Kratom and Acetaminophen And Codeine: 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
Kratom
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.
Combining kratom with acetaminophen and codeine can be dangerous. Both codeine and kratom slow down your breathing and calm your nervous system. Taken together, that effect can add up and become serious, causing very slow or shallow breathing, deep drowsiness, or worse. Kratom also touches serotonin pathways, which can raise the risk of a reaction called serotonin syndrome (agitation, sweating, fast heartbeat, shakiness).
On top of that, kratom can slow down a liver enzyme (CYP3A) that helps clear parts of this medicine, so more can build up in your body. Please don't stop or change anything on your own. Talk with your pharmacist or doctor. This is something your care team can help you manage safely.
Direction: Additive risk, increased hazard. Kratom and codeine (an opioid CNS depressant) produce additive respiratory and CNS depression; kratom's serotonergic activity adds serotonin syndrome risk.
- PK component: Kratom inhibits CYP3A, potentially increasing exposure of CYP3A substrates, more pronounced at higher doses or chronic use.
- PD component: Additive CNS depression plus multi-receptor (opioid, adrenergic, serotonergic) effects.
- Evidence: Probable; FAERS signals include hospitalizations, life-threatening events, and fatalities.
- Severity/Onset: Major; onset unspecified.
Management: Avoid the combination where possible. If co-used, monitor closely for sedation, respiratory rate, and serotonin syndrome; individualize opioid dosing. Variable alkaloid content makes effects unpredictable.
What happens
Increased CYP3A substrate exposure, increased risk of CNS depression and serotonin syndrome
Interaction Deep Dive
When kratom is taken together with a CNS depressant and a serotonergic agent, serious consequences can result, including respiratory depression, serotonin syndrome, or death 1. Kratom also acts as a CYP3A inhibitor, so it can raise the exposure of CYP3A substrates, an effect that is more pronounced at higher kratom doses or with long-term use 2. Within the FDA Adverse Event Reporting System (FAERS) database, 1223 kratom-related adverse events were recorded from June 2008 through 2024; a large number of these involved interactions between kratom and other medications (particularly opioids and CNS agents) and encompassed serious outcomes such as hospitalizations, life threatening conditions, and deaths. Because kratom acts through multiple receptors (opioid, adrenergic, and serotonergic) and because its alkaloid content varies across formulations, predicting drug interactions is difficult. Close monitoring is advised 1.
Why it happens (mechanism)
Inhibition of CYP3A-mediated metabolism by kratom; additive CNS depression; additive serotonergic effects
How to manage this interaction
Keep taking your prescribed acetaminophen and codeine as directed, and talk with your pharmacist or prescriber before using kratom with it.
- Because both can slow breathing and cause heavy sedation, your care team may want to avoid this combination or watch you more closely.
- Watch for warning signs: very slow or shallow breathing, extreme sleepiness, confusion, agitation, sweating, fast heartbeat, or muscle twitching. Seek emergency help if these occur.
- Kratom products vary a lot in strength, so effects are hard to predict. Tell your provider exactly what you are taking.
- Any opioid dose changes should be individualized by your care team, not adjusted on your own.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) An open-label crossover study in healthy adults (N=12) assessed the intake of a single, low dose of kratom tea (2 g) along with oral midazolam (a CYP3A probe substrate; 2.5 mg) and oral dextromethorphan (a CYP2D6 probe substrate; 30 mg). Kratom produced a modest rise in midazolam geometric mean AUC (1.39; 90% CI, 1.23 to 1.57) and Cmax (1.5; 90% CI, 1.32 to 1.7); no change in dextromethorphan AUC or Cmax was seen. The half life of midazolam was not significantly changed when kratom was used concurrently, which points to inhibition of first-pass metabolism, chiefly intestinal CYP3A. The participants (median age, 30 years) had prior kratom exposure and agreed to refrain from concomitant medications and botanical or other natural products (including kratom) throughout the study 2.
Common questions
Can I take Kratom and Acetaminophen And Codeine together?
Using kratom with acetaminophen and codeine adds up their breathing- and nervous-system-slowing effects and raises serotonin syndrome risk, so avoid the combination and check with your pharmacist or doctor first. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Kratom and Acetaminophen And Codeine 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 Kratom and Acetaminophen And Codeine interaction managed?
Keep taking your prescribed acetaminophen and codeine as directed, and talk with your pharmacist or prescriber before using kratom with it. Because both can slow breathing and cause heavy sedation, your care team may want to avoid this combination or watch you more closely. Watch for warning signs: very slow or shallow breathing, extreme sleepiness, confusion, agitation, sweating, fast heartbeat,… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Kratom or Acetaminophen And Codeine 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)
- Dhoble LR, Gour A, McCurdy CR, et al: Evaluating the drug interactions in kratom usage: clinical application. Expert Opin Drug Metab Toxicol 2025; 21(8):949-959. PubMed
- Tanna RS, Nguyen JT, Hadi DL, et al: Clinical assessment of the drug interaction potential of the psychotropic natural product kratom. Clin Pharmacol Ther 2023; 113(6):1315-1325. PubMed
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