Bupropion has a long list of interactions, some dangerous and some that simply make the medication less effective. The most critical ones involve MAO inhibitors, alcohol, seizure-lowering drugs, and certain antibiotics. Beyond those, several common supplements, other antidepressants, and even abrupt withdrawal from substances like benzodiazepines can cause serious problems.
MAO Inhibitors and Related Drugs
The most dangerous combination is bupropion with any monoamine oxidase inhibitor (MAOI). These include older antidepressants like phenelzine and tranylcypromine. Taking both together can trigger severe spikes in blood pressure. If you’re switching from an MAOI to bupropion or vice versa, a washout period of at least two weeks is required between stopping one and starting the other.
Two medications that people don’t always realize act as MAOIs are linezolid (an antibiotic) and intravenous methylene blue (used in certain medical procedures). The FDA lists both as contraindicated with bupropion. If you need urgent treatment with either drug, bupropion must be stopped first, and you’d need to be monitored for two weeks or until 24 hours after the last dose, whichever comes first. Methylene blue given by mouth or in very low intravenous doses carries an unclear level of risk, but the potential for interaction still exists.
Alcohol
Alcohol and bupropion are a bad combination in both directions. Drinking while taking bupropion raises your seizure risk, and even one or two drinks can pose a problem. But the flip side is equally important: if you’re a regular drinker and suddenly stop while on bupropion, the abrupt withdrawal itself lowers your seizure threshold further. That combination of bupropion plus alcohol withdrawal can cause tremors, confusion, dizziness, loss of coordination, and seizures.
This means you shouldn’t start bupropion if you’re currently drinking heavily and plan to quit cold turkey. Your prescriber needs to know your drinking habits so they can plan a safe approach.
Drugs That Lower the Seizure Threshold
Bupropion already carries a dose-dependent seizure risk on its own. One emergency department study found that therapeutic-dose bupropion was the third leading cause of drug-related new-onset seizures, behind only cocaine intoxication and benzodiazepine withdrawal. Adding other medications that lower the seizure threshold compounds this risk.
The categories to watch include:
- Benzodiazepine withdrawal: If you’re taking a benzodiazepine and stop abruptly while on bupropion, seizure risk climbs significantly. This applies to drugs like alprazolam, lorazepam, and diazepam.
- Barbiturate withdrawal: The same principle applies. Stopping barbiturates or antiepileptic drugs suddenly while on bupropion is contraindicated.
- Stimulants and cocaine: These further lower the seizure threshold.
Bupropion is also contraindicated if you have a seizure disorder or conditions that increase seizure risk, including severe head injury, brain tumors, or a history of stroke.
Eating Disorders
Bupropion is contraindicated in anyone with a current or prior diagnosis of bulimia or anorexia nervosa. Clinical data showed a higher incidence of seizures in patients with these conditions compared to the general population taking bupropion. This isn’t a relative caution; it’s a hard contraindication listed on the label. If you have a history of either condition, even if it was years ago, your prescriber needs to know.
SSRIs, SNRIs, and Serotonin Syndrome
Bupropion is sometimes prescribed alongside an SSRI or SNRI, but this combination carries risk. Post-marketing data show a possible interaction that increases the chance of serotonin syndrome, a potentially life-threatening condition where excess serotonin activity causes a cluster of symptoms: agitation, hallucinations, rapid heart rate, unstable blood pressure, high body temperature, exaggerated reflexes, loss of coordination, nausea, vomiting, and diarrhea.
Australia’s drug safety authority has received reports of serotonin syndrome specifically linked to bupropion combined with SSRIs or SNRIs. This risk is highest when starting the combination or increasing doses. Serotonin syndrome has also been reported with bupropion overdose alone. If your doctor has prescribed both, the combination isn’t automatically off-limits, but you should know what symptoms to watch for, particularly in the first few weeks.
Drugs That Change Bupropion Levels
Bupropion is broken down in the liver by a specific enzyme called CYP2B6. Other medications that block or speed up this enzyme can push bupropion levels too high or too low in your bloodstream.
Medications that slow bupropion’s breakdown (raising its levels and potentially its side effects) include the blood thinner clopidogrel, the antidepressant sertraline, and ticlopidine. On the other side, medications that speed up bupropion’s breakdown (making it less effective) include carbamazepine, which is a strong accelerator, rifampin (an antibiotic used for tuberculosis), and phenobarbital. If you’re taking any of these, your bupropion dose may need adjustment.
Dopamine-Boosting Medications
Bupropion increases dopamine activity in the brain, so combining it with other dopamine-boosting drugs can cause an overload. Amantadine, used for Parkinson’s disease and sometimes for flu prevention, has been linked to neurotoxic effects when added to bupropion. In published case reports, three elderly patients developed dizziness, vertigo, agitation, tremors, and difficulty walking after the combination. The symptoms resolved within 72 hours of stopping both drugs. The likely explanation is that the two medications together pushed dopamine activity too high.
Levodopa and other dopamine agonists used for Parkinson’s disease carry similar theoretical risks. If you take any medication for movement disorders, your prescriber should evaluate the combination carefully.
Supplements and Herbal Products
St. John’s Wort, a widely used herbal supplement for mood, interacts with bupropion. According to the Mayo Clinic, St. John’s Wort can reduce bupropion’s effectiveness. This likely happens because St. John’s Wort speeds up the liver enzymes that break bupropion down, similar to how carbamazepine and rifampin work. If you’re relying on bupropion for depression or smoking cessation, adding St. John’s Wort could undermine the benefit without you realizing it.
St. John’s Wort also has its own serotonergic activity, which adds another layer of concern given the serotonin syndrome risk already associated with bupropion. Stopping St. John’s Wort if you’re already taking it is worth discussing with whoever prescribed your bupropion.