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Melatonin

Common Name(s): Circadin, MEL, Melatonin, MLT, N-acetyl-5-methoxytryptamine

Clinical Overview

Use

A large amount of clinical trial data exists to support melatonin's role in reducing sleep onset latency in many sleep-related disorders in both adults and children. Evidence is less clear for improvements in sleep duration or quality. Increased healing rates in gastric and duodenal ulcers have been found in a small number of studies when melatonin was used as adjunctive therapy. Treatment of irritable bowel syndrome, infertility, endometriosis-associated pelvic pain, hypertension, anxiety, headache, osteopenia, and tinnitus have also been studied.

Dosing

Adjunctive therapy in cancer: Dosages of up to 20 mg/day have been used in trials. Analgesia: 3 to 5 mg at bedtime. Anesthesia premedication, pediatric: A dose of 0.5 mg/kg (maximum, 20 mg) has been used in children undergoing elective surgery to reduce surgical propofol anesthetic doses. Insomnia: 3 to 5 mg daily in the evening over 4 weeks. Independent studies have not yet clarified the efficacy of sustained-release preparations. Jet lag: In general, lower doses (0.5 to 2 mg) preflight and higher doses (5 mg) postflight over a period of up to 4 days appear to be adequate. Sleep/delirium in critically ill patients: 3 to 10 mg nightly for 3 to 4 nights. Pediatric: Melatonin 2 to 5 mg has been used in children.

Contraindications

Until it is studied more thoroughly, melatonin is contraindicated for patients with autoimmune diseases.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Melatonin has been used in many conditions as an adjunct to standard therapy. Melatonin may interact with several medications, alcohol, and cannabis.

Adverse Reactions

Possible adverse effects include dizziness, enuresis, excessive daytime somnolence, headache, nausea, insomnia, nightmares, and transient depression. Drowsiness may be experienced within 30 minutes after taking melatonin and may persist for approximately 1 hour; as a result, melatonin may affect driving ability. Use of the animal tissue-derived product is discouraged because of the risk of contamination or viral transmission.

Toxicology

Studies are limited. There is little or no evidence of major toxicities with melatonin, even at high doses.

Source

Endogenous melatonin is a hormone produced by the pineal gland in all vertebrates. It is also produced in extrapineal organs, such as the eye, GI tract, bone, skin, lymphocytes, platelets, and thymus. Melatonin secretion is inhibited by environmental light and stimulated by darkness. Secretion starts at 9 PM and peaks between 2 and 4 AM at approximately 200 pg/mL. The duration of melatonin production varies throughout the year, with shorter periods occurring during the summer months and longer periods occurring during the winter months. Nocturnal secretion of melatonin is highest in children and decreases with age. In addition to being produced in vertebrates, melatonin is also found in plants, bacteria, unicellular eukaryotes, and invertebrates.

Melatonin is a dietary supplement and has not been approved by the US Food and Drug Administration. It is derived as a synthetic product or from animal pineal tissue. Use of the animal tissue-derived product is discouraged because of a risk of contamination or viral transmission. Melatonin, along with serotonin, tryptophan, anthocyanins, and phenolic compounds, is also present in large quantities in some plants, including Jerte Valley cherries.1, 2, 3, 4 An analysis of 31 commonly available commercial melatonin supplement products found in grocery stores and pharmacies found melatonin content to range from 0.37% to 465% of its label claim in over 71% of the products analyzed. Products with the least variability were tablets and sublingual tablets; liquids had the next lowest variability. Additionally, 8 (26%) of the supplements were found to be contaminated with serotonin at levels of 1 to 75 mcg. No correlation in mislabeling was found with manufacturer or product type.161

The melatonin receptor agonists agomelatine (Valdoxan), ramelteon (Rozerem), and tasimelteon (Hetlioz) are available and are being studied in depression and sleep disorders.5, 6, 7, 8, 9

History

Early animal studies of melatonin in the mid-1960s revealed its ability to affect sexual function, skin color, and other mammalian functions. It is a mediator of photo-induced antigonadotropic activity in photoperiodic mammals, and it affects thermoregulation and locomotor activity rhythms in birds. Early studies showed that diurnal variations in estrogen secretion in rats could be regulated by changes in melatonin synthesis and release, induced by the daily cycle of light and dark via the efferent limb of the reflex in the sympathetic innervation of the pineal gland. Continual darkness depresses the estrous cycle. Studies in the 1990s led to widely expanded uses of melatonin, including easing insomnia, combating jet lag, preventing pregnancy (in large doses), protecting cells from free-radical damage, boosting the immune system, preventing cancer, and extending life.3, 10, 11

Chemistry

Chemically, melatonin is N-acetyl-5-methoxytryptamine, an indoleamine. Tryptophan and serotonin are precursors of melatonin because N-acetyltransferase and hydroxyindole-O-methyltransferase enzymes are involved in its synthesis. It can be isolated from the pineal glands of beef cattle or synthesized from 5-methoxyindole as a starting material via 2 different chemical reactions. It is a relatively low molecular weight hormone of 232 Da and is a pale yellow crystalline material. Methods for detecting melatonin in human fluids and tissue have been described.1, 10, 12

A systematic review of pharmacokinetic studies in adult patients and volunteers revealed the bioavailability of orally dosed melatonin to be approximately 15% (range, 9% to 33%) and time to maximum plasma concentration (Cmax) was about 50 minutes for an immediate-release formulation. Study designs and analysis methods varied extensively; however, other factors that may impact the kinetics of melatonin included age, caffeine, smoking, and oral contraceptive use.146 Substantial inter-individual variability has been documented in bioavailability, Cmax, and area under the curve (AUC). A crossover study in 12 healthy male volunteers administered 10 mg of melatonin by oral and IV routes found extensive variations in Cmax (2,500.5 to 8,057.5 pg/mL and 174,775 to 440,362.5 pg/mL, respectively) as well as total AUC (232,696.1 to 546,285.4 pg/mL and 7,063,347.4 to 18,964,804 pg/mL, respectively). Elimination half-lives were 47 to 61 minutes and 35.8 to 43 minutes, respectively. Oral bioavailability ranged from 1.7 to 4.7% (mean, 2.5%).160

Uses and Pharmacology

Analgesia

Clinical data

Antinociceptive effects of melatonin have been demonstrated in various animal pain models including acute, inflammatory, and neuropathic pain.156 Melatonin as adjunctive therapy has been reported to improve sleep, severity of pain, tender point count, and global physician assessment in patients suffering from fibromyalgia.89, 90, 91 Additionally, patients with temporomandibular disorder taking 5 mg of melatonin for 28 days experienced significant improvements in pain scores (mean, −44%), pressure pain threshold (mean, 39%), and sleep quality (mean, 42%) compared with placebo; effects on pain and sleep quality were independent of each other. Doses of concomitant analgesics were also significantly decreased in the melatonin group (P < 0.01).131 A randomized, parallel, double-blind, placebo-controlled, dose-response trial in 61 healthy white Brazilian adults found a dose-dependent analgesic effect on pain threshold and tolerance with sublingual doses of melatonin at 0.05, 0.15, and 0.25 mg/kg (maximum, 20 mg). Both heat and pressure pain thresholds and tolerance were significantly increased with a single 0.15 mg/kg dose. Statistically significant increases in sedation were observed with the 0.15 and 0.25 mg/kg doses compared to the 0.05 mg/kg dose and placebo. No adverse effects besides sedation were experienced.156 Similarly, significantly lower doses of sedatives (eg, hydroxyzine, lorazepam, IV propofol) were needed in high-risk ICU patients who were given melatonin 3 mg twice daily at 8 pm and midnight starting on day 3 of ICU admission compared to controls in a double-blind, randomized controlled trial (n=82). Melatonin also led to significantly earlier weaning from neuroactive drugs (P=0.002) and mechanical ventilation (P=0.046), lower costs, reduction in deep sedation states, improved agitation/sedation scores (P=0.05), and improvements in several neurological indicators (ie, pain, anxiety, agitation, or need for physical restraints [P<0.01 for each]). No clinically relevant side effects associated with melatonin were observed.162

Antioxidant

Improved oxidative status has been reported in exercise studies,82, 83 and in nonalcoholic fatty liver disease,84 muscular dystrophy,85 ocular diseases,86 cystic fibrosis,47 and metabolic syndrome.22, 87 Topical melatonin may exhibit an antioxidant-related photoprotective effect.88, 135

Persistent adverse hepatic side effects induced by statin drugs were significantly reduced by the addition of melatonin to statin therapy in 60 adults (41 women, all postmenopausal) with hyperlipidemia. Patients received dietary advice, recommendations to maintain statin therapy at 20 mg/day, and were randomized to either melatonin 5 mg twice daily or placebo. After 6 months, all elevated enzyme values (eg, AST, ALT, GGT, ALP) were significantly reduced in the melatonin group compared to placebo (P<0.001). The decrease in total cholesterol, but not triglycerides, was also significant in the group receiving the low-dose statin plus melatonin (−41.6 mg/dL) compared to low-dose statin plus placebo (−19.3 mg/dL; P<0.05). The only reported side effect attributed to melatonin use was mild fatigue in 20% of 30 melatonin users for the first 2 weeks following the morning dose. These effects were attributed to the high antioxidant activity of melatonin and its metabolites that are produced during hepatic metabolism of melatonin.168

Bone metabolism

Animal data

In conjunction with a small clinical study, administration of melatonin in a mouse model of multiple sclerosis (MS) demonstrated a significant improvement in MS clinical scores (P<0.05). Induction of MS resulted in an approximate 2-fold increase in serum procalcitonin levels (P<0.01), as well as a significant decrease in serum 25-hydroxyvitamin D (P<0.01), calcium (P<0.001), and osteocalcin (P<0.05). Administration of melatonin significantly improved all of these parameters (P<0.05).184

Clinical data

A double-blind, randomized, placebo-controlled trial evaluated the effect of melatonin (1 or 3 mg nightly) given over 1 year on bone mineral density in postmenopausal white women with osteopenia (n = 81); daily calcium (800 mg) and vitamin D3 (20 mcg) were also provided as supplements. Compared to placebo, bone mineral density was increased in a dose-dependent manner in the femoral neck, which was significant (by 2.3%) for the 3 mg/day group (P < 0.01), but no difference was observed in the lumbar spine, forearm, whole body, or other hip locations. Urinary calcium was also significantly decreased in the melatonin groups (by 28.3% with 3 mg, P = 0.04) compared to placebo; however, no changes were seen in biochemical markers of bone turnover. Melatonin was well tolerated; 3 patients discontinued treatment due to diarrhea, hangover effects, and difficulties swallowing the pill, whereas 1 patient in the placebo group stopped due to reduced quality of sleep.157 In 23 patients with MS, melatonin levels were found to be significantly lower than those of 23 healthy controls (P<0.05) and a significant inverse relationship was observed to serum procalcitonin levels (r=−0.945; P=0.0001). Additionally, a marker of bone matrix synthesis, osteocalcin, was found to be significantly decreased in MS patients compared to controls (P<0.05).184

Cancer

Clinical data

Meta-analyses of clinical trials of melatonin have been conducted.15, 17 Thus far, limited clinical studies have been performed, primarily in the treatment of solid tumors, with melatonin as adjunctive therapy. The majority of these trials were open-label studies with small numbers of participants. Significantly increased 1-year survival rates were found, with a pooled relative risk (RR) of 0.63 (95% confidence interval [CI] 0.53 to 0.74; P < 0.001),16 as well as a decrease in chemotherapy-related adverse effects, including thrombocytopenia, neurotoxicity, and fatigue.15, 16, 17 Trials report using dosages of melatonin up to 20 mg/day.15 A 28-day randomized, double-blind study (n = 48) evaluating melatonin 20 mg/day for cachexia in adult patients with advanced cancers was halted early after interim analysis showed no benefit compared with placebo.134 Several larger clinical trials are ongoing in the United States.17

Cardiovascular effects

Animal data

Studies in animals have been conducted for cardiovascular conditions, including hypertension, hypertrophy, reperfusion injury, and coronary syndromes.18, 19

Clinical data

A meta-analysis of clinical trials evaluating the effect of melatonin on nocturnal hypertension has been conducted.20 Seven studies met inclusion criteria, with only a subgroup analysis of trials that used sustained-release preparations showing decreases in blood pressure. Systolic blood pressure decreased by 6 mm Hg (95% CI, −10.7 to −1.5) and diastolic by 3.5 mm Hg (95% CI, −6.1 to −0.9). Immediate-release preparations showed no effect.20 Another study found that melatonin increased blood pressure by a similar amount in patients stable on nifedipine.21 Antioxidant and anti-inflammatory effects of melatonin in cardiovascular disease have been considered; however, clinical trials are limited.22, 23, 24

Circadian misalignment/Jet lag

Clinical data

Melatonin's ability to modulate circadian rhythms has prompted several studies in shift workers and military personnel, as well as in the prevention of jet lag.64 Circadian disturbances are also frequently reported in hemodialysis patients.132

Available studies are limited by the small number of participants and a focus on subjective ratings of effects with little or no evidence of actual changes in circadian shift (ie, changes in oral temperature or cortisol levels). Several melatonin regimens have been examined: 3 to 10 mg daily for various durations, using either rapid- or sustained-release preparations.64 A double-blind, placebo-controlled, randomized clinical trial (n = 67) documented short-term improvements in sleep at 3 months with 3 mg nightly of melatonin but benefits were not sustained at 6-, 9-, or 12-month follow-ups. A major limitation of the study was high drop-out rates (37%).132

However, there is little information on the best dose or formulation, with studies using different dosage regimens. In general, lower doses (0.5 to 2 mg) preflight and higher doses postflight over a period of up to 4 days appear to be adequate.64, 65

Dementia/Delirium

Clinical data

The role of melatonin in dementia and delirium in elderly patients has been discussed; however, clinical trials are limited.75, 76, 77 Data from 5 trials included in a Cochrane meta-analysis do not support the use of melatonin in dementia.78 A systematic review and meta-analysis of randomized placebo-controlled trials investigating the effects of melatonin on sleep quality and cognition in patients with dementia found no significant effect in primary or secondary outcome measures. A total of 520 patients were enrolled in the 7 studies that met inclusion criteria, 5 included patients with only Alzheimer’s disease and 2 included Alzheimer’s disease and other dementias including vascular dementia. All but 1 study administered melatonin 10 mg for 10 days to 3.5 years; 1 study used a sustained-release formulation of 2.5 mg × 8 weeks. Studies were of low to moderate quality.154 The American Psychiatric Association (APA) guideline watch for the treatment of patients with Alzheimer disease and other dementias (2014) did not find enough definitive new evidence to change the 2007 guideline recommendations for alternative agents, including melatonin.166

Sleep deprivation is a major contributing factor to the development of delirium, an acute state of mental confusion, which is common in ICU patients and often leads to adverse outcomes. Sleep disturbance in these patients has been associated with low melatonin secretion as well as disruptive environmental factors, and methods to quantify sleep and sleep-like states are often unreliable. Limited data suggest a potential benefit of melatonin supplementation on sleep and delirium in ICU patients.147, 151 Modest but insignificant effects on sleep have been documented in small trials where melatonin 3 mg × 3 days significantly increased plasma levels but failed to produce significant impacts on sleep, delirium, or agitation.150, 151

Dermatitis

Clinical data

Adjunctive melatonin was shown to improve atopic dermatitis and related sleep problems in children enrolled in a double-blind, randomized, placebo-controlled, crossover trial (n = 48). Children 1 to 18 years of age (mean age, 7 years) with atopic dermatitis involving at least 5% total body surface area with sleep problems occurring more than 3 days/week in the previous 3 months were advised to avoid caffeinated drinks and continue usual medications for atopic dermatitis. After randomization to melatonin (3 mg/day) or placebo at bedtime for 4 weeks, a 2-week washout, and alternate treatment for 4 weeks, Scoring Atopic Dermatitis (SCORAD) index (by 9.1) and sleep-onset latency (by 21.4 minutes) improved significantly with melatonin compared to placebo. No adverse events were reported.155

GI disorders

Animal data

Studies in rodents have found that melatonin exhibits antiulcer activity, protecting against colonic immune injury and improving duodenal and gastric motility.25

Clinical data

Melatonin exhibits antioxidant effects, inhibits hydrochloric acid and pepsin secretion, and acts as an immunostimulant. Melatonin receptors are found in the smooth muscle of the intestine, and enterochromaffin cells found in the GI tract secrete considerable amounts of melatonin.12, 25 Accelerated healing rates have been demonstrated in several small clinical trials evaluating melatonin alone or as adjunctive therapy in gastric and duodenal ulcers.26, 27, 28, 29

Some studies evaluating the efficacy of melatonin in irritable bowel syndrome and ulcerative colitis reported improved symptoms; however, results have been equivocal.30, 31, 32 In a 2013 double-blind, placebo-controlled study (n = 80), significant beneficial effects of melatonin were found for symptoms of constipation-predominant irritable bowel syndrome in postmenopausal women but not in those with diarrhea-predominant disease.128 Administration of melatonin 3 mg fasting and 5 mg at bedtime for 6 months resulted in a decreased intensity of visceral pain and abdominal bloating in 70% as well as improved constipation in 50% of women with constipation-predominant disease. Additionally, a significant inverse relationship was observed in symptom scores and excretion of urinary 6-sulfatoxymelatonin in the constipation-predominant group versus healthy controls (mean: −9.3 mcg per 24 hr in severe disease versus 11.4 mcg per 24 hr, respectively); these values were higher than healthy controls in the diarrhea-predominant group whose beneficial changes were no better than placebo.128

Headache

Clinical data

Melatonin has been investigated for preventive use in headaches, including cluster and migraine headaches, with limited evidence for efficacy.71, 72, 73, 74

Insomnia, adults

Clinical data

Although the administration of melatonin has been shown to shift melatonin secretion and circadian rhythm patterns, a direct hypnotic effect has not been clearly established. Decreased circulating melatonin serum levels have been found in people of all ages with insomnia, as well as in healthy elderly individuals.

A 2005 meta-analysis of 17 clinical trials evaluating melatonin's effect on "sleep" found small decreases in sleep-onset latency of 4 minutes (95% CI, 2.5 to 5.4).42 Overall, sleep duration was not affected by melatonin. Similarly, a 2010 meta-analysis of studies in adults and children with delayed sleep phase syndrome found that exogenous melatonin reduced sleep-onset latency by 23.27 minutes (95% CI, 4.83 to 41.72 minutes) but had no effect on wake time or total sleep times.43 However, a randomized clinical trial conducted in young adults with delayed sleep phase syndrome (n = 40) found the combination of bright light plus melatonin over 3 months improved daytime sleepiness, fatigue, and cognitive function; additionally, rise time and bedtime improved by 2 hours and 1 hour, respectively.126 Similar results for delayed sleep phase disorder were noted in other studies with improvements in sleep onset time, rise time, total wake time, and sleep efficiency.138, 185 Studies published before April 2012 evaluating the effect of melatonin on primary sleep disorders (ie, insomnia, delayed sleep phase syndrome) were assessed in a meta-analysis that involved 1,683 patients.127 Statistically significant effects were found in reducing sleep latency (fell asleep 7 minutes earlier), increasing total sleep time (slept 8 minutes longer), and overall sleep quality; higher doses and longer duration of therapy were associated with greater effects on sleep latency and time but not quality. Doses ranged from 0.1 to 3 mg and durations ranged from 7 to 182 days.127 Improvement in sleep disorder secondary to traumatic brain injury was documented in a small triple-blind, randomized, placebo-controlled crossover trial conducted in 35 participants. Significant improvements in sleep quality (P<0.0001), sleep efficiency (P=0.04), and a few other secondary end points (ie, daytime fatigue, anxiety) were achieved with sustained-release melatonin 2 mg nightly for 4 weeks.186

In a large meta-analysis, melatonin was not found to be beneficial for patients with secondary sleep disorders or sleep disorders accompanying sleep restriction.44 Trial data from studies of sleep disorders in Parkinson disease, adults with intellectual disabilities, and cystic fibrosis continue to be reported, with equivocal results.45, 46, 47, 48, 49 The addition of prolonged-release melatonin 2 mg/day for 24 weeks was reported in a randomized, double-blind, placebo-controlled trial (N = 80) to significantly improve cognition and sleep maintenance in patients with mild to moderate Alzheimer disease, particularly in those with insomnia comorbidity. Sleep efficiency, as evaluated by the Pittsburgh Sleep Quality Index (PSQI), was also improved with prolonged-release melatonin.145 Data from company-sponsored trials are unconvincing. Sleep disturbance, common among breast cancer survivors, was improved overall (by a PSQI score of 1.67 points, P = 0.001) in postmenopausal breast cancer survivors who received melatonin 3 mg nightly for 4 months in a double-blind, randomized, placebo-controlled trial (n = 95). Adverse effects that led to discontinuation by 4 participants included headaches, insomnia, and nightmares (all grade 1 or 2); all 4 were in the melatonin group. No significant effect was found on mood or hot flashes between groups.152

Exogenous supplementation with controlled-release melatonin 3 mg was shown to induce sleep in all 8 pulmonary intensive care unit (ICU) patients in a double-blind, placebo-controlled pilot study and resulted in awakening patterns similar to matched controls in the general ward.148 Another small randomized, double-blind controlled trial (N = 24) also found a modest improvement in nightly sleep time (by 1 hour) and quality (by 7%, P = 0.04) in critically ill tracheostomy patients who received melatonin 10 mg oral solution compared to placebo; however, these effects were not significantly different overall when considering all 4 nights of the study. Carry-over effects were suspected with this dose and supraphysiological levels were noted in the morning. Pharmacokinetic measurements revealed rapid absorption with administration of oral solution with biexponential declines in plasma concentrations.149

Melatonin may be particularly useful when traditional hypnotics are contraindicated.

Results of a randomized controlled-trial confirmed results of 2 previous trials regarding the lack of benefit of melatonin over placebo for short-term benzodiazepine withdrawal outcomes in adults taking benzodiazepines long-term (longer than 1 month) for insomnia.143 However, because beta-blockers suppress endogenous nighttime melatonin secretion, that possibly explains the reported side effect of insomnia; the effect of nightly melatonin supplementation in hypertensive patients treated with beta-blockers was investigated. In a double-blind, randomized, placebo-controlled, parallel trial, 16 patients received melatonin 2.5 mg nightly for 3 weeks. Compared to placebo, melatonin significantly increased total sleep time by 36 minutes (P = 0.046) and sleep efficiency by 7.6% (P = 0.046), and decreased sleep onset latency to stage 2 by 14 minutes (P = 0.001). No adverse effects were observed.158

Based on trials of melatonin 2 mg, the American Academy of Sleep Medicine clinical practice guideline for the pharmacologic treatment for chronic insomnia (2017) suggests that melatonin not be used as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. Benefits are considered to be approximately equal to risks (Weak; Very Low).124

Insomnia, children

Clinical data

The effects of melatonin for insomnia or other sleep disorders in children with attention deficit hyperactivity disorder; epilepsy; brain injury; visual impairment; atopic dermatitis; and neurodevelopmental disorders, including autism spectrum disorders and Smith-Magenis syndrome among others, have been evaluated.50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 155, 187 Adjunctive melatonin was shown to improve atopic dermatitis and related sleep problems in children enrolled in a double-blind, randomized, placebo-controlled, crossover trial (n = 48) in Taiwan. Children 1 to 18 years of age (mean age, 7 years) with atopic dermatitis involving at least 5% of total body surface area, with sleep problems occurring more than 3 days/week in the previous 3 months were advised to avoid caffeinated drinks and continue usual medications for atopic dermatitis throughout the study. Children with documented sleep disorders were excluded. After 1:1 randomization to melatonin (3 mg/day) or placebo at bedtime for 4 weeks, a 2-week washout, and alternate treatment for 4 weeks, Scoring Atopic Dermatitis (SCORAD) score (by 9.1) and sleep-onset latency (by 21.4 minutes) improved significantly with melatonin compared to placebo. No adverse events were reported.155 Children with autism spectrum disorder or neurogenetic disorders were found to sleep almost an hour longer on average after 13 weeks of sustained-release melatonin (titrated from 2 up to 10 mg/night) compared to approximately 10 minutes longer with placebo (P=0.034) in a double-blind, randomized trial (n=95). Sleep latency also improved significantly with melatonin vs placebo with children falling asleep faster (39.6 minutes vs 12.51 minutes, respectively; P=0.011).187

The outcomes of studies in children have been similar to those in adults; however, the trials have generally had smaller numbers of participants and wide-ranging dosage regimens, making generalized statements on efficacy difficult to support.61, 62, 63

The American Academy of Sleep Medicine updated clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders (2015) recommends the use of strategically timed melatonin in children and adolescents for the treatment of DSWPD and ISWRD in those with comorbid neurological disorders (Weak).124

Reproductive system

Animal data

Melatonin supplementation in domestic cats prolonged the interestrus interval but had no effect on delaying puberty.33 In red deer,34 and similarly in lambs35 and goats,36 melatonin has been used to influence ovulation with some success. Melatonin has been investigated for its potential to reduce adhesion formation following uterine surgery.37

Clinical data

A randomized, unblinded study evaluated the effect of melatonin 3 mg nightly on oocyte count, finding in favor of melatonin. Subsequent pregnancy rates following in vitro fertilization were similar between groups, but live birth data were not reported.38 Another similar study found an increase in mature oocytes retrieved with melatonin 3 mg daily, and equivalent fertilization and pregnancy rates.39 It has been suggested that melatonin protects granulose cells undergoing luteinization.40 A meta-analysis of 5 studies published prior to April 2013, lacked sufficient high quality data to determine effect or benefit of melatonin supplementation during controlled ovarian stimulation in women undergoing assisted reproductive technology.129 Studies in men suggest that melatonin may have a protective role on spermatozoa through free-radical scavenging activities.41

Melatonin was found to improve daily pain, dysmenorrhea, dysuria, dyschezia and sleep quality as well as modulate secretion of brain-derived neurotrophic factor (BNDF) in a phase II, double-blind, placebo-controlled randomized clinical trial (n = 40). Compared with placebo, women with endometriosis-associated pelvic pain treated with melatonin 10 mg for 8 weeks reported almost 40% less pain and dysmenorrhea. Additionally, it was observed that the effect on BDNF secretion occurred independently of analgesic mechanisms.130 A Cochrane systematic review and meta-analysis of dietary supplements for dysmenorrhea identified only low or very low quality studies with very small sample sizes. No strong evidence of effectiveness was found for the treatment of dysmenorrhea with melatonin 10 mg, specifically dysmenorrhea secondary to endometriosis, compared to placebo. Supplementation was started at the onset of menstruation for 8 weeks. Data were unsuitable for analysis.153

Schizophrenia

Clinical data

The role of melatonin in schizophrenia and bipolar disorder has been discussed.79, 80 A triple-blind, randomized, placebo-controlled trial (n=86) evaluated the role of supplementary melatonin in facilitating benzodiazepine reduction or discontinuation in patients with schizophrenia or bipolar disorder. Prolonged-release melatonin (2 mg nightly) administered for 24 weeks in parallel with the gradual reduction (10% to 20% every 2 weeks) in benzodiazepine or benzodiazepine-like drugs did not significantly reduce mean daily dosage, cessation, or withdrawal symptoms of the benzodiazepine drugs compared to placebo.81, 164 A double-blind, randomized, controlled trial found melatonin 5 mg/day for 8 weeks to significantly counteract adverse metabolic effects (ie, fat mass, diastolic blood pressure) caused by second-generation antipsychotics compared with placebo, particularly in patients with bipolar disorder, but not in patients with schizophrenia. 137

Surgery

Melatonin has been used with equivocal results in perioperative anxiety, appearing to be more effective than placebo and less effective than midazolam.66, 67, 68, 69, 70 No effect on improved outcomes, including rate of infection or length of stay in intensive care unit, has been observed.92, 93 Additionally, a systematic review found that reported effects on perioperative anxiety, pain, sleep quality, oxidative stress, emergence behavior, anesthetic dose, steal anesthetic induction, and safety were unreliable due to extreme heterogeneity and variability in study design. However, a double-blind, randomized comparator study in 92 children undergoing elective surgery documented significantly lower mean propofol doses in those premedicated with melatonin (propofol 2.08 mg/kg) compared to midazolam (propofol 2.95 mg/kg; P<0.001). The mean total dose of propofol was also significantly reduced in the melatonin group (69.2 mg vs 100.8 mg; P<0.001). Presurgical sedation and postsurgical recovery were found to be similar between groups. Melatonin and midazolam were dosed at 0.5 mg/kg with a maximum dose of 20 mg.163 Qualitative review of individual randomized clinical trials suggested that melatonin improved sleep quality and emergence behavior.140 The combination of melatonin plus alprazolam as surgical premedication was found to produce a maximum reduction in anxiety compared with either agent alone or placebo, and was significantly different compared with placebo (P = 0.008). Increased sedation scores were significant at 60 minutes between the combination and melatonin alone (P = 0.001) as well as placebo (P = 0.008).142

The risk of developing depressive symptoms during the 3 months following breast cancer surgery was significantly reduced with melatonin (6 mg daily X 3 months) compared with placebo (RR, 0.25; 95% CI, 0.077 to 0.8; number needed to treat, 3). No significant differences were found in other subjective outcomes including anxiety, sleep, general well-being, fatigue, pain, or sleepiness.141

Tardive syndromes

The American Academy of Neurology guidelines for the treatment of tardive syndromes (2013), including tardive dyskinesia (TDS), concludes that data are conflicting with melatonin in treating TDS; at 2 mg daily it is possibly ineffective but at 10 mg daily it is possibly effective.125

Tinnitus

Limited studies have evaluated the effect of melatonin on tinnitus. A prospective, open-label trial of melatonin 3 mg nightly over 4 weeks found both statistically and clinically significant improvements for up to the 8-week measurement point.94 A randomized, double-blind, crossover trial (N = 61) of melatonin 3 mg at night over 30 days found decreases in tinnitus intensity, as well as improved sleep quality.95 The American Association of Otolaryngology – Head and Neck Surgery clinical practice guidelines for tinnitus (2014) recommend against the use of melatonin or other dietary supplements for treating patients with persistent, bothersome tinnitus (moderate-quality aggregate evidence).139

Other uses

Roles for melatonin in systemic sclerosis,96 postoperative pericardial adhesion formation,97 peripheral nerve regeneration,98 tardive dyskinesia,99, 100 reduction of intraocular pressure,66 and severe burns101 have been suggested. A role in diseases related to the immune system has yet to be clarified. Until then, melatonin should be avoided in people with autoimmune disease.102, 103

Adjunctive use of melatonin with olanzapine and lithium was investigated for effects on olanzapine-induced weight gain in 38 adolescents 11 to 17 years of age who were treatment-naive and newly diagnosed with bipolar I disorder. Using a double-blind, randomized, placebo-controlled design, patients with a normal body mass index received standard treatment with adjunctive melatonin (3 mg/day) or placebo for 12 weeks. Those in the melatonin group experienced less of an increase in body weight that was not significantly different from placebo (5.8 kg vs 8.2 kg, respectively, P=0.065).165

Dosing

An analysis of 31 commonly available commercial melatonin supplement products found in grocery stores and pharmacies found melatonin content to range from 0.37% to 466% of its label claim in over 71% of the products analyzed. The results were across brands, doseform, and lot. The largest variation was found in chewable tablets that showed a 478% increase (almost 9 mg of melatonin compared to the label claim of 1.5 mg). Lot-to-lot variability within a single product varied up to 465% of labeled content. Products with the least variability were tablets and sublingual tablets; liquids had the next lowest variability. Additionally, 8 (26%) of the supplements were found to be contaminated with serotonin at levels of 1 to 75 mcg. The majority of those containing serotonin were herbal combination products that also contained extracts such as passionflower, hops, and valerian. No correlation in mislabeling was found with manufacturer or product type.161

Melatonin has a short plasma half-life (20 to 50 min), and plasma levels return to baseline within 24 hours after discontinuation of long-term dosing of less than 10 mg/day. Doses of melatonin 5 mg produce peak blood levels 25 times higher than physiological levels but do not alter endogenous melatonin production.1, 12, 104 Topical, transdermal, intravenous, and sublingual routes have been used.88, 93, 122, 123

Adjunctive therapy in cancer

Trials report using oral dosages of melatonin up to 20 mg/day.15

Analgesia

Melatonin 3 to 5 mg given orally at bedtime for 28 days has improved pain, pain threshold, and sleep quality in patients with temporomandibular disorder (TMD) as well as fibromyalgia. Concomitant analgesic doses were also reduced in TMD patients.89, 90, 91, 131

Anesthesia premedication, pediatric

A dose of 0.5 mg/kg (maximum, 20 mg) has been used in children undergoing elective surgery to reduce surgical propofol anesthetic doses.163

Insomnia

Melatonin 3 to 5 mg given orally 3 to 4 hours before an imposed sleep period over 4 weeks.42, 60 Prolonged-release melatonin 2 mg nightly as an add-on to standard therapy was shown to have positive effects on sleep maintenance in patients with insomnia and comorbid Alzheimer disease.145 Independent studies have not yet clarified the efficacy of sustained-release preparations.

Cognitive function and sleep in mild to moderate Alzheimer’s disease

2 mg doses were used in clinical trials.145

Jet lag

There is little information on the best dose or formulation because studies have used different dosage regimens. In general, lower oral doses (0.5 to 2 mg) preflight and higher oral doses (5 mg) postflight over a period of up to 4 days appear to be adequate.64, 65

Children 6 months to 14 years of age with sleep disorders

Melatonin 2 to 5 mg orally has been used.61, 62

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Studies have examined the positive effects of melatonin on oocyte production.38, 39

Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 substrates. Monitor therapy.105

Alcohol: Alcohol (ethyl) may enhance the adverse/toxic effect of melatonin. Alcohol (ethyl) may diminish the therapeutic effect of melatonin.169

Benzodiazepines: Melatonin may enhance the sedative effect of benzodiazepines.169, 170, 171

Calcium Channel Blockers (Dihydropyridine): Melatonin may diminish the antihypertensive effect of calcium channel blockers (dihydropyridine). Monitor therapy.106, 107, 108

Cannibis: Cannabis may decrease the serum concentration of CYP1A2 substrates (high risk with inducers). This interaction has only been described with smoked cannabis herb (ie, marijuana).172, 173, 174, 175

Cimetidine: Cimetidine may increase the serum concentration of melatonin.169

CYP1A2 Inducers (Moderate): CYP1A2 inhibitors (moderate) may decrease the metabolism of CYP1A2 substrates (high risk with Inhibitors).109

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Consider therapy modification.109, 110

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 substrates. Monitor therapy.109

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 substrates. Consider therapy modification.109

Cyproterone: May decrease the serum concentration of CYP1A2 substrates. Monitor therapy.111

Deferasirox: May increase the serum concentration of CYP1A2 substrates. Monitor therapy.112

Fluvoxamine: Fluvoxamine may increase the serum concentration of melatonin.176, 177

Hypnotics (Nonbenzodiazepine): Melatonin may enhance the sedative effect of hypnotics (nonbenzodiazepine).169, 170, 171

Imipramine: Melatonin may enhance the adverse/toxic effect of imipramine.169

Obeticholic Acid: Obeticholic acid may increase the serum concentration of CYP1A2 substrates (high risk with inhibitors).178

Peginterferon Alfa-2b: Peginterferon alfa-2b may increase the serum concentration of CYP1A2 substrates (high risk with inhibitors).179, 180

Teriflunomide: Teriflunomide may decrease the serum concentration of CYP1A2 substrates (high risk with Inducers).181

Thioridazine: Melatonin may enhance the adverse/toxic effect of thioridazine.169

Vemurafenib: Vemurafenib may increase the serum concentration of CYP1A2 substrates (high risk with inhibitors).182, 183

Adverse Reactions

Most clinical studies note an absence of adverse reactions associated with melatonin administration.113 Minor adverse reactions have included headache, transient depression, enuresis, dizziness, nausea, insomnia, nightmares, and excessive daytime somnolence.44, 114, 149, 152 Diarrhea has been reported as adverse effects in clinical trials and a case report.157, 159 Reducing the dose from 5 mg/day to 1.8 mg/day improved sleep while eliminating persistent diarrhea in a 49-year-old female.159

Single case reports in the literature are associated with fixed drug eruption,115 psychotic episode,116 painful gynecomastia,117 and autoimmune hepatitis.118 However, melatonin was not definitively identified as the causal agent in any of these reports. Because older case reports exist of seizures associated with exogenous melatonin administration, there has been concern about melatonin’s effect on seizure control in children with severe neurological disorders.119 A review of the evidence on melatonin and seizures found a paucity of relevant data from which to draw firm conclusions, with the current evidence suggesting that melatonin neither improves or worsens seizures.136

Acute administration of melatonin was found to significantly impair glucose tolerance, especially when administered in the morning. The area under the curve and maximum concentration of plasma glucose was increased 186% and 21% (P < 0.001 for each), respectively, 15 minutes after melatonin 5 mg administration in the morning and 54% and 27% (P < 0.001 for each), respectively, after an evening dose.144

Drowsiness may be experienced within 30 minutes after taking melatonin and may persist for approximately 1 hour. Melatonin should be used with caution in elderly patients and with morning dosing and driving.120, 121

In 64 Chinese male students, exogenously administered melatonin was observed to significantly increase reactive aggression (P=0.038) compared to placebo and was not attributed to inhibitory actions, sleepiness, or other potential factors (ie, noise perception, emotional states, circadian preference).167

Toxicology

Toxicological studies are limited. A median lethal dose has not been determined, even at extremely high doses. Researchers gave human volunteers melatonin 6 g each night for 1 month and found no major problems, except for stomach discomfort or residual sleepiness.2, 113

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