What is the recommended starting dose and titration schedule for extended‑release melatonin in healthy adults and in older adults (≥65 years) or those with mild cognitive impairment?

Extended-Release Melatonin Dosing

For healthy adults, start with 3 mg of immediate-release melatonin rather than extended-release formulations, as extended-release has shown no advantage over immediate-release for sleep disorders and may be less effective for sleep onset. 1, 2

Dosing for Healthy Adults

• Start with 3 mg immediate-release melatonin taken 1.5-2 hours before desired bedtime 1
• If ineffective after 1-2 weeks, titrate upward in 3 mg increments to a maximum of 12-15 mg 1, 3
• Avoid extended-release formulations as they appear less effective than immediate-release for sleep onset issues 1
• Lower doses (0.1-3 mg) may be more effective than higher doses due to potential receptor desensitization and saturation at doses ≥10 mg 3

The American Academy of Sleep Medicine explicitly recommends against extended-release formulations for most sleep disorders in healthy adults, as immediate-release formulations more effectively address sleep onset latency. 1, 2 Extended-release melatonin was designed to mimic physiologic melatonin profiles, but clinical evidence does not support superiority over immediate-release preparations. 2

Dosing for Older Adults (≥65 years)

• For elderly patients, start with 1-2 mg immediate-release melatonin taken 30-60 minutes before bedtime 4
• If specifically using extended-release formulation, use 2 mg prolonged-release melatonin, which has shown significant reduction in sleep latency in patients aged 65-80 years 1, 4
• Evaluate effectiveness after 3 weeks of consistent use 4
• Maximum studied doses range from 1-6 mg, with no clear dose-response relationship established 5

The rationale for lower starting doses in elderly patients is to mimic normal physiological circadian rhythm while avoiding prolonged blood levels that extend into morning hours. 4 Older adults may exhibit altered melatonin disposition, and pharmacokinetic studies show that even low doses (0.4 mg) can maintain elevated melatonin levels for extended periods. 6

Dosing for Mild Cognitive Impairment

• Start with 1-2 mg immediate-release melatonin taken before bedtime 4
• Higher doses up to 25 mg have been studied in MCI populations and were well-tolerated, though efficacy data remains limited 7
• The American Academy of Sleep Medicine suggests against melatonin for irregular sleep-wake rhythm disorder in older adults with dementia due to lack of benefit and potential for detrimental effects on mood and daytime functioning 3

A 2024 feasibility trial in MCI patients used 25 mg nightly for 12 weeks with good tolerability, though no significant efficacy differences were found compared to placebo. 7 However, this high dose is not recommended for routine clinical practice given the lack of demonstrated benefit and potential for receptor desensitization. 3

Titration Schedule

• Assess response after 1-2 weeks using sleep diaries tracking sleep latency, total sleep time, and night awakenings 1
• If no improvement and no adverse effects, increase by 3 mg increments 1, 3
• Do not exceed 12-15 mg as higher doses increase risk of morning grogginess, headache, and receptor desensitization 1, 3
• If morning grogginess occurs, reduce dose rather than switching formulations 3

Treatment Duration

• Limit treatment to 3-4 months maximum for chronic insomnia due to insufficient long-term safety data 3
• Reassess need for continued therapy every 3-6 months 3
• For circadian rhythm disorders (not primary insomnia), longer-term use may be appropriate 3
• When discontinuing after prolonged use, taper gradually over several weeks to minimize rebound insomnia 3

Important Clinical Caveats

• Extended-release formulations provide no clinical advantage over immediate-release for most sleep disorders and may be less effective for sleep onset 1, 2
• Pharmacokinetic data shows extended-release melatonin (4 mg) maintains elevated levels (>300 pg/mL) for 6 hours, with longer time to peak (1.56 vs 0.6 hours) and elimination half-life (1.63 vs 0.95 hours) compared to immediate-release 8
• Use caution in patients taking warfarin or those with epilepsy due to potential interactions 1, 4
• Choose United States Pharmacopeial Convention Verified formulations when possible, as melatonin is regulated as a dietary supplement with variable quality control 4, 3
• The American Academy of Sleep Medicine provides only a weak recommendation against melatonin for primary insomnia in adults due to minimal effects on sleep latency, total sleep time, and sleep quality 9, 1
• Morning grogginess and "hangover" effects are more common with higher doses and extended-release formulations due to prolonged blood levels 3