Assessment of Abuse Potential of Three Indazole-Carboxamide Synthetic Cannabinoids 5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA.

5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA are three potent indazole-carboxamide synthetic cannabinoids (SCs) that have been widely abused in recent years. However, the pharmacological research on these compounds remains limited, especially in vivo research data. The purpose of the present study was to investigate the pharmacological effects of 5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA in mice, comparing their in vivo effects with those caused by Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive substance in cannabis. We evaluated the cannabinoid-specific pharmacological effects of 5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA using the tetrad assay (locomotion inhibition, hypothermia, analgesia and catalepsy). Then we conducted conditioned place preference (CPP) and precipitated withdrawal assay to assess the rewarding effect and physical dependence, with Δ9-THC as a positive control. The results showed that all of the three SCs exhibited potential tetrad effects in a dose-dependent manner, with median effective dose (ED50) values ranging from 0.03 to 0.77 mg/kg. In the CPP tests, they all exhibited a significant biphasic effect of conditioned place preference (CPP) and conditioned place aversion (CPA). A significant increase in paw tremors and head twitches was observed in the rimonabant-precipitated withdrawal assay, indicating that the repeated administration of these SCs can lead to potential physical dependence. All effective doses were lower than Δ9-THC. These findings strongly suggested that the three SCs exhibited similar but stronger cannabinoid-specific tetrad effects, rewarding effect and physical dependence compared with Δ9-THC, indicating their high abuse potential and possible threats to human health. The rank order of abuse potential for these drugs was 5F-ADB > MDMB-4en-PINACA > ADB-4en-PINACA > Δ9-THC.