Comprehensive evaluation of the toxicological effects of commonly encountered synthetic cathinones using in silico methods

Abstract Synthetic cathinones (SCs), a group of new psychoactive substances (NPS), are designer molecules with hallucinogenic and psychostimulatory effects. Although the structural similarities of SCs to amphetamines suggest that they may have similar toxicity profiles to those of amphetamine congeners, little is known about SCs from a toxicological point of view. In the present study, the toxicity profiles of commonly encountered SCs (n = 65), listed in the 2020 Report of the United Nations Office on Drugs and Crime (UNODC), were evaluated using in silico methods. We aimed to gain a deeper understanding of key toxicological endpoints: acute oral toxicity (LD50), mutagenicity, genotoxicity, and carcinogenicity prediction using EPA TEST (v.5.1.2 and 4.2.1), VEGA (v.1.2.3), and ProTox (v.3.0). Physicochemical and pharmacokinetic (ADME) properties were estimated using SwissADME and pkCSM. 2,3-MDMC (41) was predicted to be the most lethal SC by the VEGA KNN and the EPA TEST v.5.1.2 with an oral rat LD50 value of 105.17 and 117.77 mg/kg, respectively. 4-BEC (2) was the only molecule with a consensus score of positive prediction greater than 0.90 in both TEST mutagenicity models. 2,3-MDMC (41) and methylone (52) were predicted as carcinogenic by VEGA carcinogenicity CAESAR, ISS, IRFMN-ISSCAN-CGX, oral classification, and ProTox models. These two SCs were predicted to be active by VEGA chromosomal aberration (CORAL) and in vitro micronuclei-inducing activity (IRFMN-VERMEER) models. Our results concluded that given the prolonged exposure duration and age range, the genotoxic and carcinogenic potential of SCs should be considered, among other known toxic effects.