Opioid drugs include a large number of agonists, antagonists, and mixed agonists/antagonists (Table 2). Heroin, the most commonly abused opioid, can be injected, snorted, or smoked. Commercial street heroin contains a variety of pharmacologically active and inactive adulterants.

Heroin overdose, with coma, pinpoint pupils, and respiratory depression, is sometimes associated with seizures, but their occurrence in that setting is so unusual that other possible causes such as concomitant cocaine use, ethanol withdrawal, or CNS infection should be sought. In a case-control study, heroin use, either past or current, was a risk factor for new-onset seizures independent of head trauma, infection, stroke, ethanol, or other drugs.⁴⁵ For provoked seizures (i.e., caused by an underlying precipitant such as infection or trauma) the odds ratio (OR) was 3.65; for unprovoked seizures it was 2.57. The risk was greatest if heroin had been used on the same day as the seizure, but in no patient was there clinical evidence of overdose, and the risk persisted after a year of abstinence.

The pharmacologic basis of this risk is unclear. In animals, opioids are variably proconvulsant or anticonvulsant depending on species, seizure model, rate of administration, and particular agent (e.g., μ-, δ-, or κ-agonist). In some models, effects are blocked by the antagonist naloxone; in others they are not.^4,55

Seizures or myoclonus are a well-recognized feature of meperidine toxicity, attributable to its active metabolite normeperidine.²⁹ Seizures are also anecdotally described as a toxic effect of fentanyl, pentazocine, and propoxyphene.

Except in neonates seizures are not a feature of opioid withdrawal, which produces flu-like symptoms and intense craving. In newborns of opioid-dependent mothers, withdrawal causes tremor, screaming, fever, tachypnea, tachycardia, vomiting, explosive diarrhea, and sometimes death.²¹ Seizures and myoclonus are described, but can be difficult to distinguish from jitteriness. The diagnosis requires exclusion of hypoglycemia, hypocalcemia, intracranial hemorrhage, CNS infection, and withdrawal from other drugs or ethanol.

Psychostimulant drugs include amphetamine-like agents, whose principal action is to release monoamines at synaptic nerve endings, and cocaine, which blocks monoamine synaptic reuptake (Table 3). Cocaine is the only recreationally used psychostimulant with local anesthetic properties, which probably contributes to its epileptogenicity. Amphetamine-like drugs are taken parenterally or orally, and methamphetamine is often smoked. Cocaine hydrochloride is taken parenterally or intranasally; alkaloidal cocaine (“crack”) is smoked.⁵

Amphetamine-like drugs tend to cause seizures in the setting of obvious overdose (fever, hypertension, cardiac arrhythmia, delirium, or coma).³ With cocaine, seizures more often occur in the absence of other signs of toxicity; they can appear immediately or several hours after use, perhaps attributable to pharmacologically active metabolites.^25,34,43 A focal signature to seizures suggests a structural lesion such as cocaine-related
intracerebral hemorrhage. Status epilepticus (SE) following cocaine use is often refractory to conventional anticonvulsant therapy.

In different reports, the prevalence of seizures among cocaine-intoxicated patients ranged from 1% to 9.3%.^8,34,48,52 Seizures are more likely to occur after smoking crack than after snorting cocaine hydrochloride, probably a dosage effect. A seizure can be new onset with no other contributing factor than cocaine, or it can be triggered by cocaine in a known epileptic.⁴⁸ In animals (and probably humans), repeated administration of cocaine progressively lowers seizure threshold until seizures occur at doses that were originally subthreshold (“kindling,” “reverse tolerance”).^13,41

Methylenedioxymethamphetamine (“ecstasy”) has pharmacological properties of both amphetamine-like psychostimulants and hallucinogenic agents such as mescaline. Popular on college campuses, it is usually taken orally in groups, including “rave” parties (dancing to loud fast music for hours at a time). Overdose can cause seizures, delirium, coma, and death.^30,59

Phenylpropanolamine, available over-the-counter as a decongestant or appetite suppressant, and sold by mail order as a “legal stimulant,” was banned by the U.S. Food and Drug Administration (FDA) after it was shown to increase the risk of stroke. Seizures are described at recommended doses.⁴²

“Dietary supplements” containing ephedra alkaloids (“ma huang”) became popular in North America and Europe during the 1990s, and both seizures and stroke were described in users. In 2003, the FDA banned these products.²⁴

Sedative/hypnotic agents include barbiturates, benzodiaze- pines, and nonbarbiturate/nonbenzodiazepine agents. Recreational barbiturate use is either parenteral or oral; short-acting agents are most popular. Although available as street drugs, benzodiazepines have much less abuse potential. Other sedative drugs vary in their addiction liability. Glutethimide, for example, is a well-recognized street drug, often combined with codeine (“hits,” “loads”). Buspirone, by contrast, does not appear to be abused.⁵

Barbiturates and benzodiazepines potentiate γ-amin- obutyric acid (GABA) neurotransmission through stereospecific receptors on the GABA receptor–chloride channel complex. GABA receptor downregulation is probably a major mechanism of seizures during barbiturate or benzodiazepine withdrawal.

Short-acting barbiturates are most likely to produce seizures on the second or third day of abstinence; full-blown delirium tremens sometimes follows. In a study of human volunteers, abrupt withdrawal from secobarbital or pentobarbital after several months of a daily dose of 400 mg produced paroxysmal EEG changes without symptoms in one-third of the subjects. Withdrawal from 600 mg daily produced minor symptoms in half the subjects and a seizure in 10%. Withdrawal from 900 mg daily produced seizures in three-fourths and delirium tremens in two-thirds.²⁰

Following withdrawal from benzodiazepines, anxiety and tremor are common but can be difficult to distinguish from the symptoms for which the drug was being taken in the first place. Seizures and delirium tremens do occur, however, usually within 24 hours of stopping a short-acting agent and within several days of stopping a long-acting agent.¹⁸ As with barbiturates, seizures are dose-related and unlikely in patients taking recommended therapeutic doses.⁶