In utero exposure to cannabidiol disrupts select early-life behaviors in a sex-specific manner

Abstract

Cannabidiol (CBD), one of the main components of cannabis, is generally considered safe. CBD crosses the placenta and its use during pregnancy is steadily increasing, the impact of gestational CBD’s effects on prenatal life and neurodevelopment are poorly understood. Here, we combined behavioral approaches and deep learning analysis to assess the sex-dependent neonatal behavior of CBD exposed progeny. Gestating C57BL6/J dams were exposed daily with vehicle or CBD (3 mg/Kg, s.c.), from gestational day 5 to 18. Body weight, pup ultrasound vocalizations (USVs, PND 10) and homing behavior (PND 13) were quantified in the progeny. Thus, male (but not female) pups from CBD-treated dams gained more weight than sham. There were sex-dependent differences in the coarse characteristics of ultrasonic vocalizations. Prenatally-CBD exposed male pups emitted shorter calls, whereas CBD females made more high frequency calls when compared with their control counterparts. There were significant qualitative changes in the syllabic USV repertoire reflected in call typologies and communication patterns. Finally, the homing behavior test showed that CBD-exposed females presented a greater vulnerability to gestational CBD than males. Only CBD-exposed female pups showed reduced motor and discriminatory abilities. Together the results suggest a sexual divergence in the consequences of in utero CBD exposure on neonates at early developmental ages, which may be predictive of adult psychopathology. Given the extent of cannabis and CBD use worldwide, these findings challenge the idea that CBD is a universally safe compound and reveal the need for additional studies on the effect of perinatal CBD exposure.

Prenatal Exposure to Cannabis: Effects on Childhood Obesity and Cardiometabolic Health

“…Of these, 432 were excluded for the following reasons: commentaries or reviews ( n = 71); neurodevelopment, cognitive, or behavioral outcomes ( n = 72); other unrelated health outcomes ( n = 86); studies of hemp oil, synthetic or endogenous cannabinoids, or the endocannabinoid system ( n = 36); polysubstance use or drugs other than cannabis ( n = 24); characteristics or reasons for cannabis use ( n = 43); prevalence studies ( n = 18); biomarker studies ( n = 16); cessation or prevention studies ( n = 9); health policy analyses ( n = 3); effects of pre-conception cannabis use ( n = 3); abstracts or reports presenting insufficient data ( n = 2); and papers focused entirely on unrelated exposures and outcomes ( n = 50). Thus, 47 epidemiologic studies [ 3 , 4 , 14 – 18 , 19 ••, 20 – 28 , 29 •, 30 – 33 , 34 ••, 35 – 58 ] and 12 animal models [ 59 , 60 ••, 61 , 62 , 63 ••, 64 , 65 ••, 66 •, 67 – 70 ] presenting original data met the inclusion criteria for this review.…”

“…Table 2 summarizes the 12 animal studies included in this review [ 59 , 60 ••, 61 – 70 ]. Wistar rats were the most common model, followed by C57BL/6 J mice and Sprague-Dawley rats.…”

“…Compared to non-exposed offspring, Δ9-THC-exposed offspring are born smaller, “catch-up” in as little as 12 days [ 60 ••, 62 ], and begin to surpass the size of non-exposed offspring by age 6 months [ 65 ••]. Prenatal CBD may impact postnatal growth in a sex-specific manner, with males being more susceptible to this environmental insult [ 61 , 67 ], but the evidence is not conclusive [ 70 ].…”

Decoding sex-specific vocal repertoire and syntactic usage in the Fragile X mouse model of autism

“…USVs were elicited through a rapid maternal separation procedure conducted on male and female pups at PND 10 29 . Each mouse was individually placed in an empty plastic container measuring 11 x 7 x 3.5 cm, which was located inside a sound-attenuating isolation box.…”

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

“…This method of measuring Cannabis consumption in humans makes comparing cannabinoid doses and exposures between clinical assessments and pre-clinical smoke exposure models challenging. Whereas prior preclinical studies have explored injection, inhalation, and oral administration of isolated THC or CBD [34][35][36][37]55,56,[62][63][64][65], administering THC and/or CBD alone fails to take into consideration the potential effects of other phytocannabinoids, terpenes, and flavonoids of the Cannabis plant as well as the smoke of a combusted product [10,66,67]. Our group has previously worked to establish rat models of Cannabis smoke exposure in the contexts of absence epilepsy [82], cognition [68], and prenatal exposure during pregnancy on offspring health and behaviour [57].…”