Seizures have been reported in humans receiving excessive single oral doses (700 mg) or large intravenous doses (300 mg). However, there have been several rare cases of people having grandqmal seizures at doses as low as 100–400 mg orally.

An Australian study found that of 97 confirmed new-onset seizures, eight were associated with tramadol, and that in the authors' First Seizure Clinic, "tramadol is the most frequently suspected cause of provoked seizures"...... Seizures caused by tramadol are most often tonic-clonic seizures, more commonly known in the past as grand mal seizures. Also when taken with SSRIs, there is an increased risk of serotonin toxicity, which can be fatal.

Fewer than 1% of users have a presumed incident seizure claim after their first tramadol prescription. Risk of seizure claim increases two- to six-fold among users adjusted for selected comorbidities and concomitant drugs. Risk of seizure is highest among those aged 25–54 years, those with more than four tramadol prescriptions, and those with a history of alcohol abuse, stroke, or head injury.

The next thing I knew, Jon was practically on top of me, screaming into my ear. I had no idea where I was, and I couldn't move. He was saying....that I had a full blown seizure and had flipped nearly upside down.