Why is bupropion (Wellbutrin) contraindicated with Monoamine Oxidase Inhibitor (MAOi) drugs?

Bupropion and MAOIs: A Dangerous Combination

Bupropion is absolutely contraindicated with MAOIs due to the increased risk of hypertensive reactions that can lead to significant morbidity and mortality. 1 This combination poses a serious risk to patient safety and should never be used together.

Mechanism of Interaction

The contraindication between bupropion and MAOIs is based on several pharmacological mechanisms:

1. Hypertensive Crisis Risk: Bupropion inhibits the reuptake of dopamine and norepinephrine. When combined with MAOIs, which prevent the breakdown of these same neurotransmitters, dangerously high levels can accumulate, leading to hypertensive crisis 1

2. Enhanced Toxicity: Studies in animals demonstrate that the acute toxicity of bupropion is significantly enhanced by MAO inhibitors such as phenelzine 1

3. Dopaminergic Effects: Both medications affect dopamine pathways, creating a potentially dangerous synergistic effect 2

FDA Requirements and Guidelines

The FDA drug label for bupropion explicitly states:

• Bupropion is contraindicated for use with MAOIs 1
• At least 14 days must elapse between discontinuation of an MAOI and initiation of treatment with bupropion 1
• Conversely, at least 14 days should be allowed after stopping bupropion before starting an MAOI antidepressant 1

Clinical Implications

Timing Requirements

• Starting bupropion after MAOI: Wait at least 14 days after stopping an MAOI
• Starting MAOI after bupropion: Wait at least 14 days after stopping bupropion

Special Considerations

• This contraindication applies to both irreversible MAOIs (like phenelzine) and reversible MAOIs (like linezolid and methylene blue) 1
• The contraindication is listed in multiple clinical guidelines for obesity management and smoking cessation where bupropion is used 3

Potential Consequences of Combined Use

Combining bupropion with MAOIs can lead to:

1. Hypertensive crisis: Potentially fatal elevation in blood pressure
2. Serotonin syndrome: Although bupropion has milder effects on serotonergic activity compared to SSRIs, cases of serotonin syndrome have been reported when bupropion was combined with other serotonergic agents 4
3. CNS toxicity: Symptoms may include agitation, tremor, ataxia, and dizziness

Alternative Approaches

For patients requiring antidepressant therapy who cannot safely use this combination:

• Consider non-MAOI antidepressants if a patient is already on bupropion
• Consider non-bupropion options (like SSRIs, SNRIs, or TCAs) if a patient requires an MAOI
• If switching between these medications is necessary, adhere strictly to the 14-day washout period

Common Pitfalls to Avoid

1. Overlooking the contraindication: Some clinicians may not be aware that bupropion, despite being primarily a dopamine/norepinephrine reuptake inhibitor, is contraindicated with MAOIs

2. Inadequate washout periods: Failing to wait the full 14 days between stopping one medication and starting the other

3. Missing reversible MAOIs: Remember that antibiotics like linezolid and methylene blue are also MAOIs and should not be combined with bupropion 1

4. Misattributing early symptoms: Early signs of adverse interaction may be misinterpreted as worsening of the underlying psychiatric condition 4

The absolute contraindication between bupropion and MAOIs is based on serious safety concerns and is consistently emphasized across multiple clinical guidelines and the FDA drug label.