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: Report of an Outbreak of a New Psychoactive Substance in Adolescents Adam Blumenberg, MD, MA,a Adrienne Hughes, MD,a Andrew Reckers, BA,b Ross Ellison, BS,b Roy Gerona, PhDb

Flualprazolam is a nonregistered drug in the family and abstract constitutes a new psychoactive substance (NPS). Since 2014, a growing number of designer have become available over the Internet and on the counterfeit drug market. In June 2019, a cluster of patients intoxicated with flualprazolam was identified by the Oregon Poison Center. As an emerging drug of abuse, the clinical characteristics of flualprazolam have been poorly characterized thus far. Over a one-week period, 6 teenagers aDepartment of Emergency Medicine, School of Medicine, Oregon Health and Science University, Portland, Oregon; and presented to local emergency departments after ingesting illegally obtained bClinical Toxicology and Environmental Biomonitoring counterfeit , which led to sedation. Other symptoms included Laboratory, University of California, San Francisco, San slurred speech, confusion, and mild respiratory depression. All 6 patients Francisco, California had resolution of their symptoms within 6 hours of ingestion. Blood and Dr Blumenberg conceptualized, researched, wrote, urine samples, as well as a tablet fragment, were obtained from 3 and edited the manuscript; Dr Hughes helped conceptualize and wrote sections of the manuscript; patients. The tablet and biological samples were analyzed by using liquid Mr Ellison and Mr Reckers analyzed and interpreted chromatography–quadrupole time-of-flight mass spectrometry and were analytes, wrote sections of the manuscript, and found to contain the NPS flualprazolam without other drugs or intoxicants. helped edit the manuscript; Dr Gerona analyzed and interpreted analytes, wrote sections of the With this case series, we add to the medical literature a clinical description manuscript, researched, and helped edit the of an emerging drug of abuse. Flualprazolam appears to share the clinical manuscript; and all authors approved the final properties of other benzodiazepines. As flualprazolam and other NPSs manuscript as submitted and agree to be accountable for all aspects of the work. become more common, physicians must be aware of their availability and DOI: characteristics. Sedation lasting ,6 hours was observed in 6 of 6 patients https://doi.org/10.1542/peds.2019-2953 exposed to flualprazolam. No effects that would be unexpected from Accepted for publication Dec 30, 2019 benzodiazepine intoxication were seen among the patients. Specifically, none Address correspondence to Adam Blumenberg, MD, MA, Emergency Medicine and Toxicology, Oregon developed prolonged symptoms or required intubation and mechanical Health and Science University, 3181 SW Sam Jackson ventilation, ICU admission, or antidotal therapy. Park Rd, Portland, OR. E-mail: adamblumenbergmd@ gmail.com PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). In June 2019, the Oregon Poison The benzodiazepine class of drugs bind Copyright © 2020 by the American Academy of Center identified an outbreak of to g-aminobutyric acid A (GABA-A) Pediatrics central nervous system (CNS) receptors, leading to CNS depression. FINANCIAL DISCLOSURE: The authors have indicated depression among adolescents. Unlike , which stimulate they have no financial relationships relevant to this The patients developed symptoms the GABA-A receptor directly, article to disclose. at school and required evaluation benzodiazepines enhance the effect of FUNDING: No external funding. and treatment at local emergency GABA on its receptor through allosteric POTENTIAL CONFLICT OF INTEREST: The authors have departments. Further assessment modulation. This leads to enhanced indicated they have no potential conflicts of interest revealed intoxication with chloride permeability in the to disclose. a new psychoactive substance postsynaptic neuron, subsequent (NPS) colloquially referred to hyperpolarization, and diminished To cite: Blumenberg A, Hughes A, Reckers A, as “Hulk,” which on analysis, was probability of generating an action et al. Flualprazolam: Report of an Outbreak of revealed to be the benzodiazepine potential.1 Whereas overdose of opioids a New Psychoactive Substance in Adolescents. Pediatrics. 2019;146(1):e20192953 flualprazolam. or barbiturates often leads to

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 146, number 1, July 2019:e20192953 CASE REPORT respiratory depression or apnea, the classic benzodiazepine toxidrome is a coma with normal vital signs. , the first benzodiazepine, was synthesized because of demand for a with less risk of respiratory depression. Subsequent benzodiazepines, such as , were created via modification of chlordiazepoxide’s molecular structure.2 Death from isolated benzodiazepine toxicity is rare; FIGURE 1 however, in combination with , Comparative structures of flualprazolam, , and alprazolam. opioids, or other , death from respiratory depression or aspiration is more common.3 benzodiazepines.9 Although common reported clinical findings. flualprazolam has not been studied One individual (patient 3) developed Flualprazolam is a nonregistered drug directly, rat studies of fluorinated mild respiratory depression in the benzodiazepine family and diazepam analogues vary in potency (respiratory rate of 10 breaths per constitutes an NPS.4 Since the early from one-half to 10-fold10; therefore, minute) that was unresponsive to 2000s, there has been a rise in the the pharmacodynamic effects of 0.4-mg naloxone, which was given rate of NPS exposures worldwide fluorinated alprazolam cannot be empirically because of the unknown because of Internet purchasing. surmised on the basis of chemical identity of the drug. Two of the 6 There have been .800 unique NPSs structure alone. patients (patients 2 and 6) were reported to the United Nations Office initially drowsy but asymptomatic at on Drugs and Crime between 2009 11 fi fl Mei et al identi ed ualprazolam the time of evaluation. All patients and 2017 and 22 tons of NPS seized in postmortem blood; however, at who were symptomatic recovered by law enforcement in 2016 alone.5 present, there are no data on the within 6 hours, and all were Typically, NPSs are synthesized by clinical effects or pharmacology of discharged from the hospital’s simple structural modification or fl ualprazolam. Correlations between emergency department. substitution of existing recreational dose and response, duration of action, drugs, pharmaceuticals, or their metabolism, and onset of action are 6 active metabolites. In the United unknown. In this case series, we add ANALYSIS States, the incidence of exposures to fi to the medical literature the rst A urine immunoassay (MEDTOX designer benzodiazepines in fi description of con rmed clinical PROFILE-V; MEDTOX Diagnostics, particular has been rising since fl ualprazolam intoxication. Inc., Burlington, NC) for common 2014.7 drugs of abuse was performed in 5 Flualprazolam is structurally patients, all of whom tested positive CASES related to the US Food and Drug for benzodiazepines (detection Administration–approved Over a 7-day period, 6 teenagers were threshold 150 ng/mL nordiazepam). pharmaceuticals alprazolam and transported to local emergency The results of a urine test for triazolam, differing in chemical departments from a single high patient 1 were also positive for composition by the presence of school after ingesting an illegally cannabinoids (detection threshold a fluorine atom on the ortho obtained substance colloquially 50 ng/mL; 11-nor-9-carboxy-d-9- position of the phenyl moiety, as named Hulk. All 6 received the drug tetrahydrocannabinol). A pale green seen in Fig 1. All 3 compounds are as a free sample from a single tablet in the possession of patient 3 .8 As student, believing that the substance had the markings “S903,” which is a benzodiazepine, expected clinical was commercial Xanax. The clinical intended to identify the tablet as 2 mg effects of flualprazolam would characteristics and laboratory results of alprazolam. An analysis of a tablet include sedation, anxiolysis, amnesia, for the patients who were exposed fragment (Fig 2) in the possession and potentially respiratory are summarized in Table 1. Five of of patient 6 revealed that the depression. In overdose, alprazolam the patients were boys; their ages tablet contained 2.77 mg/g of appears to have greater toxicity than ranged from 14 to 16 years. Lethargy flualprazolam, or ∼2.75 to 3 mg of other pharmaceutical and slurred speech were the most flualprazolam per intact tablet. No

Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 BLUMENBERG et al TABLE 1 Clinical and Laboratory Characteristics of Patients Intoxicated With Flualprazolam Patient Age Sex Clinical Presentation at Emergency Department Urine Immunoassay for Drugs of Flualprazolam No. Abuse Concentration (LC- QTOF/MS) 1 16 Male Lethargy and slurred speech Positive for benzodiazepines and Urine: 72.1 ng/mL cannabinoids 2 15 Male Asymptomatic Not obtained Not obtained 3 16 Male CNS depression, slurred speech, and mild respiratory depression Positive for benzodiazepines Urine: 19.4 ng/mL unresponsive to 0.4-mg intravenous naloxone Blood: 14.6 ng/mL 4 16 Female Lethargy and slurred speech Positive for benzodiazepines Urine: 3.0 ng/mL 5 14 Male Lethargy and confusion Positive for benzodiazepines Not obtained 6 14 Male Asymptomatic Positive for benzodiazepines Not obtained

alprazolam or other drugs were a-hydroxyalprazolam and the inactive 100%B, 7.5 to 10 minutes = 100%B, detected in the tablet. Blood from metabolite 2-(3-(hydroxymethyl)-5- and 10.01 to 12 minutes = 5%B. The patient 3 and urine from patients 1, 3, methyl-4-triazolyl)-5- LC-QTOF/MS ionized the analytes in and 4 were analyzed by using liquid chlorbenzophenone.12,13 Triazolam is positive polarity with an electrospray chromatography–quadrupole time-of- metabolized by P450 CYP3A to the ionization source at 2 GHz in flight mass spectrometry (LC-QTOF/ chlorinated analogues of expected extended dynamic range and auto MS). The concentrations of alprazolam metabolites.14,15 Urine of MS/MS modes. The concentration flualprazolam in the urine were patients 1, 3, and 4 had formula was quantified by using the area ratio 72.1 ng/mL in patient 1, 19.4 ng/mL matches to the predicted fluorinated of flualprazolam to the internal in patient 3, and 3.0 ng/mL in patient analogues of expected alprazolam standard (-d6). The lower 4. The concentration of flualprazolam metabolites. limit of quantitation of flualprazolam in the serum of patient 3 was in all 3 matrix types (drug product, 14.6 ng/mL, within the therapeutic Analyses of the drug product and serum, and urine) was 1 ng/mL. The range of alprazolam (10–100 ng/mL) patient biological samples were representative intra- and interday and above the peak range of performed by using LC-QTOF-MS precision of the method ranged triazolam (1.7–9.4 ng/mL). The urine (Agilent LC 1260-QTOF/MS 6550; between 1.76% coefficient of and blood tested with LC-QTOF/MS Agilent, Santa Cruz, CA). The drug variation (CV) and 7.36%CV and contained no antipsychotics, product was pulverized and extracted 0.88%CV to 6.58%CV for low (5 antiemetics, antimicrobial agents, in . The serum sample was ng/mL), medium (20 ng/mL), and , opioids, or prepared for analysis via protein high (200 ng/mL) quality control unaccounted benzodiazepines. precipitation (95:5 vol/vol levels, respectively. acetonitrile/methanol). Urine Alprazolam is metabolized by samples were deconjugated by using cytochrome P450 CYP3A to the active Helix pomatia b-glucuronidase type DISCUSSION metabolites 4-hydroxyalprazolam and H3 (500 U/0.5 mL reaction vol) In this case series, we add to the before running at 1:5 and 1:25 medical literature the first dilutions. The drug product and description of clinical toxicity from serum samples were evaporated and flualprazolam with identification of reconstituted at 9:1 (acetonitrile/ flualprazolam in tablet form and in water). Chromatographic separation the urine and sera of 5 patients of analytes before mass spectrometry without other medications or drugs. was achieved by using an Agilent Flualprazolam appears to have led to Poroshell 120 EC-C18 column (2.7 CNS depression, which is an expected µ 3 M, 2.1 10 mm) with gradient effect of benzodiazepines. All patients elution between mobile phase A had sufficient clinical improvement (water with 0.05% formic acid and within 6 hours such that they could 5 mM ammonium formate) and be discharged from the hospital. mobile phase B (acetonitrile with 0.05% formic acid). The elution Urine samples from all patients who FIGURE 2 gradient was as follows: 0 to 0.5 underwent LC-QTOF/MS analysis Recovered pill fragment of flualprazolam with minute = 5%B, 1.5 minutes = 30%B, had detectable concentrations of a penny for scale. 4.5 minutes = 70%B, 7.5 minutes = flualprazolam as well as positive

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 146, number 1, July 2019 3 fi urine immunoassay results. Clinical ndings of other designer ABBREVIATIONS Several articles have been benzodiazepines (such as published on the high cross- and ) were similar to CV: coefficient of variation reactivity of benzodiazepine those of registered benzodiazepines, CNS: central nervous system analogues to benzodiazepine assays namely drowsiness, lethargy, slurred GABA: g-aminobutyric acid in urine drug screens contrary to speech, and respiratory depression.7 LC-QTOF/MS: liquid other NPSs, such as synthetic As of July 2019, there have been no chromatography– cannabinoids and cathinones, published reports on clinical quadrupole time-of- that evade detection from urine intoxication with flualprazolam. flight mass drug screens.16,17 This makes it spectrometry fl challenging to distinguish cases of In these 6 patients, ualprazolam NPS: new psychoactive substance benzodiazepine analogue intoxication displayed the expected clinical effects from those of prescription of a benzodiazepine. The molecular structure is similar to that of benzodiazepines, especially if no REFERENCES unusual signs and symptoms are alprazolam and triazolam, and it 1. Zhu S, Noviello CM, Teng J, Walsh RM Jr., observed. Hence, intoxications from likely has an identical mechanism of Kim JJ, Hibbs RE. Structure of a human benzodiazepine analogues may be action. As an emerging NPS, 18 flualprazolam may be encountered synaptic GABAA receptor. Nature. 2018; underreported. – more frequently in the future.6 In 559(7712):67 72 Formula matches to predicted March 2018, the Center for Forensic 2. Sternbach LH. The Benzodiazepine Story. In: Priest RG, Filho UV, Amrein R, Skreta M, fluorinated analogues of alprazolam Science Research and Education fi fl eds. 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