State of Cannabis research.
Since the recent legalization of recreational cannabis, there is an increased interest in research into both the pulmonary effects of inhaled cannabis, as well as improving our understanding of the endocannabinoid system. The most common method of cannabinoid intake is via inhalation; at which time the lungs receive both biologically active and toxic combustion compounds. In comparison to cigarettes, research to date has found a different puffing topography is used for marijuana, where each puff tends to be larger in volume, employing a deeper inhalation and longer breath hold1. On the other hand, natural and synthetic cannabinoids have shown promising therapeutic potential as antiemetics, anti-inflammatories and analgesics. It is therefore timely to obtain a greater overview of where pre-clinical cannabis research currently stands: starting with how subject models are generated to measurements of lung function after exposure to cannabis smoke or cannabinoid isolates.
Using the inExpose system, researchers can create accurate and reproducible models of smoke exposure using standardized or customizable puffing volumes and frequencies. In a recent publication of Toxicology and Applied Pharmacology2, Dr. Rahman’s group exposes various cell lines (Ex: BEAS-2B and NHBE) to aerosolized Cannabinol (CBD) oil using the inExpose to investigate the role of CBD on oxidative stress and lipopolysaccharide (LPS) induced inflammatory response. Using a Behar buffing profile, (51mL puff, 2 puffs per minute) for a period of 30-minutes, CBD demonstrated both pro- and anti-inflammatory effects by ROS levels, and significantly attenuated LPS-induced NF-kB activity along with IL-8 and MCP-1. CBD also showed antagonistic action with steroids, where the anti-inflammatory potential of steroids was overridden when used in conjunction with CBD.
Once a cannabis exposure model is created, the next step is to investigate the in-vivo effects of cannabinoids on respiratory physiology and lung mechanics. Ribeiro et al3 investigate the therapeutic and anti-inflammatory effects of CBD in murine models of Lipopolysaccharide (LPS)-induced Acute Lung Injury (ALI). Using the flexiVent system, they show that treatment with CBD in LPS-treated mice significantly attenuates the pulmonary effects of a bronchoconstrictor in a dose-response methacholine challenge for resistance, elastance, and central vs peripheral tissue resistances. Other studies show that CB2 specific ligands worsen lung function parameters at baseline and exacerbate airway hyperreactivity in mouse models of OVA-induced asthma4.
These results show that understanding pulmonary repercussions of cannabis smoke along with the role of the endocannabinoid system in development and function of the pulmonary system is critical.
Other researchers use plethysmography to investigate the role of cannabinoid (CB) receptors on breathing rhythmogenesis in conscious, unrestrained subjects. Tree et al5 look specifically at the CB receptor 1 (CB1R) agonist WIN55,212-2 and CB1R antagonist AM251 and their effects on ventilatory parameters during normoxic and hypoxic conditions in neonate mice. Administration of pre-natal CB1R agonist leads to an increase in tidal volume at baseline, and an impaired ventilatory and apneic response to hypoxia. Additionally, pre-treatment with CB1R antagonist revealed a depressive role of endocannabinoid signalling on ventilation and apneas. Overall, this study showed that the endocannabinoid pathway modulates respiratory and offers a certain level of protection against apneas in neonates.
1Wu, TC., et al. (1988). Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med, 318:347–51. https://doi:10.1056/NEJM198802113180603
2Muthumalage, T., & Rahman, I. (2019). Cannabidiol differentially regulates basal and LPS-induced inflammatory responses in macrophages, lung epithelial cells, and fibroblasts. Toxicology and Applied Pharmacology, 382(1): https://doi.org/10.1016/j.taap.2019.114713
3Ribeiro, A., et al. (2015). Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacology and Immunotoxicology, 1, https://doi.org/10.3109/08923973.2014.976794
4Frei, R.B., et al. (2016). Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice. Allergy, 71(7): 944-956. https://doi.org/10.1111/all.12858
5Tree, K.C., et al. (2014). In utero cannabinoid exposure alters breathing and the response to hypoxia in newborn mice. European Journal of Neuroscience, 40(1): https://doi.org/10.1111/ejn.12588