Acute, Chronic, and Prenatal Exposure to Cannabidiol (CBD) Differentially Affects Anxiety and Successful Birthrate in Mice

Abstract

As the medicalization of marijuana occurs across the United States, the main non‐psychoactive component of the marijuana, cannabidiol (CBD), has gained recognition. Given that anxiety is the most common type of mental illness in the United States, our objective was to access the therapeutic potential of CBD administration. We hypothesized that CBD could mitigate anxiety for chronic but not acute treatments in mice and would not have long‐term behavioral consequences when administered perinatally. Our methods employed 3‐mo. Kv1.3‐/‐ (KO) anxiety prone mice, or wildtype (WT) mice that were treated either acutely (daily for 1 wk), chronically (18 doses over 1 mo.), or throughout gestation and lactation (daily). Mice in the acute and chronic treatment groups were randomly assigned to intraperitoneal injection of drug (CBD = 10 or 20 mg/kg) or vehicle solution. CBD administered to dams was provided orally via strawberry jam (100 mg/kg). The effect of perinatal exposure to CBD was assessed at 3 mo. of age. Mice were behaviorally assessed using five tasks: the elevated plus maze (EPM), the light‐dark box (LDB), the marble burying test, a 1‐ and 24‐hour memory test, and an object attention test for ADHD. Mice treated acutely with the drug exhibited decreased obsessive compulsive behavior (buried less marbles) in only male mice, and the required dose to produce this behavior was higher for KO mice. In the LDB test, CBD lessened anxiety for both sexes, yet WT females required a lower CBD dose than WT male mice; in KO mice, CBD was anxiogenic rather than anxiolytic for both sexes. When mice were challenged with the EPM, mice spent more time in the closed arms regardless of sex, genotype, or drug treatment. The only exception was CBD treated female KO mice exhibited anxiety in the EPM, spending more time in the closed arms following drug treatment. Although acute CBD decreased obsessive compulsive behavior, when administered chronically the drug had no effect in either WT or KO mice. Similar to acute CBD administration in WT mice, chronic drug administration lessened anxiety in the LDB (increased time in the light compartment). However, in KO mice, chronic administration of CBD was without effect in the LDB. For mice treated perinatally, there was no significant drug effect for litter size (p = 0.3619), time to birth (p = 0.4210), or maternal weight gain (p = 0.1588). CBD‐treated offspring had a lower survival rate in that 48.5% of CBD‐treated pups died before weaning age (23 days) whereas only 5.7% of jam treated pups died prior to weaning (p = 0.0355). In conclusion, our data suggest that CBD may act as an anxiolytic drug in WT mice with dose and sex dependency. CBD failed to alleviate anxiety in KO mice, suggesting that CBD may not be affective in subjects that already have trait anxiety rather than situation anxiety. CBD had no effect on object memory or ADHD‐like behaviors regardless of dose, duration, or genotype.