmée M. S.
- Venue
- Drugs & Aging
- Published
- 2014-05-07
- Volume
- 31
- Issue
- 6
- Pages
- 441-451
- ISSN
- 1170-229X (ISSN-L)
- 1179-1969
- OpenAlex
- W2038533484
- Cited by
- 92
- References
- 47
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 12 · 2023: 6 · 2022: 14 · 2021: 7 · 2020: 14 · 2019: 7 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 1
- FWCI
- 0.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Drugs & Aging (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- melatonin, melatonin supplementation, dose-response relationship, older adults, circadian rhythm, serum melatonin, urinary melatonin, saliva melatonin, immediate-release formulation, sleep disorders
- MeSH terms
- Administration, Oral, Aged, Aged, 80 and over, Circadian Rhythm, Dose-Response Relationship, Drug, Humans, Sleep Initiation and Maintenance Disorders, Melatonin, Middle Aged, Saliva, Dietary Supplements
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