Triggers of highly lethal seizures induced by novel stimulants: A systematic review focused on synthetic cathinones and phenethylamines

Abstract

Synthetic cathinones and phenethylamines are increasingly prevalent novel psychoactive substances with stimulant and hallucinogenic properties. They are associated with acute symptomatic seizures, often with lethal outcomes. Current management is usually limited to symptomatic therapy, as serotonin and sympathomimetic toxidromes are widely regarded as the main seizure-inducing mechanisms. However, intoxications frequently involve severe organ toxicities or metabolic disturbances with high epileptogenic potential, which may be preventable or treatable. This review aimed to assess seizure mechanisms beyond central monoaminergic toxicity to identify additional factors and improve seizure management. A systematic search of PubMed and Web of Science (2003–2024) identified reports describing individual human cases of acute intoxication with synthetic cathinones or phenethylamines, published in English and providing detailed clinical data. Inclusion criteria were met by 42 cases from 34 reports. A descriptive synthesis was performed to summarize observed patterns across substance groups. Most seizures occurred in previously healthy young adults and resulted in death in nearly 50 % of cases, with higher fatality among cathinone users. Serotonin and sympathomimetic toxidromes were present in most cases, supporting a primary role in seizure generation. However, intracranial hemorrhage and cerebral edema (often precipitated by hypertensive crisis), hypoglycemia, and hyponatremia likely contributed to seizures in several cases. Based on these findings, we recommend that young adults presenting with seizures and signs of monoaminergic toxicity, in whom synthetic cathinone or phenethylamine intoxication is confirmed or suspected, should be promptly assessed for focal brain injury and metabolic disturbances to identify treatable causes and potentially improve outcomes.