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Triazolobenzodiazepine

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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]

Adverse effects

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Because bromazolam is relatively new, epidemiologically 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 are benzodiazepines 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 could 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

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Pharmacokinetics

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Metabolism

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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

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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

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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

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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]

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Chemistry

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Synthesis

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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.

Society and culture

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Legal status

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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 chloro 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] 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] The Indiana Department of Health reported that bromazolam represented 73% of all novel or designer benzodiazepines detected in the first six months of 2023. Of 1,051 blood toxicology samples containing bromazolam reported between January and June 2023, 83% were fentanyl positive, suggesting that bromazolam is commonly mixed with fentanyl.[27]

In the United Kingdom, Bromazolam is a Class C controlled substance.

See also

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References

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As bromazolam gains traction in Florida’s substance misuse scene, knowing its consequences becomes critical. In this blog post, we’ll dig into the complexities of bromazolam, explaining its makeup, risks, and the worrisome rise in overdoses around the state. We’ll also list the common dangers that this benzodiazepine derivative brings to people’s physical and mental health and introduce avenues to seek assistance and support for yourself or a loved one.

Bromazolam, a benzodiazepine derivative, poses a significant threat in Florida’s substance abuse landscape due to its composition and the alarming rise in overdoses. Its insidious nature jeopardizes physical and mental well-being. Those in need of assistance and support can turn to Hanley Center, a comprehensive care facility in Florida that offers tailored treatments to address the complexities of bromazolam-related issues.

What is Bromazolam?

Bromazolam, a synthetic benzodiazepine conceived in the 1970s but never brought to market as a medicinal drug, surfaced in the addiction landscape in 2016 and has been gaining momentum since 2022. With properties akin to Xanax, offering hypnotic and anxiety-reducing effects, its increasing presence underscores the necessity of acknowledging its impact. The urgency of deploying personalized treatment approaches becomes paramount for individuals navigating the complexities of benzodiazepine-related challenges on the path to recovery.

Dangers of Bromazolom

In 2021, bromazolam accounted for only 4% of circulating novel benzodiazepines, as per the CFSRE. However, their recent estimate suggests a significant increase, with bromazolam now constituting 73% of the supply of novel benzodiazepines in the first six months of 2023. The dangers of misuse of the drug include a range of mild side effects to life-threatening consequences.

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Dangers of Misusing Bromazolam (from least to severe to most severe)

• Drowsiness and Dizziness: Misuse of bromazolam can lead to mild side effects like drowsiness and dizziness, affecting cognitive functions.
• Loss of Coordination: Users may experience a decline in coordination, impacting motor skills and increasing the risk of accidents.
• Respiratory Depression: Bromazolam misuse can cause respiratory depression, where breathing becomes dangerously slow and shallow, posing a significant health risk.
• Coma: In severe cases, the drug can induce a coma, representing a critical and potentially life-threatening state of unconsciousness.
• Death: The most severe consequence of bromazolam misuse is death, often resulting from respiratory failure or complications arising from its potent effects.

Rise in Florida’s Bromazolam Overdose Cases

The escalating threat of bromazolom cases has the attention of the state’s top law enforcement officials, who are leading a campaign to educate residents about a surge in overdoses and deaths nationwide. Reports indicate bromazolam’s presence spiked from 1% to 13% in toxicology cases, with severe side effects such as respiratory depression and even death. In response, Florida’s Attorney General, Ashley Moody, urges against using illicit substances, emphasizing the lethal potential. Bromazolam, part of novel benzodiazepines, lacks strict regulation, making it more unpredictable than its prescribed counterparts. Its rising prevalence, often laced with fentanyl, underscores a critical public health crisis.

Florida’s Drug-Related Outcomes Surveillance & Tracking System (FROST) reveals startling data when comparing harm from Bromazolam misuse with opioids. Among the data on deaths from benzos in Palm County, you can see a striking similarity in the number of deaths between the two drug groups. In the first two quarters of 2022, benzos misuse was reported in 159 deaths in Palm Beach County, while opioid misuse is associated with 161 deaths.

Getting Help at Hanley Center

Hanley Center serves as a light of hope for people with benzodiazepine addiction, providing evidence-based, age- and gender-specific therapies for a more targeted approach to recovery. The organization ensures a thorough understanding of the difficulties related to benzodiazepine abuse by employing tried-and-true research methods. By personalizing solutions to meet gender requirements, Hanley Center creates an atmosphere where people may address the unique issues they encounter. With a focus on evidence-based treatments, Hanley Center offers a structured and supportive environment to help patients achieve long-term recovery from benzodiazepine abuse.

Hanley Center is a well-known care provider offering a range of treatment programs targeting the recovery from substance use, mental health issues, and beyond. Our primary mission is to provide a clear path to a life of healing and restoration. We offer renowned clinical care for mental illnesses and have the compassion and professional expertise to guide you toward lasting wellness. For information on our programs, call us today: 561-841-1033.

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