Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae^[1] to humans, at levels that vary in a daily cycle.Melatonin has a chemical formula of C₁₃H₁₆N₂O₂  ^{and a molecular mass of 232.278 g/mol.} It plays a role in the regulation of the circadian rhythm of several biological functions.^[2] Many biological effects of melatonin are produced through activation of melatonin receptors,^[3] while others are due to its role as a pervasive and extremely powerful antioxidant^[4] with a particular role in the protection of nuclear and mitochondrial DNA.^[5]. Products containing either or both of isolated or synthesized melatonin have been available as a health supplement in the United States since 1993,^[6] and met with good consumer acceptance and enthusiasm.^[7] However, over-the-counter sales remain illegal in many other countries including some members of the European Union and New Zealand,^[8] and the U.S. Postal Service lists melatonin among items prohibited by Germany.^[9]

Biosynthesis

In higher animals and humans, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase. Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives information from the retina about the daily pattern of light and darkness. Both SCN rhythmicity and melatonin production are affected by non-visual light information traveling not through the optic nerve, but through the recently-identified retinohypothalamic tract (RHT). The light/dark information reaches the SCN via a subpopulation of inner retinal ganglion cells, which are intrinsically-photosensitive photoreceptor cells, distinct from those involved in the visual system. These cells represent approximately 2% of retinal ganglion cells in humans and express the non-visual photopigment melanopsin.^[10] The sensitivity of melanopsin fits with that of a vitamin A-based photopigment with a peak sensitivity at 484 nm (blue light).^[11] This photoperiod cue entrains the circadian rhythm, and the resultant production of specific "dark"- and "light"-induced neural and endocrine signals regulates behavioral and physiological circadian rhythms.Melatonin may also be produced by a variety of peripheral cells such as bone marrow cells,^[12][13] lymphocytes and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood but it does not seem to be regulated by the photoperiod. Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.^[14][15]

Distribution

Melatonin produced in the pineal gland 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.

Roles in the animal kingdom

Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock.^[16] In animals and in some conditions also in humans^[17] the profile of melatonin synthesis and secretion is affected by variable duration of night which occurs in summer compared to winter. The change in duration of secretion thus serves as a biological signal for the organisation of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behaviour, coat growth and camouflage coloring in seasonal animals.^[17] In seasonal breeders which do not have long gestation periods, and which 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^[18] and hamsters.^[19] 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.Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.^[20][21]

Roles in humans

Circadian Rhythm

In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, located in the center of the brain on the dorsal surface of diencephalon. The melatonin signal forms part of the system that regulates the circadian cycle by chemically causing drowsiness, but it is the central nervous system that controls the daily cycle in most components of the paracrine and endocrine systems^[22][23] rather than the melatonin signal (as was once postulated).

Light dependence

Production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness" and its onset each evening is called the Dim-Light Melatonin Onset (DLMO). Secretion of melatonin, and 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.

Until recent history, humans in temperate climates were exposed to up to 18 hours of darkness in the winter. In the modern world, artificial lighting reduces this to typically eight hours or less per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Since it is principally blue light that suppresses melatonin,^[24] wearing glasses that block blue light^[25] in the hours before bedtime may avoid melatonin loss. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.

Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers,^[26] and the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world.^[27] As inadequate as blood concentrations may be in brightly lit environments, some scientists now believe that a person's overnight output of melatonin can be further jeopardized each time he or she interrupts his or her sleep and turns on a bright light (suggesting that using a less-bright nightlight would be safer). Others suggest that such short exposures do no harm.^[28]

Antioxidant

Besides its primary function as synchronizer of the biological clock, melatonin may exert a powerful anti-oxidant activity. In many lower life forms, it serves only this purpose.^[29]. Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.^[4] Melatonin is a direct scavenger of OH, O2−, and NO.^[30] 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 regain their antioxidant properties. 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.^[31] Recent research indicates that the first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine or AFMK rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neutralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. 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.^[29]. In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.^[32] It also has been found to be effective in protecting against brain injury caused by ROS release in experimental hypoxic brain damage.^[33] The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.^[34][35][36]

Immune system

While it is clear that melatonin interacts with the immune system,^[37][38] 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.^[39] and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease^[40] including viral and bacterial infections. Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor^[41] 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 immunostimulatorand 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.^[42]

Dreaming

Many supplemental melatonin users have reported an increase in the vividness or frequency of dreams. Extremely high doses of melatonin (50mg) dramatically increased REM sleep time and dream activity in both narcoleptics and those without narcolepsy.^[43] Many psychoactive drugs, such as LSD and cocaine, increase melatonin synthesis.^[43] 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.^[43]It has been suggested that psychotropic drugs be readmitted in the field of scientific inquiry and therapy.^[44] If so, melatonin may be prioritized for research in this reemerging field of psychiatry.^[45]

Autism

Individuals with autism spectrum disorders 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 ASMT gene, which encodes the last enzyme of melatonin synthesis.^[46]

Medical indications

Melatonin has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), circadian rhythm sleep disorders and sexual dysfunction. A study by Alfred J. Lewy and other researchers at Oregon Health & Science University found that it may ameliorate circadian misalignment and SAD.^[47] As of 2006 it is known to affect the timing of endogenous melatonin production during long-term melatonin treatment in rats.^[48] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.^[49]

Treatment of circadian rhythm disorders

Exogenous melatonin, usually taken orally in the afternoon and/or evening, is, together with light therapy upon awakening, the standard treatment for delayed sleep phase syndrome and non-24-hour sleep-wake syndrome. See Phase response curve, PRC. It appears to have some use against other circadian rhythm sleep disorders, such as jet lag and the problems of people who work rotating or night shifts.

Preventing ischemic damage

Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain^[50] and the heart;^[51] however, this has not been tested in humans.

Learning, memory and Alzheimer's

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,^[52] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer's disease. Thus, melatonin may be effective for treating Alzheimer's Disease.^[53] 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.^[54]

ADHD

Attention-deficit hyperactivity disorder (ADHD) is commonly treated with methylphenidate (e.g. Ritalin) which may cause insomnia in approximately 94% of its users.^{[citation needed]} Research shows that after melatonin is administered to the patients, 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.^[55]

Fertility

Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.^[56]

However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement.^[57]

Headaches

Several clinical studies indicate that supplementation with melatonin is an effective preventive treatment for migraines and cluster headaches.^[58][59]

Depression

Melatonin has been shown to be effective in treating one form of depression, seasonal affective disorder, [1] and is being considered for bipolar and other disorders where circadian disturbances are involved.^[60]

Other

Some studies have shown that melatonin has potential for use in the treatment of various forms of cancer, HIV, and other viral diseases; however, further testing is necessary to confirm this.^[61]

Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).^[62]

Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms. (*Quoted from Ross Histology and Wheather's Functional Histology.)

Use as a dietary supplement

The primary motivation for the use of melatonin as a supplement may be as a natural aid to better sleep, with other incidental benefits to health and well-being due to its role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.

Studies from Massachusetts Institute of Technology say that melatonin pills sold as supplements contain three to ten times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of sleep. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses are just as effective at improving sleep quality.^[63] Large doses of melatonin can even be counterproductive: Lewy & al^[64] provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve" (PRC). In their study, 0.5 mg of melatonin was effective while 20 mg was not.

Safety of supplementation

Melatonin is available without prescription in most cases in the United States and Canada, while it is available only by prescription or not at all in some other countries. The hormone is available as oral supplements (capsules, tablets or liquid) and transdermal, the "melatonin sleep patch".Sold as a dietary supplement in the USA, not as a drug, often in health food and other grocery stores and some drug stores, Food and Drug Administration (FDA) regulations that apply to medications currently are not applicable to melatonin.^[2] Safety and efficacy of melatonin products may not be assessed.Because of concerns of transmission of viruses through melatonin derived from animal sources melatonin derived from cow or sheep pineal glands should not be administered.^[2][65]Melatonin is practically nontoxic and exhibits almost no short-term side effects. No studies have as yet been conducted to determine whether there are any long-term side effects. There are, however, case reports about patients who have taken the supplement for years.Ingesting melatonin supplements may cause some unwanted side effects, especially at high doses (~more than 3 mg/day): hormone fluctuations, irritability, increased sleep disturbances including vivid nightmares[2] and reduced blood flow (see below).

Exogenous melatonin normally does not affect the endogenous melatonin profile, merely advancing the phase of endogenous melatonin production in time if taken at an appropriate time of day.In individuals with auto-immune disorders, there is concern that melatonin supplementation may exacerbate symptoms due to stimulation of the immune system.^[66]Melatonin can cause somnolence, and therefore caution should be shown when driving, operating machinery, etc. When taken several hours before bedtime in accordance with the Phase Response Curve for melatonin in humans, the dosage should be so tiny as to not cause tiredness/sleepiness.

Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate the symptoms by reducing nerve activity in those who experience the condition, the study found.^[67]

References