Clinical, physiologic, 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 legalization has prompted concerns about respiratory health. Objective. To investigate clinical and airway epithelial transcriptomic features associated with cannabis smoking.  Methods. This cross-sectional study analyzed 139 cannabis-smoking participants categorized by joint-year exposure (low: =5; moderate: >5-20; high: >20), and 57 never-smokers. We evaluated respiratory symptom questionnaire scores, lung function measurements, and chest computed tomography and hyperpolarized 129Xe 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 (ALI) cell cultures, we quantified epithelial MUC5AC protein and correlated its expression with clinical outcomes. Results. Among cannabis-smoking individuals (48% male and 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 FEV1/FVC and FEF25-75, more radiographic emphysema, and more ventilation abnormalities than never-smokers. Airway epithelial brushings from cannabis-smoking individuals demonstrated increased type 2 immune response, decreased type 17 immune response, and higher MUC5AC gene expression than non-cannabis-smoking individuals. 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. Overall design: RNA-seq profiling of airway epithelial samples from cannabis-smoking and non-cannabis individuals.