TOXICOLOGY & ADDICTION MEDICINE
Bupropion Toxicity: More Than Just Seizures By Adrienne Perotti, PharmD and Jesse Albano, PharmD, on behalf of the Toxicology Writing Group of the SAEM Academic Emergency Medicine Pharmacists Interest Group
Background
SAEM PULSE | MAY-JUNE 2025
Bupropion is very lipophilic, has a large volume of distribution and is metabolized through the liver with active metabolites. It is available in several formulations (Table 1), and these properties can increase the duration of effects and prolong toxicity in overdose. Currently, no antidote exists for bupropion overdose and treatment is primarily supportive. This review discusses treatment strategies in massive ingestions and explores controversies surrounding specific interventions.
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Bupropion, a unique atypical antidepressant, is now the most common antidepressant associated with fatalities in overdose. Structurally, bupropion is a beta-keto amphetamine—a substituted cathinone—used to treat major depressive disorder, seasonal affective disorder and smoking cessation. Its off-label uses include treatment for attention-deficit disorders, obesity, and compulsive eating disorders.
Bupropion is highly lipophilic, has a large volume of distribution and is metabolized through the liver with active metabolites It is available in several formulations (Table 1), and these properties increase the duration of effects and prolong toxicity in overdose. Currently, no antidote exists for bupropion overdose, and treatment is primarily supportive. This review discusses treatment strategies in massive ingestions and explores controversies surrounding specific interventions.
Mechanism of Toxicity
The precise mechanism of bupropion toxicity is not fully understood. As a substituted cathinone, bupropion shares structural similarities with amphetamines and other sympathomimetics. It is proposed that its central inhibition of dopamine and norepinephrine reuptake, along with its antagonism of nicotinic receptors, play a role in toxicity. While bupropion does not directly inhibit serotonin 5-HT receptors,
its increase in norepinephrine release may enhance serotonin neuronal firing, leading to potential serotonergic toxicity. The primary toxic effects of bupropion overdose are outlined in (Table 2). The neurotoxic effects are thought to result from alterations in dopamine and norepinephrine levels within the corticolimbic and striatal pathways. The most significant morbidity and mortality are often attributed to the cardiotoxic effects of bupropion overdose. Similar to tricyclic antidepressants, bupropion causes QT-interval and QRS prolongation, which can lead to ventricular arrhythmias. Like most medications that prolong the QT interval, bupropion affects the human ethera-go-go-related gene (hERG) channel delayed rectifier potassium current (IKr) in the heart. Unlike tricyclic antidepressants and antiarrhythmics, which cause QRS prolongation and arrhythmias due to sodium channel blockade, bupropion inhibits myocardium gap junction intercellular communication (GJIC).