What are the potential interactions between modafinil (Provigil), bupropion (Wellbutrin), and tesofensine?

Interactions Between Modafinil, Bupropion, and Tesofensine

The combination of modafinil and bupropion carries significant risk for seizures and cardiovascular effects, and adding tesofensine—a triple monoamine reuptake inhibitor—would amplify these risks through overlapping mechanisms on norepinephrine, dopamine, and serotonin systems. 1

Primary Concerns with Modafinil + Bupropion

Seizure Risk

• Bupropion lowers the seizure threshold with a documented 0.1% seizure risk when used alone for smoking cessation 2
• The combination of bupropion with modafinil increases seizure risk through additive CNS stimulation 1
• Case reports document seizures in breastfed infants exposed to bupropion, demonstrating the drug's proconvulsant properties 2
• Monitor continuously for any signs of seizure activity or lowered seizure threshold 1

Cardiovascular Effects

• Both medications independently increase blood pressure and heart rate 1
• Modafinil commonly causes hypertension as an adverse effect 3
• Bupropion can cause hypertension, particularly at higher doses 2
• Check blood pressure and heart rate at baseline and monitor regularly during treatment 1

Overlapping Side Effects

• Insomnia and sleep disturbances occur with both agents 1
• Headache, nervousness, and anxiety are common to both medications 1, 3
• Decreased appetite and weight loss may be additive 3

Adding Tesofensine to This Combination

Pharmacologic Mechanism Creates Triple Jeopardy

• Tesofensine inhibits reuptake of norepinephrine, dopamine, AND serotonin—the exact neurotransmitter systems already being manipulated by modafinil and bupropion 4, 5
• Bupropion is a dopamine/norepinephrine reuptake inhibitor 1
• Modafinil affects dopaminergic pathways, though through different mechanisms than classical stimulants 3
• Tesofensine's appetite suppression works through alpha-1 adrenoceptor and dopamine D1 receptor stimulation 5

Compounded Risks

• The abuse potential study of tesofensine specifically compared it against bupropion, showing similar profiles 4
• Adding tesofensine to modafinil + bupropion would create excessive noradrenergic and dopaminergic stimulation 5
• Cardiovascular effects would be substantially amplified through multiple adrenergic mechanisms 5
• Seizure threshold would be further compromised through additive CNS stimulation 1

Drug Interaction Specifics

Modafinil Interactions

• Modafinil is a known inducer and inhibitor of multiple cytochrome P450 isoenzymes 3
• It can reduce effectiveness of hormonal contraceptives through enzyme induction 2
• Caution needed with any medication metabolized by CYP450 system 2

Bupropion Interactions

• Bupropion interacts with medications that lower seizure threshold 2
• It affects beta-blocker metabolism, causing bradycardia and cardiac arrest in combination with propranolol 6
• Maximum daily dose is 450 mg regardless of formulation 2

Tesofensine Considerations

• No published data exists on tesofensine interactions with other stimulants or monoamine reuptake inhibitors 4
• Its triple mechanism suggests high potential for dangerous interactions with modafinil and bupropion 5

Dosing Considerations If Combination Is Unavoidable

Start Low Strategy

• Modafinil: Begin at 100 mg once daily in morning, maximum 400 mg/day 1, 3
• Bupropion SR: Start 100 mg once daily, titrate to 100-150 mg twice daily, never exceed 450 mg/day 2, 1
• Tesofensine should not be added to this combination due to lack of safety data and overlapping mechanisms 4, 5

Monitoring Protocol

• Weekly blood pressure and heart rate checks for first month 1
• Assess for sleep disturbances, anxiety, tremor, or agitation at each visit 1, 3
• Screen for seizure precursors: myoclonic jerks, confusion, or altered consciousness 1
• Obtain baseline ECG if any cardiac history 6

Special Populations

Pregnancy

• Bupropion shows possible increased risk for left ventricular outflow tract obstruction (0.279% vs 0.07%) and ventricular septal defects (aOR 2.9) 2
• Modafinil has limited pregnancy data with no established safety profile 2
• Avoid this combination entirely in pregnancy 2

Elderly Patients

• Reduce modafinil dose to 100 mg in elderly due to decreased clearance 1, 3
• Start bupropion at lowest dose and titrate slowly 2
• Increased fall risk from orthostatic hypotension with combined adrenergic effects 1

Hepatic Impairment

• Modafinil dose reduction required in hepatic disease 3
• Bupropion metabolism is impaired with liver dysfunction 2

Renal Impairment

• Modafinil acid metabolite accumulates substantially in severe renal insufficiency 3
• Dose adjustments necessary for creatinine clearance <30 mL/min 3

Clinical Bottom Line

Do not combine all three medications. The modafinil-bupropion combination alone requires careful monitoring for seizures and cardiovascular effects 1. Adding tesofensine would create dangerous synergy through overlapping monoamine reuptake inhibition affecting norepinephrine, dopamine, and serotonin simultaneously 4, 5. If modafinil and bupropion must be used together, start with reduced doses, monitor weekly initially, and never add tesofensine to this regimen 1.