More Fake Xanax....

 

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.

The Problem With Benzodiazepines.....

I want to thank David Allen for the inspiration for this post when he commented that as an addiction psychiatrist, I was probably seeing a skewed sample of people addicted to benzodiazepines and that might be why I have such a jaundiced view of them.  I use the above bubble diagram to illustrate how benzodiazepines are prescribed by docs like me with a strong bias toward preventing addiction compared with physicians who have no such bias.  To make sure that we are on the same page, benzodiazepines are all technically tranquilizers or sedatives.  They marked a therapeutic advance from the earlier barbiturate class  in that their therapeutic index (ratio of the drug that produces toxicity in 50% of patients to the dose that produces a therapeutic response in 50% of patients) is much greater than earlier tranquilizers like barbiturates.  The practical measure is that it takes much higher doses to produce respiratory arrest and death.  Despite the increased safety these drugs are addictive.  People can develop a tolerance and in some people they produce a euphorigenic effect, very similar to the effect of alcohol.  Some people describe benzodiazepines as "alcohol in a pill."  Unfortunately we do not know the percentage of people where that occurs or how to detect them. There are many common clinical situations where the safety margin of benzodiazepines is cancelled out by other factors.  Mixing them with alcohol and opiates are two of the most common dangerous situations and if you are treating addiction - you see that happen all of the time.

Rather than list the entire table of benzodiazepines, I am going to list the commonest ones that I see being abused.  In order from the most frequently abuse that group would include alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin), and diazepam (Valium).  Of those compounds Xanax Bars or 2 mg alprazolam tablets seem to be the most commonly abused by far.  The maximum recommended dose of alprazolam is 4 mg/day and I frequently have seen people taking 8-20 mg/day in combination with other street drugs.  Benzodiazepines have all been generic for a long time so they are very inexpensive to purchase if you have a prescription.  If you don't have a prescription and acquire them illegally the "street value" of a drug is a sign of abusability.  The average street value of alprazolam is about $5 for a 2 mg bar.  The immediate risk of using benzodiazepines excessively is accidentally overdosing on the single drug or in combination with alcohol and other drugs of abuse.  There is also a significant seizure risk from abrupt withdrawal when the supply of medications have been used.  The abuse of benzodiazepine like compounds that are more typically used for sleep like zolpidem (Ambien) or eszopiclone (Lunesta) does happen but it is more likely to occur in combination with alcohol for alcohol related insomnia.  A common example would be a person with alcohol dependence who takes zolpidem at night so that they can sleep through the entire night.  Without it they would predictably wake up at 2 or 3 AM from the withdrawal effects of alcohol.  Chronic use of benzodiazepines whether by prescription or acquisition from illegal sources can lead to tolerance and chronic withdrawal symptoms that can last for months if the drug or medication is stopped.  That fact alone should be considered as part of the risk of taking benzodiazepines - even in the situation where the person does not have an addiction and has anxiety that they do not believe can be treated by any other means.  In my experience, I am not sure that kind of anxiety exists.

Another common problem with benzodiazepines is that they can be psychologically debilitating, even if the person affected never takes the pill.  It is all part of the behavioral pharmacology of addicting drugs.  It usually starts out with a panic attack.  That panic attack can result in people going to the emergency department once or twice because they believe they are having a heart attack.  Somewhere along the line a physician prescribes alprazolam to take "in case of a panic attack."  That starts to happen and even if the panic attacks are rare, brief, and situational - the person affected starts to believe they need to carry alprazolam around with them wherever they go "in case" of another panic attack.  They may not have had a panic attack in years, but they are more anxious about whether they are carrying a pill when they get on a plane, cross a bridge, etc.  The pill have taken on Talisman-like features based on their using it for a condition that for most people fades away over time.  Some  who don't know the sequence of events might suggest "what's the harm" if somebody develops such a belief system around a pill.  In my estimation the harm is that the person's normal conscious state has been transformed and they have exchanged one form of anxiety for another.  The debilitating effects of anxiety depend on the illusion that your life needs to be modified in a certain way to accommodate it.  Proving to yourself that is not true is one of the best ways to adapt.        

Despite those reservations, I have prescribed a lot of benzodiazepines in my career.  They are very good medications to use in controlled environments for acute alcohol and sedative hypnotic withdrawal, acute seizures, catatonia,  akathisia, and various agitation syndromes associated with acute psychosis and mania.  The goal is typically to get the patient off the medication before they are discharged and to avoid treating patients with addiction with benzodiazepines.  Benzodiazepines are also useful for the first month in treating panic attacks, but that typically takes a lot of work.  The work involved is convincing the patient that a medication that seems to work rapidly is not a good one to take for the long haul.  The other dimension that is operating here that is rarely commented on and never explicit is whether the person receiving the benzodiazepine enjoys taking it.  Medications that are potentially addictive lead to an array of problems that are not there with drugs than are not addicting.  The main one is that they tend to be viewed as solutions for everything.  Instead of just anxiety or panic people will take them for insomnia, stress, or just to wind down at the end of the day.  Medications that reinforce their own use have the problem of inventing new uses that they were never prescribed for and that can lead to escalating doses of the medication.  In some complicated situations benzodiazepines are added to treat anxiety.  They have been used in psychiatric patients with multiple problems and been shown to add no benefit.  They are commonly added to multiple medications including opioids in patients with chronic pain with no additional benefit.

Benzodiazepines are a big problem in primary care.  The NSDUH survey illustrates that most people with an addiction are not aware of it and further that only a small minority seek treatment and find it.  That same survey suggests that about 1.5 million Americans start using tranquilizers and sedatives (they do not have a unique benzodiazepine category) for non-medical use very year.  Even if it is apparent to a primary care physician and their patient that an addiction to benzodiazepines exits, there are significant obstacles to reversing the process.  Although there are protocols for slowly tapering the medication on the Internet, it takes a very highly motivated person and ideal circumstances to accomplish this.  Outpatient detox from urgent care, the emergency department or an outpatient clinic is problematic because the same medication that the patient is not able to control is being given to them to self administer at home.  It is common that the detox medications are all taken the same day or in some cases at once.  Structured detoxification in the American health care system is practically impossible to find, especially in the case of benzodiazepines that require careful attention to seizure prevention, the prevent of withdrawal delirium, and adequate treatment of chronic withdrawal symptoms when they emerge.  Some primary care clinics are taking the preventive approach of not starting benzodiazepines in the first place.

Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.

There is a lot of resistance to the ideas of addiction docs when benzodiazepines and their long term effects are discussed among physicians.  There is always a physician who claims that they have successfully treated a person with an alcohol use disorder with benzodiazepines or they have people who have stayed on low doses for decades in order to treat their anxiety.  I see the failures.  It leads to the question of how many people are capable of staying sober, not developing a tolerance to benzodiazepines, and not experiencing a negative impact on their life.

As far as I know there are no good studies that address that question and I would not expect that there will be.  Any study that allowed subjects to mix alcohol, opiates, and benzodiazepines would be unethical and should not be approved by any Human Subjects Committee.


George Dawson, MD, DFAPA


Supplementary:

This article was subsequently edited and modified for the Psychiatric Times.  The edited version reads better.