Melatonin - Aspirin, Codeine Phosphate Interaction
Herbal: Melatonin
Also Known As: N-Acetyl-5-Methoxytryptamine
Drug: Aspirin, Codeine Phosphate
Brand names:
Aspirin w/ Codeine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
May 04, 2025
Interaction Details
Aspirin, Codeine Phosphate is classified as belonging to the following category: Cns Depressants
Theoretically, taking melatonin might increase the sedative effects of CNS depressants.
Melatonin has sedative effects. Theoretically, concomitant use of melatonin with alcohol, benzodiazepines, or other sedative drugs might cause additive sedation.
Interaction Rating
Likelihood of Occurrence
PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
Pharmacist Analysis
Melatonin can interact with drugs that cause sedation or CNS depression, such as benzodiazepines, opioids, and alcohol, leading to additive effects (i.e., additive sedation and drowsiness effects).
This interaction can increase drowsiness and impair cognitive and motor functions, which may be unsafe for activities that require alertness and concentration, such as driving or operating heavy machinery.
However, if you are using melatonin solely for sleep at night, the interaction is generally not of significant concern.
Nevertheless, it is advisable to consult with a healthcare provider before taking melatonin with other medications, especially those that affect the central nervous system.
References
- Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31.
Interaction Details
Aspirin, Codeine Phosphate is classified as belonging to the following category: Seizure Threshold Lowering Drugs
Theoretically, taking melatonin with drugs that lower the seizure threshold might increase the risk of seizure activity.
Some clinical evidence suggests that melatonin may increase the frequency of seizures in certain patients, particularly children with neurological disabilities.
Interaction Rating
Likelihood of Occurrence
PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
References
- Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998;351:1254.
- Stewart LS. Endogenous melatonin and epileptogenesis: facts and hypothesis. Int J Neurosci 2001;107:77-85..
Interaction Details
Aspirin, Codeine Phosphate is classified as belonging to the following category: Cytochrome P450 2D6 (Cyp2D6) Substrates
Theoretically, melatonin might increase levels of drugs metabolized by CYP2D6.
Laboratory research suggests that certain lots of melatonin inhibit CYP2D6. Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2D6 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Interaction Rating
Likelihood of Occurrence
PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
Pharmacist Analysis
There is some evidence to suggest that melatonin may inhibit the activity of the CYP2D6 enzyme (a type of metabolizing enzyme).
CYP2D6 is responsible for metabolizing many drugs, including some antidepressants, antipsychotics, and beta blockers. When this enzyme is inhibited, it can lead to increased levels of these drugs in the body, which can cause side effects or toxicity.
Studies are conflicting as some have shown that melatonin can inhibit CYP2D6 while others have found no significant effect of melatonin on CYP2D6 activity.
Overall, the potential interaction between melatonin and drugs metabolized by CYP2D6 is still unclear and may depend on factors such as the dose of melatonin, the specific drug being metabolized, and individual differences in metabolism.
It is always recommended to consult with a healthcare provider before taking any new supplements or medications, especially if you are taking other medications or have underlying health conditions.
References
- Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31.
Interaction Details
Aspirin, Codeine Phosphate is classified as belonging to the following category: Anticoagulant/Antiplatelet Drugs
Theoretically, melatonin may have anticoagulant effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
There are isolated case reports of minor bleeding and decreased prothrombin activity in people taking melatonin with warfarin (Coumadin). The mechanism, if any, of this interaction is unknown. Taking melatonin orally seems to decrease coagulation activity within one hour of dosing in healthy men.
Interaction Rating
Likelihood of Occurrence
PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
References
- Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev 2002;2:CD001520.
- Wirtz, P. H., Spillmann, M., Bartschi, C., Ehlert, U., and von Kanel, R. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res 2008;44(2):127-133.
- U.S.Food and Drug Administration. Special Nutritionals Adverse Events Monitoring System: registered case reports.
Melatonin Overview

Melatonin - More Interactions
Melatonin interacts with 1425 drugs
Interaction Rating Key
These severity listings are for informational use only. Never start, stop or otherwise change your therapy before speaking with your provider.
Major | The combined use of these agents is strongly discouraged as serious side effects or other negative outcomes could occur. |
Moderate | Use cautiously under the care of a healthcare professional or avoid this combination. A significant interaction or negative outcome could occur. |
Minor | Be aware that there is a chance of an interaction. Watch for warning signs of a potential interaction. |
Unknown | No interactions have been reported or no interaction data is currently available. |
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Parts of this content are provided by the Therapeutic Research Center, LLC.
DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.
© 2021 Therapeutic Research Center, LLC
Drug descriptions are provided by MedlinePlus.