Background    Melatonin is a naturally occurring hormone classified as a dietary supplement in the United States (US) (1). It can be purchased over the counter (OTC) without a prescription and therefore is unregulated by the FDA. Many clinicians who care for seriously ill patients are asked about the use of melatonin to regulate the circadian rhythm and treat insomnia and other common symptoms in serious illness care. This Fast Fact reviews melatonin’s pharmacology and its potential uses in the adult palliative care population, while acknowledging the emerging evidence for the pediatric population (2).  

Pharmacology    Melatonin is an endogenous metabolite of tryptophan and serotonin, released cyclically from the pineal gland according to the body’s circadian rhythm. With age, the pineal gland produces less melatonin, hence, supplements may be more suitable for older patients and less helpful for children. Plasma levels naturally increase in the evening to encourage sleep onset and maintenance (3). Oral doses of 5 mg produce blood levels 25 times higher than normal but do not appear to alter endogenous production (4). Oral melatonin is rapidly absorbed; bioavailability ranges from 10-56% (5). This range may be due to extensive first pass metabolism, or variations between manufactured formulations. Due to its high lipophilicity, melatonin crosses the blood brain barrier quickly; onset and peak concentration are within 50 minutes and 2 ½ hours respectively (6). Its terminal half-life is only ~45 minutes; however, its duration of action is equal to four elimination half-lives (or about 3-5 hours) (7).    

Dosing    Melatonin is available in 1 mg, 3 mg, 5 mg, and 10 mg immediate-release, and 3 mg and 5 mg controlled-release oral tablets. A typical starting dose in adults is 1-3 mg once daily, with a more conservative dose of 0.5 mg in geriatric patients. In children, recommended doses range from 0.5 mg to 6 mg per day. Melatonin should be administered within 1 hour of bedtime to supplement the body’s endogenous nocturnal surge.  Lower doses should be used in liver failure (5). 

Research data     

• Insomnia: there is insufficient evidence to support the use of melatonin for primary insomnia disorders in adults or in insomnia related to moderate to severe dementia.  However, short term use of melatonin (less than three months) may be effective in adults with delayed sleep phase syndrome (sleep that is delayed 2 or more hours beyond the conventional bedtime) (8-10). Most studies in the pediatric population are conducted in children with neurodevelopmental comorbidities (ADHD, autism, etc); supporting data in children without neurodevelopmental comorbidities is insufficient (2).   
• Anti-tumor effects: melatonin has been examined as an adjuvant to chemotherapy due to its antioxidant and immunomodulatory effects that theoretically could lead to anti-tumor and survival benefits at daily doses of 6-20 mg, especially for older patients. However, its role as an oncologic adjuvant needs further research and is not standard of care (11-13).  
• Delirium: an emerging role is in the prevention and management of delirium for adults. Case reports have shown success in treating severe post-operative delirium refractory to antipsychotics or benzodiazepines (14). One randomized, double-blinded, placebo-controlled study concluded that melatonin 0.5 mg/day was associated with a lower risk of delirium in hospitalized elderly patients (15).  Additionally, ramelteon, a melatonin receptor agonist, demonstrated similar benefit in a small randomized, placebo-controlled study preventing delirium among hospitalized elderly patients (16). More research is needed to establish the role of both melatonin and ramelteon for delirium (17).  
• Cancer-related symptoms:  placebo-controlled trials have not shown clear benefit for patients with cancer related fatigue; effects on patient-report quality of life in advanced cancer have been mixed (18,19). Melatonin dosed at 6-20 mg/day may lead to a significant reduction of chemotherapy-induced toxicities and symptoms such as asthenia, neurotoxicity, stomatitis, depression, anorexia (20,21). 

Adverse effects   Melatonin is relatively nontoxic in appropriate doses when used short term in adults (4). The most common side effect is excess sedation (4). Caution should be exhibited in the post organ transplant population as melatonin’s immune-boosting effects could increase the risk of graft rejection (22). Of note, since it is an unregulated supplement, dosages, even active ingredients may vary. While generally safe in children, there is mixed data on whether it may delay pubertal onset (23-24).  

Cost    Melatonin is rather inexpensive but is usually not covered by most private insurances or Medicare. Prices over the counter range from $5-15 for a ninety-count bottle.  

Summary   Melatonin is a naturally occurring hormone that has limited benefit in treatment of primary sleep disorders but may have a potential benefit for older patients in the prevention and management of delirium, cancer related symptoms, and secondary-related sleep disorders.  

References 

1. National Institute of Health. Dietary Supplements: What You Need To Know. Accessed 10 June 2015. Available at: http://ods.od.nih.gov/HealthInformation/DS_WhatYouNeedToKnow.aspx; 2011.  
2. Skrzelowski M, Brookhaus A, Shea LA, et al.  Melatonin use in pediatrics: evaluating the discrepancy in evidence-based on country and regulations regarding production. JPPT 2021; 26(1):4-20. 
3. Axelrod J, Shein HM, Wurtman RJ. Stimulation of C14-melatonin synthesis from C14-tryptophan by noradrenaline in rat pineal in organ culture. Proc Natl Acad Sci U S A. 1969 Feb;62(2):544-9. 
4. Mahmoud F, Sarhill N, Mazurczak MA. The therapeutic application of melatonin in supportive care and palliative medicine. Am J Hosp Palliat Care. 2005 Jul-Aug;22(4):295-309. 
5. Di WL, Kadva A, Johnston A, Silman R. Variable bioavailability of oral melatonin. N Engl J Med. 1997 Apr 3;336(14):1028-9. 
6. Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015 May 27. [Epub ahead of print] 
7. Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015 May 27. [Epub ahead of print] 
8. Buscemi N1, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med. 2005 Dec;20(12):1151-8. 
9. McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in Alzheimer’s disease. Cochrane Database Syst Rev. 2014 Mar 21;3:CD009178. 
10. Xu J, Wang LL, Dammer EB, Li CB, Xu G, Chen SD, Wang G. Melatonin for Sleep Disorders and Cognition in Dementia: A Meta-Analysis of Randomized Controlled Trials. Am J Alzheimers Dis Other Demen. 2015 Jan 22. pii: 1533317514568005. [Epub ahead of print] 
11. Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012 May;69(5):1213-20 
12. Sookprasert A, Johns NP, Phunmanee A, Pongthai P, Cheawchanwattana A, Johns J, Konsil J, Plaimee P, Porasuphatana S, Jitpimolmard S. Melatonin in patients with cancer receiving chemotherapy: a randomized, double-blind, placebo-controlled trial. Anticancer Res. 2014 Dec;34(12):7327-37. 
13. Lissoni P, Rovelli F, Brivio F, et al. Five-year survival with high-dose melatonin and other antitumor pineal hormones in advanced cancer patients eligible for the only palliative therapy. Research Journal of Oncology 2018; 2(1):2 
14. Hanania M, Kitain E. Melatonin for treatment and prevention of postoperative delirium. Anesth Analg. 2002;94:338-9. 
15. Al-Aama R, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. In J Geriatr Psychiatry. 2011;26:687-694. 
16. Hatta K, Kishi Y, et al. Preventive effects of ramelteon on delirium: a randomized placebo controlled trial.  JAMA Psychiatry 2014; 71:397-403. 
17. Ting Ng K, Yi Teoh W, Jing Khor A. The effect of melatonin on delirium on hospitalized patients: a systematic review and meta-analyses with trial sequential analysis. Journal of Clin Anesthesia 2020; 59:74-81. 
18. Rasmussen CL, Olsen MK, Johnsen AT, et al.  Effects of melatonin on physical fatigue and other symptoms in patients with advanced cancer receiving palliative care: a double-blind placebo-controlled crossover trial. Cancer 2015; 121(20):3727-3736. 
19. Ginzac A, Dubois S, Hager M-O, et al. Quality of life for older patients with cancer: a review of the evidence supporting melatonin use.  Aging Clinical and Experimental Research 2020; 32:2459-2468. 
20. Wang Y, Jin B, Ai F, et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol 2012; 69:1213-20. 
21. Hansen MV, Andersen LT, Madsen MT, et al. Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Breast Cancer Res 2014; 145:683-695. 
22. Fildes JE, Yonan N, Keevil BG. Melatonin–a pleiotropic molecule involved in pathophysiological processes following organ transplantation. Immunology. 2009 Aug;127(4):443-9. 
23. Boafo A, Greenham S, Alenezi S, , et al. Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician’s perspective. Nat Sci Sleep. 2019;11.
24. van Geijlswijk IM, Mol RH, Egberts TCG, et al. Evaluation of sleep, puberty and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia. Psychopharmacology (Berl). 2011;216(1). 

Authors Affiliations: University of Pittsburgh Medical Center; UPMC Health System. 
Conflict of Interest: The authors have disclosed no relevant conflicts of interest. 
Version History: Copy edited by Sean Marks MD. First electronically published October 2015; reviewed and updated in February 2024.