Melatonin in Humans

Circadian rhythm

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 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.

It is believed that 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 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.

Terman ''et al.'' devised a formulation that mimics that gradual washout (vs. the spikes in blood concentration and rapid washout associated with most over-the-counter melatonin tablets). When used several hours before sleep, the compound shifts the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.

It is principally blue light, around 460 to 480nm, that suppresses melatonin, 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.

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.

Melatonin is an antioxidant that can easily cross cell membranes and the blood-brain barrier. Melatonin is a direct scavenger of OH, O₂⁻, and NO. 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.

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.

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, play a role in preventing cardiac arrhythmia and possibly increase longevity; it has been shown to increase the average life span of mice by 20% in some studies as well.

Immune system

While it is known that melatonin interacts with the immune system, 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, and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease

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.

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.

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.

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.

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.

At this time, no 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 we 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 taken by older adults.

It has been reported in one study that while elderly people have different gene expression levels in 100 of 10,000 genes, administration of melatonin may reverse this change in gene expression thus making the genes of elderly people similar to those of younger people.

One study conducted by researchers of the University of Granada’s Institute of Biotechnology found that 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.

The researchers hope these results can also be applied to humans.

Melanin production

Along with melanocyte-stimulating hormone, melatonin controls the dispersion of melanin throughout melanocyte cells.

Melatonin controls pigmentation changes by aggregation of melanin into the melanocytes within the skin, causing the skin to change color. This is responsible for the change in skin color due to amount of sleep or the appearance of those who are sleep deprived, since melatonin also controls the circadian cycle.

This interaction is also responsible for the skin color of elderly people, since melatonin production reduces with age.