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

Doxepin has significant interactions with more than 100 different medications, supplements, and substances. Some are potentially life-threatening — making it critical to give your prescriber and pharmacist a complete list of everything you take before starting doxepin. This guide covers the most important interactions to know.

Contraindicated Combinations: Never Mix These with Doxepin

These combinations are medically contraindicated — meaning they should never be used together:

• MAOIs (monoamine oxidase inhibitors): Including phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl, Emsam), and isocarboxazid (Marplan). Combining doxepin with an MAOI can cause a potentially fatal drug reaction. You must wait at least 14 days after stopping an MAOI before starting doxepin, and at least 14 days after stopping doxepin before starting an MAOI.
• Intravenous methylene blue: A medication used in some procedures that has MAOI-like properties. Tell any treating physician or anesthesiologist that you are on doxepin.
• Linezolid (Zyvox): An antibiotic with MAOI properties. If you need linezolid urgently, your doxepin may need to be stopped first.

Major Interactions: Use with Caution or Avoid

These combinations significantly increase the risk of serious side effects:

• SSRIs and SNRIs (sertraline, fluoxetine, paroxetine, venlafaxine, etc.): Combining with doxepin raises serotonin levels excessively, risking serotonin syndrome (symptoms: rapid heartbeat, high fever, muscle stiffness, tremor, sweating, confusion). SSRIs like fluoxetine and paroxetine also inhibit CYP2D6 — the enzyme that metabolizes doxepin — causing doxepin blood levels to rise unpredictably.
• Other TCAs and serotonergic drugs: Any medication that raises serotonin levels — including St. John's Wort, tramadol, lithium, tryptophan, triptans (for migraines), and other antidepressants — can increase the risk of serotonin syndrome when combined with doxepin.
• Alcohol: One of the most important interactions. Alcohol is a CNS depressant that dramatically potentiates doxepin's sedating effects. Combining them increases the risk of dangerous over-sedation, respiratory depression, and impaired judgment. Avoid alcohol while taking doxepin.
• CNS depressants (benzodiazepines, opioids, sleep medications, muscle relaxants): Combining doxepin with medications like lorazepam, alprazolam, zolpidem, or oxycodone greatly amplifies sedation and can cause respiratory depression, especially in elderly patients or at higher doses.
• QT-prolonging medications: Doxepin can prolong the cardiac QT interval at higher doses. Taking it with other QT-prolonging drugs (some antipsychotics, certain antibiotics like azithromycin, antifungals) multiplies this risk. This can lead to dangerous heart arrhythmias including torsade de pointes.

Moderate Interactions: Monitor Closely

• Cimetidine (Tagamet): This common heartburn medication inhibits liver enzymes, increasing doxepin blood levels and risk of side effects. OTC cimetidine users should tell their doctor.
• CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion): These common antidepressants block the enzyme primarily responsible for doxepin metabolism. If added to a doxepin regimen, doxepin plasma levels may increase significantly — potentially requiring dose reduction.
• Anticholinergic medications: Combining doxepin with other anticholinergic drugs (oxybutynin, diphenhydramine, hydroxyzine, some antipsychotics, some bladder medications) increases anticholinergic burden, worsening dry mouth, constipation, confusion, and urinary retention — especially in elderly patients.
• Tolazamide (diabetes medication): A case of severe hypoglycemia has been reported with concurrent use of doxepin and tolazamide. Monitor blood sugar carefully if using both.

Food and Supplement Interactions

• Food (for Silenor): Taking doxepin insomnia tablets within 3 hours of a meal significantly slows absorption and can cause excessive next-day drowsiness. Always take Silenor at least 3 hours after eating.
• St. John's Wort: This popular herbal supplement raises serotonin levels. Combining with doxepin increases the risk of serotonin syndrome. Do not use St. John's Wort while taking doxepin.
• Cannabis (marijuana): Cannabis can increase CNS depression and anxiety. Tell your doctor if you use cannabis.

Genetic Factors: CYP2D6 and CYP2C19

Doxepin is primarily metabolized by two liver enzymes: CYP2D6 and CYP2C19. Some people are genetically "poor metabolizers" of these enzymes, meaning they break down doxepin more slowly — leading to higher drug levels and increased side effects at standard doses. If you've had unusual reactions to other medications metabolized by CYP2D6, tell your prescriber. Pharmacogenomic testing can help identify your metabolizer status before starting doxepin.

What to Tell Your Doctor and Pharmacist

Before starting doxepin, provide a complete list of all:

• Prescription medications (including psychiatric drugs, heart medications, antibiotics, antifungals)
• Over-the-counter medications (especially allergy pills, sleep aids, antacids)
• Vitamins and supplements (especially St. John's Wort, melatonin, tryptophan)
• Alcohol and recreational drug use

Your pharmacist is often the best first resource for drug interaction checks — they have access to interaction databases and can flag concerns your prescriber may not have noticed. For a broader overview of what to watch for with doxepin, see our guide on doxepin side effects.