Background <p>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.</p> Methods <p>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.</p> Results <p>In tests for locomotor depression, all the test compounds were more potent than ∆⁹-THC (ED₅₀ = 3.3&#xa0;mg/kg) except for FUB-144, 5Cl-AKB-48, and ADB-FUBIATA (ED₅₀ &gt; 6.1&#xa0;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&#xa0;mg/kg) except for FUB-144 (ED₅₀ = 1.44&#xa0;mg/kg), and 5Cl-AKB-48 (ED₅₀ = 3.21&#xa0;mg/kg). ADB-FUBIATA and MDA-19 tested in doses up to 100&#xa0;mg/kg, failed to fully substitute for the discriminative stimulus of ∆⁹-THC.</p> Conclusion <p>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.</p> Support <p>Supported by NIDA contract N01DA-18–8936; N01DA-23–8936.</p>