question: BackgroundThe United States (US) is in the middle of an opioid overdose epidemic that has spanned over two decades and continues to escalate. Methadone is long-acting full opioid agonist which has been approved to treat opioid use disorder (OUD). Methadone can cause respiratory depression that may result in mortality. The restrictions on methadone availability including take-home dosing were loosened during the COVID-19 pandemic although there have been concerns about the high street value of diverted methadone. This report examined how fatal overdoses involving methadone have changed over the past two-decades including during the pandemic. MethodsThe Center for Disease Control and Preventions Wide-ranging Online Data for Epidemiologic Research (WONDER) database, which draws data from death certificates, was used to find the unintentional methadone related overdose death rate from 1999-2020. Unintentional methadone deaths were defined using the International Statistical Classification of Diseases (ICD), 10th revision codes: X40-44 with only data which was coded for methadone (T40.3). Data from the Automation of Reports and Consolidated Orders System (ARCOS) on methadone overall use, narcotic treatment programs use, and pain management use was gathered for all states, including the District of Columbia, for 2020 and corrected for population. ResultsThere have been dynamic changes over the past two-decades in overdoses involving methadone. Overdoses increased from 1999 (0.9/million) to 2007 (15.9) and declined until 2019 (6.5). Overdoses in 2020 (9.6) were 48.1% higher than in 2019 (t(50) = 3.05, p < .005). The correlations between overall methadone use (r(49) = +0.75, p < 0.001), and narcotic treatment program use (r(49) = +0.77, p < 0.001) were positive, strong, and statistically significant. However, methadone use for pain treatment was not associated with overdoses (r(49) = -.08, p = .57). ConclusionsOverdoses involving methadone significantly increased by 48.1% in 2020 relative to 2019. This mortality increase is much larger than the 5.3% elevation in calls involving methadone reported to poison control centers in the year following the March 16, 2020 loosening of methadone take-home regulations. Policy changes that were implemented following the COVID-19 pandemic involving methadone may warrant reconsideration.