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Melatonin

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 systemsrather 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.

Light dependence

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.

Antioxidant

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, mitochodrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a better protector against mitochondrial oxidative stress.

Immune system

While it is known that melatonin interacts with the immune system,[49][50] the details of those interactions are unclear. Antiinflammatory effect seems to be the most relevant and most documented in the literature.[51] 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,[52] and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease[24] including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.[53]

Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor.[54] This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human T lymphocytes. In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.[55]

Although it has not yet been clearly demonstrated whether melatonin increases non-specific immunity with resulting contraindication in autoimmune diseases, an increase in the production of IL-2 and IL-1 was noted in cultured splenocytes.[56]


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 people both with and without narcolepsy.[57] 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.[57]

Autism

Some individuals with autism spectrum disorders (ASD) may have lower than normal levels of melatonin.[58] 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.[59]

Multiple small studies have demonstrated that 2 to 10 mg of melatonin may benefit children with ASD who have trouble falling asleep and/or maintaining sleep.[60] A small 2011 randomized crossover trial found that the administration of melatonin, when compared to placebo, decreased sleep latency and increased total sleep time, but had no effect on the number of night time awakenings.[61] At this time, no official guidelines exist for the use of melatonin in children with ASD.

Aging

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.[62][63][64] This may explain why older adults go to bed earlier, wake up earlier, and have more sleep problems than children do.[65]

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.[66] Consuming melatonin may neutralize oxidative damage and delay the neurodegenerative process of aging.[45] 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.[67]

Diabetes

Single-nucleotide polymorphisms of the human melatonin MT2 receptor have been linked to an increased risk of developing type 2 diabetes.[68] Furthermore women with low levels of melatonin secretion have been found to more likely to develop type 2 diabetes than women with high levels.[69]
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. Other studies warn against potential side effects

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