|Molecular formula||C 13 H 16 N 2 O 2|
|External identifiers / databases|
|Mechanism of action||
Replacement of the naturally insufficiently produced hormone
|Molar mass||232.28 g mol −1|
117 ° C
|As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .|
Melatonin is a metabolite of the tryptophan metabolism. Its formation is controlled in the brain in the pineal gland (epiphysis) by the circadian pacemaker in the suprachiasmatic core and is inhibited by light. When it is dark in the biological night , this inhibition is lifted, production increases and with it the secretion of melatonin. Other places of production in the body are the intestines and the retina of the eye. The melatonin concentration increases during the night by a factor of three (in older people) to twelve (in young people), the maximum is reached around three o'clock in the morning - with a seasonally changing rhythm. The secretion is slowed down by daylight. The role of melatonin in jet lag and shift work is generally recognized, but the use of melatonin in this context is controversial. By coordinating the circadian-rhythmic processes in the body, it unfolds its effect as a timer. The melatonin- induced deep sleep phase stimulates the release of the growth hormone somatropin . Corresponding chronic disorders lead to premature somatopause . Other important melatonin effects are its action as an antioxidant . The antigonadotropic effect (reduction in size of the sex glands ) and the downregulation of many biological and oxidative processes are also important, which is particularly important when taking melatonin. A decrease (but also an increase) in the melatonin level in the blood causes sleep disorders or disorders of the sleep-wake rhythm.
The biosynthesis is carried out serotonin selected from the amino acid tryptophan is obtained in two steps: first serotonin with acetyl coenzyme A N -acetyliert as catalyst affects the enzyme serotonin N -acetyltransferase (AANAT). Then the product is N -Acetylserotonin with S -Adenosylmethionin means of Acetylserotonin- O -methyltransferase methylated . The first step is rate-limiting, and the activity of its enzyme is indirectly regulated by daylight.
After passage through the liver, 90% of melatonin is metabolized to 6-OH-melatonin by biotransformation using cytochrome P450 monooxygenases and excreted in the urine in the form of sulfated (60–70%) or glucuronidated (20–30%) derivatives .
No uniform definition of deficit has yet been established for melatonin. This is all the more astonishing as it is used therapeutically on a large scale (see below). While there are corresponding concentration data for other hormones, which can be used to orientate yourself whether a hormone substitution, i.e. a replacement of something missing, is necessary (see Addison's disease ), these are completely absent with melatonin.
In addition to large inter-individual differences, the circadian darkness-dependent synthesis of melatonin also makes it difficult to establish routine laboratory values easily.
However, a high degree of epiphyseal calcification can be regarded as an indication of an individual melatonin deficiency. The first evidence can be found in correlations between an increased proportion of calcified tissue and corresponding symptoms such as reduced sleep quality or insufficient stability of the circadian system.
Effects and medical uses
In winter, when daylight lasts only a few hours, the daily rhythm of melatonin production can shift and lengthen. As a result, tiredness , sleep disorders and winter depression can occur. As a countermeasure, it is recommended to use the short period of daylight for walks. Alternatively, light therapy can also be used.
Problems sleeping and memory
A melatonin level that is too low can be associated with insomnia. With increasing age, the body produces less melatonin, the average length of sleep decreases and sleep problems occur more frequently (" senile bed escape "). The melatonin balance can also be disturbed by the time change during shift work and long-distance travel ( jetlag ).
Restful sleep is important for a functioning memory . One of the reasons for this could be the influence of melatonin on the hippocampus . This region in the brain is important for learning and remembering. Due to the effects of melatonin, the neurophysiological basis of learning and memory, the synaptic plasticity , is subject to a clear day-night rhythm.
Antioxidant effects of melatonin
In addition to its function of synchronizing the biological clock, melatonin is a powerful radical scavenger and an antioxidant with a broad spectrum of activity. In many underdeveloped creatures, this is the only known function of melatonin. Melatonin is an antioxidant that can easily penetrate cell membranes and the blood-brain barrier.
As an antioxidant, melatonin is a direct radical scavenger for oxygen and nitrogen compounds such as OH, O2 and NO. Melatonin, along with other antioxidants, also works to improve the effectiveness of these other antioxidants. Melatonin has been shown to have twice the antioxidant effects of vitamin E, and it is believed that melatonin is the most potent lipophilic antioxidant. An important feature of melatonin that sets it apart from other classic free radical scavengers is that its metabolites are also free radical scavengers, which is known as a cascade reaction. Melatonin also differs from other classic antioxidants such as vitamin C and vitamin E in that melatonin has amphiphilic properties. Compared to synthetic antioxidants with an effect on the mitochondrion (MitoQ and MitoE), melatonin proved to be a comparable protection against mitochondrial oxidative stress.
Studies on the effects of melatonin on cancer
The systematic review with a meta-analysis of randomized controlled trials on the treatment of solid tumors with melatonin, which was published in the Journal of Pineal Research in November 2005 , resulted in reduced death rates. Melatonin reduced the risk of death within one year to 66% compared to treatment without melatonin. The effect of melatonin was the same with different dosages and also with different types of cancer. No serious undesirable side effects were found. The significant reduction in the risk of death, the low rate of undesirable side effects and the low cost of cancer treatment with melatonin suggest that there is great potential for the use of melatonin in cancer treatment. To confirm the efficacy and safety of melatonin in the treatment of cancer, however, confirmation by other independent randomized controlled trials (RCTs) is required.
Clinical studies (review by the National Cancer Institute , May 2013) in kidney, breast, colon, lung, and brain cancers suggest that melatonin has anti-cancer effects in conjunction with chemotherapy and radiation therapy; however, the study results are not entirely clear.
Melatonin for fibromyalgia
Symptoms of fibromyalgia include long-term and widespread pain in muscles, tendons, and connective tissues with no specific cause. One study found that patients had significantly reduced symptoms when they took melatonin alone or in combination with the antidepressant fluoxetine ( Prozac ).
In the short term - over a maximum period of two to three months - melatonin has hardly any side effects. Occasionally, the following side effects have occurred:
- Drowsiness and lack of concentration
- Irritability, nervousness
- Chest, abdomen and extremities pain, headache
- Rashes, itching
For safety reasons, melatonin should not be used during pregnancy and breastfeeding as well as in the case of severe allergies.
If melatonin is taken together with anti-epileptic drugs, antidepressants (SSRIs), and antithrombotic drugs, there may be interactions between the various drugs.
In contrast to short-term administration, the risks and side effects of long-term use are still completely unexplored. For this reason, one should also refrain from taking it continuously.
Melatonin in foods
Melatonin is found in plant-based foods and, in very small quantities, in animal-based foods . Cranberries have the highest melatonin content (up to 9,600 µg / 100 g dry weight). Further sources of melatonin are some types of mushrooms ( Edel-Reizker , common boletus , cultured mushrooms , real chanterelles ), some types of grain ( corn , rice , wheat , oats , barley ), mustard seeds , dried tomatoes and paprika and some types of wine.
The concentration of melatonin in the blood is significantly higher after eating foods containing melatonin. The consumption of melatonin-rich foods has a positive effect on sleep behavior.
|Cranberry, dried||2,500-9,600 µg / 100 g|
|Noble irritant , dried||1,290 µg / 100 g|
|Common boletus, dried||680 µg / 100 g|
|Cultured mushrooms, dried||430-640 µg / 100 g|
|Corn, dried||1-203 µg / 100 g|
|Real chanterelle, dried||140 µg / 100 g|
|Lentil seedlings, dried||109 µg / 100 g|
|Kidney bean seedlings, dried||52.9 µg / 100 g|
|Rice, dried||0-26.4 µg / 100 g|
|Tomato, dried||25.0 µg / 100 g|
|Mustard seeds, dried||12.9-18.9 µg / 100 g|
|Wine||0-13.0 µg / 100 ml|
|wheat||12.5 µg / 100 g|
|Paprika, dried||9.3 µg / 100 g|
|oats||0-9.1 µg / 100 g|
|barley||0-8.2 µg / 100 g|
|salmon||0.37 µg / 100 g|
|Eggs, raw||0.15 µg / 100 g|
|Cow's milk||0-0.4 ng / 100 ml|
Melatonin is not only produced by humans, but by all mammals in the dark at night, and accordingly also by cows, according to the mechanism described above. In lactation melatonin passes from the blood into the milk . The milk contains different amounts of melatonin depending on the time of day or night and the feed base of the cows. In particular, the return of dairy farming to a special light regime that corresponds to the natural light conditions during the day / night, as well as grass- and herb-based feeding lead to a high nocturnal melatonin level in the cow. If this milk is recorded separately, it contains up to 0.04 micrograms of melatonin per liter. By freeze-drying , the concentration may be 100-fold increased. Compared to some plant foods, the melatonin content is extremely low. The sleep-promoting benefit of whey powder obtained from such milk (so-called "night milk crystals") is scientifically implausible and is assessed differently.
USA and Canada
Melatonin supplements are available over the counter as dietary supplements in Canada and the United States . Different healing effects are advertised in the USA:
- Migraine prophylaxis
- Stimulation of hair growth
- Scavenging free radicals and as a result of its proven antioxidant abilities:
- Increased secretion of the body's own growth hormones
European Union countries
Melatonin has been approved by the European Commission in the EU as a medicinal product ( Circadin ) for the short-term treatment of primary insomnia (poor sleep quality) in patients aged 55 and over since 2007 . Circadin contains two milligrams of melatonin in a retarded form. The recommended dose is two milligrams one to two hours before bed and after the last meal and should be sustained for three weeks. In Germany, when used as a medicinal substance, melatonin is a prescription substance according to the Medicinal Prescription Ordinance; medicinal products containing melatonin require a prescription regardless of the dose. In many cases, sustained-release melatonin preparations are reimbursable, so that the costs are covered by health insurance.
For use in dietetic foods, melatonin is in accordance with the entry in the Community list drawn up by the European Commission in accordance with Article 13 of Regulation (EC) No. 1924/2006 (Health Claims) with the health-related information “Melatonin helps to alleviate the subjective feeling of jet lag at. "and" Melatonin helps to shorten the time to fall asleep. " The permissible single dose and the wording for the user information are also specified. This was preceded by corresponding scientific evaluations by the European Food Safety Authority (EFSA), which were published in 2010 and 2011. The inclusion in the community list allows certain health claims for melatonin, but does not mean the approval of melatonin-containing foods. The so-called "health claims" are intended exclusively for food and not for drugs. Such foods are now available as “supplementary balanced diets” in some countries of the European Union (e.g. Austria) with up to 5 mg melatonin per capsule from various manufacturers.
In Germany in 2010 , the Federal Office for Consumer Protection and Food Safety (BVL) reported products containing melatonin as “supplementary balanced diets”. Complementary balanced diets are dietary foods . The notification procedure at the BVL does not involve the approval of melatonin-containing products as dietetic foods. The Federal Office forwards the notifications to the official food control of the federal states. This is responsible for complaining about non-marketable products and removing them from the market. There are already approved drugs on the market with a concentration of two milligrams or more of melatonin per daily dose. Whether products with a melatonin concentration of two milligrams or more per daily dose can therefore also be placed on the market as (e.g. dietetic) foods must be checked on a case-by-case basis and is the responsibility of the responsible authorities. There are numerous substances that are used in both medicines and food. Each product has to be checked for itself and a decision has to be made on the classification.
Melatonin preparations were also brought onto the market in Germany as dietary supplements. In 2018, the Munich Administrative Court ruled that a pharmacological effect of melatonin-containing foods was not demonstrable if the recommended dose does not exceed 1 mg per day, and that marketing as a dietary supplement is therefore not illegal.
In Austria, too, products with different dosages are sold as dietary supplements.
There are various studies that prove the good effectiveness of melatonin (here: retarded, i.e. prolonged release of the active ingredient) for people aged 55 and over. Proven effects include the sustainable shortening of the time to fall asleep, the improvement of the quality of sleep and the improvement of morning alertness and daily performance. According to the studies, the main advantage of prolonged-release melatonin is the simultaneous improvement in both sleep quality and morning wakefulness (evidence of restful sleep) in patients with insomnia.
There are also various studies that have examined the effectiveness of melatonin on jet lag symptoms. The data on this are quite different. A large meta-analysis , published in a Cochrane Review, indicates a significant effectiveness of melatonin in a dosage of 0.5 to 5 mg in the treatment of jet lag symptoms. At all of these dosages, melatonin has similar effectiveness. However, less than 5 mg takes the shortest time to fall asleep. The more time zones are crossed, the greater the effect; it is also more pronounced for flights to the east than for flights to the west. These studies examined subjective parameters of sleep, but also other symptoms such as daytime sleepiness and well-being. Another meta-analysis could not find any significant advantage of melatonin in jet lag symptoms. There was no significant shortening of the time to fall asleep in sleep disorders due to shift work. The total duration of sleep could not be significantly increased either. The study also showed that interactions with anti- thrombotic drugs and anti- epileptic drugs are possible. Short-term use of melatonin (<3 months) has no harmful consequences. The selection of the studies (only short-term use, dosage, selected endpoints ) was criticized in this meta-analysis .
The substance agomelatine has a chemical structure similar to melatonin . In contrast to melatonin, agomelatine not only has an affinity for the melatonin receptors of the MT 1 and MT 2 types but also antagonistic properties at the serotonin receptor 5-HT 2c . Agomelatine is used as a medicinal substance in the treatment of depression.
Tasimelteon is another substance derived from melatonin that acts as an agonist at MT 1 and MT 2 receptors. Tasimelteon is approved in the EU as an orphan drug for the treatment of sleep-wake disorders with deviations from the 24-hour rhythm in blind people without light perception.
Melatonin was discovered and named in 1958 by the US dermatologist Aaron B. Lerner , who already described the sedative effect on humans. In 1990 Franz Waldhauser discovered that the administration of melatonin shortened the early phases of sleep and extended REM sleep .
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