What are the current data on the long‑term safety and adverse effects of melatonin use in adults?

Long-Term Safety Profile of Melatonin in Adults

Based on the most recent high-quality evidence, melatonin demonstrates a favorable long-term safety profile with only mild, self-limiting adverse effects (primarily daytime sleepiness, headache, and dizziness), though robust data beyond 6-12 months remains limited, and the American Academy of Sleep Medicine recommends against routine long-term use for chronic insomnia beyond 3-4 months due to insufficient extended safety data. 1, 2, 3

Key Safety Findings from Long-Term Studies

Duration of Available Evidence

• The longest prospective controlled trials extend to 29 weeks in adults, with most studies lasting 4 weeks or less 2
• One open-label study followed patients for 6-12 months and found no tolerance development, withdrawal symptoms, or suppression of endogenous melatonin production 4
• Pediatric studies have documented safe use up to 24 months in children with autism spectrum disorders 1
• A 4-year follow-up in children with ADHD using doses up to 10 mg detected no serious adverse events 5

Most Common Adverse Effects

• Daytime sleepiness/somnolence: 1.66% incidence (most frequent adverse effect) 1, 2
• Headache: 0.74% incidence 1, 2
• Dizziness: 0.74% incidence 2
• Nausea and hypothermia: 0.62% incidence 5, 2
• These effects are generally mild to moderate, self-limiting, and resolve spontaneously within days or immediately upon discontinuation 2, 6

Serious Adverse Events

• A 2022 meta-analysis of high-dose melatonin studies (≥10 mg) found no detectable increase in serious adverse events (Rate Ratio = 0.88 [0.52,1.50], p = .64) or withdrawals due to adverse events 7
• Very few clinically significant adverse events have been reported across all studies, including agitation, fatigue, mood swings, nightmares, skin irritation, and palpitations 2
• No life-threatening adverse events have been identified in systematic reviews 2, 6

Dose-Related Safety Considerations

Lower Doses Are Safer and Often More Effective

• Higher doses (10 mg) may cause receptor desensitization without improving efficacy, while increasing adverse effects like morning grogginess and headache 1
• The American Academy of Sleep Medicine recommends starting with 3 mg immediate-release melatonin, titrating in 3 mg increments only if needed, with a maximum of 15 mg 1
• Doses ranging from 0.5-5 mg produce comparable improvements in sleep parameters, making higher doses unnecessary 1

Adverse Effects More Common at Higher Doses

• Morning "hangover" effects occur more frequently with higher doses due to melatonin's half-life extending into morning hours 1
• Gastrointestinal upset is reported more frequently at higher doses 1
• A 2022 meta-analysis found that high-dose melatonin (≥10 mg) increased the risk of drowsiness, headache, and dizziness (Rate Ratio = 1.40 [1.15,1.69], p < .001) 7

Special Populations and Precautions

Populations Requiring Caution

• Patients taking warfarin: Potential drug interactions have been reported to the World Health Organization 1
• Patients with epilepsy: Case reports suggest caution is warranted 1, 6
• Patients with diabetes or metabolic concerns: Melatonin has been associated with impaired glucose tolerance in healthy individuals after acute administration 1
• Older adults with dementia: The American Academy of Sleep Medicine recommends avoiding melatonin for irregular sleep-wake rhythm disorder in this population due to lack of benefit and potential for detrimental effects on mood and daytime functioning 1

Pregnancy and Breastfeeding

• Due to lack of human studies, pregnant and breastfeeding women should not take exogenous melatonin 6

Drug Interactions

Significant Interactions

• Fluvoxamine markedly increases interaction risk by inhibiting CYP1A2, the primary pathway for melatonin metabolism 1
• CNS depressants and alcohol produce additive sedation and impair psychomotor performance when combined with melatonin 1
• Serotonergic polypharmacy: When used with multiple serotonergic agents (SSRIs, SNRIs, TCAs), start at low doses and monitor for serotonin syndrome 1

Safe Combinations

• No documented interactions exist between melatonin and most SSRIs (sertraline has been used safely with melatonin) 1
• Melatonin can be used safely with stimulant medications like Adderall XR and Ritalin in adolescents 8

Concerns About Long-Term Effects That Have Been Disproven

Reproductive and Growth Development

• Concerns about effects on pubertal development appear unfounded: A questionnaire-based study following children/adolescents for approximately 3 years (mean dose ~3 mg) found no significant differences in pubertal development compared to non-users 5
• No evidence of growth hormone dysregulation has been documented 5

Endogenous Melatonin Suppression

• Long-term use (6-12 months) does not suppress endogenous melatonin production, as measured by nocturnal urinary 6-sulfatoxymelatonin excretion 4

Tolerance and Withdrawal

• No evidence of tolerance development has been found in studies up to 12 months 4
• Discontinuation after 12 months of continuous use was not associated with rebound insomnia or withdrawal symptoms; residual benefit was observed instead 4

Critical Limitations in Current Evidence

Primary Knowledge Gaps

• The scarcity of studies extending beyond 6 months is the primary limitation in assessing long-term safety 5, 3
• Most controlled trials involve treatment durations of 4 weeks or less 2
• 37% of high-dose melatonin studies made no mention of adverse events at all 7
• Many older studies did not conform to CONSORT guidelines or Cochrane risk-of-bias criteria 2

Quality of Evidence Issues

• The American Academy of Sleep Medicine rates the overall quality of evidence for melatonin as "very low" due to potential publication bias, heterogeneity, and imprecision 9
• Wide confidence limits in meta-analyses reflect the paucity of suitable data 7
• Better safety reporting in future long-term trials is needed 7, 3

Product Quality Concerns

Regulatory Status and Variability

• Melatonin is regulated as a dietary supplement in the US, raising significant concerns about purity and reliability of stated doses 1
• Melatonin concentration of marketed preparations varies widely between product labels and manufacturers 5
• Choose United States Pharmacopeial Convention (USP) Verified formulations for reliable dosing and purity 1, 5

Clinical Recommendations for Long-Term Use

Maximum Recommended Duration

• The American Academy of Sleep Medicine recommends limiting melatonin therapy for chronic insomnia to a maximum of 3-4 months 1
• For circadian rhythm disorders (delayed sleep-wake phase disorder, non-24-hour sleep-wake rhythm disorder), longer-term use may be appropriate as these conditions require ongoing chronobiotic therapy 1

Monitoring and Reassessment Algorithm

• Periodic reassessment every 3-6 months is indicated to determine lowest effective dose and continued need 1
• Consider tapering frequency (every other or every third night) rather than daily use 1
• If discontinuing after prolonged use, taper gradually over several weeks to months, lowering dose by smallest increment possible in successive steps of at least several days 1
• Monitor for morning grogginess (indicates dose too high), mood changes, and any metabolic concerns if diabetes risk factors present 1, 8

When to Avoid Long-Term Melatonin

• The American Academy of Sleep Medicine suggests clinicians not use melatonin as first-line treatment for chronic insomnia based on weak evidence showing benefits approximately equal to harms 9, 1
• Melatonin has only small effects on sleep latency with little effect on wake after sleep onset or total sleep time when used as a hypnotic rather than as a circadian rhythm regulator 1

Common Clinical Pitfalls to Avoid

• Timing errors: Taking melatonin in the morning or afternoon worsens circadian misalignment 1
• Excessive dosing: Starting with doses >5 mg increases adverse effects without improving efficacy 1
• Inadequate monitoring: Failing to document concurrent medications and monitor for enhanced sedation, blood pressure changes, or mood alterations 5
• Product selection: Using non-USP-verified products leads to unreliable dosing 1, 5
• Ignoring contraindications: Using in patients with dementia, during pregnancy, or with strong CYP1A2 inhibitors 1, 6