Continuing Education Activity

Bupropion toxicity demands rapid recognition and coordinated management. Widely prescribed for depression and smoking cessation, bupropion is generally safe at therapeutic doses; however, overdose can produce serious neurologic and cardiovascular complications, including agitation, tachycardia, conduction abnormalities, and delayed-onset seizures that may progress to status epilepticus and death. Extended-release formulations further complicate care by prolonging symptom onset and increasing the risk of sudden deterioration. Because no specific antidote exists, early identification, vigilant monitoring, and timely supportive interventions are critical to improving outcomes.

This activity, designed for healthcare professionals, emphasizes risk stratification, recognition of delayed toxicity, and the importance of interprofessional collaboration in both emergency and inpatient settings. Participants will strengthen their ability to recognize early warning signs of toxicity, differentiate bupropion overdose from other toxidromes, and implement appropriate stabilization and monitoring strategies. Learners will gain practical insight into seizure management, treatment of cardiac complications, and indications for toxicology consultation or escalation to the intensive care unit. Additionally, this activity highlights the role of coordinated teamwork among physicians, advanced practitioners, nurses, pharmacists, and mental health professionals to enhance patient safety and continuity of care. By reinforcing clinical decision-making and promoting structured, team-based management, this CME activity strengthens healthcare professionals' knowledge and confidence in responding effectively to bupropion toxicity and in improving patient-centered outcomes.

Objectives:

• Identify early clinical features of bupropion toxicity, including seizures, tachyarrhythmias, altered mental status, and QRS or QT abnormalities.
• Select appropriate diagnostic studies and monitoring strategies to guide ongoing management and disposition decisions.
• Apply appropriate treatment interventions for seizures and dysrhythmias associated with bupropion toxicity.
• Coordinate patient evaluation, monitoring, escalation of care, and follow-up to ensure timely and effective interprofessional management.

Introduction

Bupropion hydrochloride is an antidepressant of the aminoketone (cathinone) class, first introduced in 1985. FDA-approved for the treatment of major depressive disorder, seasonal affective disorder, and smoking cessation, bupropion is available in immediate-release (IR), sustained-release (SR), and extended-release (XL) formulations.[1] Off-label uses include sexual dysfunction secondary to antidepressant use, generalized anxiety disorder, ADHD, methamphetamine use disorder, and bipolar depression

At therapeutic doses, adverse effects are generally nonspecific and include dry mouth, constipation, headache, nausea, agitation, insomnia, and weight loss. Manufacturers temporarily withdrew bupropion in 1986 after reports of new-onset seizures in patients with bulimia, and reintroduced it in 1989 at lower recommended dose ranges. Because bupropion lowers the seizure threshold, its use in patients with preexisting seizure risk factors, such as a history of seizure disorder, an eating disorder, or those undergoing ethanol or CNS depressant withdrawal, creates an unacceptably high risk of seizures, even at standard doses, making these conditions contraindications. The estimated seizure risk is approximately 0.1% at doses below 300 mg/day and increases to 0.4% at doses up to 450 mg/day.[1]

In overdose, bupropion commonly causes seizures, tachycardia, and agitation.[1] Severe toxicity may include status epilepticus, cardiac arrhythmias, cardiogenic shock, and death. Extended-release formulations can cause delayed-onset seizures that occur up to 24 hours after ingestion.[2] Management is primarily supportive, as no specific antidote exists. Early stabilization with airway, breathing, and circulation assessment, continuous cardiac monitoring, and prompt treatment of seizures with benzodiazepines are essential. Clinicians should strongly consider consulting a regional poison center or a medical toxicologist for cases of moderate to severe toxicity. Patients with significant toxicity often require prolonged observation or intensive care monitoring due to the risk of delayed neurologic and cardiovascular complications.

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 (SR, XL) 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.[3][4]

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.[5]

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 pro-convulsant 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.[6] Studies reveal sustained exposure to bupropion increases neuronal firing at serotonin receptors in animal models, a finding proposed as a potential mechanism underlying this syndrome.[7]

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 is not attributable to cardiac fast sodium channel blockade but rather to myocardial gap junction inhibition.[8] However, multiple mechanisms may contribute in 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 IR, SR, and XL 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 suspected patient experiencing an 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%.[9] Additional findings may include hypertension, hypotension, delirium, hyperreflexia, clonus, central nervous system depression, tremors, numbness, and dystonia.[10]

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 vital-sign assessment. A 12-lead 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 co-ingestions, 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 SR and XL 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.[11][12][13] 

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 GABA-agonists are preferred. Patients with seizures refractory to treatment with benzodiazepines and barbiturates may require sedation and intubation with bedside EEG monitoring to evaluate for continued seizure activity.

Clinicians treat life-threatening arrhythmias in accordance with Advanced Cardiac Life Support (ACLS) 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.[14] 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.[12] Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a potential treatment option for refractory cardiogenic shock or cardiac arrest.[15] Notably, experts do not recommend ILE in patients with pulseless electrical activity due to the possibility of interference with epinephrine and extracorporeal treatments.[16] 

Patients with seizures, hemodynamic instability, life-threatening arrhythmias, or severe delirium require intensive care monitoring. Because delayed seizures can occur, particularly with SR and XL 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.[2] 

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.[10] Non-toxicologic 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 co-ingestants, and underlying comorbid conditions. A retrospective review of 1,065 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 co-ingest benzodiazepines demonstrate lower odds of seizure (OR 0.32); however, the benefit of prophylactic benzodiazepine therapy remains uncertain. Another retrospective study involving 423 patients identifies tachycardia (OR 6.7) and altered mental status (OR 3.9) as predictors of seizure, with no seizures occurring in initially asymptomatic patients.[9][17]

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 SSRI overdose, highlighting the comparatively greater morbidity and mortality risk.[18]

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; and
• Severe altered mental status with loss of airway protection.[19]

Consultations

Consultation with a regional poison center or medical toxicologist can offer anticipatory guidance and guide both disposition and treatment options.

Deterrence and Patient Education

Bupropion toxicity most commonly occurs after intentional or unintentional overdose but may also develop at therapeutic doses in susceptible patients. Because bupropion lowers the seizure threshold and has stimulant properties, toxicity can produce serious central nervous system and cardiovascular complications, including agitation, tachycardia, conduction abnormalities, status epilepticus, and cardiogenic shock. Delayed-onset seizures make early recognition and appropriate counseling essential to prevent morbidity and mortality.

Healthcare professionals play a critical role in reducing the risk of bupropion toxicity through proactive patient education and safe prescribing practices. Clinicians should instruct patients to take the medication exactly as prescribed and to avoid doubling the dose when they miss a dose. Clinicians should counsel patients on the importance of adhering to maximum daily dose limits and spacing doses appropriately to minimize the risk of seizures. Screening for contraindications, such as seizure disorders, eating disorders, abrupt alcohol or sedative withdrawal, and concurrent use of other pro-convulsant medications, is essential before initiating therapy. Regular medication reconciliation to identify potential drug interactions, particularly those involving CYP2B6 inhibitors or other agents that may increase seizure risk, is essential. Patients should also be warned against crushing, splitting, or chewing extended-release tablets, as this can result in rapid drug absorption and toxicity.

Safe storage practices are equally important. Patients should keep bupropion in child-resistant containers and out of reach of children and adolescents, as exploratory ingestions can occur. For individuals with depression or suicidal ideation, prescribing limited quantities and ensuring close follow-up may reduce the risk of intentional overdose.

Clinicians should educate patients and caregivers to recognize early warning signs of toxicity, such as severe agitation, confusion, hallucinations, persistent tachycardia, or seizures, and to seek immediate medical attention if these occur. Providing the Poison Control Center number (1-800-222-1222 in the United States) further supports rapid access to expert guidance. Through careful prescribing, interprofessional communication, and targeted patient counseling, healthcare teams can significantly reduce preventable exposures and improve patient safety.

Pearls and Other Issues

• Bupropion toxicity is most frequently associated with seizures; other emergent risks include dysrhythmias and cardiogenic shock.
• Treatment is mainly supportive, with benzodiazepines used first-line for seizures. Anti-epileptic drugs, particularly phenytoin, are generally not recommended.
• ILE therapy is an option to treat refractory status epilepticus or hemodynamic instability.
• An ECG is necessary to evaluate for conduction delays. However, traditional treatment for QRS widening with boluses of sodium bicarbonate may be ineffective, given bupropion's unique mechanism of conduction delay.
• Children and adolescents younger than 13 are more likely to experience unintentional ingestions and present earlier for medical care. Adolescents 14 and older are more often female and present with greater clinical severity, higher rates of tachycardia, sustained tachycardia, altered mental status, and seizures.[20]

Enhancing Healthcare Team Outcomes

Bupropion toxicity is a potentially life-threatening condition characterized by prominent neurologic and cardiovascular effects. Patients may present with agitation, tremor, tachycardia, hallucinations, cardiac conduction abnormalities, or seizures, which can occur hours after ingestion due to delayed absorption from extended-release formulations. Severe toxicity may progress to status epilepticus, malignant dysrhythmias, cardiogenic shock, or central nervous system depression requiring intubation. Because clinical deterioration can be unpredictable, prompt evaluation, continuous monitoring, and early supportive management are essential to prevent complications and stabilize the patient.

Effective management of bupropion toxicity relies on coordinated interprofessional care. Physicians and advanced practitioners must rapidly assess airway, breathing, and circulation; obtain a focused history that includes the timing of ingestion and possible co-ingestants; initiate appropriate monitoring; and consult medical toxicology or a poison center when indicated. Nurses play a vital role in continuous cardiac and neurologic monitoring, early recognition of clinical deterioration, seizure precautions, medication administration, and patient advocacy. Pharmacists contribute essential expertise by identifying drug interactions, recommending evidence-based treatments for seizures and dysrhythmias, assisting with dosing strategies, and supporting medication safety initiatives. Collaboration with emergency medical services, critical care, emergency medicine, psychiatry, medical toxicology, psychology, and respiratory therapy further strengthens care delivery, particularly in severe cases requiring intensive care or extracorporeal support.

Clear communication among team members promotes timely escalation of care, reduces medical errors, and ensures consistent implementation of treatment protocols. Coordinated discharge planning, including psychiatric evaluation when appropriate, medication counseling, and follow-up care, supports long-term safety and reduces the risk of recurrence. Through strong clinical skills, deliberate strategy, and structured interprofessional collaboration, healthcare teams enhance patient-centered care, improve clinical outcomes, optimize safety, and reinforce high-performing team dynamics in the management of bupropion toxicity.

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Disclosure: Andrew Alberter declares no relevant financial relationships with ineligible companies.

Disclosure: Andrew Chambers declares no relevant financial relationships with ineligible companies.

Disclosure: David Schaffer declares no relevant financial relationships with ineligible companies.