Melatonin [mel-uh-toh-nin] is a naturally occurring hormone found in animals, plants, and microbes. In animals, circulating levels of melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions.

Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant (a molecule that neutralizes free radicals), with a particular role in the protection of nuclear and mitochondrial DNA. Products containing melatonin have been available over-the-counter in the United States since the mid-1990s. In many other countries, the sale of this neurohormone is not permitted or requires a prescription.

Melatonin has been identified in many plants including feverfew, St John’s wort, rice, corn, tomato, and fruits such as bananas and cherries. The physiological roles of melatonin in plants involve regulation of their response to photoperiod, defense against harsh environments, and to function as 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.

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, 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 second 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.

Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (a sex hormone that triggers ovulation in women and production of testosterone in men) and follicle-stimulating hormone (a sex hormone that triggers the growth of follicles in the ovaries and the production of sperm in the testes) 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 (a hormone that plays a key role in regulating energy intake and energy expenditure, including appetite/hunger and metabolism), lowering its levels.

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 pigment sensitive to blue frequencies of light; 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.

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 SCN) that controls the daily cycle in most components of the endocrine systems rather than the melatonin signal (as was once postulated). Human melatonin production decreases as a person ages. It is believed that as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.

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.

Besides its function as synchronizer of the biological clock, melatonin was found to be a powerful free radical scavenger and wide spectrum antioxidant 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. 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. 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.

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.

Exogenous melatonin taken in the evening is, together with light therapy upon awakening, is the standard treatment for delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome where circadian rhythms are not entrained 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 DSPS 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.

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.’ Unwanted effects in some people may include headaches, nausea, next-day grogginess, irritability, hormone fluctuations, vivid dreams, nightmares, reduced blood flow and hypothermia.

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. 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 epidermal melanophores. 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 rat urine 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.’

3 Comments to “Melatonin”

  1. I use melatonin for deeper sleep

  2. Thank you very much. I found this fascinating and easy to digest.

  3. Reblogged this on in lieu of a lot and commented:
    Sleep and Sex – just chemicals.

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