Neurotoxicity of synthetic cathinones: Can metabolism play a role?

Synthetic cathinones represent the largest group of new psychoactive substances (NPS) seized in Europe and are associated with serious neurotoxic events. Despite undergoing extensive metabolic degradation, the precise contribution of metabolites to the initiation of neurotoxic events remains unclear.

Motivated by alarming reports of neurotoxic effects associated with the use of synthetic cathinones, we investigated the role of metabolic keto reduction, one of the primary metabolic pathways of this NPS class, in these effects. To this end, selected cathinones and their reduced metabolites were synthetically prepared, and their neurotoxicity was subsequently evaluated in a human neuroblastoma SH-SY5Y cell line. Differentiated SH-SY5Y cells were exposed to cathinones and reduced metabolites at different concentrations ranging from 0.1 to 10 mM. Cell viability was evaluated using the MTT colorimetric assay. Statistical analysis was done using a two-tailed t-student test for independent samples, and a p-value less than 0.05 was considered statistically significant.

Following MTT reduction assays conducted over a 24-hour period, among the 10 reduced metabolites tested, only one displayed neurotoxicity levels that did not exceed those of its parent cathinone. Notably, the presence of longer aliphatic N-substituents and aromatic chlorine substituents was correlated with heightened toxicities. The high Hill slopes obtained for these reduced metabolites underline their risk, as even a slight increase in dose might significantly escalate the neurotoxic risk.

Our results constitute the first evidence of the key role of metabolic keto reduction in the onset of neurotoxic events associated with synthetic cathinones. This can explain the distinct inter-individual susceptibilities of these events. 

Fundação para a Ciência e Tecnologia (FCT) is acknowledged for funding the projects: UIDB/00100/2020 (DOI: 10.54499/UIDB/00100/2020) and UIDP/00100/2020 (DOI:10.54499/UIDP/00100/2020) to Centro de Química Estrutural, LA/P/0056/2020 (DOI 10.54499/LA/P/0056/2020) to the Associate Laboratory Institute of Molecular Sciences; UIDB/04046/2020 (DOI:10.54499/UIDB/04046/2020) and UIDP/04046/2020 (DOI: 10.54499/UIDP/04046/2020) to BioISI-Biosystems & Integrative Sciences Institute; UIDB/04565/2020 and UIDP/04565/2020 to Institute for Bioengineering and Biosciences;  LA/P/0140/2020 to the Associated laboratory Institute for Health and Bioeconomy and through Investimento RE-C05-i02 – Missão Interface N.o01/C05-i02/22. Joint funding from FCT and the COMPETE Program through grant RNEM-LISBOA-01-0145-FEDER-022125. FCT is also acknowledged for the PhD grant 2022.11339.BD to RPL.