Apparent Inverse Relationship between Cannabinoid Agonist Efficacy and Tolerance/Cross-Tolerance Produced by Δ9-Tetrahydrocannabinol Treatment in Rhesus Monkeys

Synthetic cannabinoids (CBs) [naphthalen-1-yl-(1-pentylindol-3- yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3- yl) methanone (JWH-073)] are marketed, sold, and used as alternatives to cannabis. Synthetic CBs appear to have effects similar to those of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the drug primarily responsible for the behavioral effects of cannabis. However, synthetic CB products produce atypical effects (e. g., hypertension, seizures, and panic attacks). One potential explanation for atypical effects is CB1 receptor agonist efficacy, which is reportedly higher for JWH-018 and JWH-073 compared with Delta(9)-THC. The goal of this study was to test a prediction from receptor theory that tolerance/cross-tolerance (i.e., resulting from daily Delta(9)-THC treatment) is greater for a low-efficacy agonist compared with a high-efficacy agonist. Rhesus monkeys discriminated 0.1 mg/kg Delta(9)-THC i.v. from vehicle, and sensitivity to CB1 agonists was determined before and after 3 and 14 days of Delta(9)-THC treatment (1 mg/kg per day s.c.). (1R, 3R, 4R)-3-[2-Hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl) cyclohexan-1-ol (CP-55,940), a prototype high-efficacy CB1 receptor agonist, JWH-018, and JWH-073 substituted for the discriminative stimulus effects of Delta(9)-THC. Three days of Delta(9)-THC treatment produced less tolerance/cross-tolerance than 14 days of Delta(9)-THC treatment. Three days of Delta(9)-THC did not result in cross-tolerance to CP-55,940, JWH-073, and JWH-018; in contrast, as reported previously, 3 days of Delta(9)-THC treatment decreased sensitivity to Delta(9)-THC 3-fold. Fourteen days of Delta(9)-THC decreased sensitivity to Delta(9)-THC, CP-55,940, JWH-018, and JWH-073 9.2-fold, 3.6-fold, 4.3-fold, and 5.6-fold, respectively. The greater loss of sensitivity to Delta(9)-THC relative to CP-55,940 and JWH-018 suggests that differences in CB1 receptor agonist efficacy are important in vivo and might underlie differences in the dependence liability and adverse effects of synthetic CBs versus cannabis.