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Background: In 2020, there were 36.7 million reported falls among older adults (65+) in the United States. Ethanol and other sedating substances may increase fall risk among older adults due to their effect on cognitive and physical function. We estimate the prevalence of these substances in blood specimens of older adults presenting with a fall injury at selected trauma centers. Methods: The initial study collected blood specimens from May 2020 through July 2021 from adults undergoing a trauma team evaluation at selected United States Level 1 trauma centers. We limited our study to older adults evaluated after a fall (n = 1,365) and selected a random sample (n = 300) based on age, sex, and trauma-center quotas. Medical health records and blood specimens obtained at trauma center presentation were analyzed. We estimated the prevalence of ethanol, benzodiazepines, cannabinoids, and opioids in the blood specimens. Two-sample tests of binomial proportions and Chi-square two-tailed tests were used to compare prevalence estimates of substances by demographic characteristics. Results: At least one substance was detected among 31.3% of samples analyzed. Prevalences of specific substances detected were 9.3% (95% CI: 6.0–12.6%) for benzodiazepines, 4.3% (95% CI: 2.0–6.7%) for cannabinoids, 8.0% (95% CI: 5.2–11.7%) for ethanol, and 15.0% (95% CI: 10.9–19.1%) for opioids. There were 18 deaths (6%; 95% CI: 3.6–9.3%). One-third of decedents had at least one substance detected in their blood. Discussion: Opioids were the most frequently detected substance, followed by benzodiazepines, ethanol, and cannabinoids. Substance use prevalence was not uniform across demographics, with differences observed by sex and age. Conclusions: This study provides insight into the frequency of the presence of substances that may contribute to fall risk and serious injury among older adults. Screening older adults for substances that impair cognitive and physical function can enhance clinical fall prevention efforts. [ABSTRACT FROM AUTHOR]

Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS) and new structural scaffolds have emerged on the recreational drug market since the enactment of Chinese SCRA analog controls in 2021. This study reports the first SCRAs to be detected with a bromide at the 5 position (5′Br) on the phenyl ring of the indazole core and without a tail moiety. ADB‐5′Br‐INACA (ADMB‐5′Br‐INACA) and MDMB‐5′Br‐INACA were detected in seized samples from Scottish prisons, Belgian customs, and US forensic casework. The brominated analog with a tail moiety, ADB‐5′Br‐BUTINACA (ADMB‐5′Br‐BUTINACA), was also detected in Scottish prisons and US forensic casework. The metabolites of these compounds and the predicted compound MDMB‐5′Br‐BUTINACA were identified through incubation with primary human hepatocytes to aid in their toxicological identification. The bromide on the indazole remains intact on metabolites, allowing these compounds to be easily distinguished in toxicological samples from their non‐brominated analogs. Glucuronidation was more common for tail‐less analogs than their butyl tail‐containing counterparts. Forensic toxicologists are advised to update their analytical methods with the characteristic ions for these compounds, as well as their anticipated urinary markers: amide hydrolysis and monoOH at tert‐butyl metabolites (after β‐glucuronidase treatment) for ADB‐5′Br‐INACA; monoOH at tert‐butyl and amide hydrolysis metabolites for ADB‐5′Br‐BUTINACA; and ester hydrolysis metabolites with additional metabolites for MDMB‐5′Br‐INACA and MDMB‐5′Br‐BUTINACA. Toxicologists should remain vigilant to the emergence of new SCRAs with halogenation of the indazole core and tail‐less analogs, which have already started to emerge. [ABSTRACT FROM AUTHOR]

A quantitative gas chromatography mass spectrometry (GC/MS) method was developed for delta‐9‐tetrahydrocannabinol (delta‐9‐THC), delta‐8‐tetrahydrocannabinol (delta‐8‐THC), tetrahydrocannabinolic acid (THCA), and cannabidiol (CBD) in matrices including plant material, liquids and oils, waxes, edibles, and bath and body products. Samples were prepared by homogenization, extraction of the cannabinoids into solvent, liquid/liquid extraction, and derivatization. The GC/MS method was validated from 0.15% to 5.00% (weight basis) to encompass the 0.3% legal distinction between hemp and marijuana. Validation was performed assessing imprecision/bias, calibration model, recovery, interferences, limit of detection, matrix matching, carryover, accuracy, and an assessment of CBD conversion to delta‐9‐THC. The calibration curves were quadratic weighted 1/x with r2 > 0.990. The method had a detection limit of 0.075% in plant material for each analyte. Analyte recovery was greater than 70% in plant material. Carryover was not observed up to concentrations equivalent to 100% analyte, and no forensically significant conversion of CBD to delta‐9‐THC was observed. One cannabinoid isomer, 9(R)‐delta‐7‐tetrahydrocannabinol (9(R)‐delta‐7‐THC), was determined to interfere with the quantitation of delta‐9‐THC, but could be differentiated based on mass spectrum. The method was determined to be suitable for quantitation of delta‐9‐THC, delta‐8‐THC, delta‐9‐THCA, and CBD and was able to differentiate hemp samples from marijuana samples. [ABSTRACT FROM AUTHOR]

Due to the increase in the use of novel psychoactive substances (NPS) and their overall prevalence, it is important to have effective and reliable screening technologies to detect NPS in biological matrices. Enzyme-linked immunosorbent assays (ELISA) are among the most popular screening methods. To evaluate the effectiveness of ELISA for NPS detection, five subclasses of NPS (novel synthetic opioids, fentanyl analogs, stimulants, benzodiazepines and hallucinogens) were evaluated in whole blood for their cross-reactivity on commercially available ELISA kits. A variety of novel synthetic opioids were tested at concentrations of 1–80 ng/mL and 50–2000 ng/mL and demonstrated no cross-reactivity to a morphine ELISA plate at either concentration range. Fentanyl analogs were tested at concentrations ranging from 0.01 to 1 ng/mL and had cross-reactivities ranging from 8% to 178% on the fentanyl ELISA kit used. Both para-chloro fentanyl (178%) and acryl fentanyl (164%) showed cross-reactivities well above that of fentanyl. Novel stimulants were tested at concentrations of 0.5–40 ng/mL and 20–2,000 ng/mL. 4-Fluoroamphetamine was the only novel stimulant with cross-reactivity (3,354%) to the amphetamine ELISA plate. Novel benzodiazepines were tested at concentrations of 1–40 ng/mL on a benzodiazepine plate. Cross-reactivities ranged from 36.1% to 263%, with desalkylflurazepam having the highest cross-reactivity. Finally, novel hallucinogens were tested at concentrations of 0.5–10 ng/mL on a phencyclidine (PCP) ELISA plate, which produced no cross-reactivity and then with 10–1,000 ng/mL, which gave results from 56.6% to 151%. Both hydroxy-PCP (151%) and chloro-PCP (137%) showed cross-reactivities above that of PCP. This research has demonstrated the utility of using ELISA-based screening for novel benzodiazepines, hallucinogens and for fentanyl analogs; however, there is limited application and risk of false-negative results for the other drug classes due to low or non-existent cross-reactivities. [ABSTRACT FROM AUTHOR]

Previous research has evaluated the extent to which cocaine and other drugs were detectable on currency in the USA. The literature was in agreement that the majority of bills exhibited some degree of contamination. With the increase of fentanyl in the illicit drug supply, this study was designed to evaluate the extent that fentanyl, cocaine, methamphetamine and other substances were present on circulating currency in 2022. A quantitative assay using liquid chromatography–triple quadrupole mass spectrometry was developed and validated to detect six analytes: fentanyl, 4-anilino- N -phenethylpiperidine, acetylfentanyl, benzylfentanyl, cocaine and methamphetamine. One-dollar bills were collected from 13 cities across the country. Sample preparation consisted of soaking the bills in methanol followed by liquid–liquid extraction. Chromatographic separation was achieved using a C18 analytical column and gradient elution with ammonium formate in water (5 mM, pH 3) and 0.1% formic acid in acetonitrile. The quantitative working range for this assay was 0.1 μg to 1.0 μg per bill (equivalent to 1 ng/mL to 100 ng/mL of extract). Fentanyl was detected on the majority (63%) of samples, with 61% of samples having ≥0.1 μg of fentanyl and 4% of samples having ≥1.0 μg. Cocaine and methamphetamine were detected on 100% and 98% of bills, respectively, typically in amounts >1.0 μg. The remaining fentanyl-related substances were detected in 15% of samples in amounts no >0.69 μg per bill and exclusively in the presence of fentanyl. Unsurprisingly, areas of the country with higher incidence of fentanyl use yielded higher frequency of contaminated bills and higher concentrations. Human exposure to drugs on currency is unlikely to have any significant impacts toxicologically or pharmacologically; however, our research findings suggest that paper currency could serve as a useful substrate for surveillance of drug trends regionally, nationally and/or internationally. [ABSTRACT FROM AUTHOR]

Synthetic cathinones emerged on the novel psychoactive substance (NPS) drug market as alternatives to controlled stimulants and entactogens such as methamphetamine and 3,4-methylenedioxymethamphetamine. The majority of synthetic cathinones can be subclassified into two groups: beta-keto amphetamines (i.e. NPS with the suffix "drone") and beta-keto methylenedioxyamphetamines (i.e. NPS with the suffix "lone"). Although a significant number of beta-keto amphetamines have been identified, beta-keto methylenedioxyamphetamines have dominated the NPS market, including notable drugs like methylone, butylone, N -ethyl pentylone (ephylone), eutylone and now N,N -dimethylpentylone. N,N -Dimethylpentylone, also known as dipentylone or beta-keto-dimethylbenzodioxolylpentanamine, emerged into the illicit drug supply <2 months of the international control of eutylone (September 2021). A novel standard addition method was developed and validated for N,N -dimethylpentylone, pentylone and eutylone, and 18 postmortem cases were quantitated using the method described in this manuscript. The resulting blood concentration range for N,N -dimethylpentylone in this case series was 3.3 to 970 ng/mL (median: 145 ng/mL, mean: 277 ± 283 ng/mL). Pentylone, a metabolite of N,N -dimethylpentylone, was detected in all cases (range: 1.3–420 ng/mL, median: 31 ng/mL and mean: 88 ± 127 ng/mL). Due to the rise in identifications of N,N -dimethylpentylone in postmortem investigations as well as the potential misidentification of N,N -dimethylpentylone as N -ethyl pentylone, samples testing positive for pentylone should be additionally confirmed for the presence of N,N -dimethylpentylone. Based on prior trends of new synthetic cathinones, it can be theorized that N,N -dimethylpentylone may predominate the US synthetic stimulant market for the next 1–2 years; however, given the emergence of additional closely related isomeric compounds, it is important to utilize methodology capable of differentiating N,N -dimethylpentylone from its isomers (N -isopropylbutylone, N -ethyl pentylone, N -ethyl N -methyl butylone, hexylone, N -propylbutylone, diethylone and tertylone). [ABSTRACT FROM AUTHOR]

Illicit opioids, consisting largely of fentanyl, novel synthetic opioids, and adulterants, are the primary cause of drug overdose fatality in the United States. Xylazine, an alpha-2 adrenergic agonist and veterinary tranquilizer, is being increasingly detected among decedents following illicit opioid overdose. Clinical outcomes in non-fatal overdose involving xylazine are unexplored. Therefore, among emergency department patients with illicit opioid overdose, we evaluated clinical outcome differences for patients with and without xylazine exposures. This multicenter, prospective cohort study enrolled adult patients with opioid overdose who presented to one of nine United States emergency departments between 21 September 2020, and 17 August 2021. Patients with opioid overdose were screened and included if they tested positive for an illicit opioid (heroin, fentanyl, fentanyl analog, or novel synthetic opioid) or xylazine. Patient serum was analyzed via liquid chromatography quadrupole time-of-flight mass spectroscopy to detect current illicit opioids, novel synthetic opioids, xylazine and adulterants. Overdose severity surrogate outcomes were: (a) cardiac arrest requiring cardiopulmonary resuscitation (primary); and (b) coma within 4 h of arrival (secondary). Three hundred and twenty-one patients met inclusion criteria: 90 tested positive for xylazine and 231 were negative. The primary outcome occurred in 37 patients, and the secondary outcome occurred in 111 patients. Using multivariable regression analysis, patients positive for xylazine had significantly lower adjusted odds of cardiac arrest (adjusted OR 0.30, 95% CI 0.10–0.92) and coma (adjusted OR 0.52, 95% CI 0.29–0.94). In this large multicenter cohort, cardiac arrest and coma in emergency department patients with illicit opioid overdose were significantly less severe in those testing positive for xylazine. [ABSTRACT FROM AUTHOR]

Xylazine, an alpha-2 receptor agonist used in veterinary medicine for its sedative and muscle-relaxant effects, has been reported in forensic toxicology casework since the 1980s. It is not approved for human use, but it is used as an adulterant in heroin and illicit fentanyl. The prevalence and concentrations of xylazine in 2.5 years (January 2019–June 2021) of driving under the influence of drugs (DUID) and medico-legal death investigation (MDI) cases was investigated, including other drugs detected in combination with xylazine. Of over 170,000 cases screened for xylazine, 97% were classified as MDI. Over the course of the study period, the prevalence and geographical spread of xylazine increased. Overall, 2.8% of DUID and 2.1% of MDI cases screened positive for xylazine with concentrations of 5.1–450 ng/mL (mean = 36 ng/mL) and 5.0–11,000 ng/mL (mean = 41 ng/mL), respectively. Two MDI cases which had xylazine concentrations of 9,100 and 11,000 ng/mL were drug overdose suicides that did not involve any opioids. Opioids, primarily fentanyl and/or a fentanyl byproduct/metabolite were detected in 100% of DUID and all but two MDI cases. After opioids, stimulants, phyto-cannabinoids and benzodiazepines were the most common drug classes detected in conjunction with xylazine in both DUID and MDI casework. In summary, xylazine exposure continues to increase, mostly through the adulteration of illicit opioids. There is an extensive overlap in the concentrations between living and deceased individuals, making it difficult to interpret the role of the drug in MDI or DUID cases without other case information. [ABSTRACT FROM AUTHOR]

An important role of modern forensic and clinical toxicologists is to monitor the adverse events of novel psychoactive substances (NPS). Following a prior review from 2013 to 2016, this critical literature review analyzes and evaluates published case reports for NPS from January 2017 through December 2020. The primary objective of this study is to assist in the assessment and interpretation of these cases as well as provide references for confirmation methods. Chemistry, pharmacology, adverse events and user profiles (e.g. polypharmacy) for NPS are provided including case history, clinical symptoms, autopsy findings and analytical results. Literature reviews were performed in PubMed and Google Scholar for publications using search terms such as NPS specific names, general terms (e.g. 'designer drugs' and 'novel psychoactive substances'), drug classes (e.g. 'designer stimulants') and outcome-based terms (e.g. 'overdose' and 'death'). Government and website drug surveillance databases and abstracts published by professional forensic science organizations were also searched. Toxicological data and detailed case information were extracted, tabulated, analyzed and organized by drug category. Case reports included overdose fatalities (378 cases), clinical treatment and hospitalization (771 cases) and driving under the influence of drugs (170 cases) for a total of 1,319 cases providing details of adverse events associated with NPS. Confirmed adverse events with associated toxidromes of more than 60 NPS were reported including synthetic cannabinoid, NPS stimulant, NPS hallucinogen, NPS benzodiazepine and NPS opioid cases. Fifty of these NPS were reported for the first time in January 2017 through December 2020 as compared to the previous 4 years surveyed. This study provides insight and context of case findings described in the literature and in digital government surveillance databases and websites during a recent 4-year period. This review will increase the awareness of adverse events associated with NPS use to better characterize international emerging drug threats. [ABSTRACT FROM AUTHOR]

Toxic adulterants are drug or chemical agents used to add bulk volume to traditional drugs of abuse such as cocaine and heroin. These cutting agents include levamisole, metamizole, noxiptillin, phenacetin and xylazine as well as common legal drugs such as acetaminophen, caffeine, diphenhydramine, lidocaine, quinine, quetiapine and tramadol. Because they possess pharmacological activity they result in exposure of the user, but also in the case of pregnant women, the developing fetus, to potential drug toxicity. We describe the development, validation and implementation of a rapid (48 second sample-to-sample) test based on a qualitative data-dependent liquid chromatography–quadrupole time of flight mass spectrometry method for the analysis of toxic adulterating substances in umbilical cord tissue (UCT) samples. The method provides a means of studying potential in utero exposure to these agents. Library spectra comparison at three different collision energies was used in conjunction with retention time and accurate mass to identify these substances in UCT. Analytically based reporting limits were established to determine positivity rates of adulterants in UCT utilizing a standard addition approach. The method was applied to authentic cocaine and opioid positive UCT to screen for toxic adulterants. There were a total of 82 potential adulterant positives found in a 30-sample cohort of authentic UCT samples, with an average of 2.7 substances per case. Lidocaine was the predominant finding followed by caffeine, and diphenhydramine all of which could result from non-illicit drug exposure, however, there were positives for levamisole, phenacetin, noxiptillin and xylazine none of which are approved in the United States for human therapeutic use. This initial set of data established a preliminary positivity rate of potentially toxic adulterants in UCT samples positive for cocaine or opioid use. [ABSTRACT FROM AUTHOR]

The opioid epidemic in the USA has been associated with an increasing mortality rate in large part due to the emergence and proliferation of synthetic opioids over the last 15 years. Fentanyl and its analogs have played a large part in these statistics due to their potency and toxicity. Fluorofuranylfentanyl (FFF) is a fentanyl analog that emerged in the USA in 2018 and was associated with numerous adverse events and deaths. During this study, a liquid chromatography tandem mass spectrometry workflow was developed to accurately identify the isomer of FFF present (ortho- vs. meta- vs. para-) in medicolegal death investigation cases from Pinellas County, Florida. FFF was quantified in central and peripheral blood samples collected at autopsy. In addition, the metabolism of FFF was studied using liquid chromatography quadrupole time-of-flight mass spectrometry. para- FFF was quantitatively confirmed in 29 postmortem cases; no other isomer of FFF was detected. Central blood concentrations ranged between 0.66 and 73 ng/mL (mean = 11 ± 14 ng/mL, median = 10 ng/mL) and peripheral blood concentrations ranged between 0.53 and 23 ng/mL (mean = 5.7 ± 6.4 ng/mL, median = 2.7 ng/mL). A comparison of central to peripheral blood concentrations was evaluated to determine the possibility of postmortem redistribution. The metabolism of ortho- FFF was studied and found to undergo metabolic processes similar to fentanyl, producing ortho- fluorofuranyl-norfentanyl, fluoro-4-anilino- N -phenethylpiperidine, and hydroxylated species. The results of this study demonstrate the toxicity of FFF and its implication in medicolegal death investigations. Laboratories must remain aware of new or re-emerging fentanyl analogs, as they pose significant risks to public health and public safety. [ABSTRACT FROM AUTHOR]

Novel psychoactive substances (NPS) continue to represent a threat to public health and safety. The number of new drugs in the latest emergent synthetic opioid class—the 2-benzylbenzimidazole analogs—also called the nitazenes—has begun to dominate the current new synthetic opioid (NSO) subclass of NPS. We describe a liquid chromatography–tandem quadrupole mass spectrometry method for the quantification of nine analogs and/or metabolites of drugs in this series: isotonitazene, metonitazene, protonitazene, etonitazene, clonitazene, flunitazene, N -desethyl isotonitazene, 5-amino isotonitazene and 4ʹ-hydroxy nitazene in human whole blood, urine, and tissue. Samples were prepared for analysis using a basic liquid–liquid extraction. Chromatographic separation was achieved using a C-18 analytical column. Multiple reaction monitoring mode was used for detection. The calibration range for the analytes was 0.5–50 ng/mL (except for 5-amino isotonitazene, which was 1.0–50 ng/mL). The limit of detection was 0.1 ng/mL, and the limit of quantitation was 0.5 ng/mL. The method had no carryover or interferences. Ionization enhancement was observed but did not affect quantitation. All analytes passed the method validation assessment. Authentic human samples suspected of containing NSOs were obtained from a medical examiner and coroner offices, as well as partnering forensic toxicology laboratories. Isotonitazene was confirmed in 92 blood samples, and its metabolites were confirmed across various matrices. Metonitazene (n  = 35), flunitazene (n  = 5), protonitazene (n  = 3), etodesnitazene (n  = 2) and butonitazene (n  = 1) were also detected in cases. These newly emerging 2-benzylbenzimidazole analogs were commonly found in combination with NPS benzodiazepines and opioids (e.g. flualprazolam, fentanyl). Nitazene analogs are potent esoteric drugs that may not be identified during routine toxicological screening, and specialized assays based on sensitive instrumentation are needed to accurately characterize these NSOs. [ABSTRACT FROM AUTHOR]

Synthetic opioids constitute one of the fastest-growing groups of new psychoactive substances (NPS) worldwide. With fentanyl analogues being increasingly controlled via classwide scheduling, many non-fentanyl-related opioids are now emerging on the recreational opioid market, rendering the landscape highly complex and dynamic. While new compounds are entering the supply in rapid and unpredictable manners, some recent patterns have become apparent. Many of these newly emerging opioids are being pirated from early patent literature and/or research papers, synthesized and sold online through various channels. Burdened by the identification of every newly emerging drug, many toxicology labs struggle to keep up. Moreover, by the time a 'new' drug is controlled via legislative measures, illicit drug markets will have already adapted and diversified as manufacturers work to avoid the restricted product(s). Hence, the typical life cycle of an NPS opioid is generally short (less than 6 months to 1 year), with only a few drugs escalating to significant numbers of detections. In this review, we summarize the key events in the emergence, rise and subsequent decline of two non-fentanyl opioids—isotonitazene and brorphine. These two opioids sequentially dominated the NPS opioid market in 2019 and 2020. Both isotonitazene and brorphine remained in circulation for over a year, each contributing to hundreds of deaths and adverse events. By detailing the life cycles of these opioids from their earliest synthesis as described in scientific literature to their subsequent rise and fall on recreational markets, this review illustrates the new characteristic life cycle of synthetic opioids in the 'post-fentanyl-analogue' era. [ABSTRACT FROM AUTHOR]

In the past 3 years, widespread interest in cannabinoid products containing delta-8 tetrahydrocannabinol (delta-8 THC) has increased ([1]), as have debates about its legal status ([[2], [4]]) in the USA. Of 118 randomly selected cases in which delta-8 THC was identified, the mean delta-8 THC and delta-9 THC concentrations are shown in Table I. A distribution of calculated delta-8 THC concentrations is depicted in Figure 1, and the distribution of the delta-8 THC to delta-9 THC ratio is shown in Figure 2. There were six delta-8 THC positive cases in which no delta-9 THC was present, with delta-8 THC concentrations ranging from 1.7 to 6.2 ng/mL. [Extracted from the article]

Non-pharmaceutical fentanyl and its analogs have driven striking increases in opioid-associated overdose deaths. These highly potent opioids can be found at low concentrations in biological specimens. Little is known regarding the concentrations of these substances among survivors of non-fatal overdoses. In a locale where fentanyl is responsible for the majority of non-fatal opioid overdoses, we compared the concentration of fentanyl in blood to naloxone dosing in the presence and absence of a concurrent sedative-hypnotic exposure. In this pilot study, we enrolled adult patients presenting to the emergency department (ED) who: (1) arrived after an overdose requiring naloxone for the reversal of respiratory depression; and (2) who required venipuncture or intravenous access as part of their clinical care. Blood specimens (n = 20) underwent comprehensive toxicology testing, including the quantitation of fentanyl, fentanyl analogs, and naloxone, as well as the detection of common sedative-hypnotics and a wide range of other illicit and pharmaceutical substances. We then compared fentanyl concentrations to naloxone dosing in participants with and without a concomitant sedative-hypnotic exposure. Nineteen of twenty participants (95%) were exposed to fentanyl prior to their overdose; the remaining participant tested positive for heroin metabolites. No participants reported pharmaceutical fentanyl use. Fentanyl analogs – acetylfentanyl or carfentanil – were present in three specimens. In 11 cases, fentanyl and its metabolites were the only opioids identified. Among the fentanyl-exposed, blood concentrations ranged from <0.1–19 ng/mL with a mean of 6.2 ng/mL and a median of 3.6 ng/mL. There was no relationship between fentanyl concentration and naloxone dose administered for reversal. We detected sedative-hypnotics (including benzodiazepines, muscle relaxants, and antidepressants) in nine participants. Among the sedative-hypnotic exposed, fentanyl concentrations were lower, but naloxone dosing was similar to those without a concomitant exposure. In this study, we found that: 1) fentanyl was present in the blood of nearly all participants; 2) fentanyl concentrations were lower among study participants with concomitant sedative-hypnotic exposure; and 3) the dose of naloxone administered for overdose reversal was not associated with the measured fentanyl concentration in blood specimens. Our results underscore the role that tolerance and concomitant drug exposure play in the precipitation and resuscitation of management of opioid overdose. [ABSTRACT FROM AUTHOR]

We report a method for the detection and quantitation of 12 drugs and 2 metabolites in the same structural class as the illicit mu-opioid agonist U-47700 in human whole blood. These substances are either known or suspected to be present as potential novel opioids in illicit drug markets. The general class of these drugs was developed in pharmaceutical research programs in the 1970s, but these drugs have recently become of concern for overdoses and death in opioid users in the USA and internationally. The scope of analysis included the following compounds: methylenedioxy U-47700, ethylenedioxy U-47700, ethylenedioxy U-51754, U-69593, U-47931E (bromadoline), U-47700, U-48800, U-49900, U-51754, U-50488, propyl U-47700 and isopropyl U-47700. Additionally, two metabolites N,N -didesmethyl U-47700 and desmethyl U-47700 were also included in the scope. Drugs were extracted from human whole blood using solid-phase extraction, and the extracts were analyzed by liquid chromatography--tandem mass spectrometry. The assay was validated with respect to bias, carryover, interference, within-run and between-run precision, and accuracy. Eight medicolegal death investigation cases that had screened positive for U-48800 by liquid chromatography--time-of-flight mass spectrometry were successfully confirmed and quantified using this method. The mean and median concentrations of U-48800 in these cases were 2.5 (±2.1) and 1.8 ng/mL, respectively, with a range of concentrations of 0.27–6.2 ng/mL. Case history information including the presence of other drugs in combination are described and discussed. [ABSTRACT FROM AUTHOR]

Metonitazene is considered a new psychoactive substance (NPS) and emerging potent synthetic opioid, causing increased public health concern beginning in 2020. Metonitazene joins a growing list of new synthetic opioids (NSOs) contributing to deaths among people who use drugs in the United States and other parts of the world. Metonitazene (a 2‐benzylbenzimidazole analogue) first appeared in mid‐2020 in the recreational drug supply and subsequently began proliferating in death investigation casework towards the end of 2020. Screening and metabolite discovery were performed by liquid chromatography quadrupole time‐of‐flight mass spectrometry. Quantitative confirmation was performed by liquid chromatography tandem quadrupole mass spectrometry. Metonitazene was confirmed in 20 authentic forensic postmortem cases with an average concentration in blood at 6.3 ± 7.5 ng/ml (median: 3.8 ng/ml, range: 0.5–33 ng/ml, n = 18) and in urine at 15 ± 13 ng/ml (median: 11 ng/ml, range: 0.6–46 ng/ml, n = 14). Metonitazene was the only opioid identified in 30% of cases but was also found in combination with fentanyl (55%) and NPS benzodiazepines, opioids, and hallucinogens (45%). Medical examiners included metonitazene as a drug responsible for the cause of death, and the manner of death was always ruled to be an accident. The metabolism of metonitazene was found to be similar to that of isotonitazene, a closely related analogue. Toxicology laboratories and death investigators should ensure that metonitazene is included in forensic testing protocols, all while remaining vigilant for subsequent NSOs to emerge. [ABSTRACT FROM AUTHOR]

This report describes updates to the National Safety Council's Alcohol, Drugs and Impairment Division's recommendations for drug testing in driving under the influence of drug (DUID) cases and motor vehicle fatalities. The updates are based on a survey of drug testing practices in laboratories in the USA and Canada, a comprehensive review of the prior recommendations and data and research on drugs most frequently detected in DUID cases. A consensus meeting was held with representative forensic science practitioners and the authors of this report to update recommendations. No changes were made to the Tier I scope; however, there were changes to cutoffs of some analytes for blood, urine and oral fluid. Due to increased prevalence in DUID cases, trazodone and difluoroethane were added to the Tier II scope. For clarification, Tier I cutoffs reflect free concentrations, and hydrolysis is recommended but not required. The consensus panel concluded that urine is an inferior matrix to blood and oral fluid as it may represent historical use or exposure unrelated to observed impairment; therefore, future iterations of these recommendations will not include urine as a recommended matrix. Laboratories currently testing urine should work with traffic safety partners to encourage the use of blood and oral fluid as more appropriate specimens and adjust their capabilities to provide that testing. [ABSTRACT FROM AUTHOR]

Novel illicit benzodiazepines are among the most active areas of new illicit drug manufacture and use. We describe a method for the detection and quantification of etizolam and its metabolite α-hydroxyetizolam, flubromazolam, clonazolam, diclazepam, delorazepam, bromazepam, flubromazepam, phenazepam, flualprazolam, flunitrazolam, and nitrazolam in human whole blood. After addition of internal standards, samples are buffered and extracted using a liquid–liquid extraction. Analysis is performed using positive-ion electrospray tandem mass spectrometry for detection and quantitation. Calibration ranges were established based on the method performance and differed from compound to compound. Replicates at the lowest calibration point for each compound performed within 5% of CV (Coefficient of Variation). The correlation coefficient was >0.990 for all compounds. Relative standard deviation for all compounds was ≤10% of CV and accuracy was  ±10% for both within- and between-run experiments. The maximum average intra- and inter-run imprecision were 5.7%. The maximum average intra- and inter-run imprecision was −8.7%. As part of evaluating the scope for relevancy, samples testing positive in immunoassay but confirmed to be negative in traditional benzodiazepine confirmation method were re-analyzed using this method. The presence of at least one novel benzodiazepine was identified in 70% of these samples. The appearance of these novel "designer" benzodiazepines demonstrates the challenge for toxicology testing and the need for continually updated confirmation methods. [ABSTRACT FROM AUTHOR]