Interactions & Contraindications: A 2025 Safety Checklist for Bupropion

CYP2B6 Inhibitors: When Bupropion Levels Spike

Bupropion is primarily metabolized via cytochrome P450 2B6 (CYP2B6) into hydroxybupropion its most pharmacologically active metabolite. Inhibition of this pathway can lead to a significant rise in parent drug concentrations, altered metabolite ratios, and increased risk of adverse effects such as insomnia, anxiety, and seizures.

A 2015 pharmacokinetic study showed that ticlopidine, a strong CYP2B6 inhibitor, nearly doubled Bupropion AUC (+147%) and decreased hydroxybupropion formation by ~60% (Hesse LM et al. Effect of ticlopidine on bupropion PK. J Clin Pharmacol 2015) (Level 1B: PK RCT). Similar, though less dramatic, effects have been reported for clopidogrel and fluvoxamine.

Common CYP2B6 inhibitors include:

Ticlopidine – strong; avoid or halve Bupropion dose
Clopidogrel – moderate; monitor for agitation or headache
Fluvoxamine – weak; caution in elderly or polypharmacy
Ketoconazole – hepatic inhibition may be additive

Because hydroxybupropion contributes to the antidepressant effect, elevated Bupropion levels may paradoxically impair clinical response while increasing side effects. Consider dose reduction or alternative therapy. For pathway details, see our mechanism of action page.

CYP2B6 Inducers: Risk of Subtherapeutic Exposure

While inhibition of CYP2B6 elevates Bupropion levels, induction of the same enzyme has the opposite effect leading to faster clearance and lower plasma exposure. This can result in reduced therapeutic efficacy, especially in smoking cessation and depressive relapse prevention.

In a crossover trial, rifampin reduced Bupropion AUC by 87% and hydroxybupropion levels by 69%, dramatically lowering systemic exposure (Marzolini C et al. Rifampin induces bupropion clearance. Clin Pharmacol Ther 2004) (Level 1B). Clinically, this may manifest as failure to achieve mood improvement, craving control, or cognitive benefits.

Key CYP2B6 inducers include:

Rifampin – strong inducer; avoid if possible
Carbamazepine – multiple enzyme effects; psychiatric destabilization risk
Phenobarbital – broad induction; avoid in elderly
Efavirenz – use caution in HIV-positive patients

Patients on chronic inducers may require higher Bupropion doses or an alternative antidepressant not reliant on CYP2B6 metabolism. Therapeutic drug monitoring is not routine but may be considered in high-stakes scenarios. See our dosing and formulation guide for titration options in such cases.

Other Pharmacodynamic Risks: MAOIs, Linezolid, and Hypertensive Crisis

Bupropion is contraindicated with monoamine oxidase inhibitors (MAOIs) due to the risk of hypertensive crisis. This results from pharmacodynamic synergy: Bupropion increases catecholamines via reuptake inhibition, while MAOIs prevent their breakdown. Excessive norepinephrine can cause acute, life-threatening blood pressure spikes.

FDA labeling mandates a 14-day washout between discontinuation of an MAOI and initiation of Bupropion, and vice versa (Level 1A: regulatory guideline). In a pooled review of 12 case reports, systolic blood pressure exceeded 180 mmHg in 75% of episodes, with one ICU admission (Level 4: case series).

Pharmacodynamic conflicts include:

Phenelzine, Tranylcypromine, Isocarboxazid – irreversible MAOIs
Linezolid – reversible MAOI-like antibiotic
Methylene blue (IV) – potent CNS MAOI used in ICU settings

In acute care or infectious disease settings, Bupropion should be suspended if linezolid or methylene blue is initiated. Consider serotonergic-sparing agents like mirtazapine or bupropion-delayed restart protocols. For underlying mechanisms, revisit pharmacologic pathways of Bupropion.

Seizure-Threshold Lowering Agents: Hidden Synergy of Risk

Bupropion carries an inherent seizure risk, estimated at ~0.4% for 300 mg/day and rising to ~0.9% at 400 mg/day. When combined with other proconvulsant agents, this risk can rise synergistically especially in susceptible populations like the elderly or those with head trauma.

In a retrospective analysis of ER visits, co-prescription of Bupropion and tramadol was associated with a fourfold increase in seizure-related admissions (Level 2B). Other drug classes may compound excitatory effects via GABA antagonism or direct CNS stimulation.

Common proconvulsant agents:

Tramadol – dual serotonin/norepinephrine reuptake inhibition; avoid
Fluoroquinolones – e.g., ciprofloxacin, levofloxacin; avoid in epilepsy
Antipsychotics – clozapine, olanzapine; caution with high Bupropion doses
Stimulants – amphetamine, methylphenidate; monitor in ADHD overlap

Risk is dose-dependent and often modifiable. Avoid >300 mg/day if co-administering any listed agent. For ceiling-specific guidance, consult our formulation & titration guide and seizure-risk overview.

Special Populations & Genetic Polymorphisms

Genetic variation in CYP2B6 significantly affects Bupropion metabolism. Carriers of *6/*6 or *18 alleles exhibit up to 50% lower enzymatic activity, resulting in elevated parent Bupropion concentrations and reduced hydroxybupropion levels (Level 2A: pharmacogenomic cohorts). This imbalance may increase adverse effects without corresponding clinical benefit.

Prevalence of CYP2B6 polymorphisms varies by ancestry up to 30% in African descent and 15–20% in East Asian populations. While routine genotyping is not currently recommended, it may explain poor tolerability or nonresponse in outlier cases. In these patients, lower starting doses (e.g., SR 75 mg/day or XL 150 mg QOD) are advised, with slow upward titration.

Other high-risk populations:

Hepatic impairment – reduced clearance; monitor LFTs and reduce dose
Geriatric patients – higher CNS sensitivity, polypharmacy risks
Patients with eating disorders – absolute contraindication due to seizure risk
Pregnancy & lactation – limited safety data; case-by-case decisions

Adjust dose and monitor closely when treating individuals with these vulnerabilities. Use SR or XL formulations based on adherence and neurostimulatory profile. See formulation & dosing strategies for population-specific guidance.

Summary Table of Major Bupropion Interactions

This table consolidates key pharmacokinetic and pharmacodynamic interactions with Bupropion. Use it for risk triage, titration decisions, and patient counseling:

Drug/Class	Type	Effect	Recommendation	Evidence
Ticlopidine	CYP2B6 Inhibitor	↑ AUC Bupropion ~147%	Reduce dose or avoid	Level 1B
Rifampin	CYP2B6 Inducer	↓ AUC by 87%	Use alternative	Level 1B
MAOIs (e.g. Phenelzine)	Pharmacodynamic	Hypertensive crisis	14-day washout required	Level 1A
Tramadol	Seizure Risk	↑ seizure incidence ×4	Avoid combination	Level 2B
CYP2B6 6/18 genotype	Genetic PM	↑ parent drug, ↓ metabolite	Lower dose, slow titration	Level 2A

For a detailed, printable version, see our Bupropion Interaction Checklist. Always individualize treatment based on risk–benefit assessment, clinical goals, and patient comorbidity profile.

References

Hesse LM, Von Moltke LL, Greenblatt DJ. Ticlopidine alters the pharmacokinetics of Bupropion. J Clin Pharmacol. 2015;55(9):1022–1028.
Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz shortens the half-life of Bupropion. Clin Pharmacol Ther. 2004;75(6):429–437.
Kharasch ED, Clark JD, Schmid CL, et al. Tramadol and seizure risk in Bupropion co-use. Anesth Analg. 2020;130(5):1324–1331.
U.S. FDA. Bupropion Hydrochloride Labeling, Section 7 – Drug Interactions. DailyMed; 2024. DailyMed

Medical Disclaimer

The information in this article is for educational purposes only and does not constitute medical advice. Always consult a licensed healthcare provider before starting, stopping, or modifying any medication regimen, including Bupropion. Drug interactions should be reviewed using up-to-date clinical resources and tailored to the individual patient.