# Behavioral pharmacology of novel synthetic indazole, indole, and benzimidazole cannabinoids in rodents

## TL;DR

This study examines how new synthetic cannabinoids affect rodent behavior, revealing differences in potency and effects compared to natural THC.

## Contribution

The study introduces behavioral pharmacology data for eleven novel synthetic cannabinoids in rodent models, highlighting their relative potency and effects.

## Key findings

- Most synthetic cannabinoids were more potent than ∆9-THC in causing locomotor depression.
- FUB-144, 5Cl-AKB-48, and ADB-FUBIATA showed weak effects in behavioral assays.
- Behavioral differences suggest structural changes impact pharmacological outcomes.

## Abstract

Synthetic cannabinoids (SC) are created as alternatives to delta-9-tetrahydrocannabinol (∆9-THC) and can cause serious side effects like hallucinations and death. The DEA has identified eleven concerning synthetic cannabinoids: ADB-BUTINACA, ADB-HEXINACA, ADB-4en-PINACA, ADB-FUBIATA, 4F-MDMB-BICA, 4F-ABUTINACA, FUB-144, FUB-AKB-48, 5F-EMB-PICA, 5Cl-AKB-48, and MDA-19. These compounds were tested in rodent models to evaluate their effects on locomotion, discrimination, and potency relative to ∆9-THC.

The eleven SC were tested for locomotor activity in Swiss-Webster mice and drug discrimination (DD) in Sprague–Dawley rats trained to discriminate ∆9 THC.

In tests for locomotor depression, all the test compounds were more potent than ∆9-THC (ED50 = 3.3 mg/kg) except for FUB-144, 5Cl-AKB-48, and ADB-FUBIATA (ED50 > 6.1 mg/kg), which produced weak locomotor depressant effects. Similarly, in the DD assay, most compounds substituted fully with greater potency t than ∆9 -THC (ED50 = 0.55 mg/kg) except for FUB-144 (ED50 = 1.44 mg/kg), and 5Cl-AKB-48 (ED50 = 3.21 mg/kg). ADB-FUBIATA and MDA-19 tested in doses up to 100 mg/kg, failed to fully substitute for the discriminative stimulus of ∆9-THC.

In summary, slight structural differences led to shifts in behavioral pharmacology outcomes in rodent models, which helped predict their potency relative to ∆9-THC. Therefore, future research on emerging SCs, along with structure–activity relationships at the receptor level, should include behavioral pharmacology testing of SCs to better predict their abuse potential and toxicity.

Supported by NIDA contract N01DA-18–8936; N01DA-23–8936.