Melatonin

Clinical study of melatonin continues to elucidate the role of melatonin in a variety of neurologic, hormonal, gastrointestinal, and neoplastic disorders The effects of melatonin as a hormone were first noted in 1917, when dark-skinned tadpoles fed a pineal gland extract were noted to develop lighter skin. Melatonin was isolated from the pineal gland in 1958. Commercial melatonin products are primarily synthesized from 5-methoxyindole; rarely, commercial products are derived from animal (bovine) pineal glands. Use of animal based melatonin products is not recommended due to the potential risk of contamination from animal-based infectious prions and viruses, which may cause serious illness. Oral melatonin is included in the Natural Health Products ingredients/monograph database for Health Canada.1 In Europe, melatonin is available by prescription only under the brand name Circadin, which is marketed as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.2 The American Sleep Disorder Association considers melatonin an experimental drug and does not recommend its use without medical supervision. Melatonin has been classified as an orphan drug by the U.S. Food and Drug Administration (FDA) since 1993 for circadian rhythm sleep disorders in blind patients who have no light perception, a condition often known as non-24-hour sleep-wake disorder (non-24), a condition that occurs when the blind patient cannot synchronize their circadian rhythms to a light-dark cycle. In 2013, an additional orphan drug designation was granted by the FDA for the use of melatonin for the treatment of neonatal hypoxic ischemic encephalopathy. Melatonin is also available over the counter in the U.S., and products are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA).

NOTE: In the US, nutraceuticals are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA). Consequently, scientific data supporting claimed benefit(s) are not always available for nutraceuticals as they are for traditional pharmaceuticals since nutraceuticals are not regulated as drugs. Consumers should also note that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products.

Synthesis and secretion of endogenous melatonin is controlled by enzymes secreted by the hypothalamus which are activated by darkness and depressed by environmental light. Exactly how melatonin induces sleep is not clear, but it is probably not through a direct hypnotic effect. In patients with jet lag or circadian rhythm disorders, endogenous melatonin secretion does not correspond to the social or solar sleep-wake cycles imposed by their surroundings, and they experience sleep disruption. Administration of exogenous melatonin appears to re-set the body to the environmental clock and allow patients to normalize physiologic and behavioral sleep patterns. Exogenous melatonin maximally advances delayed rhythms when administered before endogenous melatonin levels begin to increase in the evening hours. In addition to circadian phase-shifting effects, melatonin has been shown to decrease nocturnal core body temperature, which helps to facilitate sleep. To date, pharmacological tolerance to melatonin has not been described.

Melatonin is involved in other physiologic processes besides the sleep-wake cycle. Secretion of melatonin from the pineal gland is highest during the pediatric years and tends to decrease with age. This age-related secretion performs important endocrine functions. It is thought that higher pre-pubertal melatonin levels are responsible for keeping the hypothalamic-pituitary-gonadal axis in quiescence, and that decreasing melatonin levels with age play a role in the onset of adolescence and sexual maturation. Melatonin receptors have been found in all male and female sexually responsive tissues, indicating that melatonin has a significant role in normal reproductive capacity. Exogenous melatonin can suppress the release of gonadotropin releasing hormone and lutenizing hormone, leading to anovulation and changes in steroid responsive tissues, especially in higher doses. Contraceptive activity has been noted when women are given melatonin in combination with norethindrone.

Melatonin also exhibits immunostimulatory and antioxidant actions. In neurodegenerative disease models, melatonin appears to neutralize oxidizing free radicals, specifically by preventing the reduction of antioxidant enzyme activity, and reducing beta-amyloid mediated lipid peroxidation of cell membranes. These actions appear to decrease apoptosis of neuronal cells. Further research is needed to determine if melatonin may preserve function in neurologic diseases where free radicals have been implicated as partially causative of the conditions. In epilepsy, the rise and fall of endogenous melatonin levels may influence seizure activity. Melatonin may play a role in certain cancers, and in some cases, may have antiproliferative effects on some tumors. The actions and role of melatonin in other body processes, such as regulation of the gastrointestinal system, continues to be investigated. Melatonin may also stimulate the activity of natural killer (NK) cells, lymphocytes, and various cytokines. Further study in well-controlled trials should answer further questions regarding melatonin’s neurologic, immunologic, and oncostatic activities.

Melatonin administration follows a different pharmacokinetic profile than that of the endogenous hormone. Melatonin crosses the blood-brain barrier, and also traverses the placenta in pregnancy. Some accumulation of melatonin in fat tissue may occur with prolonged daily administration. The primary metabolic pathway occurs via the liver via oxidative metabolism via CYP1A (isoenzymes CYP1A2 and CYP1A1), with minor roles by CYP2C19 and possibly CYP2C9. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. Elimination of melatonin is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as unchanged, active melatonin. The mean elimination half-life (T1/2) after oral administration of immediate-release melatonin is roughly 45 minutes; with intravenous administration, the half-life is approximately 28 minutes.3 The terminal half-life is 3.5 to 4 hours and the excretion of the primary metabolite is completed within 12 hours following a single oral dose of an extended-release product.2

Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP1A1

Melatonin is primarily and predominantly metabolized by CYP1A2, with some metabolism by CYP1A1, CYP1B1, and minor contributions by CYP2C9 and CYP2C19.[40912] [57065] Melatonin may exhibit significant interactions with potent CYP1A2 inhibitors, such as fluvoxamine.[26229] Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations only; the clinical relevance of the finding is unknown.2

• Route-Specific Pharmacokinetics

Oral Route

After oral administration, melatonin undergoes significant first-pass hepatic metabolism to 6-sulfaoxymelatonin, producing a melatonin bioavailability averages 15% (range: 9—33%); the time to maximum concentrations (Tmax) averages 50 minutes (range: 15 minutes to 210 minutes). Sublingual and oral spray delivery systems may result in greater melatonin bioavailability due to less first-pass metabolism.3 The presence of food appears to delay the time to maximal absorption and lowers maximal concentration, so bedtime doses should be taken without food.2

• Special Populations

Hepatic Impairment

Melatonin is primarily and predominantly metabolized by oxidative hepatic metabolism. Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin (the major, inactive metabolite) compared with controls.2

Renal Impairment

The effect of any stage of renal impairment on melatonin pharmacokinetics has not been sufficiently studied.2 In patients with normal renal function, a minimal amount of melatonin is excreted unchanged in the urine. A clinical study in patients with renal impairment indicated there is no accumulation of melatonin after repeated daily dosing of 2 mg oral doses at bedtime.2

Geriatric

Melatonin metabolism is known to decline with age. Across a range of doses, higher exposure (AUC) and maximal concentrations (Cmax) have been reported in older patients compared to younger patients, reflecting the lower metabolism of melatonin in the elderly. The Cmax levels are approximately 500 pg/mL and the AUC 3000 pg x h/mL in younger adults versus a Cmax of approximately 1200 pg/mL and an AUC approximately 5000 pg x h/mL in elderly patients age 55 to 69 years.2

Gender Differences

A 3- to 4-fold increase in maximal concentration (Cmax) is apparent for adult women compared to men. However, no pharmacodynamic differences between males and females were found despite differences in blood levels.2

Other

Smoking

Patients who are tobacco smokers have increased melatonin clearance due to the induction of CYP1A2 by tobacco.3 2

Critically Ill patients

Critically ill patients appear to have altered melatonin absorption and clearance.3

In the same analysis, meta-regression showed that trials using higher melatonin doses reported significantly greater effects on total sleep time, and a trend towards greater effects on sleep latency (p = 0.05). Sleep quality was not affected by higher doses.5 Melatonin is considered the first-choice treatment when a hypnotic is indicated in patients over 55 years of age according to the British Association for Psychopharmacology consensus on evidence-based treatment of insomnia, parasomnia, and circadian rhythm sleep disorders.6 One product, Circadin, is approved in the Europe at a dose of 2 mg PO once daily, given 1 to 2 hours before bedtime and after food; dosing may be continued for up to 13 weeks.2

Sublingual dosage (e.g., quick dissolve tablets for sublingual use; other sublingual tablets):

Adults: 0.5 to 10 mg sublingually before bedtime as needed. Most manufacturers recommend that the dose be placed under the tongue for 30 seconds before swallowing. Doses should generally be taken 30 minutes to 1 hour before bedtime. Use as directed on individual product labels.7 Some studies have shown that melatonin doses of 0.3 to 1 mg produce physiological melatonin levels in the circulation; however, in most studies, higher doses (2 mg or more) are needed to obtain beneficial sleep effects.4 Max: 10 mg/day sublingually. In a meta-analysis evaluating melatonin in primary sleep disorders, melatonin demonstrated a significant benefit in reducing sleep latency, increasing total sleep time, and improving sleep quality compared to placebo.5 Melatonin is considered the first-choice treatment when a hypnotic is indicated in patients over 55 years of age according to the British Association for Psychopharmacology consensus on evidence-based treatment of insomnia, parasomnia, and circadian rhythm sleep disorders.6

• for the adjunctive treatment of insomnia† related to major depressive disorder (MDD):

Oral dosage:

Adults: 5 to 10 mg PO prior to bedtime. In a 4-week placebo-controlled study of 19 patients with major depressive disorder treated with fluoxetine, the 10 patients who received concomitant slow-release melatonin at 9 PM for sleep reported significantly improved sleep quality scores vs. those receiving fluoxetine alone. Use of melatonin avoided the need for additional hypnotics. No differences in improvement of depressive symptoms or side effects were reported between the 2 groups.8

For the treatment of jet-lag†:

Oral or Sublingual dosage (immediate release formulations):

Adults: 3 to 6 mg PO or sublingually (follow product label instructions) taken nightly at 2200 to 2400 hours local time after destination arrival may help adaptation to different time zones. Melatonin may be administered for up to 5 nights as needed. Treatment may not completely eliminate all jet-lag symptoms.9 More study is needed.

For the treatment of non-24-hour sleep-wake disorder† and related circadian rhythm sleep disorders† in blind individuals without light perception:

NOTE: Melatonin has been designated as an orphan drug by the FDA for this indication.

Oral dosage (delayed-release product, Circadin):

Adults: Circadin delayed-release melatonin 2 mg PO once nightly at bedtime. Circadin is an approved drug in Europe for the treatment of insomnia in older adults 2; the product has been designated an orphan drug by the FDA for Non-24. In a small pilot study, 13 totally blind subjects living in normal social environments were randomized to receive either Circadin delayed-release melatonin 2 mg PO once nightly at bedtime or placebo for 6 weeks. Active treatment followed 2-weeks of placebo run-in, and active treatment was followed by 2 weeks of placebo for discontinuation. The primary endpoint was demonstration of clinically meaningful effects on sleep duration (upper confidence interval [CI] limit more than 20 minutes). Outcome measures included daily voice recorded sleep diary, quality of life measures, and safety. The mean nightly sleep duration improved by 43 minutes in the melatonin delayed-release group and 16 minutes in the placebo group (mean difference: 27 minutes, 95% CI: -14.4 to 69 minutes; p = 0.18; effect size: 0.82) and met the primary endpoint. Mean sleep latency decreased by 29 minutes with melatonin over placebo (p = 0.13; effect size: 0.92) and nap duration decreased in the melatonin but not in the placebo group. The effects of melatonin persisted during the 2 week discontinuation period. Adverse events were mild or moderate and similar between melatonin and placebo. A larger study powered to demonstrate a significant effect is warranted.[60058]

Oral or Sublingual dosage (immediate-release dosage forms marketed as dietary supplements):

Adults: 5 to 10 mg PO or sublingually (follow product label instructions) once daily at bedtime has been used in the blind to entrain circadian rhythms to a 24-hour day and improve sleep patterns.[25465] 10 Once the patients sleep patterns are entrained, doses have been slowly reduced over a 3-month period to a maintenance dosage of 0.5 mg PO at bedtime.10

For the treatment of various sleep disorders due to circadian rhythm disruption†, including delayed sleep phase syndrome†:

• for the treatment of circadian rhythm disruption† secondary to environmentally imposed alterations in sleep schedules (e.g., rotating-shift work†) in adults:

Oral or Sublingual dosage (immediate-release dosage forms):

Adults: 5 to 10 mg PO or sublingually (follow specific product directions) taken at 7 AM or 8 AM prior to daytime sleep periods, or similar doses taken 2 hours prior to bedtime at night have been used. Melatonin may subjectively improve sleep quality or wake-time alertness in short-term (4 to 6 days) use.9 Clinical improvements in the duration of sleep or waking cognitive performance have not been proven.11

• For the treatment of various sleep disorders in pediatric patients due to circadian rhythm disruption†, including delayed sleep phase syndrome†, such as occurs with ADHD, autism spectrum disorders (ASD), developmental disabilities, or other neuro-psychiatric conditions:

Oral or Sublingual dosage (immediate-release dosage forms):

Children and Adolescents: 2 to 5 mg PO or sublingually (follow specific product instructions) at bedtime is initially recommended. Doses as high as 10 mg at bedtime have been used after titration. Range: 0.3 to 10 mg PO at bedtime. Sleep usually occurs within 1 hour of administration and the supplement has been well tolerated. Several small, randomized controlled trials of short-duration (1 to 5 weeks) suggest the efficacy and relative safety in regulating sleep patterns in pediatric patients with autism spectrum disorders (ASD) and various neurologic conditions; however, experts agree larger studies are needed and that long-term effects of use in pediatric patients are unknown.9 12 [60024] [61149]

For the treatment of persistent, bothersome, idiopathic tinnitus†:

Oral or Sublingual dosage (immediate-release dosage forms):

Adults: Dosage and efficacy not established. 3 mg PO or sublingually (follow specific product label) at bedtime is the most frequently used dose. Clinical guidelines recommend against the use of melatonin for treating patients with persistent, bothersome tinnitus based on trials and systematic reviews with methodological concerns and with a bias for assessing benefit over harm.13 Another study demonstrated potential benefit for patients with concomitant sleep disturbance due to tinnitus, but the study lacked randomization, blinding, or placebo control.14 One small double-blind, placebo-controlled, crossover trial reported a 26% improvement in tinnitus and related symptoms with melatonin treatment vs. placebo as assessed by rating scales and subjective interviews at 30-days in an outpatient neurology clinic; adverse effects included bad dreams and fatigue.15

Maximum Dosage Limits

No specific maximum dosage information is available; the following are general guidances from the published literature.

• Adults

10 mg/day PO for insomnia.

• Geriatric

10 mg/day PO for insomnia.

• Adolescents

Safety and efficacy have not been established.

• Children

Safety and efficacy have not been established.

• Infants

Not indicated.

• Neonates

Not indicated.

Patients with Hepatic Impairment Dosing

Patients with hepatic impairment are recommended to consult their health care provider prior to melatonin use. Melatonin is primarily metabolized by oxidative hepatic metabolism. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, exogenous use of melatonin is not recommended in patients with hepatic impairment.2

Patients with Renal Impairment Dosing

Specific guidelines for dosage adjustments in renal impairment are not available at this time; use with caution due to lack of sufficient pharmacokinetic and clinical data. In one study, the use of mutliple days of bedtime doses (2 mg) did not result in accumulation in patients with renal impairment.2

†Off-label indication

Route-Specific Administration

Oral Administration

Because the presence of food delays absorption, oral bedtime doses are recommended to be taken after, but not with, evening meals, and approximately 1 to 2 hours before bedtime.2

Following administration of melatonin to promote sleep, patients should confine their activities to those necessary to prepare for bed.

Including melatonin.16 Impurities may cause allergic reactions or side effects. While melatonin supplements and pharmaceuticals are now almost exclusively produced synthetically, there may be available melatonin supplements derived from the pineal glands of beef cattle, and these should be avoided by those with bovine protein hypersensitivity. The use of animal-source melatonin products is also not recommended due to a potential risk of exposure to infection (e.g., bovine spongiform encephalopathy, also known as “mad cow disease”) or other contamination.17 18

Patients who develop angioedema, hypersensitivity or other serious allergic-type events due to melatonin should not be rechallenged with the dietary supplement.2 1 Patients with asthma should seek health care professional advice prior to melatonin use, as melatonin may play a role in the expression of asthma symptoms.1

Melatonin may cause drowsiness. Driving or operating machinery, or performing other tasks that require mental alertness should be avoided after ingestion of melatonin; patients should confine their activities to those necessary to prepare for bed. Sedation occurring after melatonin use during waking hours may indicate excessive dosage.[25471] Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use and have been reported in the use of melatonin analogs.19 The use of alcohol and other CNS depressants may increase the risk of such behaviors. Patients should also be advised to avoid ethanol ingestion in combination with melatonin as additive effects may occur. Discontinuation of melatonin should be considered for a patient who reports any complex sleep behavior.

Exogenous melatonin should be used with caution in patients with hepatic disease and should be avoided in patients with severe hepatic impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment.2 Patients with hepatic disease should consult their health care provider prior to the use of melatonin.

Melatonin acts on the central nervous system and has sedative effects. Melatonin should be used with caution when patients are being treated for a psychiatric condition or neurological disease, such as a seizure disorder, by a health care professional, particularly if they are on prescription medication for such problems; seizures have been reported as a potential adverse effect of melatonin use.120 Melatonin is not recommended for people who are on prescribed neurologic, psychotropic, or hypnotic medications without the supervision of a qualified health care professional. The failure of insomnia to remit after 7 to 10 days of self-treatment or within 4 weeks of prescription melatonin use may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Exacerbation of insomnia and emergence of cognitive and behavioral abnormalities have been seen with melatonin analogs and other hypnotics in clinical use. In primarily depressed patients, worsening of depression (including suicidal ideation and completed suicides) have been reported in association with the use of various hypnotics. As with other melatonin analogs, the emergence of any new changes in mood, cognition, or behavior in a patient taking melatonin requires further evaluation of the patient.19

Patients who are undergoing treatment for certain conditions should not use melatonin without a health professional’s supervision due to the potential role of melatonin in hormonal, cellular, and immunomodulatory functions. For example, melatonin appears to influence insulin, glucose, lipid metabolism and antioxidant capacity and thus melatonin supplements may influence glycemic control in patients with diabetes mellitus. Patients with diabetes should monitor their blood sugar. Patients with various other types of endocrine disease should get approval of their health care provider prior to use. There is also evidence that melatonin influences the regulation of certain types of cancer, and until these effects are more fully understood, patients with breast cancer or other neoplastic disease should only use melatonin with the approval of their cancer specialist. Melatonin is not recommended for use in patients with autoimmune disease or a history of organ transplant due to lack of clinical data and a lack of interaction data with drugs used to treat these conditions.2 1

As a hormone, melatonin modulates steroid hormone actions, including those in reproductive and mammary tissues. Melatonin and melatonin analogs have been associated with an effect on reproductive hormones in adults (e.g., decreased testosterone levels and increased prolactin levels). It is not known how chronic or intermittent chronic use of melatonin affects reproductive risk or development in males or females.19 Melatonin appears to have important in the regulation of sperm counts, and also has effects related to ovulation in females. Until more is known about its effects on fertility, male and female patients with infertility and those patients who are trying to conceive should avoid melatonin unless their prescriber recommends supplementation.

Melatonin should be considered to be contraindicated in pregnancy at this time.1 In pregnant women, endogenous melatonin crosses the placenta and enters the fetal circulation, and appears to be responsible for setting circadian rhythm influences in utero. Melatonin receptors in the fetus are widespread in both central and peripheral tissues from the third week of fetal development. The administration of exogenous melatonin could potentially disrupt circadian entrainment and other pineal gland influences.21 Thus, fetal exposure to exogenous melatonin use in the mother may be of concern. Effects in non-clinical animal studies of melatonin were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use; however, the data are limited.2 In animal studies, ramelteon, a melatonin analog, produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose.19 The potential effects of melatonin on the duration of labor and/or obstetric delivery, for either the mother or the fetus, have not been studied. Melatonin has no established use in labor and delivery.

Melatonin should generally be avoided in women who are breast-feeding their infants.2 1 Reports describing the use of melatonin dietary supplements in women who are breast-feeding are lacking; however, it is likely to be excreted in human milk. Endogenous melatonin passes into human milk and concentrations have been measured in the breast-milk of lactating women; the results coincided with the women’s daily circadian rhythm of melatonin with undetectable levels during the day and high levels at night.22

Safety and efficacy of melatonin have not been established in pediatric patients under 18 years of age.2 Due to a lack of scientific data and an unknown potential for side effects, melatonin should not be used in infants or very young children. Further study is needed to determine if melatonin may be used safely in pre-pubescent and pubescent pediatric patients. Several small, randomized controlled trials suggest the efficacy and relative safety of short-term supplemental melatonin in treating insomnia in children who have autism spectrum disorders (ASD) and other neurologic disorders; however, experts agree larger studies are needed.[60024] 9 12 Melatonin and melatonin analogs have been associated with an effect on reproductive hormones in adults (e.g., decreased testosterone levels and increased prolactin levels). It is not known what effect chronic or intermittent chronic use of melatonin would have on the reproductive and gonadal function of pre-pubescent or pubescent pediatric patients.19 Education regarding proper sleep hygiene and establishing developmentally appropriate and consistent bedtime schedules are first-line interventions for any child.[60024] Caregivers are encouraged to seek the advice of the health care provider prior to the use of melatonin in children.

Prolonged sedation and drowsiness during waking hours have been noted; patients experiencing excessive drowsiness during waking hours following melatonin use at bedtime may need to consume a lower bedtime dosage. One study reported that subjective drowsiness from melatonin may affect attention and concentration while driving; patients should determine how melatonin affects them before participating in activities requiring alertness.[25471] Other CNS and psychiatric adverse reactions include dizziness, abnormal dreams, unspecified sleep disturbances, nightmares, and seizures in the published literature.[60032] 20 In primarily depressed patients, worsening of depression (including suicidal ideation) have been reported. Hallucinations, as well as behavioral changes such as bizarre behavior, anxiety, agitation, and mania have been reported with the use of melatonin analogs.19 Neuro-psychiatric symptoms may occur unpredictably. Complex sleep-related behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use, including melatonin analogs.19 The use of alcohol and other hypnotics should be avoided when possible since these may increase the risk of such symptoms. Somnambulism (sleep walking) has been reported when melatonin was used in conjunction with zolpidem.[60032] As with other melatonin analogs, the emergence of any new changes in mood, cognition, or behavior requires further evaluation of the patient. Discontinuation of melatonin should be considered for patients who report any complex sleep behavior, worsening depression, or any other unusual changes in moods or behaviors. During excessive melatonin dosage (e.g., 24 to 30 mg of ingestion), impaired cognition, lethargy, disorientation, short-term amnesia, acute psychosis and confusion have been reported.23 24 In these cases, the temporal association of melatonin ingestion to the clinical course of the patients supported melatonin as the causative agent.

Gastrointestinal (GI) adverse effects of melatonin appear to be infrequent with a few days of use. Much less is known regarding the long term administration of this hormone. Most clinical trials have involved <= 6 months of daily melatonin administration. Infrequent or rare GI adverse reactions reported in the published literature include abdominal pain, dyspepsia, pyrosis (heartburn), nausea, vomiting, constipation, flatulence, and difficulty swallowing.20 [60032]

Melatonin may rarely cause allergic or dermatologic reactions. Rash (unspecified), including fixed drug eruptions and exanthema, with or without pruritus, have been reported after melatonin administration. Other reported dermatologic effects include hyperhidrosis (increased sweating) and hot flashes.[60032] Rarely, angioedema and anaphylactoid reactions have been reported with the melatonin analog, ramelteon; however, no reports of such reactions to melatonin are found in the published literature.19 A report of “difficulty swallowing and breathing” was reported in one clinical study of melatonin for jet lag; this might have represented an allergic response.[60032] Patients experiencing a serious allergic reaction to melatonin should discontinue the agent and not be rechallenged.

Cardiovascular (CV) adverse effects of melatonin appear to be infrequent or rare with a few days of use. Much less is known regarding the long term administration of this hormone. Most clinical trials have involved <= 6 months of daily melatonin administration. Infrequent or rare CV reactions reported in the published literature include palpitations and sinus tachycardia.[60032]

One case report exists in the literature describing a temporal association of melatonin use for insomnia with the development of autoimmune hepatitis confirmed by liver biopsy. Discontinuation of the melatonin and the administration of corticosteroid therapy resulted in symptomatic and clinical improvements.25 A case of autoimmune hepatitis has been reported in the literature due to ramelteon, a melatonin agonist.26

Adverse events reported with melatonin appear to be infrequent or rare with a few days of use. Much less is known regarding the long term administration of this hormone. Most clinical trials have involved <= 6 months of daily melatonin administration. Infrequent or rare general adverse reactions reported in the published literature include naso-pharyngitis, arthralgia, and swelling of the arms/legs (fluid retention) following air travel.

11. Jorgensen KM, Witting MD. Does exogenous melatonin improve day sleep or night alertness in emergency physicians working night shifts? Ann Emerg Med 1998;31:699-704.

12. McArthur AJ, Budden SS. Sleep dysfunction in Rett Syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol 1998;40:186-92.

13. Tunkel DE, Bauer CA, Sun GH, et al. Clinical practice guideline: tinnitus. Otolaryngol Head Neck Surg. 2014;151(2 Suppl):S1-S40.

14. Megwalu UC, Finnell JE, Piccirillo JF. The effects of melatonin on tinnitus and sleep. Otolaryngol Head Neck Surg. 2006;134:210-213.

15. Rosenberg SI, Silverstein H, Rowan PT, et al. Effect of melatonin on tinnitus. Laryngoscope 1998;108:305-10.

16. Williamson BL, Tomlinson AJ, Mishra PK, et al: Structural characterization of contaminants found in commercial preparations of melatonin:similarities to case-related compounds from L-tryptophan associated with eosinophilia-myalgia syndrome. Chem

17. Naylor S, Gleich GJ. Over-the-counter melatonin products and contamination. Am Fam Physician. 1999;59:284, 287-8.

18. Norton SA. Raw animal tissues and dietary supplements. N Engl J Med 2000;343:304–305.

19. Rozerem (ramelteon) package insert. Lincolnshire, IL: Takeda Pharmaceuticals; 2010 Nov.

20. Waldron DL, Bramble D, Gringras P: Melatonin: Prescribing practices and adverse events. Arch Dis Child 2005;90(11):1206-1207.

21. Davis FC. Melatonin: role in development. J Biol Rhythms 1997;12:498-508.

22. Illnerova H, Buresova M, Presl J. Melatonin rhythm in human milk. J Clin Endocrinol Metab 1993;77:838—41.

23. Holliman BJ, Chyka PA. Problems in assessment of acute melatonin overdose. South Med J 1997;90:451-3.

24. Force RW, Hansen L, Bedell M. Psychotic episode after melatonin. Ann Pharmacother 1997;31:1408.

25. Hong YG, Riegler JL. Is melatonin associated with the development of autoimmune hepatitis? J Clin Gastroenterol 1997;25:376-8.

26. Fourman LT, Robert Meyer B. Autoimmune hepatitis in association with ramelteon. J Clin Gastroenterol. 2013 Apr 29.