Products containing melatonin have been available over-the-counter as a dietary supplement in the United States since before 1994. 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.

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. Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.

Melatonin has been identified in many plants. when other animals consume melatonin-containing food, blood levels of melatonin do increase.

Many animals use the variation in duration of melatonin production each day as a seasonal clock.

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.

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. The sensitivity of melanopsin is consistent with that of a vitamin A-based photopigment with a peak sensitivity at 484 nm (blue light). 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.

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 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).

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.

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 480 nm , that suppresses melatonin, 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.

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.

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.

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. 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.

Immune system

While it is known that melatonin interacts with the immune system,

Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor. 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 and is used as an adjuvant in some clinical protocols; 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.

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. 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.

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.

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.

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.

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.

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

Preventing ischemic damage

Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain and the heart; 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,

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.

Delirium

A randomized placebo-controlled trial, showed that low dose (0.5 mg) melatonin supplementaion to elderly patients admitted to acute Medicine services, significantly reduced delirium.

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.

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. One study reported that three mg of melatonin taken in the evening raised prolactin levels in six out of seven women. Melatonin also lowers FSH levels. It is believed that these hormonal changes could in some women impair fertility.

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.

Headaches

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

Mood disorders

Melatonin has been shown to be effective in treating one form of depression, seasonal affective disorder, and is being considered for bipolar and other disorders where circadian disturbances are involved. 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.

Cancer

A systematic review of unblinded clinical trials involving a total of 643 cancer patients using melatonin found a reduced incidence of death. Another clinical trial is due to be completed in 2012. 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. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers.

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.

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.

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. 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. 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.

A veterinarian may recommend melatonin for dogs suffering from aggression or separation anxiety.

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. Prolonged release melatonin has shown good results in treating insomnia in older adults.

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." However, a 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.

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)."

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.

Large doses of melatonin can even be counterproductive: Lewy et al.

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. 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." 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 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, manufactured by Neurim Pharmaceuticals. The European Medicines Agency (EMA) has approved Circadin 2 mg (prolonged-release melatonin) for patients who are aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.

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 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 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 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.

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 .

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.

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.

• Ramelteon

• 5-Methoxytryptamine

• Agomelatine

• Tasimelteon

• Risks and benefits of sun exposure

• Discovery and development of melatonin receptor agonists

• Melatonin information from MedlinePlus

• Melatonin entry in TiHKAL ??? info