Melatonin

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Not to be confused with melanin or Melanotan (disambiguation).
Melatonin
File:Melatonin2.svg
File:Melatonin-3d-CPK.png
Systematic (IUPAC) name
N-[2-(5-methoxy-1H-indol-3-yl)ethyl]
ethanamide
Clinical data
Routes of
administration		 In humans: orally, as capsules, tablets or liquid, sublingually, or as transdermal patches. In lab animals: also injection.
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: OTC
Pharmacokinetic data
Bioavailability 30 – 50%
Metabolism Hepatic via CYP1A2 mediated 6-hydroxylation
Biological half-life 35 to 50 minutes
Excretion Urine
Identifiers
CAS Number 73-31-4
ATC code N05CH01 (WHO)
PubChem CID 896
IUPHAR/BPS 224
DrugBank APRD00742
ChemSpider 872
Chemical data
Formula C13H16N2O2
Molar mass 232.278 g/mol[[Script error: No such module "String".]]
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Melatonin (pronounced /ˌmɛləˈtoʊnɪn/ (13px listen)), also known chemically as N-acetyl-5-methoxytryptamine,[1] is a naturally occurring compound found in animals, plants, and microbes.[2][3] In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions.[4]

Many biological effects of melatonin are produced through activation of melatonin receptors,[5] while others are due to its role as a pervasive and powerful antioxidant,[6] with a particular role in the protection of nuclear and mitochondrial DNA.[7]

In mammals, 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.[8]

It may also be produced by a variety of peripheral cells such as bone marrow cells,[9][10] 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.

Melatonin-rich plant feed, such as rice, ingested by chicks has been shown to reach and bind to melatonin receptors in their brains.[11] No food has been found to elevate plasma melatonin levels in humans.[12]

Products containing melatonin have been available over-the-counter as a dietary supplement in the United States since before 1994.[13] In many other countries, sale of the hormone remains illegal or requires a prescription, and the U.S. Postal Service lists melatonin among items prohibited by Germany.[14]

History

Melatonin is related to the mechanism by which some amphibians and reptiles change the color of their skin and, indeed, it was in this connection the substance first was discovered.[15][16] As early as 1917, McCord and Allen discovered (J Exptl Zool, 1917) that extract of the pineal glands of cows lightened frog skin.[12] 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 and named the hormone melatonin in 1958.[17] In the mid-70s Lynch et al. demonstrated[18] that the production of melatonin exhibits a circadian rhythm in human pineal glands. The discovery that melatonin is an antioxidant was made in 1993.[19]

In plants

Melatonin in plants has multiple roles including regulation of the photoperiod, in plant defense responses, and as a scavenger of reactive oxygen species.[3]

In animals

Many animals use the variation in duration of melatonin production each day as a seasonal clock.[20] In animals including humans[21] 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 organisation of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behaviour, coat growth and camouflage colouring in seasonal animals.[21] In seasonal breeders which do not have long gestation periods and which 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[22] and hamsters.[23]

In mammals

Melatonin produced in the pineal gland, which is outside of the blood-brain barrier, acts as an endocrine hormone since it is released into the blood. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.[citation needed]

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 the levels; see leptin.

Light/dark information reaches the suprachiasmatic nuclei (SCN) via retinal photosensitive ganglion cells, intrinsically photosensitive photoreceptor cells, distinct from those involved in image forming (that is, these light sensitive cells are a third type in the retina, in addition to rods and cones). These cells represent approximately 2% of the retinal ganglion cells in humans and express the photopigment melanopsin.[24] The sensitivity of melanopsin is consistent with that of a vitamin A-based photopigment with a peak sensitivity at 484 nm (blue light).[25] This photoperiod cue entrains the circadian rhythm, and the resultant production of specific "dark"- and "light"-induced neural and endocrine signals which regulate behavioral and physiological circadian rhythms. Melatonin is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.[8]

In humans

Circadian rhythm

In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, 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 (more specifically, the SCN) that controls the daily cycle in most components of the paracrine and endocrine systems[26][27] 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 08:00 (8 AM).[28]

In humans, 90% of melatonin is cleared in a single passage through the liver, a small amount is excreted in urine,[29] and a small amount is found in saliva.

Light dependence

Production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness". Its onset each evening is called the Dim-Light Melatonin Onset (DLMO). Secretion of melatonin as well as its level in the blood, peaks in the middle of the night, and gradually falls during the second half of the night, with normal variations in timing according to an individual's chronotype.

It is principally blue light, around 480nm, that suppresses melatonin,[30] increasingly with increased 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. Wearing glasses that block blue light in the hours before bedtime may avoid melatonin loss. Kayumov et al. showed that light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions.[31] 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.

Antioxidant

Besides its function as synchronizer of the biological clock, melatonin also exerts a powerful antioxidant activity. The discovery of melatonin as an antioxidant was made in 1993.[19] In many less complex life forms, this is its only known purpose.[32] Melatonin is an antioxidant that can easily cross cell membranes and the blood-brain barrier.[6] Melatonin is a direct scavenger of OH, O2−, and NO.[33] Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, on the other hand, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.[34]

Recent research indicates that the first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (or AFMK) rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neutralize up to 10 ROS/RNS (reactive oxygen species/reactive nitrogen species) since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.[32]

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[35] It also has been found to be effective in protecting against brain injury caused by ROS release in experimental hypoxic brain damage in newborn rats.[36] Melatonin's antioxidant activity may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.[37][38][39]

Immune system

While it is known that melatonin interacts with the immune system,[40][41] the details of those interactions are unclear. 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 result from melatonin acting on high affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production,[42] and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease[43] including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.[44]

Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor.[45] This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human T lymphocytes. When taken in conjunction with calcium, it is an immunostimulator[citation needed] and is used as an adjuvant in some clinical protocols[citation needed]; conversely, the increased immune system activity may aggravate autoimmune disorders. In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.[46]

Dreaming

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 both people with and without narcolepsy.[47] Many psychoactive drugs, such as cannabis and lysergic acid diethylamide (LSD), increase melatonin synthesis.[47] It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.[47]

Autism

Individuals with autism spectrum disorders (ASD) may have lower than normal levels of melatonin. A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the ASMT gene, which encodes the last enzyme of melatonin synthesis.[48]

Current and potential medical indications

Melatonin has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), circadian rhythm sleep disorders and sexual dysfunction. Studies by Alfred J. Lewy at Oregon Health & Science University and other researchers have found that it may ameliorate circadian misalignment and SAD.[49] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[50]

Treatment of circadian rhythm disorders

Exogenous melatonin taken in the evening is, together with light therapy upon awakening, the standard treatment for delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome. 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 DSPS than in people with insomnia.[29]

Taken 30 to 90 minutes before bedtime, melatonin supplementation acts as a mild hypnotic. It causes melatonin levels in the blood to rise earlier than the brain's own production accomplishes. This usage is now commonly used in sleep and relaxation drinks, such as Dream Water.[51]

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),[52] 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 a small oral dose melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.[53]

Preventing ischemic damage

Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain[54] and the heart;[55] however, this has not been tested in humans.

Learning, memory and Alzheimer's

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[56] 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.[57] Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates which seem to underlie the neurotoxicity of this protein, causing death of neurons and formation of neurofibrillary tangles, the other neuropathological landmark of Alzheimer's disease.[57]

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.[58] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their bodies' production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called sundowning, which has been shown in many studies to be effectively treated with melatonin supplements in the evening.[59]

ADHD

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.[60]

Fertility

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.[61] However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement.[62] One study reported that three mg of melatonin taken in the evening raised prolactin levels in six out of seven women.[63] Melatonin also lowers FSH levels. It is believed that these hormonal changes could in some women impair fertility.[1]

Toxicology

Melatonin has a very low toxicity in rats. Rat maternal toxicity: the no observable adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL was >= 200 mg/kg/day.[64]

Headaches

Several clinical studies indicate that supplementation with melatonin is an effective preventive treatment for migraines and cluster headaches.[65][66]

Mood disorders

Melatonin has been shown to be effective in treating one form of depression, seasonal affective disorder,[67] and is being considered for bipolar and other disorders where circadian disturbances are involved.[68] It has been observed that bipolar disorder might have, as a "trait marker" (something which is characteristic of being bipolar, that does not change with state), supersensitivity to light, i.e. a greater decrease in melatonin secretion in response to light exposure at night.[69] This could be contrasted with drug-free recovered bipolar people not showing light hypersensitivity.[70]

Cancer

A systematic review of unblinded clinical trials involving a total of 643 cancer patients using melatonin found a reduced incidence of death.[71] Another clinical trial is due to be completed in 2012.[72] Melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes, and it has been shown that women with the brightest bedrooms have an increased risk for breast cancer.[73] Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers.[74]

Gallbladder stones

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.[75] 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 restored normal function by reducing inflammation after induced Cholecystitis, whether administered before or after onset of inflammation.[75] Relatively speaking, 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.[76]

Amyotrophic lateral sclerosis

In animal models, melatonin has been shown to ameliorate glutamate-induced neuronal death, possibly 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.[77]

Obesity

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.[78] Interestingly, the weight loss effect of melatonin does 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.[79] BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. In this way, the fat is burned. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials since substantial amounts of active BAT have been identified in adult humans.

Other

Histologically, it is believed that melatonin has some effects for sexual development in higher organisms.[80] It is involved in the seasonal timing of reproduction in rodents, at least.

Exogenous melatonin has also been used in a small clinical trial by Kunz D and Bes F to treat Periodic Limb Movement Disorder, a common neurological condition which, when severe, adversely affects sleep and causes excessive daytime fatigue. The sufferer is affected by mini arousals (often without noticing) during sleep when the limb movements occur in a frequent rhythmic fashion, often involving leg kicking but sometimes also involving the arms. Partners are often the first to notice the condition. In the trial, 7 out of the 9 taking part showed significant improvement.[citation needed]

A veterinarian may recommend melatonin for dogs suffering from aggression or separation anxiety.[citation needed]

Use as medication

File:Walgreens Melatonin-2010-20-07.jpg
A bottle of melatonin tablets

The hormone melatonin is used to treat circadian rhythm sleep disorders and some types of insomnia.

Studies have found that the use of melatonin can help entrain the circadian clock to environmental cycles and have beneficial effects for the treatment of certain forms of insomnia.[81] Prolonged release melatonin has shown good results in treating insomnia in older adults.[82]

Other studies have found that for certain 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."[83] However, a 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.[29]

In another study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome", ... "There is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."[84]

Dosage

Studies from Massachusetts Institute of Technology have said that melatonin pills sold as supplements contain three to ten times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for a more rapid sleep onset. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses (for example 0.3 mg as opposed to 3 mg) are just as effective.[85] Large doses of melatonin can even be counterproductive: Lewy et al.[86] provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve" (PRC). In one of their subjects, 0.5 mg of melatonin was effective while 20 mg was not.

Availability and safety

Melatonin is available without prescription in most cases in the United States and Canada, while it is available only by prescription or not at all in some other countries. The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.

Dietary supplement

In the USA, because it is sold as a dietary supplement and not as a drug, the Food and Drug Administration (FDA) regulations that apply to medications are not applicable to melatonin.[4] 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."[87] In addition, the industry has been required to report to the FDA "all serious dietary supplement related adverse events" and the FDA has, within the cGMP guidelines, recently begun enforcement of that requirement.

Pediatrics

While the packaging of melatonin often warns against use in children, at least one long-term study[88] 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.

Prolonged release for older patients

Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, distributed by Neurim Pharmaceuticals. The European Medicines Agency (EMEA) has approved Circadin 2 mg (prolonged-release melatonin) for patients who are aged 55 or over, as monotherapy for the short-term treatment of primary insomnia characterized by poor quality of sleep .[89]

Side effects

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[90] in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances which are secondary to other diagnoses and, second, for sleep disorders such as jet lag and shift work which accompany sleep restriction.

The study concluded that There is evidence that melatonin is safe with short term use.

A similar analysis[84] 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).

Some unwanted effects in some people, especially at high doses (~3 mg/day or more) may include: headaches, nausea, next-day grogginess or irritability, hormone fluctuations, vivid dreams or nightmares[91] and reduced blood flow.

While no large, long-term studies which might reveal side effects have been conducted, there do exist case reports about patients who have taken melatonin for years.[92]

Melatonin can cause somnolence (drowsiness), and therefore caution should be shown when driving, operating machinery, etc.

In individuals with auto-immune disorders, there is concern that melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.[93][94]

Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate symptoms by reducing nerve activity in those who experience the condition, the study found.[95]

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.[4][96]

See also

References

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  1. ↑ http://www.sleepdex.org/melatonin.htm
  2. ↑ Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti EM (2003). "Melatonin in plants". Advances in Experimental Medicine and Biology. 527: 593–7. PMID 15206778. 
  3. ↑ 3.0 3.1 Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ (2009). "Phytomelatonin: a review". Journal of Experimental Botany. 60 (1): 57–69. doi:10.1093/jxb/ern284. PMID 19033551. 
  4. ↑ 4.0 4.1 4.2 Altun A, Ugur-Altun B (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. 
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  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  7. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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  12. ↑ 12.0 12.1 Coates, Paul M. (2005). Encyclopedia of Dietary Supplements. Marc R. Blackman, Gordon M. Cragg, Mark Levine, Joel Moss, Jeffrey D. White. CRC Press. pp. 457–466. ISBN 0824755049. Retrieved 2009-03-31. 
  13. ↑ Ratzburg, Courtney (Undated). "Melatonin: The Myths and Facts". Vanderbilt University. Retrieved 2007-12-02.  Check date values in: |date= (help)
  14. ↑ USPS. "Country Conditions for Mailing — Germany". Retrieved 2008-01-15. 
  15. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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  17. ↑ Lerner AB, Case JD, Takahashi Y (1960). "Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands". J Biol Chem. 235: 1992–7. PMID 14415935. 
  18. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  19. ↑ 19.0 19.1 Tan DX, Chen LD, Poggeler B, Manchester LC, Reiter RJ (1993). "Melatonin: a potent, endogenous hydroxyl radical scavenger". Endocr J (1): 57–60. 
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  48. ↑ Melke J, Botros HG, Chaste P (2008). "Abnormal melatonin synthesis in autism spectrum disorders". Mol Psychiatry. 13 (1): 90–8. doi:10.1038/sj.mp.4002016. PMC 2199264 Freely accessible. PMID 17505466. 
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  86. ↑ Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA (2002). "Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period". Chronobiol Int. 19 (3): 649–58. doi:10.1081/CBI-120004546. PMID 12069043.  line feed character in |title= at position 81 (help)
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  96. ↑ "Melatonin Information from Drugs.com". 
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