Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatalCannabissmoke exposure

Abstract

Cannabis sativa has gained popularity as a 'natural substance', leading many to falsely assume that it is not harmful. This assumption has been documented amongst pregnant mothers, many of whom consider Cannabis use during pregnancy as benign. The purpose of this study was to validate a Cannabis smoke exposure model in pregnant rats by determining the plasma levels of cannabinoids and associated metabolites in the dams after exposure to either Cannabis smoke or injected cannabinoids. Maternal and fetal cytokine and chemokine profiles were also assessed after exposure. Pregnant Sprague-Dawley rats were treated daily from gestational day 6-20 with either room air, i.p. vehicle, inhaled high-δ9-tetrahydrocannabinol (THC) (17.98% THC, 0.1% cannabidiol [CBD]) smoke, inhaled high-CBD (0.1% THC, 12.83% CBD) smoke, 3 mg/kg i.p. THC, or 10 mg/kg i.p. CBD. Our data reveal that THC and CBD, but not their metabolites, accumulate in maternal plasma after repeated exposures. Injection of THC or CBD was associated with fewer offspring and increased uterine reabsorption events. For cytokines and chemokines, injection of THC or CBD up-regulated several pro-inflammatory cytokines compared to control or high-THC smoke or high-CBD smoke in placental and fetal brain tissue, whereas smoke exposure was generally associated with reduced cytokine and chemokine concentrations in placental and fetal brain tissue compared to controls. These results support existing, but limited, knowledge on how different routes of administration contribute to inconsistent manifestations of cannabinoid-mediated effects on pregnancy. Smoked Cannabis is still the most common means of human consumption, and more preclinical investigation is needed to determine the effects of smoke inhalation on developmental and behavioural trajectories.

Repeated Exposure to High-THCCannabisSmoke during Gestation Alters Sex Ratio, Behavior, and Amygdala Gene Expression of Sprague Dawley Rat Offspring

“…Given the differences in the effects of inhaled vapor or smoke containing THC, analyses of blood levels of THC and its metabolites would help in understanding these differing effects. While we did not measure blood levels of cannabinoids following smoke exposure in this study, acute exposure to the smoke from 300 mg of high-THC containing Cannabis results in plasma levels of 10–25 ng/ml after 30 min ( Barnard et al, 2022 ; Black et al, 2023 ) that drop to <5 ng/ml 75 min after exposure ( Roebuck et al, 2022 ). Extrapolating the plasma levels following exposure to 300 mg of Cannabis flower to 200 mg of Cannabis flower suggests the present exposure protocol likely produced peak plasma levels that approach the low end of typical blood levels detected in humans ( Newmeyer et al, 2016 ).…”

“…The exposure protocol was developed for use in adult rats and has been shown to result in measurable THC concentrations in plasma, as well as behavioral changes immediately following smoke exposure ( Barnard et al, 2022 ; Roebuck et al, 2022 ). Recent pharmacokinetic data from the plasma of pregnant rat dams confirm that repeated exposures to high-THC Cannabis smoke results in THC levels of ∼20–25 ng/ml 30 min following the initiation of exposure ( Black et al, 2023 ). During and after Cannabis smoke exposure, we quantified an array of maternal and offspring parameters related to acute effects of smoke exposure on the pregnant dams, litter health, and behavior of the male and female offspring in early adulthood.…”