Can an adult without a history of seizures, uncontrolled hypertension, serious heart disease, bipolar disorder, or recent monoamine oxidase inhibitor use safely take Wellbutrin (bupropion) together with Vyvanse (lisdexamfetamine)?

Can You Take Wellbutrin with Vyvanse?

Yes, an adult without seizure history, uncontrolled hypertension, serious heart disease, bipolar disorder, or recent MAOI use can safely take Wellbutrin (bupropion) together with Vyvanse (lisdexamfetamine), but this combination requires careful monitoring for blood pressure elevation, seizure risk, and serotonin syndrome.

Critical Safety Screening Before Combining

Before initiating this combination, you must verify the absence of absolute contraindications to bupropion:

• Seizure disorders or conditions predisposing to seizures (history of head trauma, brain tumor, stroke, epilepsy) are absolute contraindications 1
• Uncontrolled hypertension must be ruled out, as both medications can elevate blood pressure and heart rate 1
• Current or recent MAOI use (within 14 days) is contraindicated due to serotonin syndrome risk 1
• Eating disorders (bulimia or anorexia nervosa) increase seizure risk and contraindicate bupropion 1
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs is an absolute contraindication 1

Mechanism of Interaction and Serotonin Syndrome Risk

While guidelines note that caution should be exercised when combining serotonergic drugs with stimulants, the risk appears manageable with proper monitoring:

• Stimulants (including amphetamine class medications like Vyvanse) can potentially contribute to serotonin syndrome when combined with other serotonergic agents, though bupropion has minimal direct serotonergic activity 2
• Start the combination at low doses and increase slowly, monitoring especially in the first 24-48 hours after dosage changes 2
• Watch for serotonin syndrome symptoms: mental status changes (confusion, agitation), neuromuscular hyperactivity (tremors, clonus, hyperreflexia), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis) 2

A case report documents serotonin syndrome with bupropion combined with SSRIs, likely due to bupropion's inhibition of cytochrome P450 2D6 increasing SSRI levels 3. However, this mechanism is less relevant with Vyvanse, which is not metabolized via this pathway.

Seizure Risk Management

The combination warrants heightened vigilance for seizure risk:

• Bupropion carries a dose-dependent seizure risk of approximately 0.1% (1 in 1,000) at 300 mg/day, increasing at higher doses 1
• Maximum daily dose must not exceed 450 mg/day to maintain acceptable seizure risk 1
• Gradual dose titration is mandatory: start bupropion at 37.5-150 mg once daily for 3 days, then increase to 150 mg twice daily if tolerated 1
• Bupropion overdose (≥2.7g) can cause seizures, encephalopathy, and cardiovascular effects 4

Cardiovascular Monitoring Protocol

Both medications can elevate blood pressure and heart rate, requiring systematic monitoring:

• Measure blood pressure and heart rate at baseline before initiating the combination 1
• Monitor blood pressure and heart rate periodically, especially during the first 12 weeks of treatment 1
• Patients with uncontrolled hypertension should not receive this combination until blood pressure is adequately controlled 1

Dosing Strategy for the Combination

For bupropion initiation in a patient already on Vyvanse:

• Start bupropion SR 150 mg once daily in the morning for 3 days 1
• If tolerated, increase to 150 mg twice daily (300 mg total), with the second dose before 3 PM to minimize insomnia 1
• Maximum therapeutic dose is 300-400 mg/day depending on formulation (SR vs XL) 1

Timing considerations:

• Administer first bupropion dose in the morning to leverage activating properties 1
• Give second dose before 3 PM to prevent insomnia, particularly important when combined with a stimulant 1

Monitoring Timeline and Follow-Up

• Week 1-2: Assess for early adverse effects including agitation, insomnia, blood pressure elevation, and any signs of serotonin syndrome 1
• Weeks 2-4: Monitor for neuropsychiatric symptoms, particularly in patients under 24 years (black box warning for suicidal ideation) 1
• Week 6-8: Assess therapeutic efficacy; if inadequate response, consider dose adjustment rather than premature discontinuation 1

Clinical Advantages of This Combination

This combination may offer specific benefits:

• Bupropion has lower rates of sexual dysfunction compared to SSRIs, making it advantageous for patients concerned about this side effect 1
• Bupropion is associated with minimal weight gain or even weight loss, unlike many other antidepressants 1
• The activating properties of bupropion complement stimulant therapy for patients with depression characterized by low energy or apathy 1

Common Pitfalls to Avoid

• Do not exceed 450 mg/day of bupropion as seizure risk increases substantially at higher doses 1, 5
• Do not administer the second bupropion dose late in the day as this will compound insomnia risk from the stimulant 1
• Do not misinterpret early behavioral activation as worsening depression; this typically occurs in the first month and improves with dose reduction 2
• Do not combine with MAOIs or within 14 days of MAOI discontinuation due to severe interaction risk 1