Xanax 2 mg “bars” are currency for drug users on the
street. Xanax or alprazolam is a
benzodiazepine like drug that has been around since 1981. That was my third year in medical school and
the intense marketing of the drug had just begun. A few years later as a psychiatry resident I
attended my first American Psychiatric Association (APA) convention in Los
Angeles. As I was walking around with 2 colleagues,
we noticed a large light show that consisted of a Xanax tablet inscribed on the
wall of the convention center in bright red laser light.
Like all new medications there is a period of
experimentation and off label use. In
that time some extraordinary doses of alprazolam were suggested to treat panic
attacks. There was also the suggestion
that alprazolam may have special properties and that it might be an
antidepressant because it was not structurally like the other
benzodiazepines. Over time it was
apparent that it was an addicting medication that could lead to tolerance and
withdrawal phenomena in the context of dose escalation and uncontrolled
use. I have never seen any good studies
looking at the addiction potential but it is highly desired and easily
accessible on the street and has significant street value. A good comparison molecule for addiction
potential is chlordiazepoxide. It is
also in the benzodiazepine class but is considerably less potent and probably
has a much longer time to effect. Both those properties make it far less euphorigenic
and lessen the addiction potential. Over the course of my career – I have never
seen a person using excessive amounts of chlordiazepoxide and when used for
detoxification from alcohol – even in high doses – it seems to work without any
euphoria or disinhibitory effect.
About ten years ago, the people I was assessing at the time
described a new trend. Fentanyl was
being pressed into tablets identical to Xanax bars. I asked several people how they knew that was
true and they personally witnessed the process. Of course, you must believe
that what is described as fentanyl really is.
For safety’s sake you also must believe that these street chemists know
the difference between milligrams and micrograms. I am not recommending that
anyone believe people dealing or distributing street drugs – I am just
explaining how the people I was seeing rationalized that decision. I was seeing
a skewed sample of people who had survived the experience of taking these fake
Xanax bars. They were also not risk averse – but were clearly looking
for higher highs after developing tolerance to opioids, benzodiazepines, or
both. Many sought out sources of fentanyl and fake Xanax bars was only part of
that scene.
Fentanyl is not the only way to make fake Xanax. The MMWR (1) describes 3 cases of bromazolam
being disguised as Xanax. As can be seen
from the structures at the top of this post – both molecules
are nearly identical. The only
difference is that alprazolam has a chlorine atom at the identical location
that bromazolam has a bromine atom. Despite
the similarity – chlorine is more electronegative and would be expected to
significantly alter the electron distribution and polarity of alprazolam - so
receptor binding would probably be affected.
The CDC paper says that bromazolam was synthesized in 1976 –
about the time that alprazolam was originally coming on the scene. I searched
my access to the medicinal chemistry literature and did not find any papers on
synthesis of series of these compounds with different properties. I did find a much more recent paper on the
search for Novel Psychoactive Substances (NPS) in the population-based
toxicology of British Columbia over a 2 year span from August 1, 2019 to August
31, 2021. During that time the researchers
focused on identifying novel compounds and plotting the percentage of positive samples
over time. In the case of bromazolam,
the percentage of samples increased from 0% to 5% (Figure 4). The CDC paper suggests a similar very rapid
increase in bromazolam on the street as evidenced by drug seizures and deaths
over the past three years.
The CDC paper also describes an intentional ingestion by two
25-year-old men and a 20-year-old woman of a substance they believed was
alprazolam. It was bromazolam. All three required emergency hospitalization
after they were found unresponsive 8 hours later.. They all developed seizures and one
progressed to status epilepticus and coma. Vital signs were variable with
tachycardia, hypertension, and hyperthermia. All three were intubated for
ventilatory support. All three had myocardial damage as indicated by elevated
troponin levels. One of the men had
persistent neurological deficits (aphasia) at the time of discharge on day 11. The other man was discharged on day 4 with
hearing deficits. The woman required transfer to another hospital on day 11 due
to status epilepticus despite multiple anticonvulsant medications. She was lost to follow up. Subsequent toxicology (serum or plasma)
showed bromazolam with no fentanyl or other opioids in all of their samples.
The case reports from the CDC are instructive because of the
relatively catastrophic outcomes at least in the short term in otherwise
healthy young adults.. We do not know
the specifics of the ingestion and what findings were directly attributable to
the drug as opposed to secondary effects like hypoxia. The relative lack of information about the
drug suggest to me that it was abandoned in early development for some
reason. None of these are good signs in
terms of the safety of the Xanax supply available through non-prescription sources.
It seems as likely that drug distributors are likely to substitute anything
ranging from fentanyl to non-approved benzodiazepines and both can have disastrous
consequences.
It is no secret that there is a never-ending stream of toxic
drugs being sold on the street as intoxicants. Bromazolam as Xanax is just the
latest iteration. We are in the midst of a multi-decade drug epidemic fueled by a combination of unlimited demand in the United States and
various criminal and state interests set to profit immensely off this problem.
We also now have people who are spinning drug dealers and the drug supply as a
harm reduction intervention that should go unchecked on that basis. All that I can do is remind people that
suppliers of these drugs are not your friends and they cannot be trusted. The
contents of this post are just a small part of that evidence. And a sober life
is a better life so that not starting to use these drugs at the outset is the
best path.
George Dawson, MD, DFAPA
Supplementary:
A note on nomenclature. Alprazolam or Xanax is commonly considered a benzodiazepine but it is not. Complex molecules have naming conventions based on IUPAC (International Union of Pure and Applied Chemistry) nomenclature. These are complicated, require some knowledge of organic chemistry, and are hardly ever used in the medical literature. Organic chemists and medicinal chemists have advised me that they are also hardly ever used in their professions outside of publications where they are required. Structural formulas are generally more useful for direct comparisons. Chemistry publications typically have both.
What is used is a general classification
based on structures that are more readily identified. I will illustrate what I mean using
alprazolam, bromazolam, and a classic benzodiazepine – diazepam or Valium. In the table below both the IUPAC name and the
chemical structure shows that the key difference is the 1,2,4 triazolo moiety. Moieties in organic chemistry are
recognizable parts of molecules that are typically used in naming and designing syntheses. The triazolo structure
is a 5-member ring that consists of 3 nitrogen atoms and 2 carbon atoms. It is visible in the drawings of both
alprazolam and bromazolam in the lowest part of the drawing. The blue dots in these drawings are nitrogen
atoms. Technically alprazolam and bromazolam are triazolobenzodiazepines and
diazepam is a benzodiazepine. This may account for differences at the clinical
level in terms of cross reactivity for detoxification purposes and likelihood of
certain complications – like withdrawal seizures.
References:
1: Ehlers PF, Deitche
A, Wise LM, et al. Notes from the Field: Seizures, Hyperthermia, and Myocardial
Injury in Three Young Adults Who Consumed Bromazolam Disguised as Alprazolam —
Chicago, Illinois. February 2023. MMWR
Morb Mortal Wkly Rep 2024;72:1392–1393. DOI: http://dx.doi.org/10.15585/mmwr.mm725253a5
2: Skinnider MA,
Mérette SAM, Pasin D, Rogalski J, Foster LJ, Scheuermeyer F, Shapiro AM.
Identification of Emerging Novel Psychoactive Substances by Retrospective
Analysis of Population-Scale Mass Spectrometry Data Sets. Anal Chem. 2023 Nov
28;95(47):17300-17310. doi: 10.1021/acs.analchem.3c03451. Epub 2023 Nov 15.
PMID: 37966487.
3: Mérette SAM,
Thériault S, Piramide LEC, Davis MD, Shapiro AM. Bromazolam Blood
Concentrations in Postmortem Cases-A British Columbia Perspective. J Anal
Toxicol. 2023 Apr 14;47(4):385-392. doi: 10.1093/jat/bkad005. PMID: 36715069.
4: Wagmann L, Manier
SK, Felske C, Gampfer TM, Richter MJ, Eckstein N, Meyer MR.
Flubromazolam-Derived Designer Benzodiazepines: Toxicokinetics and Analytical
Toxicology of Clobromazolam and Bromazolam. J Anal Toxicol. 2021 Nov
9;45(9):1014-1027. doi: 10.1093/jat/bkaa161. PMID: 33048135.
5: Papsun DM,
Chan-Hosokawa A, Lamb ME, Logan B. Increasing prevalence of designer
benzodiazepines in impaired driving: A 5-year analysis from 2017 to 2021. J
Anal Toxicol. 2023 Nov 1;47(8):668-679. doi: 10.1093/jat/bkad036. PMID:
37338191.
Graphics Credit
I drew the molecules in the top drawing with MolView. The thumbnails in the table are from PubChem.
