Cannabidiol potentiates Δ 9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats

Rationale: The interactions between Δ 9- tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models. Objectives: The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses. Methods: Adolescent rats were treated with ascending daily THC doses over 21 days (1 then 3 then 10 mg/kg). Some rats were given equivalent CBD doses 20 min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB 1 and 5-HT 1A receptor binding were assessed. Results: CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB 1 receptor binding and no drug effects on 5-HT 1A receptor binding were observed. Conclusions: CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs.