Bromazolam

Last updated

Bromazolam
Bromazolam.svg
Legal status
Legal status
Identifiers
  • 8-bromo-6-phenyl-1-methyl-4H-benzo[f] [1,2,4]triazolo[4,3-a] [1,4]diazepine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C17H13BrN4
Molar mass 353.223 g·mol−1
3D model (JSmol)
  • Brc1cc2C(=NCc3nnc(C)n3c2cc1)c4ccccc4
  • InChI=1S/C17H13BrN4/c1-11-20-21-16-10-19-17(12-5-3-2-4-6-12)14-9-13(18)7-8-15(14)22(11)16/h2-9H,10H2,1H3
  • Key:KCEIOBKDDQAYCM-UHFFFAOYSA-N

Bromazolam (XLI-268) is a triazolobenzodiazepine (TBZD) which was first synthesised in 1976, but was never marketed. [2] It has subsequently been sold as a designer drug, first being definitively identified by the EMCDDA in Sweden in 2016. [3] It is the bromo instead of chloro analogue of alprazolam and has similar sedative and anxiolytic effects to it and other benzodiazepines. [4] [5] Bromazolam is a non subtype selective agonist at the benzodiazepine site of GABAA receptors, with a binding affinity of 2.81 nM at the α1 subtype, 0.69 nM at α2 and 0.62 nM at α5. [6] The "common" dosage range for users of bromazolam was reported to be 1–2 mg, suggesting its potency is similar to alprazolam. [7]

Contents

Adverse effects

Because bromazolam is relatively new, epidemiological research regarding the individual's health effects as well as the effects on the public health are quite scarce. Most of the knowledge about the effects are known from case studies and individual reports.

The typical effects of benzodiazepines used in medical science are muscle relaxation, amnesia, sedation, anxiolysis and anticonvulsive activity (used to treat epilepsy). Therefore benzodiazepines are frequently used to treat illnesses such as anxiety, insomnia, muscle spasms or epilepsy. [8] [9]

According to studies even short use of bromazolam could lead to tolerance and psychological, as well as physical dependence. [5] Benzodiazepine-like compounds are rarely fatal when taken alone but can cause central nervous system depression when combined with other medication or drugs. [10]

Common adverse effects of benzodiazepines are somnolence, impaired balance, ataxia, loss of coordination, impaired thinking and self-assessment capability, muscle weakness, confusion, slurred speech, blurred vision, amnesia, dizziness, drowsiness, lethargy, fatigue and palpitations. At high doses, they may induce delirium, auditory and visual hallucinations, seizures, deep sleep and coma. [5] [11]

To study the potential addictive nature of bromazolam a two-lever drug discrimination test was performed. Rats trained to discriminate against the benzodiazepine midazolam were used to evaluate the abuse potential of bromazolam. They found that bromazolam resulted in full dose-dependent substitution with an ED50 of 0.54 mg/kg. In comparison the ED50 of midazolam and diazepam were 0.09 and 0.66 respectively. [7]

Pharmacology

Pharmacokinetics

Metabolism

Not many studies have been conducted on the biotransformation of bromazolam, mainly because this drug is relatively new. However, in a study of Wagmann et al. (2020), the biotransformation of bromazolam is studied in depth. The results of this study are described in the text below. [8]

Blood plasma and urine of two individuals suspected of taking bromazolam were analysed for bromazolam and its metabolites. Bromazolam was detected in all four of the samples. One of the urine samples contained 8 bromazolam metabolites these were: phenyl-hydroxy bromazolam, 4-hydroxy bromazolam, α-hydroxy bromazolam, α-4-dihydroxy bromazolam, bromazolam N-glucuronide, phenyl-hydroxy bromazolam glucuronide, α-hydroxy bromazolam glucuronide, and 4-hydroxy bromazolam glucuronide. In the blood plasma sample of the same individual only the three mono-hydroxylated metabolites were found. [8]

The urine of the other individual only contained two metabolites, which were also found in the other urine sample, and the blood plasma did not show any metabolite of bromazolam present in the body.

A study where pooled human liver S9 fractions (pHLS9) were incubated with bromazolam was conducted. Seven, out of the eight urine, bromazolam metabolites were found in the pHLS9 samples. Phenyl-hydroxylated glucuronide bromazolam was not found in the pHLS9 samples. [8]

Several monooxygenases and glucuronosyltransferases have been screened, in vitro, for activity of the biotransformation of bromazolam. Out of the eight metabolites found in a urine sample seven metabolites have been linked to monooxygenases and glucuronosyltransferases activity. [8]

Phase I

Phenyl-hydroxy bromazolam, 4-hydroxy bromazolam, α-hydroxy bromazolam, and α-4-dihydroxy bromazolam. The formation of phenyl-hydroxy bromazolam was catalysed by CYP2B6, CYP2C19, and CYP3A4. 4-hydroxy bromazolam, as well as α-hydroxy bromazolam, were formed by CYP2B6, CYP2C19, CYP3A4, and CYP3A5. Additionally, CYP2C9 was found to catalyse the formation of α-hydroxy bromazolam as well. α-4-dihydroxy bromazolam was only found in incubations with CYP3A4. [8]

Phase II

Bromazolam N-glucuronide, phenyl-hydroxy bromazolam glucuronide, α-hydroxy bromazolam glucuronide, and 4-hydroxy bromazolam glucuronide, were detected as phase II metabolites.

Bromazolam N-glucuronidation was found to be catalysed by UGT1A4 and UGT2B10.  The formation of α-hydroxy bromazolam glucuronide was catalysed by UGT2B4. And 4-hydroxy bromazolam glucuronidation was catalysed by UGT1A3, UGT1A6, UGT1A9, UGT2B7 and UGT2B15.

The enzyme responsible for the catalysis for the phenyl-hydroxy bromazolam glucuronidation formation was not identified. [8]

Pharmacodynamics

Benzodiazepine like compounds are acting as positive allosteric modulators to the gamma-aminobutyric acid GABAA receptor. GABA is the main inhibitor of neurotransmitters in the brain and modulates the activity of many neurons.

Benzodiazepines bind to the GABAA receptor inducing a conformational change leading to an increased affinity to GABA.

The allosteric binding site is situated in a "pocket" created by the alpha and gamma subunits. The pharmacological effects on benzodiazepines vary based on which alpha subunit of the GABAA receptor the benzodiazepine binds to.

The sedative, anterograde amnesic, anticonvulsant actions, and the addictive nature of benzodiazepines, are due to the binding to the α1 subunit of the (GABA)A receptor. Binding to the α2 subunit will cause the anxiolytic effects, and binding to the α2, α3, and α5 subunits will lead to the myorelaxant effects. [9]

According to research done by the WHO bromazolam binds to the α1, α2, and α5 subunits. [12]

Chemistry

Synthesis

The synthetic pathway of the synthesis is executed as follows: In the initial step, 2-Amino-5-bromobenzophenone undergoes acylation, leveraging its amino group with a lone pair on the nitrogen atom. This lone pair facilitates a nucleophilic attack, where the nitrogen attacks the carbon of chloroacetyl chloride, inducing a negatively charged oxygen. Subsequently, the oxygen re-establishes the carbon-oxygen double bond, expelling a chloride ion, leading to the formation of bromoacetamide-2-chloro-5-benzophenone. [13] [14]

Following this, bromoacetamide-2-chloro-5-benzophenone engages in a nucleophilic substitution reaction with ammonium hydroxide as a nucleophile, replacing the second chloride ion with ammonia. This reaction yields 2-amino-N-(2-benzoyl-4-bromophenyl)acetamide. [13] [15]

Upon the formation of 2-amino-N-(2-benzoyl-4-bromophenyl)acetamide, an intramolecular reaction ensues, resulting in 7-bromo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one, characterized by a seven-membered ring known as diazepine. [16]

Subsequently, through the aid of acetohydrazide, another acylation event takes place, giving rise to a 1,2,4-triazole ring and ultimately yielding the synthesis of Bromazolam. [14] [17] [18] [19] This synthesis can also be used to synthesize alprazolam by using 2-amino-5-chlorobenzophenone as the starting material. The synthesis of Bromazolam is shown below.

Proposed synthesis bromazolam Synthesis bromazolam.png
Proposed synthesis bromazolam

Society and culture

In the United States, bromazolam is unscheduled at the federal level. However a number of states such as Virginia have placed bromazolam into Schedule 1 at the state level, but this does not include the 6-(2-chlorophenyl) analog phenazolam. [20] [21]

Despite being unscheduled there have been several arrests in the United States for mismarketing bromazolam as alprazolam, typically in the shape of brand name Xanax tablets which constitutes a counterfeit drug charge among others. [22]

In Illinois, at least 1 person has been arrested for "unlawful possession of a controlled substance, a Class 4 felony." for the possession of less than 15 grams (½ oz.) of bromazolam, similar to being charged for unlawful possession of alprazolam in Illinois. It's unknown if this arrest involved counterfeit Xanax shaped tablets or powder. [23] However bromazolam is not scheduled in Illinois. [24]

In June 2022, the U.S. Department of Justice reported that bromazolam seizures were "surging" across the United States, driven in part by increasing detections alongside fentanyl. [25]

In Canada, illicit opioids such as heroin or fentanyl analogues are mixed with bromazolam and sold at the street level; the product is sometimes referred to as "benzo-dope." [26]

In the United Kingdom, Bromazolam is a Class C controlled substance.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Alprazolam</span> Benzodiazepine medication

Alprazolam, sold under the brand name Xanax and others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the management of anxiety disorders, especially panic disorder and generalized anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken orally.

<span class="mw-page-title-main">Imidazopyridine</span> Class of compounds

An imidazopyridine is a nitrogen containing heterocycle that is also a class of drugs that contain this same chemical substructure. In general, they are GABAA receptor agonists, however recently proton pump inhibitors, aromatase inhibitors, NSAIDs and other classes of drugs in this class have been developed as well. Despite usually being similar to them in effect, they are not chemically related to benzodiazepines. As such, GABAA-agonizing imidazopyridines, pyrazolopyrimidines, and cyclopyrrones are sometimes grouped together and referred to as "nonbenzodiazepines." Imidazopyridines include:

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions and, to a lesser extent, bicarbonate ions.

<span class="mw-page-title-main">Nordazepam</span> Benzodiazepine derivative medication

Nordazepam is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

<span class="mw-page-title-main">Adinazolam</span> Triazolobenzodiazepine drug

Adinazolam is a tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It possesses anxiolytic, anticonvulsant, sedative, and antidepressant properties. Adinazolam was developed by Jackson B. Hester, who was seeking to enhance the antidepressant properties of alprazolam, which he also developed. Adinazolam was never FDA approved and never made available to the public market; however, it has been sold as a designer drug.

<span class="mw-page-title-main">Bretazenil</span> Chemical compound

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.

<span class="mw-page-title-main">Pagoclone</span> Chemical compound

Pagoclone is an anxiolytic agent from the cyclopyrrolone family, related to better-known drugs such as the sleeping medication zopiclone. It was synthesized by a French team working for Rhone-Poulenc & Rorer S.A. Pagoclone belongs to the class of nonbenzodiazepines, which have similar effects to the older benzodiazepine group, but with quite different chemical structures. It was never commercialised.

<span class="mw-page-title-main">GABA receptor agonist</span> Category of drug

A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.

<span class="mw-page-title-main">Pazinaclone</span> Chemical compound

Pazinaclone (DN-2327) is a sedative and anxiolytic drug in the cyclopyrrolone family of drugs. Some other cyclopyrrolone drugs include zopiclone and eszopiclone.

<span class="mw-page-title-main">L-838,417</span> Chemical compound

L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. The compound was developed by Merck, Sharp and Dohme.

<span class="mw-page-title-main">SL651498</span> Chemical compound

SL651498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.

<span class="mw-page-title-main">ELB-139</span> Chemical compound

ELB-139 (LS-191,811) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.

<span class="mw-page-title-main">TPA-023</span> Chemical compound

TPA-023 (MK-0777) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. It is a mixed, subtype-selective ligand of the benzodiazepine site of α1, α2, α3, and α5-containing GABAA receptors, where it acts as a partial agonist at benzodiazepine sites of the α2 and α3-containing subtypes, but as a silent antagonist at α1 and α5-containing subtypes. It has primarily anxiolytic and anticonvulsant effects in animal tests, but with no sedative effects even at 50 times the effective anxiolytic dose.

<span class="mw-page-title-main">TP-13</span> Chemical compound

TP-13 is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. It is a subtype-selective partial agonist at GABAA receptors, binding selectively to GABAA receptor complexes bearing α2 and α3 subunits. It has modest anticonvulsant activity although less than that of diazepam, and its main effect is likely to be selective anxiolytic action, as seen with other related α2/3-preferring agonists such as L-838,417.

<span class="mw-page-title-main">L-655,708</span> Chemical compound

L-655,708 (FG-8094) is a nootropic drug invented in 1996 by a team working for Merck, Sharp and Dohme, that was the first compound developed which acts as a subtype-selective inverse agonist at the α5 subtype of the benzodiazepine binding site on the GABAA receptor. It acts as an inverse agonist at the α1, α2, α3 and α5 subtypes, but with much higher affinity for α5, and unlike newer α5 inverse agonists such as α5IA, L-655,708 exerts its subtype selectivity purely via higher binding affinity for this receptor subtype, with its efficacy as an inverse agonist being around the same at all the subtypes it binds to.

<span class="mw-page-title-main">SH-053-R-CH3-2′F</span> Benzodiazepine drug

SH-053-R-CH3-2′F is a drug used in scientific research which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more subtype-selective than most other drugs of this class, having high selectivity, binding affinity and efficacy at the α5 subtype of the GABAA receptor. This gives much tighter control of the effects produced, and so while SH-053-R-CH3-2′F retains sedative and anxiolytic effects, it does not cause ataxia at moderate doses. SH-053-R-CH3-2′F also blocks the nootropic effects of the α5-selective inverse agonist PWZ-029, so amnesia is also a likely side effect.

GABA<sub>A</sub> receptor positive allosteric modulator GABAA receptor positive modulators

In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.

<span class="mw-page-title-main">GABA analogue</span> Class of drugs

A GABA analogue is a compound which is an analogue or derivative of the neurotransmitter gamma-Aminobutyric acid (GABA).

<span class="mw-page-title-main">Desmethylzopiclone</span> Major metabolite of the hypnotic medication zopiclone

Desmethylzopiclone, also known as SEP-174559, is an active metabolite of the sedative-hypnotic drug zopiclone.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ Manchester KR, Lomas EC, Waters L, Dempsey FC, Maskell PD (January 2018). "The emergence of new psychoactive substance (NPS) benzodiazepines: A review". Drug Testing and Analysis. 10 (1): 37–53. doi: 10.1002/dta.2211 . PMID   28471096.
  3. ↑ "Europol 2016 Annual Report on the implementation of Council Decision 2005/387/JHA. EMCDDA" (PDF). European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and European Union Agency for Law Enforcement Cooperation (Europol). 2017.
  4. ↑ Waters L, Manchester KR, Maskell PD, Haegeman C, Haider S (May 2018). "The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines". Science & Justice. 58 (3): 219–225. doi:10.1016/j.scijus.2017.12.004. PMID   29685303.
  5. 1 2 3 Zawilska JB, Wojcieszak J (July 2019). "An expanding world of new psychoactive substances-designer benzodiazepines". Neurotoxicology. 73: 8–16. doi:10.1016/j.neuro.2019.02.015. PMID   30802466. S2CID   73461430.
  6. ↑ Clayton T, Poe MM, Rallapalli S, Biawat P, Savić MM, Rowlett JK, et al. (2015). "A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model". International Journal of Medicinal Chemistry. 2015: 430248. doi: 10.1155/2015/430248 . PMC   4657098 . PMID   26682068.
  7. 1 2 "Critical review report: Bromazolam" (PDF). 20 October 2023.
  8. 1 2 3 4 5 6 7 Wagmann L, Manier SK, Felske C, Gampfer TM, Richter MJ, Eckstein N, et al. (November 2021). "Flubromazolam-Derived Designer Benzodiazepines: Toxicokinetics and Analytical Toxicology of Clobromazolam and Bromazolam". Journal of Analytical Toxicology. 45 (9): 1014–1027. doi:10.1093/jat/bkaa161. PMID   33048135.
  9. 1 2 Tan KR, Rudolph U, Lüscher C (April 2011). "Hooked on benzodiazepines: GABAA receptor subtypes and addiction". Trends in Neurosciences. 34 (4): 188–197. doi:10.1016/j.tins.2011.01.004. PMC   4020178 . PMID   21353710.
  10. ↑ Dear JW, Bateman DN (March 2016). "Benzodiazepines". Medicine. 44 (3): 145. doi:10.1016/j.mpmed.2015.12.025.
  11. ↑ Orsolini L, Corkery JM, Chiappini S, Guirguis A, Vento A, De Berardis D, et al. (September 2020). "'New/Designer Benzodiazepines': An Analysis of the Literature and Psychonauts' Trip Reports". Current Neuropharmacology. 18 (9): 809–837. doi:10.2174/1570159X18666200110121333. PMC   7569319 . PMID   31933443.
  12. ↑ "Critical review report: Bromazolam" (PDF). Expert Committee on Drug Dependence. 2023.
  13. 1 2 Safaei-Ghomi J, Hatami A (January 2008). "Facile and Efficient One‐Pot Protocol for Synthesis of 5‐Phenyl‐1,4‐benzodiazepine‐2‐one Derivatives". Synthetic Communications. 38 (2): 297–302. doi:10.1080/00397910701750078. ISSN   0039-7911.
  14. 1 2 Wade LG, Simek JW (2017). Organic chemistry (Ninth global ed.). Harlow: Pearson Education Limited. ISBN   978-1-292-15110-6.
  15. ↑ Brown TL, LeMay HE, Bursten BE, Murphy CJ, Woodward PM, Stoltzfus MW (2022). Chemistry: the central science (15th global edition in SI units ed.). Harlow: Pearson. ISBN   978-1-292-40761-6.
  16. ↑ Batlle E, Lizano E, Viñas M, Pujol MD (2019-03-13), "1,4-Benzodiazepines and New Derivatives: Description, Analysis, and Organic Synthesis", Medicinal Chemistry, IntechOpen, doi: 10.5772/intechopen.79879
  17. ↑ US20040082573A1,Cook J, Huang Q, He X, Li X, Yu J, Han D, Lelas S, McElroy J,"Anxiolytic agents with reduced sedative and ataxic effects",issued 2004-04-29
  18. ↑ US7618958B2,Cook J, Zhou H, Huang S, Sarma PV,"Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects",issued 2009-11-17
  19. ↑ US8835424B2,Cook J, Huang S, Edwankar R, Namjoshi OA,"Selective agents for pain suppression",issued 2014-09-16
  20. ↑ "Chapter 34". law.lis.virginia.gov. Archived from the original on 2023-03-23.
  21. ↑ "Warren County Grand Jury of February 2023 indictments". Royal Examiner. 18 February 2023.
  22. ↑ "Florida Man Sentenced for Selling Counterfeit Drugs on the Dark Net". Eastern District of Virginia. United States Department of Justice. 24 August 2021.
  23. ↑ Cousins S (9 August 2021). "Drug charges filed recently in Madison County". The Telegraph.
  24. ↑ "720 ILCS 570/". Illinois Controlled Substances Act. State of Illinois.
  25. ↑ Papsun DM, Krotulski AJ, Mastrovito R, Walton SE, Logan BK (15 June 2022). "Bromazolam Prevalence Surging Across the United States Driven In Part by Increasing Detections Alongside Fentanyl". NCJRS Virtual Library. U.S. Department of Justice.
  26. ↑ "Bromazolam Warning about deadly street drug bromazolam". 9 December 2022.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.