Which medications interact with melatonin?

Melatonin Drug Interactions

Melatonin has clinically significant interactions with warfarin, fluvoxamine (a potent CYP1A2 inhibitor), and potentially with other serotonergic medications, antihypertensive drugs, and CNS depressants, requiring careful monitoring or dose adjustments when used concurrently.

Critical Drug Interactions Requiring Caution or Avoidance

Anticoagulants

• Warfarin: The American Academy of Sleep Medicine explicitly recommends using melatonin with caution in patients taking warfarin due to potential interactions reported to the World Health Organization 1, 2
• This interaction may enhance anticoagulant effects, increasing bleeding risk 1

CYP1A2 Inhibitors

• Fluvoxamine (an SSRI) is a potent CYP1A2 inhibitor that can significantly impair melatonin metabolism, as melatonin's principal metabolic pathway (6-hydroxylation) is mediated by hepatic CYP1A2 3
• Fluvoxamine has greater potential for drug-drug interactions compared to other SSRIs due to its effects on multiple CYP enzymes including CYP1A2 4
• 5-methoxypsoralen is the only drug shown to impair melatonin 6-hydroxylation at pharmacologically relevant concentrations in human hepatic studies 3

Serotonergic Medications

• A case report documented severe sedation in a 19-year-old taking citalopram, nortriptyline, and oxycodone when melatonin was added, likely due to a pharmacokinetic interaction between melatonin and citalopram involving CYP1A2, CYP2C19, and CYP3A7 inhibition 5
• While no documented interactions between melatonin and SSRIs exist in general, and melatonin has been used safely with sertraline 1, the case above suggests caution with certain combinations
• The American Academy of Child and Adolescent Psychiatry warns that combining multiple serotonergic drugs (including SSRIs, SNRIs, TCAs, tramadol, dextromethorphan) requires starting at low doses, slow titration, and monitoring for serotonin syndrome symptoms 4

CNS Depressants and Sedatives

• Melatonin has additive CNS depressant effects when combined with benzodiazepines, other sedative-hypnotics, antipsychotics (like olanzapine), or alcohol 6
• The American Academy of Sleep Medicine warns that combining melatonin with valproate and olanzapine requires close monitoring for excessive sedation, confusion, or falls due to additive CNS depressant effects 6
• General guidance advises caution with concomitant CNS depressants and alcohol use due to additive effects on psychomotor performance 4

Antihypertensive Medications

• Melatonin may interact with antihypertensive drugs, potentially affecting blood pressure and heart rate, with effects influenced by dosage and dose timing 7
• These cardiovascular effects appear dose-dependent and may require monitoring 7

Medications with Minimal or No Interaction Risk

Generally Safe Combinations

• Diazepam, tamoxifen, and acetaminophen do not impair melatonin metabolism at therapeutic concentrations 3
• 17-Ethinylestradiol does not suppress melatonin 6-hydroxylation, though it inhibits sulphation of 6-hydroxymelatonin at a step unlikely to cause clinical interactions 3
• Lamotrigine and spironolactone have no documented clinically significant interactions with melatonin 1

Special Populations Requiring Extra Caution

Epilepsy

• The American Academy of Sleep Medicine recommends caution in patients with epilepsy based on case reports suggesting potential concerns 1, 2

Diabetes or Metabolic Concerns

• Melatonin has been associated with impaired glucose tolerance in healthy individuals after acute administration, warranting periodic fasting glucose monitoring in patients with diabetes risk factors 1

Practical Management Algorithm

When prescribing melatonin:

1. Screen for high-risk medications: Specifically ask about warfarin, fluvoxamine, and other CYP1A2 inhibitors 1, 3

2. Assess CNS depressant burden: Document all sedating medications including benzodiazepines, antipsychotics, mood stabilizers, and opioids 6, 5

3. Start with lowest effective dose: Use 3 mg immediate-release melatonin taken 1.5-2 hours before bedtime to minimize interaction risk 1

4. Time administration appropriately: Avoid morning or afternoon dosing, which worsens circadian misalignment and may reduce efficacy of other medications 1

5. Monitor closely in first 1-2 weeks: Watch for excessive sedation, changes in bleeding parameters (if on warfarin), or mood changes 1, 5

6. Choose verified formulations: Select United States Pharmacopeial Convention Verified products for reliable dosing, as melatonin is regulated as a dietary supplement with variable quality 1, 8

Important Caveats

• Product-dependent CYP inhibition has been demonstrated with different melatonin formulations, meaning interaction potential may vary between brands 5
• The American Academy of Sleep Medicine recommends against long-term melatonin use (beyond 3-4 months) for chronic insomnia due to insufficient safety data, though longer use may be appropriate for circadian rhythm disorders 1
• Avoid alcohol consumption, which interacts with both melatonin and psychiatric medications 1
• Melatonin should be avoided in older adults with dementia due to detrimental effects on mood and daytime functioning 1, 8