Potential drug interactions with melatonin

Physiol Behav. 2014 May 28:131:17-24. doi: 10.1016/j.physbeh.2014.04.016. Epub 2014 Apr 13.


Possible interactions of melatonin with concurrently administered drugs were investigated in in vitro studies utilising human hepatic post-mitochondrial preparations; similar studies were conducted with rat preparations to ascertain whether rat is a suitable surrogate for human. Drugs were selected based not only on the knowledge that the 6-hydroxylation of exogenous melatonin, its principal pathway of metabolism, is mainly mediated by hepatic CYP1A2, but also on the likelihood of the drug being concurrently administered with melatonin. Hepatic preparations were incubated with either melatonin or 6-hydroxymelatonin in the presence and absence of a range of concentrations of interacting drug, and the production of 6-sulphatoxymelatonin monitored using a radioimmunoassay procedure. Of the drugs screened, only the potent CYP1A2 inhibitor 5-methoxypsoralen impaired the 6-melatonin hydroxylation at pharmacologically relevant concentrations, and is likely to lead to clinical interactions; diazepam, tamoxifen and acetaminophen (paracetamol) did not impair the metabolic conversion of melatonin to 6-sulphatoxymelatonin at concentrations attained following therapeutic administration. 17-Ethinhyloestradiol appeared not to suppress the 6-hydroxylation of melatonin but inhibited the sulphation of 6-hydroxymelatonin, but this is unlikely to result in an interaction following therapeutic intake of the steroid. Species differences in the inhibition of melatonin metabolism in human and rat hepatic post-mitochondrial preparations were evident implying that the rat may not be an appropriate surrogate of human in such studies.

Keywords: 17-Ethinyloestradiol; 5-Methoxypsoralen; CYP1A2; Drug interactions; Melatonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methoxypsoralen
  • Acetaminophen / pharmacology
  • Analgesics, Non-Narcotic / pharmacology
  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Antineoplastic Agents, Hormonal / pharmacology
  • Central Nervous System Depressants / pharmacology*
  • Diazepam / pharmacology
  • Drug Interactions
  • Estrogens / pharmacology
  • Fluvoxamine / pharmacology
  • Humans
  • Hypnotics and Sedatives / pharmacology
  • Male
  • Melatonin / analogs & derivatives*
  • Melatonin / metabolism*
  • Melatonin / pharmacology*
  • Methoxsalen / analogs & derivatives*
  • Methoxsalen / pharmacology
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / metabolism*
  • Middle Aged
  • Rats, Wistar
  • Tamoxifen / pharmacology


  • Analgesics, Non-Narcotic
  • Antidepressive Agents, Second-Generation
  • Antineoplastic Agents, Hormonal
  • Central Nervous System Depressants
  • Estrogens
  • Hypnotics and Sedatives
  • Tamoxifen
  • 6-sulfatoxymelatonin
  • Acetaminophen
  • 5-Methoxypsoralen
  • Melatonin
  • Fluvoxamine
  • Diazepam
  • 6-hydroxymelatonin
  • Methoxsalen