The purpose of this R01 proposal is to deepen our knowledge of the primary cause of drug overdose deaths in the U.S. today: novel psychoactive synthetic opioids, the majority of which are fentanyl analogues. Using a nationwide registry of patients who present to emergency departments, novel fentanyl analogue overdose will be studied in terms of its epidemiology, analytical confirmation, clinical risk factors, and treatment needs, by a uniquely qualified multidisciplinary team with an extensive track record of collaboration in the field. The scope of the U.S. opioid epidemic is broadening, with drug overdose deaths nearly tripling from 1999-2015. For the first time ever, in 2015 U.S. drug overdose deaths surpassed 50,000 (52,404), of which 33,091 (63.1%) involved an opioid. Overdose deaths continued to increase in 2016 to 63,600. Opioid overdoses cost Americans $504 billion in 2015 (2.8% of gross domestic product), up from six times the prior estimates in 2013. There was a 27% increase in nationwide Emergency Department visits for opioid overdoses last year alone. Strategies to mitigate this trend by decreasing the availability and abuse potential of prescription opioids have been followed by an increase in illicit opioid use. While initially the predominance of illicit opioid overdoses were a result of heroin exposure, the changing face of global drug commerce introduced synthetic opioid fentanyl analogues into the drug supply, where they are now estimated to have surpassed heroin as the primary cause of drug overdose deaths. Using nearly 70 hospital centers nationwide with bedside evaluation of patients, over 10,000 overdose patients have been enrolled in the Principal Investigator’s prior study giving this proposal momentum and feasibility. Our specific aims are four-fold: (1) To derive and validate clinical predictors of adverse health consequences of fentanyl analogue overdose; (2) To confirm fentanyl analogue exposure via state-of-the-art toxicology testing; (3) To investigate treatment utilization, duration, and disparities for fentanyl analogue overdose; and (4) To assess epidemiology of analytically-confirmed fentanyl analogue overdose. To achieve these Specific Aims, we will prospectively enroll a national sampling of patients. We will implement the rapid dissemination of alerts and information to the public and public health entities on adverse effects of fentanyl analogues. At the completion of the proposed research, the field of drug abuse will be significantly advanced to the benefit of thousands of victims of the U.S. opioid epidemic.