Which drugs should not be taken with amitriptyline? A Guide to Dangerous Drug Interactions

October 9, 2025 •

4 min read

According to the U.S. Food and Drug Administration (FDA), amitriptyline carries a black box warning about interactions with other medications, particularly monoamine oxidase inhibitors (MAOIs). It is crucial for patients to understand which drugs should not be taken with amitriptyline to prevent serious health complications, ranging from excessive sedation to potentially fatal heart and nervous system issues.

Quick Summary

A guide to dangerous drug interactions with amitriptyline, detailing high-risk combinations with MAOIs, SSRIs, CNS depressants, anticholinergics, and substances like alcohol and St. John's wort to ensure medication safety. Always consult a healthcare provider.

Key Points

MAOIs are strictly prohibited: Never take monoamine oxidase inhibitors with amitriptyline due to the risk of life-threatening serotonin syndrome.
Caution with other antidepressants: Combining amitriptyline with SSRIs or SNRIs requires extreme caution and medical supervision due to the risk of serotonin syndrome and increased drug levels.
Avoid alcohol and CNS depressants: The combination of amitriptyline with alcohol, opioids, and other sedatives can cause excessive drowsiness, impaired coordination, and slowed breathing.
Beware of heart rhythm issues: Avoid other medications that can cause QT prolongation, as amitriptyline can increase the risk of dangerous heart arrhythmias.
Check for anticholinergic effects: Be aware of interactions with anticholinergic drugs, like some antihistamines, which can worsen side effects such as dry mouth and constipation.
Inform your doctor about all supplements: Certain supplements, particularly St. John's wort, can cause serious interactions and should be avoided.
Limit grapefruit consumption: Grapefruit and its juice can dangerously increase amitriptyline levels in the body.

Amitriptyline is a tricyclic antidepressant (TCA) prescribed for depression, nerve pain, and migraine prevention. While effective, it has a significant potential for dangerous interactions with other medications and substances due to its effects on neurotransmitters and various bodily systems. Knowing these interactions is vital for anyone taking this medication.

Drugs That are Absolutely Contraindicated with Amitriptyline

There are certain drug classes and individual medications that should never be combined with amitriptyline due to the risk of severe or life-threatening adverse effects.

Monoamine Oxidase Inhibitors (MAOIs)

The combination of amitriptyline with an MAOI is strictly forbidden and can cause a life-threatening condition called serotonin syndrome. Serotonin syndrome is caused by excessive serotonin levels in the brain and can lead to severe symptoms. A dangerous drug interaction can occur even after stopping an MAOI, so a minimum of 14 days must pass between discontinuing an MAOI and starting amitriptyline.

Examples of MAOIs include:

Isocarboxazid (Marplan)
Phenelzine (Nardil)
Selegiline (Eldepryl)
Tranylcypromine (Parnate)
Linezolid (Zyvox), an antibiotic with MAOI properties
Methylene blue, an antiseptic

Certain Heart Medications

Amitriptyline can affect heart rate and rhythm, increasing the risk of a dangerous heart rhythm condition called QT prolongation. Combining it with other drugs that have the same effect can lead to severe arrhythmias. For this reason, certain heart medications should be avoided.

Examples of drugs that prolong the QT interval include:

Quinidine
Procainamide
Cisapride
Pimozide
Terfenadine

Specific Dietary Supplements

Some over-the-counter supplements can have dangerous interactions. St. John's wort, often used for depression, should not be taken with amitriptyline as it can significantly increase the risk of serotonin syndrome. Other supplements like tryptophan can also increase serotonin levels and pose a risk.

Drug Interactions Requiring Extreme Caution and Monitoring

Some medications can be taken with amitriptyline under close medical supervision, but often require dose adjustments and careful monitoring.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Combining amitriptyline with other antidepressants like SSRIs (e.g., fluoxetine, sertraline) and SNRIs (e.g., duloxetine) is generally not recommended due to the increased risk of serotonin syndrome. Additionally, some SSRIs like fluoxetine and paroxetine can inhibit the liver enzymes that metabolize amitriptyline, causing its levels in the body to rise to toxic levels.

CNS Depressants and Alcohol

Both amitriptyline and Central Nervous System (CNS) depressants slow down brain activity. Combining them can cause excessive drowsiness, dizziness, confusion, and dangerously slowed breathing. Alcohol, benzodiazepines (e.g., Xanax, Valium), opioids (e.g., oxycodone, morphine), muscle relaxants, and some antihistamines (e.g., Benadryl) fall into this category and should be used with extreme caution or avoided entirely.

Anticholinergic Medications

Amitriptyline has anticholinergic effects, which can cause side effects like dry mouth, constipation, and urinary retention. Combining it with other anticholinergic drugs will intensify these effects and can lead to more serious complications like paralytic ileus.

Examples of anticholinergic drugs include:

First-generation antihistamines (like diphenhydramine)
Medications for overactive bladder (like oxybutynin)
Some medications for Parkinson's disease

Medications and Substances to Approach with Caution

Metabolism-Affecting Drugs

Some medications can interfere with the liver's metabolism of amitriptyline. Cimetidine (Tagamet HB) and quinidine can increase amitriptyline blood levels, leading to more side effects. Conversely, rifapentine can decrease amitriptyline levels, potentially reducing its effectiveness.

Grapefruit and Grapefruit Juice

Consuming grapefruit or grapefruit juice can inhibit the liver enzyme that processes amitriptyline, causing an increase in its blood levels and raising the risk of serious side effects and toxicity.

Table: Common Amitriptyline Interactions


Interaction Type	Interacting Drug Class	Risk Involved	Management Strategy
Serotonin Syndrome	MAOIs (Phenelzine, Isocarboxazid, Selegiline)	Potentially fatal, with symptoms like fever, agitation, and rapid heart rate.	Absolute contraindication; a 14-day washout period is required.
Serotonin Syndrome / Toxicity	SSRIs and SNRIs (Fluoxetine, Sertraline, Duloxetine)	Increased risk of serotonin syndrome and higher amitriptyline levels due to metabolic inhibition.	Close monitoring; dose adjustment or alternative therapy needed.
Excessive Sedation	CNS Depressants (Alcohol, Benzodiazepines, Opioids)	Severe drowsiness, confusion, impaired coordination, and respiratory depression.	Avoid concurrent use; extreme caution and low dosage if necessary.
Anticholinergic Toxicity	Anticholinergics (Diphenhydramine, Oxybutynin)	Intensified side effects like dry mouth, blurred vision, and urinary retention.	Avoid combining where possible; monitor closely for side effects.
Cardiac Arrhythmias	QT-prolonging agents (Quinidine, Cisapride)	Increased risk of dangerous heart rhythm irregularities.	Avoid concurrent use; amitriptyline is contraindicated after a recent heart attack.

Conclusion: Prioritize Open Communication

Amitriptyline is a powerful medication with a complex profile of potential drug interactions. Taking it with contraindicated medications like MAOIs or substances that increase serotonin can be life-threatening. Other combinations, such as with CNS depressants, require significant caution to prevent severe side effects. The risks are heightened when combining with other antidepressants, certain heart medications, or anticholinergic drugs.

It is paramount for patient safety that you always provide your healthcare provider and pharmacist with a complete list of all medications, over-the-counter drugs, supplements, and herbal products you are taking. Never start or stop any medication without consulting a doctor, as they can assess your specific health needs and ensure the safety of your treatment plan.

For more detailed information on specific drug interactions, consult authoritative sources like the U.S. National Library of Medicine or discuss your medication regimen with a healthcare professional.

National Library of Medicine

Frequently Asked Questions

No, it is highly recommended to avoid drinking alcohol while on amitriptyline. The combination of these two CNS depressants can lead to excessive drowsiness, impaired coordination, and potentially dangerous respiratory depression.

Serotonin syndrome is a potentially life-threatening condition caused by too much serotonin in the brain. Symptoms can include agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle stiffness, tremors, and sweating.

Combining amitriptyline with SSRIs (like sertraline or fluoxetine) is generally not recommended without extreme caution and close medical supervision due to the significant risk of serotonin syndrome and increased drug levels.

OTC pain relievers like acetaminophen are generally considered safe with amitriptyline, but it is always best to consult your pharmacist or doctor before taking any new medication, including those over-the-counter.

St. John's wort should not be taken with amitriptyline as it can significantly increase the risk of serotonin syndrome. You must tell your doctor about all herbal and dietary supplements you take.

You must wait at least 14 days after discontinuing an MAOI before starting amitriptyline to avoid a severe and dangerous drug interaction.

Yes, you should avoid consuming grapefruit and grapefruit juice while on amitriptyline. This can increase the levels of the medication in your body and raise the risk of serious side effects.