Effects of cannabidiol with and without other cannabinoids and terpenes on short-term and long-term stress-related behaviors

Abstract

Introduction: Stress-related disorders, such as anxiety and post-traumatic stress disorder, are a primary reason for treatment (and self-medication) with medical cannabis products. Research suggests endocannabinoids regulate neurotransmitters involved in stress but whether phytocannabinoids such as cannabidiol (CBD) reduce stress behaviors is not fully established. To that end, we sought to examine how CBD with and without other cannabinoids or terpenes might alter behavior in mouse models of short-term and long-term responses to acute stressors. Methods: For short-term stress responses, adult male C57Bl/6J mice received a 30-60-minute restraint stress followed by testing with open field and light-dark box tests. Mice were treated with vehicle, CBD (10mg/kg), or CBD with low dose delta-9-tetrahydrocanabinol (THC, 2.5mg/kg and 7.5 mg/kg CBD for 10mg/kg total cannabinoid content) 45-60 minutes prior to stress exposure. For long-term stress behavior, mice underwent conditioned place avoidance to restraint plus predator odor contexts, with controls receiving individual stressors or no stress. Avoidance to the stress paired context was examined 1, 7, and 28 days later. Groups received vehicle, CBD (3.07 mg/ml CBD, 3mg/kg cannabigerol, low terpenes), CBD+THClo-terp (3.07 mg/ml CBD, 3mg/kg cannabigerol, 0.76 mg/ml THC, low terpenes), or CBD+THChi-terp (3.29 mg/ml CBD, 3mg/kg cannabigerol, 0.76 mg/ml THC, high terpenes) 30-45 minutes after stress exposure. Researchers were blinded to treatment conditions during all analyses. Results: In the short-term experiments, mice treated with CBD trended towards an increase in the time spent and decreased latency to enter the light side of the light-dark box compared to vehicle, suggesting reduced anxiety-like behaviors. Additionally, CBD treated mice showed reductions in freezing, immobility time, and latency to enter the center of the open field compared to vehicle treated mice, with no differences in the time spent in the center of the field. CBD+THC treatment showed no significant differences compared to vehicle. In the long-term experiments, mice exposed to restraint plus predator odor showed reduced time spent in the stress paired chamber on days 1, 7, and 28 post-stress, although there did appear to be stress susceptible and resilient mice in this paradigm. Avoidance behaviors were not seen when stressors were presented individually or if no stress was used. In this paradigm, CBD+THClo-terp was the only treatment to reduce avoidance behavior at the post-stress time points tested. Conclusions: These results suggest that CBD has a differential effect on anxiety-like behaviors based on type of stress, post-stress timing of behavioral testing, and CBD/THC/cannabigerol/terpene content. Further studies are needed to uncover the effect of phytocannabinoids on short-term and long-term stress responses as well as related neurotransmitters and circuitries driving these effects.