What are the potential interactions between Wellbutrin (bupropion) and Vyvanse (lisdexamfetamine)?

Drug Interaction Between Wellbutrin (Bupropion) and Vyvanse (Lisdexamfetamine)

The combination of bupropion and lisdexamfetamine can be used together with caution, but requires careful monitoring for cardiovascular effects, seizure risk, and serotonin syndrome, as both medications have stimulant properties and overlapping mechanisms that can potentiate adverse effects.

Primary Safety Concerns

Seizure Risk

• Bupropion significantly lowers the seizure threshold, with a documented 0.1% seizure risk in clinical trials 1
• The combination with stimulants like lisdexamfetamine (which is converted to dextroamphetamine) may further increase seizure risk through additive CNS stimulation 2
• This combination is contraindicated in patients with seizure disorders, eating disorders, or any condition that lowers seizure threshold 1

Cardiovascular Effects

• Both medications can independently increase blood pressure and heart rate 1
• Monitor vital signs including blood pressure and pulse regularly, as the combination may produce additive cardiovascular effects 1
• Patients with pre-existing hypertension or cardiovascular disease require particularly close monitoring 1

Serotonin Syndrome Risk

• While bupropion primarily affects dopamine and norepinephrine, it has mild serotonergic effects that can contribute to serotonin syndrome when combined with other agents 3
• Stimulants including amphetamines (the active metabolite of lisdexamfetamine) are listed as agents requiring caution when combined with other serotonergic drugs 2
• Watch for symptoms including mental status changes (agitation, confusion), neuromuscular hyperactivity (tremors, clonus, hyperreflexia), and autonomic instability (hypertension, tachycardia, diaphoresis) 2

Pharmacokinetic Considerations

• Bupropion is a moderate inhibitor of CYP2D6, which could theoretically affect metabolism of other medications, though lisdexamfetamine is not primarily metabolized through this pathway 4
• No direct pharmacokinetic interaction between these specific agents has been well-documented 2, 5
• Lisdexamfetamine is a prodrug converted to dextroamphetamine through hydrolysis rather than hepatic metabolism, reducing the likelihood of significant metabolic drug interactions 2

Required Monitoring Protocol

Initial Assessment (Before Starting Combination)

• Baseline blood pressure and heart rate 1
• Screen for personal or family history of seizures 1
• Assess for eating disorders (anorexia, bulimia) which increase seizure risk with bupropion 1
• Evaluate for substance use disorders 2

Ongoing Monitoring

• Check vital signs (blood pressure and pulse) at each visit, particularly in the first 1-2 weeks after initiation or dose changes 1
• Monitor for neuropsychiatric symptoms including agitation, irritability, insomnia, anxiety, or unusual behavioral changes 1
• Assess for suicidality, especially during the first 1-2 months of treatment and in patients under age 24 1
• Watch for signs of serotonin syndrome: confusion, agitation, tremor, muscle rigidity, fever, tachycardia 2

Dosing Considerations

• Start bupropion at lower doses (100-150 mg daily for SR formulation) when combining with stimulants 1
• Lisdexamfetamine typical starting dose is 20-30 mg daily, titrated by 10 mg weekly to maximum 70 mg daily 2
• Avoid exceeding maximum recommended doses: bupropion 450 mg/day, lisdexamfetamine 70 mg/day 2, 1

Common Adverse Effects to Anticipate

• Neuropsychiatric effects: insomnia, agitation, anxiety, irritability (most common with this combination) 1
• Gastrointestinal effects: nausea, dry mouth, decreased appetite 1
• Cardiovascular: elevated blood pressure, increased heart rate 1
• Headache and dizziness 1

Absolute Contraindications

• Current or prior seizure disorder 1
• Current or prior diagnosis of bulimia or anorexia nervosa 1
• Abrupt discontinuation of alcohol or sedatives (increases seizure risk) 1
• Concurrent MAOI use or within 14 days of MAOI discontinuation 2, 5
• Uncontrolled hypertension 1

Clinical Context

This combination is sometimes used intentionally to treat comorbid ADHD and depression, as bupropion has dopaminergic effects that may complement stimulant therapy 2. However, the combination requires more vigilant monitoring than either agent alone 1, 5. The risk-benefit analysis favors use when both conditions require treatment and monotherapy has been inadequate, but only with appropriate safety monitoring in place 4.