What are the side effects and safety considerations of melatonin?

Melatonin Side Effects and Safety Profile

Melatonin demonstrates a favorable safety profile with predominantly mild, self-limiting adverse effects when used at appropriate doses of 3-5 mg, though long-term safety data beyond 3-4 months remains limited. 1

Most Common Adverse Effects

The most frequently reported side effects in clinical trials include:

• Daytime sleepiness/somnolence (1.66%) – the most common adverse effect, particularly with higher doses 1, 2
• Headache (0.74%) – second most frequent complaint 1, 3
• Dizziness (0.74%) 1, 3
• Nausea and gastrointestinal upset – more common at higher doses 1
• Morning grogginess and "hangover" effects – associated with higher doses due to melatonin's half-life extending into morning hours 1

Dose-Related Safety Considerations

Lower doses (3 mg) are safer and often more effective than higher doses (10 mg), as higher doses cause receptor desensitization and increased adverse effects without improving efficacy. 1

• Start with 3 mg immediate-release melatonin taken 1.5-2 hours before bedtime 1, 3
• If ineffective after 1-2 weeks, increase by 3 mg increments up to maximum 15 mg 1
• Higher doses (10 mg) associated with more frequent morning headache, sleepiness, and GI upset 1

Serious or Clinically Significant Effects

While rare, the following warrant attention:

• Impaired motor function with higher doses 1
• Mood effects: agitation, mood swings, increased depressive symptoms in some individuals 1, 4, 2
• Nightmares (reported in some cases) 2
• Impaired glucose tolerance after acute administration in healthy individuals 3, 4
• Hypothermia (0.62%) 2

No life-threatening or serious adverse reactions have been documented across all age groups when used at appropriate doses. 1, 3

Critical Drug Interactions and Precautions

High-Risk Interactions

• Warfarin: Use with caution; potential interactions reported to WHO; monitor INR more frequently when initiating or discontinuing melatonin 1, 3, 4
• Fluvoxamine: Markedly increases interaction risk by inhibiting CYP1A2 (primary melatonin metabolism pathway) – avoid this combination or use extreme caution 1
• CNS depressants (benzodiazepines, sedative-hypnotics, antipsychotics) and alcohol: Additive sedation and impaired psychomotor performance 1

Moderate-Risk Interactions

• Multiple serotonergic agents (SSRIs, SNRIs, TCAs, tramadol): Start low, titrate slowly, monitor for serotonin syndrome 1
• Photosensitizing medications: Periodic ophthalmological/dermatological monitoring recommended 3, 4

Safe Combinations

• No documented interactions with most SSRIs (sertraline), spironolactone, or lamotrigine 1

Special Population Warnings

Avoid or Use Extreme Caution

• Older adults with dementia: American Academy of Sleep Medicine recommends avoiding melatonin for irregular sleep-wake rhythm disorder due to lack of benefit and potential harm, including detrimental effects on mood and daytime functioning 1
• Epilepsy patients: Use with caution based on case reports 1, 3, 4
• Pregnant/breastfeeding women: Should not take melatonin due to lack of human safety data 5
• Patients with diabetes or metabolic concerns: Monitor fasting glucose periodically 1, 4

Pediatric Safety

• Safe for children ≥6 years at weight-based dosing (0.15 mg/kg or 3-5 mg depending on comorbidities) 1
• No serious adverse reactions documented in children 1, 3
• Long-term use up to 24 months studied in autism spectrum disorder with continued safety 1
• No significant effects on pubertal development (Tanner stages) after ~3 years of use 1

Duration of Safe Use

The American Academy of Sleep Medicine recommends limiting melatonin use for chronic insomnia to a maximum of 3-4 months due to insufficient long-term safety data. 1

• Most clinical trial data supports use of 4 weeks or less 1
• For circadian rhythm disorders (delayed sleep-wake phase, non-24-hour rhythm), longer-term use may be appropriate as these require ongoing chronobiotic therapy 1
• Pediatric populations: documented safe use up to 24 months in autism spectrum disorder 1
• Periodic reassessment every 3-6 months recommended 1

Product Quality and Purity Concerns

Critical caveat: Melatonin is regulated as a dietary supplement in the U.S., raising significant concerns about purity and reliability of stated doses. 1, 3

• Choose United States Pharmacopeial Convention (USP) Verified formulations for reliable dosing and purity 1, 3, 4
• Different formulations may lead to variable efficacy between brands 1

Cardiovascular Safety

• Safe in perioperative and cardiac surgery patients: Society for Perioperative Assessment and Quality Improvement recommends continuing through perioperative period 3
• Prospective trial of 500 cardiac surgery patients showed reduced delirium without cardiac complications 3
• Not listed as contraindication by American Heart Association, American College of Cardiology, or Heart Failure Society 3

Common Pitfalls to Avoid

• Timing errors: Never take in morning or afternoon – worsens circadian misalignment 1
• Excessive dosing: Higher doses do not improve efficacy and increase side effects 1
• Ignoring interactions: Always document concurrent medications before prescribing 4
• Long-term use without reassessment: Periodic attempts to reduce frequency/dose indicated 1
• Using for wrong indication: Not recommended as first-line for chronic insomnia (benefits ≈ harms) 1