Acetaminophen And Codeine and St John's Wort: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
St John's Wort
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Let's talk about taking your acetaminophen with codeine alongside St. John's wort. Codeine is a "prodrug," meaning your body has to convert it into its active pain-relieving form. St. John's wort can speed up the liver enzymes that handle codeine, so less of it becomes the active drug. That can mean your pain isn't controlled as well, and if your body has gotten used to the opioid, you could feel withdrawal symptoms.
There's also a separate concern: both can raise serotonin, so together they may cause a reaction called serotonin syndrome (agitation, sweating, fast heartbeat, shakiness). The good news is your care team can manage this safely by watching how you respond and adjusting things as needed.
Direction: St. John's wort induces CYP3A4, shifting codeine metabolism toward norcodeine and reducing CYP2D6-mediated conversion to morphine (the active metabolite). Net effect: reduced opioid efficacy and possible withdrawal in dependent patients. Codeine is a prodrug, so less active morphine means less analgesia.
- Second mechanism: additive serotonergic effects, risk of serotonin syndrome.
- Evidence: theoretical; severity: major; onset unspecified.
- Management: monitor for decreased efficacy/withdrawal; codeine dose may need individualization. If St. John's wort is stopped, CYP3A4 induction resolves, so monitor for sedation/respiratory depression and consider dose reduction. Monitor for serotonin syndrome; discontinue if suspected.
What happens
Reduced opioid efficacy, precipitation of opioid withdrawal, and an increased risk of serotonin syndrome
Interaction Deep Dive
Taking codeine together with St. John's wort (an inducer of CYP3A4) can lower codeine concentrations, raise norcodeine concentrations, and decrease CYP2D6-mediated metabolism, which in turn produces lower morphine levels; the net effect may be diminished efficacy or the emergence of a withdrawal syndrome in patients who have become physically dependent. Should the two agents need to be given together, keep a close watch for reduced effectiveness or indications of opioid withdrawal syndrome, and increase the codeine dose if warranted. When St. John's wort is being stopped, weigh lowering the codeine dose and monitor the patient carefully for signs of sedation or respiratory depression. Furthermore, because St. John's wort is a serotonergic agent, its combination with codeine has led to serotonin syndrome; if the two must be used concurrently, observe the patient closely for signs and symptoms of serotonin syndrome and stop treatment if it is suspected12.
Why it happens (mechanism)
Induction of CYP3A4-mediated metabolism of codeine; additive serotonergic effects
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. Here is how this is typically handled:
- Your team may monitor you more closely for pain that isn't well controlled or for signs of opioid withdrawal (restlessness, sweating, aches, nausea).
- Your codeine dose may need to be adjusted and individualized by your care team.
- If you ever stop the St. John's wort, tell your prescriber first, since your codeine dose may need to come down to avoid too much sedation.
- Watch for serotonin syndrome: agitation, shivering, fast heartbeat, sweating, or confusion. Get medical help if these occur.
Ask your pharmacist before starting or stopping any herbal product.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and St John's Wort together?
St. John's wort can make codeine work less well and may trigger opioid withdrawal, plus there's a serotonin syndrome risk; don't start or stop either on your own, and check with your pharmacist or doctor so they can adjust and monitor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and St John's Wort interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Acetaminophen And Codeine and St John's Wort interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. Here is how this is typically handled: Your team may monitor you more closely for pain that isn't well controlled or for signs of opioid withdrawal (restlessness, sweating, aches, nausea). Your codeine dose may need to be adjusted and individualized by your care team. If you ever stop the St. John's wort, tell your p… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or St John's Wort need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (2)
- Product Information: Codeine sulfate oral solution, codeine sulfate oral solution. Hikma Pharmaceuticals USA Inc(per FDA), Berkeley Heights, NJ, 2023. DailyMed
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. Hikma Pharmaceuticals USA Inc. (per FDA), Berkeley Heights, NJ, 2023. DailyMed
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