Safety of higher doses of melatonin in adults: A systematic review and meta‐analysis
Zoe Menczel Schrire, Craig L Phillips, Julia L Chapman, Shantel L Duffy, Grace Wong, Angela L D’rozario, Maria Comas, Isabelle Raisin, Bandana Saini, Christopher J Gordon, Andrew C Mckinnon, Sharon L Naismith, Nathaniel S Marshall, Ronald R Grunstein, Camilla M Hoyos
Journal of Pineal Research, doi:10.1111/jpi.12782
Melatonin is commonly used for sleep and jetlag at low doses. However, there is less documentation on the safety of higher doses, which are being increasingly used for a wide variety of conditions, including more recently COVID-19 prevention and treatment. The aim of this review was to investigate the safety of higher doses of melatonin in adults. Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020. Randomised controlled trials investigating high-dose melatonin (≥10 mg) in human adults over 30 years of age were included. Two investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of three investigators. 79 studies were identified with a total of 3861 participants. Studies included a large range of medical conditions. The metaanalysis was pooled data using a random effects model. The outcomes examined were the number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs. A total of 29 studies (37%) made no mention of the presence or absence of AEs. Overall, only four studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset, melatonin did not cause a detectable increase in SAEs (Rate Ratio = 0.88 [0.52, 1.
References
Abdelgadir, Gordon, Akobeng, Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis, Arch Dis Child,
doi:10.1136/archdischild-2017-314181Andersen, Kücükakin, Werner, Rosenberg, Gögenur, Absence of analgesic effect of intravenous melatonin administration during daytime after laparoscopic cholecystectomy: a randomized trial, J Clin Anesth,
doi:10.1016/j.jclinane.2014.03.008Anderson, Lincoln, Wu, Endocrinology: melatonin potentiates testosterone-induced suppression of luteinizing hormone secretion in normal men, Hum Reprod
Besag, Vasey, Lao, Wong, Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: a systematic review, CNS Drugs,
doi:10.1007/s40263-019-00680-wBlack, Clarke, Barnes, Stussman, Nahin, Use of complementary health approaches among children aged 4-17 years in the United States: National Health Interview Survey, 2007-2012, Natl Health Stat Rep
Bourne, Mills, Minelli, Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial, J Crit Care
Buscemi, Vandermeer, Hooton, The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis, J Gen Intern Med,
doi:10.1111/j.1525-1497.2005.0243.xCagnacci, Elliott, Amplification of pulsatile LH secretion by exogenous melatonin in women, J Clin Endocrinol Metab
Cagnacci, Soldani, Melatonin enhances cortisol levels in aged women: reversible by estrogens, J Pineal Res
Cagnacci, Soldani, Ss, Melatonin enhances cortisol levels in aged but not young women, Eur J Endocrinol
Carman, Post, Buswell, Goodwin, Negative effects of melatonin on depression, Am J Psychiatry
Castro, Carrizo, De Rincón, Effectiveness of melatonin in tardive dyskinesia, Invest Clin
Celinski, Konturek, Konturek, Melatonin or ltryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole, J Pineal Res
Celinski, Konturek, Slomka, Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease-14 months follow up, J Physiol Pharmacol
Cerea, Vaghi, Ardizzoia, Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations, Anticancer Res
Chiodera, Volpi, Capretti, Giuliani, Caffarri et al., Melatonin inhibits oxytocin response to insulin-induced hypoglycemia, but not to angiotensin II in normal men, J Neural Transm
Chojnacki, Błońska, Chojnacki, The effects of melatonin on elevated liver enzymes during statin treatment, Biomed Res Int
Clarke, Black, Stussman, Barnes, Nahin, Trends in the use of complementary health approaches among adults: United States, 2002-2012, Natl Health Stat Rep
Coiro, Volpi, Capretti, Different effects of naloxone on the growth hormone response to melatonin and pyridostigmine in normal men, Metabolism
Council, Dietary Supplements: A Framework for Evaluating Safety
De Zanette, Vercelino, Laste, Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dummy, controlled trial, BMC Pharmacol Toxicol
Dolberg, Hirschmann, Grunhaus, Melatonin for the treatment of sleep disturbances in major depressive disorder, Am J Psychiatry
Dowling, Mastick, Colling, Carter, Singer et al., Melatonin for sleep disturbances in Parkinson's disease, Sleep Med
Emser, Dechoux, Weiland, Wirz-Justice, Melatonin decreases the amplitude of the b-wave of the human electroretinogram, Experientia
Erland, Saxena, Melatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content, J Clin Sleep Med,
doi:10.5664/jcsm.6462Fabbro, Dev, Hui, Palmer, Bruera, Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial, J Clin Oncol
Fernando, Wallace, Vollenhoven, Melatonin in assisted reproductive technology: a pilot double-blind randomized placebo-controlled clinical trial. Clinical trial, Front Endocrinol,
doi:10.3389/fendo.2018.00545Foley, Steel, Adverse events associated with oral administration of melatonin: a critical systematic review of clinical evidence, Complement Ther Med,
doi:10.1016/j.ctim.2018.11.003Forrest, Mackay, Stoy, Stone, Darlington, Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin, Br J Clin Pharmacol
Fraschini, Cesarani, Alpini, Esposti, Stankov, Melatonin influences human balance, Neurosignals
Ghaderi, Banafshe, Mirhosseini, The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment, Addict Biol
Ghielmini, Pagani, Jong, Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer, Br J Cancer
Gonciarz, Gonciarz, Bielanski, The effects of longterm melatonin treatment on plasma liver enzymes levels and plasma concentrations of lipids and melatonin in patients with nonalcoholic steatohepatitis: a pilot study, J Physiol Pharmacol
Grunhaus, Hirschman, Dolberg, Schreiber, Dannon, Coadministration of melatonin and fluoxetine does not improve the 3-month outcome following ECT, J ECT
Gögenur, Kücükakin, Jensen, Reiter, Rosenberg, Melatonin reduces cardiac morbidity and markers of myocardial ischemia after elective abdominal aortic aneurism repair: a randomized, placebo-controlled, clinical trial, J Pineal Res,
doi:10.1111/jpi.12138Hartz, Furu, Bratlid, Handal, Skurtveit, Hypnotic drug use among 0-17 year olds during 2004-2011: a nationwide prescription database study, Scand J Public Health
Hernández-Velázquez, Camara-Lemarroy, González-González, Effects of melatonin on the acute inflammatory response associated with endoscopic retrograde cholangiopancreatography: a randomized, doubleblind, placebo-controlled trial, Rev Gastroenterol Mex
Higgins, Altman, Gotzsche, The Cochrane Collaboration's tool for assessing risk of bias in randomised trials, BMJ
Hoffmann, Farker, Dittgen, Hoffmann, A melatonin preparation with a pulsatile liberation pattern: a new form of melatonin in replacement therapy, Neurosignals
Ismail, Mowafi, Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia, Anesth Analg
Juybari, Pourhanifeh, Hosseinzadeh, Hemati, Mehrzadi, Melatonin potentials against viral infections including COVID-19: current evidence and new findings, Virus Res,
doi:10.1016/j.virusres.2020.198108Kimland, Bardage, Järleborg, Ljung, Iliadou, Pediatric use of prescribed melatonin in Sweden 2006-2017: a register based study, Eur Child Adolesc Psychiatry
Kirby, Clayton, Rivera, Comperatore, Melatonin and the reduction or alleviation of stress 1, J Pineal Res
Kücükakin, Klein, Lykkesfeldt, Reiter, Rosenberg et al., No effect of melatonin on oxidative stress after laparoscopic cholecystectomy: a randomized placebocontrolled trial, Acta Anaesthesiol Scand,
doi:10.1111/j.1399-6576.2010.02294.xKücükakin, Wilhelmsen, Lykkesfeldt, Reiter, Rosenberg et al., No effect of melatonin to modify surgical-stress response after major vascular surgery: a randomised placebo-controlled trial, Eur J Vasc Endovasc Surg,
doi:10.1016/j.ejvs.2010.06.014Leibenluft, Feldman-Naim, Turner, Wehr, Rosenthal, Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder, J Clin Psychiatry,
doi:10.4088/jcp.v58n0902Lemoine, Zisapel, Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia, Expert Opin Pharmacother,
doi:10.1517/14656566.2012.667076Lissoni, Pelizzoni, Perego, A study of heart-pineal interactions: atrial natriuretic peptide response to melatonin administration in healthy humans, J Pineal Res,
doi:10.1111/j.1600-079x.1990.tb00705.xLu, Liu, Li, Yang, Zhang, Melatonin therapy adds extra benefit to varicecelectomy in terms of sperm parameters, hormonal profile and total antioxidant capacity: a placebocontrolled, double-blind trial, Andrologia,
doi:10.1111/and.13033Madsen, Isbrand, Andersen, The effect of MElatonin on Depressive symptoms, Anxiety, CIrcadian and Sleep disturbances in patients after acute coronary syndrome (MEDACIS): study protocol for a randomized controlled trial, Trials,
doi:10.1186/s13063-017-1806-xMadsen, Zahid, Hansen, The effect of melatonin on depressive symptoms and anxiety in patients after acute coronary syndrome: The MEDACIS randomized clinical trial, J Psychiatr Res,
doi:10.1016/j.jpsychires.2019.09.014Martinez-Nicolas, De, Galván, The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes, Chronobiol Int,
doi:10.3109/07420528.2015.1069830Mills, Wu, Seely, Guyatt, Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis, J Pineal Res,
doi:10.1111/j.1600-079X.2005.00258.xOnseng, Johns, Khuayjarernpanishk, Beneficial effects of adjuvant melatonin in minimizing oral mucositis complications in head and neck cancer patients receiving concurrent chemoradiation, J Altern Complement Med,
doi:10.1089/acm.2017.0081Ostadmohammadi, Soleimani, Bahmani, The effects of melatonin supplementation on parameters of mental health, glycemic control, markers of cardiometabolic risk, and oxidative stress in diabetic hemodialysis patients: a randomized, double-blind, placebo-controlled trial, J Ren Nutr,
doi:10.1053/j.jrn.2019.08.003Paccotti, Terzolo, Torta, Acute administration of melatonin at two opposite circadian stages does not change responses to gonadotropin releasing hormone, thyrotropin releasing hormone and ACTH in healthy adult males, J Endocrinol Invest,
doi:10.1007/bf03348172Page, Mckenzie, Bossuyt, The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews, Center for Open Science
Pappolla, Chyan, Poeggeler, An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer's disease, J Neural Transm
Persson, Glimelius, Rönnelid, Nygren, Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomized pilot study, Nutrition,
doi:10.1016/j.nut.2004.05.026Quera-Salva, Claustrat, Melatonin: physiological and pharmacological aspects related to sleep: the interest of a prolonged-release formulation (Circadin( ® )) in insomnia, Encephale,
doi:10.1016/j.encep.2018.06.005Ramos, Farré-Alins, Egea, López-Muñoz, Reiter et al., Melatonin's efficacy in stroke patients; a matter of dose? A systematic review, Toxicol Appl Pharmacol,
doi:10.1111/jpi.12782byCochraneChinaRaygan, Ostadmohammadi, Bahmani, Reiter, Asemi, Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: a randomized, double-blind, placebocontrolled trial, Clin Nutr,
doi:10.1016/j.clnu.2017.12.004Santamaria, Giorgianni, Myo-inositol and melatonin in the menopausal transition, Gynecol Endocrinol
Scheuer, Pommergaard, Rosenberg, Gögenur, Dose dependent sun protective effect of topical melatonin: a randomized, placebo-controlled, double-blind study, J Dermatol Sci,
doi:10.1016/j.jdermsci.2016.08.007Sookprasert, Johns, Phunmanee, Melatonin in patients with cancer receiving chemotherapy: a randomized, double-blind, placebo-controlled trial, Anticancer Res
Steffenak, Wilde-Larsson, Nordström, Skurtveit, Hartz, Increase in psychotropic drug use between 2006 and 2010 among adolescents in Norway: a nationwide prescription database study, Clin Epidemiol
Sterne, Savović, Page, RoB 2: a revised tool for assessing risk of bias in randomised trials, BMJ
Sugden, Psychopharmacological effects of melatonin in mouse and rat, J Pharmacol Exp Ther
Sánchez-López, Ortiz, Pacheco-Moises, Efficacy of melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing remitting multiple sclerosis, Arch Med Res
Yousaf, Seet, Venkatraghavan, Abrishami, Chung et al., Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials, Anesthesiology,
doi:10.1097/ALN.0b013e3181e7d626
