Indications

For the self-treatment of mild insomnia†:

Oral dosage: Adults: 0.3 to 10 mg PO before bedtime as needed. Doses usually should be taken 30 minutes to 1 hour before bedtime. Use as directed on individual product labels. Doses of 0.3 to 1 mg appear to produce physiological melatonin levels in the circulation; however, in most studies, higher doses (2 mg or more) are needed to obtain beneficial effects.(4) Max: 10 mg/day PO. 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. 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.

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.(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 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)

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 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.