Cannabis use has been associated with an increased incidence of psychiatric disorders, yet the underlying neurobiological processes mediating these associations are poorly understood. Whereas exposure to Δ9-tetrahydrocannabinol (THC) has been associated with the development or exacerbation of psychosis, treatment with cannabidiol (CBD) has been associated with amelioration of psychosis. In this study, we demonstrate a complex effect of CBD in mouse models of psychosis, based on factors, including dose, strain, and genotype. Adult GluN1 knockdown (GluN1KD) and dopamine transporter knockout (DATKO) mice (almost equally balanced for male/female) were acutely treated with vehicle, THC (4 mg/kg), CBD (60, 120 mg/kg), or THC:CBD (1:15, 4:60 mg/kg) and tested in behavioral assays. GluN1KD and DATKO mice displayed hyperactivity, impaired habituation, and sensorimotor gating, along with increased stereotypy and vertical activity. THC, alone and in combination with CBD, produced a robust "dampening" effect on the exploratory behavior regardless of strain or genotype. CBD exhibited a more complex profile. At 60 mg/kg, CBD had minimal effects on horizontal activity, but the effects varied in terms of directionality (increase vs. decrease) in other parameters; effects on stereotypic behaviors differ by genotype, while effects on vertical exploration differ by strain×genotype. CBD at 120 mg/kg had a "dampening" effect on exploration overall, except in GluN1KD mice, where no effect was observed. In terms of sensorimotor gating, both THC and CBD had minimal effects, except for 120 mg/kg CBD, which exacerbated the acoustic startle response. Here, we present a study that highlights the complex mechanism of phytocannabinoids, particularly CBD, in models of psychosis-like behavior. These data require careful interpretation, as agonism of the cannabinoid receptor 1 (CB) resulting in a decrease in locomotion can be misinterpreted as "antipsychotic-like" activity in murine behavioral outputs of psychosis. Importantly, the THC-mediated decrease in hyperexploratory behavior observed in our models (alone or in combination) was not specific to the genetic mutants, but rather was observed regardless of strain or genotype. Furthermore, CBD treatment, when comparing mutants with their wild-type littermate controls, showed little to no "antipsychotic-like" activity in our models. Therefore, it is not only important to consider dose when designing/interpreting therapeutically driven phytocannabinoid studies, but also effects of strain or genetic vulnerability respective to the general population.