Characterizing Adulterant and Polysubstance Use Research Priorities through Syringe Residue Analysis in Kentucky.

Polysubstance use is rising and linked to heightened overdose rates and increased treatment challenges, further exacerbated by increasing detection of adulterants (e.g., xylazine) in the street drug supply. Harm reduction groups provide sterile syringes in exchange for used ones, creating a unique opportunity to characterize prevalent polysubstance combinations and inform translational and preclinical research We analyzed residues from used syringes (N=3,168) obtained from several harm reduction organizations in Jefferson County, KY (Jan-Dec 2025) for the presence of substances using gas chromatography mass spectrometry (GC-MS). We classified compounds as adulterants (e.g., diphenhydramine [DPH]/Benadryl), byproducts/precursors of synthesis (e.g., 4-ANPP), and recreational drugs (e.g., meth). We excluded byproducts/precursors and determined the most frequent substance and pairs/trios containing one or more recreational substance. Results. Of 3,168 syringes, 2,522 (79.61%) tested positive for substances. Out of those positive, the top recreational substances were meth (n=1,387; 54.99%), fentanyl (n=1,220; 48.37%), and heroin (n=653; 25.89%). Top adulterants were DPH (n=1021; 40.48%), dimethyl sulfone (n=749; 29.69%), and lidocaine (n=736; 29.18%). The most common pairs were DPH+fentanyl (n=670; 26.57%), lidocaine+fentanyl (n=659; 26.13%), dimethyl sulfone+meth (n=621; 24.62%), and fentanyl+heroin (n=484; 19.19%). The most common trios were DPH+lidocaine+fentanyl (n=369; 14.63%), DPH+fentanyl+heroin (n=327; 12.97%), lidocaine+fentanyl+heroin (n=297; 11.77%), diphenhydramine+xylazine+fentanyl (n=273; 10.82%), and meth+lidocaine+fentanyl (n=262; 10.39%). Our findings highlight evolving patterns of multiple-opioid and opioid-stimulant polysubstance use, generating insights that can be rapidly applied to strengthen clinical, preclinical, and translational polysubstance research. These insights allow for investigations into biobehavioral mechanisms and consequences of emerging use patterns, accelerating development of novel therapeutics.