TY - JOUR T1 - Differential Drug–Drug Interactions of the Synthetic Cannabinoids JWH-018 and JWH-073: Implications for Drug Abuse Liability and Pain Therapy JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 350 LP - 361 DO - 10.1124/jpet.113.206003 VL - 346 IS - 3 AU - Lisa K. Brents AU - Sarah M. Zimmerman AU - Amanda R. Saffell AU - Paul L. Prather AU - William E. Fantegrossi Y1 - 2013/09/01 UR - http://jpet.aspetjournals.org/content/346/3/350.abstract N2 - Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug–drug interactions. Drug–drug interactions between JWH-018 and JWH-073 were investigated in vivo for Δ9-tetrahydrocannabinol (Δ9-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of Δ9-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the Δ9-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug–drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug–drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective Δ9-THC–like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor–binding assay suggests multiple CB1R-SCB binding sites. ER -