The author(s) shown below used Federal funding provided by the U.S. Department of Justice to prepare the following resource: Document Title: Toxicological Time Travel: Retrospective Datamining of Analytical Time-of-Flight Mass Spectrometry (TOFMS) Data for Evaluating the Rise and Fall of Novel Opioid and Fentanyl Analog Use in the United States Author(s): Amanda LA Mohr, MSFS, D-ABFT-FT, Judith Rodriguez Salas, MS, Barry K Logan, Ph.D., F-ABFT Document Number: 255883 Date Received: December 2020 Award Number: 2017-DN-BX-0169 This resource has not been published by the U.S. Department of Justice. This resource is being made publically available through the Office of Justice Programs’ National Criminal Justice Reference Service. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. Title: Toxicological Time Travel: Retrospective Datamining of Analytical Time-of-Flight Mass Spectrometry (TOFMS) Data for Evaluating the Rise and Fall of Novel Opioid and Fentanyl Analog Use in the United States Authors: Amanda LA Mohr, MSFS, D-ABFT-FT, Judith Rodriguez Salas, MS, and Barry K Logan, PhD, F-ABFT Organization: Center for Forensic Science Research and Education at the Fredric Rieders Family Foundation, Willow Grove, PA, USA Award Number: 2017-DN-BX-0169 This resource was prepared by the author(s) using Federal funds provided by the U.S. Department of Justice. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. Abstract Since 2013, the use of novel illicit opioids has been increasing. There are several new drugs and analogs of fentanyl that have emerged on the illicit drug market and account for many of the deaths that have occurred. There are challenges however in the timely identification of these new substances, and in alerting key stakeholders in public health and safety about the changes in the markets. The data are further limited by the lack of available reference standards, as well as the ability of overburdened crime laboratories and toxicology laboratories to develop and validate new methods, resulting in delays of months between the appearance of a new drug and the laboratories’ ability to detect and report it. There is substantial variability between laboratories in terms of what is being tested for and reported. These limitations all impact the degree to which the data are actionable and help public health and safety agencies to intervene and reduce drug deaths. To address these concerns, this project sought to data-mine raw electronic analytical data acquired using Liquid Chromatography Time of Flight Mass Spectrometry (LCTOFMS) from postmortem and driving under the influence of drugs (DUID) cases, and to find earlier and more timely identifications of new substances. The data-mining process, which involves repeated re- interrogation of the raw data against a continually updated database of emerging opioid drugs, has allowed the identification of key emerging opioids not included in the scope at the time of original analysis. From the data, time-course trend plots, geographic distribution heat maps, and basic demographic descriptions of populations dying from use of legacy opioids, and novel and emerging opioids were turned into reports. These reports were generated every three months, and disseminated within the public health, criminal justice, and forensic science communities to provide timely and updated information related to opioid trends in the United States. 2 This resource was prepared by the author(s) using Federal funds provided by the U.S. Department of Justice. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. Based on the application of the data-mining techniques developed under this award, throughout 2018 and into 2019 we were able to report within days of the close of each quarter that fentanyl positivity steadily increased, while heroin positivity remained relatively stable. Legacy prescription semi-synthetic opioids remained stable. The positivity for novel opioids in forensic cases significantly dropped in 2019, as scheduling of fentanyl analogs led to a reduction in their production and trafficking. By maintaining an updated and comprehensive scope, several emerging opioids were identified in 2018 and 2019. Once it became known that they were present in the United States, retrospective data-mining identified these emerging opioids in forensic toxicology casework performed during times when the compounds were not included in the scope of initial testing. This included 12 emerging opioids in 2018, and seven in 2019. This research project resulted in the development of a real-time monitoring and early warning system for legacy and emerging opioid trends in the United States. Combining seized drug and analytical toxicological intelligence data, we were able to substantially reduce the lag time between new identifications of the drug in the street drug supply, and their detection in toxicological (postmortem and DUID) cases. On many occasions these new analytes were identified in cases several months prior to any awareness of their presence in the US drug market. The data demonstrate that opioid positivity has continued to increase throughout 2019, specifically for fentanyl, ahead of typical public health data systems, and that novel classes of emerging opioids have continued to appear on a recurring basis throughout the period of study supporting the proposal that resources should be allocated on an ongoing basis to support this successful approach to monitoring US drug markets. 3 This resource was prepared by the author(s) using Federal funds provided by the U.S. Department of Justice. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. 1. Introduction There are concerns from anecdotal reports from emergency room admissions, poison center calls, drug treatment admissions, drug possession and trafficking arrests, crime laboratory statistics, and medical examiner’s data that the illicit use and abuse of both prescription opioids, such as morphine, fentanyl, and oxycodone, and traditionally abused opioids, most notably heroin, are increasing. The Centers for Disease Control (CDC) reported that since 1999 the number of synthetic opioid deaths have tripled (1, 2). Moreover, between 2014 to 2018 there was a steep increase in those numbers, reaching the highest mortality rates ever reported. In 2014, the CDC reported that more people died from drug overdoses than any other year on record, and the majority (60.9%) of those overdose deaths involved an opioid (3, 4). By 2018, there were more than 67,000 drug overdose deaths in the United States, with a 10% increase in synthetic opioid deaths from 2017 to 2018 (9% in 2017 to 9.9% in 2018) (3–6). Beginning in 2013, novel opioid agonists became the next wave of the designer drug epidemic. Many novel opioid agonists that have been identified over the last seven years are now contributing to the opioid death statistics at an increasing, but poorly documented, rate (7). A study performed by Bowen et al. showed correlation between drugs mentioned in public drug- related forums and reported deaths for that specific drug (8). The increase in the number of posts for a specific compound, such as carfentanil, led to an increase in positivity in toxicological cases, just weeks after the postings. These novel opioid agonists pose the same public health dangers as other novel psychoactive substance (NPS) classes including ease of accessibility over the internet, new drug introductions following scheduling, requirement for specialized toxicology testing, lack of certified reference material, limited knowledge of effects in humans, and misrepresentation to users. In addition to these challenges, there is also concern that these novel opioid agonists are 4 This resource was prepared by the author(s) using Federal funds provided by the U.S. Department of Justice. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. present in the routine illicit heroin and fentanyl drug supply, increasing the pool of potential victims. The market is complex with many novel drugs, and the information resources that allow public health and public safety agencies to assess the spread of new drugs as they enter the marker is significantly lacking. In efforts to regulate the rapid emergence of new synthetic opioids, the Drug Enforcement Administration (DEA) temporarily scheduled core structure fentanyl-related compounds, based on their structure and not on their toxicity/potency (9). Traditional laboratory approaches to drug screening will typically fail to detect the novel opioids due to little or no cross-reactivity on traditional immunoassay tests (10). Some fentanyl derivatives do cross-react on some immunoassay platforms like enzyme-linked immunosorbent assay (ELISA), but if they are not in the scope of a confirmatory assay, they will result in screen positive results that fail to confirm (11). The most common screening approach is using gas chromatography mass spectrometry (GCMS); however, this technique lacks the necessary sensitivity required for detecting many NPS, and heavily relies on spectral libraries being regularly updated with the most current compounds. Many laboratories follow routine targeted testing for the presence of drugs but may not see compounds that are present outside of that scope. In many cases, standard reference material may not be available to confirm the identity of these compounds, and forensic laboratories that follow best practices and generally accepted accreditation standards will not report drugs as being present when they have not verified them against an authentic standard in their laboratory.