The full effects of long-term exogenous (dietary) supplementation in humans have not yet been ascertained. Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement and is not regulated as a pharmaceutical drug. A prescription-only, timed release melatonin product for people aged 55 and over was approved for use by the European Medicines Agency in 2007, despite having shown only small effects, and in Australia in 2009.
Melatonin has been 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 of melatonin in plants involve regulation of their response to photoperiod, defense against harsh environments, and the function of an antioxidant. The latter may be the original function of melatonin in organisms with the others being added during evolution. Melatonin also regulates plant growth by its ability to slow root formation, while promoting above ground growth.
Melatonin has been reported in foodstuffs 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.
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.
In mammals, melatonin is biosynthesized in four enzymatic steps from the essential dietary amino acid tryptophan, with serotonin produced at the third step. Melatonin is secreted into the blood by the pineal gland in the brain. Known as the "hormone of darkness," it is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals. It may also be produced by a variety of peripheral cells such as bone marrow cells, lymphocytes, and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood, but it does not seem to be regulated by the photoperiod.
Light/dark information reaches the suprachiasmatic nuclei (SCN) from retinal photosensitive ganglion cells, which are intrinsically photosensitive photoreceptor cells that are distinct from those involved in the primary (at least, from one point of view) image formation function of the eye (that is the rods and cones of the retina). These cells represent approximately 2% of all retinal ganglion cells in humans and express the photopigment melanopsin.
Melanopsin, often confused with melatonin because of its similar name, is structurally unrelated to the hormone. It is a conventional 7-transmembrane opsin protein with the usual vitamin A-like cis-retinal cofactor having a peak absorption at 484 nm, in the blue light part of the visible spectrum. The photoperiod cue created by blue light (from a blue image of the sky) entrains a circadian rhythm, and thus governs resultant production of specific "dark"- and "light"-induced neural and endocrine signals that regulate behavioral and physiological circadian rhythms associated with melatonin. Melatonin is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.
In humans, melatonin is produced by the pineal gland, a small endocrine gland located in the center of the brain but outside the blood–brain barrier. The melatonin signal forms part of the system that regulates the sleep–wake cycle by chemically causing drowsiness and lowering the body temperature, but it is the central nervous system (specifically the suprachiasmatic nuclei, or SCN) that controls the daily cycle in most components of the paracrine and endocrine systems rather than the melatonin signal (as was once postulated).
Infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 AM.
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.
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.
Production of melatonin by the pineal gland is inhibited by light to the retina and permitted by darkness. Its onset each evening 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.
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.
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.
Research has supported the anti-aging properties of melatonin. Younger children hit their peak melatonin production at night, and some researchers believe that the level of melatonin peaks earlier as people get older. This may explain why older adults go to bed earlier, wake up earlier, and have more sleep problems than children do.
Some studies have shown that melatonin plays a crucial part in the aging process and that it may act as an anti-aging agent when administered to older mice. It has been reported in one study that administration of melatonin in elderly mice may reverse this change in expression of some 13 genes, thus making them similar to those of younger mice. Consuming melatonin may neutralize oxidative damage and delay the neurodegenerative process of aging. When small amounts of melatonin were administered to lab mice, it reduced the oxidative damage caused by aging and delayed the inflammatory process, which in turn increased the longevity of the mice.
Single-nucleotide polymorphisms of the human melatonin MT2 receptor have been linked to an increased risk of developing type 2 diabetes. Furthermore women with low levels of melatonin secretion have been found more likely to develop type 2 diabetes than women with high levels.
While the packaging of melatonin often warns against use in children, at least one long-term study does assess effectiveness and safety in children. No serious safety concerns were noted in any of the 94 cases studied by means of a structured questionnaire for the parents. With a mean follow-up time of 3.7 years, long-term medication was effective against sleep onset problems in 88% of the cases. Other studies warn against potential side effects
A 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.
For many types of sleep disorders, melatonin is not effective. A 2006 review found that although it is safe for short term use (of three months or less), there is "no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder."
In a 2005 study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating delayed sleep phase disorder (DSPD), there is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."
Exogenous (externally derived) 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.
A very small dose taken several hours before bedtime in accordance with the phase response curve for melatonin in humans (PRC) doesn't 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.
Learning, memory and Alzheimer's
Melatonin receptors appear to be important in mechanisms of learning and memory in mice, and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). The first published evidence that melatonin may be useful in Alzheimer's disease was the demonstration that this neurohormone prevents neuronal death caused by exposure to the amyloid beta protein, a neurotoxic substance that accumulates in the brains of patients with the disorder. Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates that, it seems, underlie the neurotoxicity of this protein, causing death of neurons and formation of neurofibrillary tangles, the other neuropathological landmark of Alzheimer's disease.
Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can also result in the formation of neurofibrillary tangles. Studies in rats suggest that melatonin may be effective for treating Alzheimer's disease. These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their bodies' production of melatonin. Another study has implicated heightened afternoon agitation found in many Alzheimer's patients, called sundowning, with a phase delay in core body temperature. This may suggest a possible connection to melatonin production.
A randomized placebo-controlled trial showed that low-dose melatonin supplementation to 72 elderly patients admitted to acute medicine services significantly reduced delirium.
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.
Melatonin has been shown to be effective in treating seasonal affective disorder, a form of depression, and is being considered for bipolar and other disorders in which circadian disturbances are involved. It was observed in 1985 that bipolar disorder might have elevated sensitivity to light, i.e., a greater decrease in melatonin secretion in response to light exposure at night, as a "trait marker" (a characteristic of being bipolar, which does not change with state). This could be contrasted with drug-free recovered bipolar patients showing normal light sensitivity.
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. In guinea pigs, melatonin administration in a dose about 50-100 times typical restored normal function by reducing inflammation after induced cholecystitis, whether administered before or after onset of inflammation. 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.
Amyotrophic lateral sclerosis
In animal models, melatonin has been shown to ameliorate glutamate-induced neuronal death, it is presumed due to its antioxidant effects. In a clinical safety study involving 31 ALS patients, high-dose rectal melatonin (300 mg/day for 2 years) was shown to be tolerated well.
Melatonin is involved in energy metabolism and body weight control in small animals. Many studies show that chronic melatonin supplementation in drinking water reduces body weight and abdominal fat in experimental animals, especially in the middle-aged rats and the weight loss effect did not require the animals to eat less and to be physically more active. A potential mechanism is that melatonin promotes the recruitment of brown adipose tissue (BAT) as well as enhances its activity. This effect would raise the basal metabolic rate by stimulating thermogenesis, heat generation through uncoupling oxidative phosphorylation in mitochondria. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials, since substantially active BAT has been identified in adult 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.
Several medical studies involving adult patients indicate that melatonin can be beneficial in the treatment of tinnitus.
Melatonin was used to treat periodic limb movement disorder, a common neurological condition, which, when severe, adversely affects sleep and causes excessive daytime fatigue, in a small trial conducted by Kunz D and Bes F. In this condition, the sufferer is affected by mini arousals during sleep and limb movements that occur in a frequent rhythmic fashion. This often involves leg kicking, but sometimes also involves arm movement. Those affected are often not aware of the condition, and partners are often the first to notice the condition. 7 out of the 9 participants in the trial showed significant improvement.
A research team in Italy has found that melatonin supplementation in the evening in perimenopausal women produces an improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause. One study reported that melatonin taken in the evening raised prolactin levels in six out of seven women.
Melatonin appears to cause very few side-effects in the short term, up to three months, when healthy people take it at low doses. A systematic review in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances that are secondary to other diagnoses and, second, for sleep disorders such as jet lag and shift work that accompany sleep restriction.
The study concluded that "There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use".
A similar analysis by the same team a year earlier on the efficacy and safety of exogenous melatonin in the management of primary sleep disorders found that: "There is evidence to suggest that melatonin is safe with short-term use (3 months or less)."
Melatonin has been found to lower FSH levels.[better source needed] Effects of the hormone on human reproduction remain unclear, although it was with some effect tried as a contraceptive in the 1990s.
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 parkinsonian symptoms, whereas reduction in melatonin by pinealectomy or exposure to bright light can improve recovery from parkinsonisms symptoms. Melatonin may exacerbate neurodegeneration in advanced Parkinson's disease.
Legal availability of melatonin varies in different 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 UK) or not at all (although its possession and use may not be illegal). It is widely available on the Internet.
The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.
The use of melatonin derived from animal pineal tissue may carry the risk of contamination or the means of transmitting viral material. The synthetic form of this medication does not carry this risk.
In the US it is sold as a dietary supplement (sometimes combined with other ingredients, such as vitamins and herbal extracts) and not as a 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.
As reported in the New York Times in May 2011, melatonin is sold in grocery stores, convenience stores, and clubs in both beverage and snack forms. 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.
Circadin 2mg, prolonged-release melatonin
Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. The European Medicines Agency (EMA) has approved Circadin 2 mg (prolonged-release melatonin) 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.
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 epidermalmelanophores. 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."
^ abHardeland R (July 2005). "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance". Endocrine27 (2): 119–30. doi:10.1385/ENDO:27:2:119. PMID16217125.
^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. PMID11462772.
^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.
^European Medicines Agency. "Circadin, melatonin". European Public Assessment Report (EPAR). European Medicines Agency. Retrieved 5 June 2013.
^Bioactivity of grape chemicals for human health. Iriti M and Faoro F, Nat Prod Commun., 2009 May, 4(5), pages 611-634, PubMed
^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. PMID22016420.
^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 Soc85 (3): 607–23. doi:10.1111/j.1469-185X.2009.00118.x. PMID20039865.
^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. PMID11600041.
^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. PMID21342247.
^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. PMID7773197.
^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. PMID23137025.
^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. PMID14529560.
^ abArendt J, Skene DJ (February 2005). "Melatonin as a chronobiotic". Sleep Med Rev9 (1): 25–39. doi:10.1016/j.smrv.2004.05.002. PMID15649736. "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."
^Chen HJ (July 1981). "Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition". Neuroendocrinology33 (1): 43–6. doi:10.1159/000123198. PMID7254478.
^ abChallet E (December 2007). "Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals". Endocrinology148 (12): 5648–55. doi:10.1210/en.2007-0804. PMID17901231.
^ abcTan 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. PMID17198536.
^Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (July 2005). "A review of the multiple actions of melatonin on the immune system". Endocrine27 (2): 189–200. doi:10.1385/ENDO:27:2:189. PMID16217132.
^Arushanian EB, Beĭer EV (2002). "[Immunotropic properties of pineal melatonin]". Eksp Klin Farmakol (in Russian) 65 (5): 73–80. PMID12596522.
^Lewis, Alan (1999). Melatonin and the Biological Clock. McGraw-Hill. p. 23. ISBN0-87983-734-9.
^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. PMID19379289.
^Sharma M, Palacios-Bois J, Schwartz G, Iskandar H, Thakur M, Quirion R, Nair NP (February 1989). "Circadian rhythms of melatonin and cortisol in aging". Biological Psychiatry25 (3): 305–319. doi:10.1016/0006-3223(89)90178-9. PMID2914154.
^Brown GM, Young SN, Gauthier S, Tsui H, Grota LJ (September 1979). "Melatonin in human cerebrospinal fluid in daytime: its origin and variation with age". Life Science25 (11): 929–936. doi:10.1016/0024-3205(79)90498-3. PMID513940.
^Hoebert M, van der Heijden KB, van Geijlswijk IM, Smits MG (August 2009). "Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia". J. Pineal Res.47 (1): 1–7. doi:10.1111/j.1600-079X.2009.00681.x. PMID19486273.
^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 Opin23 (10): 2597–605. doi:10.1185/030079907X233098. PMID17875243.
^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". Neuropsychopharmacology28 (12): 2117–23. doi:10.1038/sj.npp.1300254. PMID12865893.
^Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA (2006). "Melatonin as antioxidant, geroprotector and anticarcinogen". Biochim. Biophys. Acta1757 (5–6): 573–89. doi:10.1016/j.bbabio.2006.03.012. PMID16678784.
^Larson J, Jessen RE, Uz T, Arslan AD, Kurtuncu M, Imbesi M, Manev H (January 2006). "Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice". Neurosci. Lett.393 (1): 23–6. doi:10.1016/j.neulet.2005.09.040. PMID16203090.
^Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK (March 1997). "Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide". J. Neurosci.17 (5): 1683–90. PMID9030627.
^Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghiso J (March 1998). "Inhibition of Alzheimer beta-fibrillogenesis by melatonin". J. Biol. Chem.273 (13): 7185–8. doi:10.1074/jbc.273.13.7185. PMID9516407.
^Wang XC, Zhang J, Yu X, Han L, Zhou ZT, Zhang Y, Wang JZ (February 2005). "Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat". Sheng Li Xue Bao57 (1): 7–12. PMID15719129.
^Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M (July 2011). "Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial". Int J Geriatr Psychiatry26 (7): 687–94. doi:10.1002/gps.2582. PMID20845391.
^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. PMID12783318.
^Lewy AJ, Nurnberger JI, Wehr TA, Pack D, Becker LE, Powell RL, Newsome DA (June 1985). "Supersensitivity to light: possible trait marker for manic-depressive illness". Am J Psychiatry142 (6): 725–7. PMID4003592.
^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. PMID16207291.
^ abKoppisetti 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. PMID18338264.
^Weishaupt JH, Bartels C, Pölking E, Dietrich J, Rohde G, Poeggeler B, Mertens N, Sperling S, Bohn M, Hüther G, Schneider A, Bach A, Sirén AL, Hardeland R, Bähr M, Nave KA, Ehrenreich H (November 2006). "Reduced oxidative damage in ALS by high-dose enteral melatonin treatment". J. Pineal Res.41 (4): 313–23. doi:10.1111/j.1600-079X.2006.00377.x. PMID17014688.
^Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, Rasmussen DD (February 2000). "Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat". Endocrinology141 (2): 487–97. doi:10.1210/en.141.2.487. PMID10650927.
^Tan DX, Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ (March 2011). "Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity". Obes Rev12 (3): 167–88. doi:10.1111/j.1467-789X.2010.00756.x. PMID20557470.
^Nedergaard J, Bengtsson T, Cannon B (August 2007). "Unexpected evidence for active brown adipose tissue in adult humans". Am J Physiol Endocrinol Metab.293 (2): E444–E452. doi:10.1152/ajpendo.00691.2006. PMID17473055.
^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. PMID9008723.
^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. PMID18979313.
^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. PMID17641465.
^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. PMID21859051.
^Terzolo M, Revelli A, Guidetti D, Piovesan A, Cassoni P, Paccotti P, Angeli A, Massobrio M (August 1993). "Evening administration of melatonin enhances the pulsatile secretion of prolactin but not of LH and TSH in normally cycling women". Clin. Endocrinol. (Oxf)39 (2): 185–91. doi:10.1111/j.1365-2265.1993.tb01772.x. PMID8370131.
^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. PMID11600532.
^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. PMID11027741.
^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. PMID11602091.
^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. PMID19905996.
^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. ISBN978-0-444-89583-7.
^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. PMID10478864.
^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. PMID11445596.
^ abRodriguez RR (January 13, 2010). "Warning Letter". Inspections, Compliance, Enforcement, and Criminal Investigations. U.S. Food and Drug Administration.
^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. PMID16596313.
^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. PMID22252727.
^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. Rhythms20 (4): 291–303. doi:10.1177/0748730405277492. PMID16077149. "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."