The emergence of high-efficacy synthetic cannabinoids as drugs of abuse in readily available K2/‘Spice’ smoking blends has exposed users to much more potent and effective substances than the phytocannabinoids present in cannabis. Increasing reports of adverse reactions, including dependence and withdrawal, are appearing in the clinical literature. Here we investigated whether the effects of one such synthetic cannabinoid, 1-pentyl-3-(1-naphthoyl)indole (JWH-018), would be altered by a prior history of Δ9-tetrahydrocannabinol (Δ9-THC) exposure, in assays of conditioned taste aversion and conditioned place preference. In the conditioned taste aversion procedure, JWH-018 induced marked and persistent aversive effects in mice with no previous cannabinoid history, but the magnitude and duration of these aversive effects were significantly blunted in mice previously treated with an ascending dose regimen of Δ9-THC. Similarly, in the conditioned place preference procedure, JWH-018 induced dose-dependent aversive effects in mice with no previous drug history, but mice exposed to Δ9-THC before place conditioning showed reduced aversions at a high JWH-018 dose and apparent rewarding effects at a low dose of JWH-018. These findings suggest that a history of Δ9-THC exposure ‘protects’ against aversive effects and ‘unmasks’ appetitive effects of the high-efficacy synthetic cannabinoid JWH-018 in mice. This pattern of results implies that cannabinoid-naive individuals administering K2/‘Spice’ products for the first-time may be at an increased risk for adverse reactions, whereas those with a history of marijuana use may be particularly sensitive to the reinforcing effects of high-efficacy cannabinoids present in these commercial smoking blends.