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Social determinants of health (SDOH) play a critical role in the risk of harmful drug use. Examining SDOH as a means of differentiating populations with multiple co-occurring substance use disorders (SUDs) is particularly salient in the era of prevalent opioid and stimulant use known as the "Third Wave". This study uses electronic medical records (EMRs) from a safety net hospital system from 14,032 patients in Kentucky from 2017 to 2019 in order to 1) define three types of SUD cohorts with shared/unique risk factors, 2) identify patients with unstable housing using novel methods for EMRs and 3) link patients to their residential neighborhood to obtain quantitative perspective on social vulnerability. We identified patients in three cohorts with statistically significant unique risk factors that included race, biological sex, insurance type, smoking status, and urban/rural residential location. Adjusting for these variables, we found a statistically significant, increasing risk gradient for patients experiencing unstable housing by cohort type: opioid-only (n = 7385, reference), stimulant-only (n = 4794, odds ratio (aOR) 1.86 95 % confidence interval (CI): 1.66–2.09), and co-diagnosed (n = 1853, aOR = 2.75, 95 % CI: 2.39 to 3.16). At the neighborhood-level, we used 8 different measures of social vulnerability and found that, for the most part, increasing proportions of patients with stimulant use living in a census tract was associated with more social vulnerability. Our study identifies potentially modifiable factors that can be tailored by substance type and demonstrates robust use of EMRs to meet national goals of enhancing research on social determinants of health. • Unstable housing risk varies by substance use disorder (SUD) type. • Neighborhood-level social vulnerability differed by SUD-type. • Unique/shared factors emerged for clinical cohorts with one or more SUD. [ABSTRACT FROM AUTHOR]