*5.3. Human Clinical Trials*

The usage of cannabinoids for pulmonary disorders in humans is encumbered by numerous reports of lung injury, pneumonia and respiratory depression related to recreational use, especially of synthetic cannabinoids [139–141]. The respiratory failure was assumed to be CB1-mediated via the mitogen-activated protein kinase (MAPK) pathway and aggravated by cumulative central nervous system depression; however, due to small sample sizes and high bias risks more information is needed to confirm these findings [142].

Genetic studies have shown that mutations of the Q63R variant of the CB2 receptor increase the severity of acute infections with RSV in children, confirming the role of cannabinoids in modulating the immune response and carrying on their known antiinflammatory effects [128].

One of the few trials investigating the role of cannabinoids in lung inflammations is the recently published randomized controlled trial (RCT) on the use of lenabasum in patients with cystic fibrosis [143]. This Phase 2 trial showed fewer pulmonary exacerbations, a decrease in Immunoglobulin G and IL-8 levels, and a significant reduction in neutrophil and eosinophil infiltration in the sputum of patients taking 1 or 5 mg lenabasum daily for a month. An RCT investigating the anti-inflammatory effects of smoked cannabis in the pain and inflammation of patients with radiated lung cancer is still in Phase 1 [144].

A clinical trial published in 1973 showed that THC inhalation causes bronchodilation in healthy subjects [145]. Subsequently, several studies emerged attempting to apply these beneficial effects to patients with various inflammatory lung conditions. However, the results of the ensuing studies were not substantial. A clinical trial investigating the role of inhaled cannabis in the management of advanced chronic obstructive pulmonary disease showed no benefits in terms of lung function and exercise performance [146]. Furthermore, in their study, Gong et al. showed that the oral administration of 2 mg nabilone does not produce significant bronchodilation in asthmatic patients compared to a placebo [147]. In a previous study, THC was shown to be unsuitable for clinical use in asthma, because when it was administered in aerosols it produced bronchodilation in some asthmatic patients but caused bronchoconstriction, coughing and discomfort in others [148]. Oral THC did not show better results in asthmatic patients because it caused inconsistent bronchodilation, central nervous system effects and, in some cases, bronchoconstriction [149].

Positive results were obtained in a clinical trial testing the benefits of using a vaporizer to improve respiratory symptoms in frequent cannabis smokers [150]. This suggests that finding alternate vehicles of administration may improve the clinical results in future studies.
