Hormone secreted by the pineal gland of most vertebrates. It appears to be important in regulating sleeping cycles; more is produced at night, and test subjects injected with it become sleepy. Melatonin may be involved in seasonal affective disorder. In mammals other than humans, melatonin may act as a cue to breeding and mating in season.
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Melatonin is a naturally occurring hormone found in most animals, including humans, and some other living organisms, including algae. Circulating levels vary in a daily cycle, and melatonin is important in the regulation 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 with a particular role in the protection of nuclear and mitochondrial DNA.
The use of melatonin as a drug can entrain (synchronize) the circadian clock to environmental cycles and can have beneficial effects for treatment of certain insomnias. Its therapeutic potential may be limited by its short biological half-life, poor bioavailability, and the fact that it has numerous non-specific actions. In recent studies though, prolonged release melatonin has shown good results in treating insomnia.
Products containing melatonin have been available as a dietary supplement in the United States since 1993, and met with good consumer acceptance and enthusiasm. However, over-the-counter sales remain illegal in many other countries including some members of the European Union and New Zealand, and the U.S. Postal Service lists melatonin among items prohibited by Germany.
Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives information from the retina about the daily pattern of light and darkness. Both SCN rhythmicity and melatonin production are affected by non-image-forming light information traveling through the recently-identified retinohypothalamic tract (RHT).
The light/dark information reaches the 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 fits 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 regulates behavioral and physiological circadian rhythms.
Melatonin 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.
During the night, melatonin regulates leptin, lowering the levels; see Leptin.
Until recent history, humans in temperate climates were exposed to only about six hours of daylight in the winter. In the modern world, artificial lighting reduces darkness exposure to typically eight or fewer hours per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Since it is principally blue light that suppresses melatonin, wearing glasses that block blue light in the hours before bedtime may avoid melatonin loss. 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.
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 bathrooms 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, and the effect of modern lighting practice, including light pollution, on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world.
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 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.
Many psychoactive drugs, such as LSD, increase melatonin synthesis. 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. It has been suggested that psychotropic drugs be readmitted in the field of scientific inquiry and therapy. If so, melatonin may be prioritized for research in this reemerging field of psychiatry.
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. 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.
Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).
Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms (quoted from Ross Histology and Wheather's Functional Histology).
The primary motivation for the use of melatonin as a supplement may be as a natural aid to better sleep. Incidental benefits to health and well-being may accumulate, due to melatonin's role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.
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 enhancement of sleep. 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 at improving sleep quality. Large doses of melatonin can even be counterproductive: Lewy et al 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.
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 is available as oral supplements (capsules, tablets or liquid) and as transdermal patches.
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 will, by June 2010, ensure that all production of dietary supplements must comply with current good manufacturing practices, and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling. In addition, the industry is now required to report to the FDA "all serious dietary supplement related adverse events."
Melatonin is practically nontoxic and appears to exhibit almost no 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. These Canadian researchers found no trials showing evidence of effects on sleep onset latency in subjects with secondary sleep disorders or in subjects with disorders accompanying sleep restriction. Seventeen randomised controlled trials with 651 participants showed no evidence of adverse effects of melatonin with short term use. The study concludes: "There is evidence that melatonin is safe with short term use." In most of their analyses they are able to state that there is no significant difference between melatonin and placebo; even the most common adverse events reported; headache, dizziness, nausea and drowsiness; did not significantly differ for melatonin vs. placebo. 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 some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome," and that evidence suggests that melatonin is safe with short-term use, three months or less.
Some unwanted effects in some people, especially at high doses (~more than 3 mg/day) may include: headaches, nausea, next-day grogginess or irritability, hormone fluctuations, vivid dreams or nightmares and reduced blood flow (see below).
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.
If taken several hours before bedtime according to the phase response curve (PRC) for melatonin, it merely advances the phase of melatonin production. If taken 30 to 90 minutes before bedtime, it advances the period of melatonin's presence in the blood. Melatonin can cause somnolence (drowsiness), and therefore caution should be shown when driving, operating machinery, etc. When taken several hours before bedtime in accordance with the PRC for melatonin in humans, the dosage should be so tiny as to not cause tiredness/sleepiness.
In individuals with auto-immune disorders, there is concern that melatonin supplementation may exacerbate symptoms due to stimulation of the immune system.
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.
Because of concerns of transmission of viruses through melatonin derived from animal sources, melatonin derived from cow or sheep pineal glands is no longer administered. The synthetic form does not carry this risk.