What is the evidence behind the use of melatonin for sleep disorders?

Evidence Behind Melatonin for Sleep Disorders

The evidence for melatonin varies substantially by sleep disorder type and patient population, with the strongest support for circadian rhythm disorders and specific pediatric populations, while showing limited or negative evidence for common insomnia in older adults with dementia. 1

Circadian Rhythm Sleep-Wake Disorders

Children and Adolescents with Neurologic Disorders

• The American Academy of Sleep Medicine suggests using strategically timed melatonin (2-10 mg administered 1 hour before planned bedtime) for irregular sleep-wake rhythm disorder (ISWRD) in children/adolescents with neurologic disorders. 1
• Evidence shows improvements in total sleep time and sleep onset latency, though confidence intervals crossed predetermined thresholds for clinically significant change (MODERATE level evidence). 1
• This recommendation is based on a double-blind randomized controlled crossover trial in 16 children with autism spectrum disorder. 1
• Long-term safety data in pediatric populations remain limited despite no serious adverse reactions reported to date. 1

Older Adults with Dementia and ISWRD

• The American Academy of Sleep Medicine suggests clinicians AVOID melatonin for ISWRD in older people with dementia. 1
• Multiple well-designed trials failed to show improvement in total sleep time compared to placebo. 1
• One study demonstrated detrimental effects on mood and daytime functioning despite some sleep improvements. 1
• The risk-benefit ratio suggests potential harms outweigh possible benefits in this population (LOW level evidence). 1

Advanced Sleep-Wake Phase Disorder (ASPD)

• Data supporting melatonin efficacy in ASPD is lacking. 1
• Morning melatonin administration may theoretically delay sleep phase but can produce problematic soporific effects causing residual morning sleepiness. 1

REM Sleep Behavior Disorder

• The American Academy of Sleep Medicine recommends immediate-release melatonin (3-12 mg) as an evidence-based treatment for isolated REM sleep behavior disorder in adults. 1, 2
• Studies demonstrated clinically significant improvements in dream enactment and vocalization episode frequency (LOW certainty evidence due to imprecision and observational study bias). 1
• Benefits outweigh risks, with relatively small medication costs compared to potential high costs of injury from dream enactment. 1

Important Caveat on Melatonin Formulations

• Melatonin is not FDA-regulated in the United States, leading to potential variability in efficacy between brands. 1
• Products labeled with the U.S. Pharmacopeia Verification Mark provide the most consistent dosing among currently available options. 1, 3

General Dosing Recommendations

By Age Group

• Children: 0.5-3 mg 4
• Adolescents: 3-5 mg (generally avoid exceeding 5 mg) 3, 4
• Adults: 1-5 mg 4
• Elderly: 1-6 mg 4

Timing and Administration

• Start with 3 mg immediate-release melatonin taken 1.5-2 hours before desired bedtime. 3
• Lower doses (3 mg) are often more effective than higher doses (10 mg), which may cause receptor desensitization or saturation. 3
• If ineffective after 1-2 weeks, increase by 3 mg increments. 3

Safety Profile

Common Adverse Events

• Daytime sleepiness (1.66%), headache (0.74%), dizziness (0.74%), and hypothermia (0.62%) are most frequently reported. 5
• Most adverse events resolve spontaneously within days or immediately upon withdrawal. 5
• No life-threatening or major clinically significant adverse events identified in systematic reviews. 5

Specific Concerns

• Melatonin has been associated with impaired glucose tolerance in healthy women after acute administration. 3
• Potential for both hypotension and hypertension at higher doses. 3
• Morning grogginess more common with higher doses. 3

Long-term Safety

• Scarcity of evidence from long-term randomized controlled trials limits conclusions regarding safety of continuous therapy over extended periods. 5
• No evidence of dependence or addiction, even at high doses. 4, 6

Mechanism of Action

• Melatonin works by binding to M1 and M2 receptors, helping normalize circadian rhythms. 3
• It synchronizes circadian rhythms and improves sleep onset, duration, and quality. 6
• Centrally involved in anti-oxidation, circadian rhythm maintenance, sleep regulation, and neuronal survival. 6

Clinical Pitfalls

• Do not use melatonin as monotherapy—it should be part of comprehensive sleep hygiene approaches. 3
• Avoid combination treatments of light therapy plus melatonin in demented elderly patients with ISWRD (WEAK AGAINST recommendation). 1
• Monitor for morning grogginess and adjust dosing accordingly. 3
• Choose USP-verified formulations for reliable dosing and purity given lack of FDA regulation. 1, 3