Chronic Adolescent Δ⁹-Tetrahydrocannabinol Treatment of Male Mice Leads to Long-Term Cognitive and Behavioral Dysfunction, Which Are Prevented by Concurrent Cannabidiol Treatment

Abstract

Introduction: The high prevalence of adolescent cannabis use, the association between this use and later psychiatric disease, and increased access to high-potency cannabis highlight the need for a better understanding of the long-term effects of adolescent cannabis use on cognitive and behavioral outcomes. Furthermore, increasing Δ9-tetrahydrocannabinol (THC) in high-potency cannabis is accompanied by a decrease in cannabidiol (CBD), thus an understanding of the interactions between CBD and THC in the neurodevelopmental effects of THC is also important. The current study examined the immediate and long-term behavioral consequences of THC, CBD, and their combination in a mouse model of adolescent cannabis use.Materials and Methods: Male CD1 mice received daily injections of THC (3 mg/kg), CBD (3 mg/kg), CBD+THC (3 mg/kg each), vehicle, or remained undisturbed in their home cage (no handling/injections), either during adolescence (postnatal day [PND] 28–48) or during early adulthood (PND 69–89). Animals were then evaluated with a battery of behavioral tests 1 day after drug treatment, and again after 42 drug-free days. The tests included the following: open field (day 1), novel object recognition (NOR; day 2), marble burying (day 3), elevated plus maze (EPM; day 4), and Nestlet shredding (day 5).Results: Chronic administration of THC during adolescence led to immediate and long-term impairments in object recognition/working memory, as measured by the NOR task. In contrast, adult administration of THC caused immediate, but not long term, impairment of object/working memory. Adolescent chronic exposure to THC increased repetitive and compulsive-like behaviors, as measured by the Nestlet shredding task. Chronic administration of THC, either during adolescence or during adulthood, led to a delayed increase in anxiety as measured by the EPM. All THC-induced behavioral abnormalities were prevented by the coadministration of CBD+THC, whereas CBD alone did not influence behavioral outcomes.Conclusion: These data suggest that chronic exposure to THC during adolescence leads to some of the behavioral abnormalities common in schizophrenia. Interestingly, CBD appeared to antagonize all THC-induced behavioral abnormalities. These findings support the hypothesis that adolescent THC use can impart long-term behavioral deficits; however, cotreatment with CBD prevents these deficits.

Species‐specific susceptibility to cannabis‐induced convulsions

“…Overall, these data are consistent with THC pharmacokinetic differences not being able to explain fully these differences in seizure behaviour. A pertinent difference was that plasma CBD levels were also consistently higher in the dog than rat; thus, our data are also consistent with increased CBD levels in dogs acting to ameliorate the proconvulsant effects of long‐term THC seen in rats, as reported recently for CBD prevention of chronic THC‐induced long‐term behavioural abnormalities in mice (Murphy et al ., ).…”

A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects

“…In the preclinical literature, CBD has been shown to reverse THC-induced adverse effects on social and cognitive tasks [2,12,22]. Co-administration of CBD with THC, 3mg each, daily for 3 weeks during adolescence prevented the development of THC-induced cognitive and behavioural impairments in mice [23], and an open-label trial of prolonged CBD administration in humans (200mg/day for 10 weeks) improved psychological symptoms and cognition, and increased hippocampal subfield volumes in cannabis users [24,25]. While many studies have focused on the amelioration of THC effects by CBD, there is also evidence to suggest that CBD can potentiate the effects of THC.…”

The United Chemicals of Cannabis: Beneficial Effects of Cannabis Phytochemicals on the Brain and Cognition

“…For example, CBD (0.5 mg/kg) increased visual learning and memory, and procedural learning in Rhesus monkeys co-administered Δ9-THC (0.2 or 0.5 mg/kg) compared to those administered Δ9-THC alone; however, spatial working memory was further impaired by combined treatment (reviewed in [7]). Chronic Δ9-THC exposure in adolescent mice (3 mg/kg daily) reduced recognition memory that persisted into adulthood, but this was not apparent in the group receiving CBD (3 mg/kg CBD) co-treatment during Δ9-THC exposure [13]. On the other hand, research shows that there are no beneficial effects of CBD on cognition, including verbal learning and memory, social recognition, executive function, spatial memory or conditioned learning, when administered to healthy subjects (humans or rodents) (reviewed in [7,13]).…”

“…Chronic Δ9-THC exposure in adolescent mice (3 mg/kg daily) reduced recognition memory that persisted into adulthood, but this was not apparent in the group receiving CBD (3 mg/kg CBD) co-treatment during Δ9-THC exposure [13]. On the other hand, research shows that there are no beneficial effects of CBD on cognition, including verbal learning and memory, social recognition, executive function, spatial memory or conditioned learning, when administered to healthy subjects (humans or rodents) (reviewed in [7,13]).…”