What are the long-term risks of prolonged melatonin (melatonin) use in patients with Delayed Sleep Phase Syndrome (DSPS)?

Long-Term Risks of Melatonin for Delayed Sleep Phase Syndrome

Long-term physiologic studies are needed to accurately ascertain any serious chronic risks of melatonin use in DSPS, as current evidence shows generally favorable safety profiles but data beyond several months remain limited, particularly since melatonin supplements are not subject to FDA oversight. 1

Current Evidence on Long-Term Safety

The American Academy of Sleep Medicine's 2015 clinical practice guideline explicitly acknowledges a critical knowledge gap: properly powered long-term studies have not been conducted to identify serious chronic risks of melatonin therapy. 1 This is particularly concerning given that:

• Melatonin is regulated as a dietary supplement rather than an FDA-approved medication, raising significant concerns about purity and reliability of stated doses 1, 2
• Most clinical trial data supporting melatonin use in DSPS lasted 4 weeks or less 2
• Safety data beyond 29 weeks in adults is extremely limited 2, 3

Documented Adverse Effects from Available Studies

Common Short-Term Side Effects

The most frequently reported adverse events in clinical trials include:

• Daytime sleepiness (1.66%) 2, 3
• Headache (0.74%) 2, 3
• Dizziness (0.74%) 2, 3
• Nausea (more frequent with higher doses) 2

Dose-Related Concerns

Higher doses (10mg) are associated with more frequent adverse effects including morning headache, morning sleepiness, and receptor desensitization that may disrupt normal circadian signaling. 2 The American Academy of Sleep Medicine recommends starting with 3mg and titrating in 3mg increments only if necessary, up to a maximum of 15mg. 2

Special Safety Concerns

Specific Populations Requiring Caution

The American Academy of Sleep Medicine identifies particular safety concerns for:

• Children and those of reproductive age - though long-term studies up to 24 months in pediatric populations with autism showed no significant differences in pubertal development (Tanner stages) compared to non-users 2, 4
• Patients taking warfarin - potential interactions have been reported to the World Health Organization 1, 5
• Patients with epilepsy - use with caution based on case reports 1, 5
• Patients with metabolic concerns - melatonin has been associated with impaired glucose tolerance in healthy individuals after acute administration 2, 5

Mood and Psychiatric Effects

Melatonin has been associated with increased depressive symptoms in some individuals, requiring monitoring for mood alterations. 5

Practical Management Algorithm for Long-Term Use

Initial Treatment Phase

• Start with 3mg immediate-release melatonin taken 1.5-2 hours before desired bedtime 2
• Choose United States Pharmacopeial Convention Verified formulations for reliable dosing and purity 2, 5
• Assess response after 1-2 weeks 2

Ongoing Monitoring

For intended long-term use, periodic attempts to reduce frequency and dose are indicated to minimize side effects and determine lowest effective dose. 2 Specifically:

• Reassess need for continued therapy every 3-6 months 2
• Consider tapering frequency (every other or every third night) rather than daily use 2
• Monitor for enhanced sedation, changes in blood pressure, and mood alterations 5
• If metabolic concerns exist, monitor fasting glucose periodically 5

Treatment Duration Considerations

The American Academy of Sleep Medicine recommends against long-term use of melatonin for chronic insomnia beyond 3-4 months due to insufficient safety data. 2 However, for specific circadian rhythm disorders like DSPS, melatonin may be used longer-term as these conditions require ongoing chronobiotic therapy rather than short-term hypnotic treatment. 2

Critical Caveat: Relapse Rates

A significant practical concern from long-term follow-up data: 91.5% of DSPS patients reported relapse to pretreatment sleeping patterns within 1 year of ending melatonin treatment. 6 This suggests that:

• DSPS may require indefinite treatment rather than time-limited therapy 1
• Discontinuation should be attempted at least once yearly (preferably during summer holidays) to reassess need 4
• Combined treatment with bright light therapy may help maintain benefits over time 7

Product Quality Concerns

A major safety concern is that melatonin supplements are not subject to FDA oversight, leading to significant variability in purity and actual melatonin content between products. 1, 2 This creates potential for:

• Inconsistent dosing between brands 2
• Contamination with unlabeled substances 2
• Variable efficacy that may be mistaken for treatment failure 1

Bottom Line for Clinical Practice

While no life-threatening or major clinically significant adverse events have been identified in available studies 3, the scarcity of evidence from long-term randomized controlled trials limits definitive conclusions regarding safety of continuous melatonin therapy over extended periods. 3 The American Academy of Sleep Medicine explicitly states that research is needed to determine whether treatments are required indefinitely or can be discontinued. 1

For DSPS specifically, the balance favors cautious long-term use with regular monitoring, given that the condition itself significantly impairs quality of life and typically requires ongoing chronobiotic therapy. 2