ABSTRACT
Since the start of the COVID-19 global pandemic, our understanding of the underlying disease mechanism and factors associated with the disease severity has dramatically increased. A recent study investigated the relationship between substance use disorders (SUD) and the risk of severe COVID-19 in the United States and concluded that the risk of hospitalization and death due to COVID-19 is directly correlated with substance abuse, including opioid use disorder (OUD) and cannabis use disorder (CUD). While we found this analysis fascinating, we believe this observation may be biased due to comorbidities (such as hypertension, diabetes, and cardiovascular disease) confounding the direct effect of SUD on severe COVID-19 illness. To answer this question, we sought to investigate the causal relationship between substance abuse and medication-taking history (as a proxy trait for comorbidities) with the risk of COVID-19 adverse outcomes. Our Mendelian randomization analysis confirms the causal relationship between OUD and severe COVID-19 illness but suggests an inverse causal effect for cannabinoids. Considering that COVID-19 mortality is largely attributed to disturbed immune regulation, the possible modulatory impact of cannabinoids in alleviating cytokine storms merits further investigation.