What are melatonin's side effects, drug interactions, contraindications, and recommended dosing guidelines?

Melatonin Side Effects, Drug Interactions, Contraindications, and Dosing

Melatonin has a favorable safety profile with only mild, self-limiting adverse effects at appropriate doses (3-5 mg), but higher doses increase side effects without improving efficacy, and long-term use beyond 3-4 months is not recommended for chronic insomnia due to insufficient safety data. 1, 2

Common Side Effects

The most frequently reported adverse effects in clinical trials include:

• Daytime sleepiness/somnolence (1.66%) - most common side effect, particularly with higher doses 3, 1
• Headache (0.74%) - second most common adverse effect 3, 2
• Dizziness (0.74%) - occurs at similar frequency to headache 3, 2
• Nausea and gastrointestinal upset - more frequent at higher doses (≥10 mg) 2, 4
• Morning grogginess and "hangover" effects - more common with higher doses due to melatonin's half-life extending into morning hours 2

Important caveat: Most adverse effects are mild, self-limiting, and resolve spontaneously within days without dose adjustment or immediately upon withdrawal 3

Dose-Related Side Effects

Lower doses (3-5 mg) are more effective and safer than higher doses:

• Higher doses (10 mg) cause receptor desensitization or saturation, disrupting normal circadian signaling 2
• Morning headache and sleepiness occur more frequently with doses ≥10 mg 2
• Impaired motor function can occur with higher doses 2
• Start with 3 mg immediate-release melatonin, titrate in 3 mg increments only if needed, maximum 15 mg 2, 5

Serious Drug Interactions and Contraindications

Warfarin Interaction

• Use with caution in patients taking warfarin - potential interactions reported to WHO 5, 6
• Monitor INR more frequently when initiating or discontinuing melatonin in anticoagulated patients 7

Epilepsy

• Exercise caution in patients with epilepsy based on case reports suggesting potential harm 5, 6

Other Precautions

• Photosensitizing medications - requires periodic ophthalmological/dermatological monitoring 5
• Impaired glucose tolerance - melatonin associated with impaired glucose tolerance in healthy individuals after acute administration 5, 2
• Mood effects - associated with increased depressive symptoms in some individuals 5
• Avoid in older adults with dementia for irregular sleep-wake rhythm disorder due to detrimental effects on mood and daytime functioning 2

Contraindications in Special Populations

• Pregnant and breastfeeding women - should not take melatonin due to lack of human safety studies 4
• Older adults with dementia - avoid for irregular sleep-wake rhythm disorder (lack of benefit, potential harm) 2

Recommended Dosing Guidelines

Adults

• Initial dose: 3 mg immediate-release melatonin 2, 5
• Timing: 1.5-2 hours before desired bedtime 2, 5
• Titration: Increase by 3 mg increments only if ineffective after 1-2 weeks 2
• Maximum dose: 15 mg 2
• Duration: Maximum 3-4 months for chronic insomnia 1, 2

Children (ages 6+)

• Without comorbidities: 0.15 mg/kg (approximately 1.6-4.4 mg) 2
• With psychiatric comorbidities: 3 mg if <40 kg, 5 mg if >40 kg 2
• Timing: 1.5-2 hours before bedtime 2
• Long-term use up to 24 months documented as safe in autism spectrum disorder 2

Specific Conditions

• REM sleep behavior disorder: 3-12 mg at bedtime 2
• Jet lag: 0.5-5 mg close to target bedtime (10pm-midnight) at destination 6

Product Quality Concerns

Critical caveat: Melatonin is regulated as a dietary supplement in the US, raising significant concerns about purity and reliability of stated doses 2, 5

• Choose United States Pharmacopeial Convention (USP) Verified formulations for more reliable dosing and purity 2, 5
• Different formulations can lead to variable efficacy between brands 2

Long-Term Safety Considerations

• Long-term use beyond 3-4 months not recommended for chronic insomnia due to insufficient safety data 1, 2
• Available long-term studies (up to 29 weeks in adults, 24 months in children) show favorable safety profiles with no serious adverse effects, dependency, or tolerance 3, 2
• Periodic reassessment every 3-6 months recommended if continuing therapy 2, 5
• If discontinuing after prolonged use, taper gradually over several weeks to months to minimize rebound insomnia 2

Timing Precautions

Avoid taking melatonin in the morning or afternoon - this worsens circadian misalignment and can cause daytime sleepiness 5, 6

Lifestyle Interactions

• Avoid alcohol consumption - interacts with melatonin effects 5
• Limit caffeine after 2:00 PM - counteracts melatonin's effects 5

No Documented Interactions

Melatonin has been used safely with SSRIs (including sertraline), spironolactone, and lamotrigine with no clinically significant interactions reported 2