4,4′-DMAR in-vivo acute cardiotoxicity: differences between (±)cis-4,4′-DMAR and its coadministration with the (±)trans-4,4′-DMAR isomer

Backgrounds/aims Synthetic stimulants represent the largest group of new psychoactive substances and include the aminorex class, which possess anorectic properties and a pharmacological profile similar to that of amphetamine. Among these, 4,4 '-dimethylaminorex (4,4 '-DMAR) is one of the best-known synthetic stimulants with a chiral structure, which gives rise to two stereoisomers [(+/-)cis-4,4 '-DMAR and (+/-)trans-4,4 '-DMAR] with distinct pharmacological and toxicological characteristics. This substance has been detected in cases of intoxication and deaths among adults and adolescents. Although 4,4 '-DMAR can also induce respiratory impairments, tachycardia, and sudden cardiac death/arrest, clinical and preclinical investigations of its cardiorespiratory toxicity remain limited. Thus, this study aimed to investigate the cardiorespiratory effects of (+/-)cis-4,4 '-DMAR (1, 3, and 10 mg/kg) administration and the coadministration of 1 mg/kg (+/-)cis-4,4 '-DMAR and 30 mg/kg (+/-)trans-4,4 '-DMAR in awake CD-1 male mice.Methods We evaluated heart rate, breathing rate, and cardiac (ECG) and respiratory (plethysmography) electrical parameters. The most severe effects were observed after administration of 10 mg/kg (+/-)cis-4,4 '-DMAR and coadministration of 1 mg/kg (+/-)cis-4,4 '-DMAR and 30 mg/kg (+/-)trans-4,4 '-DMAR.Results These treatments induced tachycardia and narrow-QRS arrhythmias, characterized by an increase in the corrected QT/QT interval, tachypnea, and a decrease in relaxation time, with varying degrees of intensity, probably due to differences in metabolism. Moreover, immunohistochemical analysis of the heart specimens revealed significant alterations in inflammation/oxidative stress markers in cardiomyocytes and blood vessel walls, accompanied by cytoarchitectural changes.Conclusions These findings provide the first evidence of the severe toxicity of 4,4 '-DMAR to the cardiac and respiratory systems, highlighting the importance of dosage and stereoisomer coadministration. This serves as a warning of the complex nature and potential dangers of intoxication.