What Medications Cannot Be Taken With Amitriptyline? A Guide to Serious Drug Interactions

October 6, 2025 •

4 min read

With over 720 known drug interactions, it is crucial to understand what medications cannot be taken with amitriptyline to prevent serious health complications. This guide explores the most significant drug combinations to avoid while on this tricyclic antidepressant.

Quick Summary

Certain drug combinations with amitriptyline pose significant risks, including monoamine oxidase inhibitors (MAOIs) due to serotonin syndrome risk and central nervous system depressants causing excessive sedation. Other critical interactions involve medications affecting heart rhythm and those with anticholinergic properties.

Key Points

Monoamine Oxidase Inhibitors (MAOIs): Never take MAOIs and amitriptyline together. A 14-day washout period is required when switching due to the risk of fatal serotonin syndrome.
Serotonergic Drug Combinations: Use extreme caution when combining amitriptyline with SSRIs, SNRIs, certain opioids (like tramadol), and St. John's Wort to avoid serotonin syndrome.
Central Nervous System (CNS) Depressants: Avoid alcohol, sedatives, opioids, and certain antihistamines, as combining them with amitriptyline can cause excessive drowsiness, confusion, and slowed breathing.
Anticholinergic Overload: Be aware of other medications with anticholinergic properties (e.g., some antihistamines, bladder drugs) to prevent severe constipation, urinary retention, and cognitive issues.
QT-Prolonging Risks: Do not mix amitriptyline with other drugs known to prolong the QT interval (e.g., certain antiarrhythmics, antipsychotics) due to the heightened risk of serious heart rhythm problems.
Metabolism Inhibitors: Be cautious with medications like fluoxetine or cimetidine that inhibit the CYP2D6 enzyme, as this can increase amitriptyline levels and the risk of toxicity.
Always Consult a Healthcare Provider: The potential for drug interactions is high; always inform your doctor or pharmacist of all medications, including over-the-counter and herbal supplements, before starting amitriptyline.

Understanding Amitriptyline's Interaction Mechanisms

Amitriptyline is a tricyclic antidepressant (TCA) that works by increasing the levels of certain neurotransmitters, such as serotonin and norepinephrine, in the brain. However, its broad pharmacological profile means it affects several other systems in the body, leading to numerous potential drug interactions. Knowing the mechanisms behind these interactions is key to understanding why certain medications must be avoided.

Key interaction mechanisms include:

Serotonergic effects: By increasing serotonin levels, amitriptyline can contribute to serotonin syndrome, a potentially life-threatening condition, when combined with other serotonergic drugs.
Central Nervous System (CNS) depression: Amitriptyline causes drowsiness and sedation. When combined with other CNS depressants, this effect can be significantly enhanced, leading to profound sedation, confusion, and even respiratory depression.
Anticholinergic effects: Amitriptyline blocks the action of acetylcholine, causing side effects like dry mouth, constipation, and blurred vision. Taking other anticholinergic drugs can worsen these effects to a dangerous degree.
Cytochrome P450 enzyme inhibition: Amitriptyline is broken down by liver enzymes, particularly CYP2D6. Other medications that inhibit this enzyme can cause amitriptyline levels to build up in the body, increasing the risk of toxicity.
QT prolongation: Amitriptyline can affect the heart's electrical activity, prolonging the QT interval. Combining it with other drugs that have the same effect can lead to severe arrhythmias.

Serious Contraindications and Drug Categories to Avoid

Monoamine Oxidase Inhibitors (MAOIs)

The combination of amitriptyline and MAOIs is strictly contraindicated and can lead to a severe, potentially fatal condition called serotonin syndrome. A washout period of at least 14 days is required when switching between these medications. Examples of MAOIs include:

Isocarboxazid
Phenelzine
Tranylcypromine
Selegiline
Linezolid (an antibiotic with MAOI properties)
Methylene blue (given by injection)

Serotonergic Medications

While not strictly forbidden like MAOIs, combining amitriptyline with other drugs that increase serotonin levels should be done with extreme caution and under close medical supervision due to the risk of serotonin syndrome. The risk and severity depend on the specific medication and dosage. This category includes:

Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft)
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs): e.g., Venlafaxine, Duloxetine
Opioid pain medications: e.g., Tramadol, Fentanyl, Oxycodone
Triptans for migraines: e.g., Sumatriptan
Herbal supplements: St. John's Wort

Central Nervous System (CNS) Depressants

Combining amitriptyline with other substances that cause CNS depression can lead to heightened sedation, impaired coordination, confusion, and dangerously slowed breathing. Examples include:

Alcohol: Drinking alcohol can intensify the sedative effects of amitriptyline.
Opioids: e.g., Hydrocodone, Morphine
Benzodiazepines: e.g., Alprazolam (Xanax), Diazepam (Valium)
Sedatives and sleeping pills: e.g., Zolpidem (Ambien)
Muscle relaxants
First-generation antihistamines: e.g., Diphenhydramine (Benadryl)

Anticholinergic Medications

Combining amitriptyline with other drugs that block acetylcholine can lead to severe anticholinergic effects, which are particularly risky for the elderly. This can cause severe constipation (potentially leading to ileus), urinary retention, blurred vision, and cognitive impairment. These include:

First-generation antihistamines: Diphenhydramine
Medications for overactive bladder: Oxybutynin, Tolterodine
Medications for Parkinson's disease: Benztropine
Antipsychotics: Olanzapine, Quetiapine

Medications that Prolong the QT Interval

To prevent serious heart rhythm problems, it is crucial to avoid combining amitriptyline with other drugs that prolong the QT interval. Examples include:

Certain antiarrhythmics: Quinidine, Sotalol, Amiodarone
Some antipsychotics: Pimozide, Thioridazine
Antibiotics: Some macrolides like Azithromycin

Comparison of Major Amitriptyline Drug Interactions


Interaction Category	Mechanism of Risk	Primary Risk	Examples of Medications	Management	Citations
MAOIs	Extreme increase in serotonin levels	Serotonin Syndrome (life-threatening)	Isocarboxazid, Phenelzine, Selegiline, Linezolid	Strictly contraindicated; minimum 14-day washout period required.
SSRIs & SNRIs	Increased serotonin levels; enzyme inhibition	Serotonin Syndrome, increased amitriptyline toxicity	Fluoxetine, Sertraline, Venlafaxine	Monitor closely; dose adjustment needed; avoid if possible.
CNS Depressants	Additive CNS depressive effects	Profound sedation, respiratory depression	Alcohol, Opioids, Benzodiazepines, Sleep aids, Antihistamines	Avoid or use with extreme caution; patient education vital.
Anticholinergics	Additive anticholinergic effects	Worsened side effects (constipation, urinary retention, confusion)	Diphenhydramine, Oxybutynin, Antipsychotics	Monitor closely, especially in the elderly; careful dosing.
QT-Prolonging Drugs	Additive effect on heart rhythm	Severe arrhythmia, sudden cardiac death	Quinidine, Sotalol, Pimozide	Generally avoided; requires careful cardiac monitoring if necessary.
Sympathomimetics	Increased norepinephrine levels	High blood pressure, tachycardia	Pseudoephedrine	Avoid or monitor blood pressure very closely.
Metabolism Inhibitors	Inhibition of CYP2D6 liver enzyme	Increased amitriptyline blood levels and toxicity	Cimetidine, Fluoxetine, Paroxetine	Dose adjustment or alternative medication may be necessary.

Conclusion

Amitriptyline's complex pharmacological profile means it interacts with a wide range of medications and substances, some of which can cause life-threatening reactions like serotonin syndrome or severe cardiac issues. Many other combinations can lead to excessive sedation or dangerously amplify common side effects. The key to safe treatment is comprehensive communication with your healthcare provider. Always disclose every medication, supplement, and herbal product you are taking before starting or stopping amitriptyline. Never adjust doses or combine medications on your own. Given the risks, understanding what medications cannot be taken with amitriptyline is a critical aspect of patient safety.

For more information on the complexities of drug interactions, you can consult reliable sources such as the FDA's drug interaction resources.

https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers

Frequently Asked Questions

No, you should avoid or strictly limit alcohol consumption while taking amitriptyline. Both are central nervous system depressants, and combining them can cause severe drowsiness, dizziness, and confusion, significantly impairing judgment and coordination.

Serotonin syndrome is a potentially fatal condition caused by an excess of serotonin in the body. Since amitriptyline increases serotonin levels, combining it with other serotonergic drugs like SSRIs, SNRIs, or MAOIs can lead to a dangerous build-up, causing symptoms like agitation, rapid heartbeat, high blood pressure, and tremors.

Combining amitriptyline with other antidepressants, especially MAOIs, is highly dangerous and contraindicated. When considering use with SSRIs or SNRIs, extreme caution is necessary, and it should only be done under very careful medical supervision due to the risk of serotonin syndrome and altered drug metabolism.

If you suspect you have experienced a drug interaction or are showing symptoms of serotonin syndrome (e.g., agitation, confusion, fast heart rate), seek immediate medical attention or call emergency services. Do not wait for the symptoms to worsen.

You should be very cautious with OTC medications. Avoid cough and cold remedies containing dextromethorphan or antihistamines like diphenhydramine, as they can increase sedation and the risk of serotonin syndrome. Always read labels and consult a pharmacist before taking any OTC drugs.

No, certain herbal supplements, most notably St. John's Wort, can interact dangerously with amitriptyline by further increasing serotonin levels, posing a risk for serotonin syndrome. Always disclose all supplements to your doctor.

Amitriptyline can affect heart rhythm, specifically prolonging the QT interval. Combining it with other medications that have the same effect (e.g., quinidine, sotalol) can increase the risk of severe, potentially fatal, heart arrhythmias.