Melatonin Information

Facts

Melatonin is a hormone that helps regulate sleep and wake cycles. It is produced in the pineal gland.
The synthesis of melatonin displays a circadian rhythm that is reflected in serum melatonin concentrations. Synthesis and release of melatonin are stimulated by darkness and inhibited by light. Melatonin concentrations peak a few hours after darkness and taper through the remainder of the night.
Many blind individuals with no pupillary light reflexes and no conscious visual perception have light-induced suppression of melatonin secretion.
In the biosynthesis of melatonin, tryptophan is first converted by tryptophan hydroxylase to 5-hydroxytryptophan, which is then decarboxylated to serotonin. The synthesis of melatonin from serotonin is catalyzed by two enzymes (arylalkylamine N-acetyltransferase and hydroxyindole-O-methyltransferase) both of which are largely confined to the pineal gland.
As synthesis of melatonin increases, the hormone enters the bloodstream through passive diffusion. Melatonin secretion increases soon after darkness peaks and then gradually falls during the second half of the night.
Melatonin can be found in plants and animals, although concentrations in plants are much lower than in animals.
Infants younger than three months of age secrete very little melatonin. The secretion of melatonin peaks from age one to three (325 pg per mL) and then declines gradually with age (10 to 60 pg per mL for adults).
Melatonin is rapidly metabolized in the liver by hydroxylation and conjugation with sulfuric or glucuronic acid. It is then secreted into the urine. The bioavailability of oral melatonin supplements varies widely.

Functions

Melatonin may be used in the treatment of some forms of sleep disturbances or insomnia.
Although research results are mixed, melatonin may ease some symptoms of jet lag.
Supplemental melatonin may have a hypnotic action. It is a hormone that has biological affects and that is activated through a family of G protein-coupled receptors. The putative effect of melatonin as a hypnotic may be accounted for by receptor-mediated action on the limbic system.
At high doses, melatonin may have antioxidant properties. It may inhibit metal ion-catalyzed oxidation processes, such as Fenton reactions.
Melatonin may have anti-apoptotic activity in the thymus, possibly by down-regulating the glucocorticoid receptor.
Melatonin is involved in regulation of gut motility and sensation. Preliminary results suggest that melatonin supplements may be useful for disorders such as irritable bowel syndrome. ¹³,¹⁹,²⁰

Dosage

Information regarding the precise dose of melatonin is insufficient. The reported dose range has been from 0.3 to 80 mg, but the correct dosage and timing are unclear.¹
For sleep disturbance or jet lag, no more than 0.3 to 3 mg of melatonin should be taken at bedtime. Melatonin should not be taken for longer than 2 weeks. Higher doses or prolonged periods should only be attempted under medical supervision.
Melatonin is available in capsules, liquid, lozenges, sublingual tablets, tea, and timed release tablets.

Toxicity

No apparent overdose consequences have been seen in people taking up to 24 g a day for one month, although high doses are not recommended.
Prolonged use may interfere with sleep patterns.
Melatonin begins to accumulate in fatty tissues after 2 weeks of chronic ingestion.

Dietary Sources

Drug-Supplement Interaction

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Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin) and aspirin can decrease melatonin secretion in the body.
Beta-blockers such as propranolol (Inderal) inhibit the nocturnal rise in melatonin concentrations.
Tricyclics (amitriptyline [Elavil]), monoamine oxidase inhibitors (MAOIs; isocarboxazid [Marplan]) and some other antidepressants increase the concentrations of brain melatonin.
Benzodiazepines such as diazepam (Valium) interfere with synthesis of melatonin.
Diuretics such as furosemide (Lasix) and calcium-channel blockers such as amlodipine (Norvasc) can interfere with melatonin production.
Vitamin B12 concentrations influence melatonin secretion in the body. Taking melatonin (1.5 mg of methylcobalamin per day) can improve sleeping disorders.
Alcohol and caffeine can decrease melatonin production. Avoid these substances with or prior to taking melatonin.

Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Research Summary

Topic: Sleep Disturbances or Insomnia



	Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes.
	A randomized, double-blind, placebo-controlled clinical trial investigated the efficacy of melatonin for improvement of insomnia. A total of 334 people with insomnia participated in the trial (aged 55 to 80 years). After a two-week single-blind placebo run-in period, participants were randomly assigned to receive either 2 mg melatonin or a placebo daily two hours prior to bedtime. The active trial lasted for three weeks. Melatonin supplements were found to significantly improve quality of sleep and morning alertness compared to placebo (26% vs. 15%, p=0.014). Melatonin was also found to shorten sleep latency to a clinically relevant degree compared to placebo (-24.3 vs. -12.9 minutes, p=0.028). Quality of life was significantly improved for the participants in the melatonin group (p=0.034). These results indicate that 2 mg melatonin successfully improved insomnia in this group of participants. ¹⁴
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	Effect of melatonin administration on sleep, behavioral disorders and hypnotic drug discontinuation in the elderly: a randomized, double-blind, placebo-controlled study.
	A prospective, randomized, double-blind, placebo-controlled trial investigated the impact of melatonin on sleep, behavioral disorders, and hypnotic drug use in a group of older participants. Twenty-two community-living older adults participated in the crossover design trial. Each participant received 5 mg melatonin daily for two months and received a placebo daily for two months. Sleep quality scores were significantly improved with melatonin supplements (1.78+/-0.40) when compared to baseline (3.72+/-0.45, p=0.001) and placebo (3.44+/-0.56, p=0.025). Melatonin supplements also improved depression and anxiety scores (p=0.043 and p=0.009, respectively). One participant discontinued hypnotic drug use during both melatonin and placebo; nine participants were able to discontinue hypnotic drugs during melatonin use; four participants were not able to discontinue hypnotic drugs. This prospective study indicates that melatonin may be useful for improving sleep and behavioral disorders in older people. ¹⁵
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	Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects.
	A three week randomized, placebo-controlled trial investigated the effect of prolonged-release melatonin on sleep quality and alertness for primary insomnia patients. One-hundred-seventy participants were randomly assigned to receive 2 mg prolonged-release melatonin or a placebo daily. Participants were diagnosed with primary insomnia and were aged 55 years or older. Quality of sleep was significantly improved by melatonin compared to placebo (-22.5 vs. -16.5 mm, P=0.047). Changes in sleep quality were improved in the melatonin group (0.89 vs. 0.46 units, P=0.003). Morning alertness was significantly improved by melatonin, relative to placebo (-15.7 vs. -6.8 mm, P=0.002). Improvements in quality of sleep and morning alertness were correlated (Rval=0.77, P<0.001). Rebound insomnia and withdrawal effects were not noted. this study suggests that melatonin may be useful for those with insomnia. ¹⁶
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	Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes.
	A randomized, placebo-controlled, double-blind study investigated the efficacy of melatonin for insomnia. Three-hundred-fifty-four people 55 to 80 years who have insomnia participated in the five week trial. After a 2 week single blind placebo run-in period, participants were randomized to receive 2 mg prolonged-release melatonin or a placebo for three weeks. Participants took the supplements daily before bed. Quality of sleep and morning alertness were improved by melatonin versus placebo, demonstrated by responder analysis (26% vs. 15%, p=0.014). Sleep latency was improved in the melatonin group by an amount comparable to sleep medications (-24.3 vs. -12.9 minutes, p=0.028). Melatonin was also found to improve quality of life (p=0.034). Melatonin supplements were found to improve insomnia in this study. ¹⁷
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	Randomized placebo-controlled field study of the effects of bright light and melatonin in adaptation to night work.
	A randomized, placebo controlled, crossover design trial investigated the efficacy of melatonin or bright light for assistance for adaptation to swing shift work. Seventeen people working two week rotating schedules with 12 hour shifts, one week at night followed by one week during the daytime, participated in the study. Participants consumed 3 mg melatonin 1 hour prior to bedtime, a placebo before bedtime, or scheduled 30 minutes of bright light during the first 4 hours of work daily. Subjects consuming melatonin subjectively reported less sleepiness than those consuming placebo. Melatonin consumption was also found to increase sleep by slept 15 to 20 minutes per day compared to placebo. Results from bright light exposure were intermediate between the melatonin supplement and the placebo. Overall, the melatonin supplements were found to assist with adaptation to night shift work. ⁸
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	Potential of melatonin replacement therapy in older patients with sleep disorders.
	In a study conducted with elderly melatonin-deficient insomniacs, patients were given 1 to 2 mg melatonin or placebo for 7-day periods. In the preliminary study, 1 week of treatment with 2 mg fast-release melatonin was as effective as the two-month treatment with 1 mg sustained release melatonin. Researchers concluded that melatonin deficiency seemed to be linked to sleep disorders in the elderly. Melatonin replacement may be beneficial in the initiation and maintenance of sleep in the elderly. ⁵

	Sleep-inducing effects of low doses of melatonin ingested in the evening.
	Six healthy male volunteers participated in a study that included a total of 9 test sessions with at least 5 days between sessions. Subjects were given oral doses of 0.3 or 1.0 mg melatonin at 3 time points. Researchers found that sleep onset provoked by a single dose of melatonin, resulted not from its effect on biological timing mechanisms, but from a direct action of elevated circulating melatonin concentrations. ⁶
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Topic: Antioxidant Functions of Melatonin



	Physiological levels of melatonin contribute to the antioxidant capacity of human serum.
	During nighttime, both melatonin and total antioxidant status (TAS) decrease to basal daytime values and with aging, day to night differences in melatonin and TAS change. A study on healthy volunteers from ages 2 to 89 years examined whether physiological concentrations of melatonin contribute to the antioxidant capacity of human serum. Results showed physiological melatonin concentrations in human serum, especially at night, exhibited significant antioxidative properties. ⁷
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	Therapeutic effect of melatonin in patients with functional dyspepsia.
	The antioxidant activities of melatonin may help to alleviate symptoms of ulcerlike dyspepsia. A placebo-controlled trial with 60 participants aged 19 to 39 years with functional dyspepsia investigated the effects of melatonin. Participants did not have Helicobacter pylori infection. Subjects consumed 5 mg melatonin or placebo daily in the evening for 12 weeks. In the melatonin group, symptoms completely subsided after 12 weeks for 56.6% of the participants (17 people). Symptoms were improved for 9 participants in the melatonin group (30.0%). In contrast, participants consuming the placebo did not experience improvement of symptoms (93.3% maintained current level of symptoms). Prior infection with H. pylori was found to diminish efficacy of melatonin. The results of this study suggest that melatonin may be beneficial for ulcerlike dyspepsia for people without H. pylori infection. Further studies are needed to confirm these benefits. ¹²
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Topic: Bone Formation



	Melatonin promotes osteoblast differentiation and bone formation.
	An in vitro study examined whether melatonin could modulate expression of bone sialoprotein (BSP) in two cell lines. Concentrations of 10 nm melatonin were able to stimulate transcription of genes when cells were growing in the presence of beta-glycerophosphate and ascorbic acid. Melatonin-induced gene expression of bone marker proteins occurred on the fifth day after seeding the culture dishes. The results demonstrated that melatonin is capable of promoting osteoblast differentiation and mineralization of matrix in culture and it may play an essential role in regulating bone growth. ⁹
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Topic: Sleep Disturbances on Blindness



	Entrainment of free-running circadian rhythms by melatonin in blind people.
	A study with 7 sight-impaired subjects with free running circadian rhythms were given 10 mg melatonin or placebo daily 1 hour prior to bedtime for 3 to 9 weeks. Subjects were found to spend less time awake after the initial onset of sleep and sleep efficiency was higher. Researchers found free-running circadian rhythms in blind people can be entrained to a 24-hour cycle with a daily dose of melatonin thus improving or possibly preventing sleep disorders. ¹⁰
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Topic: Perimenopause and Menopause



	Effects of melatonin in perimenopausal and menopausal women: a randomized placebo controlled study.
	A study with perimenopausal and menopausal women ages 42 to 62 took 3 mg of melatonin or placebo at bedtime for 3 and 6 months. Melatonin produced a significant diminution of luteotropic hormone in the women aged 43 to 49, but no effect was seen in the 52 to 62 year old women. The women receiving melatonin reported a general improvement in mood, a significant mitigation of depression and a recovery of pituitary and thyroid functions. Overall, researchers concluded that this showed a more juvenile pattern of regulation. ¹¹
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Topic: Irritable Bowel Syndrome



	A preliminary study of melatonin in irritable bowel syndrome.
	A small study investigated the effects of melatonin on symptoms, extracolonic symptoms, and quality of life (QOL) for people with irritable bowel syndrome (IBS). Eighteen people with IBS, aged 18 to 65 years, participated in the eight week study. Participants were randomly assigned to receive 3 mg melatonin or a placebo daily at bedtime. Overall IBS scores, extracolonic IBS scores, and QOL scores were assessed every two weeks during the trial and then at 16, 24, and 48 weeks after the end of the study period. Melatonin significantly improved overall IBS scores compared to placebo (45% vs. 16.66%, P<0.05). The posttreatment extracolonic IBS score was also significantly lower when compared to the placebo group (49.16% to 13.88%, P<0.05). The overall improvement in QOL score was greater in the melatonin group than the placebo group (43.63% vs. 14.64%, respectively). This preliminary study confirms that melatonin may help improve symptoms for people with irritable bowel syndrome. ¹³
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	Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study.
	A double-blind, placebo-controlled, crossover design study investigated the efficacy of melatonin for improving symptoms of irritable bowel syndrome (IBS). Seventeen women with IBS participated in the trial. Participants consumed 3 mg melatonin or a placebo daily at bedtime. Subjects were randomized to receive melatonin or the placebo for eight weeks followed by a four week washout period and finally a second eight week trial with melatonin/placebo assignment reversed. Mean IBS scores were significantly improved after treatment with melatonin (3.9 +/- 2.6) relative to placebo (1.3 +/- 4.0, P=0.037). The percentage of subjects achieving mild-to-excellent improvement in IBS symptoms (percent response rate) was greater in the melatonin group (88% vs. 47%, P=0.04). The results of this small trial indicate that melatonin may be beneficial for symptoms of IBS. ¹⁹
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	Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study.
	A randomized, double-blind, placebo-controlled trial investigated the efficacy of melatonin for symptoms of irritable bowel syndrome (IBS). Forty people with IBS participated in the trial. Participants were randomly assigned to receive 3 mg melatonin or a placebo daily at bedtime for two weeks. Melatonin supplements significantly decreased mean abdominal pain score, compared to placebo (2.35 vs. 0.70, p<0.001). Melatonin also significantly increased mean rectal pain threshold versus placebo (8.9 vs. -1.2 mmHg, p<0.01). Although melatonin improved symptoms of IBS in this trial, sleep disturbances were not improved. No changes in total sleep time, sleep latency, sleep efficiency, sleep onset latency, arousals, duration of stages 1-4, rapid eye movement (REM) sleep, and REM onset latency were detected. This trial suggests that effects of melatonin in IBS symptoms do not derive from alterations in sleep from melatonin. Further trials are needed to elucidate the mechanisms involved. ²⁰
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Topic: Tinnitus



	The effects of melatonin in tinnitus and sleep.
	A prospective, open-label trial investigated the effects of melatonin on tinnitus. Twenty-four people with tinnitus participated in the trial. Participants consumed 3 mg melatonin daily for four weeks of observation. During the trial, tinnitus handicap inventory (THI) score improved. Improvement from baseline was noted over four weeks, and over eight weeks. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality during the study. PSQI significantly decreased between weeks 0 and 4 (P<0.0001), and between weeks 0 and 8 (P=0.0003). The changes in PSQI and THI scores were significantly associated. In this trial, melatonin use was associated with improvements in tinnitus and sleep quality. Further studies are necessary to confirm these results. ¹⁸
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Topic: Blood Pressure



	Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension.
	A randomized, double-blind, placebo-controlled crossover trial investigated the effects of acute (single dose) or repeated (daily for 3 weeks) melatonin supplements on sleep and blood pressure. Sixteen men with untreated essential hypertension participated in the trial. The acute trial investigated changes after a single 2.5 mg melatonin supplement. The repeated trial investigated changes after 3 weeks of 2.5 mg melatonin taken daily on hour before sleep. The single dose had no affect on sleep or blood pressure. Repeated use of melatonin for 3 weeks decreased systolic and diastolic blood pressure by 6 and 4 mmHg, respectively. No change in heart rate was detected. Day-night amplitudes of the rhythms in systolic blood pressure were increased by 15% and diastolic blood pressures were increased by 25%. Repeated use of melatonin also improved sleep, however changes in blood pressure were not associated with changes in sleep. Larger studies are needed to confirm these results. ²¹
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