Melatonin
Encyclopedia
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes. In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment
of the circadian rhythm
s of several biological functions.
Many biological effects of melatonin are produced through activation of melatonin receptor
s, 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
.
In mammals, 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.
Research has shown that when bird chicks ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains. No food has been found to elevate plasma melatonin levels in humans.
Products containing melatonin have been available over-the-counter
as dietary supplement
s in the United States since the mid-1990s. In many other countries, the over-the-counter sale of this neurohormone
is not permitted or requires a prescription, and the U.S. Postal Service lists unapproved melatonin preparations among items prohibited by Germany.
, immune disorders, cardiovascular disease
s, depression
, seasonal affective disorder
(SAD), circadian rhythm sleep disorder
s and sexual dysfunction
. It may ameliorate circadian misalignment and SAD. Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine
. Melatonin is also a geroprotector
.
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 common 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 of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.
The World Health Organization in 2007 named late night shift work as a probable cancer-causing agent. Melatonin is an anti-oxidant and suppressant of tumor development that is produced at night; when someone works in artificial light, they generally have lower melatonin and may be more likely to develop cancer. Melatonin supplements may simulate the melatonin production at different times that does not occur during regular sleeping hours for people who work night shifts.
(LTP). The first published evidence that melatonin may be useful in Alzheimer's disease
was the demonstration that this neurohormone prevents neuronal death caused by exposure to the amyloid beta
protein, a neurotoxic substance that accumulates in the brains of patients with the disorder. Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates that, it seems, underlie the neurotoxicity of this protein, causing death of neurons and formation of neurofibrillary tangle
s, the other neuropathological landmark of Alzheimer's disease.
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.
.
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.
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. However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement. 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.
for migraines and cluster headache
s.
, and is being considered for bipolar
and other disorders in which circadian disturbances are involved. It has been observed that bipolar disorder
might have, as a "trait marker" (something that 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. This could be contrasted with drug-free recovered bipolar patients not showing light hypersensitivity.
of unblinded clinical trial
s 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 suspected 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.
, whether administered before or after onset of inflammation. Concentration of melatonin in the bile is 2–3 times higher than the otherwise very low daytime melatonin levels in the blood across many diurnal mammals, including humans.
patients, high-dose rectal melatonin (300 mg/day for 2 years) was shown to be tolerated well.
(BAT) as well as enhances its activity. This effect would raise the basal metabolic rate
by stimulating thermogenesis
, heat generation through uncoupling oxidative phosphorylation
in mitochondria. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials, since substantially active BAT has been identified in adult humans.
, a commonly used agent for this purpose. The mechanism of melatonin in protection against ionizing radiation is thought to involve scavenging of free radicals. It is estimated that nearly 70% of biological damage caused by ionizing radiation is attributable to the free radical, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been suggested as a radioprotective agent, with the proposed advantages of being broadly protective, readily available, orally self-administered, and without major known side effects.
.
Increased proliferation of cultured neural stem cells obtained from mice nervous tissue occurred when treated with melatonin.
Melatonin was used to treat Periodic limb movement disorder, a common neurological condition, which, when severe, adversely affects sleep and causes excessive daytime fatigue, in a small trial conducted by Kunz D and Bes F. In this condition, the sufferer is affected by mini arousals during sleep and limb movements that occur in a frequent rhythmic fashion. This often involves leg kicking, but sometimes also involves arm movement. Those affected are often not aware of the condition, and partners are often the first to notice the condition. 7 out of the 9 participants in the trial showed significant improvement.
In recent trial for use in IBS
treatment, melatonin relieved some symptoms, as published in 2010
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.
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, reduced blood flow, and hypothermia
.
While no large, long-term studies that might reveal side-effects have been conducted, there do exist case reports about patients having taken melatonin for months.
Melatonin can cause somnolence
(drowsiness), and, therefore, caution should be shown when driving, operating machinery, etc.
In individuals with auto-immune disorders, there is conflicting evidence that melatonin supplementation may either ameliorate or exacerbate symptoms due to immunomodulation
.
Individuals experiencing 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 experiencing 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.
(Tanacetum parthenium), and St John's wort
(Hypericum perforatum). It occurs in trace amounts in some foods, especially cherries to about 0.17-13.46 ng/g. The physiological roles of melatonin in plants involve regulation of their response to photoperiod, defense against harsh environments, and the function of an antioxidant. The latter may be the original function of melatonin in organisms with the others being added during evolution. Melatonin has been reported in foodstuffs including bananas and grapes, rice and cereals, herbs, olive oil, wine and beer. While no food has been found to elevate plasma melatonin levels in humans, when other animals consume melatonin-containing food, blood levels of melatonin do increase.
) seasonal functions such as reproduction, behaviour, coat growth and camouflage colouring
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.
, 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 cell
s, 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 that regulate behavioral and physiological circadian rhythms. Melatonin is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.
, 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
, and a small amount is found in saliva
.
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.
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.
that can easily cross cell membrane
s 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.
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
, 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.
, 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 including viral, such as HIV
, and bacterial infections, and potentially in the treatment of cancer
.
Endogenous melatonin in human lymphocyte
s 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 splenocyte
s.
. Many psychoactive drug
s, such as cannabis
and lysergic acid diethylamide (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.
gene, which encodes the last enzyme of melatonin synthesis.
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.
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.
, 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.
s 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 (2004). Prolonged release melatonin has shown good results in treating insomnia in older adults (2007).
A 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.
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."
In a 2005 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)."
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 blind subjects, 0.5 mg of melatonin was effective while 20 mg was not. Solomon Labs tested initial doses of 30 and 60 milligrams and found very little efficacy even at those levels.
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 1958. 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. 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. (...) Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."
) to being available only on prescription or not at all (although its possession and use may not be illegal). The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.
s" (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.
(EMA) has approved Circadin 2 mg (prolonged-release melatonin) for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.
Entrainment (chronobiology)
Entrainment, within the study of chronobiology, occurs when rhythmic physiological or behavioral events match their period and phase to that of an environmental oscillation. A common example is the entrainment of circadian rhythms to the daily light–dark cycle, which ultimately is determined by...
of the circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
s of several biological functions.
Many biological effects of melatonin are produced through activation of melatonin receptor
Melatonin receptor
A melatonin receptor is a G protein-coupled receptor which binds melatonin.Three types of melatonin receptor have been cloned. The MT1 and MT2 receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 has been identified in amphibia and...
s, while others are due to its role as a pervasive and powerful antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
, with a particular role in the protection of nuclear
Nuclear DNA
Nuclear DNA, nuclear deoxyribonucleic acid , is DNA contained within a nucleus of eukaryotic organisms. In mammals and vertebrates, nuclear DNA encodes more of the genome than the mitochondrial DNA and is composed of information inherited from two parents, one male, and one female, rather than...
and mitochondrial DNA
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
.
In mammals, melatonin is secreted into the blood by the pineal gland
Pineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
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
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
, lymphocytes, and epithelial cells
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
. 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.
Research has shown that when bird chicks ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains. No food has been found to elevate plasma melatonin levels in humans.
Products containing melatonin have been available over-the-counter
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
as dietary supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
s in the United States since the mid-1990s. In many other countries, the over-the-counter sale of this neurohormone
Neurohormone
A neurohormone is any hormone produced and released by neurons.Examples include:*Thyrotropin-releasing hormone *Gonadotropin-releasing hormone *Adrenocorticotropin-releasing hormone*Oxytocin*Antidiuretic hormone *Epinephrine...
is not permitted or requires a prescription, and the U.S. Postal Service lists unapproved melatonin preparations among items prohibited by Germany.
Medical uses
Melatonin has been studied for the treatment of cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, immune disorders, cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
s, depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, seasonal affective disorder
Seasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
(SAD), circadian rhythm sleep disorder
Circadian rhythm sleep disorder
Circadian rhythm sleep disorders are a family of sleep disorders affecting, among other things, the timing of sleep. People with circadian rhythm sleep disorders are unable to sleep and wake at the times required for normal work, school, and social needs. They are generally able to get enough sleep...
s and sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
. It may ameliorate circadian misalignment and SAD. Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
. Melatonin is also a geroprotector
Geroprotector
Geroprotector is a therapeutic that aims to affect the root cause of aging and age-related diseases, and thus prolong the life span of animals. Some possible geroprotectors include melatonin, carnosine, and metformin....
.
Circadian rhythm disorders
Exogenous melatonin taken in the evening is, together with light therapyLight therapy
Light therapy or phototherapy consists of exposure to daylight or to specific wavelengths of light using lasers, light-emitting diodes, fluorescent lamps, dichroic lamps or very bright, full-spectrum light, usually controlled with various devices...
upon awakening, the standard treatment for delayed sleep phase syndrome
Delayed sleep phase syndrome
Delayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...
(DSPS) and non-24-hour sleep-wake syndrome
Non-24-hour sleep-wake syndrome
Non-24-hour sleep-wake syndrome is a chronic circadian rhythm sleep disorder, classified within Chapter VI, Diseases of the Nervous System, in the ICD-10. It can be defined as "a chronic steady pattern comprising one- to two-hour daily delays in sleep onset and wake times in an individual living...
. It appears to have some use against other circadian rhythm sleep disorders as well, such as jet lag
Jet lag
Jet lag, medically referred to as desynchronosis, is a physiological condition which results from alterations to the body's circadian rhythms; it is classified as one of the circadian rhythm sleep disorders...
and the problems of people who work rotating or night shifts
Shift work
Shift work is an employment practice designed to make use of the 24 hours of the clock. The term "shift work" includes both long-term night shifts and work schedules in which employees change or rotate shifts....
. Melatonin reduces sleep onset latency
Sleep onset latency
In sleep science, sleep onset latency is the length of time that it takes to accomplish the transition from full wakefulness to sleep, normally to the lightest of the non-REM sleep stages.-Sleep latency studies:...
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 common 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
Chronobiotic
Chronobiotic is a substance that is capable of therapeutically re-entering short - term dissociated or long - term desynchronized circadian rhythms, or prophylactically preventing their disruption following an environmental insult. In more simple words, chronobiotic is defined as the agent causes...
(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 of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.
The World Health Organization in 2007 named late night shift work as a probable cancer-causing agent. Melatonin is an anti-oxidant and suppressant of tumor development that is produced at night; when someone works in artificial light, they generally have lower melatonin and may be more likely to develop cancer. Melatonin supplements may simulate the melatonin production at different times that does not occur during regular sleeping hours for people who work night shifts.
Learning, memory and Alzheimer's
Melatonin receptors appear to be important in mechanisms of learning and memory in mice, and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiationLong-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(LTP). The first published evidence that melatonin may be useful in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
was the demonstration that this neurohormone prevents neuronal death caused by exposure to the amyloid beta
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...
protein, a neurotoxic substance that accumulates in the brains of patients with the disorder. Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates that, it seems, underlie the neurotoxicity of this protein, causing death of neurons and formation of neurofibrillary tangle
Neurofibrillary tangle
Neurofibrillary Tangles are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as Tauopathies...
s, the other neuropathological landmark of Alzheimer's disease.
Melatonin has been shown to prevent the hyperphosphorylation
Hyperphosphorylation
Hyperphosphorylation occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signalling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems or cancer are a likely outcome...
of the tau protein
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...
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
Sundowning (dementia)
In medicine, sundowning, also known as sundown syndrome, is a syndrome involving the occurrence or increase of one or more abnormal behaviors in a circadian rhythm. Sundowning typically occurs during the late afternoon, evening, and night, hence the name. It occurs in persons with certain forms of...
, which has been shown in many studies to be effectively treated with melatonin supplements in the evening.
Delirium
A randomized placebo-controlled trial showed that low-dose (0.5 mg) melatonin supplementation to elderly patients admitted to acute Medicine services significantly reduced deliriumDelirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
.
Stimulants
Research shows that after melatonin is administered to ADHDAttention-deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
patients on methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
, 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 ItalyItaly
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
has found that melatonin supplementation in the evening in perimenopausal women produces an improvement in thyroid function and gonadotropin
Gonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause. However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement. One study reported that three mg of melatonin taken in the evening raised prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
levels in six out of seven women. Melatonin also lowers FSH
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
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 treatmentPreventive medicine
Preventive medicine or preventive care refers to measures taken to prevent diseases, rather than curing them or treating their symptoms...
for migraines and cluster headache
Cluster headache
Cluster headache, nicknamed "suicide headache", is a neurological disease that involves, as its most prominent feature, an immense degree of pain in the head. Cluster headaches occur periodically: spontaneous remissions interrupt active periods of pain. The cause of the disease is currently unknown...
s.
Mood disorders
Melatonin has been shown to be effective in treating one form of depression and seasonal affective disorderSeasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
, and is being considered for bipolar
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
and other disorders in which circadian disturbances are involved. It has been observed that bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
might have, as a "trait marker" (something that 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. This could be contrasted with drug-free recovered bipolar patients not showing light hypersensitivity.
Cancer
A systematic reviewSystematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
of unblinded clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s 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 suspected 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
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
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. It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. In guinea pigs, melatonin administration restored normal function by reducing inflammation after induced CholecystitisCholecystitis
-Signs and symptoms:Cholecystitis usually presents as a pain in the right upper quadrant. This is known as biliary colic. This is initially intermittent, but later usually presents as a constant, severe pain. During the initial stages, the pain may be felt in an area totally separate from the site...
, whether administered before or after onset of inflammation. Concentration of melatonin in the bile is 2–3 times higher than the otherwise very low daytime melatonin levels in the blood across many diurnal mammals, including humans.
Amyotrophic lateral sclerosis
In animal models, melatonin has been shown to ameliorate glutamate-induced neuronal death, it is presumed due to its antioxidant effects. In a clinical safety study involving 31 ALSAmyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
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. It is interesting to note that the weight loss effect of melatonin does not require the animals to eat less and to be physically more active. A potential mechanism is that melatonin promotes the recruitment of brown adipose tissueBrown adipose tissue
Brown adipose tissue or brown fat is one of two types of fat or adipose tissue found in mammals....
(BAT) as well as enhances its activity. This effect would raise the basal metabolic rate
Basal metabolic rate
Basal Metabolic Rate , and the closely related resting metabolic rate , is the amount of daily energy expended by humans and other animals at rest. Rest is defined as existing in a neutrally temperate environment while in the post-absorptive state...
by stimulating thermogenesis
Thermogenesis
Thermogenesis is the process of heat production in organisms. It occurs mostly in warm-blooded animals, but a few species of thermogenic plants exist.-Types:...
, heat generation through uncoupling oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
in mitochondria. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials, since substantially active BAT has been identified in adult humans.
Protection from radiation
Both animal and human studies have shown melatonin to be potentially radioprotective. Moreover, it is a more efficient protector than amifostineAmifostine
Amifostine is a cytoprotective adjuvant used in cancer chemotherapy and radiotherapy involving DNA-binding chemotherapeutic agents. It is marketed by MedImmune under the trade name Ethyol.-Indications:...
, a commonly used agent for this purpose. The mechanism of melatonin in protection against ionizing radiation is thought to involve scavenging of free radicals. It is estimated that nearly 70% of biological damage caused by ionizing radiation is attributable to the free radical, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been suggested as a radioprotective agent, with the proposed advantages of being broadly protective, readily available, orally self-administered, and without major known side effects.
Other
Melatonin has been found to be beneficial in the treatment of tinnitusTinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
.
Increased proliferation of cultured neural stem cells obtained from mice nervous tissue occurred when treated with melatonin.
Melatonin was used to treat Periodic limb movement disorder, a common neurological condition, which, when severe, adversely affects sleep and causes excessive daytime fatigue, in a small trial conducted by Kunz D and Bes F. In this condition, the sufferer is affected by mini arousals during sleep and limb movements that occur in a frequent rhythmic fashion. This often involves leg kicking, but sometimes also involves arm movement. Those affected are often not aware of the condition, and partners are often the first to notice the condition. 7 out of the 9 participants in the trial showed significant improvement.
In recent trial for use in IBS
IBS
- Academia :* International Business School, Budapest, a partnership with Oxford Brookes University based in Hungary dating from 1991* International Biometric Society, an academic statistical association for mathematical and statistical methods in the biosciences...
treatment, melatonin relieved some symptoms, as published in 2010
Adverse effects
Melatonin appears to cause very few side-effectsAdverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
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
Jet lag
Jet lag, medically referred to as desynchronosis, is a physiological condition which results from alterations to the body's circadian rhythms; it is classified as one of the circadian rhythm sleep disorders...
and shift work
Shift work
Shift work is an employment practice designed to make use of the 24 hours of the clock. The term "shift work" includes both long-term night shifts and work schedules in which employees change or rotate shifts....
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.
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, reduced blood flow, and hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
.
While no large, long-term studies that might reveal side-effects have been conducted, there do exist case reports about patients having taken melatonin for months.
Melatonin can cause somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(drowsiness), and, therefore, caution should be shown when driving, operating machinery, etc.
In individuals with auto-immune disorders, there is conflicting evidence that melatonin supplementation may either ameliorate or exacerbate symptoms due to immunomodulation
Immunomodulator
An immunomodulator, also known as an immunotherapy is a substance which has an effect on the immune system.- Immunosuppressants :Inhibits immune response in organ transplantation and autoimmune diseases.- Immunostimulants :...
.
Individuals experiencing orthostatic intolerance
Orthostatic intolerance
Orthostatic intolerance is a subcategory of dysautonomia, a disorder of the autonomic nervous system occurring when an individual stands up....
, a cardiovascular condition that results in reduced blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
and blood flow
Blood flow
Blood flow is the continuous running of blood in the cardiovascular system.The human body is made up of several processes all carrying out various functions. We have the gastrointestinal system which aids the digestion and the absorption of food...
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 experiencing 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.
In plants
Melatonin has been identified in many plants including FeverfewFeverfew
Feverfew is a traditional medicinal herb which is found in many old gardens, and is also occasionally grown for ornament. The plant grows into a small bush up to around high, with citrus-scented leaves and is covered by flowers reminiscent of daisies...
(Tanacetum parthenium), and St John's wort
St John's wort
St John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
(Hypericum perforatum). It occurs in trace amounts in some foods, especially cherries to about 0.17-13.46 ng/g. The physiological roles of melatonin in plants involve regulation of their response to photoperiod, defense against harsh environments, and the function of an antioxidant. The latter may be the original function of melatonin in organisms with the others being added during evolution. Melatonin has been reported in foodstuffs including bananas and grapes, rice and cereals, herbs, olive oil, wine and beer. While no food has been found to elevate plasma melatonin levels in humans, when other animals consume melatonin-containing food, blood levels of melatonin do increase.
In animals
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 organisation of daylength-dependent (photoperiodicPhotoperiodism
Photoperiodism is the physiological reaction of organisms to the length of day or night. It occurs in plants and animals.Photoperiodism can also be defined as the developmental responses of plants to the relative lengths of the light and dark periods...
) seasonal functions such as reproduction, behaviour, coat growth and camouflage colouring
Animal colouration
Animal coloration is the general appearance of an animal resulting from the reflection or emission of light from its surfaces. The mechanisms for colour production in animals include pigments, chromatophores, structural coloration, and bioluminescence....
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 produced in the pineal glandPineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
, which is outside of the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, acts as an endocrine hormone since it is released into the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
.
By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.
Melatonin can suppress libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
by inhibiting secretion of luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
(LH) and follicle-stimulating hormone
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) from the anterior pituitary
Anterior pituitary
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
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
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
.
Light/dark information reaches the suprachiasmatic nuclei
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
(SCN) via retinal photosensitive ganglion cell
Photosensitive ganglion cell
Photosensitive ganglion cells, also called photosensitive Retinal Ganglion Cells , intrinsically photosensitive Retinal Ganglion Cells or melanopsin-containing ganglion cells, are a type of neuron in the retina of the mammalian eye.They were discovered in the early 1990sand are, unlike other...
s, 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
Rod cell
Rod cells, or rods, are photoreceptor cells in the retina of the eye that can function in less intense light than can the other type of visual photoreceptor, cone cells. Named for their cylindrical shape, rods are concentrated at the outer edges of the retina and are used in peripheral vision. On...
and cones
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
). These cells represent approximately 2% of the retinal ganglion cells in humans and express the photopigment melanopsin
Melanopsin
Melanopsin is a photopigment found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary light reflex, and other non-visual responses to light. In structure, melanopsin is an opsin, a retinylidene protein variety of...
. The sensitivity of melanopsin is consistent with that of a vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
-based photopigment, with a peak sensitivity at 484 nm (blue light). This photoperiod cue entrains the circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
, and the resultant production of specific "dark"- and "light"-induced neural and endocrine signals that 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 glandPineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
, 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
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
by chemically causing drowsiness and lowering the body temperature, but it is the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(specifically the suprachiasmatic nuclei, or SCN
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
) 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
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, a small amount is excreted in urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, and a small amount is found in saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
.
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.
Light dependence
Production of melatonin by the pineal gland is inhibited by lightLight
Light or visible light is electromagnetic radiation that is visible to the human eye, and is responsible for the sense of sight. Visible light has wavelength in a range from about 380 nanometres to about 740 nm, with a frequency range of about 405 THz to 790 THz...
and permitted by darkness
Darkness
Darkness, in contrast with brightness, is a relative absence of visible light. It is the appearance of black in a color space. When light is not present, rod and cone cells within the eye are not stimulated. This lack of stimulation means photoreceptor cells are unable to distinguish color...
. 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
Chronotype
Chronotype is an attribute of animals, including human beings, reflecting at what time of the day their physical functions are active, change or reach a certain level...
.
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
Nanometre
A nanometre is a unit of length in the metric system, equal to one billionth of a metre. The name combines the SI prefix nano- with the parent unit name metre .The nanometre is often used to express dimensions on the atomic scale: the diameter...
, 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. In many less complex life forms, this is its only known function. Melatonin is an antioxidantAntioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
that can easily cross cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s 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
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
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.
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
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
release in experimental hypoxic brain damage in newborn rats. Melatonin's antioxidant activity may reduce damage caused by some types of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, play a role in preventing cardiac arrhythmia and possibly increase longevity
Longevity
The word "longevity" is sometimes used as a synonym for "life expectancy" in demography or known as "long life", especially when it concerns someone or something lasting longer than expected ....
; it has been shown to increase the average life span of mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
by 20% in some studies as well.
Immune system
While it is known that melatonin interacts with the immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, 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
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
production, and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, and bacterial infections, and potentially in the treatment of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
Endogenous melatonin in human lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s has been related to interleukin-2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
(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
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
. When taken in conjunction with calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
, it is an immunostimulator
Immunostimulator
Immunostimulants, also known as immunostimulators, are substances that stimulate the immune system by inducing activation or increasing activity of any of its components...
and is used as an adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
in some clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders. In rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
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
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
with resulting contraindication
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
in autoimmune diseases, an increase in the production of IL-2 and IL-1
IL-1
IL-1 may refer to:* Interleukin 1, a protein* Illinois' 1st congressional district* Illinois Route 1* Building 1 of Infinite Loop , the Headquarters of Apple Inc....
was noted in cultured splenocyte
Splenocyte
A splenocyte can be any one of the different white blood cell types as long as it is situated in the spleen or purified from splenic tissue.It sometimes explicitly refers to monocytes or macrophages....
s.
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 narcolepsyNarcolepsy
Narcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
. Many psychoactive drug
Psychoactive drug
A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that crosses the blood–brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior...
s, such as cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
and lysergic acid diethylamide (LSD), increase melatonin synthesis. It has been suggested that nonpolar (lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
-soluble) indolic hallucinogenic drugs
Psychedelics, dissociatives and deliriants
This general group of pharmacological agents can be divided into three broad categories: psychedelics, dissociatives, and deliriants. These classes of psychoactive drugs have in common that they can cause subjective changes in perception, thought, emotion and consciousness...
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 ASMTAcetylserotonin O-methyltransferase
N-Acetylserotonin O-methyltransferase also known as ASMT is an enzyme that catalyzes the final reaction in melatonin biosynthesis, converting Normelatonin to melatonin. This reaction is embedded in the more general tryptophan metabolism pathway...
gene, which encodes the last enzyme of melatonin synthesis.
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 hormoneMelanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
, melatonin controls the dispersion of melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
throughout melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
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.
Use as medication
The hormone melatonin is used to treat circadian rhythm sleep disorderCircadian rhythm sleep disorder
Circadian rhythm sleep disorders are a family of sleep disorders affecting, among other things, the timing of sleep. People with circadian rhythm sleep disorders are unable to sleep and wake at the times required for normal work, school, and social needs. They are generally able to get enough sleep...
s and some types of insomnia.
Studies have found that the use of melatonin can help entrain
Entrainment (chronobiology)
Entrainment, within the study of chronobiology, occurs when rhythmic physiological or behavioral events match their period and phase to that of an environmental oscillation. A common example is the entrainment of circadian rhythms to the daily light–dark cycle, which ultimately is determined by...
the circadian clock to environmental cycles and have beneficial effects for the treatment of certain forms of insomnia (2004). Prolonged release melatonin has shown good results in treating insomnia in older adults (2007).
A 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.
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
Jet lag
Jet lag, medically referred to as desynchronosis, is a physiological condition which results from alterations to the body's circadian rhythms; it is classified as one of the circadian rhythm sleep disorders...
and shiftwork disorder."
In a 2005 study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome
Delayed sleep phase syndrome
Delayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...
, ...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
Melatonin tablets/capsules often contain three to ten times the amount needed to produce physiologic nocturnal blood melatonin levels for a more rapid sleep onset. 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. 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 blind subjects, 0.5 mg of melatonin was effective while 20 mg was not. Solomon Labs tested initial doses of 30 and 60 milligrams and found very little efficacy even at those levels.
History
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, McCord and Allen discovered (J Exptl Zool, 1917) that extract of the pineal glands of cows lightened frog skin. Dermatology professor Aaron B. LernerAaron B. Lerner
Aaron Bunsen Lerner was an American physician, researcher and professor. Born in 1920 in Minneapolis, he received his medical degree and a PhD in chemistry from the University of Minnesota in 1945. After teaching at the universities of Michigan and Oregon, he joined the Yale University School of...
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 1958. In the mid-70s Lynch et al. demonstrated that the production of melatonin exhibits a circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
in human pineal glands. The discovery that melatonin is an antioxidant was made in 1993. 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. (...) Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."
Availability
Legal availability of melatonin varies in different countries, ranging from being available without prescription (e.g., in most of North AmericaNorth America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
) to being available only on prescription or not at all (although its possession and use may not be illegal). 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, sometimes combined with other ingredients, such as vitamins and herbal extracts, 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 practiceGood Manufacturing Practice
"Good manufacturing practice" or "GMP" are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods,...
s" (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.
Food Products
As reported in the New York Times in May 2011, melatonin is sold in grocery stores, convenience stores, and clubs in both beverage and snack forms. The FDA is considering whether these food products can continue to be sold with the label "dietary supplements". On January 13, 2010, they issued a warning letter to Innovative Beverage, creators of several beverages marketed as "relaxation drinks," stating that melatonin is not approved as a food additive.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
Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. The European Medicines AgencyEuropean Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMA) has approved Circadin 2 mg (prolonged-release melatonin) for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.
See also
- RamelteonRamelteonRamelteon, marketed as Rozerem by Takeda Pharmaceuticals North America, is the first in a new class of sleep agents that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus , instead of binding to GABA A receptors, such as with drugs like zolpidem, eszopiclone, and...
- 5-Methoxytryptamine5-Methoxytryptamine5-Methoxytryptamine , also known as mexamine, is a tryptamine derivative closely related to the neurotransmitters serotonin and melatonin. 5-MT has been shown to occur naturally in the body in low levels. It is biosynthesized via the deacetylation of melatonin in the pineal gland.5-MT acts as a...
- Agomelatine
- TasimelteonTasimelteonTasimelteon is a drug which is under development for the treatment of insomnia and other sleep disorders. It is a selective agonist for the melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus of the brain, similar to older drugs such as ramelteon...
- Risks and benefits of sun exposureRisks and benefits of sun exposureThe ultraviolet radiation in sunlight, though a principal source of vitamin D3 compared to diet, is mutagenic. Supplementing diet with vitamin D3 supplies vitamin D without this mutagenic effect, but bypasses natural mechanisms that would prevent overdoses of vitamin D generated internally from...
- Discovery and development of melatonin receptor agonistsDiscovery and development of melatonin receptor agonistsMelatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression...
External links
- Melatonin information from MedlinePlusMedlinePlusMedlinePlus is a free Web site that provides consumer health information for patients, families, and Health care providers. The site brings together information from the United States National Library of Medicine, the National Institutes of Health , other U.S. government agencies, and...
- Melatonin entry in TiHKAL • info