3-CMC: Acute Effects in Male and Female Mice, Human Intoxication Case Series (Italy, 2014-2025), and Prediction of ADMET Properties.

3-chloromethcathinone (3-CMC) is a synthetic cathinone that gained relevance, having been involved in a large number of seizures and poisoning reports. Despite this, literature currently lacks information on its pharmaco-toxicological effects. This study aims to investigate the acute sensorimotor and physiological effects of 3-CMC (0.1-30 mg/kg; i.p.) in male and female CD-1 mice and its effects (1 and 10 mg/kg) on Prepulse Inhibition (PPI). Furthermore, we describe a series of 3-CMC (or CMC)-related human intoxications (Italy, 2014-2025) registered by the PCC-National Toxicology Information Centre. Finally, we predicted the ADMET properties of 3-CMC compared to 2-CMC, 4-CMC, 2-MMC, and two 3-CMC metabolites. 3-CMC induced in mice locomotor stimulation in mice, relevant tachypnoea and hypothermia, sensorimotor, and PPI alterations were observed only at high doses, with minor sex differences. All intoxications were non-fatal and involved male patients showing psychomotor agitation, psychosis, aggressiveness, CNS depression, but also cardiac arrhythmias, thoracic pain, and tachypnea. N-dealkylation, N-hydroxylation, and phenyl hydroxylation were the main predicted reactions. Drug-drug interaction potential and cardiotoxicity were suggested for all compounds. This interdisciplinary study elucidates 3-CMC effects and its associated risks, opening new objectives for future studies on CMC compounds to provide critical information to clinicians and the toxicological field.