Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-month-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow-cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations by light microscopy. Daily marijuana inhalation evoked severe bronchial hyper-reactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, neutrophil and macrophage infiltration developed after one month of marijuana smoking, lymphocyte accumulation after 2 months, macrophage-like giant cells, irregular, destroyed bronchial mucosa, goblet cell hyperplasia after 3months, and serious atelectasis, emphysema, obstructed, damaged bronchioles, endothelial proliferation at 4 months. Myeloperoxidase activity, inflammatory cell and cytokine profile correlated with these changes. Airway hyper-responsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyper-responsiveness after 2 months, and significantly later developing inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyper-responsiveness, inflammation, tissue destruction and emphysema, which are not mediated by the CB1 receptor.