Continuing Education Activity

Endogenous melatonin is a naturally produced hormone primarily synthesized and secreted in the pineal gland. Melatonin regulates the body's sleep-wake cycles by interacting with the suprachiasmatic nucleus of the hypothalamus and the retina. The best-known purpose of melatonin is its role in promoting sleep and inhibiting wake-promoting signals through interactions with its MT1 and MT2 receptors. Although melatonin is not officially approved for any indication by the US Food and Drug Administration (FDA) in the United States, exogenously supplied melatonin, which is available as a synthetic dietary supplement, mimics the regulatory functions of endogenous melatonin.

The American Academy of Family Physicians (AAFP) recognizes melatonin as the first-line pharmacological therapy for insomnia, emphasizing its crucial role in managing sleep-related concerns. Melatonin is also used for the management of posttraumatic brain injury, jet lag, neurodegenerative disorders, and migraine prophylaxis. This activity explores the safety profile of melatonin supplementation, highlighting its relatively low risk of adverse effects. This activity further elucidates the mechanism of action, pharmacology, adverse event profile, monitoring strategies, and pertinent interactions of melatonin. The interprofessional healthcare team can use melatonin as an adjunct to offer essential insights for collaborative patient care in sleep disorders.

Objectives:

• Identify appropriate indications for melatonin supplementation in managing sleep disorders and insomnia.
• Implement evidence-based dosing and timing strategies for melatonin administration tailored to individual patient needs.
• Assess patient response to melatonin therapy through regular follow-up evaluations and monitoring for efficacy and adverse effects.
• Coordinate comprehensive patient care plans, integrating melatonin supplementation as an adjunctive therapy to manage sleep disorders.

Indications

Endogenous melatonin is a naturally produced hormone primarily synthesized and secreted in the pineal gland. Melatonin regulates the body's sleep-wake cycles by interacting with the suprachiasmatic nucleus (SCN) of the hypothalamus and the retina. The best-known purpose of melatonin is its role in promoting sleep and inhibiting wake-promoting signals through interactions with its MT1 and MT2 receptors.

FDA-Approved Indications

Although not officially approved for any indication by the US Food and Drug Administration (FDA) in the United States, exogenously supplied melatonin, available as a synthetic dietary supplement, mimics the regulatory functions of endogenous melatonin. However, melatonin receptor agonists, such as ramelteon and tasimelteon, are available on the market and are FDA-approved for the treatment of insomnia.[1][2]

Off-Label Uses

Insomnia: Despite the lack of FDA approval, the American Academy of Family Physicians (AAFP) recognizes melatonin as the first-line pharmacological therapy for insomnia, emphasizing its crucial role in managing sleep-related concerns. This drug is relatively safe with a low risk of adverse effects. Research on the efficacy of melatonin supplementation for treating insomnia has shown varied results. However, a meta-analysis conducted by Ferracioli-Oda et al concluded that individuals who used melatonin experienced an average reduction in sleep onset latency by approximately 7 minutes, an increase in total sleep duration by approximately 8 minutes, and subjectively reported an improvement in the quality of their sleep, as compared to those who were given a placebo. Nevertheless, there was considerable variability in doses, study outcomes, and overall study quality.[3] 

Melatonin is endorsed by the American Academy of Sleep Medicine (AASM) for treating rapid eye movement (REM) sleep behavior disorder and circadian rhythm disorders.[4][5] In addition, melatonin has been studied and recommended primarily for the treatment of [6][7] primary insomnia (insomnia not due to secondary cause), posttraumatic brain injury,[8] age-related insomnia, jet lag disorder,[9] shift work sleep disorder, neurodegenerative disorders, and migraine prophylaxis.[10]

Research-based: Although no formal recommendations are recognized, ongoing clinical research is investigating the potential role of melatonin in the treatment of various conditions, including cancer,[11] pain syndromes, metabolic disorders, cardiovascular disorders,[12] gastrointestinal conditions, neurodegenerative disorders,[13] mental disorders, and reproductive dysfunctions.[14]

Mechanism of Action

Synthesis of Endogenous Melatonin

Endogenous melatonin is a hormone produced naturally, synthesized, and primarily secreted in the pineal gland. Melatonin production starts with tryptophan, which is converted into serotonin in other parts of the brain through a pathway. Some of this serotonin reaches the pineal gland, where it undergoes a cyclic, light-dependent process to be converted into melatonin.[15]

The conversion of serotonin to melatonin is regulated by the SCN of the hypothalamus, which coordinates the body's circadian rhythms. Information about varying light conditions, ranging from low light to darkness, is transmitted from the retina through the retinohypothalamic tract to the SCN. The SCN then communicates signals via the sympathetic nervous system to the superior cervical ganglion, which innervates the pineal gland. 

Sympathetic stimulation of the pineal gland upregulates the production of the enzyme arylalkylamine N-acetyltransferase (AA-NAT). AA-NAT converts serotonin to N-acetyl-serotonin, representing the rate-limiting step in melatonin formation. Subsequently, this intermediate is converted to melatonin. Studies in rats have demonstrated that bilateral surgical removal of the superior cervical ganglia or SCN halts AA-NAT activation and abolishes the rhythmic pattern of melatonin secretion, leading to disruptions in the sleep-wake cycle.[16][17][18]

Functions of Endogenous Melatonin

The primary role of melatonin is best known for its involvement in promoting sleep. Melatonin is released by the pineal gland into the third ventricle and the circulation. The drug regulates the body's sleep-wake cycles through interactions with the SCN of the hypothalamus and the retina, promoting sleep and inhibiting wake-promoting signals via interactions with its MT1 and MT2 receptors.[19]

Biological Mechanism of Melatonin 

Cancer suppression: Activating tumor suppressor genes such as p53, exerting oncostatic activity, modulating estrogen and androgens, immunomodulation, and increasing cytokine production, collectively contributing to cancer suppression.

Bone deposition: MT2 receptors found on osteoblasts suggest melatonin's involvement in regulating their function.

Metabolic disorders: Melatonin exhibits antioxidative and anti-inflammatory effects and regulates lipid and glucose metabolism.

Cardiovascular diseases: Melatonin demonstrates anti-hypertensive effects.

Gastrointestinal conditions: Melatonin displays antioxidative and anti-inflammatory effects.

Neurodegenerative disorders: Melatonin may activate mitochondrial cell survival pathways, potentially safeguarding against neurodegeneration induced by mitochondrial dysfunction. In addition, the drug regulates apoptosis and helps prevent vasoconstriction of cerebral arteries.

Mental disorders: Agomelatine, the melatonin receptor agonist, is recognized as an anxiolytic drug and is approved for treating depression in Europe. 

Pain syndromes: Melatonin exhibits anti-nociceptive, anti-inflammatory, and analgesic effects.

Reproductive functions: Melatonin is involved in several pathways that reduce the risk of complications, enhance gonadotropic secretion, and contribute to higher rates of mature oocytes and quality embryos.[20][21][22]

Pharmacokinetics

Absorption: The bioavailability of melatonin varies significantly, ranging from 1% to 74%, with likely dependence on the formulation and dosage.

Metabolism: Ninety percent of melatonin is metabolized in the liver, primarily mediated by the CYP1A2 enzyme, with a minor contribution from the CYP2C19 enzyme. Melatonin metabolism involves hydroxylation, converting it to 6-hydroxymelatonin. Subsequently, it undergoes conjugation with sulfuric or glucuronic acid before excretion in the urine. A smaller portion is excreted in feces.[23]

Distribution: Approximately 61% to 78% of melatonin binds to albumin, significantly influencing its distribution.[24]

Elimination: The elimination half-life of melatonin is relatively short, typically ranging from 1 to 2 hours, varying with the formulation used. In critically ill patients, medication absorption is accelerated while elimination is compromised, potentially resulting in altered pharmacokinetics and drug effects. Premature neonates often exhibit a prolonged half-life of melatonin compared to adults.[25]

Administration

Melatonin Content of Supplements

The FDA does not regulate supplements as rigorously as pharmaceutical drugs, as they are generally considered safe. However, this lack of oversight can raise concerns regarding the actual concentrations of supplements, including melatonin. A study examining 31 melatonin supplements discovered that the actual melatonin content varied widely, ranging from −83% to +478% of the labeled content.[26] 

Variable tablet content can make accurate dosing challenging and might contribute to the wide range of efficacy reported in various trials. One approach to ensure precise dosing is to seek supplements approved by the United States Pharmacopeia (USP)—an independent nonprofit organization. Choosing supplements labeled as "USP verified" can guarantee the quality and dosing accuracy of the supplements.

Melatonin Administration Routes  [27] [28]

Routes of melatonin administration include oral tablets, oral liquids, rectal suppositories, and transdermal patches.

Melatonin Formulations  [29]

Melatonin formulations include immediate-release, extended-release, and combined immediate and extended-release options.

Adult Dosage

• Effective dosing for melatonin is not well-defined as the FDA does not regulate it as a drug. Melatonin dosages used in studies have ranged from 0.1 mg to 10 mg, typically administered up to 2 hours before bedtime. The maximum dosage has not been defined in trials. 

• AASM provides recommendations regarding using melatonin for intrinsic circadian rhythm sleep-wake disorders. Specifically, for adults with delayed sleep-wake phase disorder (DSWPD), the AASM supports treatment with melatonin. Furthermore, for blind adults with non-24-hour sleep-wake rhythm disorder (N24SWD), the AASM suggests strategically timed melatonin administration. This can involve administering melatonin 1 hour before the patient's preferred bedtime or at a fixed time (for instance, 9 PM).[4]

Specific Patient Populations

Hepatic impairment: Clinicians should exercise caution when prescribing melatonin to patients with impaired liver functioning, as their ability to metabolize the medication may be reduced. However, based on several clinical trials, researchers have concluded that melatonin does not induce hepatotoxicity. The likelihood score of hepatotoxicity is rated as E, indicating an unlikely cause of clinically apparent liver injury.[30]

Renal impairment: Clinicians should exercise caution when prescribing melatonin to patients undergoing dialysis due to the increased risk of adverse effects resulting from impaired elimination of the medication.[31]

Pregnancy and breastfeeding considerations: Clinicians should advise pregnant and breastfeeding women to avoid using melatonin due to insufficient evidence of its safety in this population.[22][32]

Pediatric patients: Melatonin production usually starts around 3 months of age, with peak concentrations at 0.2 ng/mL during darkness. Supplementing infants with melatonin can result in higher levels than naturally produced by the body, and assumptions about safety based on its endogenous nature may be misleading. Therefore, the presence of elevated exogenous melatonin levels in postmortem pediatric cases warrants attention.[33]

Older patients: Although melatonin is generally considered safer than benzodiazepines, certain reports indicate a potential risk of falls and fractures in this population.[34]

Adverse Effects

Melatonin is relatively nontoxic, although some mild adverse effects have been reported with higher doses and extended-release formulations, including [35][36] drowsiness, daytime sedation, nausea, and headaches. No evidence suggests that patients develop tolerance to melatonin. However, impaired glucose tolerance has been reported in some cases.

Drug-Drug Interactions

CYP1A2 inhibitors: As melatonin is metabolized by CYP1A2, caution should be exercised when using it concurrently with potent CYP1A2 inhibitors such as fluvoxamine.[37]

Sedatives or hypnotics: Melatonin should not be combined with other drugs, including benzodiazepines, zolpidem, or eszopiclone, as this combination may result in excessive sedation.[38]

Contraindications

Despite being generally well-tolerated, melatonin supplements are rarely associated with angioedema. As melatonin is a naturally produced hormone, allergic reactions can also be caused by unregulated excipients in some formulations.[39][40] Clinicians should exercise caution when considering melatonin supplementation for patients with autoimmune diseases, such as rheumatoid arthritis or post-organ transplant. Melatonin stimulates the function of the immune system via the production of interleukins (ILs), including IL-1, IL-2, IL-6, and IL-12, interferon-gamma, helper T cells, cytotoxic T cells, and B- and T-cell precursors. However, the clinical significance of this effect remains undefined.[41]

Monitoring

Clinicians should monitor for improvements in insomnia in individuals and watch for adverse drug reactions, such as daytime sleepiness and headaches, associated with melatonin therapy when prescribing melatonin.[42]

Toxicity

Toxicity due to melatonin might present as follows:

• Melatonin demonstrates remarkably low acute toxicity according to findings from animal and human studies. At supraphysiological doses, it may result in minor adverse drug reactions such as headaches, rashes, gastritis, nightmares, and insomnia. Notably, researchers have not established an LD50 in animals even at high doses of up to 800 mg/kg, and melatonin does not cause fatalities in animal studies.

• Preliminary observations in humans suggest that long-term melatonin administration may be associated with reduced semen quality in healthy men, probably due to aromatase inhibition at the testicular level.[43]

• A recent analysis published in the morbidity and mortality report raises concerns, indicating a significant increase in annual pediatric melatonin overdose cases from 8000 in 2012 to more than 52,000 in 2021, with 15% of children requiring hospitalization due to overdoses.[44]

Enhancing Healthcare Team Outcomes

Insomnia is a common complaint observed in both outpatient and inpatient settings. Melatonin serves as a safe first-line sleep aid, potentially aiding in promoting a regular sleep cycle. Furthermore, melatonin is one of the few over-the-counter supplements that healthcare professionals can recommend for insomnia. Despite lacking FDA approval, melatonin is widely used for insomnia and jet lag disorders. Therefore, all pertinent healthcare providers must be knowledgeable about the mechanism, off-label indications, and adverse effects of melatonin.

Individuals often take melatonin as an over-the-counter supplement. However, healthcare providers can recommend melatonin for insomnia and jet lag disorders. Pharmacists should offer patient counseling regarding the potential adverse effects of melatonin and advise against its concurrent use with other central nervous system depressants, such as benzodiazepines or alcohol. In addition, it is crucial to inform patients that the FDA does not regulate supplements, and melatonin currently lacks FDA approval. Nursing staff can monitor the patient's response to melatonin therapy. Melatonin has shown efficacy in circadian rhythm sleep-wake disorders, and consultation with sleep medicine specialists is recommended for appropriate diagnosis and treatment.[4][45]

If insomnia persists despite melatonin therapy, the clinician should consider consulting a psychiatrist to explore potential underlying disorders. Furthermore, if primary sleep disorders are suspected, the patient may benefit from consultation with a sleep medicine specialist. The interprofessional collaboration of various healthcare providers, including clinicians, pharmacists, nurses, and specialists, is crucial for optimizing patient outcomes.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Neubauer DN. A review of ramelteon in the treatment of sleep disorders. Neuropsychiatr Dis Treat. 2008 Feb;4(1):69-79. [PMC free article: PMC2515902] [PubMed: 18728808]

2.

Neubauer DN. Tasimelteon for the treatment of non-24-hour sleep-wake disorder. Drugs Today (Barc). 2015 Jan;51(1):29-35. [PubMed: 25685859]

3.

Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8(5):e63773. [PMC free article: PMC3656905] [PubMed: 23691095]

4.

Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. 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. J Clin Sleep Med. 2015 Oct 15;11(10):1199-236. [PMC free article: PMC4582061] [PubMed: 26414986]

5.

Howell M, Avidan AY, Foldvary-Schaefer N, Malkani RG, During EH, Roland JP, McCarter SJ, Zak RS, Carandang G, Kazmi U, Ramar K. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2023 Apr 01;19(4):759-768. [PMC free article: PMC10071384] [PubMed: 36515157]

6.

Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, Jarbrink K, Nang EEK, Soh CK, Car J. Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action. BMC Med. 2018 Feb 05;16(1):18. [PMC free article: PMC5798185] [PubMed: 29397794]

7.

Gringras P, Nir T, Breddy J, Frydman-Marom A, Findling RL. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2017 Nov;56(11):948-957.e4. [PubMed: 29096777]

8.

Grima NA, Rajaratnam SMW, Mansfield D, Sletten TL, Spitz G, Ponsford JL. Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial. BMC Med. 2018 Jan 19;16(1):8. [PMC free article: PMC5774131] [PubMed: 29347988]

9.

Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520. [PubMed: 12076414]

10.

Gelfand AA, Goadsby PJ. The Role of Melatonin in the Treatment of Primary Headache Disorders. Headache. 2016 Sep;56(8):1257-66. [PMC free article: PMC5012937] [PubMed: 27316772]

11.

Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, Li HB. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017 Jun 13;8(24):39896-39921. [PMC free article: PMC5503661] [PubMed: 28415828]

12.

Sun H, Gusdon AM, Qu S. Effects of melatonin on cardiovascular diseases: progress in the past year. Curr Opin Lipidol. 2016 Aug;27(4):408-13. [PMC free article: PMC4947538] [PubMed: 27075419]

13.

Shukla M, Govitrapong P, Boontem P, Reiter RJ, Satayavivad J. Mechanisms of Melatonin in Alleviating Alzheimer's Disease. Curr Neuropharmacol. 2017;15(7):1010-1031. [PMC free article: PMC5652010] [PubMed: 28294066]

14.

Fernando S, Rombauts L. Melatonin: shedding light on infertility?--A review of the recent literature. J Ovarian Res. 2014 Oct 21;7:98. [PMC free article: PMC4209073] [PubMed: 25330986]

15.

Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005 Feb;9(1):11-24. [PubMed: 15649735]

16.

Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018 Aug;175(16):3190-3199. [PMC free article: PMC6057895] [PubMed: 29318587]

17.

Mul Fedele ML, Galiana MD, Golombek DA, Muñoz EM, Plano SA. Alterations in Metabolism and Diurnal Rhythms following Bilateral Surgical Removal of the Superior Cervical Ganglia in Rats. Front Endocrinol (Lausanne). 2017;8:370. [PMC free article: PMC5767240] [PubMed: 29375476]

18.

Ganguly S, Coon SL, Klein DC. Control of melatonin synthesis in the mammalian pineal gland: the critical role of serotonin acetylation. Cell Tissue Res. 2002 Jul;309(1):127-37. [PubMed: 12111543]

19.

Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008 Jul;85(3):335-53. [PubMed: 18571301]

20.

Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A. A Review of Melatonin, Its Receptors and Drugs. Eurasian J Med. 2016 Jun;48(2):135-41. [PMC free article: PMC4970552] [PubMed: 27551178]

21.

Ekmekcioglu C. Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother. 2006 Apr;60(3):97-108. [PubMed: 16527442]

22.

Voiculescu SE, Zygouropoulos N, Zahiu CD, Zagrean AM. Role of melatonin in embryo fetal development. J Med Life. 2014 Oct-Dec;7(4):488-92. [PMC free article: PMC4316124] [PubMed: 25713608]

23.

Ma X, Idle JR, Krausz KW, Gonzalez FJ. Metabolism of melatonin by human cytochromes p450. Drug Metab Dispos. 2005 Apr;33(4):489-94. [PubMed: 15616152]

24.

Carloni S, Proietti F, Rocchi M, Longini M, Marseglia L, D'Angelo G, Balduini W, Gitto E, Buonocore G. Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates. Molecules. 2017 Dec 01;22(12) [PMC free article: PMC6149762] [PubMed: 29194416]

25.

Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015 Aug;71(8):901-9. [PubMed: 26008214]

26.

Erland LA, Saxena PK. Melatonin Natural Health Products and Supplements: Presence of Serotonin and Significant Variability of Melatonin Content. J Clin Sleep Med. 2017 Feb 15;13(2):275-281. [PMC free article: PMC5263083] [PubMed: 27855744]

27.

Zetner D, Andersen LP, Rosenberg J. Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review. Drug Res (Stuttg). 2016 Apr;66(4):169-73. [PubMed: 26514093]

28.

Mistraletti G, Paroni R, Umbrello M, Moro Salihovic B, Coppola S, Froio S, Finati E, Gasco P, Savoca A, Manca D, Chiumello D, Reiter RJ, Iapichino G. Different routes and formulations of melatonin in critically ill patients. A pharmacokinetic randomized study. Clin Endocrinol (Oxf). 2019 Jul;91(1):209-218. [PubMed: 31004517]

29.

Gooneratne NS, Edwards AY, Zhou C, Cuellar N, Grandner MA, Barrett JS. Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults. J Pineal Res. 2012 May;52(4):437-45. [PMC free article: PMC3682489] [PubMed: 22348451]

30.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jan 10, 2020. Melatonin. [PubMed: 31643837]

31.

Lüdemann P, Zwernemann S, Lerchl A. Clearance of melatonin and 6-sulfatoxymelatonin by hemodialysis in patients with end-stage renal disease. J Pineal Res. 2001 Oct;31(3):222-7. [PubMed: 11589756]

32.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Feb 15, 2024. Melatonin. [PubMed: 30000923]

33.

Bishop-Freeman SC, Young KA, Labay LM, Beuhler MC, Hudson JS. Melatonin Supplementation in Undetermined Pediatric Deaths. J Anal Toxicol. 2022 Oct 14;46(8):808-816. [PubMed: 35639879]

34.

Should Melatonin Be Used as a Sleeping Aid for Elderly People? Can J Hosp Pharm. 2019 Jul-Aug;72(4):327-329. [PMC free article: PMC6699865] [PubMed: 31452545]

35.

Andersen LP, Gögenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75. [PubMed: 26692007]

36.

Rubio-Sastre P, Scheer FA, Gómez-Abellán P, Madrid JA, Garaulet M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep. 2014 Oct 01;37(10):1715-9. [PMC free article: PMC4173928] [PubMed: 25197811]

37.

Härtter S, Grözinger M, Weigmann H, Röschke J, Hiemke C. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther. 2000 Jan;67(1):1-6. [PubMed: 10668847]

38.

Otmani S, Demazières A, Staner C, Jacob N, Nir T, Zisapel N, Staner L. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol. 2008 Dec;23(8):693-705. [PubMed: 18763235]

39.

Patel RC, Kubicki SL, Cohen PR, MacFarlane DF. Melatonin-Associated Facial Swelling in an Oncology Patient: Case Report and Review of Swelling of the Face in Individuals With Head and Neck Cancer. Cureus. 2020 Oct 09;12(10):e10866. [PMC free article: PMC7652014] [PubMed: 33178519]

40.

Grigg-Damberger MM, Ianakieva D. Poor Quality Control of Over-the-Counter Melatonin: What They Say Is Often Not What You Get. J Clin Sleep Med. 2017 Feb 15;13(2):163-165. [PMC free article: PMC5263069] [PubMed: 28095978]

41.

Carrillo-Vico A, Lardone PJ, Alvarez-Sánchez N, Rodríguez-Rodríguez A, Guerrero JM. Melatonin: buffering the immune system. Int J Mol Sci. 2013 Apr 22;14(4):8638-83. [PMC free article: PMC3645767] [PubMed: 23609496]

42.

Besag FMC, Vasey MJ, Lao KSJ, Wong ICK. Adverse Events Associated with Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review. CNS Drugs. 2019 Dec;33(12):1167-1186. [PubMed: 31722088]

43.

Luboshitzky R, Shen-Orr Z, Nave R, Lavi S, Lavie P. Melatonin administration alters semen quality in healthy men. J Androl. 2002 Jul-Aug;23(4):572-8. [PubMed: 12065466]

44.

Lelak K, Vohra V, Neuman MI, Toce MS, Sethuraman U. Pediatric Melatonin Ingestions - United States, 2012-2021. MMWR Morb Mortal Wkly Rep. 2022 Jun 03;71(22):725-729. [PMC free article: PMC9169525] [PubMed: 35653284]

45.

Palagini L, Manni R, Aguglia E, Amore M, Brugnoli R, Bioulac S, Bourgin P, Micoulaud Franchi JA, Girardi P, Grassi L, Lopez R, Mencacci C, Plazzi G, Maruani J, Minervino A, Philip P, Royant Parola S, Poirot I, Nobili L, Biggio G, Schroder CM, Geoffroy PA. International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders. Front Psychiatry. 2021;12:688890. [PMC free article: PMC8222620] [PubMed: 34177671]

Disclosure: Rosemary Savage declares no relevant financial relationships with ineligible companies.

Disclosure: Nowera Zafar declares no relevant financial relationships with ineligible companies.

Disclosure: Sandesh Yohannan declares no relevant financial relationships with ineligible companies.

Disclosure: John-Mark Miller declares no relevant financial relationships with ineligible companies.