Acute Toxicity of Three Synthetic Cannabinoids: First In Vivo Preclinical Study

Background and

Objectives: Synthetic cannabinoids (SCs) are new psychoactive substances associated with acute intoxications. Experimental data obtained under controlled and comparable conditions remain limited for this category of compounds. This descriptive, hypothesis-generating screening study aimed to characterize the acute toxicity profile of three SCs, JWH-007, AM-694, and MAB-CHMINACA.

Materials and Methods: Acute toxicity was evaluated in female Swiss Albino mice, in accordance with the OECD 423 guideline, following oral and intraperitoneal administration. Animals were monitored for 14 days for behavioral and clinical signs of toxicity. At the end, histopathological examination was performed to describe organ-level changes. Serum concentrations of the tested compounds were quantified by LC-ESI-MS/MS 24 h after intraperitoneal administration.

Results: The three compounds were associated with distinct behavioral, clinical, and histopathological observations. JWH-007 was associated with transient behavioral depression and histopathological changes in peripheral organs. AM-694 was associated with histopathological changes in systemic organs and limited behavioral manifestations. MAB-CHMINACA was associated with acute behavioral toxicity and central nervous system lesions, including neuronal vacuolization, necrosis, oedema, and inflammatory changes.

Conclusions: These preliminary findings describe compound-specific in vivo toxicity patterns and may inform the design of future confirmatory studies on SCs’ toxicity. The observed behavioral and histopathological changes should be interpreted as hypothesis-generating and require statistical validation before conclusions can be drawn regarding comparative toxicity, structural class effects, or predictive value for risk stratification.