What meds cannot be taken with amitriptyline?

October 13, 2025 •

4 min read

Amitriptyline, a tricyclic antidepressant (TCA) used for depression and nerve pain, is known to have a significant number of drug interactions. Because it affects multiple chemical systems in the brain and body, it is critical to understand what meds cannot be taken with amitriptyline to avoid potentially severe or life-threatening side effects.

Quick Summary

A guide detailing critical drug interactions with amitriptyline, including major contraindications like MAOIs and caution needed with SSRIs, CNS depressants, and other substances. High-risk combinations, potential outcomes, and the importance of medical consultation are covered.

Key Points

Avoid MAOIs: Never combine amitriptyline with Monoamine Oxidase Inhibitors due to the risk of fatal serotonin syndrome or hyperpyretic crisis.
Caution with other antidepressants: Combining amitriptyline with SSRIs or other serotonergic drugs can trigger serotonin syndrome and increase toxicity.
Limit CNS depressants: The sedative effects of amitriptyline are intensified by alcohol, opioids, and benzodiazepines, which can lead to respiratory depression.
Monitor heart health: Avoid drugs that prolong the QT interval (e.g., quinidine) to prevent dangerous cardiac arrhythmias.
Be mindful of liver metabolism: Some drugs and even grapefruit juice can inhibit the enzymes that process amitriptyline, increasing its concentration and side effects.
Review all medicines: Always provide a complete list of all medications, including OTCs and supplements like St. John's Wort, to your doctor before starting or changing amitriptyline.
Watch for anticholinergic effects: Combining with other anticholinergic drugs can worsen side effects like dry mouth, blurred vision, and urinary retention.

Amitriptyline is a powerful tricyclic antidepressant (TCA) and is frequently prescribed for conditions like major depressive disorder, neuropathic pain, and migraines. While effective, it carries a high risk of adverse reactions when combined with certain medications and substances due to its mechanism of action. Amitriptyline primarily works by increasing the availability of norepinephrine and serotonin in the central nervous system, but also has effects on other receptors, which increases its potential for harmful drug interactions. This guide outlines the key medications and substances that must be avoided or used with extreme caution when taking amitriptyline.

Major Contraindications: MAOIs

Monoamine Oxidase Inhibitors (MAOIs) represent one of the most serious and life-threatening contraindications for amitriptyline. Combining these two drug classes can lead to serotonin syndrome, a potentially fatal condition caused by excessive serotonin levels. The interaction can also result in hyperpyretic crisis, characterized by extremely high body temperature, severe convulsions, and blood pressure fluctuations. Due to the severity of this risk, a minimum 14-day washout period is required when switching between an MAOI and amitriptyline.

Examples of MAOIs to Avoid:

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

Medications That Increase Serotonin

Even outside of MAOIs, combining amitriptyline with other drugs that increase serotonin levels can precipitate serotonin syndrome. The risk and severity increase with higher doses and multiple interacting medications. Symptoms can range from agitation and confusion to seizures, arrhythmias, and unconsciousness.

Other Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs): Drugs like fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) significantly inhibit the CYP2D6 enzyme that metabolizes amitriptyline, increasing both serotonin levels and amitriptyline concentration in the body.
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs): Medications such as duloxetine (Cymbalta) and venlafaxine also increase serotonin and norepinephrine, posing a similar risk.
Other Tricyclic Antidepressants (TCAs): Co-administering different TCAs can result in dangerously high drug levels.

Opioid Pain Medications

Certain opioids, particularly tramadol (Ultram), affect serotonin pathways and can contribute to serotonin syndrome when taken with amitriptyline.

Dietary Supplements

Herbal supplements like St. John's Wort and supplements containing tryptophan or SAMe can increase serotonin and should be avoided.

Central Nervous System (CNS) Depressants

Amitriptyline itself has sedative properties. Combining it with other CNS depressants can lead to excessive drowsiness, dizziness, impaired motor function, and dangerously slowed breathing, which can be fatal.

Common CNS Depressants to Avoid

Alcohol: Significantly enhances the sedative effects of amitriptyline.
Benzodiazepines: Anti-anxiety medications like alprazolam (Xanax), diazepam (Valium), and lorazepam are known depressants.
Sedatives and Sleeping Pills: Medications such as zolpidem (Ambien).
Antihistamines: First-generation antihistamines like diphenhydramine (Benadryl) have strong sedative and anticholinergic effects.
Muscle Relaxants: Drugs like baclofen and cyclobenzaprine should be used with caution.

Cardiovascular Drugs and QT Prolongation

Amitriptyline can affect heart rhythm by prolonging the QT interval, a measure of electrical activity in the heart. Combining it with other QT-prolonging drugs increases the risk of dangerous arrhythmias.

Examples of QT-Prolonging Agents

Quinidine, Procainamide, Disopyramide (Class 1A antiarrhythmics)
Cisapride
Pimozide
Certain antibiotics (e.g., sparfloxacin, grepafloxacin)

Drugs That Affect Amitriptyline Metabolism

Certain medications can inhibit the liver enzymes (specifically CYP2D6 and CYP2C19) that break down amitriptyline. This inhibition leads to higher blood levels of amitriptyline, increasing the risk of side effects and toxicity.

Inhibitors to Be Aware Of

SSRI Antidepressants: As mentioned, paroxetine and fluoxetine are strong inhibitors of CYP2D6.
Cimetidine (Tagamet): A histamine H2 blocker that can increase amitriptyline levels.
Quinidine: Also a CYP2D6 inhibitor.
Topiramate (Topamax): Can potentially increase amitriptyline concentrations.
Grapefruit Juice: Can inhibit liver enzymes, leading to increased amitriptyline levels.

Interaction Risks Summary Table


Drug Class/Substance	Example(s)	Type of Interaction	Potential Outcome	Severity
MAOIs	Phenelzine, Isocarboxazid	Additive Serotonin	Serotonin Syndrome, Hyperpyretic Crisis	High
SSRIs	Fluoxetine, Sertraline	Additive Serotonin, CYP Inhibition	Serotonin Syndrome, Increased Toxicity	High
CNS Depressants	Alcohol, Benzodiazepines, Opioids	Additive Sedation	Extreme Drowsiness, Respiratory Depression	High
QT Prolonging Drugs	Quinidine, Cisapride	Additive QT Prolongation	Dangerous Arrhythmias	High
Sympathomimetic Agents	Pseudoephedrine, Amphetamines	Additive Cardiovascular Effect	Hypertension, Tachycardia	Medium to High
CYP2D6 Inhibitors	Paroxetine, Cimetidine	Decreased Amitriptyline Metabolism	Increased Amitriptyline Toxicity	Medium to High
Grapefruit Juice	Grapefruit Juice	Decreased Amitriptyline Metabolism	Increased Amitriptyline Toxicity	Medium
Anticholinergic Drugs	Diphenhydramine, Oxybutynin	Additive Anticholinergic Effects	Severe Constipation, Urinary Retention	Medium

Conclusion

Understanding what meds cannot be taken with amitriptyline is crucial for patient safety. The risk of serious adverse effects, including life-threatening serotonin syndrome and excessive CNS depression, necessitates a thorough review of all medications and supplements before beginning or adjusting amitriptyline therapy. Patients must always provide their healthcare provider with a complete list of their current prescriptions, over-the-counter medications, and supplements to prevent dangerous interactions. For a comprehensive overview of drug interactions, reliable resources like the U.S. National Library of Medicine can be consulted.

Disclaimer: This information is for educational purposes only and is not a substitute for professional medical advice. Always consult a healthcare provider for personalized medical guidance.

Frequently Asked Questions

Combining amitriptyline with SSRIs (e.g., Zoloft, Prozac) is generally not recommended due to a significant risk of serotonin syndrome, which can be life-threatening. This combination also increases amitriptyline levels, raising the risk of toxicity. Any such combination requires strict medical supervision and careful monitoring.

Mixing amitriptyline with alcohol can dangerously increase the sedative effects of both substances, leading to excessive drowsiness, dizziness, and impaired coordination. It can also increase the risk of severe central nervous system depression and breathing problems.

Many over-the-counter cold medicines contain ingredients like antihistamines (e.g., diphenhydramine) or sympathomimetics (e.g., pseudoephedrine), which can interact with amitriptyline. These can increase sedation or blood pressure, so it is essential to consult a pharmacist or doctor before taking them.

Combining amitriptyline with opioid pain medications, especially those that also affect serotonin like tramadol, can be dangerous and increase the risk of serotonin syndrome and sedation. Discuss all pain management options with your doctor before combining these medications.

Yes, grapefruit and grapefruit juice can interact with amitriptyline. They can inhibit the liver enzyme that metabolizes amitriptyline, leading to higher drug levels in the body and an increased risk of side effects and toxicity.

Taking amitriptyline with herbal supplements like St. John's Wort is very risky. St. John's Wort increases serotonin levels and can lead to serotonin syndrome when combined with amitriptyline. Other supplements like tryptophan and SAMe also pose a risk.

If you suspect you've taken a conflicting medication, especially an MAOI, or experience symptoms like agitation, confusion, fever, or a rapid heart rate, seek immediate medical attention. For less severe interactions, contact your healthcare provider or pharmacist for guidance.