What question did this study set out to answer?

This study aims to compare the neurotoxic profiles of cannabidiol and its synthetic analogues PQM-242 and PQM-249.

February 21, 2026Open Access

Synthetic cannabidiol analogues exhibit lower toxicity than cannabidiol and protect against ethanol-induced apoptosis in SH-SY5Y cells

CACarolina Aparecida Faria AlmeidaUniversidade Federal de Alfenas GSGilles SallesMemorial Sloan Kettering Cancer Center VBVítor BrunoUniversidade de São Paulo

Key Points

This study aims to compare the neurotoxic profiles of cannabidiol and its synthetic analogues PQM-242 and PQM-249.
Exposed SH-SY5Y cells to varying concentrations of CBD and synthetic analogues.
Assessed cell viability with MTT assay and apoptosis using annexin V/propidium iodide.
Evaluated expression levels of Bax and Bcl-2 using western blot.
Determined LC50 and NOAEL values for each compound.
CBD exhibited an LC50 of 44µM, compared to >600µM for PQM-242 and PQM-249.
NOAELs for PQM-242 and PQM-249 were 100µM, whereas CBD's NOAEL was 10µM.
All compounds reduced ethanol-induced loss of cell viability and apoptosis.
PQM-242 prevented ethanol-mediated upregulation of Bax.

Abstract

Cannabidiol (CBD) shows therapeutic potential for treating alcohol use disorder (AUD); however, its neurotoxicological profile remains insufficiently characterized, especially when compared with emerging synthetic analogues designed to improve safety. This study compares the neurotoxic and mechanistic profiles of CBD and two synthetic derivatives, PQM-242 and PQM-249, and evaluates their ability to attenuate ethanol-induced cellular injury. Human SH-SY5Y neuroblastoma cells were exposed to increasing concentrations (0.1-1000µM) to generate concentration-response curves, estimate no-observed-adverse-effect levels (NOAELs), and determine cytotoxicity thresholds. Cell viability (MTT), apoptosis (annexin V/propidium iodide), and Bax and Bcl-2 expression (western blot) were assessed after 48h of exposure. CBD showed an LC50 of 44µM, whereas PQM-242 and PQM-249 displayed LC50 values >600µM, indicating markedly lower intrinsic toxicity in the proposed study model. The NOAELs for PQM-242 and PQM-249 were 100µM, compared with 10µM for CBD. For co-exposure studies, 10µM was selected to enable direct comparison under ethanol challenge (250mM). All compounds reduced ethanol-induced loss of viability and apoptosis, and PQM-242 additionally prevented ethanol-mediated Bax upregulation. Overall, PQM-242 and PQM-249 demonstrated enhanced cellular safety and maintained protective activity, supporting their further investigation as candidate molecules for AUD.

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