Clinical, physiological, imaging and molecular responses to cannabis smoking: the Canadian Users of Cannabis Smoke (CANUCK) study.

BACKGROUND: The growing popularity of cannabis smoking in an era of legalisation has prompted concerns about respiratory health. OBJECTIVE: To investigate clinical and airway epithelial transcriptomic features associated with cannabis smoking. METHODS: This cross-sectional study analysed data from 139 cannabis-smoking participants categorised by joint-year exposure (low: ≤5; moderate: >5-20; high: >20 joint-years) and 57 never-smokers. We evaluated respiratory symptom questionnaire scores, lung function measurements, chest computed tomography and hyperpolarised 129Xenon pulmonary magnetic resonance imaging measurements across groups. We compared the expression of immune response signatures and mucin genes in airway epithelial brushings collected from bronchoscopy. Using air-liquid interface cell cultures, we quantified epithelial mucin 5AC (MUC5AC) protein and correlated its expression with clinical outcomes. RESULTS: Among cannabis-smoking participants (48% male, median age of 27 years), 84% reported current or former cigarette smoking or vaping. Cannabis-smoking groups reported worse respiratory symptoms than never-smokers. High joint-year cannabis-smoking participants showed lower pre-bronchodilator forced expiratory volume in 1 s to forced vital capacity ratio, lower forced expiratory flow at 25-75% of the forced vital capacity, more radiographic emphysema and more ventilation abnormalities than never-smokers. Airway epithelial brushings from cannabis-smoking participants demonstrated an increased type 2 immune response, decreased type 17 immune response and higher MUC5AC gene expression than non-cannabis-smoking participants. Epithelial MUC5AC protein expression in cell cultures correlated with worse clinical outcomes and imaging abnormalities. CONCLUSIONS: Cannabis smoking, particularly at high exposures, is associated with worse respiratory symptoms, lower lung function, functional imaging abnormalities and dysregulated immune responses in the airway epithelium. These observations suggest respiratory harm associated with cannabis smoking and underscore the concerns for future respiratory morbidities related to persistent cannabis use.