Background: Polysubstance involvement is increasing among fatal drug overdoses. However, little is known about the epidemiology of polysubstance drug overdoses. This paper describes emerging trends in unintentional polysubstance overdose deaths in North Carolina (NC) and examines associations with individual and community factors. Methods: Using 2009–2018 NC death certificate data, we identified unintentional drug overdose deaths and commonly involved substances (opioids, stimulants, benzodiazepines, alcohol, and antiepileptics). We examined polysubstance combinations, comparing opioid and non-opioid involved deaths. We examined individual level correlates from death certificate data and community level correlates from the American Community Survey and Robert Wood Johnson Foundation County Health Rankings to quantify associations. Results: From 2009–2018, 53 % of opioid and 19 % of non-opioid overdose deaths involved multiple substances. During this period, polysubstance overdose death increased dramatically, from 2.9 to 12.1 per 100,000 persons, with the greatest increases among drug combinations involving stimulants. The most common polysubstance combinations were: opioids and stimulants (12.1 % of overdose deaths); opioids and benzodiazepines (9.0 %); opioids and alcohol (5.1 %); opioids, stimulants, and benzodiazepines (3.1 %); and opioids, benzodiazepines, and antiepileptics (2.2 %). Compared to overdoses involving opioids alone, overdoses involving combinations of opioids, stimulants, and benzodiazepines involved younger individuals (53.7 % in 15−34 years of age vs. 40.7 %). Men comprised two-thirds of overdoses involving opioids alone, however, overdoses involving opioids, benzodiazepines, and antiepileptics were predominantly among women (60.6 %). Conclusions: Polysubstance involvement has increased among overdose deaths in NC. These findings can be used to inform public health interventions addressing polysubstance deaths and associated individual and community level factors
