This is the first report regarding the characterization of the new synthetic cannabinoid 4F‐MDMB‐BINACA. 4F‐MDMB‐BINACA was first analytically confirmed in seized drug material using gas chromatography–mass spectrometry (GC‐MS), liquid chromatography–quadrupole time‐of‐flight mass spectrometry (LC‐QTOF), and nuclear magnetic resonance (NMR) spectroscopy. Subsequent to this characterization, 4F‐MDMB‐BINACA was detected in biological specimens collected as part of forensically relevant casework, including medicolegal death investigations and drug impaired driving investigations, from a variety of regions in the United States. Further analysis of biological specimens resulted in the identification of the metabolites 4F‐MDMB‐BINACA 3,3‐dimethylbutanoic acid and 4‐OH‐MDMB‐BINACA. 4F‐MDMB‐BINACA is appearing with increasing frequency as a contributory factor in deaths, creating morbidity and mortality risks for drug users. Laboratories must be aware of its presence and impact, incorporating 4F‐MDMB‐BINACA into workflows for detection and confirmation.

Methoxyacetylfentanyl and cyclopropylfentanyl are two of the newest illicit opioids that are infiltrating the heroin market. Methoxyacetylfentanyl and cyclopropylfentanyl were reported by the Drug Enforcement Administration (DEA) in their third quarter report of 2017 to have been chemically identified seven and five times, respectively, from drug evidence analyzed by the DEA's lab system; Q3 was the first time cyclopropylfentanyl was identified by the DEA's lab system, while methoxyacetylfentanyl was reported one time in Q2 2017. A method was developed using liquid chromatography tandem mass spectrometry for the quantitation of fentanyl, norfentanyl and 17 fentanyl analogs: furanylfentanyl, butyrylfentanyl, despropionylfentanyl (4-ANPP), methoxyacetylfentanyl, tetrahydrofuran fentanyl, fluoro-isobutyrylfentanyl, acrylfentanyl, para-fluorofentanyl, ortho-fluorofentanyl, carfentanil, beta-methylfentanyl, isobutyrylfentanyl, para-methylfentanyl, cyclopentylfentanyl, cyclopropylfentanyl, beta-hydroxyfentanyl and alpha-methylfentanyl. The calibration range for all compounds was 0.1-100 ng/mL. Blood samples from 42 postmortem cases involving cyclopropylfentanyl and methoxyacetylfentanyl from Florida, Illinois, Michigan and Tennessee were submitted for toxicological analysis. The mean and median concentration for the cases testing positive for cyclopropylfentanyl (n = 32) was 15.3 (±11.9) ng/mL and 12.3 ng/mL, respectively, with a range of 1.4-43.3 ng/mL. The mean (±SD) and median concentrations for the 11 cases quantitatively confirmed (3 cases were below the limit of quantitation) for methoxyacetylfentanyl was 17.7 (±11.4) ng/mL and 15.1 ng/mL respectively, with a range of 0.21-39.9 ng/mL. These novel illicit substances typically are outside the scope of routine drug testing by hospitals and toxicology laboratories or below the sensitivity levels for the detection of these substances in biological specimens. These compounds have not previously been studied in humans; therefore, it is significant to be able to associate the pharmacological effects derived from case reports to the quantitative values found in the postmortem specimens.

The recreational use of opioid drugs is a global threat to public health and safety. In particular, an epidemic of opioid overdose fatalities is being driven by illicitly manufactured fentanyl, while novel synthetic opioids (NSOs) are appearing on recreational drug markets as standalone products, adulterants in heroin, or ingredients in counterfeit drug preparations. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a prime example of a non-fentanyl NSO that is associated with numerous intoxications and fatalities. Here, we review the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection, and forensic toxicology of U-47700 and its analogs. An up-to-date summary of the human cases involving U-47700 intoxication and death are described. The evidence demonstrates that U-47700 is a potent μ-opioid receptor agonist, which poses a serious risk for overdosing and death. However, most analogs of U-47700 appear to be less potent and have been detected infrequently in forensic specimens. U-47700 represents a classic example of how chemical entities from the medicinal chemistry or patent literature can be diverted for use in recreational drug markets. Lessons learned from the experiences with U-47700 can inform scientists, clinicians, and policymakers who are involved with responding to the spread and impact of NSOs.

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