Why Bupropion XR Drug Interactions Matter

If you're taking Bupropion XR (Wellbutrin XL), understanding drug interactions isn't optional — it's essential for your safety. Bupropion XR interacts with a number of common medications, and some combinations can cause serious problems, including seizures.

This guide covers the most important interactions, what to watch for with supplements and over-the-counter medications, and exactly what to tell your doctor before starting treatment.

How Drug Interactions Work with Bupropion XR

Bupropion XR can interact with other medications in two main ways:

1. Seizure threshold: Bupropion XR lowers your seizure threshold, meaning it makes seizures more likely. Any other medication that also lowers the seizure threshold can compound this risk.
2. Enzyme inhibition: Bupropion XR is a strong inhibitor of the liver enzyme CYP2D6. This enzyme is responsible for metabolizing many common medications. When Bupropion blocks CYP2D6, blood levels of those other medications can rise — sometimes to dangerous levels.

Additionally, Bupropion is primarily metabolized by the CYP2B6 enzyme. Medications that inhibit CYP2B6 can increase Bupropion levels in your body.

Medications That Interact with Bupropion XR

Major Interactions (Avoid or Use with Extreme Caution)

• MAO Inhibitors — including Phenelzine (Nardil), Tranylcypromine (Parnate), Isocarboxazid (Marplan), and Selegiline (Emsam). Combining Bupropion XR with an MAOI can trigger a hypertensive crisis. You must wait at least 14 days after stopping an MAOI before starting Bupropion XR, and vice versa.
• Linezolid (Zyvox) and Intravenous Methylene Blue — These drugs have MAOI properties and are contraindicated with Bupropion XR.
• Other Bupropion Products — Do not take Bupropion XR with Zyban (Bupropion SR for smoking cessation), Contrave (Bupropion/Naltrexone), or Auvelity (Dextromethorphan/Bupropion). Using multiple Bupropion products increases seizure risk.
• Thioridazine (Mellaril) — Bupropion's CYP2D6 inhibition can dangerously increase Thioridazine levels, raising the risk of QT prolongation and potentially fatal heart rhythm problems.

Seizure-Risk Interactions

The following medications lower the seizure threshold and should be used cautiously with Bupropion XR:

• Antipsychotics — such as Haloperidol (Haldol), Risperidone (Risperdal), Quetiapine (Seroquel)
• Theophylline — used for asthma/COPD
• Systemic corticosteroids — like Prednisone
• Tramadol (Ultram) — a pain medication that also lowers seizure threshold
• Stimulants — including Amphetamine salts (Adderall) and Methylphenidate (Ritalin)

CYP2D6-Related Interactions

Because Bupropion XR strongly inhibits CYP2D6, it can increase blood levels of many medications metabolized by this enzyme:

• SSRIs: Paroxetine (Paxil), Fluoxetine (Prozac), Fluvoxamine (Luvox)
• Beta-blockers: Metoprolol (Lopressor), Propranolol (Inderal)
• Antiarrhythmics: Flecainide (Tambocor), Propafenone (Rythmol)
• Antipsychotics: Risperidone (Risperdal), Aripiprazole (Abilify)
• Tamoxifen (Nolvadex) — Bupropion may reduce the effectiveness of Tamoxifen by blocking its conversion to the active metabolite Endoxifen. This is clinically significant for breast cancer patients.

CYP2B6-Related Interactions

These medications can increase Bupropion XR levels by inhibiting CYP2B6:

• Ticlopidine (Ticlid)
• Clopidogrel (Plavix)

Higher Bupropion levels can increase the risk of side effects, including seizures.

Moderate Interactions

• Digoxin (Lanoxin) — Bupropion may decrease Digoxin levels, potentially reducing its effectiveness for heart conditions.
• Levodopa and Amantadine — Used for Parkinson's disease; combining with Bupropion XR may increase the risk of adverse effects like nausea, tremor, and restlessness.
• Nicotine Replacement Therapy — Patches, gum, or lozenges used with Bupropion XR may increase blood pressure. Monitor blood pressure regularly if using both.

Supplements and OTC Medications to Watch

Not all interactions involve prescription drugs. Be cautious with:

• St. John's Wort — This herbal supplement has antidepressant properties and may increase serotonergic effects or lower the seizure threshold when combined with Bupropion XR.
• Diphenhydramine (Benadryl) — An antihistamine metabolized by CYP2D6; Bupropion may increase its sedating effects.
• Dextromethorphan (DXM) — Found in many cough medicines (Robitussin DM, NyQuil). Bupropion can significantly increase DXM levels. In fact, the combination is sold as the prescription drug Auvelity — but don't combine them on your own.
• Pseudoephedrine and other stimulating decongestants — May add to Bupropion's stimulating effects and raise blood pressure.
• Melatonin — Generally considered safe with Bupropion XR and may help with Bupropion-related insomnia, but discuss with your doctor.

Food and Drink Interactions

Alcohol

This is the big one. Alcohol should be minimized or avoided while taking Bupropion XR. Alcohol lowers the seizure threshold, and combining it with Bupropion XR increases seizure risk. Alcohol can also worsen depression and reduce the effectiveness of your treatment.

If you're a regular drinker, talk to your doctor before starting Bupropion XR. Abruptly stopping heavy alcohol use while on Bupropion XR is also dangerous — alcohol withdrawal itself lowers the seizure threshold.

Food

Bupropion XR can be taken with or without food. There are no significant food interactions that affect how the drug works.

Caffeine

While not a formal drug interaction, caffeine can amplify Bupropion XR's stimulating effects. If you're experiencing insomnia, jitteriness, or anxiety, consider reducing your caffeine intake.

What to Tell Your Doctor

Before starting Bupropion XR, give your doctor a complete picture:

• All prescription medications you currently take — including psychiatric medications, heart medications, and cancer drugs
• Over-the-counter medications — especially cough/cold medicines containing Dextromethorphan, antihistamines, and decongestants
• Supplements and herbal products — including St. John's Wort, melatonin, and others
• Alcohol use — be honest about how much and how often you drink
• History of seizures or any condition that increases seizure risk
• Other Bupropion products — make sure your doctor knows if you're already taking Zyban, Contrave, or Auvelity

Keep an updated medication list on your phone. It takes 30 seconds to update and could prevent a dangerous interaction.

Final Thoughts

Bupropion XR is a safe and effective medication for most people, but it interacts with enough drugs that you need to be thorough with your doctor and pharmacist. The biggest risks come from combining it with other seizure-threshold-lowering drugs, MAO inhibitors, and alcohol.

When in doubt, ask your pharmacist — they're drug interaction experts and can check your full medication profile in seconds. And if you need help finding Bupropion XR at your pharmacy, Medfinder can help you locate it in stock.