Is melatonin safe for long-term use?

Is Melatonin Safe for Long-Term Use?

Melatonin appears reasonably safe for long-term use at appropriate doses (3-5 mg daily), though the American Academy of Sleep Medicine recommends against routine long-term use for chronic insomnia due to insufficient safety data beyond several months, while acknowledging it may be appropriate for ongoing treatment of specific circadian rhythm disorders. 1, 2

Safety Profile for Short-Term and Long-Term Use

General Safety Evidence

• Melatonin demonstrates a favorable safety profile with no serious adverse reactions documented across age groups, including children. 2, 3
• The most frequently reported adverse effects are mild and self-limiting: daytime sleepiness (1.66%), headache (0.74%), dizziness (0.74%), and nausea. 2, 3
• Most adverse effects resolve spontaneously within days without dose adjustment or immediately upon discontinuation. 3
• A perioperative guideline from the Society for Perioperative Assessment and Quality Improvement concluded that available evidence demonstrates melatonin is safe in the perioperative period. 1

The Long-Term Data Gap

• The critical limitation is that studies addressing long-term effects beyond several months are scarce. 1, 4
• Most clinical trials monitored subjects for 4 weeks or less, with the longest extending to 29 weeks. 3
• The American Academy of Sleep Medicine explicitly states that safety and efficacy in long-term treatment remains unknown due to limited data. 2
• However, systematic reviews of available long-term studies found no difference between exogenous melatonin and placebo in terms of long-term negative effects. 4

Dosing Considerations for Safety

Lower Doses Are Safer and Often More Effective

• Start with 3 mg of immediate-release melatonin, as higher doses (10 mg) may cause receptor desensitization and are associated with more frequent adverse effects like morning headache and sleepiness. 2
• If ineffective after 1-2 weeks, increase by 3 mg increments up to a maximum of 15 mg. 2
• Administer 1.5-2 hours before desired bedtime for optimal effect. 2, 5

Product Quality Concerns

• Melatonin is regulated as a dietary supplement in the U.S., raising significant concerns about purity and reliability of stated doses. 1, 2
• Choose United States Pharmacopeial Convention Verified formulations for more reliable dosing and purity. 1, 2, 5
• Melatonin concentration varies widely between product labels and manufacturers. 4

Special Populations and Precautions

Populations Requiring Caution

• Use with caution in patients taking warfarin due to potential interactions reported to the World Health Organization. 1, 5
• Exercise caution in patients with epilepsy based on case reports. 1, 5
• Avoid in older adults with dementia for irregular sleep-wake rhythm disorder due to lack of benefit and potential harm, including detrimental effects on mood and daytime functioning. 2
• Use caution in patients using photosensitizing medications, with periodic ophthalmological/dermatological monitoring recommended. 5

Metabolic and Psychiatric Considerations

• Melatonin has been associated with impaired glucose tolerance in healthy women after acute administration. 1, 5
• Melatonin has been associated with increased depressive symptoms in some individuals. 1, 5

Pediatric Safety

• The American Academy of Sleep Medicine considers melatonin safe for children ages 6 and older at weight-based dosing: 0.15 mg/kg for children without comorbidities, or 3-5 mg for children with psychiatric comorbidities. 2
• A questionnaire-based study assessing pubertal development in children/adolescents using melatonin (mean dose ~3 mg) for approximately 3 years showed no significant differences in Tanner stages compared to non-users. 2
• Long-term safety data in children is limited, though available evidence is reassuring. 2

Clinical Context: When Long-Term Use May Be Appropriate

Circadian Rhythm Disorders vs. Insomnia

• For specific circadian rhythm sleep-wake disorders (delayed sleep-wake phase disorder, non-24-hour sleep-wake rhythm disorder), melatonin may be used longer-term as these conditions require ongoing chronobiotic therapy rather than short-term hypnotic treatment. 2
• For chronic insomnia used as a hypnotic (rather than circadian rhythm regulator), melatonin has only small effects on sleep latency with little effect on wake after sleep onset or total sleep time. 2

Management Algorithm for Intended Long-Term Use

• For intended long-term use, periodic attempts to reduce frequency and dose are indicated every 3-6 months to minimize side effects and determine lowest effective dose. 2
• Consider tapering frequency (every other or every third night) rather than daily use. 2
• If discontinuing after prolonged use, taper gradually over several weeks to months by lowering dose by smallest increment possible in successive steps of at least several days. 2
• Concurrent cognitive-behavioral therapy increases successful discontinuation rates. 2

Common Pitfalls to Avoid

• Do not assume all melatonin products contain the stated dose—insist on USP Verified formulations. 1, 2, 5
• Do not start with high doses (>5 mg)—lower doses are often more effective and have fewer adverse effects. 2
• Do not use melatonin as first-line treatment for chronic insomnia when the primary issue is not circadian misalignment. 2
• Do not prescribe long-term melatonin to dementia patients for irregular sleep-wake rhythm disorder. 2
• Document concurrent medications before recommending melatonin to review for potential interactions, particularly warfarin, antiepileptics, and photosensitizing medications. 5