Melatonin

Nutrient group: Hormones & hormone-like substances

Sources and physiological effects

Dietary sources
Melatonin (N-acetyl-5-methoxytryptamine) is a metabolite of tryptophan and controls the sleep-wake rhythm of the human body. This sleep-promoting substance can also be found in small quantities in certain foods. Cows milk varying different concentrations of melatonin depending on the time of milking (day or night) and the feed. Small quantities are also contained, in walnuts, cherries or vegetable seedings.
Physiological effects
Circadian Rhythm	Adaptation of metabolic activity to circadian and seasonal rhythm
Sleep	Improvement of sleep quality
Antioxidant	Hydroxyl free radical scavenger

EFSA Health Claims

Health Claims		EFSA Opinion
Melatonin	Shortens the time its take to fall asleep. The positive effect occurs when 1 mg melatonin is taken shortly before bed. Contributes to the relief of the subjective sensation of jetlag. The positive effect occurs if at least 0.5 mg is taken on the first day of travel shortly before going to bed and on the first days after arriving at the destination.

Detailed information

Melatonin – a product of tryptophan metabolism

Melatonin (N-acetyl-5-methoxytryptamine) is a metabolite of tryptophan and is mainly formed in the pineal gland from the neurotransmitter serotonin. Both synthesis and secretion are regulated by the day- and season-dependent light-dark cycle, whereby darkness stimulates and inhibits the release of melatonin. Accordingly, melatonin levels are up to ten times higher at night than during the day. Intestinal cells with an affinity for enterochrome also have the enzymatic capacity to produce melatonin from tryptophan. In tryptophan-rich diets, higher amounts of melatonin are produced in the intestine as well (1).

Physiological functions of melatonin

The physiological functions of melatonin are manifold, and melatonin receptors can be found in many tissues. The main function of melatonin is to adapt metabolic activities to circadian and seasonal rhythms. It thus influences immune defense, sleep, sexual activity, body temperature or psychological well-being, among other things. Melatonin also has strong antioxidant effects, especially against photooxidants and hydroxyl radicals (1) (2).

Regulation of the internal clock

Melatonin is not a hypnotic. When taken at the right time, however, it strengthens the circadian system's sleep-readiness at night, resulting in a good quality and length of sleep of sufficient length and is the first choice for patients with nightmares and REM sleep-behavior disorders. Its effect is highly time dependent. Late evening intake (21:00 - 23:00) increases the amplitude of circadian rhythm, early evening (18:00 - 19:00) for late types) shifts the phase of the circadian system forward, in the morning hours the phase backward. Accordingly, melatonin must not be used before daytime sleep after a night shift (3). Melatonin also has a regulating effect on shifts in the sleep-wake rhythm, due long-haul flights over several time zones. Supplemental intake of melatonin before sleep accelerates adaptation to the new time zone and reduces the subjective feeling of jet lag – a health claim on melatonin recognized by EFSA (European Food Safety Agency).

Melatonin deficiency due to disruptive factors, depression and age

The body's own melatonin synthesis can be reduced or postponed by various factors. For example, chronic stress, insufficient light stimuli and aging processes can affect melatonin production. The body's own melatonin production decreases with age and with it that come dysregulation of various metabolic processes (e.g. age-related sleep disorders) (1). Additionally, in depression disorders, reduced melatonin levels can often be observed (1). Melatonin alone has no antidepressant effect, but since circadian rhythm disturbances are often associated with affective disorders, supplementary intake can have a positive effect on one aspect of these diseases (3) (5).

Melatonin as a potent antioxidant and its role in breast cancer prevention

In-vitro studies have shown that melatonin neutralizes hydroxyl radicals (OH) in being even more effective than glutathione. Melatonin also stimulates glutathione peroxidase (GSH-Px) activity. GSH-Px metabolizes reduced glutathione to its oxidized form, turning H₂O₂into H₂O. This process reduces the formation of OH. Melatonin also has the ability to neutralize peroxyl radicals and seems to be even more effective than vitamin E (6).

Melatonin is also becoming increasingly important in cancer prevention. However, its anticarcinogenic effect should go far beyond that of an antioxidant. Studies on completely blind women have shown that they are significantly less likely to develop breast cancer than blind women with partial vision (7) (8). The growth-inhibiting effect of melatonin on human breast cancer cells has also been demonstrated in animal experiments. In vitro melatonin showed a direct and reversible inhibition of cell proliferation in estrogen-dependent human breast cancer cells (9) (10) (11).

Reference values

Parameter

Substrate

Reference value

Description

Melatonin sulfate in urine

Urine

Reference value depends on the time of day

7:00 AM: 13-50 ng/ml

11:00 AM: 4.6 – 25 ng/ml

02:00 PM: <10 ng/ml

Night time: 60-70 ng/ml

Melatonin

Saliva

Reference value depends on the time of day

During the day (8 AM): at 5 pg/ml
Evening/Night (8 PM to midnight): at 10 pg/ml
After midnight (2 AM): >20 pg/ml

Deficiency symptoms

Impact on	Symptoms
Sleep	Melatonin deficiency can lead to sleep problems and a disturbed day-night cycle.
Nervous system	Frequent occurrence of concentration difficulties and depression.
Immune system	Increased susceptibility to infections

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	To reduce the subjective sensation of jet lag	1 - 5 mg/d
	For regulation of sleep-wake-rhythm during shift work	1 - 5 mg/d
	To treat sleeping disorders and poor sleep quality (primary insomnia = difficulty falling in or sleeping through or poor sleep quality for at least one month).	1 - 5 mg/d
	For nightmares	1 - 5 mg/d

Administration

General mode of administration
When	Sleeping disorders: Melatonin should be taken 30 minutes before bedtime. Jetlag: Consume from the first day of the trip until a few days after arrival at bedtime. Do not use before driving or working on machinery. The time of intake must be kept constant between days. If it is not possible to take it once (e.g. if you forget to take it or go to bed later), you should skip the dose. Melatonin takes effect on sleep over days and weeks. Hint: Do not use before driving or working on machinery, do not use during pregnancy or while breastfeeding. Melatonin should only be used in exceptional cases and under continuous medical supervision when taking steroid-containing drugs, SSRIs (antidepressants) and for severe allergies.
Side effects
Melatonin may cause drowsiness. Therefore, the medication should be used with caution if the effects of drowsiness could pose a safety risk.
Contraindications
Pregnancy, lactation, infants, epilepsy, renal failure, hepatic impairment

Interactions

Drug interactions
Sleeping pills (benzodiazepines)	Melatonin supports the hypnotic effects of benzodiazepines.
Antihypertensive drugs (beta blockers)	Betablockers can impair melatonin synthesis, melatonin has a positive effect on beta-blocker-induced sleep disorders.
Nutrient interactions
Amino acids	Supplementation of tryptophan improves low melatonin levels.
Vitamins	Vitamin B₆ and vitamin B₁₂ are required for melatonin biosynthesis.

References

1) Martin, M. Labormedizin in der Naturheilkunde. 3. Auflage, 2006.
2) Altun, A., Ugur-Altun, B. 2007. Melatonin: therapeutic and clinical utilization. Int J Clin Pract. 61(5):835-45.
3) Kunz, D. 2012. Melatonin taktet die innere Uhr neu. Neurologie & Psychiatrie. Vol. 14, Nr.1.
4) EFSA. 2011. Scientific opinion on the substantiation of a health claim related to melatonin and reduction of sleep onset latency (ID 1698, 1780, 4080) pursuant to Article 13 (1) of Regulation (EC) No 1924/2006. EFSA Journal. 9
5) Salgado-Delgado, R. et al. 2011. Disruption of circadian rhythms: a crucial factor in the etiology of depression. Depress Res Treat. 2011:839743.
6) Reiter, R. J. et al. 1995. A review of the evidence supporting melatonin’s role as an antioxidant. Journal of Pineal Research. 18(1):1-11.
7) Flynn-Evans, E. E. et al. 2009. Total visual blindness is protective against breast cancer. Cancer Causes Control. 20(9):1753-6
8) Sánchez-Barceló, E. J. et al. 2003. Melatonin and mammary cancer: a short review. Endocr Relat Cancer. 10(2):153-9.
9) Verkasalo, P. K. et al. 1995. Inverse association between breast cancer incidence and degree of visual impairment in Finland. British Journal of Cancer. 80: 1459–1460.
10) Nooshinfar, E. et al. 2016. Melatonin promotes ATO-induced apoptosis in MCF-7 cells. Proposing novel therapeutic potential for breast cancer. Biomedicine & Pharmacotherapy. 83:456-465.
11) Mao, L. et al. 2016. Melatonin represses metastasis in Her2-postive human breast cancer cells by suppressing RSK2 expression. Molecular Cancer Research. 14(11):1159-1169.

References Interactions

Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.
Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.