Synthetic cannabinoids as potent recreational drugs disrupt the endocannabinoid system in the brain, leading to severe mental and behavioral consequences. Cumyl-PINACA or SGT-24 is a synthetic agonist designed to bind cannabinoid receptor 1 (CB1) with very high affinity, yet the molecular mechanisms underlying its central toxic effects are poorly understood.In this study, we investigated the response of rat cortical neurons and astrocytes to SGT-24 at nanomolar concentrations (0.1 - 1000 nM). The effects of SGT-24 were dose- and time-dependent, as well as cell-specific. In neurons, 10 nM SGT-24 caused an immediate dysregulation of mitochondrial membrane potential (ΔΨm), ATP depletion, and activation of caspases, resulting in early apoptotic cell death characterized by the reduction and shortening of dendrites, cell shrinkage, and chromatin condensation. The reduction in neuronal viability and the initiation of apoptotic processes were prevented by selective antagonists of CB1 and cannabinoid-like receptors peroxisome proliferator-activator receptor gamma (PPAR-γ) and transient receptor potential cation channel subfamily V member 1 (TrpV1). In astrocytes, SGT-24 was effective at 10-fold higher concentrations (100 nM) and induced a progressive dysregulation of ΔΨm and ATP depletion, leading to early apoptosis and subsequent necroptosis. CB1 and PPAR-γ antagonists protected astrocyte viability and prevented cell death.SGT-24 is neurotoxic upon acute exposure to brain cells and acts on both cannabinoid and non-cannabinoid receptors. A deeper understanding of the complexity of synthetic cannabinoids' actions would contribute to the development of multi-target treatments for intoxication.