Melatonin and Delirium

Main Article Content

Unchana Sura-amonrattana
Varalak Srinonprasert


Melatonin is an endogenous hormone that has an important role in the regulation of the circadian rhythm and in maintaining the sleep–wake cycle. Delirium is neuropsychiatric syndrome and commonly involves disruption of the sleep–wake cycle. It is associated with significant mortality and morbidity. There are hypotheses that melatonin secretion is delayed or low in delirium patients so the role of melatonin and melatonin agonist for delirium prevention and treatment were studied. However, the therapeutic benefit of melatonin is uncertain. The aim of this review was to explain why melatonin is associated with delirium and to compile the study of the role of melatonin in the field of prevention and treatment of delirium.

Article Details

How to Cite
Sura-amonrattana U, Srinonprasert V. Melatonin and Delirium. Siriraj Med Bull [Internet]. 2021 Mar. 22 [cited 2024 Jun. 18];14(2):37-53. Available from:
Review Article


Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W. Isolation of melatonin, the pineal gland factor that lightens melanocytes1. Journal of the American Chemical Society. 1958;80(10):2587-.

Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep medicine reviews. 2005;9(1):11-24.

Ekmekcioglu C. Melatonin receptors in humans: biological role and clinical relevance. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2006;60(3):97-108.

Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005;27(2):101-110.

Becker-André M, Wiesenberg I, Schaeren-Wiemers N, André E, Missbach M, Saurat JH, et al. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 1994;269(46):28531-28534.

Winczyk K, Pawlikowski M, Karasek M. Melatonin and RZR/ROR receptor ligand CGP 52608 induce apoptosis in the murine colonic cancer. Journal of pineal research. 2001;31(2):179-182.

Guardiola-Lemaitre B. Toxicology of melatonin. Journal of biological rhythms. 1997;12(6):697-706.

Nogueira LM, Sampson JN, Chu LW, Yu K, Andriole G, Church T, et al. Individual variations in serum melatonin levels through time: implications for epidemiologic studies. PloS one. 2013;8(12):e83208.

Waldhauser F, Ehrhart B, Förster E. Clinical aspects of the melatonin action: impact of development, aging, and puberty, involvement of melatonin in psychiatric disease and importance of neuroimmunoendocrine interactions. Experientia. 1993;49(8):671-681.

Wu YH, Feenstra MG, Zhou JN, Liu RY, Torano JS, Van Kan HJ, et al. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. The Journal of clinical endocrinology and metabolism. 2003;88(12):5898-5906.

Brugger P, Marktl W, Herold M. Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet. 1995;345(8962):1408.

Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004;43(2):192-197.

Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem. 2002;2(2):167-179.

Esposito E, Paterniti I, Mazzon E, Bramanti P, Cuzzocrea S. Melatonin reduces hyperalgesia associated with inflammation. Journal of pineal research. 2010;49(4):321-331.

Danilov A, Kurganova J. Melatonin in Chronic Pain Syndromes. Pain and Therapy. 2016;5(1):1-17.

Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC. Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis. Journal of pineal research. 1993;14(4):151-168.

Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, et al. Melatonin--a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann N Y Acad Sci. 1994;738:419-420.

Karaaslan C, Suzen S. Antioxidant properties of melatonin and its potential action in diseases. Curr Top Med Chem. 2015;15(9):894-903.

Xin Z, Jiang S, Jiang P, Yan X, Fan C, Di S, et al. Melatonin as a treatment for gastrointestinal cancer: a review. Journal of pineal research. 2015;58(4):375-387.

Hardeland R, Poeggeler B, Srinivasan V, Trakht I, Pandi-Perumal SR, Cardinali DP. Melatonergic drugs in clinical practice. Arzneimittel-Forschung. 2008;58(1):1-10.

Carocci A, Catalano A, Sinicropi MS. Melatonergic drugs in development. Clin Pharmacol. 2014;6:127-137.

Maldonado JR. Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. International journal of geriatric psychiatry. 2018;33(11):1428-1457.

Peters R. Ageing and the brain. Postgrad Med J. 2006;82(964):84-88.

Namyen J, Permpoonputtana K, Nopparat C, Tocharus J, Tocharus C, Govitrapong P. Protective Effects of Melatonin on Methamphetamine-Induced Blood–Brain Barrier Dysfunction in Rat Model. Neurotoxicity Research. 2020.

Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000;29(3-4):222-230.

Spinedi E, Cardinali DP. Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer s Disease and Melatonin.
. Neuroendocrinology. 2018.

Balan S, Leibovitz A, Shen-Or Z, Ruth M, Chana W, Yassica B, et al. The Relation Between the Clinical Subtypes of Delirium and the Urinary Level of 6-SMT. The Journal of neuropsychiatry and clinical neurosciences. 2003;15:363-366.

Mistraletti G, Paroni R, Umbrello M, D'Amato L, Sabbatini G, Taverna M, et al. Melatonin Pharmacological Blood Levels Increase Total Antioxidant Capacity in Critically Ill Patients. Int J Mol Sci. 2017;18(4):759.

Maldonado JR. Neuropathogenesis of delirium: review of current etiologic theories and common pathways. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2013;21(12):1190-1222.

Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin. 2008;24(4):789-856, ix.

Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. International journal of geriatric psychiatry. 2011;26(7):687-694.

Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA psychiatry. 2014;71(4):397-403.

Jaiswal SJ, McCarthy TJ, Wineinger NE, Kang DY, Song J, Garcia S, et al. Melatonin and Sleep in Preventing Hospitalized Delirium: A Randomized Clinical Trial. The American journal of medicine. 2018;131(9):1110-7.e4.

Bush SH, Lacaze-Masmonteil N, McNamara-Kilian MT, MacDonald AR, Tierney S, Momoli F, et al. The preventative role of exogenous melatonin administration to patients with advanced cancer who are at risk of delirium: study protocol for a randomized controlled trial. Trials. 2016;17:399.

Hanania M, Kitain E. Melatonin for treatment and prevention of postoperative delirium. Anesth Analg. 2002;94(2):338-339, table of contents.

Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010;4(3):169-173.

de Jonghe A, van Munster BC, Goslings JC, Kloen P, van Rees C, Wolvius R, et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2014;186(14):E547-556.

Artemiou P, Bily B, Bilecova-Rabajdova M, Sabol F, Torok P, Kolarcik P, et al. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients. Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. 2015;12(2):126-133.

Ford AH, Flicker L, Passage J, Wibrow B, Anstey M, Edwards M, et al. The Healthy Heart-Mind trial: melatonin for prevention of delirium following cardiac surgery: study protocol for a randomized controlled trial. Trials. 2016;17:55.

Ford AH, Flicker L, Kelly R, Patel H, Passage J, Wibrow B, et al. The Healthy Heart-Mind Trial: Randomized Controlled Trial of Melatonin for Prevention of Delirium. Journal of the American Geriatrics Society. 2020;68(1):112-119.

Ibrahim MG, Bellomo R, Hart GK, Norman TR, Goldsmith D, Bates S, et al. A double-blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomised patients. Crit Care Resusc. 2006;8(3):187-191.

Fan Y, Yuan L, Ji M, Yang J, Gao D. The effect of melatonin on early postoperative cognitive decline in elderly patients undergoing hip arthroplasty: A randomized controlled trial. Journal of clinical anesthesia. 2017;39:77-81.

Abbasi S, Farsaei S, Ghasemi D, Mansourian M. Potential role of exogenous melatonin supplement in delirium prevention in critically ill patients: A Double-Blind Randomized Pilot Study. Iran J Pharm Res. 2018;17(4):1571-1580.

Baumgartner L, Lam K, Lai J, Barnett M, Thompson A, Gross K, et al. effectiveness of melatonin for the prevention of intensive care unit delirium. Pharmacotherapy. 2019;39(3):280-287.

Burry L, Scales D, Williamson D, Foster J, Mehta S, Guenette M, et al. Feasibility of melatonin for prevention of delirium in critically ill patients: a protocol for a multicentre, randomised, placebo-controlled study. BMJ open. 2017;7(3):e015420.

Campbell AM, Axon DR, Martin JR, Slack MK, Mollon L, Lee JK. Melatonin for the prevention of postoperative delirium in older adults: a systematic review and meta-analysis. BMC geriatrics. 2019;19(1):272.

Yang CP, Tseng PT, Pei-Chen Chang J, Su H, Satyanarayanan SK, Su KP. Melatonergic agents in the prevention of delirium: A network meta-analysis of randomized controlled trials. Sleep medicine reviews. 2019;50:101235.

Ng KT, Teoh WY, Khor AJ. The effect of melatonin on delirium in hospitalised patients: A systematic review and meta-analyses with trial sequential analysis. Journal of clinical anesthesia. 2020;59:74-81.

Kimura R, Mori K, Kumazaki H, Yanagida M, Taguchi S, Matsunaga H. Treatment of delirium with ramelteon: initial experience in three patients. Gen Hosp Psychiatry. 2011;33(4):407-409.

Furuya M, Miyaoka T, Yasuda H, Yamashita S, Tanaka I, Otsuka S, et al. Marked improvement in delirium with ramelteon: five case reports. Psychogeriatrics. 2012;12(4):259-262.

Ohta T, Murao K, Miyake K, Takemoto K. Melatonin receptor agonists for treating delirium in elderly patients with acute stroke. J Stroke Cerebrovasc Dis. 2013;22(7):1107-1110.

Tsuda A, Nishimura K, Naganawa E, Otsubo T, Ishigooka J. Ramelteon for the treatment of delirium in elderly patients: a consecutive case series study. International journal of psychiatry in medicine. 2014;47(2):97-104.

Miura S, Furuya M, Yasuda H, Miyaoka T, Horiguchi J. Novel Therapy With Ramelteon for Hypoactive Delirium: A Case Report. Journal of clinical psychopharmacology. 2015;35(5):616-618.

Yeh T-C, Yeh C-B, Tzeng N-S, Mao W-C. Adjunctive treatment with melatonin receptor agonists for older delirious patients with the sundowning phenomenon. J Psychiatry Neurosci. 2015;40(2):E25-E6.

Furuya M, Miyaoka T, Yasuda H, Wake R, Hashioka S, Miura S, et al. Ramelteon as adjunctive therapy for delirium referred to a consultation-liaison psychiatry service: a retrospective analysis. International journal of geriatric psychiatry. 2015;30(9):994-995.

Pinkhasov A, James SA, Fazzari M, Singh D, Lam S. Role of ramelteon in reduction of as-needed antipsychotics in elderly patients with delirium in a general hospital setting. Clinical drug investigation. 2017;37(12):1137-1141.

Clayton-Chubb DI, Lange PW. Moderate dose melatonin for the abatement and treatment of delirium in elderly general medical inpatients: study protocol of a placebo controlled, randomised, double blind trial. BMC geriatrics. 2016;16:54.

Tsuda A, Nishimura K, Naganawa E, Otsubo T, Ishigooka J. Successfully treated delirium in an extremely elderly patient by switching from risperidone to ramelteon. Psychiatry Clin Neurosci. 2013;67(2):130.

Thom R, Bui M, Rosner B, Teslyar P, Levy-Carrick N, Wolfe D, et al. Ramelteon is Not Associated With Improved Outcomes Among Critically Ill Delirious Patients: A Single-Center Retrospective Cohort Study. Psychosomatics. 2019;60(3):289-297.