Acetaminophen And Codeine and Ethanol: 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
Ethanol
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.
Your pain medicine contains acetaminophen (the same ingredient in Tylenol), and mixing it with alcohol can be hard on your liver. When you drink regularly, your body speeds up how it breaks down acetaminophen and makes more of a byproduct that can damage liver cells, while also using up the natural protection your liver relies on.
This buildup happens over time, not all at once. The good news is this is very manageable. Keep your total acetaminophen under 4 grams in 24 hours and let your doctor or pharmacist know if you drink 3 or more drinks a day. They can help you use this medicine safely.
Effect: Increased risk of hepatotoxicity with concurrent chronic ethanol and acetaminophen use. Direction: ethanol induces CYP2E1, shifting acetaminophen metabolism toward the reactive metabolite NAPQI, with hepatic glutathione depletion reducing detoxification capacity.
- Onset: delayed; Evidence: probable.
- Peak risk: after brief (~12 h) abstinence, when CYP2E1 remains induced but ethanol no longer competes for the enzyme.
- Higher risk in chronic alcohol users and underlying liver disease, even at therapeutic doses.
Management: Limit acetaminophen to
What happens
An increased risk of hepatotoxicity
Interaction Deep Dive
When alcohol and acetaminophen are taken together, CYP2E1-mediated conversion of acetaminophen into NAPQI, a metabolite that is highly toxic to the liver, may be enhanced. Patients should be counseled to keep acetaminophen intake at or below 4 grams over any 24 hour period and to inform their physician if they routinely consume 3 or more alcoholic drinks daily5. Individuals with chronic alcoholism face a greater likelihood of hepatotoxicity from acetaminophen, whether at therapeutic doses or in overdose, than patients who do not drink 678910. Among habitual alcohol users, the peak risk of acetaminophen toxicity is seen following a short (12 hour) period of alcohol abstinence, because CYP2E1 remains induced while ethanol is no longer available to compete for CYP2E1 11. The likelihood of acute liver failure rises in those with preexisting liver disease as well as in those who drink alcohol while using acetaminophen 122.
Why it happens (mechanism)
Accumulation of the hepatotoxic acetaminophen metabolite NAPQI by ethanol induction of CYP2E1; depletion of glutathione
How to manage this interaction
Keep taking your medicine as prescribed, but be mindful of the acetaminophen it contains.
- Stay at or below 4 grams of acetaminophen in 24 hours, counting all sources (other combination products, cold medicines, OTC Tylenol).
- Tell your doctor or pharmacist if you regularly have 3 or more alcoholic drinks per day or have any liver problems. Your dose may need to be adjusted and individualized, and your team may monitor your liver more closely.
- Ask before adding any new product, since many contain hidden acetaminophen.
If you notice yellowing skin or eyes, dark urine, nausea, or right-side belly pain, contact your care team promptly.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
a) The alcohol-acetaminophen syndrome refers to the onset of acute toxic liver effects in chronic alcoholics who take acetaminophen at doses that are usually regarded as non-toxic. Serious hepatotoxicity may occur in these individuals following acetaminophen intake as small as 4 grams within 24 hours. Individuals with alcohol-acetaminophen syndrome carry a poorer prognosis than non-alcoholic patients experiencing acetaminophen overdose, even though the former group has taken smaller doses of acetaminophen. Total mortality in alcohol-acetaminophen syndrome is roughly 19%, and rises above 75% when acute liver failure occurs. About 95% of acetaminophen undergoes conjugation via glucuronide and sulfate pathways, while only 5% of the drug is oxidized by cytochrome P450 2E1 (CYP2E1). This oxidation produces N-acetyl-p-benzoquinoneimine (NAPQI), a substance that is strongly hepatotoxic. After intake of therapeutic amounts of acetaminophen in non-alcoholics, NAPQI is detoxified through conjugation with glutathione. When acetaminophen overdose occurs, glutathione reserves are quickly exhausted, leaving NAPQI to produce hepatic damage. In alcoholics, alcohol competes with acetaminophen for CYP2E1 metabolism. The joint effect of CYP2E1 induction and glutathione depletion leads to accumulation of NAPQI and increased acetaminophen toxicity 11.
b) Up to now clinicians have accepted the possibility that chronic alcoholics face a heightened risk of acetaminophen (paracetamol) hepatotoxicity, yet there is not enough evidence to support the claimed major toxic interaction. Chronic alcohol intake produces only a modest (roughly two-fold) and short-lasting induction of cytochrome P450 2E1 (CYP2E1), and there is no matching rise in the toxic metabolic activation of acetaminophen. The protective effect of alcohol is linked to inhibition of the toxic metabolic activation of acetaminophen. The timing of ethanol and acetaminophen intake is essential because the protective effect of ethanol vanishes once ethanol is eliminated. Chronic alcoholics are likely to face the greatest risk from the effects of acetaminophen during the first few days of alcohol withdrawal, since the metabolic activation of acetaminophen is no longer offset by the inhibitory effects of circulating ethanol. All patients who consume alcohol in excess should be regarded as high risk following acetaminophen overdose and be treated with N-acetylcysteine accordingly until additional studies are performed 13.
Common questions
Can I take Acetaminophen And Codeine and Ethanol together?
Combining alcohol with acetaminophen-containing pain medicine raises the risk of liver damage, so keep acetaminophen under 4 grams a day and tell your care team if you drink heavily or have liver issues. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Ethanol interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Acetaminophen And Codeine and Ethanol interaction managed?
Keep taking your medicine as prescribed, but be mindful of the acetaminophen it contains. Stay at or below 4 grams of acetaminophen in 24 hours, counting all sources (other combination products, cold medicines, OTC Tylenol). Tell your doctor or pharmacist if you regularly have 3 or more alcoholic drinks per day or have any liver problems. Your dose may need to be adjusted and individualized, and y… 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.
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Ethanol 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 (13)
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- Product Information: Butalbital acetaminophen oral tablets, butalbital acetaminophen oral tablets. Burel Pharmaceuticals LLC (per DailyMed), Mason, OH, 2022. DailyMed
- Bellville JW, Forrest WH Jr, Shroff P, et al: The hypnotic effects of codeine and secobarbital and their interaction in man. Clin Pharmacol Ther 1971; 12:607-612. PubMed
- Linnoila M & Hakkinen S: Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving. Clin Pharmacol Ther 1974; 15:368. PubMed
- Product Information: Tylenol(R), acetaminophen. McNeil-PPC, Inc. Fort Washington, PA, USA, 2000. DailyMed
- Barker JD Jr, de Carle DJ, & Anuras S: Chronic excessive acetaminophen use and liver damage. Ann Intern Med 1977; 87:299-301. PubMed
- McClain CJ, Kromhout JP, & Peterson FJ: Potentiation of acetaminophen hepatotoxicity by alcohol. JAMA 1980; 244:251-253. DOI
- Johnson MW, Friedman PA, & Mitch WE: Alcoholism, nonprescription drugs and hepatotoxicity. The risk from unknown acetaminophen ingestion. Am J Gastroenterol 1981; 76:530-533.
- McJunkin B, Barwick KW, Little WC, et al: Fatal massive hepatic necrosis following acetaminophen overdose. JAMA 1976; 236:1874-1875. DOI
- Licht H, Seeff LB, & Zimmerman HJ: Apparent potentiation of acetaminophen hepatotoxicity by alcohol (letter). Ann Intern Med 1980; 92:511. PubMed
- Draganov P, Durrence H, Cox C, et al: Alcohol-acetaminophen syndrome. Postgrad Med 2000; 107:189-195. DOI
- Product Information: Butalbital acetaminophen oral capsules, butalbital acetaminophen oral capsules. Mayne Pharma (per DailyMed), Greenville, NC, 2019. DailyMed
- Prescott L: Paracetamol, alcohol and the liver. J Clin Pharmacol 2000; 49:291-301. PubMed
Keep reading about Acetaminophen And Codeine
Keep reading about Ethanol
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist