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

Clinical Overview


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.


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.


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


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


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.


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


1. de Almeida EA, Di Mascio P, Harumi T, et al. Measurement of melatonin in body fluids: standards, protocols and procedures. Childs Nerv Syst. 2011;27(6):879-891.21104186
2. Wehr TA. Photoperiodism in humans and other primates: evidence and implications. J Biol Rhythms. 2001;16(4):348-364.11506380
3. Webb SM, Puig-Domingo M. Role of melatonin in health and disease. Clin Endocrinol (Oxf). 1995;42(3):221-234.7758227
4. Garrido M, Espino J, González-Gómez D, et al. The consumption of a Jerte Valley cherry product in humans enhances mood, and increases 5-hydroxyindoleacetic acid but reduces cortisol levels in urine. Exp Gerontol. 2012;47(8):573-580.22583983
5. Howland RH. A benefit-risk assessment of agomelatine in the treatment of major depression. Drug Saf. 2011;34(9):709-731.21830835
6. Goodwin GM, Emsley R, Rembry S, Rouillon F; Agomelatine Study Group. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(8):1128-1137.19689920
7. Fornaro M, Prestia D, Colicchio S, Perugi G. A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation. Curr Neuropharmacol. 2010;8(3):287-304.21358978
8. Liu J, Wang LN. Ramelteon in the treatment of chronic insomnia: systematic review and meta-analysis. Int J Clin Pract. 2012;66(9):867-873.22897464
9. Spadoni G, Bedini A, Rivara S, Mor M. Melatonin receptor agonists: new options for insomnia and depression treatment. CNS Neurosci Ther. 2011;17(6):733-741.21554566
10. Windholz M, ed. Merck Index. 11th ed. Rahway, NJ: Merck and Co; 1989.
11. Bowman WC, Rand MJ. Textbook of Pharmacology. 2nd ed. St. Louis: Blackwell Scientific Publications; 1980.
12. Carpentieri A, Díaz de Barboza G, Areco V, Peralta López M, Tolosa de Talamoni N. New perspectives in melatonin uses. Pharmacol Res. 2012;65(4):437-444.22311380
15. Wang YM, Jin BZ, Ai F, et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: A meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012;69(5):1213-1220.22271210
16. Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ. Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs. 2012;21(6):819-831.22500582
17. Seely D, Wu P, Fritz H, et al. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012;11(4):293-303.22019490
18. Reiter RJ, Tan DX, Paredes SD, Fuentes-Broto L. Beneficial effects of melatonin in cardiovascular disease. Ann Med. 2010;42(4):276-285.20455793
19. Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ. Clinical aspects of melatonin in the acute coronary syndrome. Curr Vasc Pharmacol. 2009;7(3):367-373.19601861
20. Grossman E, Laudon M, Zisapel N. Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials. Vasc Health Risk Manag. 2011;7:577-584.21966222
21. Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol. 2000;49(5):423-427.10792199
22. Koziróg M, Poliwczak AR, Duchnowicz P, Koter-Michalak M, Sikora J, Broncel M. Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome. J Pineal Res. 2011;50(3):261-266.21138476
23. Cook JS, Sauder CL, Ray CA. Melatonin differentially affects vascular blood flow in humans. Am J Physiol Heart Circ Physiol. 2011;300(2):H670-H674.21148765
24. Reiter RJ, Manchester LC, Fuentes-Broto L, Tan DX. Cardiac hypertrophy and remodelling: pathophysiological consequences and protective effects of melatonin. J Hypertens. 2010;28 (suppl 1):S7-S12.20823719
25. Mozaffari S, Rahimi R, Abdollahi M. Implications of melatonin therapy in irritable bowel syndrome: a systematic review. Curr Pharm Des. 2010;16(33):3646-3655.21128901
26. Kandil TS, Mousa AA, El-Gendy AA, Abbas AM. The potential therapeutic effect of melatonin in gastro-esophageal reflux disease. BMC Gastroenterol. 2010;10:7.20082715
27. Celinski K, Konturek PC, Konturek SJ, et al. Effects of melatonin and tryptophan on healing of gastric and duodenal ulcers with Helicobacter pylori infection in humans. J Physiol Pharmacol. 2011;62(5):521-526.22204799
28. Celinski K, Konturek SJ, Konturek PC, et al. Melatonin or L-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole. J Pineal Res. 2011;50(4):389-394.21362032
29. Klupińska G, Poplawski T, Drzewoski J, et al. Therapeutic effect of melatonin in patients with functional dyspepsia. J Clin Gastroenterol. 2007;41(3):270-274.17426465
30. Song GH, Leng PH, Gwee KA, Moochhala SM, Ho KY. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut. 2005;54(10):1402-1407.15914575
31. Lu WZ, Gwee KA, Moochhalla S, Ho KY. Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2005;22(10):927-934.16268966
32. Chojnacki C, Wisniewska-Jarosinska M, Walecka-Kapica E, Klupinska G, Jaworek J, Chojnacki J. Evaluation of melatonin effectiveness in the adjuvant treatment of ulcerative colitis. J Physiol Pharmacol. 2011;62(3):327-334.21893693
33. Faya M, Carranza A, Priotto M, et al. Long-term melatonin treatment prolongs interestrus, but does not delay puberty, in domestic cats. Theriogenology. 2011;75(9):1750-1754.21353299
34. Asher GW, Archer JA, Ward JF, Scott IC, Littlejohn RP. Effect of melatonin implants on the incidence and timing of puberty in female red deer (Cervus elaphus). Anim Reprod Sci. 2011;123(3-4):202-209.21190800
35. Sawalha MN, Kridli RT, Jawasreh KI, Meza-Herrera CA. The use of melatonin and progestagen-eCG to initiate reproductive activity in prepuberal Awassi ewe lambs. Trop Anim Health Prod. 2011;43(7):1345-1350.21512725
36. Zarazaga LA, Gatica MC, Celi I, Guzmán JL. Reproductive performance is improved during seasonal anoestrus when female and male Murciano-Granadina goats receive melatonin implants and in Payoya goats when females are thus treated. Reprod Domest Anim. 2012;47(3):436-442.22022882
37. Attar R, Yildirim G, Kumbak B, Ficicioglu C, Demirbag S, Yesildaglar N. Efficacy of melatonin and hyaluronate/carboxymethylcellulose membrane in preventing adhesion reformation following adhesiolysis in a rat uterine model. J Obstet Gynaecol Res. 2011;37(2):125-131.21159036
38. Eryilmaz OG, Devran A, Sarikaya E, Aksakal FN, Mollamahmutoğlu L, Cicek N. Melatonin improves the oocyte and the embryo in IVF patients with sleep disturbances, but does not improve the sleeping problems. J Assist Reprod Genet. 2011;28(9):815-820.21748445
39. Batioğlu AS, Sahin U, Gürlek B, Oztürk N, Unsal E. The efficacy of melatonin administration on oocyte quality. Gynecol Endocrinol. 2012;28(2):91-93.21770829
40. Taketani T, Tamura H, Takasaki A, et al. Protective role of melatonin in progesterone production by human luteal cells. J Pineal Res. 2011;51(2):207-213.21585519
41. Espino J, Bejarano I, Ortiz A, et al. Melatonin as a potential tool against oxidative damage and apoptosis in ejaculated human spermatozoa. Fertil Steril. 2010;94(5):1915-1917.20152967
42. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev. 2005;9(1):41-50.15649737
43. van Geijlswijk IM, Korzilius HP, Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep. 2010;33(12):1605-1614.21120122
44. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ. 2006;332(7538):385-393.16473858
45. Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson's disease. Mov Disord. 2011;26 (suppl 3):S42-S80.22021174
46. Braam W, Didden R, Maas AP, Korzilius H, Smits MG, Curfs LM. Melatonin decreases daytime challenging behaviour in persons with intellectual disability and chronic insomnia. J Intellect Disabil Res. 2010;54(1):52-59.19888921
47. de Castro-Silva C, de Bruin VM, Cunha GM, Nunes DM, Medeiros CA, de Bruin PF. Melatonin improves sleep and reduces nitrite in the exhaled breath condensate in cystic fibrosis—a randomized, double-blind placebo-controlled study. J Pineal Res. 2010;48(1):65-71.20025642
48. Rahman SA, Kayumov L, Shapiro CM. Antidepressant action of melatonin in the treatment of Delayed Sleep Phase Syndrome. Sleep Med. 2010;11(2):131-136.20044310
49. Kunz D, Mahlberg R. A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder. J Sleep Res. 2010;19(4):591-596.20561180
50. Wheeler B, Taylor B, Simonsen K, Reith DM. Melatonin treatment in Smith Magenis syndrome. Sleep. 2005;28(12):1609-1610.16408422
51. Weiss MD, Wasdell MB, Bomben MM, Rea KJ, Freeman RD. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry. 2006;45(5):512-519.16670647
52. Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol. 2001;16(2):86-92.11292231
53. Bendz LM, Scates AC. Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder. Ann Pharmacother. 2010;44(1):185-191.20028959
54. De Leersnyder H, Zisapel N, Laudon M. Prolonged-release melatonin for children with neurodevelopmental disorders. Pediatr Neurol. 2011;45(1):23-26.21723455
55. Elkhayat HA, Hassanein SM, Tomoum HY, Abd-Elhamid IA, Asaad T, Elwakkad AS. Melatonin and sleep-related problems in children with intractable epilepsy. Pediatr Neurol. 2010;42(4):249-254.20304327
56. Galland BC, Elder DE, Taylor BJ. Interventions with a sleep outcome for children with cerebral palsy or a post-traumatic brain injury: a systematic review. Sleep Med Rev. 2012;16(6):561-573.22609124
57. Khan S, Heussler H, McGuire T, et al. Melatonin for non-respiratory sleep disorders in visually impaired children. Cochrane Database Syst Rev. 2011;(11):CD008473.22071850
58. Sander J, Shamdeen MG, Gottschling S, Gortner L, Gräber S, Meyer S. Melatonin does not influence sleep deprivation electroencephalogram recordings in children. Eur J Pediatr. 2012;171(4):675-679.22124712
59. Wright B, Sims D, Smart S, et al. Melatonin versus placebo in children with autism spectrum conditions and severe sleep problems not amenable to behaviour management strategies: a randomised controlled crossover trial. J Autism Dev Disord. 2011;41(2):175-184.20535539
60. van Geijlswijk IM, van der Heijden KB, Egberts AC, Korzilius HP, Smits MG. Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT. Psychopharmacology (Berl). 2010;212(3):379-391.20668840
61. Guénolé F, Godbout R, Nicolas A, Franco P, Claustrat B, Baleyte JM. Melatonin for disordered sleep in individuals with autism spectrum disorders: systematic review and discussion. Sleep Med Rev. 2011;15(6):379-387.21393033
62. Rossignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol. 2011;53(9):783-792.21518346
63. Hollway JA, Aman MG. Pharmacological treatment of sleep disturbance in developmental disabilities: a review of the literature. Res Dev Disabil. 2011;32(3):939-962.21296553
64. Paul MA, Miller JC, Gray GW, Love RJ, Lieberman HR, Arendt J. Melatonin treatment for eastward and westward travel preparation. Psychopharmacology (Berl). 2010;208(3):377-386.20013115
65. Arendt J. Managing jet lag: some of the problems and possible new solutions. Sleep Med Rev. 2009;13(4):249-256.19147377
66. Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg. 2009;108(4):1146-1151.19299777
67. Yousaf F, Seet E, Venkatraghavan L, Abrishami A, Chung F. Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials. Anesthesiology. 2010;113(4):968-976.20823763
68. Özcengiz D, Gunes Y, Ozmete O. Oral melatonin, dexmedetomidine, and midazolam for prevention of postoperative agitation in children. J Anesth. 2011;25(2):184-188.21327805
69. Kain ZN, MacLaren JE, Herrmann L, et al. Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery. Anesthesiology. 2009;111(1):44-49.19546692
70. Gitto E, Aversa S, Salpietro CD, et al. Pain in neonatal intensive care: role of melatonin as an analgesic antioxidant. J Pineal Res. 2012;52(3):291-295.22141591
71. Moura LM, Bezerra JM, Fleming NR. Treatment of hemicrania continua: case series and literature review. Rev Bras Anestesiol. 2012;62(2):173-187.22440373
72. Francis GJ, Becker WJ, Pringsheim TM. Acute and preventive pharmacologic treatment of cluster headache. Neurology. 2010;75(5):463-473.20679639
73. Alstadhaug KB, Odeh F, Salvesen R, Bekkelund SI. Prophylaxis of migraine with melatonin: a randomized controlled trial. Neurology. 2010;75(17):1527-1532.20975054
74. Dhillon KS, Singh J, Lyall JS. A new horizon into the pathobiology, etiology and treatment of migraine. Med Hypotheses. 2011;77(1):147-151.21530095
75. de Jonghe A, Korevaar JC, van Munster BC, de Rooij SE. Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia. Are there implications for delirium? A systematic review. Int J Geriatr Psychiatry. 2010;25(12):1201-1208.21086534
76. de Jonghe A, van Munster BC, van Oosten HE, et al. The effects of melatonin versus placebo on delirium in hip fracture patients: study protocol of a randomised, placebo-controlled, double blind trial. BMC Geriatr. 2011;11:34.21729284
77. Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011;26(7):687-694.20845391
78. Jansen SL, Forbes DA, Duncan V, Morgan DG. Melatonin for cognitive impairment. Cochrane Database Syst Rev. 2006;(1):CD003802.16437462
79. Anderson G, Maes M. Melatonin: an overlooked factor in schizophrenia and in the inhibition of anti-psychotic side effects. Metab Brain Dis. 2012;27(2):113-119.22527998
80. Livianos L, Sierra P, Arques S, García A, Rojo L. Is melatonin an adjunctive stabilizer? Psychiatry Clin Neurosci. 2012;66(1):82-83.22250617
81. Baandrup L, Fagerlund B, Jennum P, et al. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial—the SMART trial protocol. BMC Psychiatry. 2011;11:160.21975110
82. Ochoa JJ, Díaz-Castro J, Kajarabille N, et al. Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males. J Pineal Res. 2011;51(4):373-380.21615492
83. Maldonado MD, Manfredi M, Ribas-Serna J, Garcia-Moreno H, Calvo JR. Melatonin administrated immediately before an intense exercise reverses oxidative stress, improves immunological defenses and lipid metabolism in football players. Physiol Behav. 2012;105(5):1099-1103.22212240
84. Gonciarz M, Gonciarz Z, Bielanski W, et al. The effects of long-term melatonin treatment on plasma liver enzymes levels and plasma concentrations of lipids and melatonin in patients with nonalcoholic steatohepatitis: a pilot study. J Physiol Pharmacol. 2012;63(1):35-40.22460459
85. Chahbouni M, Escames G, López LC, et al. Melatonin treatment counteracts the hyperoxidative status in erythrocytes of patients suffering from Duchenne muscular dystrophy. Clin Biochem. 2011;44(10-11):853-858.21515247
86. Siu AW, Maldonado M, Sanchez-Hidalgo M, Tan DX, Reiter RJ. Protective effects of melatonin in experimental free radical-related ocular diseases. J Pineal Res. 2006;40(2):101-109.16441546
87. Kedziora-Kornatowska K, Szewczyk-Golec K, Kozakiewicz M, et al. Melatonin improves oxidative stress parameters measured in the blood of elderly type 2 diabetic patients. J Pineal Res. 2009;46(3):333-337.19317795
88. Dreher F, Gabard B, Schwindt DA, Maibach HI. Topical melatonin in combination with vitamins E and C protects skin from ultraviolet-induced erythema: a human study in vivo. Br J Dermatol. 1998;139(2):332-339.9767255
89. Citera G, Arias MA, Maldonado-Cocco JA, et al. The effect of melatonin in patients with fibromyalgia: a pilot study. Clin Rheumatol. 2000;19(1):9-13.10752492
90. Acuna-Castroviejo D, Escames G, Reiter RJ. Melatonin therapy in fibromyalgia. J Pineal Res. 2006;40(1):98-99.16313505
91. Hussain SA, Al-Khalifa II, Jasim NA, Gorial FI. Adjuvant use of melatonin for treatment of fibromyalgia. J Pineal Res. 2011;50(3):267-271.21158908
92. Nickkholgh A, Schneider H, Sobirey M, et al. The use of high-dose melatonin in liver resection is safe: first clinical experience. J Pineal Res. 2011;50(4):381-388.21480979
93. Kücükakin B, Wilhelmsen M, Lykkesfeldt J, Reiter RJ, Rosenberg J, Gögenur I. No effect of melatonin to modify surgical-stress response after major vascular surgery: a randomised placebo-controlled trial. Eur J Vasc Endovasc Surg. 2010;40(4):461-467.20638874
94. Megwalu UC, Finnell JE, Piccirillo JF. The effects of melatonin on tinnitus and sleep. Otolaryngol Head Neck Surg. 2006;134(2):210-213.16455366
95. Hurtuk A, Dome C, Holloman CH, et al. Melatonin: can it stop the ringing? Ann Otol Rhinol Laryngol. 2011;120(7):433-440.21859051
96. Todisco M. Effectiveness of a treatment based on melatonin in five patients with systemic sclerosis. Am J Ther. 2006;13(1):84-87.16428927
97. Saeidi M, Sobhani R, Movahedi M, Alsaeidi S, Samani RE. Effect of melatonin in the prevention of postoperative pericardial adhesion formation. Interact Cardiovasc Thorac Surg. 2009;9(1):26-28.19383636
98. Turgut M, Kaplan S. Effects of melatonin on peripheral nerve regeneration. Recent Pat Endocr Metab Immune Drug Discov. 2011;5(2):100-108.22074585
99. Shamir E, Barak Y, Plopsky I, Zisapel N, Elizur A, Weizman A. Is melatonin treatment effective for tardive dyskinesia? J Clin Psychiatry. 2000;61(8):556-558.10982197
100. Castro F, Carrizo E, Prieto de Rincón D, et al. Effectiveness of melatonin in tardive dyskinesia. Invest Clin. 2011;52(3):252-260.21950196
101. Maldonado MD, Murillo-Cabezas F, Calvo JR, et al. Melatonin as pharmacologic support in burn patients: a proposed solution to thermal injury-related lymphocytopenia and oxidative damage. Crit Care Med. 2007;35(4):1177-1185.17312564
102. Cutolo M, Maestroni GJ. The melatonin-cytokine connection in rheumatoid arthritis. Ann Rheum Dis. 2005;64(8):1109–1111.16014678
103. Maestroni GJ. The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs. 2001;10(3):467-476.16014678
104. Aldhous M, Franey C, Wright J, Arendt J. Plasma concentrations of melatonin in man following oral absorption of different preparations. Br J Clin Pharmacol. 1985;19(4):517-521.3994899
105. Zytiga [package insert]. Horsham, PA: Centocor Ortho Biotech Inc; April 2011.
106. Lusardi P, Piazza E and Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol. 2000;49(5):423-427.10792199
107. Lew MJ and Flanders S. Mechanisms of melatonin-induced vasoconstriction in the rat tail artery: a paradigm of weak vasoconstriction. Br J Pharmacol. 1999;126(6):1408-1418.10217535
108. Mei YA, Lee PP, Wei H, et al. Melatonin and its analogs potentiate the nifedipine-sensitive high-voltage-activated calcium current in the chick embryonic heart cells. J Pineal Res. 2001;30(1):13-21.11168902
109. Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol. 2003;43(5):443-469.12751267
110. U.S. Food and Drug Administration. Guidance for industry: drug interaction studies — study design, data analysis, implications for dosing, and labeling recommendations. Accessed March 18, 2013.
111. Androcur [package insert]. Toronto, Ontario: Bayer Inc; February 2011.
112. Exjade [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2011.
113. Seabra ML, Bignotto M, Pinto LR Jr, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29(4):193-200.11068941
114. Andersen IM, Kaczmarska J, McGrew SG, Malow BA. Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol. 2008;23(5):482-485.18182647
115. Bardazzi F, Placucci F, Neri I, D'Antuono A, Patrizi A. Fixed drug eruption due to melatonin. Acta Derm Venereol. 1998;78(1):69-70.9498035
116. Force RW, Hansen L, Bedell M. Psychotic episode after melatonin. Ann Pharmacother. 1997;31(11):1408.9391704
117. De Bleecker JL, Lamont BH, Verstraete AG, Schelfhout VJ. Melatonin and painful gynecomastia. Neurology. 1999;53(2):435-436.10430450
118. Hong YG, Riegler JL. Is melatonin associated with the development of autoimmune hepatitis? J Clin Gastroenterol. 1997;25(1):376-378.9412927
119. Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet. 1998;351(9111):1254.9643754
120. Graw P, Werth E, Kräuchi K, et al. Early morning melatonin administration impairs psychomotor vigilance. Behav Brain Res. 2001;121(1-2):167-172.11275293
121. Otmani S, Metzger D, Guichard N, et al. Effects of prolonged-release melatonin and zolpidem on postural stability in older adults. Hum Psychopharmacol. 2012;27(3):270-276.22350925
122. Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. Br J Anaesth. 1999;82(6):875-880.10562782
123. Naguib M, Samarkandi AH. The comparative dose-response effects of melatonin and midazotam for premedication of adult patients: a double blinded, placebo-controlled study. Anesth Analg. 2000;91(2):473-479.10910871
124. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.27998379
125. Bhidayasiri R, Fahn S, Weiner WJ, Gronseth GS, Sullivan KL, Zesiewicz TA; American Academy of Neurology. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;81(5):463-469.23897874
126. Wilhelmsen-Langeland A, Saxvig IW, Pallesen S, et al. A randomized controlled trial with bright light and melatonin for the treatment of delayed sleep phase disorder: effects on subjective and objective sleepiness and cognitive function. J Biol Rhythms. 2013;28(5):306-321.24132057
127. Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS ONE. 2013;8(5):e63773.23691095
128. Chojnacki C, Walecka-Kapica E, Lokieć K, et al. Influence of melatonin on symptoms of irritable bowel syndrome in postmenopausal women. Endokrynol Pol. 2013;64(2):114-120.23653274
129. Seko LM, Moroni RM, Leitao VM, Teixeira DM, Nastri CO, Martins WP. Melatonin supplementation during controlled ovarian stimulation for women undergoing assisted reproductive technology: systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2014;101(1):154-161.24182414
130. Schwertner A, Conceição dos Santos CC, Costa GD, et al. Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain. 2013;154(6):874-881.23602498
131. Vidor LP, Torres IL, Custódio de Souza IC, Fregni F, Caumo W. Analgesic and sedative effects of melatonin in temporomandibular disorders: a double-blind, randomized, parallel-group, placebo-controlled study. J Pain Symptom Manage. 2013;46(3):422-432.23195393
132. Russcher M, Koch BC, Nagtegaal E, et al. Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial. Br J Clin Pharmacol. 2013;76(5):668-679.23432361
134. Del Fabbro E, Dev R, Hui D, Palmer L, Bruera E. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. J Clin Oncol. 2013;31(10):1271-1276.23439759
135. Sierra AF, Ramírez ML, Campmany AC, Martínez AR, Naveros BC. In vivo and in vitro evaluation of the use of a newly developed melatonin loaded emulsion combined with UV filters as a protective agent against skin irradiation. J Dermatol Sci. 2013;69(3):202-214.23159282
136. Jain S, Besag FM. Does melatonin affect epileptic seizures? Drug Saf. 2013;36(4):207-215.23532506
137. Romo-Nava F, Gonzalez DA. Fresan-Orellana A, et al. Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord. 2014;16(4):410-421.24636483
138. Saxvig IW, Wilhelmsen-Langeland A, Pallesen S, Vedaa O, Nordhus IH, Bjorvatn B. A randomized controlled trial with bright light and melatonin for delayed sleep phase disorder: effects on subjective and objective sleep. Chronobiol Int. 2014;31(1):72-86.24144243
139. Tunkel DE, Bauer CA, Sun GH, et al. Clinical Practice Guideline: Tinnitus. Otolaryngol Head Neck Surg. 2014;151(2 suppl):S1-S40.25273878
140. Andersen LP, Werner MU, Rosenberg J, Gogenur I. A systematic review of peri-operative melatonin. Anaesthesia. 2014;69(10):1163-1171.24835540
141. Hansen MV, Andersen LT, Madsen MT, et al. Effet of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Breast Cancer Res Treat. 2014;145:683-695.24756186
142. Pokharel K, Tripathi M, Gupta PK, Bhattarai B, Khatiwada S, Subedi A. Premedication with oral alprazolam and melatonin combination: a comparison with either alone – a randomized controlled factorial trial. Biomed Res Int. 2014; 2014:356964.24527443
143. Lahteenmakl R, Puustinen J, Bahlberg T, et al. Melatonin for sedative withdrawal in older patients with primary insomnia: a randomized double-blind placebo-controlled trial. Br J Clin Pharmacol. 2014;77(6):975-985.24286360
144. Rubio-Sastre P, Scheer FA, Gomez-Abellan P, Madrid JA, Garaulet M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep. 2014;37(10):1715-1719.25197811
145. Wade AG, Farmer M, Harari G, et al. Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer’s disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 2014;9:947-961.24971004
146. Harpsoe NG, Andersen LP, Gogenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015;71:901-909.26008214
147. Mo Y, Scheer CE, Abdallah GT. Emerging role of melatonin and melatonin receptor agonists in sleep and delirium in intensive care unit patients. J Intensive Care Med. 2015 Jun 19. pii:0885066615592348 [epub ahead of print]26092575
148. Shilo L, Dagan Y, Smorjik Y, et al. Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int. 2000;17(1):71-76.10672435
149. Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care. 2008;12(2):R52.18423009
150. Ibrahim MG, Bellomo R, Hart GK, et al. A double-blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomised patients. Crit Care Resusc. 2006;8:187-191.16930101
151. Foreman B, Westwood AJ, Claassen J, Bazil CW. Sleep in the neurological intensive care unit: feasibility of quantifying sleep after melatonin supplementation with environmental light and noise reduction. J Clin Neurophysiol. 2015;32:66-74.25647773
152. Chen WY, Giobbie-Hurder A, Gantman K, et al. A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes. Breast Cancer Res Treat. 2014;145(2):381-388.24718775
153. Pattanittum P, Kunyanone N, Brown J, et al. Dietary supplements for dysmenorrhoea. Cochrane Database Syst Rev. 2016;3:CD002124.27000311
154. Xu J, Wang LL, Dammer EB, et al. Melatonin for sleep disorders and cognition in dementia: a meta-analysis of randomized controlled trials. Am J Alzheimers Dis Other Demen. 2015;30(5):439-447.25614508
155. Chang YS, Lin MH, Lee JH, et al. Melatonin supplementation for children with atopic dermatitis and sleep disturbance: a randomized clinical trial. JAMA Pediatr. 2016;170(1):35-42.26569624
156. Stefani LC, Muller S, Torres IL, et al. A phase II, randomized, double-blind, placebo controlled, dose-response trial of the melatonin effect on pain threshold of healthy subjects. PLoS ONE. 2013;8(10):e74107.25947930
157. Amstrup AK, Sikjaer T, Heickendorff L, Mosekilde L, Rejnmark L. Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. J Pineal Res. 2015;59:221-229.26036434
158. Scheer FA, Morris CJ, Garcia JI, et al. Repeated melatonin supplementation improves sleep in hypertensive patients treated with betablockers: a randomized controlled trial. Sleep. 2012;35:1395–402.23024438
159. Grilo-Bensusan I, Gomez-Delgado E, Gomez-Regife L. Melatonin as a probable cause of diarrhoea. Rev Esp Enferm Dig. 2015;107(2):119-120.25659397
160. Andersen LP, Werner MU, Rosenkilde MM, Harpsoe NG, Fuglsang H, Rosenberg J, Gogenur I. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers. BMC Pharmacol Toxicol. 2016;17:8.26893170
161. Erland LA, Saxena PK. Melatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content [published online ahead of print November 14, 2016]. J Clin Sleep Med.2785574410.5664/jcsm.6462
162. Mistraletti G, Umbrello M, Sabbatini G, et al. Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol. 2015;81(12):1298-1310.25969139
163. Gitto E, Marseglia L, D’Angelo G, et al. Melatonin versus midazolam premedication in children undergoing surgery: a pilot study. J Paediatr Child Health. 2016;52(3):291-295.26515269
164. Baandrup L, Lindschou J, Winkel P, Gluud C, Glenthoj BY. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: a randomised, placebo-controlled, blinded trial. World J Biol Psychiatry. 2016;17(7):514-524.26086792
165. Mostafavi SA, Solhi M, Mohammadi MR, Akhondzadeh S. Melatonin for reducing weight gain following administration of atypical antipsychotic olanzapine for adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol. 2017;27(5):440-444.28339282
166. Rabins PV, Rovner BW, Rummans T, Schneider LS, Tariot PN. Guideline watch (October 2014): practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. Accessed July 22, 2017.
167. Liu J, Zhong R, Xiong W, Liu H, Eisenegger C, Zhou X. Melatonin increases reactive aggeresion in humans. Psychopharmacology (Berl). 2017;234(19):2971-2978.28733812
168. Chojnacki C, Blonska A, Chojnacki J. The effects of melatonin on elevated liver enzymes during statin treatment. Biomed Res Int. 2017;2017:3204504.28630863
169. Circadin (melatonin) [prescribing information]. St Leonards, New South Wales: Aspen Pharma Pty Ltd; June 2016.
170. Otmani S, Demazieres A, Staner C, et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol. 2008;23(8):693-705.18763235
171. Suhner A, Schlagenhauf P, Hofer I, Johnson R, Tschopp A, Steffen R. Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med. 2001;72(7):638-646.11471907
172. Jusko WJ, Gardner MJ, Mangione A, Schentag JJ, Koup JR, Vance JW. Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci. 1979;68(11):1358-1366.41932
173. Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM. Enhanced biotransformation of theophylline in marihuana and tobacco smokers. Clin Pharmacol Ther. 1978;24(4):405-410.688731
174. Gardner MJ, Tornatore KM, Jusko WJ, Kanarkowski R. Effects of tobacco smoking and oral contraceptive use on theophylline disposition. Br J Clin Pharmacol. 1983;16(3):271-280.6626419
175. Chetty M, Miller R, Moodley SV. Smoking and body weight influence the clearance of chlorpromazine. Eur J Clin Pharmacol. 1994;46(6):523-526.7995319
176. Hartter S, Grozinger M, Weigmann H, Roschke J, Hiemke C. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther. 2000;67(1):1-6.10668847
177. Facciola G, Hidestrand M, von Bahr C, Tybring G. Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. Eur J Clin Pharmacol. 2001;56(12):881-888.11317475
178. Ocaliva (obeticholic acid) [prescribing information]. New York, NY: Intercept Pharmaceuticals Inc; May 2016.
179. PegIntron (peginterferon alfa-2b) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; September 2015.
180. Gupta SK, Kolz K, Cutler DL. Effects of multiple-dose pegylated interferon alfa-2b on the activity of drug-metabolizing enzymes in persons with chronic hepatitis C. Eur J Clin Pharmacol. 2011;67(6):591-599.21161196
181. Aubagio (teriflunomide) [prescribing information]. Cambridge, MA: Genzyme Corporation; October 2014.
182. Zelboraf (vemurafenib) [prescribing information]. South San Francisco, CA: Genentech USA Inc; August 2015.
183. Zelboraf (vemurafenib) [product monograph]. Mississauga, Ontario, Canada: Hoffmann-La Roche Limited; March 2016.
184. Ghareghani M, Scavo L, Arnoult D, Zibara K, Farhadi N. Melatonin therapy reduces the risk of osteoporosis and normalizes bone formation in multiple sclerosis. Fundam Clin Pharmacol. 2018;32(2):181-187.29193274
185. Sletten TL, Magee M, Murray JM, Gordon CJ, Lovato N, Kennaway DJ, Gwini SM, Bartlett DJ, Lockley SW, Lack LC, Grunstein RR, Rajaratnam SM, Delayed Sleep on Melatonin (DelSoM) Study Group. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: a double-blind, randomised clinical trial. PLoS Med. 2018;15(6):e1002587.29912983
186. Grima NA, Rajaratnam SM, Mansfield D, Sletten TL, Spitz G, Ponsford JL. Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial. BMC Med. 2018;16(1):8.29347988
187. Gringras P, Nir T, Breddy J, Frydman-Marom A, Findling RL. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2017;56(11):948-957.29096777


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