Sex Differences in Plasma, Adipose Tissue, and Central Accumulation of Cannabinoids, and Behavioral Effects of Oral Cannabis Consumption in Male and Female C57BL/6 Mice

BACKGROUND: Cannabis edibles are an increasingly popular form of cannabis consumption. Oral consumption of cannabis has distinct physiological and behavioral effects compared with injection or inhalation. An animal model is needed to understand the pharmacokinetics and physiological effects of oral cannabis consumption in rodents as a model for human cannabis edible use. METHODS: Adult male and female C57BL/6 mice received a single dose of commercially available cannabis oil (5 mg/kg Δ⁹-tetrahydrocannabinol [THC]) by oral gavage. At 0.5, 1, 2, 3, and 6 hours post exposure, plasma, hippocampus, and adipose tissue were collected for THC, 11-OH-THC, and THC-COOH measures. RESULTS: We report delayed time to peak THC and 11-OH-THC concentrations in plasma, brain, and adipose tissue, which is consistent with human pharmacokinetics studies. We also found sex differences in the cannabis tetrad: (1) female mice had a delayed hypothermic effect 6 hours post consumption, which was not present in males; (2) females had stronger catalepsy than males; (3) males were less mobile following cannabis exposure, whereas female mice showed no difference in locomotion but an anxiogenic effect at 3 hours post exposure; and (4) male mice displayed a longer-lasting antinociceptive effect of oral cannabis. CONCLUSIONS: Oral cannabis consumption is a translationally relevant form of administration that produces similar physiological effects as injection or vaping administration and thus should be considered as a viable approach for examining the physiological effects of cannabis moving forward. Furthermore, given the strong sex differences in metabolism of oral cannabis, these factors should be carefully considered when designing animal studies on the effects of cannabis.