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 Δ⁹-tetrahydrocannabinol (Δ⁹-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 Δ⁹-THC. The goal of this study was to test a prediction from receptor theory that tolerance/cross-tolerance (i.e., resulting from daily Δ⁹-THC treatment) is greater for a low-efficacy agonist compared with a high-efficacy agonist. Rhesus monkeys discriminated 0.1 mg/kg Δ⁹-THC i.v. from vehicle, and sensitivity to CB(1) agonists was determined before and after 3 and 14 days of Δ⁹-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 Δ⁹-THC. Three days of Δ⁹-THC treatment produced less tolerance/cross-tolerance than 14 days of Δ⁹-THC treatment. Three days of Δ⁹-THC did not result in cross-tolerance to CP-55,940, JWH-073, and JWH-018; in contrast, as reported previously, 3 days of Δ⁹-THC treatment decreased sensitivity to Δ⁹-THC 3-fold. Fourteen days of Δ⁹-THC decreased sensitivity to Δ⁹-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 Δ⁹-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.