Involuntary 5F-ADB-related intoxication following e-cigarette use.

The detection of synthetic cannabinoid (SC) intoxication cases is challenging, even more when the involved SC identification is requested in a forensic context. This situation can be complicated by new modes of SC consumption, non-specific symptomatology, and analytical pitfalls. To illustrate these issues, we report the case of a 16-year-old man who presented symptoms evocating of a seizure disorder in the minutes following the use of a friend's e-cigarette. At admission in the emergency department, his electroencephalogram was interpreted as coherent with a recent seizure episode. 5F-ADB, a third generation SC, was detected in the e-liquid and in an early collected (H2 after the e-cigarette use) serum sample (0.50 µg/L), but not in urine samples (H18 and H38). One 5F-ADB metabolite, O-desmethyl-5F-ADB (M5), was detectable in urine up to at least 38 h after intoxication. Neither 5F-ADB nor its metabolites could be detected in victim's hair sampled 3 months after the intoxication. Although leading to a non-specific symptomatology, acute SC intoxication should be considered when the case history is related to e-cigarette or e-liquid use. Early biological samples are recommended, even if analytical screening can be positive for SC metabolites in urine sampled until 2 days after exposure. Accordingly, data from the literature and the present case underscore the relevance of adding both main 5F-ADB metabolites (M5 and 5-OH-pentyl-ADB) to mass spectrum databases used for toxicological screening in order to reduce the risk of false-negative results in intoxication cases involving 5F-ADB.

Trends and Geographic Patterns in Drug and Synthetic Opioid Overdose Deaths - United States, 2013-2019.

Deaths involving synthetic opioids other than methadone (synthetic opioids), which largely consist of illicitly manufactured fentanyl; psychostimulants with abuse potential (e.g., methamphetamine); and cocaine have increased in recent years, particularly since 2013 (1,2). In 2019, a total of 70,630 drug overdose deaths occurred, corresponding to an age-adjusted rate of 21.6 per 100,000 population and a 4.3% increase from the 2018 rate (20.7) (3). CDC analyzed trends in age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, heroin, and prescription opioids during 2013-2019, as well as geographic patterns in synthetic opioid- and psychostimulant-involved deaths during 2018-2019. From 2013 to 2019, the synthetic opioid-involved death rate increased 1,040%, from 1.0 to 11.4 per 100,000 age-adjusted (3,105 to 36,359). The psychostimulant-involved death rate increased 317%, from 1.2 (3,627) in 2013 to 5.0 (16,167) in 2019. In the presence of synthetic opioid coinvolvement, death rates for prescription opioids, heroin, psychostimulants, and cocaine increased. In the absence of synthetic opioid coinvolvement, death rates increased only for psychostimulants and cocaine. From 2018 to 2019, the largest relative increase in the synthetic opioid-involved death rate occurred in the West (67.9%), and the largest relative increase in the psychostimulant-involved death rate occurred in the Northeast (43.8%); these increases represent important changes in the geographic distribution of drug overdose deaths. Evidence-based prevention and response strategies including substance use disorder treatment and overdose prevention and response efforts focused on polysubstance use must be adapted to address the evolving drug overdose epidemic.

Correlations between opioid mortality increases related to illicit/synthetic opioids and reductions of medical opioid dispensing - exploratory analyses from Canada.

BACKGROUND: North America has been experiencing a persistent epidemic of opioid-related overdose mortality, which has increasingly been driven by fatalities from illicit, toxic opioids in most recent years. Patterns of synthetic opioid availability and related mortality are heterogeneous across Canada, and differing explanations exist as to their differentiated proliferation. We examined the perspective that heterogeneous province-based variations in prescription opioid availability, facilitated by various control strategies, post-2010 may have created regionally differential supply gaps for non-medical opioid use substituted by synthetic opioid products with differential impacts on mortality risks and outcomes in Canada. METHODS: We examined annual, prescription opioid dispensing rates and changes in the ten Canadian provinces (for the periods of 1) 2011-2018, 2) 'peak-year'-to-2018) in Defined Daily Doses/1000 population/day, derived from data from a large representative, stratified sample of community pharmacies projected to a Canada total. Annual, provincial opioid-related mortality rates and changes for years 2016-2018 were calculated from federal data. We computed correlation values (Pearson's R) between respective province-based change rates for prescription opioid dispensing and opioid-related mortality for the two over-time scenarios. RESULTS: All but one province featured reductions in prescription opioid dispensing 2011-2018; seven of the ten provinces had increases in opioid mortality 2016-2018. The correlation between changes in opioid dispensing (2011-2018) and in opioid-mortality (2016-2018) was r = 0.63 (df = 8, p-value: 0.05); the correlation was r = 0.57 (df = 8, p-value: 0.09) for changes in opioid dispensing 'peak year'-to-2018, respectively. CONCLUSIONS: Quasi-significant results indicate that recent increases in opioid-related deaths driven by illicit, synthetic opioids tended to be larger in provinces where reductions in prescription opioid availability have been more extensive. It is a plausible explanation that these reductions created supply gaps for non-medical opioid use increasingly filled by illicit, synthetic opioids differentially contributing to opioid-related deaths, generating un-intended adverse effects for previous interventions. General prevention measures to reduce opioid availability, and targeted prevention for at-risk opioid users exposed to toxic drug supply may be include counteractive effects and require coordinated reconciliation.

Case Report: Synthetic Cannabinoid Deaths in State of Florida Prisoners.

Between March 2017 and November 2018, 54 prisoner fatal overdose cases submitted to the University of Florida Forensic Toxicology Laboratory involved synthetic cannabinoids including 5F-ADB, FUB-AMB, 5F-AMB, MDMB-FUBINACA and AB-CHMINACA. Analysis of blood and urine samples was performed at NMS Labs (Horsham, PA) by liquid chromatography/tandem mass spectrometry screening, confirmatory and quantitative methods validated according to Scientific Working Group for Forensic Toxicology guidelines. This work highlights the importance of effective communication between toxicologists and medical examiners/coroners, and the value of public-private partnerships to provide coverage while laboratories work to update instrumentation and validate their own new methods to keep up with the challenges of emerging substances.

Regional trends in suspected synthetic cannabinoid exposure from January 2016 to September 2019 in the United States.

BACKGROUND: The unpredictable physiologic and pharmacologic effects of synthetic cannabinoids (SCs) are continuously changing as the chemical structure of SCs evolve to avoid classification as a Schedule I drug under the Controlled Substances Act in the U.S. This results in unpredictable pharmacologic effects and subsequent sequelae. Little is known about national or regional trends of SC clusters. The objective of this study is to investigate trends in SC exposure using emergency department (ED) syndromic data. METHODS: We analyzed ED syndromic data to detect quarterly trends from January 2016 through September 2019 for SC-related exposures within 59 jurisdictions in 47 states by U.S. region. Pearson chi-square tests detected quarter-to-quarter changes and Joinpoint regression assessed trends over time. RESULTS: From January 2016 to September 2019, 21,714 of 303.5 million ED visits involved suspected SC exposures. Nationally, SC-related exposures decreased by 1.9 % (p = .04) on average per quarter, yet exposures increased in the Midwest by 6.3 % (p = .002) and in the Northeast by 3.2 % (p = .03) on average per quarter, and decreased on average per quarter by 7.7% (p ≤ .001) in the Southeast and 11.4 % in the West (p ≤ .001). Known SC exposures that may align with clusters were identified in quarter-to-quarter monitoring. CONCLUSIONS: Only a small proportion of ED visits were related to suspected SC exposure. Although we did identify a small decrease in national SC exposures, there was wide variation by region. Additional efforts are needed to understand variation and to develop prevention and response strategies.

Racial/Ethnic and Age Group Differences in Opioid and Synthetic Opioid-Involved Overdose Deaths Among Adults Aged ≥18 Years in Metropolitan Areas - United States, 2015-2017.

Among the 47,600 opioid-involved overdose deaths in the United States in 2017, 59.8% (28,466) involved synthetic opioids (1). Since 2013, synthetic opioids, particularly illicitly manufactured fentanyl (IMF), including fentanyl analogs, have been fueling the U.S. overdose epidemic (1,2). Although initially mixed with heroin, IMF is increasingly being found in supplies of cocaine, methamphetamine, and counterfeit prescription pills, which increases the number of populations at risk for an opioid-involved overdose (3,4). With the proliferation of IMF, opioid-involved overdose deaths have increased among minority populations including non-Hispanic blacks (blacks) and Hispanics, groups that have historically had low opioid-involved overdose death rates (5). In addition, metropolitan areas have experienced sharp increases in drug and opioid-involved overdose deaths since 2013 (6,7). This study analyzed changes in overdose death rates involving any opioid and synthetic opioids among persons aged ≥18 years during 2015-2017, by age and race/ethnicity across metropolitan areas. Nearly all racial/ethnic groups and age groups experienced increases in opioid-involved and synthetic opioid-involved overdose death rates, particularly blacks aged 45-54 years (from 19.3 to 41.9 per 100,000) and 55-64 years (from 21.8 to 42.7) in large central metro areas and non-Hispanic whites (whites) aged 25-34 years (from 36.9 to 58.3) in large fringe metro areas. Comprehensive and culturally tailored interventions are needed to address the rise in drug overdose deaths in all populations, including prevention strategies that address the risk factors for substance use across each racial/ethnic group, public health messaging to increase awareness about synthetic opioids in the drug supply, expansion of naloxone distribution for overdose reversal, and increased access to medication-assisted treatment.

Detection and quantification of 5F-ADB and its methyl ester hydrolysis metabolite in fatal intoxication cases by liquid chromatography-high resolution mass spectrometry.

5F-ADB (methyl 2-{[1-(5-fluoropentyl)-1H-indazole-3-carbonyl]amino}-3,3-dimethylbutanoate) is a frequently abused new synthetic cannabinoid that has been sold since at least the end of 2014 on the drug market. It has been classified as an illicit drug in most European countries, and also in Turkey, Japan, and the United States. In this study, 5F-ADB and its methyl ester metabolite were determined in the blood and urine samples taken from fatal cases using liquid chromatography-highresolution mass spectrometry (LC-HRMS). The extraction of samples was performed using a solid-phase extraction method, followed by LC-HRMS analysis. The method was fully validated for linearities, limits of detection (LODs), limits of quantification (LOQs), recoveries, matrix effects, process efficiencies, accuracies, precisions, and stabilities and was applied to 70 blood and 36 urine samples from fatal cases where 5F-ADB was the only drug detected. The LODs were between 0.08 and 0.10ng/mL, and LOQs were between 0.10 and 0.12ng/mL for both blood and urine samples. 5F-ADB and its methyl ester hydrolysis metabolite were found at the blood concentrations ranging from 0.10 to 1.55ng/mL (mean=0.40ng/mL) and 0.15 to 23.4ng/mL (mean=2.69ng/mL), respectively. 5F-ADB was not detected in any urine samples. 5F-ADBmethyl ester hydrolysis metabolite was detected in 35 urine samples with a detection range of 0.28-72.2ng/mL and a mean of 9.02ng/mL. The synthetic cannabinoid 5F-ADB and its methyl ester metabolite were identified and quantified in authentic human blood and/or urine specimens obtained from 70 fatal cases. The method was successfully applied to postmortem blood and urine samples.

The novel psychoactive substance 3-methylmethcathinone (3-MMC or metaphedrone): A review.

3-Methylmethcathinone (3-MMC or metaphedrone) is a synthetic cathinone, recently introduced in the market of the new psychoactive substances (NPS), initially to replace mephedrone (4-methylmethcathinone or 4-MMC), and rapidly widespread among drug users. 3-Methylmethcathinone is legally controlled in many countries, but is still easily available for purchase from websites, and frequently found in recreational settings. Most toxicological data on this drug come from human case reports of intoxications. Thus, further investigation on their pharmacological and toxicological properties is necessary to evaluate its potential harmful effects. The present work provides a review on the available data about 3-MMC legal status, chemistry, patterns of use, prevalence, biological effects, toxicokinetics, toxicity and factors affecting stimulant/toxicological effects.

Evolution of clinical characteristics and outcomes of synthetic cannabinoid receptor agonist exposure in the United States: analysis of National Poison Data System data from 2010 to 2015.

BACKGROUND AND AIMS: New synthetic cannabinoid receptor agonists (SCRAs) are synthesized each year to evade US governmental regulation and sold for recreational use. Our aim was to estimate the changes in the clinical effects and patient disposition associated with SCRA exposure from 2010 to 2015. DESIGN: A retrospective observational cohort study. SETTING: National Poison Data System that collects data on reports of poisonings from US poison centers. PARTICIPANTS: A total of 19 388 isolated SCRA cases between 1 January 2010 and 31 December 2015 were identified. The mean age was 24.6 years and 77.8% were male. MEASUREMENTS: Primary outcome was the change in the trend of patient disposition, i.e. treated and released versus hospitalization (e.g. non-critical care, critical care unit or psychiatry) between 2010 and 2015. Secondary outcomes included the trends in the clinical effects and their duration, and therapeutic interventions nationally and regionally. FINDINGS: Reports of SCRA exposure peaked in 2011 (n = 5305) and 2015 (n = 5475). The majority of patients required supportive care and were treated and released from an emergency department. Hospitalization increased by annual percentage change in the log odds (APCO) of 21.0% (P < 0.0001) during the 6 years, with significant increases in admissions to critical care units and non-critical care units. Overall, tachycardia (32.1%), agitation/irritation (25.6%) and drowsiness/lethargy (20.4%) were the most frequently reported clinical effects from SCRA exposure. Clinical effects resolved within 2-8 hours in 52.8% of cases, but their duration increased markedly by 2015. Regionally, the largest number of SCRA cases was reported in the South (n = 9374, 48.6%). SCRA cases in the Northeast were hospitalized more frequently (27.4%), with cases in the Midwest being admitted more frequently to critical care units (15.3%). However, there were no significant differences in clinical toxicity or disposition among the regions. CONCLUSION: Hospitalization resulting from toxicity from synthetic cannabinoid receptor agonists exposure in the United States increased significantly between 2010 and 2015.

Synthetic drug intoxication in children: recognition and management in the emergency department.

When children and adolescents present to the emergency department with agitation or mental status changes, intoxication from synthetic drug use should be in the differential diagnosis. Identifying the responsible compound(s) may be difficult, so asking the patient broad questions and utilizing appropriate diagnostic studies, when indicated, will aid in making the diagnosis and help identify more-serious complications. This issue discusses the challenges presented by the changing chemical formulations of synthetic cannabinoids, cathinones, and phenethylamines; outlines common presentations of intoxication from these substances; and summarizes best practices for evaluating and managing patients who present with intoxication after consumption of these synthetic drugs of abuse.

Corrected US opioid-involved drug poisoning deaths and mortality rates, 1999-2015.

BACKGROUND AND AIMS: Most prior estimates of opioid-involved drug poisoning mortality counts or rates are understated because the specific drugs leading to death are frequently not identified on death certificates. This analysis provides corrected national estimates of opioid and heroin/synthetic opioid-involved counts and mortality rates, as well as changes over time in them from 1999 to 2015. METHODS: Data on drug poisoning deaths to US residents from 1999 to 2015, obtained from the Centers for Disease Control and Prevention (CDC) Multiple Cause of Death (MCOD) files, were used with the drugs involved in fatal overdoses imputed when not identified on the death certificates. RESULTS: The official CDC figure that 33 091 drug deaths involved opioids in 2015 is an undercount, with the actual number being approximately 39 999. Corrected counts and rates of any opioid and heroin/synthetic opioid-involved drug deaths are 20-35% higher in every year than reported figures. The corrections almost always raise the changes estimated to have occurred since 1999, with the largest differences observed in 2011 for any opioids (5677 deaths and 1.7 per 100 000) and in 2015 for heroin/synthetic opioids (3228 deaths and 1.0 per 100 000). However, percentage growth since 1999 is sometimes slower when based on corrected rather than reported fatality data, and with sensitivity to the choice of base years. CONCLUSIONS: Death certificate reports understate the prevalence of and changes over time in opioid and heroin/synthetic opioid-involved drug mortality in the United States. Adjustments imputing the drugs involved for cases where none are identified on the death certificates are likely to provide more accurate estimates.