[APHA] Nationwide, mail-based drug checking to prevent drug-related harms in an ever-changing drug supply

<strong>Background</strong> Street drugs change constantly, but we don't find out what's in them until it's too late, when people are either dead or arrested: There is no opportunity for recovery or prevention. Analytical chemistry can be harnessed to provide people who use drugs (and health professionals) with real-time information on the drug supply and attendant physiological harms. <strong>Intervention</strong> We describe the development and success of a novel, low-threshold, mail-based drug checking program serving health departments, harm reduction organizations, drug user unions, paramedics, clinics, hospitals, and researchers. Unlike law enforcement drug information systems, samples are provided anonymously and voluntarily. Samples are analyzed using untargeted gas chromatography-mass spectrometry (GCMS). Crucially, lab results are provided directly to sample donors, inverting traditional post-hoc result dissemination, allowing people to make better decisions about what they put in their bodies. Aggregate patterns are displayed in "live reports" updated daily using Python-based machine learning tools. <strong>Results</strong> Between March 2022 and March 2025, a total of 11,578 drug samples were collected by 166 public health programs, originating in 243 counties in 40 states. Using GCMS, 404 unique substances were identified in the unregulated drug supply. Most commonly identified substances were fentanyl (n=5,738), methamphetamine (n=2,775), xylazine (n=2,086), acetaminophen (n=2,024), cocaine (n=2,015), and heroin (1,642). Fentanyl was almost always found with other substances, averaging 4.7 (95% CI: 4.6, 4.8) substances per sample in addition to fentanyl. Carfentanil was found in n=68 samples from 9 states; nitazenes n=133 from 14 states. During Summer 2024, the drug checking community of practice was the first-in-the-nation to identify and characterize the adulterant bis(2,2,6,6-tetrametyl-4-piperidyl) sebacate (n=1,082; 14 states), demonstrating proof of concept. <strong>Implications</strong> Drug checking is a viable public health paradigm in the United States. While festival drug checking extends back to the 1970s, modern problems with synthetic opioids provide renewed urgency for point-of-care expansion.