The overdose epidemic is driven by illicit fentanyl and fentanyl analogues, often combined with synthetic simulants. The addition of new psychoactive substances (NPS), a broad classification of new substances constituting a diverse range of chemicals including stimulants and hallucinogens as well as research chemicals related to benzodiazepine and opioid classes, to the illicit drug market further complicates the drug supply. People who use drugs want to know what is in their drugs and will adjust their use and take more preventative actions in response. Unfortunately, the ability to test, detect and report substance exposure including NPS at overdose accurately within the healthcare system does not exist given current clinical toxicology testing protocols. The Emergency Department (ED) standard for drug exposure evaluation is urine drug screen testing (UDS). UDS has limitations in analytical selectivity and scope which can lead to incorrect provider assumptions regarding drug exposure. Additionally, UDS omits evaluation of NPS and other pharmaceuticals, including active cut, that can increase overdose risk, resulting in an incomplete picture of drug exposure and supply safety. Our goal is to evaluate current toxicology testing protocols in the Emergency Department to positively impact patient, provider, and public health outcomes including clinical care, drug supply surveillance, and harm reduction outreach. The specific aims for the proposed study are: (1) Evaluate the utility of standard hospital UDS to test for drug exposure in the evolving drug supply dominated by illicit synthetics via comparison to liquid chromatography quadruple time-of-flight mass spectrometry (LC-QTOF-MS) toxicology testing; (2) Determine whether LC-QTOF-MS toxicology testing results from ED non-fatal drug overdose cases match findings in post-mortem toxicology testing from drug overdose fatalities using the Rhode Island State Unintentional Drug Overdose Reporting System (SUDORS) to assess future application for early drug supply biosurveillance; and (3) Measure feasibility and acceptability to patients of biological drug checking feedback using toxicology testing results after an ED visit for drug-overdose. We will enroll 100 ED patients with non-fatal unintentional drug overdose at Rhode Island Hospital over one year comparing toxicology testing results from a standard-of-care hospital UDS protocol to LC-QTOF-MS. Results of LC-QTOF-MS toxicology testing in non-fatal drug overdose will then be compared to toxicology testing results from unintentional opioid-involved drug overdose fatalities (SUDORS) to evaluate whether toxicology testing results from non-fatal drug overdoses treated in the ED reflect substances causing overdose death. We will also evaluate the feasibility and acceptability of incorporating detailed toxicology data into harm reduction efforts. Enrolled patients will be provided results of comprehensive toxicology testing results ...