Fake Xanax: Designer Emerging Benzodiazepine Epidemic Linked to Morbidity and Mortality a Narrative Review

Benzodiazepines are a widely used class of drug that bind to a component of the GABA_A receptor complex, ultimately leading to depression of the central nervous system [1, 12]. In addition to having antiseizure properties, benzodiazepines also have sedative-hypnotic, anxiolytic, muscle relaxant, and amnesic effects [1]. These properties are a result of the activation of the benzodiazepine and GABA_A receptors on the GABA receptor complex. Activation of the benzodiazepine receptor leads to increased frequency in the opening of the GABA_A Cl⁻ channel when GABA is present. This causes an influx of chloride anions leading to membrane hyperpolarization, and ultimately neuronal inhibition and CNS depression [1, 12]. There are dozens of benzodiazepines currently in use for indications such as acute seizures, anxiety disorders (e.g., alprazolam, lorazepam, and oxazepam), insomnia (e.g., estazolam, flurazepam, and temazepam), induction of amnesia (midazolam), seizure disorders (e.g., clobazam), spastic disorders, and agitation [1]. Some of the most important benzodiazepines are midazolam and lorazepam which are used for the treatment of convulsive status epilepticus with the latter being a first-line drug for the treatment of convulsive status epilepticus [13]. Some common adverse effects of benzodiazepines include respiratory depression, respiratory arrest, confusion, headaches, syncope, nausea, vomiting, diarrhea, tremors, and most commonly, drowsiness [1]. Older individuals, particularly over the age of 65, tend to be more susceptible to these adverse effects while those with a history of alcohol or barbiturate misuse tend to be resistant to the CNS depressant properties of benzodiazepines [12]. Benzodiazepines also have severe drug–drug interactions when combined with substances like ethanol, other benzodiazepines, and sedatives. Taken with any of these other substances may result in a synergistic effect on respiratory depression. Lorazepam and oxazepam should also not be concurrently administered with uridine diphosphate glucuronosyltransferases (UGTs), as it may increase metabolism and decrease efficacy due to lorazepam and oxazepam being metabolized by UGTs [1].

While the development of physical dependence is less common, tolerance and psychological dependence are quite frequent with individuals taking benzodiazepines. Additionally, a pronounced withdrawal syndrome can occur upon discontinuation of benzodiazepines after long-term use [12]. Rebound insomnia can also occur, where the duration and quality of the individuals sleep are reduced [14].

While benzodiazepines have a relatively high margin of safety, overdoses do occur. However, this is usually due to combining alcohol or other drugs with benzodiazepines. Overdose from benzodiazepines alone mostly involves elderly patients, young children, iatrogenic overdosing, or suicides [12]. In the case of an overdose, patients may be administered flumazenil, a benzodiazepine antagonist, in an effort to prevent benzodiazepine from binding to the GABA_A receptor thus reducing their toxic effects [15].

Etizolam is a thienodiazepine derivative, differing from traditional benzodiazepines in that it has a thiophene ring in place of a benzene ring. Etizolam is a full agonist at GABA_A receptors, and when bound increases GABAergic signaling leading to the opening of GABA-induced chloride channels. The influx of chloride ions then leads to neuronal hyperpolarization, and ultimately CNS depression [5, 16]. According to a study of 10 designer benzodiazepines, etizolam was shown to be the most euphoric and among the most potent of the drugs studied [17]. This is likely due to etizolam’s high affinity towards GABA_A α1 subunit-containing receptors. Binding of α1 subunit-containing receptors produces an anxiolytic effect while α2 and α3 subunit-containing receptors produce a sedative effect when bound [16].

Etizolam has a half-life of 5–7 h, which is shorter than many benzodiazepines such as alprazolam (8–15 h), lorazepam (9–19 h), and diazepam (20–70 h), but longer than midazolam (1.5–3 h) [5, 18, 19] (Table 1). Etizolam’s oral bioavailability of 93% is typical when compared to classic benzodiazepines [16]. Diazepam and lorazepam both have a slightly lower oral availability of 90%, while alprazolam has an oral bioavailability of 80–100% [18, 20, 21]. Midazolam, however, is an outlier, with an oral bioavailability of only 40–50% due to extensive first pass metabolism [19]. Etizolam’s plasma protein bound distribution is average compared to other benzodiazepines at 92.8% [22]. Somewhat similar to diazepam (98%), lorazepam (90%), and midazolam (94–98%), while alprazolam has a lower plasma protein bound distribution of 80% [18, 20, 21, 23]. Liver enzyme CYP3A4 is a main player in the metabolism of etizolam as well as many other benzodiazepines. Therefore, when administered with a CYP3A4 inhibitor such as itraconazole, its metabolism is inhibited, while a CYP3A4 inducer such as carbamazepine increases metabolism [5, 24]. CYP3A4 is also the metabolizer for alprazolam, diazepam, and midazolam [19‐21]. Lorazepam, on the other hand, undergoes enterohepatic recirculation and direct glucuronidation without prior cytochrome p450 metabolism, and therefore it has no CYP metabolizer [18].

Adverse effects associated with using etizolam are similar to those reported with benzodiazepines and include slurred speech, severe sedation, unconsciousness, and depression of the respiratory center in the medulla [25]. A comparison of observed adverse effects of etizolam compared to other designer benzodiazepines can be found in Table 2. Additionally, etizolam is believed to be significantly more dangerous when combined with other medications, as most reported overdoses involving etizolam typically involve polypharmacy—including coadministration with several other drugs such as prescription opioids, heroin, and alcohol [26]. These dangerous effects are especially concerning related to the fact that etizolam may be used as a substitute for other drugs such as alprazolam. Counterfeit drugs, which are marketed as Xanax, may also contain other drugs such as fentanyl. This further increases the risk of toxicity from drug–drug interactions [27].

Etizolam has been associated with various adverse effects and dangers. It poses a significant global health risk related to its association with counterfeit pharmaceuticals and concerning prevalence within the illicit drug market. Demonstrating the prevalence and potential dangers of etizolam in counterfeit tablets, Blakey et al. conducted a dosage survey of designer benzodiazepines in counterfeit pharmaceuticals and found etizolam was the most frequently detected compound in the illicit tablets. Researchers also found etizolam to have the most significant variation in dosage in visually similar counterfeit tablets, ranging from 0.7 to 8.3 mg per tablet [32]. The potency of etizolam is reported to be similar to that of alprazolam, but with some counterfeit tablets containing a significantly higher dose than the recommended therapeutic dose of alprazolam, this poses significant risks to individuals who unknowingly consume these products. Several case reports have highlighted the potential risks and toxic effects of etizolam, including severe adverse effects, overdose, multidrug intoxication, withdrawal, death, and even drug intoxication of children.

Arens et al. identified a series of patients presenting to a California emergency department after ingesting counterfeit alprazolam tablets containing etizolam. Two of the patients, a man in his late twenties and a women in her late thirties, developed rhabdomyolysis, demand cardiac ischemia, and compression neuropathy [27].

Shapiro et al. detailed a case of a 30-year-old man presenting for assistance with detoxification from etizolam. The patient described taking an average dosage of 50 mg per day for several months but had recently increased his dosage to 100 mg or more daily. He was also concurrently taking diclazepam the week of admission [33]. Typical recreational dosages of etizolam and diclazepam are 0.25–3 mg and 1 mg, respectively [34]. The patient obtained the prohibited benzodiazepines via the Internet. Patient described a history of withdrawal seizures and withdrawal symptoms of anxiety, temperature sensitivity, and sensitivity to light and sound. Lorazepam, a metabolite of diclazepam, was found on the urine toxicology screen, and etizolam and lorazepam were both found on a benzodiazepine confirmation panel [33].

O’Connell et al. detailed an overdose of etizolam in a 31-year-old man found unresponsive beside an empty syringe believed to contain heroin. It was also known that the patient had been ingesting multiple etizolam tablets throughout the day. Upon arrival at the hospital, he intravenously administered 0.2 mg of flumazenil, which resulted in immediate and complete reversal of his overdose symptoms. His serum concentration of etizolam was 103 ng/mL [35]. Typical plasma concentrations after consumption of a single therapeutic dose of etizolam (1–3 mg) range from 2 to 30 ng/mL [28].

Drevin et al. describe a case of a 42-year-old French man presenting to the hospital with acute etizolam and cocaine intoxication. As a result of his state of agitation, the patient was placed in restraints and midazolam and loxapine succinate were administered. His plasma concentration of etizolam was 64 ng/mL [36].

Kolbe et al. described a lethal etizolam and caffeine overdose of a 49-year-old German man. The deceased had purchased counterfeit alprazolam. Toxicologic testing revealed etizolam concentrations in femoral blood and cardiac blood to be 770 ng/mL and 2820 ng/mL, respectively. Hair samples taken from the deceased also revealed the presence of alprazolam, indicating repeated use of the drug. Researchers concluded that the cause of death was a result of “acute toxic effects of etizolam and caffeine” [37]. The impact of designer benzodiazepines on vulnerable populations, such as children, is a subject of concern. Love et al. described a unique case of etizolam exposure to three boys aged 6, 9, and 10. Each of the boys presented to the Oregon emergency department with lethargy, impaired coordination, dilated pupils, and drooling after ingesting etizolam disguised as Pez candy [38]. Thus, counterfeit benzodiazepines present a notable threat to public health, leading to potential dangers such as multidrug intoxication, challenges with withdrawal, and, in some cases, fatal overdoses.