Is it safe to use modafinil (Provigil) and Wellbutrin (bupropion) together?

Modafinil and Wellbutrin (Bupropion) Combination

The combination of modafinil and bupropion can be used together with caution, but requires close monitoring for increased seizure risk, cardiovascular effects (elevated blood pressure and heart rate), and overlapping stimulant side effects including insomnia, anxiety, and agitation. 1, 2

Key Safety Concerns

Seizure Risk (Primary Concern)

• Bupropion lowers the seizure threshold in a dose-dependent manner, and the combination with modafinil may theoretically increase this risk through additive CNS stimulation 1, 2
• The maximum daily bupropion dose should not exceed 450 mg to minimize seizure risk 1
• This combination is contraindicated in patients with history of seizures, seizure disorders, or eating disorders (bulimia/anorexia) 2, 3

Cardiovascular Effects

• Both medications independently cause cardiovascular stimulation, creating potential for additive effects on blood pressure and heart rate 1, 2
• Screen for uncontrolled hypertension before initiating combination therapy 2
• Monitor blood pressure and heart rate regularly throughout treatment 1

Overlapping Stimulant Effects

• Increased risk of insomnia, anxiety, agitation, appetite suppression, and unintended weight loss due to overlapping stimulant properties 1, 2
• Both medications affect dopamine and norepinephrine systems, creating potential for additive stimulant effects 2

Dosing Strategy

Initial Approach

• Start with lower doses of both medications when used concomitantly 1, 2
• Modafinil: Consider starting at 100 mg daily (rather than standard 200 mg), with maximum daily dose of 400 mg 1
• Bupropion SR: Start at 100-150 mg daily, with maintenance dose of 100-150 mg twice daily 1, 3
• Titrate carefully to minimize adverse effects 3

Pharmacokinetic Consideration

• Modafinil is a moderate P-gp and CYP inducer that could theoretically reduce bupropion plasma concentrations, though this specific interaction has not been formally studied 2
• This may require higher bupropion doses for efficacy, but must be balanced against seizure risk 2

Monitoring Requirements

Essential Monitoring Parameters

• Seizure activity or signs of lowered seizure threshold 1
• Blood pressure and heart rate changes 1
• Sleep disturbances and insomnia 1
• Signs of excessive stimulation: anxiety, agitation, appetite suppression 2

Clinical Follow-up

• Close monitoring is essential, particularly during initiation and dose adjustments 1, 2
• Consider intermittent rather than continuous daily dosing of stimulants when clinically appropriate 2

Special Populations

Pregnancy and Breastfeeding

• Both medications have limited safety data in pregnancy 1, 2
• Bupropion shows possible risk for cardiovascular malformations 1, 3
• Both drugs cross the placenta and are present in breast milk 2
• If treatment is necessary during pregnancy or breastfeeding, use the lowest effective doses 2
• Monitor breastfed infants for irritability, poor feeding, and sleep disturbances 2

Elderly Patients

• Start with lower doses, particularly modafinil (100 mg) 1
• Increased sensitivity to cardiovascular and CNS effects may occur 1

Clinical Context and Evidence

Supporting Evidence

• One case report demonstrated successful treatment of a depressive narcoleptic patient with bupropion 300 mg/day combined with modafinil, showing the combination can be effective and tolerated 4
• Modafinil combined with SSRIs has shown enhanced antidepressant effects and was generally well tolerated 5
• Bupropion combinations with other antidepressants have demonstrated superior efficacy compared to monotherapy 6, 7

Evidence Limitations

• No formal studies specifically examine the combination of bupropion and modafinil 2
• Most interaction data comes from in vitro studies or small clinical trials that may not reflect real-world polypharmacy scenarios 2
• The theoretical seizure risk is based on known mechanisms rather than documented cases with this specific combination 2

Common Pitfalls to Avoid

• Do not use this combination in patients with eating disorders (bulimia/anorexia), as bupropion is absolutely contraindicated due to significantly elevated seizure risk 2
• Do not exceed bupropion 450 mg daily when combined with modafinil 1
• Do not ignore cardiovascular monitoring, even in younger patients without known cardiac disease 1, 2
• Do not start both medications at full doses simultaneously—titrate gradually 1, 2