Both healthcare professionals and the public have been bombarded with news reports about the opioid crisis. However, the opioid crisis is just the latest in a more than decade-long trend of emerging drugs that are chemically similar to well-known drugs, but that may behave very differently inside the body and are difficult for laboratories to identify and classify using existing technologies.
The most recent wave of novel psychoactive substances (NPS) emerged in the 2000s. As law enforcement and laboratories found and identified new members of drug classes such as cathinones and cannabinoids in drug seizures, the Drug Enforcement Administration (DEA) provided temporary scheduling, making these drugs illegal. In response, manufacturers—often located overseas—simply switched to producing other compounds. The constantly shifting landscape affected forensic laboratories at all levels, as criminalists and toxicologists struggled to identify unknown substances and their effects in people. In addition, no one system existed to share this information efficiently.
Experts at the Center for Forensic Science Research and Education (CFSRE) in Pennsylvania tackled this problem with the ingenuity laboratorians are known for. Alex Krotulski, PhD; Amanda Mohr, associate director; Melissa Fogarty, laboratory manager; and Barry Logan, PhD, executive director, thought they could develop new information and rapidly disseminate it, shortening the lifecycle of some of these dangerous drugs.
Beginning in 2015, CFSRE began work on four National Institute of Justice (NIJ)-funded projects aimed at developing new methods to find NPS as quickly as possible. The result: NPS Discovery, an open-access database that today allows laboratories to rapidly share information on these drugs as soon as they are found.
Why Are Emerging Drugs Hard to Identify?
Identifying NPS is challenging: You cannot find what you are not looking for. For example, a laboratory cannot identify an unknown peak in a chromatogram as a particular drug without a standard reference material, and test results cannot be confirmed without a validated method. Even if a lab suspects the presence of an NPS—through ambiguous assay development or intelligence on drug use in the area—it cannot easily add the drug to its existing test methods, especially if a standard for that drug does not yet exist. The relatively short “use lives” of many NPS is also a barrier. In response to changing legislation, new drugs can appear and then disappear again within months (Figure 1).
Another challenge is the highly geographic nature of drug-use trends. For example, phencyclidine (commonly referred to as PCP) is largely remembered as the drug of choice for California biker gangs in the 1960s but is now so infrequently seen that many labs may not even routinely test for it. However, according to Peter Stout, PhD, chief executive officer for the Houston Forensic Science Center in Texas, PCP was the second-most-prevalent drug seen in their driving under the influence of drugs (DUID) samples from 2014 to 2019.
With the often short-lived fads for one NPS or another, geographical disparities may be heightened, meaning information must be shared nationally in order to benefit criminalists and toxicologists attempting to identify new drugs on their turf.
Solving the Problem With New Technology and Information Sharing
In 2015, as part of an NIJ-funded study to identify NPS in blood, urine, and oral fluid samples from attendees of electronic dance music festivals (1), Krotulski, Mohr, Fogarty, and Logan developed a method for an instrument that forensic laboratories were just starting to use for drug testing: The liquid chromatography quadrupole time-of-flight mass spectrometer (LC-QTOF-MS). LC-QTOF-MS can capture a wide range of components and gives highly accurate results.
The team developed a rapid LC-QTOF-MS method that required only 15 minutes of analysis time—critical for labs with burgeoning drug caseloads. The testing setup also allowed for more exploration of samples to find emerging NPS stimulants and hallucinogens, as well as their metabolites.
In 2017, the research team greatly expanded their efforts. Through a graduate research fellowship, Krotulski broadened the scope of the previously developed LC-QTOF-MS method to include more drugs and proposed sample-mining on existing toxicology samples from the forensic toxicology reference laboratory NMS Labs, which has a relationship with CFSRE, to gain further knowledge of drug trends (2). By retesting extracts from NMS Labs using an expanded scope of testing (e.g., sample-mining), the CFSRE team discovered NPS that were not initially targeted in the samples. The team reanalyzed these samples and used data mining for others, combing through previously acquired data files for newly identified NPS.
The CFSRE team members also wanted to expand their testing for synthetic cannabinoids, which would require a different method from synthetic cathinones and other NPS. The researchers ultimately developed and validated a new nontargeted 7-minute method for synthetic cannabinoids (3). Using this method, they retested authentic case samples from NMS Labs using the more sensitive LC-QTOF-MS instrumentation, and developed a workflow to re-process data from broad screening tests performed by NMS Labs using slightly older, less sensitive instrumentation (LC-TOF-MS) and a new, more extensive database containing all NPS discovered by the team with the previous efforts, and focusing on fentanyl and other novel opioids (4).
The outcomes of these research efforts have been far-reaching. The CFSRE team developed and validated the most comprehensive and sophisticated methodologies and workflows in the United States for the characterization of NPS in forensic samples. They have also built an extensive mass spectral database laboratories can use for comparative purposes in crime labs and medical examiner’s offices. All reports and information generated through these efforts are freely available on NPS Discovery.
The Need for Information Sharing
Sharing information from multiple sources is vital in forensic toxicology: Trends seen in postmortem cases may not align with clinical overdose cases. Stout noted the curious patterns of methamphetamine in Houston, where a third of all seized drug samples contain methamphetamine, but methamphetamine is not often seen in the city’s DUIDs. “It is really difficult to tell from the perspective of lab results why that is. It could be differences in interdiction,” Stout said. “It could be drivers on meth[amphetamine] are not easily spotted. Seems unlikely that all that meth[amphetamine] is just passing through [without being used by residents].”
To acquire data from as many sources as possible, the CFSRE team sought out other collaborations. One, funded by the Centers for Disease Control and Prevention through the Organized Crime Drug Enforcement Task Force, brought samples of drugs from seizures by Customs and Border Protection to be analyzed using the methods developed by the CFSRE team. This added to the body of timely knowledge about NPS in the U.S
With a mountain of data and new information before them, Krotulski, Mohr, Fogarty, and Logan realized they had to get this information out to those who need it—forensic scientists, of course, but also clinicians and clinical laboratorians who might be faced with apparent overdoses from unknown drugs, law enforcement officers seeing increased or unusual adverse effects from drugs, and policymakers and legislators struggling to keep up with legislating these emerging drugs. This is the true value of NPS Discovery as a resource.
Developing NPS Discovery as a National Data-Sharing Tool
Beginning in 2018, the CFSRE researchers produced monographs (Figure 2, example monograph) for each newly discovered drug, as well as trend reports (Figure 3, example trend report) showing the positivity and prevalence of all NPS identified over the previous quarter.
Then in 2019, CFSRE began issuing public health alerts to inform clinicians and emergency room personnel, as well as law enforcement officers, forensic scientists, and other interested parties, about NPS adverse intoxications, mass overdoses, and fatalities. These alerts describe the clinical effects of new drugs and may include recommendations for clinicians, public health officials, forensic laboratory personnel, and medical examiners and coroners. These rapid communications may not reflect all knowledge of a new drug, but quickly alert practitioners in cases of extreme danger.
The most comprehensive task for the CFSRE team was setting up the NPS Discovery website (www.npsdiscovery.org). The website contains the monographs, trend reports, and public alerts, as well as the NPS Dashboard, also launched in 2019.The Dashboard is an interactive tool that brings together the information from NIJ-funded work and other efforts in this area (Figure 6). With the Dashboard, users can examine data related to a class of drugs or a particular drug, determine prevalence and emergence over time, as well as see information on geographical distribution, type of case, and demographics of the subject.
Although NPS have been demonstrably on the rise for over 10 years, they remain a small percentage of casework. Marijuana, methamphetamine, cocaine, heroin, and fentanyl remained the top five most encountered drugs in the 2019 National Forensic Laboratory Information System report, accounting for nearly 75% of all drug reports nationwide (5).
The database results are also limited by the service area of NMS Labs. As most of the toxicology samples come from NMS Labs, they are necessarily restricted to those labs that send them samples. Crime labs with the resources to perform their own investigations are not included. However, NMS Labs does receive toxicology samples from almost every state.
The data are only qualitative, and only one analysis has been performed due to the necessity of retesting leftover sample extracts. NPS Discovery is a starting place for labs seeking to identify an unknown, not a source for confirmation, which each lab will still have to do in accordance with its own policies. In addition, isomer pairs are usually not distinguished from each other, so the unknown may only be identifiable as one of two (or more) possibilities.
NPS Discovery in Action
The impact of the NPS Discovery products has been extensive. Recently, for example, the CFSRE team alerted stakeholders to the first appearance of novel opioids isotonitazene and brorphine in toxicology samples in the U.S.
NPS Discovery first reported on isotonitazene in November 2019. When the DEA temporarily placed it on the Schedule I list in December 2020, it referenced that CFSRE publication (6). After brorphine was first reported by NPS Discovery in June 2020 the DEA public alert published in August 2020 again referenced CFSRE work (7).
The NPS Discovery team continues to expand the scope of their efforts. CFSRE has collaborated with medical examiner and coroner offices to run casework for NPS when those offices were unable to get testing elsewhere. The team has also created clinical partnerships with hospitals in New York City, Boston, Salt Lake City, and other areas to detect NPS in samples from patients who have survived overdoses. They have also partnered with the Philadelphia Department of Public Health on testing to help inform the department and the general public of what is present and prevalent in the city so that the department may tailor its efforts.
“Our laboratory is now positioned as a national leader in NPS testing and reporting, which in turn has allowed for vast knowledge transfer from our laboratory to others leading to action and interpretation not previously available,” Krotulski said. The forensic science community, and many other stakeholders, continue to reap the benefits.
- Alex J. Krotulski et al. Monitoring changes in the novel psychoactive substance (NPS) market through enhanced identification of emerging drugs and their metabolites in biological samples. Final report to the National Institute of Justice, grant number 2015-IJ-CX-K012, June 2018, NCJ 251787. https://www.ncjrs.gov/pdffiles1/nij/grants/251787.pdf (Accessed March 2021).
- Alex J. Krotulski. A more timely process for identifying and analyzing trends in emerging novel psychoactive substances in the United States. Final report to the National Institute of Justice, grant number 2017-R2-CX-002, October 2020, NCJ 255599. https://www.ncjrs.gov/pdffiles1/nij/grants/255599.pdf (Accessed March 2021).
- Alex J. Krotulski, Amanda L.A. Mohr, and Barry K. Logan. Retrospective identification of synthetic cannabinoids in forensic toxicology casework using archived high resolution mass spectrometry data. Final report to the National Institute of Justice, grant number 2017-R2-CX-0021, November 2020, NCJ 255669. https://www.ncjrs.gov/pdffiles1/nij/grants/255668.pdf (Accessed March 2021).
- Amanda LA Mohr, Judith Rodriguez Salas, and Barry K Logan. Toxicological time travel: retrospective datamining of analytical time-of-flight mass spectrometry data for evaluating the rise and fall of novel opioid and fentanyl analog use in the United States. Final report to the National Institute of Justice, grant number 2017-DN-BX-0169, December 2020, NCJ 255883. https://www.ncjrs.gov/pdffiles1/nij/grants/255883.pdf (Accessed March 2021).
- U.S. Drug Enforcement Administration, Diversion Control Division. National Forensic Laboratory Information System: NFLISDrug 2019 Annual Report. https://www.nflis.deadiversion.usdoj.gov/DesktopModules/ReportDownloads/Reports/NFLIS-Drug-AR2019.pdf (Accessed March 2021).
- U.S. Drug Enforcement Administration, Diversion Control Division. Schedules of controlled substances: Temporary placement of isotonitazene in schedule I, 21 CFR Part 1308, Docket no. DEA-631. Federal Register 2020; 85 (118).
- U.S. Drug Enforcement Administration, Diversion Control Division. Brorphine (chemical name:1-(1-(1-(4-bromophenyl)ethyl)piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one), Public Alert, August 2020. https://www.deadiversion.usdoj.gov/drug_chem_info/brorphine.pdf (Accessed March 2021).
Frances Scott, PhD, is a physical scientist in the Office of Investigative and Forensic Sciences in the National Institute of Justice. +Email: [email protected]