A wide range of drugs can cause seizures, from common prescriptions like antidepressants and antibiotics to recreational substances and even over-the-counter antihistamines at high doses. Some drugs trigger seizures directly by disrupting the brain’s electrical balance, while others create seizure risk only when you stop taking them abruptly. Understanding which categories carry the highest risk can help you recognize potential warning signs and have informed conversations about your medications.
How Drugs Trigger Seizures in the Brain
Your brain maintains a constant balance between excitatory signals (which fire neurons) and inhibitory signals (which calm them down). The main inhibitory chemical is GABA, which acts like a brake on electrical activity. The main excitatory chemical is glutamate, which acts like an accelerator. Drugs that cause seizures tip this balance in one of two directions: they either block GABA’s calming effect or amplify glutamate’s stimulating effect. When inhibition drops or excitation spikes, neurons can fire uncontrollably, producing a seizure.
Some drugs do this at normal therapeutic doses, especially in people who are already vulnerable. Others only cause seizures at toxic doses or when combined with other medications. Certain patient-specific factors raise the risk significantly, including a prior seizure disorder, kidney impairment (which allows drugs to accumulate to toxic levels), and taking multiple seizure-lowering medications at once.
Antidepressants
Antidepressants are among the most commonly prescribed medications linked to seizures. Older tricyclic antidepressants carry the most well-established risk, and guidelines generally recommend avoiding them as a first choice in anyone with seizure concerns. Clomipramine, a tricyclic, has the highest documented risk among antidepressants, followed by amitriptyline.
Newer antidepressants like SSRIs and SNRIs were once considered much safer, but the picture is more nuanced than it appears. Patients treated with SSRIs and SNRIs actually have about twice the risk of developing seizures compared to untreated patients or those on tricyclics, with the period right after starting treatment carrying the highest risk. Among the newer drugs, venlafaxine, citalopram, sertraline, trazodone, mirtazapine, paroxetine, bupropion, and escitalopram all have a low but measurable seizure risk above 0.1% at regular doses. Fluoxetine and duloxetine appear to carry negligible risk by comparison.
Bupropion deserves special mention because its seizure risk is dose-dependent and well known. It is also classified as a different type of antidepressant (an NDRI), and guidelines suggest avoiding it as a first-line option in seizure-prone patients.
Antipsychotics
Clozapine stands out as the antipsychotic with the highest seizure risk. In a review of over 1,400 patients treated with clozapine between 1972 and 1988, 2.8% experienced generalized tonic-clonic seizures during treatment. Life-table analysis predicted a cumulative 10% risk of seizures after 3.8 years of use. The risk is clearly dose-related: patients on high doses (600 mg per day or more) had a 4.4% seizure rate, compared to 2.7% at medium doses and 1.0% at low doses. Rapid dose increases also raise the risk. Despite this, most patients who experienced clozapine-related seizures were able to continue the medication after a dose reduction or the addition of a seizure-prevention drug.
Other antipsychotics can also lower the seizure threshold. Quetiapine ranks relatively high among psychiatric medications for seizure risk, appearing just after clomipramine in comparative analyses.
Antibiotics
All beta-lactam antibiotics, the broad family that includes penicillins, cephalosporins, and carbapenems, can induce seizures. They do this by binding to GABA receptors in the brain and blocking their inhibitory function. Among the carbapenems, imipenem carries the highest risk by a significant margin because it binds GABA receptors much more strongly than its relatives. In patients with meningitis treated with imipenem, one-third experienced seizures. Meropenem, ertapenem, and doripenem sit at the opposite end of the risk spectrum, and meropenem is considered safe enough to be approved for treating meningitis.
Cefepime, a cephalosporin now available as a generic, has also been flagged for neurological side effects including seizures, delirium, and reduced consciousness. These effects are most common in patients with impaired kidney function, since the drug accumulates when the body cannot clear it efficiently.
Pain Medications
Tramadol is the pain medication most frequently associated with seizures. It lowers the seizure threshold on its own, but the risk climbs substantially when it is combined with antidepressants. The interaction is particularly concerning with antidepressants that inhibit a specific liver enzyme called CYP2D6, including fluoxetine, paroxetine, duloxetine, doxepin, and bupropion. These drugs slow the breakdown of tramadol, allowing it to build up in the body. Research in older nursing home residents found that the combination of tramadol with CYP2D6-inhibiting antidepressants was associated with a significantly increased risk of seizure-related medical encounters, especially when the antidepressant was an SSRI without additional pain-relieving properties.
Over-the-Counter Antihistamines
Diphenhydramine, the active ingredient in Benadryl and many sleep aids, can cause seizures in overdose. A study of 282 patients with diphenhydramine poisoning found that severe symptoms, including seizures, coma, and delirium, occurred in 14 to 18% of cases. Moderate toxicity began at doses above 300 mg, but seizures and other severe effects appeared primarily above 1,000 mg. The risk of seizures and coma increased further in patients who ingested more than 1,500 mg. At recommended doses (25 to 50 mg), diphenhydramine does not pose a seizure risk for most people.
Recreational and Illicit Drugs
Cocaine is one of the most common causes of drug-induced seizures seen in emergency departments. It floods the brain with excitatory activity while simultaneously interfering with normal electrical signaling. Methamphetamine and other stimulants carry similar risks through overlapping mechanisms.
Synthetic cannabinoids, sold under names like Spice and K2, cause seizures through a mechanism distinct from natural marijuana. Unlike THC, which is a partial activator of cannabinoid receptors in the brain, synthetic cannabinoids are full activators. This stronger activation may powerfully suppress GABA’s calming signals without the counterbalancing effects that natural cannabis compounds like CBD provide. Emergency departments in the United States and Europe have seen a rising number of patients presenting with seizures after smoking these products, including people with no prior neurological history. Natural marijuana, by contrast, is not typically associated with seizures and some cannabis-derived compounds are actually used to treat epilepsy.
Withdrawal Seizures
Some drugs cause seizures not when you take them, but when you stop. This happens because the brain adapts to the constant presence of a calming substance. When that substance disappears, the brain is left in an overexcited state with too little inhibition.
Alcohol
Alcohol withdrawal is one of the most dangerous and common causes of withdrawal seizures. Seizures typically occur 12 to 48 hours after the last drink in heavy, long-term drinkers. The risk is highest in people who have gone through withdrawal before, a phenomenon called kindling, where each successive withdrawal episode becomes more severe.
Benzodiazepines
Benzodiazepine withdrawal seizures are most likely after abrupt cessation of long-term, high-dose use. The timeline depends on which benzodiazepine you were taking. Short-acting benzodiazepines produce withdrawal symptoms within one to two days, peaking at one to two weeks. Long-acting benzodiazepines have a slower, generally less severe withdrawal that starts two to seven days after the last dose and peaks around day 20. In both cases, a gradual taper rather than abrupt discontinuation dramatically reduces seizure risk.
Baclofen
Baclofen, a muscle relaxant commonly prescribed for spasticity, can cause seizures when stopped suddenly. Patients on chronic therapy are at the highest risk. Withdrawal can also produce agitation, hallucinations, psychosis, dangerously high body temperature, and worsening spasticity. These symptoms typically arise when the drug is stopped without a proper tapering schedule, whether intentionally or by accident, such as when a prescription lapses. Abrupt withdrawal from intrathecal baclofen (delivered via a pump directly to the spinal cord) is especially dangerous, with multiple case reports documenting severe outcomes.
Who Is Most at Risk
Having an existing seizure disorder is the single strongest risk factor for drug-induced seizures. Even drugs with a low overall seizure rate become significantly more dangerous in someone whose brain is already prone to abnormal electrical activity. Kidney impairment matters for many of the drugs on this list, particularly antibiotics like cefepime and imipenem, because reduced kidney function allows the drug to reach toxic concentrations. Taking multiple medications that each lower the seizure threshold, such as combining tramadol with an antidepressant, compounds the risk in ways that may not be obvious from looking at either drug alone.
Interestingly, age and gender do not appear to be independent risk factors for complications from drug-induced seizures. The drug itself, the dose, and the patient’s underlying health conditions matter far more than demographics.