Characterizing patterns of opioid and stimulant use by route and associations with non-fatal overdose and xylazine use in people who have injected drugs from Baltimore, MD, 2023-2024.

Background: The fourth wave of the overdose epidemic in the United States (US) is characterized by deaths involving fentanyl with stimulants. Understanding patterns of substance use as novel drugs continue to emerge is critical to inform overdose prevention. Among people with a history of injection drug use in Baltimore, MD, we examined opioid-stimulant use by route and the association of injection with non-fatal overdose and xylazine use. Methods: We included 1132 participants in the AIDS Linked to the IntraVenous Experience cohort with a study visit in 2023-2024. We characterized participants by self-reported past-six-month use of any opioid and any stimulant by route using descriptive statistics. Adjusted associations were estimated using targeted minimum loss-based estimation. Results: Most participants were Black (68 %), male (67 %), and older (median: 56 years). 53 % reported using both opioids and stimulants; these participants were more likely to report using other substances, non-fatal overdose, depressive symptoms, and homelessness. Among participants using both, those injecting both were more likely to report non-fatal overdose and xylazine use than those using by non-injection (overdose: PD = 22.3 %, 95 % CI= 17.2 %-27.5 %; xylazine: PD = 13.3 %, 95 % CI = 4.7 %-21.9 %). Conclusions: We provide one of the most comprehensive summaries of substance use during the fourth wave in Baltimore, a city with the highest rate of fatal overdose in the US during the study period. Use of multiple substances was common, and many participants reported injection. Overdose prevention should be targeted to those injecting both drugs as this pattern had heightened overdose risk.