|Systematic (IUPAC) name|
|Routes||In humans: orally, as capsules, tablets, or liquid, sublingually, or as transdermal patches. In lab animals: also injection.|
|Bioavailability||30 – 50%|
|Metabolism||Hepatic via CYP1A2 mediated 6-hydroxylation|
|Half-life||35 to 50 minutes|
|Mol. mass||232.278 g/mol|
|(what is this?)|
Melatonin i//, chemically N-acetyl-5-methoxytryptamine, is a hormone found in animals, plants, fungi and bacteria. It is synthesized in animal cells directly from the amino acid tryptophan, but in other organisms through the Shikimic acid pathway, in response to dark-light periods (photoperiod). The penultimate enzyme, aralkylamine N-acetyltransferase (AANAT), is the key regulator of melatonin synthesis from tryptophan, as its gene AANAT is directly influenced by photoperiod.
In animals, melatonin controls the daily night-day cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions. Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA.
The hormone can be used as a sleep aid and in the treatment of sleep disorders. It can be taken orally as capsules, tablets, or liquid. It is also available in a form to be used sublingually, and there are transdermal patches. There have been few clinical trials, particularly long-term ones, in the use of melatonin in humans.
- 1 Discovery
- 2 Biosynthesis
- 3 Animals
- 4 Plants
- 5 Functions
- 6 Exogenous melatonin
- 7 Medical uses
- 8 Sleep disorders
- 9 Adverse effects
- 10 Availability
- 11 See also
- 12 References
- 13 Further reading
- 14 External links
Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin. As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermal melanophores. In 1958 dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin. In the mid-70s Lynch et al. demonstrated that the production of melatonin exhibits a circadian rhythm in human pineal glands. The discovery that melatonin is an antioxidant was made in 1993. The first patent for its use as a low dose sleep aid was granted to Richard Wurtman at MIT in 1995. Around the same time, the hormone got a lot of press as a possible treatment for many illnesses. The New England Journal of Medicine editorialized in 2000: "The hype and the claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance to human health. With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear. Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."
Melatonin biosynthesis involves four enzymatic steps from the essential dietary amino acid tryptophan, which follows a serotonin pathway. L-tryptophan is first converted to 5-hydroxy-L-tryptophan (5-HTP) by an enzyme, tryptophan 5-hydroxylase. 5-HTP is then decarboxylated (CO2 removal) by 5-hydroxytryptophan decarboxylase to produce serotonin. This point is the rate limiting stage such that further reaction is determined by light-dark conditions. Only in darkness, the key enzyme, aralkylamine N-acetyltransferase (AANAT) is activated and converts serotonin to N-acetyl serotonin, which is ultimately converted to melatonin by the final enzyme, acetylserotonin O-methyltransferase.
In bacteria, protists, fungi, and plants melatonin is synthesized indirectly with tryptophan as an intermediate product of the shikimic acid pathway. In these cells synthesis starts with d-erythrose-4-phosphate and phosphoenolpyruvate, and in photosynthetic cells with carbon dioxide. The rest of the reactions are similar, but with slight variations in the last two enzymes.
In vertebrates, melatonin secretion is regulated by norepinephrine. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphoryates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). At daylight, noradrenergic stimulation stops and the protein is immediately destroyed by proteasomal proteolysis. Production is again started in the evening, which is called the dim-light melatonin onset (DLMO).
It is principally blue light, around 460 to 480 nm, that suppresses melatonin, proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light. The incandescent light bulb widely used in the twentieth century produced relatively little blue light. Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. Kayumov et al. showed that light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.
When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.
In vertebrates, melatonin is produced at nighttime by the pineal gland, a small endocrine gland located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the suprachiasmatic nuclei (SCN) from retinal photosensitive ganglion cells of the eyes. rather than the melatonin signal (as was once postulated). Many animals use the variation in duration of melatonin production each day as a seasonal clock. In animals including humans the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth and camouflage coloring in seasonal animals. In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds and hamsters. Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin. During the night, melatonin regulates leptin, lowering its levels.
Melatonin is identified in many plants including feverfew (Tanacetum parthenium), St John's wort (Hypericum perforatum), rice, corn, tomato, grape and other edible fruits. The physiological roles in plants include regulation of their response to photoperiod, defense against harsh environments, and the function of an antioxidant. It also regulates plant growth by its ability to slow root formation, while promoting above-ground growth.
In animals, the primary function is regulation of day-night cycles. Infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 AM. Human melatonin production decreases as a person ages. Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times. In humans, 90% of melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva.
Besides its function as synchronizer of the biological clock, melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant as discovered in 1993. In many less complex life forms, this is its only known function. Melatonin is an antioxidant that can easily cross cell membranes and the blood–brain barrier. This antioxidant is a direct scavenger of radical oxygen and nitrogen species including OH, O2−, and NO. Melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant. Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant. An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also scavengers in what is referred to as the cascade reaction. Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic properties. When compared to synthetic, mitochondrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a better protector against mitochondrial oxidative stress.
While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. Antiinflammatory effect seems to be the most relevant and most documented in the literature. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production, and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.
Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement. It is sold freely over-the-counter in both the US and Canada without any regulation as a pharmaceutical drug. The Food and Drug Administration (FDA) regulations applying to medications are not applicable to melatonin. However, new FDA rules required that by June 2010 all production of dietary supplements must comply with "current good manufacturing practices" (cGMP) and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling." The industry has also been required to report to the FDA "all serious dietary supplement related adverse events", and the FDA has (within the cGMP guidelines) begun enforcement of that requirement.
Melatonin has been reported in foods including cherries to about 0.17–13.46 ng/g, bananas and grapes, rice and cereals, herbs, olive oil, wine and beer. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains. When humans consume foods rich in melatonin such as banana, pineapple and orange the blood levels of melatonin significantly increase.
As reported in the New York Times in May 2011, beverages and snacks containing melatonin are sold in grocery stores, convenience stores, and clubs. The FDA is considering whether these food products can continue to be sold with the label "dietary supplements". On January 13, 2010, they issued a warning letter to Innovative Beverage, creators of several beverages marketed as "relaxation drinks," stating that melatonin is not approved as a food additive because it is not generally recognized as safe.
Melatonin has been studied for insomnia in the elderly. Prolonged release melatonin has shown good results in treating insomnia in older adults (2007). It may improve circadian misalignment and SAD. Basic research indicates that melatonin may play a role in modulating the effects of drugs of abuse such as cocaine.
Short and long term treatment of prolonged-release melatonin was found to be effective and safe, improving sleep latency, sleep quality and daytime alertness in insomnia patients.
In exploratory studies, prolonged-release melatonin has shown sleep quality improvement in patients with chronic schizophrenia as well as in patients with major depressive disorder and treating sleep-wake cycle disorders in children with underlying neurodevelopment difficulties. Additionally, as add-on to antihypertensive therapy, prolonged-release melatonin improved blood pressure control in patients with nocturnal hypertension as shown in a randomised double-blind placebo controlled study.
Melatonin taken in the evening is, together with light therapy upon awakening, the standard treatment for delayed sleep phase disorder (DSPD) and non-24-hour sleep–wake disorder where circadian rhythms are not entrained (biologically synchronized) to the environmental cycle. It appears to have some use against other circadian rhythm sleep disorders as well, such as jet lag and the problems of people who work rotating or night shifts. Melatonin reduces sleep onset latency to a greater extent in people with DSPD than in people with insomnia.
Melatonin appears to increase the amount of sleep in people after working night shifts.
A very small dose taken several hours before bedtime in accordance with the phase response curve for melatonin in humans (PRC) does not cause sleepiness but, acting as a chronobiotic (affecting aspects of biological time structure), advances the phase slightly and is additive to the effect of using light therapy upon awakening. Light therapy may advance the phase about one to two-and-a-half hours and an oral dose of 0.3 or 3 mg of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the ~2 hour advance achieved with light therapy. There was no difference in the average magnitude of phase shift induced by the 2 doses.
Research shows that after melatonin is administered to ADHD patients on methylphenidate, the time needed to fall asleep is significantly reduced. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.
A systematic review of unblinded clinical trials involving a total of 643 cancer patients using melatonin found a reduced incidence of death but that blinded and independently conducted randomized controlled trials are needed. The National Cancer Institute's review of the evidence found that it remains inconclusive.
Melatonin presence in the gallbladder has many protective properties, such as converting cholesterol to bile, preventing oxidative stress, and increasing the mobility of gallstones from the gallbladder. It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. Concentration of melatonin in the bile is 2–3 times higher than the otherwise very low daytime melatonin levels in the blood across many diurnal mammals, including humans.
Protection from radiation
Both animal and human studies have shown melatonin to be potentially radioprotective. Moreover, it is a more efficient protector than amifostine, a commonly used agent for this purpose. The mechanism of melatonin in protection against ionizing radiation is thought to involve scavenging of free radicals. It is estimated that nearly 70% of biological damage caused by ionizing radiation is attributable to the free radical, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been suggested as a radioprotective agent, with the proposed advantages of being broadly protective, readily available, orally self-administered, and without major known side effects.
Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50 mg) dramatically increased REM sleep time and dream activity in people both with and without narcolepsy.
While the packaging of melatonin often warns against use in children, available studies suggest that melatonin is an efficacious and safe treatment for ADHD and sleep-onset insomnia. However larger and longer studies are needed to establish long-term safety and optimal dosing.
Melatonin appears to cause very few side-effects in the short term, up to three months, at low doses. A systematic reviews in 2006 showed that for sleep disorders such as jet lag and shift work, melatonin is not effective although it is safe for short term use". Prolonged-release melatonin is safe with long-term use of up to 12 months.
Melatonin can cause nausea, next-day grogginess, irritability, reduced blood flow and hypothermia. Among blind people, long-term use of melatonin causes physiological problems. Individuals with orthostatic intolerance, having reduced blood pressure and blood flow to the brain when a person stands, melatonin can increase the clinical. In auto-immune disorders, there is conflicting evidence whether melatonin supplementation may either ameliorate or exacerbate symptoms due to immunomodulation.
Melatonin was thought to have a very low maternal toxicity in rats. Recent studies have found results which suggested that it is toxic to photoreceptor cells in rats' retinas when used in combination with large amounts of sunlight and increases the incidence of tumours in white mice.
In animal models, interventions that increase the bioavailability of melatonin seem to increase the severity of the symptoms of Parkinson's disease, whereas reduction in melatonin by pinealectomy or exposure to bright light can improve recovery from those symptoms. Melatonin may exacerbate neurodegeneration in advanced Parkinson's disease in rats.
The effects of long-term supplementation of melatonin in humans have not yet been thoroughly studied nor ascertained. One prescription-only, prolonged-release melatonin product, trade-name Circadin, 2 mg, is available for up to three months use by people aged 55 and over.
Immediate-release melatonin is scarcely regulated. It is available in doses from less than half a milligram to 5 mg or more. It causes blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, tablets or as liquid. It is also available for use sublingually, or as transdermal patches.
The legal availability of melatonin varies widely among countries, ranging from being available without prescription (e.g. in most of North America and Finland) to being available only on prescription (e.g. in the European Union, Norway and Australia) or not at all (although its possession and use may not be illegal). Immediate-release melatonin is widely available on the Internet as a dietary supplement.
Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. Containing 2 mg melatonin, it was shown in clinical trials of older adults to decrease time to fall asleep and improve quality of sleep and daytime functioning.
It releases melatonin gradually over 8–10 hours, mimicking the body's internal secretion profile.
The European Medicines Agency (EMA) has approved Circadin for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.
Other countries' agencies that subsequently approved the drug include:
- --the Australian Therapeutics Goods Administration (TGA),
- --the Swiss Agency for Therapeutics Products (SwissMedic),
- --the South Korean Ministry of Food and Drug Safety (MFDS) and
- --the Israeli Ministry of Health (MOH).
|Wikimedia Commons has media related to Melatonin.|
- Discovery and development of melatonin receptor agonists
- Risks and benefits of sun exposure
- "Melatonin". Sleepdex. Retrieved 2011-08-17.
- Hardeland, Rüdiger; Pandi-Perumal, S.R.; Cardinali, Daniel P. (2006). "Melatonin". The International Journal of Biochemistry & Cell Biology 38 (3): 313–316. doi:10.1016/j.biocel.2005.08.020. PMID 16219483.
- Tan, Dun-Xian; Zheng, Xiaodong; Kong, Jin; Manchester, Lucien; Hardeland, Ruediger; Kim, Seok; Xu, Xiaoying; Reiter, Russel (9 September 2014). "Fundamental Issues Related to the Origin of Melatonin and Melatonin Isomers during Evolution: Relation to Their Biological Functions". International Journal of Molecular Sciences 15 (9): 15858–15890. doi:10.3390/ijms150915858. PMC 4200856. PMID 25207599.
- Acuna-Castroviejo, D; Escames, G; Tapias, V; Rivas, I (2006). "Melatonin, mitochondria and neuroprotection". In Montilla, Pedro; Túnez, Isaac. Melatonin: Present and Future. New York, US: Nova Science Publishers. pp. 1–33. ISBN 9781600213748.
- Altun A, Ugur-Altun B (May 2007). "Melatonin: therapeutic and clinical utilization". Int. J. Clin. Pract. 61 (5): 835–45. doi:10.1111/j.1742-1241.2006.01191.x. PMID 17298593.
- Boutin JA, Audinot V, Ferry G, Delagrange P (August 2005). "Molecular tools to study melatonin pathways and actions". Trends Pharmacol. Sci. 26 (8): 412–9. doi:10.1016/j.tips.2005.06.006. PMID 15992934.
- Hardeland R (July 2005). "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance". Endocrine 27 (2): 119–30. doi:10.1385/ENDO:27:2:119. PMID 16217125.
- Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S (June 2001). "Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system". Ann. N. Y. Acad. Sci. 939: 200–15. doi:10.1111/j.1749-6632.2001.tb03627.x. PMID 11462772.
- Filadelfi AM, Castrucci AM (May 1996). "Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates". J. Pineal Res. 20 (4): 175–86. doi:10.1111/j.1600-079X.1996.tb00256.x. PMID 8836950.
- Sugden D, Davidson K, Hough KA, Teh MT (October 2004). "Melatonin, melatonin receptors and melanophores: a moving story". Pigment Cell Res. 17 (5): 454–60. doi:10.1111/j.1600-0749.2004.00185.x. PMID 15357831.
- Coates PM, Blackman MR, Cragg GM, LevineM, Moss J, White JD (2005). Encyclopedia of dietary supplements. New York, N.Y: Marcel Dekker. pp. 457–66. ISBN 0-8247-5504-9.
- McCord CP, Allen FP (January 1917). "Evidences associating pineal gland function with alterations in pigmentation". J Exptl Zool 23 (1): 206–24. doi:10.1002/jez.1400230108.
- Lerner AB, Case JD, Takahashi Y (July 1960). "Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands". J. Biol. Chem. 235: 1992–7. PMID 14415935.
- Lynch HJ, Wurtman RJ, Moskowitz MA, Archer MC, Ho MH (January 1975). "Daily rhythm in human urinary melatonin". Science 187 (4172): 169–71. Bibcode:1975Sci...187..169L. doi:10.1126/science.1167425. PMID 1167425.
- Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC (May 1993). "Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis". J. Pineal Res. 14 (4): 151–68. doi:10.1111/j.1600-079X.1993.tb00498.x. PMID 8102180.
- US patent 5449683, Wurtman RJ, "Methods of inducing sleep using melatonin", issued 1995-09-12, assigned to Massachusetts Institute of Technology
- Arendt J (August 2005). "Melatonin: characteristics, concerns, and prospects". J. Biol. Rhythms 20 (4): 291–303. doi:10.1177/0748730405277492. PMID 16077149.
There is very little evidence in the short term for toxicity or undesirable effects in humans. The extraordinary “hype” of the miraculous powers of melatonin in the recent past did a disservice to acceptance of its genuine benefits.
- Arendt J (October 2000). "Melatonin, circadian rhythms, and sleep". N. Engl. J. Med. 343 (15): 1114–6. doi:10.1056/NEJM200010123431510. PMID 11027748.
- "MetaCyc Pathway: serotonin and melatonin biosynthesis". MetaCyc.org. SRI International. Retrieved 2 November 2014.
- Norman, Anthony W.; Henry, Helen L. (2012). Hormones (3 ed.). Oxford, UK: Academic Press. pp. 352–359. ISBN 978-0-12-369444-7.
- Bochkov, Denis V.; Sysolyatin, Sergey V.; Kalashnikov, Alexander I.; Surmacheva, Irina A. (2011). "Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources". Journal of Chemical Biology 5 (1): 5–17. doi:10.1007/s12154-011-0064-8. PMC 3251648. PMID 22826715.
- Hardeland, R. (2014). "Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions". Journal of Experimental Botany 18 (pii): eru386. doi:10.1093/jxb/eru386. PMID 25240067.
- Schomerus, C.; Korf, HW (2005). "Mechanisms regulating melatonin synthesis in the mammalian pineal organ". Annals of the New York Academy of Sciences 1057 (1): 372–383. doi:10.1196/annals.1356.028. PMID 16399907.
- Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD (August 2001). "Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor". J. Neurosci. 21 (16): 6405–12. PMID 11487664.
- Cornell University, Light source spectra
- Kayumov L, Casper RF, Hawa RJ, Perelman B, Chung SA, Sokalsky S, Shapiro CM (May 2005). "Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work". J. Clin. Endocrinol. Metab. 90 (5): 2755–61. doi:10.1210/jc.2004-2062. PMID 15713707.
- Burkhart K, Phelps JR (26 December 2009). "Amber lenses to block blue light and improve sleep: a randomized trial". Chronobiol Int 26 (8): 1602–12. doi:10.3109/07420520903523719. PMID 20030543.
- Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC (October 2005). "Phase-dependent treatment of delayed sleep phase syndrome with melatonin". Sleep 28 (10): 1271–8. PMID 16295212.
- Terman MR, Wirz-Justice A (2009). Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy. Basel: S Karger Pub. p. 71. ISBN 3-8055-9120-9.
- Reiter RJ (May 1991). "Pineal melatonin: cell biology of its synthesis and of its physiological interactions". Endocr. Rev. 12 (2): 151–80. doi:10.1210/edrv-12-2-151. PMID 1649044.
- Richardson GS (2005). "The human circadian system in normal and disordered sleep". J Clin Psychiatry. 66 Suppl 9: 3–9; quiz 42–3. PMID 16336035.
- Perreau-Lenz S, Pévet P, Buijs RM, Kalsbeek A (January 2004). "The biological clock: the bodyguard of temporal homeostasis". Chronobiol. Int. 21 (1): 1–25. doi:10.1081/CBI-120027984. PMID 15129821.
- Lincoln GA, Andersson H, Loudon A (October 2003). "Clock genes in calendar cells as the basis of annual timekeeping in mammals – a unifying hypothesis". J. Endocrinol. 179 (1): 1–13. doi:10.1677/joe.0.1790001. PMID 14529560.
- Arendt J, Skene DJ (February 2005). "Melatonin as a chronobiotic". Sleep Med Rev 9 (1): 25–39. doi:10.1016/j.smrv.2004.05.002. PMID 15649736.
Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn) it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times.
- Chaturvedi CM (1984). "Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis". Australian Journal of Zoology 32 (6): 803–9. doi:10.1071/ZO9840803.
- Chen HJ (July 1981). "Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition". Neuroendocrinology 33 (1): 43–6. doi:10.1159/000123198. PMID 7254478.
- Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ (2009). "Phytomelatonin: a review". J. Exp. Bot. 60 (1): 57–69. doi:10.1093/jxb/ern284. PMID 19033551.
- Iriti M, Faoro F (2009). "Bioactivity of grape chemicals for human health". Nat Prod Commun 4 (5): 611–34. PMID 19445314.
- Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ (January 2012). "Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science". J. Exp. Bot. 63 (2): 577–97. doi:10.1093/jxb/err256. PMID 22016420.
- Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, Mayo JC, Fuentes-Broto L, Reiter RJ (August 2010). "The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness". Biol Rev Camb Philos Soc 85 (3): 607–23. doi:10.1111/j.1469-185X.2009.00118.x. PMID 20039865.
- Arnao MB, Hernández-Ruiz J (May 2006). "The physiological function of melatonin in plants". Plant Signal Behav 1 (3): 89–95. doi:10.4161/psb.1.3.2640. PMC 2635004. PMID 19521488.
- Ardura J, Gutierrez R, Andres J, Agapito T (2003). "Emergence and evolution of the circadian rhythm of melatonin in children". Horm. Res. 59 (2): 66–72. doi:10.1159/000068571. PMID 12589109.
- Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM (1986). "Human melatonin production decreases with age". J. Pineal Res. 3 (4): 379–88. doi:10.1111/j.1600-079X.1986.tb00760.x. PMID 3783419.
- Gavin ML, Scaivina MT (2009). "Why Aren't Teens Getting Enough Sleep?". How Much Sleep Do I Need?.
- Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T (November 2004). "Melatonin for treatment of sleep disorders". Evidence Report/Technology Assessment (Summary) (108): 1–7. PMID 15635761.
- Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ (1993). "Melatonin: a potent, endogenous hydroxyl radical scavenger". Endocrine J. 1: 57–60.
- Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR (November 1994). "Melatonin – a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro". Ann. N. Y. Acad. Sci. 738: 419–20. Bibcode:1994NYASA.738..419P. doi:10.1111/j.1749-6632.1994.tb21831.x. PMID 7832450.
- Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (January 2007). "One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?". J. Pineal Res. 42 (1): 28–42. doi:10.1111/j.1600-079X.2006.00407.x. PMID 17198536.
- Pohanka M (2011). "Alzheimer´s disease and related neurodegenerative disorders: implication and counteracting of melatonin". Journal of Applied Biomedicine 9 (4): 185–196. doi:10.2478/v10136-011-0003-6.
- Reiter RJ, Manchester LC, Tan DX (September 2010). "Neurotoxins: free radical mechanisms and melatonin protection". Curr Neuropharmacol 8 (3): 194–210. doi:10.2174/157015910792246236. PMC 3001213. PMID 21358970.
- Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F (1994). "Melatonin: a peroxyl radical scavenger more effective than vitamin E". Life Sci. 55 (15): PL271–6. doi:10.1016/0024-3205(94)00666-0. PMID 7934611.
- Lowes DA, Webster NR, Murphy MP, Galley HF (March 2013). "Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis". Br J Anaesth 110 (3): 472–80. doi:10.1093/bja/aes577. PMC 3570068. PMID 23381720.
- Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (July 2005). "A review of the multiple actions of melatonin on the immune system". Endocrine 27 (2): 189–200. doi:10.1385/ENDO:27:2:189. PMID 16217132.
- Arushanian EB, Beĭer EV (2002). "[Immunotropic properties of pineal melatonin]". Eksp Klin Farmakol (in Russian) 65 (5): 73–80. PMID 12596522.
- Pohanka, M (2013). "Impact of melatonin on immunity: a review". Central European Journal of Medicine 8 (4): 369–376. doi:10.2478/s11536-013-0177-2.
- Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM, Pozo D (May 2006). "The modulatory role of melatonin on immune responsiveness". Curr Opin Investig Drugs 7 (5): 423–31. PMID 16729718.
- Maestroni GJ (March 2001). "The immunotherapeutic potential of melatonin". Expert Opin Investig Drugs 10 (3): 467–76. doi:10.1517/135437188.8.131.527. PMID 11227046.
- Cutolo M, Maestroni GJ (August 2005). "The melatonin-cytokine connection in rheumatoid arthritis". Ann. Rheum. Dis. 64 (8): 1109–11. doi:10.1136/ard.2005.038588. PMC 1755599. PMID 16014678.
- Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T (November 2004). "Melatonin for treatment of sleep disorders". Evidence Report/Technology Assessment No. 108. (Prepared by the University of Alberta Evidence-based Practice Center, under Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-2. Rockville, MD: Agency for Healthcare Research and Quality. Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services. Retrieved 5 June 2013.
- "FDA Issues Dietary Supplements Final Rule" (Press release). U.S. Food and Drug Administration. 2007-06-22. Retrieved 2009-08-04.
- "FDA Tightens Up Dietary Supplement Manufacturing And Labelling". Medical News Today. 26 June 2007. Retrieved 2 September 2013.
- Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ (October 2001). "Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus)". J. Agric. Food Chem. 49 (10): 4898–902. doi:10.1021/jf010321. PMID 11600041.
- Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S (May 2011). "Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection". J. Pineal Res. 50 (4): 374–80. doi:10.1111/j.1600-079X.2010.00853.x. PMID 21342247.
- Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ (March 1995). "Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates". Biochem. Mol. Biol. Int. 35 (3): 627–34. PMID 7773197.
- Sae-Teaw M, Johns J, Johns NP, Subongkot S (October 2012). "Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers". J. Pineal Res. 55 (1): 58–64. doi:10.1111/jpi.12025. PMID 23137025.
- Catherine Saint Louis (14 May 2011). "Dessert, Laid-Back and Legal". New York Times.
- Rodriguez RR (January 13, 2010). "Warning Letter". Inspections, Compliance, Enforcement, and Criminal Investigations. U.S. Food and Drug Administration.
- Srinivasan V, Pandi-Perumal SR, Trahkt I, Spence DW, Poeggeler B, Hardeland R, Cardinali DP (2009). "Melatonin and melatonergic drugs on sleep: possible mechanisms of action". Int. J. Neurosci. 119 (6): 821–46. doi:10.1080/00207450802328607. PMID 19326288.
- Fornaro M, Prestia D, Colicchio S, Perugi G (September 2010). "A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation". Curr Neuropharmacol 8 (3): 287–304. doi:10.2174/157015910792246227. PMC 3001221. PMID 21358978.
- Turek FW, Gillette MU (November 2004). "Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists". Sleep Med. 5 (6): 523–32. doi:10.1016/j.sleep.2004.07.009. PMID 15511698.
- Wade AG, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, Zisapel N (October 2007). "Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes". Curr Med Res Opin 23 (10): 2597–605. doi:10.1185/030079907X233098. PMID 17875243.
- Cassone VM (November 1990). "Effects of melatonin on vertebrate circadian systems". Trends Neurosci. 13 (11): 457–64. doi:10.1016/0166-2236(90)90099-V. PMID 1701579.
- Lewy AJ, Sack RL, Miller LS, Hoban TM (January 1987). "Antidepressant and circadian phase-shifting effects of light". Science 235 (4786): 352–4. Bibcode:1987Sci...235..352L. doi:10.1126/science.3798117. PMID 3798117.
- Sircar R (February 2000). "Effect of melatonin on cocaine-induced behavioral sensitization". Brain Res. 857 (1–2): 295–9. doi:10.1016/S0006-8993(99)02460-9. PMID 10700581.
- Uz T, Akhisaroglu M, Ahmed R, Manev H (December 2003). "The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice". Neuropsychopharmacology 28 (12): 2117–23. doi:10.1038/sj.npp.1300254. PMID 12865893.
- Lemoine P, Zisapel N (2012). "Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia". Expert Opin Pharmacother 13 (6): 895–905. doi:10.1517/14656566.2012.667076. PMID 22429105.
- Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, Zisapel N (2000). "Melatonin improves sleep quality of patients with chronic schizophrenia". J Clin Psychiatry 61 (5): 373–7. doi:10.4088/jcp.v61n0509. PMID 10847313.
- Dolberg OT, Hirschmann S, Grunhaus L (August 1998). "Melatonin for the treatment of sleep disturbances in major depressive disorder". Am J Psychiatry 155 (8): 1119–21. PMID 9699707.
- Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM (2000). "Use of slow-release melatonin in treatment-resistant depression". J Psychiatry Neurosci 25 (1): 48–52. PMC 1407707. PMID 10721684.
- Jan JE, Hamilton D, Seward N, Fast DK, Freeman RD, Laudon M (August 2000). "Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders". J. Pineal Res. 29 (1): 34–9. doi:10.1034/j.1600-079X.2000.290105.x. PMID 10949538.
- De Leersnyder H, Bresson JL, de Blois MC, Souberbielle JC, Mogenet A, Delhotal-Landes B, Salefranque F, Munnich A (2003). "Beta 1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome". J. Med. Genet. 40 (1): 74–8. doi:10.1136/jmg.40.1.74. PMC 1735264. PMID 12525548.
- Grossman E, Laudon M, Zisapel N (2011). "Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials". Vasc Health Risk Manag 7: 577–84. doi:10.2147/VHRM.S24603. PMC 3180511. PMID 21966222.
- Liira, J; Verbeek, JH; Costa, G; Driscoll, TR; Sallinen, M; Isotalo, LK; Ruotsalainen, JH (Aug 12, 2014). "Pharmacological interventions for sleepiness and sleep disturbances caused by shift work.". The Cochrane database of systematic reviews 8: CD009776. doi:10.1002/14651858.CD009776.pub2. PMID 25113164.
- Simpson HW (1979). "Chronobiotics: Selected Agents of Potential Value in Jet Lag and other Dyschronisms". In Sheving FE, Hagberg F. Chronobiology: Principles and Application to Shifts in Schedules. Berlin: Springer. p. 433. ISBN 978-90-286-0940-2. The reference discusses several chronobiotic substances, but not melatonin.
- Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG (July 2003). "Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study". Eur. J. Pediatr. 162 (7–8): 554–5. doi:10.1007/s00431-003-1207-x. PMID 12783318.
- Dodick DW, Capobianco DJ (February 2001). "Treatment and management of cluster headache". Curr Pain Headache Rep 5 (1): 83–91. doi:10.1007/s11916-001-0015-0. PMID 11252143.
- Gagnier JJ (August 2001). "The therapeutic potential of melatonin in migraines and other headache types". Altern Med Rev 6 (4): 383–9. PMID 11578254.
- Mills E, Wu P, Seely D, Guyatt G (November 2005). "Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis". J. Pineal Res. 39 (4): 360–6. doi:10.1111/j.1600-079X.2005.00258.x. PMID 16207291.
- National Cancer Institute (May 2013). "Topics in complementary and alternative therapies (PDQ)". National Cancer Institute, National Institutes of Health. Retrieved 5 June 2013.
- Koppisetti S, Jenigiri B, Terron MP, Tengattini S, Tamura H, Flores LJ, Tan DX, Reiter RJ (October 2008). "Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review". Dig. Dis. Sci. 53 (10): 2592–603. doi:10.1007/s10620-007-0195-5. PMID 18338264.
- Tan D, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ (October 1999). "High physiological levels of melatonin in the bile of mammals". Life Sci. 65 (23): 2523–9. doi:10.1016/S0024-3205(99)00519-6. PMID 10622237.
- Meltz ML, Reiter RJ, Herman TS, Kumar KS (March 1999). "Melatonin and protection from whole-body irradiation: survival studies in mice". Mutat. Res. 425 (1): 21–7. doi:10.1016/S0027-5107(98)00246-2. PMID 10082913.
- Reiter RJ, Herman TS, Meltz ML (December 1996). "Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers". Mutat. Res. 371 (3–4): 221–8. doi:10.1016/S0165-1218(96)90110-X. PMID 9008723.
- Reiter RJ, Herman TS, Meltz ML (February 1998). "Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes". Mutat. Res. 397 (2): 203–8. doi:10.1016/S0027-5107(97)00211-X. PMID 9541644.
- Topkan E, Tufan H, Yavuz AA, Bacanli D, Onal C, Kosdak S, Yavuz MN (October 2008). "Comparison of the protective effects of melatonin and amifostine on radiation-induced epiphyseal injury". Int. J. Radiat. Biol. 84 (10): 796–802. doi:10.1080/09553000802389678. PMID 18979313.
- Shirazi A, Ghobadi G, Ghazi-Khansari M (July 2007). "A radiobiological review on melatonin: a novel radioprotector". J. Radiat. Res. 48 (4): 263–72. doi:10.1269/jrr.06070. PMID 17641465.
- Hurtuk A, Dome C, Holloman CH, Wolfe K, Welling DB, Dodson EE, Jacob A (July 2011). "Melatonin: can it stop the ringing?". Ann. Otol. Rhinol. Laryngol. 120 (7): 433–40. PMID 21859051.
- Megwalu UC, Finnell JE, Piccirillo JF (February 2006). "The effects of melatonin on tinnitus and sleep". Otolaryngol Head Neck Surg 134 (2): 210–3. doi:10.1016/j.otohns.2005.10.007. PMID 16455366.
- Rosenberg SI, Silverstein H, Rowan PT, Olds MJ (March 1998). "Effect of melatonin on tinnitus". Laryngoscope 108 (3): 305–10. doi:10.1097/00005537-199803000-00001. PMID 9504599.
- Pirodda A, Raimondi MC, Ferri GG (August 2010). "Exploring the reasons why melatonin can improve tinnitus". Med. Hypotheses 75 (2): 190–1. doi:10.1016/j.mehy.2010.02.018. PMID 20207491.
- Lewis, Alan (1999). Melatonin and the Biological Clock. McGraw-Hill. p. 23. ISBN 0-87983-734-9.
- Braam W, Smits MG, Didden R, Korzilius H, Van Geijlswijk IM, Curfs LM (May 2009). "Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis". Dev Med Child Neurol (Meta-analysis) 51 (5): 340–9. doi:10.1111/j.1469-8749.2008.03244.x. PMID 19379289.
- Bendz LM, Scates AC (January 2010). "Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder". Ann Pharmacother 44 (1): 185–91. doi:10.1345/aph.1M365. PMID 20028959.
- Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S (2005). "The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis". J Gen Intern Med 20 (12): 1151–8. doi:10.1111/j.1525-1497.2005.0243.x. PMC 1490287. PMID 16423108.
- Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G (February 2006). "Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis". BMJ 332 (7538): 385–93. doi:10.1136/bmj.38731.532766.F6. PMC 1370968. PMID 16473858.
- Lyseng-Williamson KA (2012). "Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years". Drugs Aging 29 (11): 911–23. doi:10.1007/s40266-012-0018-z. PMID 23044640.
- Brent Bauer, M.D. "Melatonin side effects: What are the risks?". Mayo Clinic. Retrieved 2011-08-17.
- Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU (October 2001). "Melatonin treatment for age-related insomnia". J. Clin. Endocrinol. Metab. 86 (10): 4727–30. doi:10.1210/jc.86.10.4727. PMID 11600532.
- Sack RL, Brandes RW, Kendall AR, Lewy AJ (October 2000). "Entrainment of free-running circadian rhythms by melatonin in blind people". N. Engl. J. Med. 343 (15): 1070–7. doi:10.1056/NEJM200010123431503. PMID 11027741.
- Ray CA (2003). "Melatonin attenuates the sympathetic nerve responses to orthostatic stress in humans". The Journal of Physiology 551 (3): 1043–8. doi:10.1113/jphysiol.2003.043182. PMC 2343280. PMID 12869610. Lay summary – ScienceDaily (September 16, 2003).
- Morera AL, Henry M, de La Varga M (2001). "Seguridad en el uso de la melatonina" [Safety in melatonin use]. Actas Esp Psiquiatr (in Spanish) 29 (5): 334–7. PMID 11602091.
- Terry PD, Villinger F, Bubenik GA, Sitaraman SV (January 2009). "Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research". Inflamm. Bowel Dis. 15 (1): 134–40. doi:10.1002/ibd.20527. PMID 18626968.
- Juszczak M, Michalska M (2006). "Wpływ melatoniny na syntezę i wydzielanie prolaktyny, hormonu luteinizującego (LH) i folikulotropowego (FSH)" [The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion]. Postepy Hig Med Dosw (Online) (in Polish) 60: 431–8. PMID 16921343.
- Srinivasan V, Spence WD, Pandi-Perumal SR, Zakharia R, Bhatnagar KP, Brzezinski A (December 2009). "Melatonin and human reproduction: shedding light on the darkness hormone". Gynecol. Endocrinol. 25 (12): 779–85. doi:10.3109/09513590903159649. PMID 19905996.
- Cohen M, van Heusden AM, Verdonk HER, Wijnhamer P (1993). "Melatonin/Norethisterone contraception". In Touitou Y, Arendt J and Pevet P. Melatonin and the Pineal Gland – From Basic Science to Clinical Application. Amsterdam: Elsevier. pp. 339–45. ISBN 978-0-444-89583-7.
- Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C (August 1999). "Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats". Toxicol. Sci. 50 (2): 271–9. doi:10.1093/toxsci/50.2.271. PMID 10478864.
- Wiechmann AF, Chignell CF, Roberts JE (February 2008). "Influence of dietary melatonin on photoreceptor survival in the rat retina: an ocular toxicity study". Exp. Eye Res. 86 (2): 241–50. doi:10.1016/j.exer.2007.10.015. PMC 2377032. PMID 18078931.
- Anisimov VN, Zavarzina NY, Zabezhinski MA, Popovich IG, Zimina OA, Shtylick AV, Arutjunyan AV, Oparina TI, Prokopenko VM, Mikhalski AI, Yashin AI (July 2001). "Melatonin increases both life span and tumor incidence in female CBA mice". J. Gerontol. A Biol. Sci. Med. Sci. 56 (7): B311–23. doi:10.1093/gerona/56.7.B311. PMID 11445596.
- Schernhammer E, Chen H, Ritz B (May 2006). "Circulating melatonin levels: possible link between Parkinson's disease and cancer risk?". Cancer Causes Control. 17 (4): 577–582. doi:10.1007/s10552-005-9002-9. PMID 16596313.
- Meng T, Zheng ZH, Liu TT, Lin L (May 2012). "Contralateral retinal dopamine decrease and melatonin increase in progression of hemiparkinsonium rat". Neurochem Res. 37 (5): 1050–6. doi:10.1007/s11064-012-0706-4. PMID 22252727.
- Ratzburg C (n.d.). "Melatonin: The Myths and Facts". Vanderbilt University. Retrieved 2007-12-02.
- "Melatonin". Drugs.com. Retrieved 2011-08-17.
- Medical News Today Circadin (Prolonged-Release Melatonin) For Primary Insomnia Recommended For Approval In The EU (27 Apr 2007)
- European Medicines Agency. "Circadin, melatonin". European Public Assessment Report (EPAR). European Medicines Agency. Retrieved 5 June 2013.
- Therapeutic Goods Administration (TGA). "Australian Public Assessment Report for Melatonin". Department of Health and Ageing, Australian Government. Retrieved 5 June 2013.
- SwissMedic (2009). "Circadin®, Retardtabletten, 2 mg (melatoninum)" (in Deutsch).
- "Circadin license application" (PDF) (in Korean). MFDS. 2014.
- Ministry of Health Israel. "Circadin leaflet".
- Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M, Zisapel N (2010). "Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety". BMC Med 8: 51. doi:10.1186/1741-7015-8-51. PMC 2933606. PMID 20712869.