Wellbutrin is not an MAOI. It belongs to a completely different class of antidepressants called aminoketones, and it works through a different mechanism than monoamine oxidase inhibitors. The confusion is understandable because both types of medication affect brain chemicals involved in mood, but they do so in fundamentally different ways.
How Wellbutrin Actually Works
Wellbutrin (bupropion) increases levels of two brain chemicals, norepinephrine and dopamine, by blocking their reabsorption after they’ve been released. Think of it like plugging a drain so these chemicals stay active longer in the spaces between nerve cells. The FDA’s prescribing information states explicitly that bupropion “does not inhibit monoamine oxidase or the re-uptake of serotonin.”
When bupropion first arrived in the U.S. in 1989, it was labeled an “atypical” antidepressant because its effects didn’t match any existing category. It wasn’t a tricyclic, wasn’t an SSRI, and wasn’t an MAOI. Its dual action on norepinephrine and dopamine was considered a novel mechanism at the time, and it remains chemically unrelated to all other major antidepressant classes.
How MAOIs Work Differently
MAOIs take a completely different approach. Instead of blocking reabsorption of brain chemicals, they disable an enzyme called monoamine oxidase, which is responsible for breaking down norepinephrine, dopamine, and serotonin. By disabling this cleanup enzyme, MAOIs allow all three chemicals to build up. This broad effect is powerful but comes with significant dietary restrictions, since monoamine oxidase also breaks down tyramine, a compound found in aged cheeses, cured meats, and fermented foods. Without the enzyme to handle tyramine, eating these foods can cause dangerous spikes in blood pressure.
Wellbutrin carries none of these dietary restrictions because it leaves monoamine oxidase completely intact.
Why the Distinction Matters
The difference between Wellbutrin and MAOIs isn’t just academic. It affects side effects, food interactions, and which other medications you can safely take.
Wellbutrin has a notably different side effect profile compared to most antidepressants. In clinical trials, patients taking bupropion experienced a slight weight loss of roughly 1.5 kg (about 3 pounds) rather than the weight gain common with many other antidepressants. It also stands out for its low rate of sexual side effects. In a large observational study of more than 6,200 patients, bupropion had the lowest incidence of sexual dysfunction among all newer antidepressants tested. The odds of developing sexual dysfunction were four to six times greater with SSRIs compared to bupropion, and bupropion’s rate was virtually identical to placebo.
MAOIs, while effective for treatment-resistant depression, require careful monitoring of food and drug interactions that Wellbutrin does not.
Wellbutrin and MAOIs Should Not Be Combined
Even though Wellbutrin is not an MAOI, the two should never be taken together. The FDA requires a minimum 14-day gap between stopping one and starting the other, in either direction. Taking them simultaneously is listed as a contraindication, meaning it is explicitly prohibited rather than simply discouraged. This washout period allows the first medication to fully clear your system before the second one begins working.
What Wellbutrin Is Approved For
Wellbutrin is FDA-approved for major depressive disorder. The same active ingredient, bupropion, is also sold under the brand name Zyban for smoking cessation, though the Wellbutrin label itself does not carry that indication. It comes in three formulations: immediate-release (taken three times daily), sustained-release or SR (twice daily), and extended-release or XL (once daily). All three deliver the same medication but differ in how quickly it’s absorbed. The typical target dose is 300 mg per day, with a maximum of 450 mg.
One important restriction: Wellbutrin is contraindicated in people with seizure disorders or eating disorders such as anorexia or bulimia, because it can lower the seizure threshold. This risk increases at higher doses, which is why the maximum daily dose exists.
Comparing Drug Classes at a Glance
- Wellbutrin (bupropion): Blocks reabsorption of norepinephrine and dopamine. No dietary restrictions. Low risk of sexual side effects and weight gain. Does not affect serotonin.
- MAOIs: Disable the enzyme that breaks down norepinephrine, dopamine, and serotonin. Require strict dietary restrictions to avoid dangerous blood pressure spikes. Broadly effective but carry more interaction risks.
- SSRIs: Block reabsorption of serotonin specifically. No dietary restrictions, but commonly associated with sexual dysfunction (40% to 50% in studies using direct questioning) and some weight changes.
Wellbutrin occupies a unique space among antidepressants. Its dopamine and norepinephrine focus, combined with zero serotonin activity, gives it a side effect profile that looks very different from both MAOIs and the more commonly prescribed SSRIs.