Melatonin

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

Medically reviewed by Drugs.com. Last updated on Jan 22, 2024.

Clinical Overview

Use

Exogenous melatonin has been extensively studied for its impact on sleep. A beneficial effect on sleep-onset latency and other sleep parameters in special populations (eg, autism spectrum disorder, shift workers, jet lag) is well supported.

In contrast, limited or equivocal data are available regarding use of melatonin to affect atopic dermatitis, bone density, cardiovascular conditions, constipation-predominant irritable bowel syndrome (IBS), infections (eg, periodontal disease), multiple sclerosis (MS), various reproductive problems (ie, in vitro fertilization rates, dysmenorrhea), tardive dyskinesia, or tinnitus. Limited data suggest a potential role for adjunctive use of melatonin in certain patient populations to reduce hepatic and other adverse effects and/or doses of pharmaceutical agents, such as analgesics, antipsychotics, anxiolytics, sedatives, and statins. No data support a role for melatonin in managing dementia- and/or delirium-related cognitive impairment, epilepsy, mood disorders, or organ transplantation graft rejection.

Dosing

Analgesia: Dosages ranging from 3 to 10 mg/day orally for various durations have been used in various pain conditions.

Insomnia: 3 to 5 mg daily in the evening over 4 weeks. Immediate-release melatonin 1 to 2 mg given 1 hour prior to bedtime may be useful in elderly patients. Controlled-release formulations should be avoided in elderly patients due to concerns for prolonged concentrations. American Academy of Sleep Medicine clinical practice guidelines recommend use of strategically timed melatonin in children and adolescents for the treatment of delayed sleep-wake phase disorder and irregular sleep-wake rhythm disorder in those with and without comorbid neurological or psychiatric disorders, based on short-term studies.

Jet lag: In general, lower doses (0.5 to 2 mg orally) preflight, and higher doses (5 mg orally) postflight over a period of up to 4 days has been recommended.

Contraindications

Because melatonin may exacerbate some autoimmune conditions while alleviating others, melatonin should be avoided in patients with autoimmune diseases.

Pregnancy/Lactation

Melatonin was beneficial in delaying early-onset pre-eclampsia. Although no adverse effects were noted in mothers, fetuses, or newborns, babies born to women receiving melatonin had birthweights less than the 10th percentile for gestation.

Given the minimal information available regarding safety and efficacy, melatonin supplementation in pregnancy and lactation is questionable and should be avoided until further research has been conducted.

Interactions

Melatonin's metabolism involves the CYP-450 system, and therefore has the propensity for numerous drug-drug interactions. Specifically, melatonin is metabolized by CYP1A2 to 6-hydroxymelatonin. Additionally, it is metabolized by CYP2C9 and CYP2C19 to metabolites such as N-acetylserotonin, 5-methoxytryptamine, and 5-methoxylated kynuramines. Additionally, melatonin may result in excessive drowsiness when given with, among others, benzodiazepines, anticholinergics, and alcohol, which all have sedating properties.

Adverse Reactions

Minor adverse reactions associated with melatonin include headache, transient depression, enuresis, dizziness, nausea, stomach cramps, irritability, insomnia, nightmares, hypothermia, and excessive daytime somnolence. 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.

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, ovaries, testes, placenta, and thymus. Melatonin secretion is inhibited by environmental light and stimulated by darkness. Secretion starts at approximately 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 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.de Almeida 2011, Garrido 2012, Webb 1995, Wehr 2001 Melatonin is also found in other foods such as chicken, lamb, fish, eggs, cow milk, strawberries, tomatoes, olives, walnuts, wines, cereals, and grapes.Bonomini 2018, Jiki 2018 Melatonin concentrations are higher in plant-based products compared with animal-based products, likely attributable to the differences in synthetic pathways.Bonomini 2018

An analysis of 31 commonly available commercial melatonin supplement products found in grocery stores and pharmacies found melatonin content ranged from 0.37% to 466% of its label claim in more than 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.Erland 2017

The melatonin receptor agonists agomelatine (Valdoxan), ramelteon (Rozerem), and tasimelteon (Hetlioz) are available and are being studied in depression and sleep disorders.Esteban-Zubero 2016, Fornaro 2010, Goodwin 2009, Howland 2011, Liu 2012, Spadoni 2011, Tordjman 2017

History

Melatonin was first discovered and isolated from beef pineal glands in 1958 by Aaron B. Lerner.Tordjman 2017 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 for 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.Bowman 1980, Webb 1995, Windoholz 1989

Chemistry

Chemically, melatonin is N-acetyl-5-methoxytryptamine, and it is 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.Carpentieri 2012, de Almeida 2011, Windoholz 1989

Uses and Pharmacology

Melatonin is readily absorbed through any route of administration and can easily cross any physiological barrier (ie, placenta, blood-brain barrier).(Siah 2014)

Pharmacokinetics

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 (C_max) 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 status, and oral contraceptive use.(Harpsoe 2015) Substantial interindividual variability has been documented in bioavailability, C_max, and area under the curve (AUC). In a crossover study in 12 healthy male volunteers administered melatonin 10 mg by oral and intravenous (IV) routes, extensive variations in C_max (2,500.5 to 8,057.5 pg/mL and 174,775 to 440,362.5 pg/mL, respectively) and total AUC (232,696.1 to 546,285.4 pg/mL and 7,063,347.4 to 18,964,804 pg/mL, respectively) were observed. 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%).(Andersen 2016)

Pharmacodynamics

Melatonin's metabolism involves the CYP-450 system, particularly CYP1A2. (Mortezaee 2018) Patients who exert a poor response to melatonin may be poor CYP1A2 metabolizers.(Relia 2018) Additionally, melatonin is metabolized by CYP2C9 and CYP2C19 to metabolites such as N-acetylserotonin, 5-methoxytryptamine, and 5-methoxylated kynuramines.(Alagiakrishnan 2016)

Analgesic effects

Pain perception (eg, heat and cold intolerance) varies throughout the day and night, which may be a reflection of melatonin fluctuations. Melatonin receptors have been identified in spinal cord tissue, where release of brain-derived neurotrophic factor (BDNF), an important mediator and central modulator of pain, has been observed; therefore, it may modulate nociception through decreasing BDNF levels.(Zhu 2017)

Animal data

Antinociceptive effects of melatonin have been demonstrated in various animal pain models, including acute, inflammatory, and neuropathic pain.(Hsieh 2017, Lin 2017, Stefani 2013)

Clinical data

Fibromyalgia

In a randomized, double-blind, double dummy clinical study of 63 women 18 to 65 years of age with fibromyalgia, the effects of melatonin 10 mg, amitriptyline 25 mg, or a combination of the two for 6 weeks were assessed on pain parameters. Melatonin alone and in combination with amitriptyline significantly decreased pain scores on the visual analog scale compared with amitriptyline alone (P<0.01), as well as improved the inhibitory pain-modulating system function.(de Zanette 2014)

General pain

In a meta-analysis of 19 trials involving 586 patients receiving melatonin and 507 patients receiving control therapy, melatonin exerted a significant antinociceptive effect (P<0.00001). In subgroup analyses, melatonin significantly decreased pain scores in patients with operation-associated pain under topical anesthesia (P=0.0004), operation-associated pain under general anesthesia (P<0.00001), inflammatory pain (P<0.00001), procedural pain (P<0.00001), and experimental pain (P=0.0003).(Zhu 2017)

Headache/Migraine

In a randomized, double-blind, placebo-controlled clinical study, 105 adults with chronic migraine headache receiving nortriptyline 10 to 25 mg or propranolol 20 to 40 mg at baseline were randomized to receive adjunctive melatonin 3 mg, sodium valproate 200 mg, or placebo for 2 months. Melatonin decreased attack frequency, attack duration, attack severity, and Migraine Disability Assessment scores; effects were similar to sodium valproate but melatonin was associated with greater tolerability.(Ebrahimi-Monfared 2017)

In a randomized, double-blind, placebo-controlled trial in adult patients who experienced 2 to 8 migraines per month, primary therapy with melatonin 3 mg or amitriptyline 25 mg for 3 months was compared with placebo for effects on migraine frequency. Use of acute migraine medications were permitted for breakthrough attacks. Mean headache frequency reduction was 2.7 headache days in the melatonin group, 2.2 days in the amitriptyline group, and 1.1 days in the placebo group. Melatonin was associated with a statistically significant improvement in headache frequency when compared with placebo (P=0.009) but not when compared with amitriptyline (P=0.19). However, regarding the number of patients with a greater than 50% improvement in headache frequency, referred to as "responders," melatonin was superior to both placebo (P<0.01) and amitriptyline (P<0.05).(Goncalves 2016)

In a case study of a 7-year-old boy with primary stabbing headache (also known as "ice pick" headache), melatonin 1.5 mg nightly was associated with a reduction in headache frequency during the first 2 weeks of therapy (from 21 episodes in 1 month to 2 episodes in 2 weeks) and complete resolution by 6 months.(Bermudez 2018)

A systematic review included 4 very low–quality clinical trials that evaluated use of melatonin for primary headaches (ie, migraine, cluster headache) in adults (N=351). The authors suggested that available evidence is insufficient to recommend the use of melatonin in these patients.(Leite 2018)

Pain in healthy patients

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 0.05, 0.15, and 0.25 mg/kg (maximum, 20 mg). Both heat and pressure pain thresholds and tolerance were 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 with the 0.05 mg/kg dose and placebo. No adverse effects besides sedation were experienced.(Stefani 2013)

Pain in intensive care unit/surgical setting

In a double-blind, randomized controlled trial (N=82), significantly lower doses of sedatives (eg, hydroxyzine, lorazepam, IV propofol) were needed in high-risk intensive care unit (ICU) patients given melatonin 3 mg twice daily at 8 PM and midnight (starting on day 3 of ICU admission until discharge) compared with controls. Melatonin also led to significantly earlier weaning from neuroactive drugs (P=0.002) and mechanical ventilation (P=0.046), lower costs, reductions in deep sedation state, improved agitation/sedation scores (P=0.05), and improvements in several neurological indicators (ie, pain, anxiety, agitation, need for physical restraints [P<0.01 for each]). No clinically relevant adverse effects associated with melatonin were observed.(Mistraletti 2015)

In a randomized clinical trial of 90 patients undergoing lumbar surgery with general anesthesia, patients were randomized to preoperative administration of melatonin 6 mg, gabapentin 600 mg, or placebo. Melatonin and gabapentin significantly reduced visual analog pain scores (P=0.02) and anxiety intensity (P=0.01) compared with placebo following lumbar surgery.(Javaherforooshzadeh 2018)

Temporomandibular disorder

In a double-blind, randomized, parallel-group, placebo-controlled study in patients with temporomandibular disorder, melatonin 5 mg for 28 days was associated with mean reductions in pain scores by 44%), increases in pressure pain threshold by 39%), and improvements in sleep quality of 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).(Vidor 2013)

Antioxidant effects

Melatonin has been suggested to exert antioxidant effects through scavenging of free radicals; stimulating antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase; and reducing pro-oxidant expression.(Karaaslan 2015)

Animal data

Animal models suggest that melatonin is able to scavenge free radicals and reduce oxidative stress associated with brain ischemia in stroke.(Ramos 2017, Watson 2016) In the setting of hemorrhagic stroke, melatonin may act by enhancing autophagy protection, alleviating inflammation, and attenuating oxidative stress.(Ramos 2017)

A murine model suggests melatonin prevented skeletal muscle damage caused by carbon tetrachloride through reducing oxidative stress parameters.(Sokolovic 2018)

In a murine model of isoproterenol-induced heart failure, melatonin reduced oxidative stress, as well as decreased mortality and improved survival time (by 17%).(Simko 2014)

Clinical data

Improved oxidative status has been reported with melatonin in studies assessing effects on exercise,(Maldonado 2012, Ochoa 2011) nonalcoholic fatty liver disease,(Gonciarz 2012) muscular dystrophy,(Chahbouni 2011) ocular diseases,(Siu 2006) periodontitis,(Reiter 2015) cystic fibrosis,(DeCastro-Silva 2010) and metabolic syndrome.(Kedziora-Kornatowska 2009, Kozirog 2011) Topical melatonin may exhibit an antioxidant-related photoprotective effect.(Day 2018)

Asthma

Animal data

Melatonin has significantly inhibited the production of mucus through suppression of gene expression in animal models of asthma.(Marseglia 2014)

Autism spectrum disorder

In autism spectrum disorder, delayed peaking of melatonin, reduced rhythm amplitude, reduced ferritin, and increased limb movements contribute to insomnia and other sleep difficulties. The existence of comorbid conditions can contribute to insomnia. Specifically, anxiety and attention-deficit/hyperactivity disorder (ADHD) can lead to arousal and delayed sleep onset. Nighttime awakenings and disruption in the sleep cycle may result from seizures and GI disorders.(Relia 2018) In theory, melatonin might be useful for reducing pain perception related to sensory processing dysfunction of autism spectrum disorder.(Gagnon 2018)

Clinical data

In a prospective, open-label study, effects of a pediatric prolonged-release melatonin formulation on insomnia were assessed in children and adolescents with autism spectrum disorder. Compared with baseline, 1 year of melatonin administration resulted in significantly more minutes asleep (P=0.007), less nightly awakenings (P=0.001), quicker onset of sleep (P<0.001), longer uninterrupted sleep (P=0.001), and better quality of sleep (P<0.001).(Maras 2018) Similar results were noted in another clinical study of children with insomnia associated with autism spectrum disorder with or without ADHD or neurogenetic disorders. After 13 weeks of treatment, pediatric prolonged-release melatonin significantly improved various sleep parameters.(Gringras 2017)

A meta-synthesis of the literature assessing melatonin and other interventions for insomnia in children with autism spectrum disorder found that melatonin, behavioral interventions, and parent education/education programs were most effective at improving various domains of sleep problems. Melatonin was associated with a strong efficiency at improving sleep latency, sleep duration, bedtime resistance, and cosleeping.(Cuomo 2017)

Autoimmune effects

Because melatonin has been shown to alleviate some autoimmune conditions while exacerbating others, melatonin should be avoided in people with autoimmune diseases.(Dos Santos 2018, Farez 2016, Jahanban-Esfahlan 2017)

Clinical data

In a 2018 systemic review and meta-analysis, melatonin reduced fasting glucose and increased the quantitative insulin sensitivity check index; however, it did not impact insulin levels, insulin resistance, or glycosolated hemoglobin levels.(Doosti-Irani 2018, Doosti-Irani 2018)

Bone metabolism

Animal data

In conjunction with a small clinical study, administration of melatonin in a mouse model of MS resulted in a significant improvement in MS clinical scores (P<0.05). Induction of MS had 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) compared to controls. Administration of melatonin significantly improved all of these parameters (P<0.05).(Ghareghani 2018)

In a murine model of osteoporosis, both melatonin and calcium carbonate alone increased bone density and calcium levels and decreased bone mineral loss, suggesting a potential role for melatonin in osteoporosis. The effects were even greater when melatonin and calcium carbonate were given in combination.(Zhu 2018) Melatonin also increased bone formation in an animal model of distraction osteogenesis.(Acikan 2018)

Clinical data

A double-blind, randomized, placebo-controlled trial evaluated the effect of melatonin (1 or 3 mg nightly) given for 1 year on bone mineral density (BMD) in postmenopausal white women with osteopenia (N=81); daily calcium (800 mg) and vitamin D₃ (20 mcg) were also provided as supplements. BMD in the femoral neck was increased in a dose-dependent manner with melatonin and was significant (by 2.3%) for the 3 mg/day group (P<0.01); no difference in BMD was observed at the lumbar spine, forearm, whole body, or at other sites at the hip. Urinary calcium was also significantly decreased in the melatonin 3 mg group (by 28.3% compared with placebo (P=0.04); 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.(Amstrup 2015) In another study comparing the correlation between serum melatonin and procalcitonin in MS patients, as well as effects of melatonin therapy (10 mg/kg) on bone metabolism and osteoporosis, melatonin levels in 23 patients with MS were found to be significantly lower than those in 23 healthy controls (P<0.05); a significant inverse relationship was observed regarding serum procalcitonin levels (r=−0.945; P=0.0001). A marker of bone matrix synthesis, osteocalcin, was found to be significantly decreased in MS patients compared with controls (P<0.05).(Ghareghani 2018)

Cancer

Animal and in vitro data

Breast cancer

Melatonin may be beneficial in breast cancer as it can selectively neutralize estrogen's effects on breast tissue and has demonstrated antiaromatase activity. It also acts as a selective estrogen receptor modulator. Melatonin regulates estradiol production through controlling enzymes involved in its synthesis, thus making it a selective estrogen enzyme modulator. In vitro data have demonstrated that melatonin was able to sensitize human breast cancer cells to ionizing radiation through reducing cell proliferation, inducing cell cycle arrest, down-regulating proteins associated with DNA repair, and increasing p53 mRNA expression. Animal models indicate that melatonin may attenuate radiation-induced adverse effects, making therapy more tolerable. Additionally, a murine model of mammary gland adenocarcinoma found melatonin exerted synergistic antitumor effects.(Griffin 2018, Kubatka 2018, Reiter 2017)

Head and neck cancer

In oral cancer cell lines, melatonin exerted inhibitory effects on the expression of proangiogenic factors.(Li 2017, Yeh 2017)

Ovarian cancer

In vitro data demonstrate that physiological doses of melatonin reduced cell numbers in estrogen-dependent BG-1 ovarian adenocarcinoma cell lines. Additionally, melatonin reduced ovarian masses in an animal model. Melatonin may be beneficial in ovarian cancer through its antiproliferative, antioxidant, proapoptotic, and antiangiogenic effects.(Chuffa 2017, Menendez-Menendez 2018)

Pancreatic cancer

Animal and in vitro studies demonstrate the potential beneficial effects of melatonin in pancreatic cancer. Specifically, it has shown proapoptotic effects; anti-inflammatory activity against inflammatory mediators; antioxidant effects by reducing the size of cancerous nodules and increasing superoxide dismutase, glutathione, and catalase activity in pancreatic cancer cells; and inhibition of vascular endothelial growth factor mRNA expression in pancreatic cancer cells.(Tamtaji 2019)

Prostate cancer

Melatonin reduced tumor growth in a rat model of prostatic adenocarcinoma. In prostate cancer, melatonin may be beneficial due to its antiproliferative, proapoptotic, and antiangiogenic effects.(Menendez-Menendez 2018)

Other cancers

In vitro and animal studies suggest potential beneficial effects of melatonin use in liver, renal, lung, gastric, colorectal, bone, and melanoma cancers, as well as leiomyosarcoma, leukemia, and glioblastoma.(Li 2017, Reiter 2017)

Clinical data

Meta-analyses of clinical trials of melatonin use in cancer have been conducted.(Seely 2012, Wang 2012) Limited clinical studies have primarily examined use in the treatment of solid tumors, with melatonin (typically 20 mg/day orally) administered as adjunctive therapy. The majority of these trials were of open-label design with small numbers of participants. Significantly increased 1-year survival rates (pooled relative risk [RR], 0.63; 95% CI, 0.53 to 0.74; P<0.001),(Seely 2012), as well as decreased chemotherapy-related adverse effects, including thrombocytopenia, neurotoxicity, and fatigue, have been observed.(Sanchez-Barcelo 2012, Seely 2012, Wang 2012)

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.(Del Fabbro 2013) In a double-blind, placebo-controlled parallel study of patients with rectal cancer, melatonin attenuated the effects of radiotherapy on blood cell count reductions.(Kouhi Habibi 2018)

Cardiovascular effects

In addition to their existence in the central and peripheral nervous systems, melatonin receptors have been identified in the cardiovascular system, including in vascular tissues, the left ventricle, and coronary arteries. Metallothionein 1 (MT₁) melatonergic receptors mediate arterial vasoconstriction and MT₂ melatonergic receptors cause vasodilation. Low levels of serum melatonin have been associated with coronary heart disease, angina, myocardial infarction (MI), and heart failure. Melatonin's effects on lowering blood pressure are complex and extend beyond vasodilatory effects. Melatonin may cause a hypotensive effect through concentration-dependent effects on vascular smooth muscle cells. At lower concentrations, but not higher concentrations, melatonin may cause contractions, which is reflective of what occurs with blood pressure reductions at night when melatonin secretion is high. Melatonin may also reduce blood pressure through reductions in oxidative stress, indirect increases in nitric oxide production, and mediation of blood pressure through central autonomic mechanisms. Melatonin has also been shown to decrease the pulsatility index in the internal carotid artery, reduce platelet aggregation, diminish lipid peroxidation, decrease oxidation of low-density lipoprotein levels, increase high-density lipoprotein levels, and decrease catecholamine levels.(Baker 2018, Jiki 2018, Pandi-Perumal 2017)

In the setting of heart failure, melatonin might be beneficial due to its antioxidant effects, causing an improvement in heart mitochondria.(Odinokova 2018) Additionally, it might be useful in heart failure due to its ability to reverse apoptosis, necrosis, fibrosis (via reduction in concentration and content of cardiac collagen), and pathological remodeling.(Nduhirabandi 2018)

Animal and in vitro data

Animal studies have shown that following removal of the pineal gland, vasoconstriction and development of hypertension occur.(Baker 2018) In a model of acute heart failure caused by isoprenaline hydrochloride in older rats, melatonin exerted cardioprotective effects through increasing 2'3'-cyclinucleotide-3'-phosphodiasterase and preventing mitochondrial dysfunction.(Odinkokova 2018) In a murine model of isoproterenol-induced heart failure, melatonin did not reduce the weight of the left or right ventricle; however, it improved weight of the lungs by 21% (P<0.05) and attenuated the lowering of systolic blood pressure. Melatonin also reduced oxidative stress, as well as decreased mortality and improved survival time (by 17%).(Simko 2014)

Following MI in mice, melatonin inhibited cardiac remodeling and dysfunction through reversal of autophagy inhibition, reduction of apoptosis, and reversal of mitochondrial dysfunction in mice.(Hu 2017)

In an atherosclerotic murine model, melatonin reduced the size of the atherosclerotic plaque through induction of mitophagy and reduction of nucleotide-binding domain–like receptor protein 3 inflammasome activation.(Ma 2018)

Animal models suggest that melatonin is able to scavenge free radicals and reduce oxidative stress associated with brain ischemia in stroke. It also has been associated with a reduction in white matter inflammation and cerebral edema. Additionally, melatonin protected against the breakdown of the blood-brain barrier following middle cerebral artery occlusion in animal studies.(Ramos 2017)

An in vitro model demonstrated that melatonin protected H9c2 cardiac cells against ischemia/reperfusion injury via decreasing apoptosis and exerting antioxidant effects. Specifically, melatonin was able to activate the nuclear erythroid 2–related factor 2 signaling pathway.(Zhang 2018)

Animal and in vitro models demonstrate beneficial effects of melatonin in pulmonary hypertension.(Jiki 2018)

Clinical data

In a nested case-control study, low nocturnal melatonin secretion was associated with an elevated risk for MI. Specifically, the greater incidence of MI was noted in women with increased body mass index (BMI).(McMullan 2017)

A meta-analysis of clinical trials evaluating the effect of melatonin on nocturnal hypertension included 7 studies meeting inclusion criteria; only a subgroup analysis of trials using sustained-release preparations showed decreases in blood pressure. Systolic blood pressure decreased by 6 mm Hg (95% CI, −10.7 to −1.5) and diastolic blood pressure decreased by 3.5 mm Hg (95% CI, −6.1 to −0.9). Immediate-release preparations showed no effect.(Grossman 2011) Antioxidant and anti-inflammatory effects of melatonin in cardiovascular disease have been considered; however, clinical trials are limited.(Cook 2011, Kozirog 2011, Reiter 2010) Results from a pilot, double-blind, randomized, placebo-controlled crossover trail in 40 African-American patients with nocturnal hypertension found no difference between night time administration of continuous-release melatonin (24 mg) and placebo. However, the order of administration significantly affected the result with those receiving placebo first experiencing lower systolic blood pressure (P=0.038) than those receiving melatonin first.(Rahbari-Oskoui 2019)

In a study of intubated adults who had experienced hemorrhagic stroke, melatonin 30 mg per night administered via nasogastric tube significantly reduced the length of stay in the ICU compared with control (8 vs 12 days; P=0.041). Although not statistically significant, melatonin was associated with a shorter duration of mechanical ventilation (4 vs 12 days; P=0.065) and ICU mortality (15% of patients vs 30% of patients; P=0.451).(Dianatkhah 2017)

Circadian misalignment/Jet lag

Melatonin is able to readjust misaligned circadian rhythms through acting upon melatonin MT₁ and MT₂ receptors in the hypothalamic suprachiasmatic nuclei.(Cingi 2018) Melatonin's ability to modulate circadian rhythms has prompted several studies in shift workers, military personnel, and individuals with jet lag.(Cingi 2018, Paul 2010) Circadian disturbances are also frequently reported in hemodialysis patients.(Russcher 2013)

Clinical data

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 immediate- or sustained-release preparations.(Paul 2010) A double-blind, placebo-controlled, randomized clinical trial (N=67) documented short-term improvements in sleep at 3 months with melatonin 3 mg nightly, but benefits were not sustained at 6-, 9-, or 12-month follow-ups. A major limitation of the study was high dropout rates (37%).(Russcher 2013)

There is little available information regarding the best melatonin dose or formulation for use in jet lag, with studies employing different dosage regimens. In general, lower doses (0.5 to 2 mg) preflight and higher doses postflight for a period of up to 4 days appear to be adequate.(Paul 2010)

Dementia/Delirium

Animal data

In a murine model, the effects of melatonin on cognitive impairment and dementia were compared in healthy nontransgenic mice and Alzheimer disease transgenic mice. Melatonin 10 mg/kg/day for 6 months reversed cognitive impairment, anxiety, and apathy in Alzheimer disease mice, and also reduced amyloid and tau protein burden in this group. Additionally, cognitive enhancement was induced in nontransgenic mice.(Corpas 2018)

In a rat model of senile dementia, melatonin reduced expressions of beta-amyloid protein and S100 beta compared with the model group (P<0.05).(Fang 2018)

Clinical data

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 effect on primary or secondary outcome measures. A total of 520 patients were enrolled in the 7 studies meeting inclusion criteria; 5 included patients with only Alzheimer disease and 2 included patients with Alzheimer disease and other dementias, including vascular dementia. All but 1 study administered melatonin 10 mg (treatment duration, 10 days to 3.5 years); 1 study used a sustained-release formulation of 2.5 mg for 8 weeks. Studies were of low to moderate quality.(Xu 2015) Another meta-analysis included 7 studies (N=462) evaluating melatonin monotherapy or placebo (treatment duration, 10 days to 24 weeks) in patients with Alzheimer disease or patients with Alzheimer disease and other dementias. Melatonin prolonged total sleep time in Alzheimer disease patients receiving melatonin (n=305; standard mean difference [SMD], 0.26; 95% CI, 0.01 to 0.51; I²=9%; P=0.04); however, melatonin did not improve cognition, as measured by the Alzheimer's Disease Assessment Cognitive Subscale and the Mini Mental State Examination, or demonstrate superiority in improvement of sleep efficacy.(Wang 2017) A 2016 Cochrane review found no evidence that melatonin at doses up to 10 mg improved any major sleep outcome over 8 to 10 weeks in patients with Alzheimer disease who were identified as having a sleep disturbance.(McCleery 2016)

The American Psychiatric Association 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 regarding alternative agents, including melatonin. The guidelines state that evidence supporting such alternative management strategies is not sufficient to warrant routine use.(Rabins 2014) The National Institute for Health and Care Excellence (NICE) guideline for assessment, management, and support for people living with dementia and their carers (2018) recommends against the use of melatonin to manage insomnia in people living with Alzheimer disease. This recommendation does not apply to other subtypes of dementia.(NICE 2018)

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 disturbances in these patients are 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.(Foreman 2015, Mo 2016) However, melatonin was not beneficial in preventing delirium in hospitalized, non-ICU patients; a 2016 Cochrane review found no evidence to suggest that melatonin or melatonin agonists reduce the incidence of delirium in this group of patients compared with placebo (risk ratio, 0.41; 95% CI, 0.09 to 1.89; 3 studies; n=529). Additionally, no difference between melatonin and placebo was observed with regards to delirium duration.(Siddiqi 2016) In a randomized clinical trial in 69 patients 65 years and older who were admitted to the hospital (non-ICU), melatonin 3 mg nightly did not improve delirium. More patients receiving melatonin experienced delirium compared to those receiving placebo (22.2% vs 9.1%, respectively; P=0.19). Melatonin also did not improve subjective or objective sleep parameters.(Jaiswal 2018)

Depression

Clinical data

Results of a meta-analysis of 3 studies (N=181) revealed that melatonin as add-on to standard therapy for major depressive episodes in patients with either unipolar or seasonal affective disorder did not provide a statistically significant effect compared to placebo.(De Crescenzo 2017)

Dermatological effects

Melatonin has been suggested to be useful in dermatological conditions such as atopic eczema/dermatitis through protection of skin integrity and antiapoptotic and antioxidant effects. It might also be effective in reducing serum total immunoglobulin E (IgE) and interleukin 4 (IL-4) levels to slow the development of atopic eczema/dermatitis.(Marseglia 2014)

Animal data

In a murine model, melatonin prevented and attenuated the effects of gamma ray–induced skin injury.(Shabeeb 2019)

Clinical data

Adjunctive melatonin improved 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 (BSA) with sleep problems occurring more than 3 days per 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, improvements in Scoring Atopic Dermatitis (SCORAD) index (by 9.1) and sleep-onset latency (by 21.4 minutes) were observed with melatonin compared to placebo. No adverse events were reported.(Chang 2016) In another similar study in children 6 to 12 years of age with atopic dermatitis, melatonin 6 mg/day for 6 weeks was improved SCORAD index, objective SCORAD index, serum total IgE levels, and Children's Sleep Habits Questionnaire score. However, melatonin did not demonstrate significant impact on pruritus scores, C-reactive protein levels, sleep-onset latency, total sleep time, weight, and BMI compared to placebo.(Taghavi 2018) Topically applied melatonin may be beneficial in protecting against erythema from ultraviolet radiation when applied prior to exposure.(Day 2018)

Diabetes

Clinical data

A systematic review and meta-analysis of randomized placebo-controlled trials investigated the effects of melatonin supplementation on diabetes parameters in patients with or without a diagnosis of diabetes. Of the 16 studies included in the review, most (n=15) were double-blind, conducted in Iran (n=11), and enrolled men and women (n=13) with sample sizes that ranged from 20 to 100. Only one study was conducted in healthy volunteers while the remaining studies enrolled patients with metabolic syndrome (n=3), type 2 diabetes (n=3), psychiatric disorders (n=3), non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (n=2), diabetes and cardiovascular disease, diabetes on hemodialysis, Parkinson disease, or polycystic ovary syndrome (n=1 each). Meta-analyses showed significant benefit with melatonin on fasting blood glucose (N=926), HbA_1c (N=310), and insulin resistance (N=293) overall compared to placebo. When combination products were excluded, significance was retained for all 3 parameters, and the respective mean differences were −3.42 mg/dL, 0.26%, and −0.6 Homeostatic Model Assessment of Insulin Resistance.(Delpino 2021)

Epilepsy

Animal and in vitro data

In a mouse model of epilepsy, melatonin 50 and 100 mg/kg intraperitoneally exerted anticonvulsant activity.(Mosinkska 2016) However, in another animal study, melatonin alone was not associated with anticonvulsant activity, but did potentiate the antiepileptic activity of phenobarbital when given concomitantly.(Forcelli 2013)

Clinical data

In a small clinical study of 10 patients between 9 and 32 years of age with intractable epilepsy, melatonin 10 mg nightly significantly decreased diurnal seizures compared with placebo (P=0.034).(Goldberg-Stern 2012)

In a 2016 Cochrane review, which was an update to a 2012 review, the authors were unable to perform a meta-analysis due to the lack of sufficient data on outcomes and poor methodological quality of the studies. Thus, it was not possible to draw conclusions regarding the benefit of melatonin in reducing seizures or improving quality of life in patients with epilepsy.(Brigo 2016)

A review of the evidence on melatonin and seizures found a paucity of relevant data from which to draw firm conclusions, with current evidence suggesting that melatonin has no effect on seizures, neither improvement nor worsening.(Jain 2013)

GI disorders

GI 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, with 400 times more melatonin found in the gut compared with the pineal gland. Food intake is believed to influence the secretion of melatonin in the gut as opposed to photoperiodicity, which occurs with the pineal gland. Melatonin can also cause both smooth muscle contractions and relaxation. Low doses of melatonin accelerate intestinal transit time while higher doses reduce gut motility.(Carpentieri 2012, Esteban-Zubero 2017, Mozaffari 2010, Siah 2014, Tordjman 2017) Melatonin has been evaluated for its effects in IBS, constipation-predominant IBS, diarrhea-prominent IBS, Crohn disease, ulcerative colitis, and necrotizing enterocolitis.(Esteban-Zubero 2017) It may be useful in these conditions due to its analgesic effects, regulatory effects on motility, effects on sleep (which can be disturbed with GI disorders), and effects on mood and stress.(Gagnon 2018, Siah 2014)

Animal data

In a study in rodents, melatonin exhibited antiulcer activity, protecting against colonic immune injury and improving duodenal and gastric motility.(Mozaffari 2010) In another study of rats, melatonin attenuated histopathological damage caused by acetylsalicylic acid.(Taslidere 2018) In a murine model, melatonin attenuated various measures of colitis.(Zielinska 2016) In another study of mice with colitis, melatonin improved resistance to oxidative stress and regulated intestinal microbial flora.(Zhu 2018) Additionally, melatonin in combination with misoprostol exerted cytoprotective and healing effects on the mucosa of rat pups with necrotizing enterocolitis.(Cekmez 2013)

Clinical data

Accelerated healing rates have been demonstrated in several small clinical trials evaluating melatonin therapy in gastric and duodenal ulcers.(Celinkski 2011, Celinkski 2011)

In a 2013 double-blind, placebo-controlled study in 80 postmenopausal women with IBS, melatonin was beneficial for symptoms of constipation-predominant IBS but not diarrhea-predominant IBS. Administration of melatonin 8 mg/day (3 mg in the morning, 5 mg at bedtime) for 6 months resulted in decreased intensity of visceral pain and abdominal bloating in 70% as well as improved constipation in 50% of women with constipation-predominant IBS. An inverse relationship was observed between symptom scores and excretion of urinary 6-sulfatoxymelatonin in the constipation-predominant group versus healthy controls (mean, −9.3 mcg per 24 hours in those with severe disease versus 11.4 mcg per 24 hours, respectively); these values were higher than healthy controls in the diarrhea-predominant group whose beneficial symptom changes were no better than placebo.(Chojnacki 2013)

A randomized, placebo-controlled study that enrolled 152 postmenopausal women found significantly lower melatonin levels in those with symptomatic H. pylori infection (chronic dyspepsia) than those with either no infection or with asymptomatic infection (P<0.001). Subsequent to a 14-day triple antibiotic therapy regimen given to the 64 symptomatic women, administration of melatonin (1 mg in the morning and 3 mg at bedtime) for 6 months led to resolution of dyspeptic symptoms in significantly more women (84.3%) than in the placebo group (43.7%; P<0.001). Fatigue (12.5%) and headache (6.2%) were reported but did not require discontinuation of treatment.(Chojnacki 2020)

Hepatic effects

Melatonin may exert hepatoprotective effects in a variety of liver diseases such as hepatic steatosis, fatty liver disease, drug-induced liver disease, hepatitis, fibrosis, and cirrhosis through antioxidant activity, improving the physiology of the mitochondria, inhibiting apoptosis, inhibiting infiltration of liver neutrophils, inhibiting necrosis, minimizing liver fibrosis, and attenuating the severity of structural changes.(Mortezaee 2018, Zhang 2017)

Animal and in vitro data

A review of the literature suggests that melatonin may exert hepatoprotective effects in liver damage resulting from adriamycin, tacrolimus, carbamazepine, phenytoin, phenobarbital, trazodone, acetaminophen, and alcohol.(Zhang 2017) It has also demonstrated beneficial effects in rat models of alcoholic liver disease and was better at improving liver damage caused by methanol intoxication than N-acetylcysteine.(Esteban-Zubero 2016)

Clinical data

Persistent adverse hepatic effects induced by statin drugs were reduced by the addition of melatonin to statin therapy in 60 adults (including 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, gamma-glutamyltransferase, alkaline phosphatase) were significantly reduced in the melatonin group compared with placebo (P<0.001). A decrease in total cholesterol, but not triglycerides, was also significant in the group receiving the low-dose statin therapy plus melatonin (−41.6 mg/dL) compared with low-dose statin therapy plus placebo (−19.3 mg/dL) (P<0.05). The only reported adverse 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 produced during hepatic metabolism of melatonin.(Chojnacki 2017)

Melatonin was beneficial in reducing parameters such high-sensitivity C-reactive protein, AST levels, cytokine levels, and diastolic blood pressure in studies of patients with nonalcoholic fatty liver disease.(Celinkski 2014, Pakravan 2017)

Infection

Melatonin may be beneficial in combating infections through several potential mechanisms, including enhancement of antigen presentation, phagocytic activity, and production of natural killer cells and monocytes; modulation of proliferation of stimulated lymphocytes and production of cytokines; antinitrosative effects; and antioxidant activity.(Daryani 2018, Hu 2017) It may be useful in neonatal sepsis through a reduction in oxidative stress.(El-Gendy 2018)

Animal and in vitro data

Animal studies have suggested a potential benefit of melatonin in treating a variety of protozoan parasitic infections (ie, Toxoplasma gondii, Entamoeba histolytica, Giardia duodenalis, Plasmodium spp., Leishmania spp., and Trypanosoma spp.).(Daryani 2018) Melatonin doses ranging from 31.25 to 125 mg/mL have been suggested to exert antibacterial activity against gram-positive and gram-negative organisms.(Hu 2017)

Clinical data

In a prospective, nonrandomized, case-control study, 40 neonates with sepsis received antibiotics as warranted, with half receiving melatonin 20 mg as a single dose given via nasogastric tube. At 72 hours after receiving melatonin, platelet count was higher in the melatonin group compared with the control group (P=0.04). At both 24 and 72 hours after receiving melatonin, C-reactive protein level and total leukocyte cell count were significantly lower in those receiving melatonin compared with controls. Lastly, significantly more patients who received melatonin had an improved outcome compared with the control group (90% vs 55%, respectively; P=0.043).(El-Gendy 2018)

In a prospective trial, treatment with melatonin 20 mg daily for 3 days plus antibiotic therapy was compared to antibiotics alone (control group) in 50 neonates with suspected necrotizing enterocolitis. Occurrence rates at 1 week were compared to those at onset of research. Significant reductions in abdominal distention, hyponatremia, thrombocytopenia, blood in stool, metabolic acidosis, and pneumatosis intestinalis were seen in the melatonin group, but not the control group (all P<0.05).(Elfrargy 2017)

A protocol was registered in August 2020 for a double-blind, randomized, placebo-controlled trial to investigate the safe and effective use of melatonin in adult patients with PCR-confirmed moderate SARS-CoV-2 in Iran. Primary outcomes will focus on improvement of recovery in clinical symptoms, oxygen saturation, and serum inflammatory parameters in patients without concomitant, underlying chronic conditions.(Ziaei 2020)

Insomnia and other sleep disorders (adults)

Decreased circulating melatonin serum levels have been found in individuals of all ages with insomnia, as well as in healthy elderly individuals. Given its effects on circadian rhythm, exogenous melatonin has been extensively studied for sleep disorders. Administration timing has an effect on the anticipated effect. Administration of exogenous melatonin in the morning can delay the circadian rhythm as well as the onset of evening fatigue. However, evening administration of melatonin advances the circadian rhythm and induces the onset of sleep.(Schroeck 2016)

Clinical data

Primary sleep disorders

Primary sleep disorders include conditions associated with sleep disturbances not attributed to medical conditions. Examples include insomnia disorder, delayed sleep phase syndrome, hypersomnolence disorder, narcolepsy, obstructive sleep apnea, central sleep apnea, and parasomnias. A 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) but had no effect on wake time or total sleep times.(Van Geijlswijk 2010) 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.(Wilhelmsen-Langeland 2013) 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.(Saxvig 2014, Sletten 2018) Studies published before April 2012 evaluating the effect of melatonin on primary sleep disorders were assessed in a meta-analysis that involved 1,683 patients. Melatonin doses ranged from 0.1 to 3 mg, and therapy durations ranged from 7 to 182 days. Melatonin demonstrated statistically significant efficacy in reducing sleep latency (fell asleep 7 minutes earlier) and increasing total sleep time (slept 8 minutes longer), with overall sleep quality significantly improved; higher doses and longer durations of therapy were associated with greater effects on sleep latency and total sleep time, but greater effects on sleep quality were not observed based on dose or duration.(Ferracioli-Oda 2013)

Secondary sleep disorders

Secondary sleep disorders occur as a result of medical or mental conditions (eg, insomnia resulting from disease states such as restless legs syndrome, Parkinson disease, and Alzheimer disease). 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 receiving prolonged-release melatonin 2 mg (ie, Circadin) or placebo nightly for 4 weeks. Significant improvements in sleep quality (P<0.0001), sleep efficiency (P=0.04), and other secondary end points (ie, daytime fatigue, anxiety) were achieved with melatonin compared with placebo.(Grima 2018) A 2018 systematic review and meta-analysis assessed the impact of melatonin therapy in 7 clinical trials of 205 patients with secondary sleep disorders. Compared with placebo, melatonin doses ranging from 3 to 6 mg nightly significantly lowered sleep onset latency (total mean difference, −2.48 minutes; 95% CI, −4.56 to −0.4); the overall estimated score of melatonin treatment was significant (z=2.33; P=0.02). Additionally, melatonin therapy significantly increased total sleep time (total mean difference, 29.27 minutes; 95% CI, 6.68 to 51.86); the overall estimated effect of melatonin was significant (z=2.54; P=0.01). However, melatonin did not significantly impact sleep efficiency (total mean difference, 1.46; 95% CI, −0.43 to 3.35; z=1.52; P=0.13).(Li 2019) In a randomized, double-blind, placebo-controlled trial (N=80), addition of prolonged-release melatonin 2 mg/day (ie, Circadin) for 24 weeks significantly improved 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.(Wade 2014) Data from company-sponsored trials are unconvincing. A 2016 Cochrane review found no evidence that melatonin, at doses up to 10 mg, improve any major sleep outcome over 8 to 10 weeks in patients with Alzheimer disease and identified as having a sleep disturbance.(McCleery 2016) In a double-blind, randomized, placebo-controlled trial (N=95) in postmenopausal breast cancer survivors, sleep disturbance, which is common among breast cancer survivors, was improved overall in those who received melatonin 3 mg nightly for 4 months (by a PSQI score of 1.67 points; P=0.001). Adverse effects that led to discontinuation in 4 participants included headache, insomnia, and nightmares (all grade 1 or 2); all 4 were in the melatonin group. No significant effect on mood or hot flashes was observed between groups.(Chen 2014) In a randomized clinical study of 40 patients with ST-segment elevation MI managed with percutaneous coronary intervention, the effects of melatonin 3 mg or oxazepam 10 mg nightly for anxiety and sleep quality were assessed. Compared with oxazepam therapy, patients receiving melatonin had a significant improvement in sleep quality (P=0.04) and anxiety (P=0.019).(Ghaeli 2018)

The NICE guideline for assessment, management, and support for people living with dementia and their caregivers (2018) recommends against the use of melatonin to manage insomnia in people living with Alzheimer disease. This recommendation does not apply to other subtypes of dementia.(NICE 2018)

Sleep disorders in hospitalized patients

Patients in ICUs may have sleep difficulties due to patient care activities, extensive monitoring, and environmental disruptions.(Lewis 2018) In a double-blind, placebo-controlled pilot study, exogenous supplementation with controlled-release melatonin 3 mg induced sleep in all 8 pulmonary ICU patients and resulted in awakening patterns similar to matched control patients in the general ward.(Shilo 2000) In another small, double-blind, randomized controlled trial (N=24), a melatonin 10 mg oral solution produced a modest improvement in nightly sleep time (by 1 hour) and quality (7% decrease in bispectral index AUC; P=0.04) in critically ill tracheostomy patients compared with placebo; however, these effects were not significantly different overall when considering all 4 nights of the study. Carryover effects were suspected with this dose and supraphysiological levels were noted in the morning. Pharmacokinetic measurements revealed rapid absorption with administration of the oral solution, with biexponential declines in plasma concentrations.(Bourne 2008) A 2018 Cochrane systematic review analyzed 4 clinical studies including 151 patients admitted to the ICU and randomized to receive melatonin or a comparator for sleep. The studies included a mix of mechanically ventilated and nonventilated patients. The authors determined the evidence to be of very low quality and insufficient to suggest that melatonin improves quality and quantity of sleep in ICU patients. There were 5 ongoing studies in the database.(Lewis 2018) In a 9-month observational comparator study (N=100), no significant differences were reported in sleep parameters for any dose of either melatonin or zolpidem by inpatients. Age of more than 65 years or use of a sleep aid at home did not change the results.(Stoianovici 2019)

Symptoms of benzodiazepine withdrawal

Results of a randomized controlled trial confirmed results of 2 previous trials regarding a 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.(Lahteenmaki 2014)

Hypertensive patients receiving beta-blockers

Beta-blocker suppression of endogenous nighttime melatonin secretion possibly explains the reported adverse effect of insomnia in hypertensive patients; the effect of nightly melatonin supplementation in hypertensive patients treated with beta-blockers was investigated in a double-blind, randomized, placebo-controlled, parallel trial (N=16). Patients were randomized to receive melatonin 2.5 mg nightly for 3 weeks or placebo. Compared with 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.(Scheer 2012)

Guideline recommendations

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 recommendation; very low–quality evidence).(Sateia 2017) The 2016 American College of Physician guidelines suggest that evidence on global and sleep outcomes is insufficient to recommend melatonin or melatonin agonists.(Wilt 2016) The 2017 European guidelines from the European Sleep Research Society state that melatonin is not generally recommended for the treatment of insomnia because of low efficacy (weak recommendation).(Riemann 2017) The Veteran’s Administration and Department of Defense (VA/DoD) clinical practice guideline for the management of chronic insomnia disorder and obstructive sleep apnea (2019) suggest against the use of melatonin for the treatment of chronic insomnia disorder (Weak).(Mysliwiec 2020)

Insomnia and other sleep disorders (children)

Clinical data

The effects of melatonin for insomnia or other sleep disorders in children with ADHD; epilepsy; cerebral palsy; visual impairment; and neurodevelopmental disorders, including autism spectrum disorders have been evaluated.(Abramova 2019, Bendz 2010, Chang 2016, Cuomo 2017, De Leersnyder 2011, Elkhayat 2010, Gagnon 2018, Galland 2012, Gringras 2017, Khan 2011, Maras 2018, Relia 2018, Williams 2020) In a double-blind, randomized, placebo-controlled, crossover trial (N=48) in Taiwan, adjunctive melatonin improved atopic dermatitis and related sleep problems in children. Children 1 to 18 years of age (mean age, 7 years) with atopic dermatitis involving at least 5% of total BSA and with sleep problems occurring more than 3 days per 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. Patients were randomized 1:1 to melatonin (3 mg/day) or placebo at bedtime for 4 weeks, then underwent a 2-week washout period followed by the alternate treatment for 4 weeks. Significant improvements in SCORAD score (by 9.1) and sleep onset latency (by 21.4 minutes) were observed with melatonin compared with placebo. No adverse events were reported.(Chang 2016) In a double-blind, randomized trial (N=95), children with autism spectrum disorder or neurogenetic disorders were found to sleep almost 1 hour longer on average after 13 weeks of sustained-release melatonin (titrated from 2 mg nightly up to 10 mg per night) compared with approximately 10 minutes longer with placebo (P=0.034). Sleep latency also improved significantly with melatonin versus placebo, with children falling asleep faster (reductions of 39.6 minutes vs 12.51 minutes, respectively; P=0.011).(Gringas 2017)

Outcome data from studies in children have been similar to those in adults; however, trials in children have generally consisted of smaller numbers of subjects and wide-ranging dosage regimens, making generalized statements on efficacy difficult to support.(Gruenole 2011, Hollway 2011, Rossignol 2011)

A review of melatonin use in pediatric special populations recommended that use of 3 to 6 mg/night in children with ADHD be considered only after stimulant drug therapy and sleep hygiene techniques have been optimized. Recommendations for children with autism were more difficult due to several confounding variables among study data.(Abramova 2019)

Guideline recommendations

Several bodies of experts have released guidelines regarding the use of melatonin in children. 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 delayed sleep-wake phase disorder and irregular sleep-wake rhythm disorder in those with and without comorbid neurological or psychiatric disorders, based on short-term studies (up to 4 weeks) (weak for recommendation). Optimal doses varied based on sleep disorder and comorbidities (range, 2 to 10 mg daily).(Auger 2015) The American Academy of Pediatrics states that melatonin appears to be effective in reducing time to sleep onset in adults (and in children, but based on considerably less data) for initial insomnia. This effect appears to last for days to weeks but not long-term. Thus, melatonin is not recommended for long-term use.(AAP 2018) The American Academy of Neurology's practice guideline on insomnia and sleep disruption in children and adolescents with autism spectrum disorder (2020) recommends a pharmaceutical-grade melatonin product or a prescription for melatonin for sleep disturbance if managing coexisting conditions and behavioral strategies have been ineffective. Low doses of 1 to 3 mg/day should be given 30 to 60 minutes before bedtime and then titrated to effect, not to exceed 10 mg/day. Parents and/or children should be counseled regarding the lack of long-term safety data and potential of adverse events, including the ability of melatonin to suppress the hypothalamic-gonadal axis and its potential to initiate precocious puberty (Level B).(Williams 2020)

Multiple sclerosis

MS is an inflammatory immune disease that impacts women in their 20s and is often associated with seasonal flare-ups, worsening in spring/summer compared with fall/winter. This seasonal association of flare-ups aligns with the concurrent decline in plasma levels of melatonin during this time period, with suppression of secretion due to longer daylight hours.(Wurtman 2017) Melatonin is believed to be effective in this disease state by controlling the effector and regulatory cell balance.(Farez 2016)

Clinical data

A case report describes a 28-year-old female with primary progressive MS who improved from an Expanded Disability Status Scale score of 8 to 6 over a period of 4 years with daily melatonin doses ranging from 50 to 300 mg. No other treatments were given. (Lopez-Gonzalez 2015) In a study of 34 patients with nocturia due to MS, sustained-release melatonin 2 mg (ie, Circadin) nightly for 6 weeks was ineffective in improving measures of nocturia, lower urinary symptoms, quality of life, and sleep quality compared with placebo. (Drake 2018)

Organ transplantation

Melatonin has been evaluated for its effects in transplant settings to help reduce graft rejection. It may also be useful in this setting due to its antioxidant and anti-inflammatory properties.(Esteban-Zubero 2016)

Animal and experimental data

Specifically, melatonin has been investigated in animal models of liver, pancreas, lung, ovary, heart, and lung transplantation with positive results. (Shiroma 2016, Stiegler 2018)

Periodontal disease

Melatonin is released by the acinar cells into the saliva; salivary melatonin levels exhibit a circadian rhythm, with highest concentrations occurring at night. Levels are lower in saliva than in circulation. Melatonin exerts both receptor-mediated and receptor-independent activities within the oral cavity. It may be useful in periodontal disease through its anti-inflammatory and antioxidant effects. Specifically, it may be useful in reducing inflammation in the gingiva and periodontium, decreasing bone loss, suppressing herpes lesions, increasing bone growth and stabilization with dental implants, and minimizing oral cancer. It may be useful in countering the negative effects of medications on the oral cavity, such as bisphosphonates and chlorhexidine.(Carpentieri 2017, Drake 2018, Reiter 2015)

Animal data

In a study of rats, melatonin reduced elevated AST, ALT, and serum urea nitrogen levels and periodontal inflammation associated with lipopolysaccharide-induced periodontitis.(Gulle 2014)

Clinical data

The effects of melatonin 10 mg at bedtime were assessed in a clinical trial of patients with generalized chronic periodontitis. After scaling and root planning, patients receiving melatonin had significantly greater clinical attachment level gain and pocket depth reduction at 3 and 6 months of therapy (P<0.01). Additionally, salivary tumor necrosis factor alpha (TNF-alpha) levels and Athens Insomnia Scale scores were significantly lower in those receiving melatonin compared with controls.(El-Sharkawy 2019)

Regenerative therapy

Melatonin has been reported to enhance the viability, differentiation, and proliferation of stem cells. (Lee 2017, Majidinia 2018)

Reproductive system

Increased oxidative stress due to higher metabolic rate and oxygen demand by organs and tissues during pregnancy may be associated with the development of pre-eclampsia, intrauterine growth restriction, and perinatal asphyxia. Melatonin plays an important role in the elimination of free radicals and reduction of oxidative damage, lipid peroxidation, and apoptosis in the placenta. Melatonin is also responsible for stimulating progesterone synthesis, which inhibits early uterine muscle contractions. (Marseglia 2016, Rodrigues Helmo 2018)

Animal data

Melatonin supplementation in domestic cats prolonged the interestrus interval but had no effect on delaying puberty.(Faya 2011) In red deer,(Asher 2011) and similarly in lambs(Sawalha 2011) and goats,(Zarazaga 2012) melatonin has been used to influence ovulation with some success.

In a murine model of polycystic ovarian syndrome (PCOS), exogenous administration of melatonin restored MT₁ and MT₂ receptors, which were down-regulated due to PCOS.(Basheer 2018)

In a murine model of preterm labor (caused by lipopolysaccharide [LPS]), melatonin administration on day 14 of pregnancy prevented preterm births in 50% of cases; all pups of melatonin-treated females were born alive and had body weights similar to the control group. In the group not receiving melatonin, incidence of preterm birth was 100%. Also, fetuses in the group not receiving melatonin showed widespread damage, including some stillborn pups and some with lack of cerebral irrigation. Melatonin prevented the LPS-induced rises in uterine prostaglandin (PG) E₂, PGF_2alpha, and cyclooxygenase-2 protein levels. Melatonin also prevented LPS-induced increases in uterine nitric oxide production, inducible nitric oxide synthase protein, and TNF-alpha levels.(Dominoguez Rubio 2014)

In a study of rats chronically consuming alcohol during pregnancy, melatonin reduced the genotoxicity associated with ethanol in the offspring. (Sousa Coelho 2018)

Clinical data

A randomized, unblinded study analyzed effects of melatonin on in vitro fertilization-embryo transfer outcomes in patients undergoing IVF and who had sleep disturbances. Mean number of retrieved oocytes, mean metaphase II oocyte counts, and G1 embryo ratio were significantly higher in those receiving melatonin 3 mg nightly compared to those not receiving melatonin. Subsequent pregnancy rates following IVF were similar between groups, but live birth data were not reported.(Eryilmaz 2011) Another similar study found an increase in mature oocytes retrieved with melatonin 3 mg daily, and equivalent fertilization and pregnancy rates.(Batioglu 2012) However, another randomized, double-blind, controlled study found melatonin was not different from placebo in regards to clinical pregnancy rates or oocyte parameters.(Fernando 2018) A meta-analysis of 5 studies published prior to April 2013 lacked sufficient high-quality data to determine effects or benefits of melatonin supplementation during controlled ovarian stimulation in women undergoing assisted reproductive technology.(Seko 2014)

In a phase 2, double-blind, placebo-controlled, randomized clinical trial in women with endometriosis-associated chronic pelvic pain (N=40), melatonin improved daily pain, dysmenorrhea, dysuria, dyschezia, and sleep quality, as well as modulated secretion of brain-derived neurotrophic factor (BNDF). Compared with placebo, melatonin 10 mg for 8 weeks was associated with reductions in daily pain scores and dysmenorrhea (by almost 40% for both). The effect on BDNF secretion occurred independently of analgesic mechanisms.(Schwertner 2013)

A 2016 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 was found supporting effectiveness of melatonin 10 mg for the treatment of dysmenorrhea, specifically dysmenorrhea secondary to endometriosis, compared with placebo. Supplementation was started at the onset of menstruation and continued for 8 weeks. Data were unsuitable for analysis.(Pattanittum 2016)

A 2017 Cochrane systematic review included 4 randomized controlled trials evaluating melatonin in women attending a reproductive clinic (n=568). No clear evidence of a difference in clinical pregnancy rates among women receiving melatonin, placebo, or no treatment was observed (odds ratio, 1.29; 95% CI, 0.91 to 1.83; P=0.15; I²=0%).(Showell 2017)

Schizophrenia and bipolar disorder

Animal and in vitro data

In an in vitro study involving olfactory neuroepithelial cells, the investigators suggested that low levels of melatonin during pregnancy may increase the risk for developing schizophrenia due to impairment in neuronal polarization and axonal formation in neuronal precursors.(Galvan-Arrieta 2017)

In a murine model of schizophrenia, melatonin administration reversed ketamine-induced social interaction deficits, memory deterioration, and changes in brain antioxidant activity, and reduced ketamine-induced hyperlocomotion. Melatonin's ability to counteract ketamine-induced behavioral changes was better than haloperidol and comparable with olanzapine. Melatonin significantly improved brain oxidative stress compared to both haloperidol and olanzapine.(Onaolapo 2017)

Clinical data

A triple-blind, randomized, placebo-controlled trial evaluated the role of supplementary melatonin in facilitating benzodiazepine dosage reduction or discontinuation in patients with schizophrenia or bipolar disorder (N=86). Prolonged-release melatonin 2 mg nightly (ie, Circadin) for 24 weeks in parallel with the gradual reduction (10% to 20% every 2 weeks) in benzodiazepine or benzodiazepine-like drugs did not reduce mean daily dosage, cessation, or withdrawal symptoms of the benzodiazepine drugs compared with placebo.(Baandrup 2011, Baandrup 2016) In a double-blind, randomized controlled trial, melatonin 5 mg/day for 8 weeks counteracted 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.(Romo-Nava 2014) In a double-blind, randomized, placebo-controlled trial in 48 adolescents 11 to 17 years of age who were treatment-naive and newly diagnosed with bipolar I disorder, adjunctive use of melatonin with olanzapine and lithium was investigated for effects on olanzapine-induced weight gain. Patients were randomized to standard treatment (olanzapine and lithium) 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 marginally significantly different from placebo (5.8 kg vs 8.2 kg, respectively; P=0.065).(Mostafavi 2017)

Surgery

Clinical data

The combination of melatonin and alprazolam as surgical premedication produced 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 arm (P=0.001) and the placebo arm (P=0.008).(Pokharel 2014) No effect on improved outcomes, including rate of infection or length of stay in the ICU, has been observed.(Kucukakin 2010, Nickkholgh 2011) According to a systematic review, 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 with those premedicated with 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 similar between groups. Melatonin and midazolam were dosed at 0.5 mg/kg, with a maximum dose of 20 mg.(Gitto 2016) Qualitative review of individual randomized clinical trials suggested that melatonin improves sleep quality and emergence behavior.(Andersen 2014) In a study of 132 children undergoing dental surgery requiring general anesthesia, midazolam 0.5 mg/kg was better than melatonin 0.5 mg/kg in regards to sedation score and IV access establishment.(Faghihian 2018)

In a double-blind, randomized trial in patients undergoing cataract surgery, oral melatonin 6 mg given 1 hour preoperatively significantly reduced pain scores during retrobulbar block compared to placebo (P<0.01). Patients in the melatonin group also required less additional pain relief (fentanyl) during the procedure than the control group (P<0.05). (Haddidi 2018)

In a double-blind, placebo-controlled trial, the risk of developing depressive symptoms during the 3 months following breast cancer surgery was significantly reduced with melatonin (6 mg daily for 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.(Hansen 2014)

In a 2015 Cochrane database review, 12 randomized controlled trials including 774 patients were reviewed. The authors concluded that melatonin given orally or sublingually before surgery can reduce preoperative anxiety in adults compared with placebo. Melatonin may also be considered equally as effective as midazolam in reducing preoperative anxiety in adults. Mixed results exist regarding melatonin's impact on postoperative anxiety but suggest a reduction compared with preoperative anxiety.(Hansen 2015)

Tardive syndromes

Animal data

In a murine model, melatonin decreased reserpine- and age-induced oral movements.(Abilio 2002)

Clinical data

The American Academy of Neurology guidelines for the treatment of tardive syndromes (2013), including tardive dyskinesia, concludes that data are conflicting regarding use of melatonin for treatment of tardive dyskinesia, with 2 mg daily being possibly ineffective but 10 mg daily being possibly effective.(Bhidayasiri 2013) The 2018 update to these guidelines lists melatonin as a treatment option with a recommendation level of "U" indicating "unknown."(Bhidayasiri 2018) According to a 2018 Cochrane review, there was low to very low certainty of evidence for melatonin with regards to treatment for antipsychotic-induced tardive dyskinesia (risk ratio, 0.89; 95% CI, 0.71 to 1.12), based on results from 2 trials (n=32).(Soares-Weiser 2018)

Tinnitus

Melatonin may be useful in the treatment of tinnitus through causing vascular changes that improve blood perfusion to the labyrinth and reducing muscular tone to relieve tensor tympani muscle spasms.(Mirrodi 2015)

Clinical data

Limited studies have evaluated the effect of melatonin on tinnitus. In a randomized clinical trial, melatonin 3 mg daily for 3 months improved Tinnitus Handicap Inventory scores in patients with tinnitus.(Abtahi 2017) In a 2015 review of the literature, melatonin was beneficial for treating tinnitus, especially in a subgroup of patients with sleep disturbance. Melatonin also seemed to be most effective in men without depression, those without previous treatment for tinnitus, and those with a history for noise exposure. Additionally, it also seems to be effective in patients with chronic tinnitus and bilateral tinnitus.(Mirrodi 2015)

Despite these findings, 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).(Tunkel 2014)

Dosing

Analgesia

Dosages ranging from 3 to 10 mg/day orally for various durations have been used in various pain conditions. Melatonin 10 mg orally daily at bedtime for 6 weeks was used in patients with pain associated with fibromyalgia.(de Zanette 2014) Melatonin 3 mg for 2 to 3 months has been used in clinical studies of migraine.(Ebrahimi-Monfared 2017, Goncalves 2016) Melatonin 6 mg has been administered preoperatively to induce reductions in visual analog pain scores(Javaherforooshzadeh 2018); a dosage of 3 mg twice daily (8 PM and midnight) has been used in ICU patients.(Mistraletti 2015) Melatonin 5 mg orally daily for 30 days was used for improvements in pain, pain threshold, and sleep quality in a clinical trial of patients with temporomandibular disorder.(Vidor 2013)

Anesthesia premedication, pediatric

A single dose of melatonin 0.5 mg/kg orally (maximum, 20 mg) has been used as premedication before induction of anaesthesia to reduce surgical propofol anesthetic doses in children (4 to 15 years of age) undergoing elective surgery.(Gitto 2016)

Cancer, adjuvant therapy

Although the ideal dose of melatonin has not been standardized, several clinical studies have shown that daily adjuvant oral doses of 10 to 40 mg are well tolerated and useful in breast cancer patients.(Kubatka 2018)

A systematic review and meta-analyses of clinical trials reports adjuvant use of oral melatonin at dosages of 20 mg/day in patients with solid tumors.(Seely 2012, Wang 2012)

Insomnia

A meta-analysis of clinical trials evaluating melatonin use in sleep disorders reports a dosage of 3 to 5 mg orally 3 to 6 hours before an imposed sleep period over 4 weeks.(Van Geijlswijk 2010) In elderly patients, immediate-release melatonin 1 to 2 mg given 1 hour prior to bedtime may be useful for insomnia; controlled-release formulations should be avoided in this population due to concerns for prolonged concentrations.(Schroeck 2016) Based on the National Institute for Health and Care Excellence (NICE) guidelines for dementia, melatonin is not recommended for the management of insomnia in patients with Alzheimer disease.(NICE 2018)

American Academy of Sleep Medicine clinical practice guidelines recommend use of strategically timed melatonin in children and adolescents for the treatment of delayed sleep-wake phase disorder and irregular sleep-wake rhythm disorder in those with and without comorbid neurological or psychiatric disorders, based on short-term studies (up to 4 weeks). Optimal doses varied based on sleep disorder and comorbidities (range, 2 to 10 mg daily).(Auger 2015) The American Academy of Pediatrics states that melatonin appears to be effective in reducing time to sleep onset in adults and children and can be used for initial insomnia; however, melatonin is not recommended for long-term use.(AAP 2018)

Jet lag

In general, lower doses (0.5 to 2 mg orally) preflight and higher doses (5 mg orally) postflight over a period of up to 4 days has been recommended to avoid symptoms.(Paul 2010)

Pregnancy / Lactation

Melatonin in human breast milk undergoes a circadian rhythm, with elevated levels occurring at night and minimal levels during the day.Tordjman 2017

Given the minimal information available regarding safety and efficacy, melatonin supplementation in pregnancy and lactation is questionable and should be avoided until further research has been conducted.

Interactions

Melatonin's metabolism involves the CYP-450 system, and therefore has the propensity for numerous drug-drug interactions.(Mortezaee 2018) Specifically, melatonin is metabolized by CYP1A2 to 6-hydroxymelatonin and is metabolized by CYP2C9 and CYP2C19 to metabolites such as N-acetylserotonin, 5-methoxytryptamine, and 5-methoxylated kynuramines.(Alagiakrishnan 2016)

Abametapir: Abametapir may increase the serum concentration of CYP1A2 substrates (high risk with inhibitors). Avoid combination.(Xeglyze June 2020)

Alcohol (ethyl): Alcohol (ethyl) may enhance the adverse/toxic effect of melatonin. Alcohol (ethyl) may diminish the therapeutic effect of melatonin. Avoid combination.(Circadin June 2016)

Benzodiazepines: Melatonin may enhance the sedative effect of benzodiazepines. Monitor therapy.(Circadin June 2016, Otmani 2008, Suhner 2001)

Broccoli: Broccoli may decrease the serum concentration of CYP1A2 substrates (high risk with inducers). Monitor therapy.(Bell 2000, McAlindon 2001, Rajoria 2011, Reed 2005)

Calcium channel blockers (dihydropyridines): Melatonin may diminish the antihypertensive effect of calcium channel blockers (dihydropyridines). Monitor therapy.(Lew 1999, Lusardi 2000, Mei 2001)

Cannabis: Cannabis may decrease the serum concentration of CYP1A2 substrates (high risk with inducers). Monitor therapy. This interaction has only been described with smoked cannabis herb (ie marijuana).(Chetty 1994, Gardner 1983, Jusko 1978, Jusko 1979)

Cimetidine: Cimetidine may increase the serum concentration of melatonin. Monitor therapy.(Circadin June 2016)

Citalopram: Citalopram may enhance the sedative effect of melatonin. No action needed.(Foster 2015)

CYP1A2 inducers (moderate): CYP1A2 inhibitors (moderate) may decrease the serum concentration of melatonin. Monitor therapy.(Circadin June 2016, Ursing 2005)

CYP1A2 inhibitors (moderate): CYP1A2 inhibitors (moderate) may increase the serum concentration of melatonin. Monitor therapy.(Circadin June 2016, Hartter 2000, Souetre 1990, Souetre 1989, Souetre 1987)

CYP1A2 inhibitors (strong): CYP1A2 inhibitors (strong) may increase the serum concentration of melatonin. Avoid combination.(Circadin June 2016, Demisch 1987, Demisch 1986, Facciola 2001, Grozinger 2000, Hartter 2000, Skene 1994, Sunami 2012, von Bahr 2000)

Estrogen derivatives: Estrogen derivatives may increase the serum concentration of melatonin. No action needed.(Abernethy 1985, Circadin June 2016, Gardner 1983, O’Connell 2006, Pollock 1999, Tornatore 1982)

Hypnotics (nonbenzodiazepine): Melatonin may enhance the sedative effect of hypnotics (nonbenzodiazepine). Monitor therapy.(Circadin June 2016, Otmani 2008, Suhner 2001)

Imipramine: Melatonin may enhance the adverse/toxic effect of imipramine. Monitor therapy.(Circadin June 2016)

Nortriptyline: Nortriptyline may enhance the sedative effect of melatonin. No action needed.(Foster 2015)()

Oxycodone: Oxycodone may enhance the sedative effect of melatonin. No action needed.(Foster 2015)

Propofol: Melatonin may enhance the therapeutic effect of propofol. Monitor therapy.(Turkistani 2007)

Thioridazine: Melatonin may enhance the adverse/toxic effect of thioridazine. Monitor therapy.(Circadin June 2016)

Tobacco (smoked): Tobacco (smoked) may decrease the serum concentration of melatonin. Monitor therapy.(Facciola 2001, Hartter 2001, Ozguner 2005, Tarquini 1994, Ursing 2005)

Adverse Reactions

Minor adverse reactions associated with melatonin include headache, transient depression, enuresis, dizziness, nausea, stomach cramps, irritability, insomnia, nightmares, hypothermia, and excessive daytime somnolence.(Alagiakrishnan 2016, Relia 2018) Diarrhea has been reported as an adverse effect in clinical trials and a case report.(Amstrup 2015, Grilo-Bensusan 2015) Reducing the dose from 5 mg/day to 1.8 mg/day improved sleep while eliminating persistent diarrhea in a 49-year-old female.(Grilo-Bensusan 2015)

A case of severe hyponatremia in an 80-year-old male was reported as "probably" caused by low-dose melatonin (1 mg/day) recently added to his therapeutic regimen (enalapril, atenolol, chlorthalidone, gliclazide, esomeprazole, atorvastatin, dutasteride, and silodosin).(Famularo 2021)

Long-term use may be associated with suppression of the hypothalamic pituitary axis and the potential for precocious puberty with discontinuation of therapy.(Relia 2018)

Older case reports exist of seizures associated with exogenous melatonin administration. A review of the evidence on melatonin use and seizures found a paucity of relevant data from which to draw firm conclusions, with current evidence suggesting that melatonin has no effect on seizures, neither improvement nor worsening.(Jain 2013)

Short-term administration of melatonin significantly impaired glucose tolerance, especially when administered in the morning. The AUC and C_max 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.(Rubio-Sastre 2014)

Drowsiness may occur 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.(Graw 2001, Otmani 2012)

In 64 Chinese male students, exogenously administered melatonin significantly increased reactive aggression (P=0.038) compared with placebo; it was determined the increased aggression was not attributed to inhibitory ability, sleepiness, or other potential factors (ie, noise perception, emotional states, circadian preference).(Liu 2017)

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.Seabra 2000, Wehr 2001

An analysis of 31 commonly available commercial melatonin supplement products found in grocery stores and pharmacies found melatonin content ranged from 0.37% to 466% of its label claim in more than 71% of the products analyzed. The results were across brands, dose forms, and lot. The largest variation was found in chewable tablets, which showed a 478% increase (almost 9 mg of melatonin compared with 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. Eight (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.Erland 2017 Therefore, health care providers should carefully consider USP-verified products as recommendations are made, ensuring they are of good quality.

References

Disclaimer

This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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