The Structural, Behavioral, and Pharmacokinetic Effects of Different Patterns of Cannabis Use on Adolescent Neurodevelopment

Abstract

Background: Roughly one third of Canadian adolescents are using cannabis, without sufficient education on how it may affect neurodevelopment. Of those who use cannabis, some are using infrequently, some are using weekly, some are using daily, and some are using daily with escalating use. Most current literature does not distinguish between these usage patterns, and it often employs vastly different methodologies which can lead to heterogeneous results. This study aims to incorporate four representative patterns of adolescent cannabis use (Controls, Weekly users, Daily users, and High Frequency users) into a translationally relevant pre-clinical model. We aim to determine the pharmacokinetic (PK), structural, and behavioural effects of each pattern of cannabis use. Methods: Rats from all four frequency groups were assigned to either a PK, structural, or behavioural cohort. Adolescent rats were exposed to cannabis or vehicle vapour over a three-week adolescent period. Following this, blood and brain samples were collected from the PK cohort both at an immediate and residual timepoint after the last vapour exposure, and the levels of cannabis constituents in each sample were analysed. Each rat in the structural cohort had two magnetic resonance imaging (MRI) scans taken, one before and one after three weeks of vapour exposure, to measure volumetric growth over adolescence. The behavioral cohort was examined for cognitive-emotional effects after three weeks of vapour exposure, using light-dark box, fear conditioning, and novel-object-context-mismatch (NOCM) paradigms. Results: PK: The blood-THC levels were higher at the immediate timepoint than at the residual timepoint. There were no significant differences between frequency groups or sexes, in any cannabis constituent levels, at either timepoint. MRI: Select regions of interest (ROIs) had opposite volumetric growth effects, which were correlated with different frequencies of cannabis exposure. Behaviour: Daily and Weekly exposed rats showed significantly less anxiety-like behaviour, but significantly more fear behaviour, than controls. There were no observed cognitive impairments during NOCM. Conclusion: Frequency of cannabis consumption was heterogeneously associated with biphasic neurodevelopmental effects, where Daily and Weekly users had opposite effects to HF. Future studies should incorporate representative patterns of cannabis exposure, to fully elucidate the associated mechanisms of these effects.