Methiodone (IC-26) a case series: an old, but novel, opioid substance causing severe toxicity

Methiodone (IC-26; 4-ethylsulfonyl-N,N-dimethyl-4,4-diphenylbutan-2-amine) is a synthetic opioid derivative of methadone that has recently emerged on the designer drug market. Data on its clinical toxicity and pharmacokinetics remain limited. We describe four cases of severe methiodone intoxication requiring intensive care unit (ICU) admission, taking place between July and November 2025. Clinical presentation, treatment, and outcomes were evaluated. In addition, systematic toxicological analysis was performed including Liquid Chromatography - High Resolution Mass Spectrometry (LC-HRMS) and targeted Liquid Chromatography - tandem Mass Spectrometry (LC-MS/MS). All patients presented with a classical opioid toxidrome, characterized by respiratory depression, miosis, and decreased consciousness. Naloxone administration resulted in clinical improvement in all cases. Methiodone plasma concentrations ranged from 0.20 to 0.64 mg/L. The elimination half-life in plasma was estimated at approximately 13 h based on one case. Metabolite analysis revealed N-dealkylation as an important metabolic pathway, with additional hydroxylation and limited glucuronidation. Methiodone was variably detected in routine immunoassays, depending on assay specificity. No electrocardiogram (ECG) clinically relevant abnormalities were observed, in contrast to observations in methadone intoxications. Methiodone is an emerging opioid capable of causing severe, but treatable, intoxication. Increased clinical and analytical awareness is essential, as further cases are likely to emerge with the ongoing evolution of the new psychoactive substance market.