Elevated blood anandamide levels in acute COVID-19 pneumonia with respiratory failure

Subsets of COVID-19 pneumonia patients with acute respiratory failure experienced long-term respiratory dysfunction and persistent radiological abnormalities. However, mechanisms contributing to persistent pulmonary dysfunction following COVID-19 remain unclear. Increased cannabinoid receptor 1 (CB₁R) expression has been reported in the lungs of patients who died from COVID-19 pneumonia. Multiple studies indicate that CB₁R overactivation exacerbates inflammation and tissue disrepair in mice, and the level of anandamide (AEA), an endogenous CB₁R agonist and endocannabinoid, is higher in the lungs of patients with pulmonary fibrosis, correlating with poor lung function. These observations suggest the potential for overactivity of the endocannabinoid/CB₁R pathway to adversely impact lung repair in COVID-19 pneumonia.

In this study, we sought to determine the relationship between circulating endocannabinoids and inflammatory mediators in patients with COVID-19 pneumonia from two independent cohorts in different geographic US locations. Endocannabinoid levels were measured using liquid chromatography coupled triple quadrupole mass spectrometry, while inflammatory cytokines and chemokines were measured using Luminex assay in blood serum collected at various time points during COVID-19 pneumonia.

We found that blood serum levels of endocannabinoid AEA were significantly elevated in acute COVID-19 pneumonia patients compared to patients with non-COVID-19-associated acute respiratory failure, and healthy controls. Further, 2-arachidonyl glycerol (2AG)] was significantly elevated in acute COVID-19 pneumonia patients on par with non-COVID acute respiratory failure patients. Levels of circulating AEA and 2AG correlated with multiple inflammatory markers.

Our findings suggest increased circulating endocannabinoid tone may be involved in the pathogenesis of COVID-19 pneumonia during the acute phase of illness.