Recreational MDMA doses do not elicit hepatotoxicity in HepG2 spheroids under normo- and hyperthermia.

MDMA (ecstasy) at recreational doses does not cause liver cell damage in a 3D human liver cell model, even under hyperthermia. The study used HepG2 spheroids to test MDMA's hepatotoxicity and found no significant reduction in cell viability, no increase in reactive oxygen species, no loss of mitochondrial membrane potential, no cell cycle arrest, and no apoptotic cell death. These results support further preclinical research into MDMA's safety for both harm reduction and therapeutic use, as non-abusive recreational and therapeutic doses overlap.

Study at a glance

Abstract

MDMA (3,4-methylenedioxymethamphetamine), an entactogen with empathogenic and prosocial effects, is widely used in music festivals and other festive settings. High MDMA doses have been associated with drug-induced liver injury and cases of hyperthermia. Although the latter condition is thought to increase MDMA hepatotoxicity, this correlation remains poorly explored for recreational MDMA doses. On the other hand, the fact that MDMA acts to extinguish fear and to reconsolidate memory could be explored as an adjunct to psychotherapy during treatment of neuropsychiatric disorders such as post-traumatic stress disorder. In this context, assessing MDMA toxicity is relevant, and tridimensional cell culture has emerged as an alternative to animal models in toxicity assessment. Herein, we have used HepG2 spheroids to evaluate MDMA-induced hepatotoxicity at recreational doses, under normo- or hyperthermia. The MTT reduction assay did not evidence significantly reduced cell viability. Moreover, MDMA did not increase reactive oxygen species production, deplete the mitochondrial membrane potential, arrest the cell cycle, or induce apoptotic cell death. These findings support further pre-clinical investigation of MDMA safety from the perspective of both harm reduction and therapy given that non-abusive recreational and therapeutic doses overlap.