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.

Counterfeit Ozempic is NOT Off-Label Ozempic

 

Glucagon like peptide (GLP)

I was content to let the FDA release and the news media handle this problem until I watched a TV news person say the following:  “Counterfeit Ozempic or off label Ozempic is potentially dangerous…..”  Off label Ozempic is NOT counterfeit Ozempic.  Off label medications are FDA approved medications that are prescribed for indication other than what is listed in the package insert.  Based on a recent table that I made from package insert information practically all GLP-1 agonists like Ozempic are prescribed off label because the FDA indication is Type 2 diabetes mellitus rather than weight management. The FDA news release is all about Ozempic look alikes being sold as the real product.  In some cases they do not contain any active ingredient and in the majority of cases what they actually contain is currently unknown. 

The FDA warning (1) about counterfeit Ozempic surfaced on 12/21/2023.  Ozempic and many drugs in this class come in an injection device, since most of the dosing is by subcutaneous (SC) injection. The FDA also warned that the needles in these devices were counterfeit and their safety and sterility could not be guaranteed.  In the warning in reference 1 they describe 5 incidents of adverse effects – none life threatening.  The confiscated pens are being analyzed to determine what is being used rather than Ozempic.  Counterfeit pens were found in at least 9 countries and in some – insulin was found (2). The FDA provides lot and serial numbers of the counterfeit medication and advises pharmacies not to use it.

The same day as this release, the FDA also warned about compounded GLP-1 agonists (3).  Compounded products are prepared by compounding pharmacies.  If medications are in short supply – compounding pharmacies can produce them. Ozempic and Wegovey are both on that list.  Both are semaglutides and adverse events have occurred with the compounded versions.  Some of the counterfeit versions contain the salt form of semaglutide compared with the FDA approved medication that is the base form.  This warning also describes counterfeit semaglutide being marketed online, concerns about counterfeit Ozempic in the US, and it encourage patients to protect themselves by only purchasing semaglutides through state licensed pharmacies.

Although it is not emphasized in the warnings, I also have concern about the injection pen device that the semaglutide is contained in.  The injectors are calibrated to deliver 0.25. 0.5, and 1 mg doses according to the prescription for each patient.  The device is supposed to click when it is at the corrected dose.  This medication and unique injector is reminiscent of other medications where the patented delivery system was so critical to the medication that it essentially extended the patent.  Unless the counterfeiters are using a very similar device the recommended doses of medication might not be delivered correctly.  Exactly how problematic that will be depends on the medication or substance that has been substituted for the semaglutide.  Even if the counterfeiters can produce a semaglutide like name brand Ozempic or Wegovey – there is no guarantee that the pen device they are using can guarantee accurate delivery of the dose.

At this time, I have not heard that there has been an attempt to synthesize the actual medication. With today’s technology I would not be surprised if that attempt was made at some point. 

That led me to think about the issue of legal and illicit drugs. At some point – knowledge obtained in the past century seems to have been replaced by the rhetoric of drug legalization. These arguments are always about drugs that reinforce their own use or what are commonly referred to as addictive drugs. The legalization myth generally skips over the harms of these drugs directly to what is often referred to as harm reduction.  That generally means that it is more harmful to insist that people stop using these drugs than providing them with safe forms to continue using or in the more extreme case to leave drug dealing and all the illicit forms intact. In the latter case, methods to test the drugs and provide safer methods of delivery offer the users an opportunity to protect themselves from suppliers who may add adulterants to the drugs or substitute a more dangerous drugs without informing them. 

GLP-1 agonists are clearly not addictive drugs as far as anyone knows at this point. But the issue I attempted to cover in this post is drug safety – specifically the safety of the drug supply to patients with a prescription. Despite the provocative way the pharmaceutical industry is covered and often villainized in the press – there is no doubt that they can and have provided a safe supply of medication to the public. There are lapses and inadequate inspections and recalls.  The current system is far from perfect. But it is clearly superior to any system being run by a criminal enterprise supplying illicit drugs. It is hard to imagine a system where you would have to personally run a chemical test on your prescription medications to make sure they were safe.  It is equally hard to imagine producing counterfeit drugs and selling them to the public like the real thing.

That is what the FDA is trying to prevent with this warning. 

  

George Dawson, MD, DFAPA

 

Supplementary:  Aware of counterfeit Ozempic or Wegovey?  Can you get it without a prescription?

It has come to my attention that many people are aware of the availability of counterfeit Ozempic and Wegovey thorough their social networks. I am very interested in how widespread this problem is right now.  Please report your  experience here anonymously in the comments section or by emailing me.

References:

1:  FDA.  FDA warns consumers not to use counterfeit Ozempic (semaglutide) found in U.S. drug supply chain.  December 21, 2023 https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-use-counterfeit-ozempic-semaglutide-found-us-drug-supply-chain

2:  National Association of Boards of Pharmacy.  Counterfeit Ozempic Found in US Retail Pharmacy.  August 7, 2023 https://nabp.pharmacy/news/blog/regulatory_news/counterfeit-ozempic-found-in-us-retail-pharmacy/

3:  FDA.  Medications Containing Semaglutide Marketed for Type 2 Diabetes or Weight Loss.  December 21, 2023 https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss

 

Peptide Structure:

Drawn with PepDraw:  https://pepdraw.com/