Nortriptyline Drug Interactions: What to Avoid and What to Tell Your Doctor

Nortriptyline has documented interactions with more than 500 other medications — ranging from serious to mild. Before starting nortriptyline, you must tell your prescriber and pharmacist about every medication, supplement, and herbal product you take. Some combinations can be life-threatening.

CRITICAL: Contraindicated Combinations (Never Take Together)

These combinations with nortriptyline are absolutely contraindicated — they can be fatal:

MAO inhibitors (MAOIs): Including phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), selegiline, rasagiline, and safinamide. Taking MAOIs with nortriptyline can cause hyperpyretic crisis (dangerously high fever), severe convulsions, and death. A washout period of at least 14 days is required after stopping an MAOI before starting nortriptyline. At least 5 weeks are required after stopping fluoxetine (due to its long half-life).

Linezolid (Zyvox) and IV methylene blue: These agents have MAOI properties. Do not start nortriptyline while taking linezolid or within 24 hours of receiving IV methylene blue.

Pimozide and thioridazine: Combining these antipsychotics with nortriptyline creates an unacceptable risk of QT prolongation and potentially fatal cardiac arrhythmias.

Serious Interactions: Use With Extreme Caution

These combinations require medical supervision, dose adjustments, and close monitoring:

SSRIs (serotonin syndrome risk): Sertraline, fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone. Combining nortriptyline with SSRIs significantly increases serotonin levels and can cause serotonin syndrome — a potentially life-threatening condition characterized by agitation, confusion, rapid heart rate, high fever, and muscle spasms.

SNRIs: Duloxetine, venlafaxine, desvenlafaxine. Similar serotonin syndrome risk as SSRIs. Additionally, duloxetine and paroxetine are CYP2D6 inhibitors that increase nortriptyline blood levels.

QT-prolonging drugs: Amiodarone, quinidine, sotalol, procainamide, dofetilide, erythromycin, clarithromycin, azithromycin, haloperidol, quetiapine, ziprasidone. All increase the risk of cardiac arrhythmias when combined with nortriptyline.

CYP2D6 inhibitors (increase nortriptyline levels): Fluoxetine, paroxetine, bupropion, quinidine, terbinafine (Lamisil). These drugs slow nortriptyline metabolism, raising blood levels and risk of toxicity. Dose adjustments are required when adding or removing these drugs.

Anticholinergic drugs (additive effects): Antihistamines (diphenhydramine, cetirizine), bladder medications (oxybutynin, tolterodine), Parkinson's medications (benztropine, trihexyphenidyl), scopolamine, and many others. Combining anticholinergics with nortriptyline increases the risk of severe constipation, urinary retention, confusion, and heat stroke (especially in elderly patients).

Clonidine: Nortriptyline blocks clonidine's blood pressure-lowering effect, potentially causing dangerous elevation in blood pressure (hypertensive crisis).

Tramadol: Increased risk of serotonin syndrome and seizures.

Moderate Interactions: Use With Care

CNS depressants and alcohol: Benzodiazepines, opioids, sleep aids, muscle relaxants. Nortriptyline significantly enhances CNS depressant effects. Alcohol response is markedly exaggerated.

Thyroid medications: Thyroid hormones may enhance TCA effects and increase risk of cardiac arrhythmias.

Cimetidine (Tagamet): Commonly available OTC for heartburn. Can significantly increase nortriptyline blood levels by inhibiting its metabolism. Avoid concurrent use if possible.

St. John's Wort: An herbal supplement that increases serotonin and can cause serotonin syndrome when combined with nortriptyline. Also reduces nortriptyline blood levels by inducing CYP enzymes. Tell your doctor about all supplements.

Signs of Serotonin Syndrome (Call 911)

Serotonin syndrome is a medical emergency. Seek emergency care immediately if you experience:

Agitation, confusion, or rapid mental status changes

Rapid heartbeat and high blood pressure

High fever and excessive sweating

Muscle twitching, stiffness, or loss of coordination

Nausea, vomiting, or diarrhea in combination with the above symptoms

What to Tell Your Doctor Before Starting Nortriptyline

Bring a complete medication list to every appointment, including:

All prescription medications (including psychiatric meds, heart medications, blood pressure drugs)

All over-the-counter medications (including sleep aids, antihistamines, heartburn medications like cimetidine)

All herbal supplements (especially St. John's Wort, valerian, kava)

Any recent or planned antibiotic prescriptions (many antibiotics prolong QT interval)

For a complete overview of all nortriptyline side effects — including what's expected versus what requires a doctor call — see: Nortriptyline Side Effects: What to Expect and When to Call Your Doctor.