Combined vapor exposure to THC and alcohol in pregnant rats: Maternal outcomes and pharmacokinetic effects

Abstract

Cannabis is the most frequently used illicit drug among pregnant women, yet the potential consequences of prenatal cannabis exposure on development are not well understood. Electronic cigarettes have become an increasingly popular route of administration among pregnant women, in part to user's perception that e-cigarettes are a safer route for consuming cannabis products. Importantly, half of pregnant women who consume cannabis also report consuming alcohol, but research investigating co-consumption of these drugs is limited, particularly with current routes of administration.The purpose of this study was to establish a co-exposure vapor inhalation model of alcohol and THC in pregnant rats, to ultimately determine the effects on fetal development. Pregnant Sprague-Dawley rats were exposed to moderate doses of THC via e-cigarettes, alcohol, the combination, or vehicle daily from gestational days 5-20. Importantly, pharmacokinetic interactions of alcohol and THC were observed during pregnancy. Combined exposure consistently increased blood alcohol concentrations, indicating that THC alters alcohol metabolism. In addition, THC levels also increased over the course of pregnancy and THC metabolism was altered by alcohol. Alcohol, but not THC, exposure during pregnancy reduced maternal weight gain, despite no group differences in food intake. Neither prenatal alcohol nor THC exposure altered gestational length, litter size, sex ratio or birth weight. However, prenatal alcohol exposure delayed eye opening, and prenatal THC exposure decreased body weights during adolescence among offspring. These individual and synergistic effects suggest that this novel co-exposure vapor inhalation paradigm can effectively be used to expose pregnant dams, exerting some effects on fetal development, while avoiding nutritional confounds, birth complications, or changes in litter size. With this model, we have demonstrated that combining THC and alcohol alters drug metabolism, which could have important consequences on prenatal development.

A Model of Combined Exposure to Nicotine and Tetrahydrocannabinol via Electronic Cigarettes in Pregnant Rats

“…As demonstrated in our lab ( Breit et al, 2020 ) and others ( Nguyen et al, 2016 ; Javadi-Paydar et al, 2018 ), THC via e-cigarettes lowers core body temperatures in female rats. Maternal body temperatures were measured before and after each vapor exposure session via a rectal thermometer, to verify this expected physiological effect and to examine effects of nicotine exposure on body temperature.…”

“…To measure maternal blood levels of each drug and their metabolites, intravenous catheters were surgically implanted prior to pregnancy following a 2-week acclimation period, as previously published ( Breit et al, 2020 ). Dams were anesthetized (4% isoflurane) and the catheter was secured under the skin on the back, with the tubing thread subdermally over the right shoulder and implanted into the right jugular vein via small incisions.…”

“…On GD 0, pregnant dams were assigned to one of four prenatal exposure groups: nicotine (36 mg/mL), THC (100 mg/mL), the combination, or the vehicle (propylene glycol). Power analyses were conducted with InStat software and indicated 10 subjects per exposure group were needed; sample sizes were determined using previously published data ( Breit et al, 2020 ) and were conducted with alpha = 0.05 and 1-beta (power) = 0.80. Additional dams were generated to ensure power in the case of pregnancy or birth complications, or if the dam was eventually deemed to not be pregnant.…”

“…THC for e-cigarette vapor inhalation was obtained through the National Institutes of Drug Abuse Drug Supply Program and was prepared as previously described ( Breit et al, 2020 ). Briefly, THC arrived dissolved in 95% EtOH; the THC was extracted using a SpeedVac concentrator and added to propylene glycol to obtain the chosen dose (100 mg/mL).…”

Maternal‐fetal transmission of delta‐9‐tetrahydrocannabinol (THC) and its metabolites following inhalation and injection exposure during pregnancy in rats

“…THC inhalation during pregnancy did not alter maternal weight gain or litter size in this study. Only a limited number of studies examined THC inhalation during pregnancy and similarly found no effect of cannabis exposure on maternal weight gain or litter size (Breit et al., 2020; Weimar et al, 2020), but do show reduced birth weight in PCE offspring (Fried, 1976; Weimar et al, 2020). Maternal weight gain and litter size were not examined following THC injection during pregnancy in this study; however, similar to inhalation exposure, previous research found no effect on maternal weight gain or litter size but reduced birth weight in PCE offspring (Natale et al, 2020).…”