Pharmaco-toxicological effects of the synthetic cannabinoids 4F-ABUTINACA, SDB-005, and JWH-018 in mice. In vitro and in vivo studies.

Background: Synthetic cannabinoids (SCs) are currently one of the most severely abused new psychoactive substances in the world. However, there remains a notable lack of pharmacological data on the newly emerged synthetic cannabinoids. In the present study, the in vitro and in vivo pharmacological effects of the fourth-generation synthetic cannabinoids 4F-ABUTINACA and SDB-005 are determined and compared to those of the first-generation synthetic cannabinoid JWH-018.

Methods: In this study, the affinities of three SCs for CB1 receptors were evaluated using surface plasmon resonance (SPR) experiments. The acute toxicity of these three SCs was assessed through the up-and-down procedure, while their cannabinoid-specific pharmacological effects were determined through tetrad assays, which examined parameters such as temperature regulation, analgesia, locomotor activity, and catalepsy. Additionally, conditioned place preference (CPP) experiments and a precipitated withdrawal tests were conducted to assess the psychoactive effects and physical dependence of the SCs.

Results: SPR experiments and acute toxicity tests demonstrated that in vitro KD values were positively correlated with in vivo ED50 potency estimates. All SCs were found to induce the classical "tetrad effects" in a dose-dependent manner. Notably, all SCs displayed significant biphasic effects in CPP experiments. Following the administration of the CB1 receptor antagonist rimonabant, a significant increase in head twitches and paw tremors was observed, indicating that the physical dependence manifested after the ingestion of SCs is mediated by the CB1 receptor.

Conclusions: These findings suggest that these SCs have cannabinoid-specific pharmacological effects and abuse potential, providing robust experimental data to support future regulatory efforts.