Long-Term Melatonin Safety Profile
Melatonin demonstrates a favorable safety profile with minimal adverse effects even with prolonged use, though robust long-term data beyond 4 years remain limited. 1, 2, 3
Evidence from Long-Term Studies
The most reassuring long-term safety data come from pediatric populations followed for extended periods:
A 4-year follow-up study of children with delayed sleep-wake phase disorder (DSWPD) and ADHD using doses up to 10 mg detected no serious adverse events, with 65% of participants continuing daily use throughout the study period 1
A prospective study extending up to 3.8 years in patients with neurodevelopmental disabilities receiving controlled-release melatonin (maximum 15 mg) similarly reported no adverse events 1
A 28-day toxicology trial in healthy male adults using 10 mg melatonin revealed no group differences in polysomnographic sleep parameters, clinical laboratory examinations, or subjective adverse events compared to placebo 1
Common Short-Term Side Effects
When adverse effects do occur, they are typically mild and self-limiting 2:
- Daytime sleepiness (1.66% incidence) 2
- Headache (0.74% incidence) 2
- Dizziness (0.74% incidence) 2
- Sleep-related disturbances (0.74% incidence) 2
- Hypothermia (0.62% incidence) 2
Most adverse effects resolve spontaneously within days without dose adjustment or immediately upon discontinuation 2
Rare but Clinically Significant Effects
A small number of more concerning adverse events have been reported, though these remain uncommon 2:
- Agitation and mood swings
- Nightmares
- Fatigue
- Skin irritation
- Palpitations
Special Population Concerns
Pediatric and Adolescent Populations
Concerns about effects on growth hormone regulation and reproductive development appear unfounded based on available evidence 1:
- A questionnaire-based study following children/adolescents for approximately 3 years (mean dose ~3 mg) found no significant differences in pubertal development (assessed by Tanner stages) compared to non-melatonin users in the general population 1
Elderly Patients
Melatonin represents a safer alternative to traditional hypnotics in older adults, who face substantial risks from benzodiazepines and other sedative-hypnotics 1, 3:
- Traditional hypnotics carry increased risks for falls, confusion, impaired motor performance, anterograde amnesia, and physiologic dependence in elderly patients 1
- Melatonin has a favorable safety profile in adults over 65 years, though evidence for prolonged use remains limited 3
Important Precautions and Monitoring
Drug Interactions and Contraindications
The American Academy of Sleep Medicine identifies several situations requiring caution 4:
- Warfarin users: Potential interactions reported to WHO; use with caution and monitor INR 4
- Epilepsy patients: Case reports suggest caution warranted 4, 5
- Photosensitizing medications: Periodic ophthalmological/dermatological monitoring recommended 4
- Glucose metabolism: Associated with impaired glucose tolerance in healthy women after acute administration 4
- Mood effects: Associated with increased depressive symptoms in some individuals 4
Dosing Considerations to Minimize Risk
Higher doses may paradoxically increase adverse effects without improving efficacy 4, 5:
- Lower doses are recommended as starting points, since higher doses can cause receptor desensitization 4
- Morning grogginess and "hangover" effects are more common with higher doses 5
- The American Academy of Sleep Medicine recommends maximum doses of 5 mg for most indications 6, 5
Critical Knowledge Gaps
The primary limitation in assessing long-term safety is the scarcity of studies extending beyond 6 months 1, 2, 7:
- Most controlled trials involve treatment durations of 4 weeks or less 1, 2
- A meta-analysis reviewing controlled trials found studies using melatonin for ≤3 months reported few adverse events 1
- No published long-term safety data exist for continuous daily use beyond approximately 4 years 7
The American Academy of Sleep Medicine recommends periodic reassessment of melatonin use due to limited long-term safety data 4
Clinical Pitfalls to Avoid
- Product quality variability: Choose United States Pharmacopeial Convention Verified formulations for reliable dosing and purity 4
- Timing errors: Take 1.5-2 hours before desired bedtime for optimal effect 4
- Excessive dosing: Start low (2 mg in elderly, 0.15 mg/kg in children) rather than using supraphysiological doses 6, 5
- Inadequate monitoring: Document concurrent medications and monitor for enhanced sedation, blood pressure changes, and mood alterations 4