Flualprazolam: Report of an Outbreak of a New Psychoactive Substance in Adolescents
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Flualprazolam: 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 benzodiazepine family and abstract
constitutes a new psychoactive substance (NPS). Since 2014, a growing
number of designer benzodiazepines 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
a
been poorly characterized thus far. Over a one-week period, 6 teenagers Department of Emergency Medicine, School of Medicine,
Oregon Health and Science University, Portland, Oregon; and
presented to local emergency departments after ingesting illegally obtained b
Clinical Toxicology and Environmental Biomonitoring
counterfeit alprazolam, which led to sedation. Other symptoms included Laboratory, University of California, San Francisco, San
Francisco, California
slurred speech, confusion, and mild respiratory depression. All 6 patients
had resolution of their symptoms within 6 hours of ingestion. Blood and Dr Blumenberg conceptualized, researched, wrote,
and edited the manuscript; Dr Hughes helped
urine samples, as well as a tablet fragment, were obtained from 3
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: https://doi.org/10.1542/peds.2019-2953
characteristics. Sedation lasting ,6 hours was observed in 6 of 6 patients
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 barbiturates, 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
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PEDIATRICS Volume 146, number 1, July 2019:e20192953 CASE REPORTrespiratory depression or apnea, the
classic benzodiazepine toxidrome
is a coma with normal vital signs.
Chlordiazepoxide, the first
benzodiazepine, was synthesized
because of demand for a sedative
with less risk of respiratory
depression. Subsequent
benzodiazepines, such as diazepam,
were created via modification of
chlordiazepoxide’s molecular
structure.2 Death from isolated
benzodiazepine toxicity is rare; FIGURE 1
however, in combination with alcohol, Comparative structures of flualprazolam, triazolam, and alprazolam.
opioids, or other sedatives, 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 Mei et al11 identified flualprazolam 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 flualprazolam. Correlations between emergency department.
substitution of existing recreational dose and response, duration of action,
drugs, pharmaceuticals, or their metabolism, and onset of action are
active metabolites.6 In the United unknown. In this case series, we add ANALYSIS
States, the incidence of exposures to to the medical literature the first A urine immunoassay (MEDTOX
designer benzodiazepines in description of confirmed clinical PROFILE-V; MEDTOX Diagnostics,
particular has been rising since flualprazolam intoxication. Inc., Burlington, NC) for common
2014.7
drugs of abuse was performed in 5
Flualprazolam is structurally patients, all of whom tested positive
related to the US Food and Drug CASES 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
triazolobenzodiazepines.8 As student, believing that the substance had the markings “S 90 3,” 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
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2 BLUMENBERG et alTABLE 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 (paroxetine-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 methanol. The serum sample was ng/mL), medium (20 ng/mL), and
antidepressants, 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
µM, 2.1 3 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
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PEDIATRICS Volume 146, number 1, July 2019 3urine immunoassay results. Clinical findings of other designer
Several articles have been benzodiazepines (such as etizolam
ABBREVIATIONS
published on the high cross- and clonazolam) 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
challenging to distinguish cases of In these 6 patients, flualprazolam NPS: new psychoactive substance
benzodiazepine analogue intoxication displayed the expected clinical effects
from those of prescription of a benzodiazepine. The molecular
benzodiazepines, especially if no structure is similar to that of
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PEDIATRICS Volume 146, number 1, July 2019 5Flualprazolam: Report of an Outbreak of a New Psychoactive Substance in
Adolescents
Adam Blumenberg, Adrienne Hughes, Andrew Reckers, Ross Ellison and Roy
Gerona
Pediatrics originally published online June 24, 2020;
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/early/2020/06/22/peds.2
019-2953
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Downloaded from www.aappublications.org/news by guest on February 18, 2021Flualprazolam: Report of an Outbreak of a New Psychoactive Substance in
Adolescents
Adam Blumenberg, Adrienne Hughes, Andrew Reckers, Ross Ellison and Roy
Gerona
Pediatrics originally published online June 24, 2020;
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2020/06/22/peds.2019-2953
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