ABSTRACT Objective U.S. drug-related overdose deaths and Emergency Department (ED) visits rose in 2020 and again in 2021. Multiple studies and the news media attributed this rise primarily to increased drug use resulting from the societal disruptions related to the coronavirus (COVID-19) pandemic. A competing explanation is that higher overdose deaths and ED visits may instead have been a continuation of pre-pandemic trends in synthetic-opioid deaths. We assess the evidence on whether increases in overdose deaths and ED visits are likely to be causally related to the COVID-19 pandemic, increased synthetic-opioid use, or some of both.Methods We use national data from the Centers for Disease Control and Prevention (CDC) on rolling 12-month drug-related deaths (2015-2021); CDC data on monthly ED visits (2019-September 2020); and ED visit data across 21states from a national ED group (January 2016-June 2022). We study drug overdose deaths per 100,000 persons during the pandemic period, and ED visits for drug overdoses, compared to predicted levels based on pre-pandemic trends.Results Mortality National overdose mortality increased from 21/100,000 in 2019 to 26/100,000 in 2020 and 30/100,000 in 2021. The 2020 increase is well-predicted by models that extrapolate pre-pandemic trends for rolling 12-month mortality to the pandemic period, consistent with higher mortality reflecting continuation of those trends. Placebo analyses (which assume the pandemic started earlier or later than March 2020) do not provide evidence for a change in trend in or soon after March 2020. State-level analyses of actual-minus-predicted mortality, relative to pre-pandemic trends, show no consistent pattern. The state-level results support state heterogeneity in overdose mortality trends, and do not support the pandemic being a major driver of overdose mortality.ED visits ED overdose visits rose during our sample period, reflecting a worsening opioid epidemic, but rose at similar rates during the pre-pandemic and pandemic periods.Conclusion The causes of rising overdose mortality in 2020 and 2021 cannot be definitely determined, but the observed increases can be largely explained by a continuation of pre-pandemic trends in synthetic-opioid deaths, principally fentanyl. In contrast to prior studies, we do not find support for the pandemic having been a principal driver of rising mortality. Policymakers need to directly address the synthetic opioid epidemic, and not expect a respite as the pandemic recedes.