Following series of synthetic cannabinoid and synthetic cathinone derivatives, the illicit drug market has begun to see increased incidence of synthetic opioids including fentanyl and its derivatives, and other chemically unrelated opioid agonists including AH-7921 and MT-45. Among the most frequently encountered compounds in postmortem casework have been furanyl fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylfuran-2-carboxamide, Fu-F) and U-47700 (trans-3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide). Both drugs have been reported to be present in the heroin supply and to be gaining popularity among recreational opioid users, but were initially developed by pharmaceutical companies in the 1970s as candidates for development as potential analgesic therapeutic agents. A method was developed and validated for the analysis of U-47700, U-50488 and furanyl fentanyl in blood specimens. A total of 20 postmortem cases, initially believed to be heroin or other opioid-related drug overdoses, were submitted for quantitative analysis. The analytical range for U-47770 and U-50488 was 1-500 and 1-100 ng/mL for furanyl fentanyl. The limit of detection was 0.5 ng/mL for all compounds. Within the scope of the method, U-47700 was the only confirmed drug in 11 of the cases, 5 cases were confirmed for both U-47700 and furanyl fentanyl, and 3 cases were confirmed only for furanyl fentanyl. The mean and median blood concentrations for U-47700 were 253 ng/mL (±150) and 247 ng/mL, respectively, range 17-490 ng/mL. The mean and median blood concentrations for furanyl fentanyl were 26 ng/mL (±28) and 12.9 ng/mL, respectively, range 2.5-76 ng/mL. Given the widespread geographical distribution and increase in prevalence in postmortem casework, toxicology testing should be expanded to include testing for "designer opioids" in cases with histories consistent with opioid overdose but with no traditional opioids present or insufficient quantities to account for death.

Novel psychoactive substances (NPS) represent significant analytical and interpretive challenges to forensic and clinical toxicologists. Timely access to case reports and reports of adverse incidents of impairment or toxicity is imperative to clinical diagnosis and treatment, as well as to interpretation of forensic results. Delays in identifying the presence of a novel intoxicating agent have significant consequences for public health and public safety. Adverse effects of intoxications with novel cannabinoids, stimulants, hallucinogens, benzodiazepines and opioids spanning January 2013 through December 2016 as reported in emergency departments, death investigations, impaired driving cases and other forensic contexts are the subject of this review. Discussion of the chemistry, pharmacology and adverse events associated with novel drug classes is summarized and described within. Adverse effects or symptoms associated with ingestion of more than 45 NPS have been abstracted and summarized in tables, including demographics, case history, clinical or behavioral symptoms, autopsy findings and drug confirmations with quantitative results when provided. Based on these findings and gaps in the available data, we provide recommendations for future toxicological testing of these evolving substances. These include development and management of a national monitoring program to provide real-time clinical and toxicological data, confirmed analytically, on emerging drugs and their known toxidromes and side effect profiles. Increased efforts should be made to analytically confirm the agents responsible for clinical intoxications involving adverse events in emergency department admissions or hospitalizations. Evidence-based community preparedness among analytical laboratories gained through active communication and sharing of toxicological findings and trends in NPS is imperative to assist in enabling early detection of new drugs in forensic and clinical populations.

The MOR reporter assay allows rapid identification of opioid activity in blood. Although the cooccurrence of opioid antagonists is currently a limitation, the bioassay's high detection capability, specificity, and untargeted nature may render it a useful first-line screening tool to investigate potential opioid intoxications.

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Novel psychoactive substances (NPS), and specifically novel opioids, continue to cause adverse events, including death, within drug-using populations. As the number of opioid-related overdoses continues to increase, laboratories have identified the emergence of new fentanyl analogues and other synthetic opioid-related drugs. Tetrahydrofuranylfentanyl (THFF) has been identified in Europe and the United States as an emerging novel opioid, causing death in at least 15 drug-using individuals to date. THFF is structurally similar to furanylfentanyl, a previously characterized novel opioid responsible for numerous adverse events, including death. In this case report, THFF, U-49900 and methoxy-phencyclidine were identified in postmortem blood and urine specimens collected after a suspected overdose. As part of the death investigation, an unknown substance was collected from the scene and analytically confirmed as THFF and U-49900. To further assist laboratories in identifying THFF ingestion, metabolic profiling was conducted using pooled human liver microsomes. Characterized metabolites were then confirmed in the specimens collected during this investigation. In total, seven metabolites were identified for THFF, most notably THF-norfentanyl and hydroxyl-THFF. THF-norfentanyl provides utility as a biomarker because it is a unique metabolite of THFF. 4-Anilino-N-phenethylpiperidine (4-ANPP) and its metabolite, hydroxyl-4-ANPP, were identified in microsomal incubations and collected specimens, but usefulness as biomarkers is limited due to commonality between other fentanyl analogues and co-ingestion as a synthesis precursor. To our knowledge, this case report is the first to document a fatality after ingestion of THFF and U-49900 in the United States.