What are the adverse effects of taking excessive melatonin?

Adverse Effects of Excessive Melatonin

Excessive melatonin doses cause more frequent adverse effects without improving efficacy, with the most common being daytime sleepiness (1.66%), headache (0.74%), and dizziness (0.74%), while higher doses above 5 mg may cause receptor desensitization and worsen outcomes compared to lower doses. 1

Common Adverse Effects by Frequency

The American Academy of Sleep Medicine reports the following adverse effect rates from clinical trials:

• Daytime sleepiness/somnolence: 1.66% (most frequent adverse effect, particularly at higher doses) 1, 2
• Headache: 0.74% 3, 1
• Dizziness: 0.74% 1, 2
• Nausea and gastrointestinal upset (more frequent at higher doses) 1, 2
• Hypothermia: 0.62% 2

Dose-Dependent Effects and Receptor Saturation

Higher doses (10 mg and above) cause receptor desensitization or saturation, potentially disrupting normal circadian signaling without providing additional benefit. 1

• Doses between 0.5 mg and 5 mg are similarly effective for most indications 1, 4
• The 5 mg dose helps people fall asleep faster than 0.5 mg, but doses above 5 mg show no additional efficacy 1, 4
• Morning grogginess and "hangover" effects occur more commonly with higher doses due to melatonin's half-life extending into morning hours 1

Serious Adverse Effects from Overdose

A case report of a 16-year-old who ingested 900 mg of melatonin (180 tablets) demonstrated:

• Extreme drowsiness and minimal responsiveness (Glasgow Coma Scale 8/15) 5
• Recovery occurred 32 hours post-ingestion with supportive care only 5
• No renal or liver dysfunction despite massive overdose 5

This case underscores melatonin's relatively low acute toxicity potential, though supportive measures and vital sign monitoring are crucial in overdose situations. 5

Timing-Related Adverse Effects

Taking melatonin at the wrong time—particularly in the morning or afternoon—worsens circadian misalignment and causes inappropriate daytime sleepiness. 1

• Optimal timing is 1.5–2 hours before desired bedtime 3, 1
• Early-day administration can delay adaptation to local time and impair daytime function 4

Special Population Concerns

Patients with Epilepsy

• Use with caution based on case reports of potential harm 1, 6, 4

Patients Taking Warfarin

• Potential drug interactions reported to WHO; monitor INR more frequently when initiating or discontinuing melatonin 1, 7, 6

Patients with Glucose Metabolism Issues

• Melatonin has been associated with impaired glucose tolerance in healthy individuals after acute administration 1, 6
• Monitor fasting glucose periodically if metabolic concerns or diabetes risk factors exist 1

Patients with Dementia

• The American Academy of Sleep Medicine recommends avoiding melatonin for irregular sleep-wake rhythm disorder in older adults with dementia due to lack of benefit and potential harm 1
• Detrimental effects on mood and daytime functioning have been observed in dementia patients 1

Drug Interactions Causing Enhanced Adverse Effects

CYP1A2 Inhibitors (Especially Fluvoxamine)

• Fluvoxamine markedly increases melatonin levels by inhibiting CYP1A2, the primary metabolic pathway, creating high risk for excessive sedation and adverse effects 1

CNS Depressants and Alcohol

• Concurrent use with benzodiazepines, sedative-hypnotics, antipsychotics, or alcohol produces additive sedation and impairs psychomotor performance 1

Multiple Serotonergic Agents

• When combined with SSRIs, SNRIs, TCAs, tramadol, or dextromethorphan, start at low doses and monitor for serotonin syndrome 1

Rare but Serious Adverse Effects

From systematic review and case reports:

• Agitation, mood swings, and increased depressive symptoms 1, 6, 2
• Nightmares 8, 2
• Palpitations and cardiovascular effects 2
• Skin irritation 2
• Hypotension 8
• Abdominal pain 8
• Impaired motor function (at higher doses) 1

Most adverse effects resolve spontaneously within days or immediately upon withdrawal. 2

Product Quality Concerns

Melatonin is regulated as a dietary supplement in the U.S., raising significant concerns about purity and reliability of stated doses. 1, 6

• Choose United States Pharmacopeial Convention (USP) Verified formulations for reliable dosing and purity 1, 6
• Variable product quality may lead to unintended overdosing or underdosing 1

Recommended Dosing to Avoid Excessive Effects

Start with 3 mg immediate-release melatonin taken 1.5–2 hours before bedtime; titrate in 3 mg increments only if ineffective after 1–2 weeks, with a maximum of 15 mg. 1

• For children 6–12 years without comorbidities: 0.15 mg/kg 3, 1
• For children with psychiatric comorbidities: 3 mg if <40 kg, 5 mg if >40 kg 1

Duration Limitations

Long-term use beyond 3–4 months for chronic insomnia is not recommended due to insufficient safety data, though ongoing use may be appropriate for specific circadian rhythm disorders. 1