Bupropion (sold as Wellbutrin, Zyban, and others) has a longer list of problematic interactions than many antidepressants. Some combinations raise your risk of seizures, others reduce the effectiveness of medications you depend on, and a few are dangerous enough to be absolute contraindications. Here’s what you need to avoid and why.
MAOIs: The Most Dangerous Combination
Combining bupropion with monoamine oxidase inhibitors is the single most critical interaction to avoid. MAOIs are an older class of antidepressant that includes phenelzine, tranylcypromine, and selegiline. Taking these together can cause a dangerous spike in blood pressure and other serious effects.
If you’re switching from an MAOI to bupropion (or vice versa), you need a washout period of at least 14 days between stopping one and starting the other. This isn’t flexible. The 14-day window exists because MAOIs take that long to fully clear your system.
Other Bupropion-Containing Products
This one catches people off guard. Bupropion is the active ingredient in several products marketed for different purposes. Wellbutrin (for depression), Zyban (for smoking cessation), Forfivo XL, and Aplenzin all contain bupropion. Taking any two of these together effectively doubles your dose, which sharply increases seizure risk. The FDA-approved maximum is 400 mg per day for the sustained-release form, and exceeding that threshold is where seizure risk climbs significantly. If you’re prescribed bupropion under one brand name, make sure no other prescription duplicates it.
Alcohol and Seizure Risk
Bupropion already lowers the seizure threshold on its own. Alcohol pushes it lower. In animal studies, alcohol reduced the dose of bupropion needed to trigger seizures by roughly 23%, from about 117 mg/kg to 89 mg/kg. That’s a meaningful shift. Heavy drinking while on bupropion is risky, but so is the opposite scenario: if you drink heavily and then suddenly stop, the abrupt withdrawal itself is a seizure trigger. Bupropion is specifically contraindicated in people undergoing abrupt alcohol withdrawal.
Moderate, occasional drinking may not cause problems for everyone, but the combination can also reduce alcohol tolerance and cause unusual neuropsychiatric effects. Many people on bupropion report feeling the effects of alcohol faster and more intensely than they expect.
Medications That Raise Bupropion Levels
Your body breaks down bupropion primarily through an enzyme called CYP2B6. Drugs that slow this enzyme down cause bupropion to build up in your bloodstream, increasing the chance of side effects and seizures. Known inhibitors of this enzyme include the blood thinner clopidogrel, the antiplatelet drug ticlopidine, the antidepressant sertraline, and the chemotherapy agent thiotepa. If you’re taking any of these alongside bupropion, your doctor may need to adjust your dose.
Tamoxifen
This interaction works in the other direction. Bupropion is a potent inhibitor of the CYP2D6 enzyme, which is the same enzyme your body uses to convert tamoxifen into its active cancer-fighting form. By blocking that conversion, bupropion can significantly reduce tamoxifen’s effectiveness. For women taking tamoxifen to treat or prevent breast cancer recurrence, this isn’t a minor concern. A 2010 review in the Journal of Clinical Oncology found indirect evidence that bupropion may have a large effect on tamoxifen metabolism. If you need an antidepressant while on tamoxifen, other options exist that don’t interfere with this pathway.
St. John’s Wort and Other Supplements
St. John’s Wort, a popular herbal supplement for mood, interacts with bupropion in two ways. It can raise serotonin levels, increasing the risk of a condition called serotonin syndrome (symptoms include agitation, rapid heart rate, high body temperature, and muscle twitching). It can also reduce bupropion’s effectiveness as an antidepressant. Either outcome is a problem, so the two should not be taken together. St. John’s Wort is contraindicated with MAOIs as well, so if you’re on any antidepressant, it’s generally best to skip it.
SAMe (S-adenosyl methionine), another supplement marketed for mood support, carries similar serotonin-related risks when combined with antidepressants.
Dextromethorphan (DXM) Cough Medicine
Bupropion slows the breakdown of dextromethorphan, the active ingredient in many over-the-counter cough suppressants like Robitussin DM, Delsym, and NyQuil. This means DXM stays in your system longer and at higher levels than expected. At normal cough-suppressant doses this interaction is usually manageable, and in fact a prescription combination of the two drugs (brand name Auvelity) has been approved specifically for depression. But taking large or frequent doses of cough medicine while on bupropion can lead to a buildup that causes dizziness, confusion, or serotonin-related side effects. Stick to the lowest effective dose of any DXM-containing product and be aware the effects may feel stronger than usual.
Caffeine
This isn’t a hard contraindication, but it’s worth knowing about. Both bupropion and caffeine can raise blood pressure, and together those effects add up. If you have a history of high blood pressure or heart disease, you may need to cut back on coffee, energy drinks, or pre-workout supplements after starting bupropion. Many people notice they feel more jittery or anxious from the same amount of caffeine they tolerated before.
Eating Disorders and Bupropion
Bupropion is contraindicated in people with anorexia nervosa or bulimia nervosa, current or past. The reason is seizures. People with eating disorders are already at higher risk for electrolyte imbalances and nutritional deficiencies that lower the seizure threshold, and bupropion pushes that threshold even lower. This applies even if the eating disorder is in remission. Other antidepressants are safer choices for this population.
Medications That Lower Seizure Threshold
Because seizure risk is bupropion’s primary safety concern, anything else that also lowers the seizure threshold compounds the problem. This includes certain antipsychotics, theophylline (used for asthma), systemic corticosteroids, stimulants, and some diabetes medications that can cause hypoglycemia (low blood sugar itself can trigger seizures). Sedatives and benzodiazepines aren’t necessarily dangerous to take with bupropion, but abruptly stopping them is, because sudden withdrawal from sedatives is another seizure trigger.
Practical Steps To Stay Safe
The thread connecting most of these interactions is seizure risk. Bupropion’s seizure rate is dose-dependent, so anything that increases the amount of bupropion in your blood, lowers your seizure threshold through another mechanism, or both, is a potential problem. A few practical rules help:
- Never double up on doses. If you miss a dose, skip it and take the next one at the regular time. Taking extra to catch up increases seizure risk.
- Swallow extended-release tablets whole. Crushing, chewing, or splitting them releases the full dose at once instead of gradually, which mimics an overdose.
- Space doses correctly. For twice-daily formulations, keep at least 8 hours between doses.
- Review everything you take. Bring a full list of prescriptions, OTC medications, and supplements to your pharmacist. Interactions with bupropion are common enough that a quick cross-check is worth the time.