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

Mirtazapine interacts with a wide range of medications, supplements, and substances. Some of these interactions are life-threatening. Knowing what to avoid — and what to tell your doctor — is essential for using mirtazapine safely.

Contraindicated: MAO Inhibitors (Never Combine)

The most dangerous interaction is with monoamine oxidase inhibitors (MAOIs). Combining mirtazapine with an MAOI — or starting mirtazapine within 14 days of stopping an MAOI — can cause potentially fatal serotonin syndrome.

MAOIs contraindicated with mirtazapine include:

Phenelzine (Nardil)

Tranylcypromine (Parnate)

Isocarboxazid (Marplan)

Selegiline (Eldepryl, Zelapar, Emsam)

Linezolid (Zyvox) — an antibiotic with MAOI activity

IV methylene blue (used in surgery/procedures)

Rule: Wait at least 14 days after stopping an MAOI before starting mirtazapine. Wait at least 14 days after stopping mirtazapine before starting an MAOI.

Major Interaction: Serotonin Syndrome Risk with Other Serotonergic Drugs

Combining mirtazapine with other drugs that increase serotonin activity raises the risk of serotonin syndrome — a potentially life-threatening condition characterized by agitation, high fever, rapid heart rate, muscle rigidity, and diarrhea.

Serotonergic drugs to use cautiously or avoid with mirtazapine:

SSRIs: Sertraline (Zoloft), fluoxetine (Prozac), escitalopram (Lexapro), paroxetine (Paxil), citalopram (Celexa)

SNRIs: Venlafaxine (Effexor), duloxetine (Cymbalta)

Triptans: Sumatriptan (Imitrex), rizatriptan (Maxalt), and others

Opioids: Tramadol, fentanyl (serotonergic at high doses)

Lithium: Used for bipolar disorder; increases serotonin risk when combined

St. John's Wort: An over-the-counter herbal supplement with serotonergic activity — often overlooked

L-tryptophan: A dietary supplement that is a serotonin precursor — contraindicated with mirtazapine

Moderate Interaction: CNS Depressants (Additive Sedation)

Mirtazapine is already significantly sedating. Combining it with other CNS depressants can dangerously amplify sedation and impair breathing.

Alcohol: Significantly increases sedation. Avoid alcohol while on mirtazapine.

Benzodiazepines: Alprazolam (Xanax), lorazepam (Ativan), diazepam (Valium) — additive sedation, impaired coordination

Opioid pain medications: Additive CNS depression; risk of respiratory depression

Sleep medications: Zolpidem (Ambien), eszopiclone (Lunesta) — excessive sedation possible

Moderate Interaction: CYP Enzyme Inducers and Inhibitors

Mirtazapine is metabolized by liver enzymes CYP1A2, CYP2D6, and CYP3A4. Drugs that affect these enzymes can change mirtazapine blood levels:

CYP inducers (decrease mirtazapine levels): Phenytoin (Dilantin), carbamazepine (Tegretol), rifampin — can reduce mirtazapine efficacy; dose may need to be increased

CYP3A4 inhibitors (increase mirtazapine levels): Ketoconazole, certain HIV medications — can raise mirtazapine to toxic levels; dose may need to be reduced

Other Notable Interactions

Warfarin: Mirtazapine at higher doses may increase warfarin's blood-thinning effect. INR should be monitored when doses change.

Clonidine: Mirtazapine may antagonize clonidine's blood pressure-lowering effect, reducing its effectiveness.

QT-prolonging drugs: Mirtazapine has indeterminate QT-prolongation risk. When combined with drugs with known QT-prolonging effects, cardiac monitoring may be warranted.

What to Tell Your Doctor Before Starting Mirtazapine

Always tell your prescriber and pharmacist about:

All prescription medications, including antibiotics, anticonvulsants, blood thinners, and psychiatric medications

Over-the-counter supplements, especially St. John's Wort, L-tryptophan, and 5-HTP

Herbal products and vitamins

Any upcoming surgical procedures (IV methylene blue used in some surgeries interacts with mirtazapine)

Also see: Mirtazapine side effects: what to expect and when to call your doctor.

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