{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T11:45:23Z","timestamp":1792151123687,"version":"4.4.0"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T00:00:00Z","timestamp":1653609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Since 2015, the North Carolina Office of the Chief Medical Examiner has investigated seven deaths of infants and toddlers, aged 2\u2009months to 3\u2009years, with exogenous melatonin detected upon toxicological analysis. Melatonin concentrations ranged from 3 to 1,400\u2009ng\/mL in postmortem whole blood. While the cause and the manner of all seven deaths were classified as undetermined, the analytical findings are noteworthy. Melatonin is generally considered a safe, natural product appearing in many over-the-counter supplements geared toward young children to facilitate calmness and improve sleep. Melatonin is a neurohormone, which regulates not only circadian rhythms and natural sleep but also other physiological functions. Endogenous melatonin production, derived from essential amino acid metabolism, does not begin until pineal gland maturation at \u223c3 months of age with concentrations in plasma peaking during periods of darkness at \u223c0.2\u2009ng\/mL. Administering commercially available melatonin supplements to infants results in levels substantially greater than endogenous sources, which should not be assumed to be safe just because of their endogenous nature. The finding of exogenous concentrations in some postmortem pediatric cases warrants attention. Several topics of interest surrounding these postmortem melatonin findings will be considered, such as minimal regulatory control over commercial products as well as the potential impact on hazardous sleeping conditions. This manuscript will outline the physiological effects of melatonin and detail the case studies from the North Carolina medical examiner system. Forensic toxicology laboratories should consider including melatonin at exogenous concentrations in their testing schemes for appropriate postmortem infant and toddler cases.<\/jats:p>","DOI":"10.1093\/jat\/bkac033","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T19:34:01Z","timestamp":1654025641000},"page":"808-816","source":"Crossref","is-referenced-by-count":24,"title":["Melatonin Supplementation in Undetermined Pediatric Deaths"],"prefix":"10.1093","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0900-457X","authenticated-orcid":false,"given":"Sandra C","family":"Bishop-Freeman","sequence":"first","affiliation":[{"name":"North Carolina Office of Chief Medical Examiner, Division of Public Health , Division of Public Health, 4312 District Dr., Raleigh, NC 27607, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina , 160 Medical Drive, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry A","family":"Young","sequence":"additional","affiliation":[{"name":"North Carolina Office of Chief Medical Examiner, Division of Public Health , Division of Public Health, 4312 District Dr., Raleigh, NC 27607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M","family":"Labay","sequence":"additional","affiliation":[{"name":"NMS Labs , 200 Welsh Rd, Horsham, PA 19044, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C","family":"Beuhler","sequence":"additional","affiliation":[{"name":"North Carolina Poison Control , 5000 Airport Center Pkwy Suite B2, Charlotte, NC 28208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason S","family":"Hudson","sequence":"additional","affiliation":[{"name":"North Carolina Office of Chief Medical Examiner, Division of Public Health , Division of Public Health, 4312 District Dr., Raleigh, NC 27607, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina , 160 Medical Drive, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"2022101415465652800_R1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.sleep.2007.10.007","article-title":"Melatonin receptors: role on sleep and circadian rhythm regulation","volume":"8 Suppl 3","author":"Dubocovich","year":"2007","journal-title":"Sleep Medicine"},{"key":"2022101415465652800_R2","doi-asserted-by":"crossref","first-page":"B293","DOI":"10.1093\/gerona\/53A.4.B293","article-title":"Endogenous melatonin levels and the fate of exogenous melatonin: age effects","volume":"53","author":"Zhdanova","year":"1998","journal-title":"The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences"},{"key":"2022101415465652800_R3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1748-7161-2-6","article-title":"Melatonin the \u2018light of night\u2019 in human biology and adolescent idiopathic scoliosis","volume":"2","author":"Grivas","year":"2007","journal-title":"Scoliosis"},{"key":"2022101415465652800_R4","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1111\/bcp.12092","article-title":"Pharmacokinetics of melatonin in preterm infants","volume":"76","author":"Merchant","year":"2013","journal-title":"British Journal of Clinical Pharmacology"},{"key":"2022101415465652800_R5","first-page":"325","article-title":"Melatonin: exceeding expectations","volume":"29","author":"Reiter","year":"2014","journal-title":"Physiology (Bethesda, Md.)"},{"key":"2022101415465652800_R6","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22031490","article-title":"Melatonin: from pharmacokinetics to clinical use in autism spectrum disorder","volume":"22","author":"Lalanne","year":"2021","journal-title":"International Journal of Molecular Sciences"},{"key":"2022101415465652800_R7","first-page":"315","article-title":"Sleep-related melatonin use in healthy children","volume":"62","author":"Janjua","year":"2016","journal-title":"Canadian Family Physician"},{"key":"2022101415465652800_R8","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.chc.2009.04.009","article-title":"Pharmacologic treatment of pediatric insomnia","volume":"18","author":"Owens","year":"2009","journal-title":"Child and Adolescent Psychiatric Clinics of North America"},{"key":"2022101415465652800_R9","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/jat\/23.3.159","article-title":"Melatonin: aeromedical, toxicopharmacological, and analytical aspects","volume":"23","author":"Sanders","year":"1999","journal-title":"Journal of Analytical Toxicology"},{"key":"2022101415465652800_R10","article-title":"Melatonin mania","volume-title":"Newsweek","author":"Gowley","year":"1995"},{"key":"2022101415465652800_R11","article-title":"Americans have turned to melatonin to soothe pandemic-induced stress. Experts worry high demand, little federal oversight, and insufficient data leave the industry ripe for scams","volume-title":"Insider","author":"Akhtar","year":"2021"},{"key":"2022101415465652800_R12","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1001\/jama.2021.23652","article-title":"Trends in use of melatonin supplements among US adults, 1999-2018","volume":"327","author":"Li","year":"2022","journal-title":"JAMA"},{"key":"2022101415465652800_R13","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1007\/BF02244899","article-title":"Effect of pharmacological daytime doses of melatonin on human mood and performance","volume":"112","author":"Dollins","year":"1993","journal-title":"Psychopharmacology"},{"key":"2022101415465652800_R14","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/0024-3205(85)90412-6","article-title":"Oral administration and distribution of melatonin in human serum, saliva and urine","volume":"37","author":"Vakkuri","year":"1985","journal-title":"Life Sciences"},{"key":"2022101415465652800_R15","first-page":"1214","volume-title":"Disposition of Toxic Drugs and Chemicals in Man","author":"Baselt","year":"2014","edition":"10th"},{"key":"2022101415465652800_R16","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1023\/A:1020107915919","article-title":"Gastrointestinal melatonin: localization, function, and clinical relevance","volume":"47","author":"Bubenik","year":"2002","journal-title":"Digestive Diseases and Sciences"},{"key":"2022101415465652800_R17","doi-asserted-by":"crossref","first-page":"163","DOI":"10.5664\/jcsm.6434","article-title":"Poor quality control of over-the-counter melatonin: what they say is often not what you get","volume":"13","author":"Grigg-Damberger","year":"2017","journal-title":"Journal of Clinical Sleep Medicine"},{"key":"2022101415465652800_R18","article-title":"Regulation of dietary supplements","author":"Dabrowska","year":"2014"},{"key":"2022101415465652800_R19","doi-asserted-by":"crossref","first-page":"4","DOI":"10.5863\/1551-6776-26.1.4","article-title":"Melatonin use in pediatrics: evaluating the discrepancy in evidence based on country and regulations regarding production","volume":"26","author":"Skrzelowski","year":"2021","journal-title":"The Journal of Pediatric Pharmacology and Therapeutics"},{"key":"2022101415465652800_R20","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s40261-015-0368-5","article-title":"The safety of melatonin in humans","volume":"36","author":"Andersen","year":"2016","journal-title":"Clinical Drug Investigation"},{"key":"2022101415465652800_R21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1177\/1925362119851107","article-title":"The importance of melatonin detection in pediatric deaths","volume":"9","author":"Labay","year":"2019","journal-title":"Academic Forensic Pathology"},{"key":"2022101415465652800_R22","first-page":"1282","article-title":"2020 Annual Report of the American Association of Poison Control Centers\u2019 National Poison Data System (NPDS): 38th Annual Report","volume-title":"Clinical Toxicology","author":"Gummin","year":"2021"},{"key":"2022101415465652800_R23","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/jpc.12840","article-title":"Potential safety issues in the use of the hormone melatonin in paediatrics","volume":"51","author":"Kennaway","year":"2015","journal-title":"Journal of Paediatrics and Child Health"},{"key":"2022101415465652800_R24","article-title":"Thinking about Melatonin to Help Kids Sleep? Ask Your Pediatrician. American Academy of Pediatrics","author":"Whalen","year":"2021"},{"key":"2022101415465652800_R25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1542\/peds.2017-0087","article-title":"Variations in cause-of-death determination for sudden unexpected infant deaths","volume":"140","author":"Shapiro-Mendoza","year":"2017","journal-title":"Pediatrics"},{"key":"2022101415465652800_R26","article-title":"Centers for Disease Control and Prevention","author":"Sudden Unexpected Infant Death and Sudden Infant Death Syndrome","year":"2021"},{"key":"2022101415465652800_R27","volume-title":"SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future","author":"Shapiro-Mendoza","year":"2018"},{"key":"2022101415465652800_R28","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1097\/01.JAA.0000546475.33947.44","article-title":"Preventing sudden infant death syndrome and other sleep-related infant deaths","volume":"31","author":"Maged","year":"2018","journal-title":"Journal of the American Academy of Physician Assistants"},{"key":"2022101415465652800_R29","doi-asserted-by":"crossref","DOI":"10.1016\/j.forsciint.2019.109962","article-title":"Case report of sudden death in a twin infant given melatonin supplementation: a challenging interpretation of postmortem toxicology","volume":"304","author":"Shimomura","year":"2019","journal-title":"Forensic Science International"},{"key":"2022101415465652800_R30","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1093\/jat\/bkw069","article-title":"Loperamide-related deaths in North Carolina","volume":"40","author":"Bishop-Freeman","year":"2016","journal-title":"Journal of Analytical Toxicology"},{"key":"2022101415465652800_R31","doi-asserted-by":"crossref","DOI":"10.1542\/peds.2016-2940","article-title":"SIDS and other sleep-related infant deaths: evidence base for 2016 updated recommendations for a safe infant sleeping environment","volume":"138","author":"Moon","year":"2016","journal-title":"Pediatrics"},{"key":"2022101415465652800_R32","doi-asserted-by":"crossref","first-page":"e406","DOI":"10.1542\/peds.2014-0401","article-title":"Sleep environment risks for younger and older infants","volume":"134","author":"Colvin","year":"2014","journal-title":"Pediatrics"},{"key":"2022101415465652800_R33","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2019.00158","article-title":"Tryptophan metabolic pathways and brain serotonergic activity: a comparative review","volume":"10","author":"H\u00f6glund","year":"2019","journal-title":"Frontiers in Endocrinology"},{"key":"2022101415465652800_R34","doi-asserted-by":"crossref","first-page":"189","DOI":"10.2174\/187152412802430129","article-title":"Melatonin and synthetic melatonergic agonists: actions and metabolism in the central nervous system","volume":"12","author":"Hardeland","year":"2012","journal-title":"Central Nervous System Agents in Medicinal Chemistry"},{"key":"2022101415465652800_R35","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1515\/bmc-2017-0009","article-title":"Breastfeeding and the gut-brain axis: is there a role for melatonin?","volume":"8","author":"Anderson","year":"2017","journal-title":"Biomolecular Concepts"},{"key":"2022101415465652800_R36","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1124\/dmd.115.067413","article-title":"Melatonin supports CYP2D-mediated serotonin synthesis in the brain","volume":"44","author":"Haduch","year":"2016","journal-title":"Drug Metabolism and Disposition"},{"key":"2022101415465652800_R37","doi-asserted-by":"crossref","first-page":"275","DOI":"10.5664\/jcsm.6462","article-title":"Melatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content","volume":"13","author":"Erland","year":"2017","journal-title":"Journal of Clinical Sleep Medicine"},{"key":"2022101415465652800_R38","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.1002\/art.30514","article-title":"Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan","volume":"63","author":"Allen","year":"2011","journal-title":"Arthritis and Rheumatism"},{"key":"2022101415465652800_R39","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1001\/jama.1990.03450130070029","article-title":"Eosinophilia-myalgia syndrome. Results of national surveillance","volume":"264","author":"Swygert","year":"1990","journal-title":"JAMA"},{"key":"2022101415465652800_R40","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1021\/tx970202h","article-title":"Structural characterization of contaminants found in commercial preparations of melatonin: similarities to case-related compounds from L-tryptophan associated with eosinophilia-myalgia syndrome","volume":"11","author":"Williamson","year":"1998","journal-title":"Chemical Research in Toxicology"},{"key":"2022101415465652800_R41","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.pharmthera.2005.06.004","article-title":"Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan","volume":"109","author":"Turner","year":"2006","journal-title":"Pharmacology & Therapeutics"},{"key":"2022101415465652800_R42","first-page":"488","article-title":"Role of melatonin in embryo fetal development","volume":"7","author":"Voiculescu","year":"2014","journal-title":"Journal of Medicine and Life"},{"key":"2022101415465652800_R43","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0379-0738(90)90234-P","article-title":"Melatonin concentrations in the sudden infant death syndrome","volume":"45","author":"Sturner","year":"1990","journal-title":"Forensic Science International"},{"key":"2022101415465652800_R44","doi-asserted-by":"crossref","first-page":"7695","DOI":"10.1073\/pnas.1617374114","article-title":"High serum serotonin in sudden infant death syndrome","volume":"114","author":"Haynes","year":"2017","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"2022101415465652800_R45","doi-asserted-by":"crossref","first-page":"434","DOI":"10.2174\/1570159X14666161228122115","article-title":"Melatonin: pharmacology, functions and therapeutic benefits","volume":"15","author":"Tordjman","year":"2017","journal-title":"Current Neuropharmacology"},{"key":"2022101415465652800_R46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2011\/892624","article-title":"Clinical uses of melatonin in pediatrics","volume":"2011","author":"S\u00e1nchez-Barcel\u00f3","year":"2011","journal-title":"International Journal of Pediatrics"},{"key":"2022101415465652800_R47","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12583","article-title":"Daytime melatonin and light independently affect human alertness and body temperature","volume":"67","author":"Lok","year":"2019","journal-title":"Journal of Pineal Research"},{"key":"2022101415465652800_R48","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1046\/j.1365-2826.2003.00989.x","article-title":"Role of melatonin in the regulation of human circadian rhythms and sleep","volume":"15","author":"Cajochen","year":"2003","journal-title":"Journal of Neuroendocrinology"},{"key":"2022101415465652800_R49","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/WNF.0000000000000355","article-title":"Hypothermia associated with melatonin ingestion in a child with autism","volume":"42","author":"Erden","year":"2019","journal-title":"Clinical Neuropharmacology"},{"key":"2022101415465652800_R50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13052-019-0714-y","article-title":"A solution based on melatonin, tryptophan, and vitamin B6 (Melamil Tripto\u00a9) for sedation in newborns during brain MRI","volume":"45","author":"Picone","year":"2019","journal-title":"Italian Journal of Pediatrics"},{"key":"2022101415465652800_R51","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1097\/PCC.0000000000002346","article-title":"Hypothermia plus melatonin in asphyctic newborns: a randomized-controlled pilot study","volume":"21","author":"Jerez-Calero","year":"2020","journal-title":"Pediatric Critical Care Medicine"},{"key":"2022101415465652800_R52","volume-title":"Drugs and Lactation Database (LactMed)","author":"Melatonin","year":"2006"},{"key":"2022101415465652800_R53","doi-asserted-by":"crossref","first-page":"e796","DOI":"10.1542\/peds.2013-1985","article-title":"The transfer of drugs and therapeutics into human breast milk: an update on selected topics","volume":"132","author":"Sachs","year":"2013","journal-title":"Pediatrics"},{"key":"2022101415465652800_R54","article-title":"Seattle Children\u2019s Hospital Research Foundation","author":"Bottle-Feeding (Formula) Questions","year":"2022"},{"key":"2022101415465652800_R55","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1007\/s40263-019-00680-w","article-title":"Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: a systematic review","volume":"33","author":"Besag","year":"2019","journal-title":"CNS Drugs"},{"key":"2022101415465652800_R56","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1007\/s00787-020-01598-1","article-title":"Pediatric use of prescribed melatonin in Sweden 2006-2017: a register based study","volume":"30","author":"Kimland","year":"2021","journal-title":"European Child & Adolescent Psychiatry"},{"key":"2022101415465652800_R57","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1210\/er.2018-00084","article-title":"Melatonin as a hormone: new physiological and clinical insights","volume":"39","author":"Cipolla-Neto","year":"2018","journal-title":"Endocrine Reviews"}],"container-title":["Journal of Analytical Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jat\/advance-article-pdf\/doi\/10.1093\/jat\/bkac033\/44245455\/bkac033.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/46\/8\/808\/46535599\/bkac033.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/46\/8\/808\/46535599\/bkac033.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T21:28:11Z","timestamp":1665782891000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jat\/article\/46\/8\/808\/6593956"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,27]]},"references-count":57,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,5,27]]},"published-print":{"date-parts":[[2022,10,14]]}},"URL":"https:\/\/doi.org\/10.1093\/jat\/bkac033","relation":{},"ISSN":["0146-4760","1945-2403"],"issn-type":[{"value":"0146-4760","type":"print"},{"value":"1945-2403","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,10,1]]},"published":{"date-parts":[[2022,5,27]]}}}