What cannot be taken with sertraline? A guide to drug and substance interactions

October 12, 2025 •

4 min read

Over 20% of adults in the United States have taken an antidepressant in the last year, with sertraline (Zoloft) being one of the most commonly prescribed. However, this medication can have potentially serious or life-threatening interactions with a wide array of other drugs, herbal supplements, and substances. Knowing what cannot be taken with sertraline is crucial for ensuring patient safety and treatment efficacy.

Quick Summary

This guide outlines the critical drug interactions and substances to avoid while taking sertraline, explaining the risks involved, including serotonin syndrome and increased bleeding. It emphasizes the importance of consulting a healthcare provider before combining any new medications or supplements to prevent adverse reactions.

Key Points

Avoid MAOIs Completely: Medications like isocarboxazid (Marplan) and the antibiotic linezolid (Zyvox) are absolute contraindications for sertraline, requiring a 14-day washout period due to the risk of life-threatening serotonin syndrome.
Beware of Serotonin Syndrome: Combining sertraline with other serotonergic agents, including certain opioids (tramadol, fentanyl), triptan migraine medications, and the herbal supplement St. John's wort, can cause a dangerous buildup of serotonin.
Monitor for Increased Bleeding: The combination of sertraline with NSAIDs (ibuprofen, naproxen, aspirin) and prescription blood thinners (warfarin, apixaban) significantly increases the risk of abnormal bleeding.
Steer Clear of Alcohol and Grapefruit: Alcohol can worsen sertraline's side effects, and grapefruit juice can increase the medication's levels in the body, both of which are generally advised against.
Consult Your Healthcare Provider: Always inform your doctor or pharmacist about all medications, supplements, and other substances you take to properly manage and prevent dangerous drug interactions.

Absolute Contraindications: Medications to Never Take with Sertraline

Certain medications are absolutely contraindicated for use with sertraline due to the high risk of severe, life-threatening complications. If you are taking any of these drugs, or have recently taken them, you must inform your doctor before starting sertraline therapy.

Monoamine Oxidase Inhibitors (MAOIs)

Combining sertraline with MAOIs is a critical drug interaction that can cause a life-threatening condition called serotonin syndrome. MAOIs are an older class of antidepressants and are also used to treat Parkinson's disease. A minimum of a 14-day washout period is required when switching from an MAOI to sertraline, or vice versa.

Examples of MAOIs to avoid include:
- Isocarboxazid (Marplan)
- Phenelzine (Nardil)
- Tranylcypromine (Parnate)
- Selegiline (Emsam, Zelapar)
- Rasagiline (Azilect)
- The antibiotic linezolid (Zyvox) is also a strong MAOI inhibitor and must be avoided.
- Intravenous methylene blue injection.

Certain Antipsychotics

Some antipsychotic drugs are strictly contraindicated with sertraline due to the risk of serious heart problems, including irregular heart rhythms (arrhythmias) like QT prolongation.

Pimozide (Orap): This antipsychotic should never be combined with sertraline.
Thioridazine: This medication is also contraindicated with sertraline.

Disulfiram and Sertraline Oral Solution

Sertraline oral concentrate contains 12% alcohol and should not be taken by patients who are also prescribed disulfiram (Antabuse), a medication for alcohol use disorder. Combining them can lead to an adverse disulfiram-alcohol reaction, with symptoms like flushing, vomiting, and palpitations.

The Risk of Serotonin Syndrome

Sertraline works by increasing serotonin levels in the brain. Taking other medications that also increase serotonin can lead to a dangerous buildup, causing a potentially fatal condition known as serotonin syndrome. Symptoms can range from mild (agitation, muscle twitching) to severe (high fever, seizures).

Other Antidepressants: Taking sertraline with other antidepressants, including other SSRIs, SNRIs (duloxetine, venlafaxine), or TCAs (amitriptyline, clomipramine), significantly raises the risk of serotonin syndrome.
Opioid Pain Relievers: Some opioids, such as tramadol and fentanyl, can increase serotonin levels and should be used cautiously or avoided with sertraline.
Migraine Medications (Triptans): Drugs like sumatriptan and rizatriptan can increase serotonin and elevate the risk when combined with sertraline.
Herbal Supplements: St. John's wort is a common herbal supplement used for depression that must be avoided, as it can cause a dangerous increase in serotonin.
Cough Medicine (Dextromethorphan): Found in many over-the-counter and prescription cough and cold remedies (e.g., Delsym), dextromethorphan is a mild serotonergic agent that can increase serotonin syndrome risk.
Other Agents: Lithium and amphetamines (e.g., Adderall) can also increase serotonin activity and should be used with extreme caution and under close medical supervision.

Increased Bleeding Risk: Sertraline, NSAIDs, and Blood Thinners

Sertraline can have an effect on blood platelets, leading to an increased risk of bleeding. This risk is compounded significantly when combined with other medications that also affect blood clotting, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and prescription blood thinners.

NSAIDs: Regular or high-dose use of NSAIDs like ibuprofen (Advil, Motrin), naproxen (Aleve), and aspirin increases the risk of serious gastrointestinal bleeding when combined with sertraline. Short-term, occasional use may be acceptable for some, but always consult a doctor first.
Blood Thinners: Patients on prescription anticoagulants (warfarin, apixaban, dabigatran, rivaroxaban) or antiplatelet drugs (clopidogrel) face a much higher risk of bleeding and should be closely monitored by their healthcare provider.

Other Notable Sertraline Interactions

Medications Affecting Heart Rhythm

Combining sertraline with drugs known to prolong the QT interval can increase the risk of dangerous arrhythmias. This includes some antibiotics (ciprofloxacin, azithromycin), antiarrhythmics (amiodarone, sotalol), and specific antipsychotics (ziprasidone).

Alcohol and Grapefruit Juice

Alcohol can exacerbate sertraline's side effects like drowsiness, dizziness, and impaired judgment. Health experts generally recommend avoiding alcohol entirely while on this medication. Grapefruit juice can increase sertraline levels in the bloodstream by inhibiting an enzyme involved in its metabolism (CYP3A4), potentially raising the risk of side effects.

Certain Seizure Medications

Sertraline can raise the blood levels of certain anti-seizure medications, such as phenytoin. Close monitoring and possible dosage adjustments are necessary if these are taken together.

Comparison of Key Sertraline Interactions


Substance/Class	Potential Risk	Recommended Action
MAOIs (Isocarboxazid, Linezolid)	Life-threatening serotonin syndrome.	Absolute contraindication. Observe a 14-day washout period.
Pimozide (Orap)	Dangerous heart rhythm problems (QT prolongation).	Absolute contraindication.
Other Serotonergic Drugs (Tramadol, Triptans, SSRIs)	Increased risk of serotonin syndrome.	Use with extreme caution under medical supervision. Monitor for symptoms.
NSAIDs (Ibuprofen, Naproxen, Aspirin)	Increased risk of internal bleeding.	Use cautiously. Consider acetaminophen as an alternative. Monitor for bleeding signs.
Blood Thinners (Warfarin, Apixaban)	Significantly increased risk of bleeding.	Close monitoring by a doctor is essential.
Alcohol	Worsened side effects like drowsiness; can impact judgment.	Avoid or limit consumption. Discuss with your doctor.
St. John's Wort	High risk of serotonin syndrome.	Absolute contraindication. Avoid entirely.
Grapefruit Juice	Increased sertraline levels, raising side effect risk.	Avoid or use with caution. Consult a doctor for supervision.

The Importance of Professional Guidance

This information is not a substitute for professional medical advice. A healthcare provider is best equipped to evaluate your medical history, current medications, and individual risk factors. Always provide your doctor and pharmacist with a complete and up-to-date list of all medications, over-the-counter products, and herbal supplements you are taking. They can help you navigate potential interactions and make informed decisions about your treatment. For more comprehensive information on sertraline, consult the National Alliance on Mental Illness (NAMI) website.

Conclusion

Sertraline is a widely used and effective medication for various mental health conditions, but it is not without risks, particularly concerning drug interactions. Severe and potentially fatal reactions, such as serotonin syndrome with MAOIs and other serotonergic drugs, and a heightened risk of bleeding with NSAIDs and anticoagulants, must be taken seriously. Interactions with substances like alcohol and herbal supplements also warrant careful consideration. By communicating openly with your healthcare team about all the substances you use, you can minimize risks and help ensure a safer, more effective course of treatment.

Frequently Asked Questions

The most dangerous interactions are with Monoamine Oxidase Inhibitors (MAOIs), including certain antidepressants and the antibiotic linezolid, which can cause life-threatening serotonin syndrome. The antipsychotic pimozide is also an absolute contraindication.

Combining sertraline with NSAIDs like ibuprofen, naproxen, or aspirin increases the risk of bleeding. While occasional use may be permitted for some, you should always consult your doctor first, especially if taking them regularly. Acetaminophen (Tylenol) is generally considered a safer pain relief alternative.

It is generally recommended to avoid alcohol while taking sertraline. The combination can heighten side effects such as drowsiness, dizziness, and impaired judgment, and alcohol can worsen underlying mood issues.

Serotonin syndrome is a potentially fatal condition caused by too much serotonin in the brain, often from combining serotonergic drugs. Symptoms include agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle twitching, heavy sweating, and diarrhea.

No, you should not take St. John's wort with sertraline. This herbal supplement increases serotonin levels and can cause serotonin syndrome, a dangerous drug reaction.

Many common cough medicines contain dextromethorphan, which can increase serotonin levels. It is best to consult your doctor or pharmacist before taking any over-the-counter cold or flu medications with sertraline to ensure there are no risky ingredients.

Yes, grapefruit juice can interact with sertraline by blocking an enzyme that metabolizes the medication. This can lead to increased sertraline levels and a higher risk of side effects. It is advisable to avoid grapefruit and grapefruit juice while on this medication.