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Monograph: Melatonin - Oral

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For Melatonin products with a sublingual route of administration, please use the 'Melatonin-Sublingual' monograph. This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredient. Notes: (i) Text in parentheses is additional optional information which can be included on the PLA and product label at the applicant's discretion. (ii) The solidus (/) indicates that the terms and/or the statements are synonymous. Either term or statement may be selected by the applicant.

Date: 2013-05-13

NHPID Name

Melatonin (O'Neil et al. 2012)

Proper Name(s)

Common Name(s)

Melatonin ( Merck 2012 , Buscemi et al. 2004 )

Source Material

Melatonin (Merck 2012)

Route Of Administration

Oral ( Buscemi et al. 2004 )

Dosage Form(s)

  • The acceptable pharmaceutical dosage forms include, but are not limited to capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets.
  • This monograph is not intended to include foods or food-like dosage forms such as bars, chewing gums or beverages.

Use(s) or Purpose(s)

Statement(s) to the effect of:

Dose(s)

Adults:

Jet lag
Dose(s): 0.5 - 10 Milligrams per day
Directions For Use:

sleep restriction/altered sleep schedule; delayed sleep phase disorder; sleep-wake cycle
Dose(s): 0.1 - 10 Milligrams 1 time per day
Directions For Use:


See Appendix 1 for examples of dosage preparations, frequencies of use and directions for use, according to cited references. The purpose of Appendix 1 is to provide guidance to industry.

Duration of use

sleep restriction/altered sleep schedule: For use beyond 4 weeks, consult a health care practitioner  (Buscemi et al. 2004, IOM 2004)
Jet lag: For occasional short-term use  (Herxheimer and Petrie 2009)
delayed sleep phase disorder: For use beyond 4 weeks, consult a health care practitioner  (Buscemi et al. 2004, IOM 2004)
sleep-wake cycle: For use beyond 4 weeks, consult a health care practitioner  (Buscemi et al. 2004, IOM 2004)

Risk Information

Statement(s) to the effect of:

Caution(s) and Warning(s):

Contraindication(s):
If you are pregnant or breastfeeding, do not use this product  (IOM 2004)

Known Adverse Reaction(s):
  • Mild gastrointestinal symptoms (nausea, vomiting, or cramping) have been known to occur in which case, discontinue use  (Herxheimer and Petrie 2009)
  • Rare allergic reactions have been known to occur in which case, discontinue use  (Herxheimer and Petrie 2009)

Non-medicinal ingredients

Must be chosen from the current Natural Health Products Ingredients Database and must meet the limitations outlined in the database.

Specifications

  • The finished product specifications must be established in accordance with the requirements described in the NHPD Quality of Natural Health Products Guide.
  • The medicinal ingredient must comply with the requirements outlined in the Natural Health Products Ingredient Database (NHPID).
  • The medicinal ingredient must comply with the requirements outlined in the Natural Health Products Ingredients Database (NHPID). In addition, the medicinal ingredient may comply with the specifications outlined in the Melatonin monograph of the British Pharmacopoeia.

References cited

  • Andrade C, Srihari BS, Reddy KP, Chandramma L. Melatonin in medically ill patients with insomnia: a double blind placebo-controlled study. Journal of Clinical Psychiatry 2001;62(1):41-5
  • Arangino S, Cagnacci A, Angiolucci M, Vacca AMB, Longu G, Volpe A, Melis GB. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. American Journal of Cardiology 1999; 83(9):1417-1419.
  • Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin improves sleep in healthy middle-aged subjects. Psychopharmacology (Berlin) 1996;126(2):179-81
  • Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Annals of Medicine 1998;30(1):122-30
  • Brown GM, Pandi-Perumal SR, Trakht I, Cardinali DP. Melatonin and its relevance to jet lag. Travel Medicine and Infectious Disease 2009;7:69-81.
  • Brusco LI, Fainstein I, Marquez M, Cardinali DP. Effect of melatonin in selected populations of sleep-disturbed patients. Biological Signals and Receptors 1999;8(1-2):126-31
  • Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, Ford I. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Medicine Reviews 2005;9:41-50
  • Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T. Melatonin for treatment of sleep disorders. Evidence Report/Technology Assessment No. 108. AHRQ Publication No. 05-E002-2. Rockville (MD): U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality. November, 2004
  • Cagnacci A, Arangino S, Angiolucci M, Melis GB, Facchinetti F, Malmusi S, Volpe A. Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy. Clinical Endocrinology 2001b;54:261-266.
  • Cagnacci A, Arangino S, Renzi A, Paoletti AM, Melis GB, Cagnacci P, Volpe A. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clinical Endocrinology (Oxford) 2001;54(3):339-46
  • Calvo JR, Guerrero JM, Osuna C, Molinero P, Carrillo-Vico A. Melatonin triggers Crohn's disease symptoms. Journal of Pineal Research 2002;32(4):277-278.
  • Carman JS, Post RM, Buswell R, Goodwin FK. Negative effects of melatonin on depression. American Journal of Psychiatry 1976;133(10):1181-1186
  • Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine 2005;27:189-200.
  • Citera G, Arias MA, Maldonado-Cocco JA, Lazaro MA, Rosemffet MG, Brusco LI, Scheines EJ, Cardinalli DP. The effect of melatonin in patients with fibromyalgia: a pilot study. Clinical Rheumatology 2000;19(1):9-13
  • Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: confirmatory result using a simplified protocol. Biological Psychiatry 1992;32(8):705-11
  • Dahlitz M, Alvarez B, Vignau J, English J, Arendt J, Parkes JD. Delayed sleep phase syndrome response to melatonin. Lancet 1991;337(8750):1121-4
  • der Marderosian A, Beutters JA, editors. 2002. The Review of Natural Health Products, 3rd edition. St. Louis (MO): Facts and Comparisons®, a Wolters Kluwer Company.
  • Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: a pathophysiologic approach, 5th edition. New York (NY): The McGraw-Hill Companies, Inc.; 2002.
  • Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. American Journal of Psychiatry 1998;155(8):1119-21
  • Dollins AB, Lynch HJ, Wurtman RJ, Deng MH, Lieberman HR. Effects of illumination on human nocturnal serum melatonin levels and performance. Physiology and Behavior 1993;53(1):153-60
  • GAO 2001: United States General Accounting Office. Report to Chairman, Special Committee on Agin, U.S. Senate. Health Products for Seniors: "Anti-Aging" Products Pose Potential for Physical and Economic Harm. September 2001. GAO-01-1129. [Consulted 2012 December 08] Available from: http://www.gao.gov/new.items/d011129.pdf
  • Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995;346(8974):541-4
  • Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep 1995;18(7):598-603
  • Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD001520. DOI: 10.1002/14651858.CD001520. (Assessed as up-to-date 2008 February 12). [Consulted 2010 September 22]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001520/full
  • Holliman BJ, Chyka PA. Problems in assessment of acute melatonin overdose. Southern Medical Journal 1997;90(4):451-453.
  • Härtter S, Nordmark A, Rose DM, Bertilsson L, Tybring G, Laine K. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. British Journal of Clinical Pharmacology 2003;56(6):679-682.
  • IOM 2004: Institute of Medicine Committee on the Framework for Evaluating the Safety of Dietary Supplements. Prototype monograph on melatonin. Dietary Supplement Ingredient Prototype Monographs, Developed as Examples for the Report Dietary Supplements: A Framework for Evaluating Safety. Institute of Medicine and the National Research Council of the National Academies, Washington (DC): National Academies Press 2004: D1-D71
  • James SP, Mendelson WB, Sack DA, Rosenthal NE, Wehr TA. The effect of melatonin on normal sleep. Neuropsychopharmacology 1987;1(1):41-4
  • Jean-Louis G, von Gizycki H, Zizi F. Predictors of subjective sleepiness induced by melatonin administration. Journal of Psychosomatic Research 1999;47(4):355-8
  • Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosomatic Medicine 2001;63(1):40-8
  • Koda-Kimble MA, editor. Applied Therapeutics: The Clinical Use of Drugs. Baltimore (MD): Lippincott Williams and Wilkins; 2001
  • Kunz D, Mahlberg R, Müller C, Tilmann A, Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. Journal of Clinical Endocrinology & Metabolism 2004;89(1):128-134
  • Lewy AJ, Bauer VK, Cutler NL, Sack RL. Melatonin treatment of winter depression: a pilot study. Psychiatry Research 1998;77(1):57-61
  • Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumor patients with poor clinical status. European Journal of Cancer 1999;35:1688-92
  • Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. British Journal of Clinical Pharmacology 2000;49:423-7
  • Maestroni GJM. The immunoneuroendocrine role of melatonin. Journal of Pineal Research 1993;14(1):1-10.
  • Martindale 2012: Sweetman SC, editor. Martindale: The Complete Drug Reference. [Internet]. London (GB): Pharmaceutical Press; Copyright 1933-2012. [Melatonin: last modified 2011 December 21; accessed 2012 December 03]. Available from: http://www.medicinescomplete.com
  • Matsumoto M. The hypnotic effects of melatonin treatment on diurnal sleep in humans. Psychiatry and Clinical Neurosciences 1999;53(2):243-5
  • McDaniel MA, Maier SF, Einstein GO. 2003. "Brain-specific" nutrients: a memory cure? Nutrition 19(11-12):957-975
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  • Murray MT, Pizzorno Jr JE, Bongiorno PB. Melatonin. In: Pizzorno Jr JE, Murray MT. Textbook of Natural Medicine. Third edition. Chapter 105, pages 1057-1064. St.Louis (MI): Churchill Livingstone Elsevier; 2006
  • NHPD LC IAS 2006: Natural Health Products Directorate Leadership Committee Issue Analysis Summary, May 15, 2006
  • Ninomiya T, Iwatani N, Tomoda A, Miike T. Effects of exogenous melatonin on pituitary hormones in humans. Clinical Physiology 2001 May;21(3):292-9
  • O'Neil MJ, Smith A, Heckelman PE, Budavari S, editors. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th edition. Whitehouse Station (NJ): Merck & Co., Inc.; 2001.
  • Peschke E, Mühlbauer E. New evidence for a role of melatonin in glucose regulation. Best practice & research. Clinical endocrinology & metabolism 2010;24(5):829-841.
  • Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. British Medical Journal 1989;298(6675):705-7
  • Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biological Psychiatry 1993;33(7): 526-30
  • Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. New England Journal of Medicine 2000;343 (15):1070-7
  • Sack RL, Lewy AJ, Blood ML, Stevenson J, Keith LD. Melatonin administration to blind people: phase advances and entrainment. Journal of Biological Rhythms 1991;6(3):249-61
  • Sanders DC, Chaturvedi AK, Hordinsky JR. Melatonin: aeromedical, toxicopharmacological, and analytical aspects. Journal of Analytical Toxicology 1999;23(3):159-67
  • Scheer FAJL, Van Montfrans GA, van Someren EJW, Mairuhu G, Buijs RM. Daily nightime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 2004;43:192-197.
  • Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, Zisapel N. Melatonin improves sleep quality of patients with chronic schizophrenia. Journal of Clinical Psychiatry 2000;61(5):373-7
  • Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998;351:1254.
  • Skene DJ, Lockley SW, Arendt J. Melatonin in circadian sleep disorders in the blind. Biological Signals and Receptors 1999;8(1-2):90-5
  • Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. Journal of Child Neurology 2001;16(2):86-92
  • Suhner A, Schlagenhauf P, Johnson R, Tschopp A, Steffen R. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiology International 1998a;15(6):655-6
  • Suhner A, Schlagenhauf P, Tschopp A, Hauri-Bionda R, Friedrich-Koch A, Steffen R. Impact of melatonin on driving performance. Journal of Travel Medicine 1998b;5(1):7-13
  • Sutherland ER, Ellison MC, Kraft M, Martin RJ. Elevated serum melatonin is associated with the nocturnal worsening of asthma. Journal of Allergy and Clinical Immunology 2003;112(3):513-517.
  • Sutherland ER, Martin RJ, Ellison MC, Kraft M. Immunomodulatory effects of melatonin in asthma. American Journal of respiratory and critical care medicine 2002;166:1055-1061.
  • Sweetman SC, editor. Martindale: The complete drug reference. 33rd edition. London (UK): Pharmaceutical Press; 2002
  • Tzischinsky O, Lavie P. Melatonin possesses time-dependent hypnotic effects. Sleep 1994;17(7):638-45
  • van Geijlswijk IM, Korzilius HP, Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep 2010;33(12)1605-1614.
  • Wirtz PH, Spillmann M, Bärtschi C, Ehlert U, von Känel R. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. Journal of Pineal Research 2008;44:127-133.
  • Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treatment for age-related insomnia. Journal of Clinical Endocrinology and Metabolism 2001;86(10):4727-30

References reviewed

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  • Aicardi J. Epilepsy in brain-injured children. Review article. Developmental Medicine and Child Neurology 1990;32:191-202.
  • Aksu F. Nature and prognosis of seizures in patients with cerebral palsy. Developmental Medicine and Child Neurology 1990;32:661-668.
  • Andrade C, Srihari BS, Reddy KP, Chandramma L. Melatonin in medically ill patients with insomnia: a double blind placebo-controlled study. Journal of Clinical Psychiatry 2001;62(1):41-5
  • Arendt J. Does melatonin improve sleep? BMJ 2006;332:550.
  • Ashwal S, Russman BS, Blasco PA, Miller G, Dansler A, Shevell M, Stevenson R. Practice parameter: diagnostic assessment of the child with cerebral palsy. Neurology 2004;62:851-863
  • Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin improves sleep in healthy middle-aged subjects. Psychopharmacology (Berlin) 1996;126(2):179-81
  • Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Annals of Medicine 1998;30(1):122-30
  • Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Current Topics in Medicinal Chemistry 2002;2(2):113-132.
  • Brusco LI, Fainstein I, Marquez M, Cardinali DP. Effect of melatonin in selected populations of sleep-disturbed patients. Biological Signals and Receptors 1999;8(1-2):126-31
  • Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, Ford I. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Medicine Reviews 2005;9:41-50
  • Burgess HJ, Revell VL, Eastman CI. A three pulse phase response curve to three milligrams of melatonin in humans. Journal of Physiology 2008;586:639-647.
  • Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. British Medical Journal, doi:10.1136/bmj.38731.532766.F6 (published 10 February 2006).
  • Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T. Melatonin for treatment of sleep disorders. Evidence Report/Technology Assessment No. 108. AHRQ Publication No. 05-E002-2. Rockville (MD): U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality. November, 2004
  • Cagnacci A, Arangino S, Renzi A, Paoletti AM, Melis GB, Cagnacci P, Volpe A. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clinical Endocrinology (Oxford) 2001;54(3):339-46
  • Cagnacci A, Elliott JA, Yen SSC. Melatonin: a major regulator of the circadian rhythm of core temperature in humans. Journal of Clinical Endocrinology and Metabolism 1992;75(2):447-452.
  • Carman JS, Post RM, Buswell R, Goodwin FK. Negative effects of melatonin on depression. American Journal of Psychiatry 1976;133(10):1181-1186
  • Citera G, Arias MA, Maldonado-Cocco JA, Lazaro MA, Rosemffet MG, Brusco LI, Scheines EJ, Cardinalli DP. The effect of melatonin in patients with fibromyalgia: a pilot study. Clinical Rheumatology 2000;19(1):9-13
  • Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: confirmatory result using a simplified protocol. Biological Psychiatry 1992;32(8):705-11
  • Cutolo M, Villaggio B, Candido F, Valenti S, Giusti M, Felli L, Sulli A, Accardo S. Melatonin influences interleukin-12 and nitric oxide production by primary cultures of rheumatoid synovial macrophages and THP-1 cells. Annals of the New York Academy of Sciences 1999;876:246-254.
  • Dahlitz M, Alvarez B, Vignau J, English J, Arendt J, Parkes JD. Delayed sleep phase syndrome response to melatonin. Lancet 1991;337(8750):1121-4
  • DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS. The absolute bioavailability of oral melatonin. Journal of Clinical Pharmacology 40:781-784.
  • Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: a pathophysiologic approach, 5th edition. New York (NY): The McGraw-Hill Companies, Inc.; 2002.
  • Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. American Journal of Psychiatry 1998;155(8):1119-21
  • Dollins AB, Lynch HJ, Wurtman RJ, Deng MH, Lieberman HR. Effects of illumination on human nocturnal serum melatonin levels and performance. Physiology and Behavior 1993;53(1):153-60
  • Ellis CM, Lemmens G, Parkes D. Melatonin and insomnia. Journal of Sleep Research 5:61-65.
  • Fauteck J-D, Schmidt H, Lerchl A, Kurlemann G, Wittkowski W. Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biological Signals and Receptors 1999;8:105-110.
  • Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995;346(8974):541-4
  • Grossman E, Laudon M, Yalcin R, Zengil H, Peleg E, Sharabi Y, Kamari Y, Shen-Orr Z, Zisapel N. 2006. Melatonin reduces night blood pressure in patients with nocturnal hypertension. The American Journal of Medicine 119:898-902.
  • Hadjipanayis A, Hadjichristodoulou C, Youroukos S. Epilepsy in patients with cerebral palsy. Developmental Medicine and Child Neurology 1997;39:659-663.
  • Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep 1995;18(7):598-603
  • IOM 2004: Institute of Medicine Committee on the Framework for Evaluating the Safety of Dietary Supplements. Prototype monograph on melatonin. Dietary Supplement Ingredient Prototype Monographs, Developed as Examples for the Report Dietary Supplements: A Framework for Evaluating Safety. Institute of Medicine and the National Research Council of the National Academies, Washington (DC): National Academies Press 2004: D1-D71
  • James SP, Mendelson WB, Sack DA, Rosenthal NE, Wehr TA. The effect of melatonin on normal sleep. Neuropsychopharmacology 1987;1(1):41-4
  • Jean-Louis G, von Gizycki H, Zizi F. Predictors of subjective sleepiness induced by melatonin administration. Journal of Psychosomatic Research 1999;47(4):355-8
  • Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosomatic Medicine 2001;63(1):40-8
  • Koda-Kimble MA, editor. Applied Therapeutics: The Clinical Use of Drugs. Baltimore (MD): Lippincott Williams and Wilkins; 2001
  • Kunz D, Mahlberg R, Müller C, Tilmann A, Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. Journal of Clinical Endocrinology & Metabolism 2004;89(1):128-134
  • Lewy AJ, Ahmed Saeeduddin, Latham Jackson JM, Sack RL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiology International 1992;9(5):380-392.
  • Lewy AJ, Bauer VK, Cutler NL, Sack RL. Melatonin treatment of winter depression: a pilot study. Psychiatry Research 1998;77(1):57-61
  • Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. British Journal of Clinical Pharmacology 2000;49:423-427.
  • Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumor patients with poor clinical status. European Journal of Cancer 1999;35:1688-92
  • Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. British Journal of Clinical Pharmacology 2000;49:423-7
  • Matsumoto M. The hypnotic effects of melatonin treatment on diurnal sleep in humans. Psychiatry and Clinical Neurosciences 1999;53(2):243-5
  • Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC. Phase-dependent treatment of delayed sleep phase syndrome with melatonin. Sleep 2005;28(10):1271-1278.
  • Neri B, De Leonardis V, Gemelli MT, Di Loro F, Mottola A. Ponchietti R, Raugei A, Cini G. Melatonin as biological response modifier in cancer patients. Anticancer Research 1998;18:1329-1332.
  • NHPD LC IAS 2006: Natural Health Products Directorate Leadership Committee Issue Analysis Summary, May 15, 2006
  • Ninomiya T, Iwatani N, Tomoda A, Miike T. Effects of exogenous melatonin on pituitary hormones in humans. Clinical Physiology 2001 May;21(3):292-9
  • NSM 2010. Natural Standard Monograph. The Authority on Integrative Medicine 2010. Melatonin. [Consulted on 2010 August 26]. Available from: http://www.naturalstandard.com/monographs/monoframeset.asp?monograph=/monographs/herbssupplements/melatonin.asp%3Fprintversion%3Dtrue
  • O'Neil MJ, Smith A, Heckelman PE, Budavari S, editors. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th edition. Whitehouse Station (NJ): Merck & Co., Inc.; 2001.
  • Pandi-Perumal SR, Smits M, Spence W, Srinivasan V, Cardinali DP, Lowe AD, Kayumov L. Dim light melatonin onset (DLMO): A tool for the analysis of circadian phase in human sleep and chronobiological disorders. Review article. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2007;31:1-11.
  • Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. British Medical Journal 1989;298(6675):705-7
  • Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biological Psychiatry 1993;33(7): 526-30
  • Pires MLN, Benedito-Silva AA, Pinto L, Souza L, Vismari L, Calil HM. Acute effects of low doses of melatonin on the sleep of young healthy subjects. Journal of Pineal Research 2001;31:326-332.
  • Pizzorno Jr JEP, Murray MT. Textbook of Natural Medicine. 3rd edition, Volume 1. St-Louis (MI): Churchill Livingstone Elsevier; 2006.
  • Reid KJ, Zee PC. Circadian rhythm sleep disorders. Handbook of Clinical Neurology 2011;99:963-977.
  • Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX. Melatonin and its relation to the immune system and inflammation. Annals of the New York Academy of Sciences 2006;917:376-386.
  • Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. New England Journal of Medicine 2000;343 (15):1070-7
  • Sack RL, Lewy AJ, Blood ML, Stevenson J, Keith LD. Melatonin administration to blind people: phase advances and entrainment. Journal of Biological Rhythms 1991;6(3):249-61
  • Sanders DC, Chaturvedi AK, Hordinsky JR. Melatonin: aeromedical, toxicopharmacological, and analytical aspects. Journal of Analytical Toxicology 1999;23(3):159-67
  • Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, Zisapel N. Melatonin improves sleep quality of patients with chronic schizophrenia. Journal of Clinical Psychiatry 2000;61(5):373-7
  • Skene DJ, Lockley SW, Arendt J. Melatonin in circadian sleep disorders in the blind. Biological Signals and Receptors 1999;8(1-2):90-5
  • Sletten TL, Vincenzi S, Redman JR, Lockley SW, Rajaratnam SMW. Timing of sleep and its relationship with the endogenous melatonin rhythm. Frontiers in neurology 2010;1:137.
  • Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. Journal of Child Neurology 2001;16(2):86-92
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Appendix 1:

Examples of dosage preparations, frequencies of use and directions for use

All uses except jet lag:

0.1-10 mg, per day (Brzezinski et al. 2005; IOM 2004; Andrade et al. 2001; Kayumov et al. 2001; Koda-Kimble 2001; Smits et al. 2001; Zhdanova et al. 2001; Citera et al. 2000; Shamir et al. 2000; Brusco et al. 1999; Jean-Louis et al. 1999; Matsumoto 1999; Dolberg et al. 1998; Lewy et al. 1998; Attenburrow et al. 1996; Garfinkel 1995; Haimov et al. 1995; Tzischinsky and Lavie 1994; Dollins et al. 1993; Dahlitz et al. 1991; James et al. 1987)

Direction for use

All uses:

  • Take once a day at or before bedtime (Murray et al. 2006; Kayumov et al. 2001; Zhdanova et al. 2001).
  • Do not drive or use machinery for 5 hours after taking melatonin (Avery et al. 1998; Suhner et al. 1998b).

Jet lag:

0.5-10 mg, per day (Brown et al. 2009; Herxheimer and Petrie 2009; Suhner et al. 1998a)

Direction for use

  • Take once a day at bedtime after darkness has fallen, while travelling and at the destination until adaptation to the new daily pattern (Herxheimer and Petrie 2009).
  • Do not drive or use machinery for 5 hours after taking melatonin (Avery et al. 1998; Suhner et al. 1998b).