Bupropion Toxicity

Etiology

Bupropion overdose, intentional or accidental, is the leading cause of toxicity. Large ingestions overwhelm normal metabolic pathways and produce severe CNS and cardiovascular effects. Extended-release (eg, sustained-release and extended-release) formulations are especially dangerous because they can cause delayed toxicity, including seizures up to 24 hours after ingestion.

Some patients may develop bupropion toxicity even at standard therapeutic doses due to underlying risk factors such as eating disorders with associated electrolyte abnormalities, preexisting seizure disorders, alcohol or sedative withdrawal, clinically significant drug interactions (particularly with CYP2B6 inhibitors), and renal or hepatic impairment. Additionally, concurrent ingestion of alcohol, stimulants, antidepressants, or other pro-convulsant medications can further amplify the risk and severity of toxicity.

Epidemiology

Antidepressants such as bupropion are commonly implicated in overdose, partly reflecting their widespread prescribing in populations at increased risk for intentional self-harm. Recreational misuse is also well documented, as bupropion is structurally related to cathinones (ß-ketoamphetamines) and may produce stimulant effects and euphoria when taken in supratherapeutic doses.[4][5] The American Association of Poison Control Centers reported more than 20,000 bupropion exposures in 2023. Among prescription medications, bupropion accounted for one of the highest numbers of poisoning-related fatalities, second only to amlodipine in this dataset.[6]

Pathophysiology

Bupropion is a norepinephrine–dopamine reuptake inhibitor; however, sympathetic or dopaminergic stimulation alone does not fully explain its toxicity. Bupropion lowers the seizure threshold in a dose-dependent manner. Seizures are common in overdose, including status epilepticus, although the specific proconvulsant mechanism is multifactorial and incompletely understood.

Case reports also describe serotonin syndrome–like toxicity in the setting of bupropion exposure. However, the mechanism is unclear, particularly when bupropion is the sole agent.[7] Studies' results reveal sustained exposure to bupropion increases neuronal firing at serotonin receptors in animal models, a finding proposed as a potential mechanism underlying this syndrome.[8]

Electrocardiographic abnormalities are well described. Prolongation of the QT interval is due to blockade of the rapid component of the delayed rectifier potassium current. QRS widening also occurs. Unlike many other drugs, QRS prolongation with QRS prolongation is not attributable to cardiac fast sodium channel blockade but rather to myocardial gap junction inhibition.[9] However, multiple mechanisms may contribute to severe overdose. These conduction abnormalities may accompany hypotension, dysrhythmias, and cardiogenic shock in severe cases.

Toxicokinetics

Peak plasma concentrations occur at approximately 1.5, 3, and 5 hours for the immediate-release, sustained-release, and extended-release formulations, respectively. Oral absorption approaches 100%, and the volume of distribution ranges from 19 to more than 40 L/kg, reflecting extensive tissue penetration. Hepatic metabolism via CYP2B6 produces the active metabolite hydroxybupropion, which is subsequently excreted in the urine.[1] The duration of action and elimination half-life vary by formulation and dose, with elimination half-lives extending up to 32 hours.

History and Physical

Clinicians should perform a thorough history and physical examination in any patient experiencing a suspected overdose to guide diagnostic and management decisions. Clinicians should identify the time of ingestion, the estimated quantity ingested, and perform a thorough medication history to identify potential drug interactions or synergistic effects that may increase the risk of seizures or cardiovascular toxicity. Determining the intent of the overdose is essential for both acute management and psychiatric risk assessment.

Physical examination findings vary, but the most commonly reported manifestations of bupropion overdose include tachycardia, seizures, and agitation. Retrospective studies report seizure rates ranging from 17% to 47%.[10] Additional findings may include hypertension, hypotension, delirium, hyperreflexia, clonus, central nervous system depression, tremors, numbness, and dystonia.[11]

Evaluation

Initial management of suspected bupropion overdose prioritizes assessment of airway, breathing, and circulation. Clinicians should promptly obtain intravenous access and initiate continuous cardiac monitoring with frequent assessment of vital signs. A 12-lead electrocardiogram (ECG) is necessary to evaluate for conduction abnormalities, including QRS or QT prolongation.

Clinicians should obtain serum acetaminophen and salicylate concentrations given the frequency of coingestions, as well as a point-of-care glucose in patients with seizures or altered mental status. Basic laboratory studies include a serum pregnancy test in patients who can get pregnant who are of childbearing age and electrolytes, to help identify electrolyte abnormalities that can perpetuate cardiac conduction abnormalities. Because delayed seizures may occur, particularly with sustained-release and extended-release formulations, extended observation, including cardiac monitoring, is often warranted. Serum bupropion concentrations are not rapidly available and do not guide acute management. 

Treatment / Management

Primary management of bupropion overdose is supportive, as no specific antidote exists. Consultation with a regional poison center or medical toxicologist is recommended, particularly in critical cases with serious organ dysfunction. Gastrointestinal decontamination with activated charcoal may be appropriate for patients presenting soon after a large overdose who have an intact or protected airway. Although unintentional overdoses may result in minor clinical effects, serious adverse events, particularly seizures, have been reported even after accidental double-dose ingestions.[12][13][14] 

Clinicians treat seizures promptly with benzodiazepines as first-line therapy. Barbiturates, such as phenobarbital, are appropriate second-line agents for refractory seizures. Phenytoin is not effective as it does not effectively treat toxin-induced seizures and fails to address the underlying mechanism. While levetiracetam is unlikely to cause harm, it is generally not recommended for drug-induced seizures, where gamma-aminobutyric acid-agonists are preferred. Patients with seizures refractory to treatment with benzodiazepines and barbiturates may require sedation and intubation with bedside electroencephalogram monitoring to evaluate for continued seizure activity.

Clinicians treat life-threatening arrhythmias in accordance with Advanced Cardiac Life Support guidelines, with adjuncts as indicated by the clinical scenario. Although QRS widening typically suggests fast sodium channel blockade in many overdoses, bupropion-induced QRS prolongation may not respond to sodium bicarbonate because the cardiotoxicity appears related to impaired myocardial gap junction communication rather than sodium channel inhibition.[15] Vasopressors treat cardiogenic shock. Toxicology experts support intravenous lipid emulsion (ILE) for severe, life-threatening toxicity, including refractory status epilepticus or hemodynamic instability; however, clinicians generally reserve it for rescue therapy.[13] Veno-arterial extracorporeal membrane oxygenation is a potential treatment option for refractory cardiogenic shock or cardiac arrest.[16][17] Notably, experts do not recommend ILE in patients with pulseless electrical activity due to the possibility of interference with epinephrine and extracorporeal treatments.[18] (B3)

Patients with seizures, hemodynamic instability, life-threatening arrhythmias, or severe delirium require intensive care monitoring. Because delayed seizures can occur, particularly with sustained-release and extended-release formulations, patients with these ingestions should undergo observation for at least 24 hours. Patients should remain asymptomatic and have stable vital signs before medical clearance for discharge or psychiatric evaluation.[3] (B2)

Differential Diagnosis

All ingestions should undergo thorough evaluation with consideration for potential co-ingestions. Bupropion may mimic features of sympathomimetic or serotonergic toxidromes and can produce clinical findings resembling anticholinergic poisoning. Clinicians should therefore consider exposure to agents with similar presentations, including amphetamines, selective serotonin reuptake inhibitors, and other stimulants, when developing a differential diagnosis.[11] Nontoxicologic conditions, such as meningitis or encephalitis, should also remain under consideration.

Prognosis

The primary influences on the overall prognosis following bupropion overdose are the ingested dose, the presence of coingestants, and underlying comorbid conditions. A retrospective review of 1065 exposures reported to the Ontario Poison Centre reveals that 52% of patients develop tachycardia, 24% demonstrate electrocardiographic abnormalities, most commonly QT or QRS prolongation, and 17% experienced seizures. Patients who coingest benzodiazepines demonstrate lower odds of seizure (OR 0.32); however, the benefit of prophylactic benzodiazepine therapy remains uncertain. Results from another retrospective study involving 423 patients identify tachycardia (OR 6.7) and altered mental status (OR 3.9) as predictors of seizure, with no seizures occurring in initially asymptomatic patients.[10][19] A large analysis of 30,026 adolescents who experienced an overdose reveals that bupropion exposure corresponds with higher rates of death (0.23% vs 0%), seizures (27% vs 8.5%), and major interventions compared with selective serotonin reuptake inhibitor overdose, highlighting the comparatively greater morbidity and mortality risk.[20]

Complications

The complications associated with bupropion toxicity are as follows:

• Cardiogenic shock
• Cardiac arrest
• Death
• Delirium and hallucinations
• Lactic acidosis
• Life-threatening dysrhythmias
• QRS widening and QT prolongation
• Respiratory failure
• Rhabdomyolysis from sustained muscle activity
• Seizures, including status epilepticus and delayed-onset seizures
• Severe altered mental status with loss of airway protection [21]