What Medications Are Most Likely to Cause Seizures?

October 12, 2025 •

3 min read

Intentional ingestion of antidepressants, particularly bupropion, is the most common cause of drug-induced seizures in children and adolescents presenting for emergency care. Understanding what medications are most likely to cause seizures is crucial for patient safety and informed medical decisions.

Quick Summary

A detailed overview of common prescription and over-the-counter medications known to lower the seizure threshold, including antidepressants like bupropion, opioids like tramadol, and various antibiotics, and the patient-specific factors that increase risk.

Key Points

High-Risk Drugs: Bupropion (Wellbutrin), tramadol (Ultram), and certain antibiotics like imipenem are among the medications most likely to cause seizures.
Dose-Dependent Risk: For many drugs, including bupropion and clozapine, the risk of seizure increases significantly with higher doses.
Core Mechanism: Most drug-induced seizures happen because a medication disrupts the brain's balance of excitatory (glutamate) and inhibitory (GABA) signals.
Patient Factors: A history of seizures, kidney or liver disease, advanced age, and head trauma can make a person more susceptible to drug-induced seizures.
Antibiotic Risk: Beta-lactam antibiotics (penicillins, cephalosporins, carbapenems) and fluoroquinolones are known to lower the seizure threshold, mainly by interfering with GABA receptors.
Opioid Caution: The opioid tramadol carries a significant seizure risk even at therapeutic doses due to its effect on serotonin and norepinephrine.
Primary Management: The first step in managing a drug-induced seizure is typically to discontinue the suspected medication, with benzodiazepines used to stop active, prolonged seizures.

Understanding the Seizure Threshold

A seizure occurs due to a disruption of normal electrical activity in the brain, resulting from an imbalance between excitatory and inhibitory signals. The 'seizure threshold' describes this balance; certain medications can lower this threshold, making a seizure more likely, even in individuals without a history of epilepsy. The primary mechanisms involve either blocking inhibitory neurotransmitters like gamma-aminobutyric acid (GABA) or enhancing excitatory ones like glutamate. While many drugs carry a risk, some classes are more frequently implicated than others.

High-Risk Medication Classes

Several classes of medication are well-documented for their potential to induce seizures. The risk is often dependent on the dose, method of administration, and individual patient risk factors.

Antidepressants

Antidepressants are among the most common causes of drug-induced seizures. Bupropion is frequently cited for its dose-dependent seizure risk, which increases significantly at higher doses. Tricyclic antidepressants also carry a relatively high risk, especially in overdose. While newer SSRIs and SNRIs are generally safer, they can still cause seizures at high doses.

Antibiotics

Certain antibiotics are known to have proconvulsive properties by interfering with GABA receptors. Carbapenems, particularly imipenem, have the highest seizure association in this class. High doses of penicillins and certain cephalosporins like cefepime can also induce seizures. Fluoroquinolones like ciprofloxacin can lower the seizure threshold, especially in vulnerable populations.

Opioid Analgesics

Tramadol is a synthetic opioid linked to seizures, which can occur even at therapeutic doses. Meperidine's seizure risk is primarily due to its metabolite, normeperidine, which can accumulate in patients with impaired kidney function.

Antipsychotics

Many antipsychotics can lower the seizure threshold. Clozapine has one of the highest risks among these medications, strongly linked to dose and plasma concentration. Both first and second-generation antipsychotics carry some level of risk.

Other Notable Medications

Stimulants used for ADHD, like methylphenidate, may lower the seizure threshold, particularly early in treatment or at high doses. Over-the-counter antihistamines such as diphenhydramine are a leading cause of drug-induced seizures, especially in overdose. Isoniazid, an antitubercular drug, is a classic cause of seizures in toxic doses.

Comparison Table of High-Risk Medications


Medication Class	Common Examples	Primary Mechanism of Seizure Risk
Antidepressants	Bupropion, Clomipramine	Catecholamine effects, GABA-A antagonism
Antibiotics	Imipenem, Cefepime, Ciprofloxacin	GABA-A receptor antagonism
Opioids	Tramadol, Meperidine	Inhibition of serotonin/norepinephrine reuptake, metabolite accumulation
Antipsychotics	Clozapine, Chlorpromazine	Varies; can involve GABA antagonism and other effects
Stimulants	Methylphenidate, Amphetamines	Increased CNS excitation
Antihistamines	Diphenhydramine	Anticholinergic effects, sodium channel blockade in overdose

Key Risk Factors

Several factors can increase an individual's susceptibility to medication-induced seizures:

High dosage or overdose
Rapid dose increases
Intravenous administration
Pre-existing conditions (history of seizures, head trauma, CNS tumor)
Renal or hepatic impairment (leading to drug accumulation)
Elderly age
Abrupt withdrawal from alcohol or sedatives
Polypharmacy (use of multiple drugs that lower seizure threshold)

Conclusion

A wide array of medications can lower the seizure threshold and potentially cause a seizure. Drugs like bupropion, tramadol, imipenem, and clozapine are among the most frequently implicated. The risk is rarely absolute and is heavily influenced by the dose, the route of administration, and a patient's underlying health conditions, especially renal function and a prior history of seizures. Management primarily involves discontinuing the offending drug and providing supportive care. In cases of prolonged seizures, benzodiazepines are the first-line treatment. Patients should always discuss their full medication list and health history with their provider to mitigate these risks.

For more information, a valuable resource is the Epilepsy Foundation.

Frequently Asked Questions

Yes. Certain OTC medications, most notably the antihistamine diphenhydramine (Benadryl), are a common cause of drug-induced seizures, especially in cases of overdose. Cough suppressants like dextromethorphan may also pose a risk.

No, the risk is highly dose-dependent. At recommended daily doses of 300 mg or less, the seizure incidence is low (around 0.1%). However, the risk increases substantially at doses above 450 mg/day.

Not necessarily, but it requires careful management. The use of psychotropic or other proconvulsant drugs in patients with epilepsy should be carefully weighed by a healthcare provider, often with close monitoring and at the lowest effective doses. Tramadol should be avoided in patients with a history of seizure disorders.

Most drug-induced seizures are self-limited. For prolonged or recurrent seizures (status epilepticus), benzodiazepines like lorazepam are the first-line treatment. The primary management is to identify and discontinue the offending drug.

Beta-lactam antibiotics are well-known to have seizure potential. Within this group, carbapenems (especially imipenem) are most frequently associated with seizures, followed by certain cephalosporins (like cefepime) and high-dose penicillins.

No. While the risk is highest with overdose, tramadol can cause seizures even at recommended therapeutic doses, particularly in patients with other risk factors.

Generally, yes. Newer antidepressants like SSRIs (e.g., Sertraline, Fluoxetine) are associated with a low risk of seizures (0.0%–0.4%), which is comparable to the general population and lower than older tricyclic antidepressants (TCAs) or bupropion.