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Review

Designer Benzodiazepines: A Review of Toxicology and Public Health Risks

by
Pietro Brunetti
1,
Raffaele Giorgetti
1,
Adriano Tagliabracci
1,
Marilyn A. Huestis
2,* and
Francesco Paolo Busardò
1
1
Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University of Ancona, Via Tronto 10, 60126 Ancona, Italy
2
Institute of Emerging Health Professions, Thomas Jefferson University, 1020 Walnut St., Philadelphia, PA 19144, USA
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2021, 14(6), 560; https://doi.org/10.3390/ph14060560
Submission received: 17 May 2021 / Revised: 8 June 2021 / Accepted: 9 June 2021 / Published: 11 June 2021
(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)
Browse Figure
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Abstract

:
The rising use of designer benzodiazepines (DBZD) is a cat-and-mouse game between organized crime and law enforcement. Non-prohibited benzodiazepines are introduced onto the global drug market and scheduled as rapidly as possible by international authorities. In response, DBZD are continuously modified to avoid legal sanctions and drug seizures and generally to increase the abuse potential of the DBZD. This results in an unpredictable fluctuation between the appearance and disappearance of DBZD in the illicit market. Thirty-one DBZD were considered for review after consulting the international early warning database, but only 3-hydroxyphenazepam, adinazolam, clonazolam, etizolam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam had sufficient data to contribute to this scoping review. A total of 49 reports describing 1 drug offense, 2 self-administration studies, 3 outpatient department admissions, 44 emergency department (ED) admissions, 63 driving under the influence of drugs (DUID) and 141 deaths reported between 2008 and 2021 are included in this study. Etizolam, flualprazolam flubromazolam and phenazepam were implicated in the majority of adverse-events, drug offenses and deaths. However, due to a general lack of knowledge of DBZD pharmacokinetics and toxicity, and due to a lack of validated analytical methods, total cases are much likely higher. Between 2019 and April 2020, DBZD were identified in 48% and 83% of postmortem and DUID cases reported to the UNODC, respectively, with flualprazolam, flubromazolam and etizolam as the most frequently detected substances. DBZD toxicology, public health risks and adverse events are reported.

1. Introduction

Benzodiazepines (BZD), important forensic and clinical toxicology drugs, are widely prescribed for neurological and psychiatric disorders and are also highly abused [1,2,3]. Discovered in the mid-1950s, BZD were designed as pharmacotherapies for anxiety, panic attacks, sleep disorders and epilepsy, and they have been used as myorelaxants during surgical and orthopedic procedures [4,5]. BZD are positive allosteric modulators that enhance the binding affinity of the inotropic γ-aminobutyric acid-A receptor (GABAA) for GABA, the major central nervous system (CNS) inhibitory neurotransmitter [6,7]. Unlike GABAA agonists that work directly on the receptor, BDZ increase the frequency of GABAA channel opening, depending only on the endogenously available GABA [8,9,10]. Due to controlled neuronal inhibition and lower CNS depression risk, BZD rapidly replaced older medications such as barbiturates, meprobamate and chloral hydrate, becoming the most prescribed drug class in the world during the 1970s [11,12]. Although they possess a high therapeutic index, BZD also come with several side effects, such as drowsiness, dizziness, fatigue, dysarthria, loss of coordination, headache and amnesia, and they have the potential of being addictive [5]. Their use was recommended for a short treatment, i.e., 4–6 weeks for insomnia, but physicians prescribed BZD for months or years, with patients finding it difficult to stop taking these medications because of withdrawal symptoms [13,14,15,16]. Controlled clinical trials confirmed that long-term administration produced tolerance and dependence [17,18]. Due to this considerable risk of abuse, in February 1984, the United Nations Commission on Narcotic Drugs placed 33 commercially available BZD under Schedule IV of the 1971 Convention on Psychotropic Substances [19,20,21,22,23]. BZD are abused at supratherapeutic doses to reinforce opioid euphoric effects and to alleviate the “crash” following stimulant abuse, or they are administrated to perpetrate drug-facilitated sexual assault, exploiting their hypnotic and amnestic side effects [16,24,25,26]. High BZD doses in combination with opioids or other CNS depressants increase the risk of death by suppression of medullary respiratory centers [27,28,29]. According to the United Nations Office of Drugs and Crime (UNODC) and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), the concomitant non-medical use of opioids and BZD was further exacerbated by the increasing emergence of designer BZD (DBZD) [30,31].
The term “DBZD” is a misnomer, as the class also includes BZD marketed in only some countries, metabolites of registered BZD and structural analogues of therapeutically approved BZD [32,33]. These new psychoactive substances (NPS) have the same chemical structure as legal BZD, with an aromatic ring fused to a 1,4-diazepine ring and an aryl group in position R5 [34,35,36,37]. Slight alterations of the BZD core at different positions generated a large number of designer compounds, mainly 1,4-benzodiazepines, triazolobenzodiazepines and thienotriazolodiazepines. [6,38,39]. The newest DBZD have a triazolo ring fused to the 1,4 diazepine core and electron-withdrawing groups (bromine, chlorine, nitro etc.) in position R8 that increase the affinity for the GABAA receptor [40,41].
Compared with classical BZD, these compounds produce strong sedation and amnesia, and they increase the risk of respiratory depression and death when used in combination with other CNS depressants [41,42]. However, they are illicit, with a relatively short life cycle in the NPS market, the majority of DBZD have not undergone clinical trials and our knowledge of their pharmacokinetics and toxicity is lacking and limited to self-reported experiences [43,44]. These substances are illegally manufactured, sometimes mimic legal medicines’ appearance, and are purchased inexpensively on the underground drug market through online platforms that facilitate anonymous trading and bypass regulatory systems [45,46]. Phenazepam and nimetazepam were the first DBZD identified in Europe on the internet in 2007, followed by etizolam in 2011 [47]. They are not strictly considered DBZD since they are approved for medical use in certain countries, but they have been implicated in several drug-related deaths in the United Kingdom between 2012 and 2013 [39,47]. In 2012 in Finland, pyrazolam, the first true DBZD not approved in any jurisdiction, was identified [48]. About thirty different DBZD have been reported to date to the UNODC Early Warning Advisory (EWA), with the majority of notifications received from European Countries [30,49,50,51,52,53]. According to the UNODC, bulk materials from India and China are brought into Europe where they are further processed and sold as fake alprazolam or diazepam [54]. Counterfeit Xanax (alprazolam) and erimin-5 (nimetazepam) tablets containing etizolam, flualprazolam and phenazepam were also seized in the United States (US), Australia, Singapore and Malaysia [30,55,56].
The misuse of DBDZ in conjunction with other drug use is a growing and widespread world health and safety concern [47,57,58]. The number of DBZD seizures and undercover purchases increased in the US from 2391 in 2018 to 6194 in 2019 according to the US National Forensic Laboratory Information System [59,60,61,62]. In 2020 amid shortages of classic drugs of abuse following COVID-19 restrictions, some drug users shifted from prescription sedatives to DBZD and novel synthetic opioids (NSO) [63,64,65,66]. Produced in clandestine laboratories, DBZD do not meet the same strict approval requirements as legal pharmaceuticals and may contain variable amounts of active ingredients or contaminants, i.e., NSO and other NPS [54]. Users generally are unaware of the presence of contaminants in a product, resulting in an increasing number of adverse health events for DBZD, including emergency room admissions and death investigations [67,68,69]. There is also increasing DBDZ prevalence in driving impairment and road traffic crashes [70,71]. According to the UNODC, between 2019 and April 2020, DBZD were identified in 48% and 83% of post-mortem and Driving Under the Influence of Drug (DUID) cases, respectively, with flualprazolam, flubromazolam and etizolam as the most frequently detected substances [54,72].
Due to the high abuse potential and life-threating consequences of DBZD use, between 2020 and 2021 clonazolam, diclazepam, etizolam, flualprazolam and flubromazolam were listed in Schedule IV of the Convention of Psychotropic Substances of 1971 [73]. Based on this public health risk, this scoping review reports the most recent emergency department (ED) admissions, DUID and postmortem investigations involving DBZD, with the objective of providing useful and updated toxicology and epidemiology data about DBZD intake to improve public health and safety efforts.

2. Results

Of 372 potentially relevant reports, 324 were excluded because they did not describe ED admissions, DUID or fatalities associated with DBZD use. No relevant reports were found for 4-chlorodiazepam, alprazolam triazolobenzophenone derivate, bentazepam, bromazolam, cinazepam, clobromazolam, cloniprazepam, difludiazepam, fluclotizolam, flunitrazolam, fonazepam, methylclonazepam, metizolam, nifoxipam, nimetazepam, nitrazolam, norfludiazepam, tofisopam or thionordazepam, which were therefore excluded from the results. In 49 reports 3-hydroxyphenazepam, adinazolam, clonazolam, etizolam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam were the sole or explicit contributory cause of poisoning, driving-impairment and death. These DBZD were included in this study (Figure 1).
A total of 254 cases describing 1 drug offense, 2 self-administration studies, 3 outpatient department admissions, 44 ED admissions, 63 DUID and 141 deaths, reported between 2008 and 2021, are summarized in Table 1. Age, sex, observations (i.e., symptoms, death scene information etc.), detected concentrations in biological matrices and co-exposure concentrations are also displayed.
Most patients and victims were young individuals of both sexes, often with a previous history of substance abuse and mental illness. Acute intoxications and deaths related to DBZD, alone or in combination with other drugs of abuse, were reported in Finland, Germany, Japan, Norway, Poland, Sweden, UK and USA. DBZD were screened using LC-HRMS (LC-QTOF-MS and LC-Orbitrap-MS) and quantified with LC-MS, LC-MS/MS, LC-DAD, GC-MS or GC-MS/MS.

2.1. Adinazolam

Adinazolam or 1-(8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)-N,N-dimethylmethanamine is a short acting triazolo-BZD with anxiolytic, antidepressant, anticonvulsant and sedative properties [121,122]. Clinical studies revealed that drowsiness and dizziness are commonly observed after oral administration of adinazolam up to 70 mg, resulting in significant amnestic and psychomotor effects at higher doses [123,124,125]. Adinazolam was never FDA approved and never introduced onto the public market; however, it started to emerge as an illegal designer drug in 2015 [126,127]. The first reported adinazolam-related death concerned a young woman found dead in her apartment next to five resealable bags with unidentified powders/crystals. In the US, since April 2020, adinazolam was identified in at least three toxicology cases in association with etizolam, fentanyl and flualprazolam [128]. One male, one female and one unknown sex individual, all of whom were aged 20–40 years and each either from Michigan, Mississippi or Rhode Island, were the decedents. Adinazolam was identified in postmortem blood samples but was neither quantified nor listed as the cause of death.

2.2. Clonazolam

6-(2-Chlorophenyl)-1-methyl-8-nitro-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, also known as clonitrazolam, is the triazolo-analogue of clonazepam [1,129]. Clonazolam is described as “insanely powerful”, producing strong sedation and amnesia at oral doses as low as 0.5 mg, resulting in easy accidental overdose [78]. It was found for the first time in seized yellow capsules by Swedish police on October 2014 and reported to the EMCDDA on January 2015 [51]. Two patients were admitted to ED after consuming clonazolam bought on the Internet. Clonazolam was not confirmed, and the dose was estimated based on the patient’s self-report. In the other four cases, clonazolam or clonazolam and etizolam (one case) were identified. The primary adverse effect was CNS depression.

2.3. Deschloroetizolam

Deschloroetizolam is a short-acting thienotriazolodiazepine that differs from etizolam by the absence of a chlorine on the benzene ring with consequent reduced potency [1]. On 1 September 2014, the UK Focal Point reported that the substance was confirmed after analysis of a blue seized tablet [50]. There are few data available on deschloroetizolam. In a self-administration study, one of the authors ingested one-half pink tablet of deschloroetizolam, about 6 mg, bought on the Internet [79]. After 15 min, the subject’s overall behavior changed rapidly; both physical and cognitive effects were described. Oral fluid was collected after 30 min. Deschloroetizolam and diclazepam’s metabolites, lorazepam and lormetazepam, were detected in a young male. The subject was found dead with injection materials and several small plastic bags labelled with different DBZD [81].

2.4. Diclazepam

Diclazepam, or 2-Chlorodiazepam, is the 2’-chloro derivative of diazepam and the positional isomer of 4-chlorodiazepam [84]. It was reported to EMCDDA by Germany in August 2013 [49]. In two of three cases displayed, subjects were admitted to the ED in a severe state of agitation and disorientation; diclazepam was detected along with stimulants and dissociatives. In the third ED admission, diclazepam was the sole drug reported. Symptoms of intoxication were mainly characterized by CNS depression and a withdrawal syndrome. The patient reported having ingested two 30 mL vials of 4 mg/mL diclazepam (240 mg) purchased online. Again, 13 drivers apprehended for DUID submitted to a clinical test of impairment (CTI). The level of impairment was assessed based on the single test results and the individual’s general condition. Common signs of impairment were found for alertness, appearance, cognitive function, motor coordination and vestibular function. Heide et al. report four additional DUID cases. Subjects were aged between 30 and 39 years; sex was not specified, and diclazepam was found in blood at concentration ranging from 5.4 ng/mL to 32 ng/mL [86]. The subjects did not show impairment. The only death reported involved a young man with a history of methamphetamine use found deceased at home. He previously told a friend that at times he took etizolam. Retrospective quantitative analysis revealed the presence of diclazepam and flubromazolam, along with opioids and stimulants. In addition, in 2013, a French patient was admitted to the ED after ingestion of two pills labelled “diclazepam” and “2-aminoindane” bought on the Internet. Upon clinical examination, the patient was anxious, but the anxiety resolved, and the patient was discharged the same day [130]. Diclazepam was neither confirmed nor quantified.

2.5. Etizolam

Etizolam, or 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-α][1,4]diazepine, is a short-acting thienotriazoldiazepine introduced in 1983 under the trade name Depas® [131,132]. It is currently used in India, Italy, Japan and Korea for the short-term treatment of insomnia, anxiety and panic attacks, but it is not approved for medical use elsewhere [55,71]. It was reported to EMCDDA in December 2011 by UK [133]. Three intoxications required ED admission. Three children were found drowsy and wobbly after eating colored pills thought to be candies. Etizolam was confirmed in one patient’s urine. In addition, a subject was found unconscious next to a syringe of heroin. He had previously ingested a large quantity of etizolam tablets. Three patients with psychiatric disorders presented at an outpatient department for etizolam detoxification after exhibiting tolerance and withdrawal. Etizolam was prescribed or illegally obtained in one case and was taken at supratherapeutic doses. For six DUID cases, three were apprehended drivers undergoing CTI, while three drivers were stopped for impaired driving and underwent a standardized field sobriety test (SFST). These results supported the diagnosis of motor and functional impairment. The other two males, ages 34 and 19 years, underwent CTI [85]. Etizolam was found in blood at concentrations of 31 ng/mL and 120 ng/mL, respectively; however, impairment was impossible to determinate or not reported. A total of 34 deaths were reported. In five cases, etizolam was found in association with diclazepam, (one case), flubromazepam (one case), flubromazolam (two cases) and flualprazolam and flubromazolam in one case. In 33 cases the cause of death was reported as accidental overdose due to polydrug toxicity; subjects were known drug users or had a history of mental disorders. In the remaining case [92], the subject was found dead in the bathroom with a suicide note in her diary. In these nine cases [92,95,97], etizolam was detected in peripheral blood at concentrations of 1–237 ng/mL. Subjects were seven males and two females between 22 and 61 years of age, residing in Japan, the UK or the US. However, etizolam was not listed as the cause of death.

2.6. Flualprazolam

Flualprazolam is the ortho fluorine analogue of alprazolam that was reported to the EMCDDA by Swedish police in January 2018 [99]. Seven young patients were transported to the ED after ingesting a BZD thought to be alprazolam. Three patients exhibited sedation and verbal impairment, two CNS depression, and two were asymptomatic. In three cases the presence of flualprazolam was not confirmed. Another thirteen DUID cases were reported. One individual was subjected to the CTI while twelve other drivers underwent SFSTs. Considerable motor and functional impairment were observed. Two biological samples screened positive for etizolam. Furthermore, Papsun et al. reported an additional 11 DUID [101]; however, demographic information and flualprazolam blood concentrations were not available. A total of 38 deaths were reported. All cases had multiple drugs; one was also positive for etizolam. In 36, the cause of death was listed as accidental overdose due to multiple drug toxicity, while in 2 cases they were ruled intentional flualprazolam poisonings. Furthermore, there were 28 additional deaths in which flualprazolam was not listed as the cause of death; these include 5 decedents from Finland, 13 from Sweden and 10 from the US. Flualprazolam blood concentrations ranged from 3 ng/mL to 620 ng/mL [101,102].

2.7. Flubromazepam

7-Bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one, well known as flubromazepam, was detected for the first time in ten seized capsules in Germany and reported to the EMCDDA in March 2013 [49]. Four subjects were admitted to the ED in a profound state of agitation and delirium, followed by rigidity and CNS depression. In one case, flubromazepam’s depressant effect was mitigated by the presence of methoxyphenidine. Only one DUID was reported. The driver was mildly impaired based on the CTI. Another apprehended, a 22-year-old driver, had a flubromazepam blood concentration of 7 ng/mL but did not show impairment on his CTI [86]. Only a single death case is included for flubromazepam. This young man was admitted to the ED in a severe state of CNS depression requiring resuscitation and mechanical ventilation; he died after six days of hospitalization. Flubromazolam and U-47700, which was also detected, were listed as the cause of death.

2.8. Flubromazolam

Flubromazolam is the triazolo-derivate of flubromazepam. It was identified in Sweden in 10 seized white tablets labelled “XANAX” and reported to EMCDDA in October 2014 [50]. It possesses strong and long-lasting depressive effect on the CNS. Eighteen patients were admitted to the ED in a severe state of CNS depression with functional and motor impairment. In 16 cases, flubromazolam was the sole drug detected, while in 2 cases subjects were also positive for meclonazepam. One patient required three days of hospitalization. After logical verbal contact was established, he admitted that he bought flubromazolam on the Internet and consumed about 3 mg approximately 19 h before ED admission [106]. Eleven flubromazolam DUID cases were reported; in two, driving impairment was assessed by CTI, while in the remaining nine, a SFST was performed by officers. Motor and functional impairment was evident in all subjects. Flubromazolam was listed as a contributory cause of death in four cases. Abdul et al. reported two additional deaths in which flubromazolam was found in femoral blood at concentrations of 8 and 16 ng/mL [108]. The two male decedents were 32 years old and 46 years old. The cause of death was not flubromazolam toxicity. Flubromazolam pharmacokinetics were assessed in a self-administration study. One of the authors ingested a 0.5 mg capsule of flubromazolam. During the following 24 h, the author observed strong sedation and considerable memory impairment.

2.9. Meclonazepam

Meclonazepam is structurally related to clonazepam and was reported for the first time to EMCDDA in August 2014 after identification in 145 seized capsules in Sweden [50]. A young man was admitted to the ED in December 2014 after ingesting approximately 100 tablets (600 mg) of meclonazepam. The subject was awake but not completely lucid.

2.10. Phenazepam and 3-Hydroxyphenazepam

Phenazepam, also known as “Bonsai”, “Zannie” or “Supersleep”, is a long-acting benzodiazepine developed in the 1970s and currently used as an anxiolytic, hypnotic and for the treatment of Alcohol Withdrawal Syndrome in the former USSR [134]. Phenazepam was reported to EMCDDA in July 2011 by Germany and UK. It is metabolized to the active metabolite 3-hydroxyphenazepam by different isoforms of CYP450 [114,135]. 3-Hydroxyphenazepam was identified in a seized white tablet and reported in October 2016 by Denmark. Three subjects were admitted to the ED after ingesting illicit phenazepam purchased on the Internet. Patients exhibited both motor and functional impairment and depressant effects. One patient had Asperger’s syndrome [110]. In May 2016, a patient was admitted to the ED after ingesting four tablets of 3-hydroxyphenazepam. There also are 19 DUID and a drug offense cases included in Table 1. Of these, 11 underwent SFST, 5 had roadside drug tests, 3 CTI, while 1 driver refused to perform SFST, and symptoms of impairment were provided by the officer’s observations. Moderate to considerable motor and functional impairments were evident in all drivers. Heide et al. reported one additional DUID of a young driver submitted for CTI [86] who also had a phenazepam blood concentration of 120 ng/mL. The driver passed his CTI and was declared not impaired. Of sixty deaths reported, phenazepam alone was listed as the sole cause of death in two cases, while the remaining were attributed to accidental overdose due to polydrug toxicity.

2.11. Pyrazolam

Pyrazolam is the triazolo analogue of bromazepam that was identified in Finland in 10 white tablets and notified to EMCDDA in August 2012 [136]. In February 2016, a young man was found dead in an advanced state of putrefaction next to five plastic bags labelled pyrazolam, diclazepam, 3F-phenmetrazine, 1-(2-fluorophenyl) propan-2-amine and diphenhydramine hydrochloride, as well as one unlabelled bag. Asphyxia promoted by polydrug intoxication was listed as the cause of death.

3. Discussion

Seventy percent of the new DBZD were introduced into the European Union (EU), representing about thirteen percent of worldwide NPS seizures [137]. The EU market is dominated by a handful of these, most notably clonazolam, diclazepam, etizolam, flualprazolam, flubromazolam and phenazepam [31,58,64,138,139,140]. Etizolam, in particular, is the “street” BZD that is most often implicated in drug related deaths. In Scotland, its numbers grew from 223 in 2016 to 752 in 2019 [141]. DBZD are a worldwide growing public health concern. In the US, more than 5000 cases regarding clonazolam, etizolam and flualprazolam were reported in the US NFLIS from Federal, State and local laboratories between October and December 2020 [142]. The Center for Forensic Sciences Research and Education confirmed this trend for the first quarter of 2021, underlining the popularity of flubromazolam [143]. Etizolam, flualprazolam and flubromazolam were recently identified in counterfeit Xanax tablets in Canada, and their use is increasing also in Central and South America, mainly in Brazil, Chile and Paraguay [54,144]. Surprisingly, no updated data on DBZD are available from Asia, although most NPS are synthesized in this area of the world. However, a small number of DBZD may be sourced from companies in India, typically as finished medicinal products [54,145,146,147].
According to the UNODC, the highest public health risk around the world is from etizolam, flualprazolam, flubromazolam and phenazepam [54,72]. DBZD are widely available on the Internet in different forms, i.e., blotters, liquids, pills, powders and tablets, and sold at low prices [148]. Etizolam and phenazepam are further diverted from the regulated market and illegally imported from those countries where they are licensed therapeutic drugs [138,149]. For most NPS placed under international control, the number of reports decreased rapidly the year after the scheduling decision [150]. However, for flualprazolam, phenazepam, flubromazolam and etizolam, enforcement was delayed two, five, seven and nine years, respectively, after formal notification [73]. The social harms produced by these drugs’ long residence on the illicit market are characterized by an increasing rate of DBZD-related deaths, involvement of criminal activity, violence, risk-taking behavior, suicide attempts and concurrent substance use disorders [151,152].
Only cases in which DBZD were the sole or a contributory cause of intoxication, impairment or death are included in Table 1, which evaluates global DBZD intake. This facilitates review of the biological concentrations in the different types of cases. Clinicians are unaware of DBZD and their contribution to drug overdoses and deaths, sometimes leading to incorrect interpretations of cause of death. Clinicians should be asking patients about substance abuse including NPS and DBZD during routine preventive care and ED visits. The patients may not be aware of the identity or concentration of DBZD in a drug product before suffering symptoms of intoxication [135]. When a DBZD is the only drug identified, it provides the opportunity to characterize its associated sedative-hypnotic toxidrome as seen in cases [45,74,77,79,80,82,84,85,86,89,90,91,98,106,109,111,113,115].
However, since few pharmacokinetics studies were performed [82,109], it is currently hard to associate concentrations in biological matrices with presumable related adverse-effects. To date, correlations between dose and response, duration of action, metabolism, and onset of action are still poorly understood, making it harder for users to accurately dose the compound they purchased, increasing the prospect of potential intoxication. The slow elimination and the hepatic transformation in active metabolites of certain DBZD (i.e., flubromazolam and phenazepam) are responsible of their accumulation in lipid-based tissues, which can lead to a delayed overdose in cases of repeated consumption [44,82,91,152,153]. There was overlap between diclazepam, etizolam and phenazepam blood concentrations in impaired and non-impaired drivers [85,86]. Similarly, blood etizolam and flualprazolam concentrations were similar in DUID cases and deaths [86,92,101,102]. This may reflect differences in tolerance that appear after frequent drug exposure. In other cases, there is too little information or analytical data to improve our knowledge about the DBZD [74,83,104], and in many cases, because polypharmacy is the rule rather than the exception, it is not possible to assign causation to a single drug because the death is due to the drug combination [78,86,88,100,101,112]. On the other hand, it is also possible that many individuals exposed to DBZD never developed significant adverse events [154]. However, a major problem is knowing that in many cases the DBZD will never be detected due to a lack of analytical method capability or even just to unawareness of the presence of this class of NPS. Furthermore, the newest DBDZ may have high cross-reactivity with common BZD immunoassays, which often do not distinguish between designer and prescribed BZD. Metabolism to licensed BZD, the sale of metabolites of prescribed BZD and the unavailability of confirmatory testing in health care centers pose the risk of an incorrect interpretation of analytical findings [5,127,155,156,157]. The roles DBZD play in deaths remains poorly understood, and how different pathologists and toxicologists attribute and interpret cause of death is largely unknown. For attributing the cause of death, each case must be assessed individually, taking into account the circumstances surrounding the death, drug tolerance and postmortem redistribution. [119,158,159]. The present data should inform interpretation of DBZD-related deaths and apprise law enforcement, clinicians and ED personnel on the dangers of DBZD.

4. Materials and Methods

31 DBZD were selected after consulting the UNODC Early Warning Advisory on NPS portal, the European Database on New Drugs, the US National Poison Data System and the Japanese Data Search System for NPS. Thereafter, a comprehensive literature search was performed using PubMed, Scopus, Google Scholar and Web of Science bibliographic databases to identify scientific reports on ED admissions, DUID and fatalities associated with DBZD use. Database-specific search features with truncations (represented by an asterisk) and multiple keywords (represented by quotation marks) were employed. The search terms employed were: acute, abuse, “access* to emergency department”, “adverse effect*”, diversion, “driving under the influence of drug*”, DUID, fatal, “illegal market”, intoxication*, lethal, misuse, overdose*, prescription, poison*, report*, schedule*, seizure* or traffic in combination with 3-hydroxyphenazepam, 4-chlorodiazepam, adinazolam, alprazolam triazolobenzophenone derivative, bentazepam, bromazolam, cinazepam, clobromazolam, cloniprazepam, clonazolam, deschloroetizolam, diclazepam, etizolam, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazolam, fonazepam, meclonazepam, metizolam, methylclonazepam, nimetazepam, nifoxipam, nitrazolam, norfludiazepam, norflunitrazepam, phenazepam, pyrazolam, thionordazepam or tofisopam. Further studies were retrieved from the reference list of selected articles and from reports from international institutions such as the World Health Organization (WHO), the EMCDDA, the US Drug Enforcement Administration (DEA) and the US Food and Drug Administration (FDA). Articles written in English and only one in Swedish were included. Databases were screened through March 2021 and references were independently reviewed by one of the authors to determine their relevance to the present article.

5. Conclusions

The outbreak of DBZD is a rising health and social concern. Clinical and forensic toxicologists are on the front line, in cooperation with public health safety institutions, to identify emerging DBZD in cases of intoxication, drug offenses and unexplained deaths. In order to decrease the availability of these substances in the global illicit drug market, more effort is needed by early warning agencies to reduce the timing between formal notifications and scheduling decisions. Further studies, professional training and analytical development are required to reduce the undercounting and underreporting of the cases in order to obtain robust and consistent epidemiological data.

Author Contributions

Conceptualization, M.A.H. and F.P.B.; investigation, P.B.; data curation, P.B. and M.A.H.; writing—original draft preparation, P.B.; writing—review and editing, P.B., M.A.H. and F.P.B.; supervision, R.G. and A.T. All authors have read and agreed to the published version of the manuscript.

Funding

This review was partially funded by the Italian Presidency of Ministers Council, Department of Antidrug Policy.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

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Pharmaceuticals 14 00560 g001 550
Figure 1. Chemical structure of “designer” benzodiazepines.
Figure 1. Chemical structure of “designer” benzodiazepines.
Pharmaceuticals 14 00560 g001
Table
Table 1. Designer benzodiazepine (DBZD) case reports.
Table 1. Designer benzodiazepine (DBZD) case reports.
CompoundStudyAge; SexObservationsConcentration †/DoseCo-Exposure Concentration(s) †Ref.
3-HydroxyphenazepamED29; MTremorUrine screen +-[74]
AdinazolamDeath24; FMultiple drugsBlood 18
Urine 82.1		U-47700 blood 1470, urine 3940
SRT blood 89.5, urine 32.5
N-Ethylhexedrone blood 58.1, urine 14
4-CIC blood 8, urine 130
4-CMC blood 1.7, urine 417		[75]
ClonazolamED25; MAgitation, Aggressivity100 mgBZD urine screen +
THC urine screen +		[76]
28; MLethargy≅15 mL of a 0.4 mg/mL solution-[77]
26; MRespiratory depression, UnconsciousSerum 6MDZ urine screen +
U-47700 serum 351
THC serum 3.3, urine screen +
THCCOOH serum 121.6, urine screen +
CIT urine screen +		[78]
34; MConfusion, LethargySerum 10.2Etizolam serum 281[79]
20; MAtaxiaUrine screen +MXE urine screen +[74]
26; FComaBlood 77 (4 h)
Blood 15 (8 h)
Blood 9 (12 h)		-[80]
DeschloroetizolamDeath31; MMulti-organ congestionBlood 11
Urine screen +		LMZ urine 258
LZP urine 115
OXZ urine 17.4
THC urine screen +		[81]
Self-administration56; MDizziness, Fatigue, Language disorder, Difficulty concentrating; Took 6 mgOral Fluid 6.5 (30 min)-[82]
DiclazepamED30; MAgitation, Confusion, Disorientation, Inability to communicate, Muscular rigidity, Myosis, Tachycardia, TachypnoeaPlasma 3.5DIP plasma 308, urine 631
MPH plasma 3
THCCOOH urine 120		[83]
39; MAgitation, Dilated pupils,
Tachycardia		Urine screen +3,4-CTMP[74]
30; MMydriasis, Respiratory depression, Unconscious, Withdrawal syndrome.240 mg-[84]
DUID18; MConsiderable impairmentBlood 57-[85]
27 *; Not reportedModerate impairmentBlood 61EtOH blood 0.053 g/L[86]
32 *; Not reportedBlood 45EtOH blood 0.084 g/L
22 *; Not reportedBlood 32-
<20; Not reportedBlood 19-
47 *; Not reportedBlood 16LZP blood 63
52 *; Not reportedBlood 11NZP blood 17
22 *; Not reportedMild impairmentBlood 35LZP blood 14
22 *; Not reportedBlood 7.7THC blood 0.7
22 *; Not reportedBlood 5.1-
37 *; Not reportedConsiderable impairmentBlood 48-
27 *; Not reportedBlood 35THC blood 1.1
32 *; Not reportedBlood 14-
Death28; MMultiple drugsBlood 70Flubromazepam blood 10
U-47700 blood 330
MAMP blood 290
AMP blood 150
DOC blood screen +		[87]
EtizolamED31; MBradypnea, UnresponsiveSerum 1036-AM urine 272
MOR urine 1000
COD urine 322		[88]
6; MAtaxia, Drowsiness, Mydriasis--[89]
9; M--
10; MUrine screen +-
OD23; MTolerance, Withdrawal syndrome2.5 mg/day for 1 month-[90]
32; MCatatonia, Withdrawal syndrome4 mg/day for 2 months, abruptly stopped-[91]
30; MBradypnea, Loss of consciousness, Seizures, Withdrawal syndromeTook 50 mg/day to 100 mg/day for several months Urine screen +LZP urine screen +[45]
DUID27 *; Not reportedMild impairmentBlood 210-[86]
<20; Not reportedBlood 120TMD blood 71
42 *; Not reportedConsiderable impairmentBlood 110-
37; MDelayed comprehension and reaction time, Impairment, Incoordination, LethargyBlood 40AMP blood screen +[71]
20; FBlood 88THC blood 11
35; MBlood 330MAMP blood screen +
AMP blood screen +
Death59; FSuicideBlood 264αOH-Etizolam blood 9.4
8OH-Etizolam blood 9.3		[92]
42; MMultiple drugsBlood 86PB blood 5082, urine 1736
PMZ blood 107, urine 806
CPZ blood 144, urine 1437		[93]
42; MMultiple drugsBlood 300
Urine 100		MDVP blood 46, urine 1300
PEN blood 160, urine 1200
EPH blood 68
OLZ blood 4200
MIR blood 570		[94]
48; MAccidental death, Multiple drugsSerum 4MTD serum 381
EDDP serum 86
MOR serum 290
COD serum 47
PGB serum 14
PAR serum screen +		[95]
40; MSerum 17MOR serum 44
COD serum 7
COC serum screen +
BE serum 1536
29; MSerum 40DZP serum screen +
Nor-DZP serum 18
OXZ serum screen +
MTD serum 133
EDDP serum 7
THC serum 2.4
THCCOOH serum 17
PGB serum 19
CYC serum 78
38; MSerum 44DZP serum 55
Nor-DZP serum 131
OXZ serum 11
MTD serum 886
EDDP serum 121
SRT serum 6
PMZ serum 57
PGB serum 13000
48; MBlood 4DZP blood 99
Nor-DZP blood 316
TMZ blood 15
OXZ blood 29
MOR blood 6
COD blood 83
AMP blood 394
AMI blood 307
NTP blood 283
PAR blood screen +
34; MBlood 8Diclazepam blood 2
COD blood 108
CIT blood 423
Nor-CIT blood 93
23; MBlood 8EtOH blood 0.77 g/L
ALP blood 300
Nor-DZP blood 5
MOR blood 5
COD blood 16
BE blood screen +
SRT blood 19
PPL blood 8
55; MBlood 7DHC blood 1681
COC blood 317
BE blood 5135
AMI blood 1859
NTP blood 582
PGB blood 22300
39; MBlood 45MTD blood 377
COC blood 18
AMI blood 885
PGB blood 6500000
38; MBlood 172DZP blood 6
Nor-DZP blood 22
LZP blood screen +
MTD blood 1233
EDDP blood 129
MOR blood 16
COD blood screen +
COC blood 10
BE blood 299
THCCOOH blood 11.2
MIR blood 27
PGB blood 35900
32; FBlood 9DZP blood 306
MTD blood 86
MOR blood 1292
COC blood 7
MIR blood 6
PAR blood 22000
43; MBlood 93DZP blood screen +
ZPC blood 65
MTD blood 2297
COC blood screen +
MIR blood 8
PGB blood 3700
42; MBlood 85DZP blood 16
MOR blood 880
37; MBlood 85MTD blood 189
PGB blood 8500
32; MBlood 4DZP blood 107
MOR blood 273
AMP blood 859
CPA blood screen +
GBP blood 2600
PGB blood 10300
PAR blood screen +
35; MBlood 16MOR blood 269
COC blood screen +
SRT blood 24
CBZ blood 2300
PGB blood 23,500
39; FBlood 1DZP blood 431
MTD v blood 634
PMZ blood 56
MIR blood 61
QTP blood 26
VPA blood screen +
PGB blood 22,800
PAR blood screen +
32; MBlood 18DZP blood 131
MOR blood 34
DHC blood 6413
HCOD blood 96
AMI blood 310
PGB blood 10,200
49; MBlood 1.5Flubromazepam blood 33
DZP blood 89
MTD blood 685
MOR blood 44
MIR blood 12
PGB blood 38,100
54; FBlood 12DZP blood 90
MTD blood 973
TMD blood screen +
COC blood 12
AMI blood 67
MIR blood 280
PGB blood 12,900
39; MBlood 4EtOH blood 0.24 g/L
DZP blood 68
MOR blood 1076
COC blood 184
CE blood 22
MIR blood 121
QTP blood 16
PAR blood screen +
49; MBlood 12CZP blood screen +
TAP blood 500
MOR blood 331
PGB blood 15,200
MIR blood screen +
28; MBlood 29EtOH blood 1.1 g/L
DZP blood 16
THC blood 57.5
MIR blood 39
PGB blood 2900
39; MBlood 3DZP blood 238
LZP blood 10
MOR blood 75
SRT blood 92
GBP blood 6700
PRO blood 598
PAR blood 15,700
33; MBlood 14Flubromazolam blood 1
DZP blood screen +
MOR blood 56
COC v blood 46
PRO blood 186
CLO blood 2060
Nor-CLO blood 1629
MIR blood 257
LTG blood 5800
GBP blood 24,600
PAR blood screen +
49; MAccidental death, Multiple drugsBlood 770
Central blood 2820
Hair 0.107		EtOH blood 0.19 g/L
THCCOOH urine 192
THC hair 0.19 ng/mg
AMP hair 3.37 ng/mg
CAF blood 190,000
COC hair 0.22 ng/mg
BE hair 0.068 ng/mg		[96]
29; MAccidental death, Multiple drugsCentral blood 45
Urine 13
Vitreous humor screen +		EtOH c blood 0.023 g/L, vitreous humor 0.014 g/L
ALP c blood 228, urine 238, vitreous humor 17
α-OH-ALP c blood and urine screen +
Nor-DZP c blood, urine and vitreous humor screen +
FEN c blood 6, urine and vitreous humor screen +
Nor-FEN c blood and urine screen +
CDP c blood screen +
DOX urine and vitreous humor screen +		[97]
34; MBlood 9
Central blood screen +
Urine screen +
Vitreous humor screen +		EtOH blood 0.023 g/L, vitreous humor 0.028 g/L
Nor-DZP blood and urine screen +
Desalkyl-FZP blood, urine and vitreous humor screen +
6-AM blood 11, c blood, urine and vitreous humor screen +
MOR blood 185, c blood, urine and vitreous humor screen +
COD p and c blood and vitreous humor screen +
HCOD c blood and vitreous humor screen +
CIT p and c blood, urine and vitreous humor screen +
DPH p and c blood, urine and vitreous humor screen +
36; MBlood 10
Urine 8
Vitreous humor screen +		Flubromazolam urine and vitreous humor screen +
ALP blood 27, urine and vitreous humor screen +
α-OH-ALP urine and vitreous humor screen +
7-Amino-CZP urine screen +
FEN blood 31, vitreous humor screen +
Nor-FEN blood and vitreous humor screen +
MTD blood and vitreous humor screen +
EDDP blood and vitreous humor screen +
MAMP blood 1212, vitreous humor screen +
AMP blood and vitreous humor screen +
28; MBlood 15
Central blood 15
Urine 20		ALP blood 179, c blood 235, urine screen +, vitreous humor 92
DZP p and c blood, urine and vitreous humor screen +
Nor-DZP p and c blood, urine and vitreous humor screen +
TMZ c blood and urine screen +
Nor-FEN c blood and vitreous humor screen +
HCOD urine screen +
MAMP p and c blood, urine and vitreous humor screen +
AMP c blood, urine and vitreous humor screen +
BE urine screen +
DOX p and c blood, urine and vitreous humor screen +
PMZ c blood and urine screen +
CPA p and c blood, urine and vitreous humor screen +
30; MBlood 187
Central blood 214
Urine 64
Vitreous humor 33		EtOH blood 0.002 g/L, vitreous humor 0.003 g/L
Flualprazolam p and c blood, urine and vitreous humor screen +
Flubromazolam blood 619, c blood 878, urine 552, vitreous humor screen +
ALP p and c blood, urine and vitreous humor screen +
DLP p and c blood, urine and vitreous humor screen +
LZP p and c blood and urine screen +
7-Amino-CZP urine screen +
FEN blood 17
Nor-FEN p and c blood, urine and vitreous humor screen +
MAMP p and c blood, urine and vitreous humor screen +
AMP p and c blood, urine and vitreous humor screen +
FlualprazolamED16; MLethargy, Slurred speechUrine 72.1Nor-DZP urine screen +
THC-COOH urine screen +		[98]
16; FUrine 3Nor-DZP urine screen +
16; MCNS depression, Mild respiratory depressionBlood 14.6
Urine 19.4		Nor-DZP urine screen +
18; MUnconsciousBlood 8COC blood screen +
THC blood screen +		[99]
DUID37 *; Not reportedConsiderable impairmentBlood 15TMD blood 65[86]
Not reportedConsiderable impairmentBlood 4.3DZP blood 25
BRP blood 1
FEN blood 6.2
COC blood 57		[100]
31; MDelayed comprehension and reaction time, Driving impairment, Incoordination, LethargyBlood 4.4THC-COOH blood screen +
LEV blood screen +		[101]
22; MBlood 8.3EtOH blood 0.01 g/L
31; MBlood 8.9Etizolam blood screen +
ALP blood screen +
DLP blood screen +
Nor-BUP blood screen +
THC blood screen +
51; MBlood 10OXY blood screen +
OXM blood screen +
47; MBlood 11CFN blood screen +
FEN blood screen +
MTD blood screen +
COC blood screen +
24; MBlood 13-
30; MBlood 39BE blood screen +
MTG blood screen +
20; MBlood 46EtOH blood 0.003 g/L
40; MBlood 46BPP blood screen +
20; MBlood 65THC blood screen +
26; MBlood 68Etizolam blood screen +
MTD blood screen +
Death28 *; Not reportedSuicideBlood 28 ng/gMIR blood 200 ng/g
VEN blood 520 ng/g		[102]
Blood 68 ng/gEtOH blood 0.04 g/L
BUP blood 0.94 ng/g, urine 17 ng/g
Nor-BUP blood 0.83 ng/g, urine 15 ng/g
Suspected overdose, Multiple drugsBlood 4 ng/gVEN blood 1300 ng/g
PGB blood 16000 ng/g
Blood 18 ng/gMTD blood 150 ng/g
Blood 17 ng/gEtOH blood 0.67 g/L, urine 1.33 g/L
BUP blood 2.8 ng/g, urine 90
Blood 19 ng/g-
Blood 14 ng/gLPM blood 60 ng/g
Blood 21 ng/g-
Blood 11 ng/gBUP blood 0.9 ng/g, urine 40
NBUP blood 0.2 ng/g
Blood 36 ng/gBUP urine 120 ng/g
NBUP urine 7.4 ng/g
PGB blood 1700 ng/g
Blood 30 ng/gEtOH blood 0.68 g/L
BUP blood 1.1 ng/g, urine200 ng/g
3F-AMP blood 10 ng/g
MAMP blood 190 ng/g
AMP blood 1000 ng/g
Blood 13 ng/gEtOH blood 1.9 g/L
Blood 33 ng/gN-ethyl-3F-AMP blood screen +
3F-AMP blood screen +
53; MSuspected overdose, Multiple drugsBlood 50FEN blood 3.4
Nor-FEN blood 0.36
4-ANPP blood screen +
ITZ blood screen +
BRP blood 10, urine 23
6-AM blood 1.5
MOR blood 66
COD blood 6.6
CIT/ESC blood 76		[100]
45; MBlood 2.5FEN blood 5
4-ANPP blood screen +
TMD blood 33
BRP blood 1, urine 1.9
THC blood 0.62
48; MBlood 5.4CZP blood screen +
FEN blood 4.7
Nor-FEN blood 1.6
Acetyl-FEN blood 1.2
4-ANPP blood screen +
BRP blood 0.1, urine 0.2
MOR blood 8
DPH blood 190
47; FBlood 13FEN blood 190
Nor-FEN blood 5.4
Acetyl-FEN 0.15
4-ANPP blood screen +
BRP blood 6.7, urine 2.1
6-AM blood 12
MOR blood 85
COD blood 7
MAMP blood 580
AMP blood 55
XYL blood 170
53; MBlood 20FEN blood 19
Nor-FEN blood 4.2
4-ANPP blood screen +
BRP blood 0.2
MOR blood 15
XYL blood 30
29; MBlood 3.67-Amino-CZP blood 5.2
FEN blood 37
Nor-FEN blood 1.3
4-ANPP blood screen +
TMD blood 70
BRP blood 1.1, urine 0.8
MAMP blood 42
AMP blood 10
DPH blood 490
22; MSuspected overdose, Multiple drugsBlood 3.2EtOH blood 0.017
Desmethyl-LPM blood screen +		[101]
53; MBlood 2.1FEN blood screen +
MTD blood screen +
COC blood screen +
GBP blood screen +
32; MBlood 2.2BE blood screen +
THC blood screen +
MTG blood screen +
CBP blood screen +
HYZ blood screen +
GBP blood screen +
29; MBlood 4.1ITZ blood screen +
MAMP blood screen +
AMP blood screen +
35; FBlood 5.2EtOH blood 0.008 g/L
BE blood screen +
THC blood screen +
38; MBlood 6.2ITZ blood screen +
FEN blood screen +
MAMP blood screen +
AMP blood screen +
HYZ blood screen +
23; FBlood 9.9FEN blood screen +
4-ANPP blood screen +
BE blood screen +
THC blood screen +
MAMP blood screen +
AMP blood screen +
23; MBlood 15FEN blood screen +
4-ANPP blood screen +
21; MBlood 29FEN blood screen +
MAMP blood screen +
AMP blood screen +
THC blood screen +
36; MBlood 63MTD blood screen +
40; MSuicideBlood 26.5DZP blood 9
Nor-DZP blood 4
MTD blood 736
EDDP blood 149
PGB blood 1900		[103]
30; MSuspected overdose, Multiple drugsBlood 3DZP blood screen +
6-AM blood screen +
MOR blood 196
COD blood 11
THC blood screen +
MIR blood screen +
PGB blood 12000
44; MBlood 35DZP blood screen +
MTD blood 549
MOR blood screen +
COC blood screen +
BE blood screen +
MDMA blood 29
MDA blood screen +
MIR blood 58
GBP blood screen +
PGB blood 18,100
40; FBlood 14.5MTD blood 711
EDDP blood 67
4F-MDMB-BINACA blood screen +
MDMB-4en-PINACA blood screen +
MIR blood 3229
PGB blood 7900
37; MBlood 14.1Etizolam blood 85
CBZ metabolites blood screen +
MTD blood 189
5F-AMB metabolites blood screen +
THC metabolites blood screen +
PGB blood 8500
51; MBlood 3.1ALP blood 68
DZP blood 367
Nor-DZP blood 364
OXZ blood 45
TMZ blood 19
MTD blood 694
EDDP blood 365
MOR blood 62
COD blood 14
BE blood screen +
SRT blood 31
PGB blood 47,000
RSP blood 35
57; MBlood 5.7COC blood 41
BE blood 718
CIT blood 707
42; FBlood 15.1MOR blood 410
COD blood 19
PGB blood 9900
42; MBlood 9ALP blood 35
CZP blood 7
DZP blood 61
Nor-DZP blood 82
NZP blood 16
BUP blood 0.5
MOR blood 197
COD blood 11
COC blood screen +
BE blood 258
MIR blood 23
PGB blood 900
FlubromazepamED25; MAgitation, Aphasia, Ataxia, Confusion, Dysarthria, Hypertension, HypostheniaBlood 411BZD urine screen +
THC urine screen +
MXP blood 247		[104]
24; MAgitation, Coma, Delirium, Mydriasis, Rigidity, Tachycardia,
Tremor		Urine screen +-[74]
47; MUrine screen +3OH-Flubromazepam urine screen +
45; MUrine screen +3OH-Flubromazepam urine screen +
DUID37; MMild impairmentBlood 600-[85]
Death24; MApnea, Coma, Rattling breath, Hypothermia, Myosis, Tachycardia, UnconsciousPlasma 830U-4770 plasma 370[105]
FlubromazolamED27; MComa, Cyanosis, Hypotension, Unconscious, Respiratory depression, TachycardiaSerum 59
Urine 105		-[106]
20; MAtaxia, Coma, Disorientation, Lethargy, Hallucinations, Hypotension, Miosis, Mydriasis, Seizures, Slurred speech, Tremor, UnconsciousUrine screen +-[74]
18; FUrine screen +-
65; MUrine screen +-
26; MUrine screen +Meclonazepam urine screen +
15; FUrine screen +-
23; MUrine screen +-
49; MUrine screen +-
27; MUrine screen +-
20; FUrine screen +-
17; FUrine screen +-
17; FUrine screen +-
19; FUrine screen +-
23; MUrine screen +-
18; MUrine screen +Meclonazepam urine screen +
35; MUrine screen +-
18; MUrine screen +-
18; MUrine screen +-
DUID20, MMild impairmentBlood 0.48-[85]
19; MConsiderable impairmentBlood 100-
17; MDriving impairment, Lethargy, Lack of balance, Slurred speechBlood 17THC blood 6.1[71]
18; MBlood 18THC blood 2.2
21; MBlood 19BE blood 348
THC blood 1.5
17; FBlood 14EtOH blood 0.014 g/L
19; FBlood 21COC blood screen +
BE blood 749
19; MBlood 7CZP blood 7
7-Amino-CZP blood 26
OXY blood screen +
THC blood 27
22; FBlood 12THC blood 2.9
35; FBlood 31THC blood 4.1
21; FBlood 8.2BE blood 356
THC blood 1
Death34; MMultiple drugsBlood screen +DZP blood 200
Nor-DZP blood 180
TMZ blood 11
MAMP blood screen +
AMP blood 70
3-FPM blood 2.4, central blood 2.6
AMI blood 440
NTP blood 290		[107]
39; MMultiple drugsBlood 70EtOH blood 0.24 g/L
Etizolam blood 4
DZP blood 68
Nor-DZP blood 365
TMZ blood 6
OXZ blood 22
6-AM blood screen +
MOR blood 1149
COD blood 289
COC blood 184
BE blood 525
CE blood 22
QTP blood 16
MIR blood 121		[108]
49; MBlood 33Etizolam blood 1.5
DZP blood 89
Nor-DZP blood 575
OXZ blood 13
TMZ blood 5
MTD blood 685
EDDP blood 100
6-AM blood screen +
MOR blood 73
COD blood 18
MIR blood 12
PGB blood 38.1
33; FBlood 1Etizolam blood 14
7-Amino-CZP blood screen +
MOR blood 91
COC blood 46
BE blood 2573
CLO blood 2060
Nor-CLO blood 1629
GBP blood 24.6
LTG blood 5.8
PRO blood 186
Self-administration44; MConsiderable impairment, delayed comprehension and reaction time, lethargy, muscle relaxation, partial amnesia, sedation0.5 mg oral ingestion
Serum 7.4 (5 h)
Serum 8.6 (8 h)
Serum 5.2 (30 h)
Hair 0.44 pg/mg (2 w)
Hair 0.60 pg/mg (4 w)		BZD urine screen +[109]
MeclonazepamED31; MAgitation, Non-reactive pupilsUrine screen +-[74]
PhenazepamED26; MAtaxia, Lack of balance, Memory impairment, Slurred speechBlood 1200BZD urine screen +
VEN blood screen +		[110]
42; MConfusion, Disorientation, MydriasisBlood 490-[111]
29; MUnresponsiveness, TachycardiaSerum 1400BZD serum screen +
U-47700 serum 240		[112]
Drug offense22 *; Not reportedModerate motor impairmentBlood 260THC blood 0.7[86]
DUID50; FBehavioral aberrations, Moderate/considerable functional disordersBlood 270-[113]
27; MBlood 310-
21; MBlood 3000-
47; FBlood 230-
47; MBlood 380-
18; MAgitation, Amnesia, Disorientation, Lack of balance, Lethargy, Mydriasis, Myosis, Non-reactive pupils, Sedation, Slurred speech, Slow reactivity, TachycardiaBlood 180THCCOOH blood 28[114]
27; MBlood 500CBP blood 6.1
22; MBlood 750TZD blood screen +
29; FBlood 310AMP blood 190
QTP blood screen +
39; MBlood 170THCCOOH urine screen +
23; MBlood 140GBP blood screen +
22; MBlood 3200-
40; MBlood 40-
24; FBlood 50-
29; MBlood 120-
21; MBlood 80-
24; MSlurred speech, Lack of balanceBlood 76BZD blood screen +[115]
22 *; Not reportedModerate impairmentBlood 170-[86]
42 *; Not reportedMild impairmentBlood 12-
Death42; MAccidental death complicated by obesity and asthma, Multiple drugsBlood 386MOR blood 116
COD blood 85, blood screen +
HCOD urine screen +		[116]
35; MMultiple drugsBlood 220DZP blood 100
Nor-DZP blood 210
OXZ blood screen +
TMZ blood screen +
MTD blood 650, urine screen +
EDDP blood screen +
IBP blood screen +		[117]
35; MBlood 2520EtOH blood 0.06 g/L
BZD blood and urine screen +
MOR blood 360, urine screen +
COD blood 380, urine screen +
PAR blood and urine screen +
Not reportedMultiple drugsBlood 9603OH-Penazepam blood 230
DZP blood screen +
Nor-DZP blood screen +
TMZ blood screen +
MOR blood 10
MOR-3-glucuronide blood 30
MOR-6-glucuronide blood 10
PRZ blood 500		[118]
Accidental overdose, Multiple drugsBlood 9603OH-Penazepam blood 270
DZP blood screen +
Nor-DZP blood screen +
DHC blood screen +
DHC-6-glucuronide blood screen +
NIC blood screen +
46; MPhenazepam intoxicationBlood 1200EtOH blood 0.22 g/L[119]
26; MBlood 1600DZP blood 160
DHC blood 160
Not reportedMultiple drugsBlood screen +MTD blood 60
MOR blood 60
COC blood screen +
AMI blood 80
GBP blood 30,000
Blood screen +Etizolam blood 34
EtOH blood 2.9 g/L
MOR blood screen +
Blood screen +DZP blood 240
MTD blood 890
MOR blood 30
DHC blood 170
GBP blood 26,000
MIR blood 100
FLX blood 140
Blood screen +EtOH blood 3 g/L
DZP blood 70
AMP blood 1500
Blood 10MTD blood 770
Blood 140EtOH blood 0.56
Blood 20MTD blood 1300
Blood 20EtOH blood 1.4
DZP blood screen +
Blood 24Etizolam blood 120
MTD blood 950
COD blood 60
AMI blood 990
Blood 38DHC blood 1100
Blood 40MTD blood 700
MOR blood 50
AMI blood 570
Blood 40MTD blood 340
DZP blood 350
Blood 40MTD blood 390
Blood 43DZP blood 510
MTD blood 900
MOR blood screen +
MIR blood 580
Blood 45Etizolam blood 73
DHC blood 300
GBP blood 42000
Blood 50DZP blood 450
MOR blood 450
Blood 60EtOH blood 0.79 g/L
BUP blood 5
AMI blood 70
Blood 60MTD blood 410
Blood 67Etizolam blood 380
MOR blood 170
Blood 80MTD blood 290
Blood 80Etizolam blood screen +
DZP blood screen +
MOR blood 590
Blood 80MTD blood 770
MOR blood 10
Blood 80Etizolam blood screen +
DZP blood screen +
MOR blood 590
Blood 90MOR blood 310
Blood 90MOR blood 560
Blood 100MTD blood 590
MOR blood 40
Blood 100MTD blood 130
DOT blood 580
Blood 100MTD blood 1200
BEG v blood screen +
Blood 100MTD blood 280
DHC blood 1600
Blood 110MTD blood 540
MOR blood 40
BEG blood screen +
Blood 110OLZ blood 420
ZPC blood 10
Blood 110EtOH blood 1.6 g/L
BUP blood screen +
Blood 110MTD blood 270
Blood 120FEN blood 55
TMD blood 1400
DOT blood 3300
GBP blood 23,000
Blood 160DZP blood 980
MOR blood 430
BEG blood screen +
Blood 200MOR blood 360
DHC blood 990
Blood 210MTD blood 180
Blood 240MTD blood 390
MIR blood 60
Blood 240DZP blood 350
MTD blood 340
Blood 240MTD blood 510
AMI blood 840
Blood 260MTD blood 240
COD blood 1100
Blood 280EtOH blood 3.1 g/L
Blood 280MTD blood 250
PGB blood 8000
Blood 330MTD blood 750
MOR blood 330
GBP blood 103000
Blood 330EtOH blood 2.5 g/L
Nor-BUP blood 13
Blood 460MTD blood screen +
Blood 550EtOH blood 3.3 g/L
Blood 640MTD blood 1100
Blood 820MTD blood 470
Blood 900DZP blood 120
MTD blood 380
DHC blood 730
AMP blood 110
Blood 1700DHC blood 4400
Blood 1700MOR blood 50
Blood screen +DZP blood 170
TMD blood 7800
DHC blood 220
PyrazolamDeath27; MMultiple drugsBlood 28
Central blood 28
Urine 500		Diclazepam blood 1, central blood 1, urine 1
DLP blood 100, central blood 250, urine 570
LMZ blood 6, central blood 4, urine 810
LZP blood 22, central blood 22, urine 820
3-FPM blood 10, central blood 9, urine 120
2F-MAMP urine 120
2F-AMP blood 89
MPA blood 2.2, urine 16
AMP blood 21, urine 75
DPH urine 340		[120]
† Concentrations are expressed as ng/mL unless specified; + Positive; * Median age; 3F-AMP—3-Fluoroamphetamine; 3-FPM—3-Fluorophenmetrazine; 3,4-CTMP—3,4-dichloromethylphenidate; 4-ANPP—N-Phenethyl-4-piperidinone; 4-CIC—4-chloro-N-isopropylcathinone; 4-CMC—4-chloromethcathinone; 4F-MDMB-BINACA—Methyl 2-[1-(4-fuorobutyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoate; 5F-AMB—N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-L-valine, methyl ester; 6-AM–6-Acetylmorphine; ALP—Alprazolam; AMI—Amitriptyline; AMP—Amphetamine; BE—Benzoylecgonine; BPP—Bupropion; BRP—Brorphine; BZD—Benzodiazepine; CBP—Cyclobenzaprine; CBZ Carbamazepine; CDP—Chlordiazepoxide; CE—Cocaethylene; CFN—Carfentanil; CIT—Citalopram; CLO—Clozapine; COC—Cocaine; COD—Codeine; CPA—Chlorpheniramine; CPZ—Chlorpromazine; CYC—Cyclizine; CZP—Clonazepam; DFSA—Drug-facilitated Sexual Assault; DIP—Diphenidine; DHC—Dihydrocodeine; DLP—Delorazepam; DOC—2,5-dimethoxy-4-chloroamphetamine; DOX—Doxylamine; DPH—Diphenhydramine; DOT—Dothiepin; DUID—Driving Under the Influence of Drug; DZP—Diazepam; ED—Emergency Department; EDDP—2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; EPH—Ephedrine; ESC—Escitalopram; EtOH—Ethanol; F—Female; FEN—Fentanyl; FLX—Fluoxetine; FZP—Flurazepam; GBP—Gabapentin; HCOD—Hydrocodone; HYZ—Hydroxyzine; IBP—Ibuprofen; ITZ—Isotonitazene; LEV—Levetiracetam; LMZ—Lormetazepam; LPM—Loperamide; LTG—Lamotrigine; LZP—Lorazepam; M—Male; MDA—Methylenedioxyamphetamine; MDMB-4en-PINACA—3-Methyl-N-[[1-(4-penten-1-yl)-1H-indazol-3-yl]carbonyl]-L-valine, methyl ester; MDMA—Methylenedioxymethamphetamine; MAMP—Methamphetamine; MDPV—3,4-Methylenedioxypyrovalerone; MDZ—Midazolam; MIR—Mirtazapine; MOR—Morphine; MPA—Methiopropamine; MPH—Methylphenidate; MTD—Methadone; MTG—Mitragynine; MXE—methoxetamine; NIC—Nicotine; MXP—Methoxphenidine; NTP—Nortriptyline; NZP—Nitrazepam; OLZ—Olanzapine; OD—Outpatient Department; OXY—Oxycodone; OXM—Oxymorphone; OXZ—Oxazepam; PAR—Paracetamol; PB—Phenobarbital; PEN—Pentedrone; PGB—Pregabalin; PMZ—Promethazine; PPL—Propranolol; PRO—Procyclidine; PRZ—Promazine; QTP—Quetiapine; RSP—Risperidone; SRT—Sertraline; TAP—Tapentadol; THC—Δ9-Tetrahydrocannabinol (Cannabis); THCCOOH—11-Nor-9-carboxy-THC; TMD—Tramadol; TMZ—Temazepam; TRZ—Trazodone; U-4770—trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methyl-benzamide; VEN—Venlafaxine; XYL—Xylazine; ZPC—Zopiclone.
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Brunetti, P.; Giorgetti, R.; Tagliabracci, A.; Huestis, M.A.; Busardò, F.P. Designer Benzodiazepines: A Review of Toxicology and Public Health Risks. Pharmaceuticals 2021, 14, 560. https://doi.org/10.3390/ph14060560

AMA Style

Brunetti P, Giorgetti R, Tagliabracci A, Huestis MA, Busardò FP. Designer Benzodiazepines: A Review of Toxicology and Public Health Risks. Pharmaceuticals. 2021; 14(6):560. https://doi.org/10.3390/ph14060560

Chicago/Turabian Style

Brunetti, Pietro, Raffaele Giorgetti, Adriano Tagliabracci, Marilyn A. Huestis, and Francesco Paolo Busardò. 2021. "Designer Benzodiazepines: A Review of Toxicology and Public Health Risks" Pharmaceuticals 14, no. 6: 560. https://doi.org/10.3390/ph14060560

APA Style

Brunetti, P., Giorgetti, R., Tagliabracci, A., Huestis, M. A., & Busardò, F. P. (2021). Designer Benzodiazepines: A Review of Toxicology and Public Health Risks. Pharmaceuticals, 14(6), 560. https://doi.org/10.3390/ph14060560

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