What medications cannot be taken with antidepressants? A comprehensive guide to dangerous interactions

October 10, 2025 •

4 min read

According to reports in Medscape, serotonin syndrome is a potentially fatal condition caused by an excess of serotonin, which is a key risk when combining certain drugs with antidepressants. This guide provides comprehensive information on what medications cannot be taken with antidepressants to help patients and caregivers understand and prevent dangerous drug interactions.

Quick Summary

This guide details dangerous medication, supplement, and food interactions with antidepressants, emphasizing the risks of serotonin syndrome and hypertensive crisis. It outlines specific classes to avoid, including MAOIs, NSAIDs, opioids, and certain OTC cold medicines.

Key Points

Serotonin Syndrome: Mixing antidepressants, especially MAOIs, with other serotonergic agents like SSRIs, opioids (tramadol), or triptans can cause a dangerous serotonin overload.
MAOI Food Interactions: MAOIs require strict dietary restrictions, as combining them with tyramine-rich foods like aged cheeses and cured meats can cause a hypertensive crisis.
Increased Bleeding Risk: SSRIs and SNRIs can increase the risk of bleeding, especially when combined with NSAIDs like ibuprofen or aspirin, requiring caution.
OTC Medication Dangers: Many over-the-counter products, particularly cold and cough medicines containing dextromethorphan or decongestants, can have dangerous interactions with antidepressants, especially MAOIs.
Avoid Herbal and Illicit Drugs: St. John's Wort, an herbal remedy for depression, can trigger serotonin syndrome when taken with antidepressants, while illicit substances like MDMA and cocaine are highly dangerous.
Washout Periods: When switching from an MAOI to another antidepressant, a mandatory drug-free 'washout period' is required to prevent a potentially fatal interaction.

Navigating the complexities of medication can be challenging, and understanding potential drug interactions is critical for safety. Antidepressants, while effective for treating depression and other mental health conditions, can react adversely with a wide range of other substances, from prescription drugs to over-the-counter (OTC) remedies and even certain foods. The most significant risks include serotonin syndrome and hypertensive crisis, which can range from mild discomfort to life-threatening emergencies.

Understanding High-Risk Interactions

The Threat of Serotonin Syndrome

Serotonin syndrome is a serious and potentially fatal condition that results from an excess of serotonin in the central nervous system. It most often occurs when multiple medications that increase serotonin levels are taken together. Symptoms can include agitation, anxiety, confusion, rapid heart rate, high blood pressure, dilated pupils, fever, tremors, muscle rigidity, and diarrhea. Severe cases can lead to seizures, kidney failure, coma, and death.

The Danger of Hypertensive Crisis

For patients taking Monoamine Oxidase Inhibitors (MAOIs), a severe interaction known as a hypertensive crisis is a major concern. This involves a dangerous and sudden spike in blood pressure that can lead to a stroke or heart attack. It happens when MAOIs are combined with certain foods or medications that contain tyramine or act as sympathomimetics, which elevate blood pressure.

High-Risk Medication Classes to Avoid

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are an older class of antidepressants that are less commonly prescribed today due to their numerous and potentially dangerous interactions. However, they are still used for certain cases of treatment-resistant depression. The list of substances to avoid is extensive:

Other Antidepressants: Never combine an MAOI with a selective serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), or tricyclic antidepressant (TCA). A washout period of at least two weeks (longer for some drugs) is required when switching between these medications.
Certain Opioids: Opioid pain medications like tramadol, meperidine (Demerol), and fentanyl can interact dangerously, leading to severe serotonin syndrome. It is crucial to inform your doctor about your antidepressant before receiving any pain medication.
Cold and Cough Medicines: Many common OTC cold and cough products contain ingredients that can interact with MAOIs. These include dextromethorphan (a cough suppressant), pseudoephedrine, and phenylephrine (decongestants).
Herbal Supplements: St. John's Wort and other supplements that affect serotonin levels are also strictly contraindicated.
Tyramine-Rich Foods: A hypertensive crisis can be triggered by eating foods high in tyramine, which MAOIs block the breakdown of. These include aged cheeses, cured meats, fermented foods, tap beers, and certain beans.

Selective Serotonin Reuptake Inhibitors (SSRIs) and SNRIs

Though generally safer than MAOIs, SSRIs and SNRIs also have important interactions to be aware of. The primary concern is combining them with other serotonergic agents or drugs that increase bleeding risk.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Combining SSRIs or SNRIs with NSAIDs like ibuprofen, aspirin, or naproxen can increase the risk of gastrointestinal bleeding. If you need pain relief, acetaminophen is often a safer alternative, but always consult a doctor or pharmacist.
Opioids and Triptans: Certain opioids (e.g., tramadol) and triptan medications for migraines can increase the risk of serotonin syndrome when combined with SSRIs/SNRIs.
Other Serotonergic Medications: A variety of drugs and supplements, including some anti-emetics (ondansetron), stimulants, and lithium, can also increase serotonin levels, raising the risk of serotonin syndrome.

Recreational Drugs and Alcohol

Recreational drugs and alcohol pose significant risks when combined with antidepressants.

Alcohol: Alcohol is a central nervous system depressant and can counteract the benefits of antidepressants, worsening symptoms of depression and anxiety. It can also increase sedation and impairment, and is strictly forbidden with MAOIs due to hypertensive crisis risk.
MDMA (Ecstasy), Cocaine, and Amphetamines: These illicit drugs drastically increase serotonin levels and, when combined with antidepressants, can cause severe and potentially fatal serotonin syndrome.

Comparison Table of Antidepressant Drug Interactions


Antidepressant Class	Interacting Drug/Substance	Potential Risk	Recommendations
MAOIs	Other Antidepressants (SSRIs, SNRIs)	Severe Serotonin Syndrome	Strict contraindication; require a washout period.
MAOIs	Tyramine-Rich Foods (aged cheese, cured meats, tap beers)	Hypertensive Crisis (dangerously high blood pressure)	Strict dietary restrictions required.
MAOIs	OTC Decongestants (pseudoephedrine)	Hypertensive Crisis	Avoid all decongestants unless explicitly approved by a doctor.
SSRIs/SNRIs	NSAIDs (ibuprofen, aspirin)	Increased risk of gastrointestinal bleeding	Use with caution; consider acetaminophen instead.
SSRIs/SNRIs	Opioids (tramadol, fentanyl)	Serotonin Syndrome	Use with caution, under strict medical supervision.
All Antidepressants	St. John's Wort	Serotonin Syndrome and reduced effectiveness	Avoid this herbal supplement.

Always Consult a Healthcare Provider

This information is not a substitute for professional medical advice. Always consult your doctor or pharmacist before taking any new medication, supplement, or herbal product. It is vital to provide them with a complete list of all drugs and supplements you are taking. Open communication ensures your treatment is safe and effective.

Conclusion

While antidepressants offer a vital pathway to managing depression and other mental health conditions, understanding their potential for dangerous interactions is a critical component of safe treatment. The risks associated with combining MAOIs with other antidepressants, certain foods, and recreational drugs are well-documented and severe. For those on more commonly prescribed SSRIs and SNRIs, vigilance is still necessary, particularly regarding NSAIDs, specific pain relievers, and herbal supplements like St. John's Wort. By prioritizing open communication with healthcare providers and being diligent about what you consume, you can navigate your treatment safely and effectively. For more information on drug interactions, consult the NIH's resource page.

Frequently Asked Questions

Serotonin syndrome is a potentially life-threatening condition caused by too much serotonin in the brain, typically resulting from combining two or more medications that increase serotonin levels. Symptoms include agitation, high blood pressure, and muscle rigidity.

Combining SSRIs or SNRIs with NSAIDs like ibuprofen or aspirin can increase the risk of gastrointestinal bleeding. It is best to consult your doctor, who may suggest acetaminophen as a safer alternative.

If you are taking an MAOI antidepressant, you must avoid foods high in tyramine, such as aged cheeses, cured meats, and fermented products. Consuming these foods can lead to a dangerous hypertensive crisis.

No, St. John's Wort should never be combined with prescription antidepressants. Both increase serotonin levels, and the combination can lead to a dangerous case of serotonin syndrome.

You should avoid OTC cold medicines containing dextromethorphan, pseudoephedrine, or phenylephrine, especially if you are taking an MAOI. Always read labels and consult your pharmacist for safe options.

It is generally recommended to avoid alcohol while taking antidepressants. Alcohol can worsen depression and anxiety symptoms, increase side effects like drowsiness, and is strictly forbidden with MAOIs due to the risk of hypertensive crisis.

A washout period is a mandatory drug-free interval required when a patient stops taking an MAOI and before starting another antidepressant. This waiting period prevents potentially fatal interactions, and its length depends on the medications involved.