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. 2024 Jan 12;12(1):13.
doi: 10.3390/pharmacy12010013.

Benzodiazepine Boom: Tracking Etizolam, Pyrazolam, and Flubromazepam from Pre-UK Psychoactive Act 2016 to Present Using Analytical and Social Listening Techniques

Anthony Mullin  1 , Mark Scott  1 , Giorgia Vaccaro  1 , Giuseppe Floresta  1   2 , Davide Arillotta  3 , Valeria Catalani  1 , John M Corkery  1 , Jacqueline L Stair  1 , Fabrizio Schifano  1 , Amira Guirguis  4
Affiliations

Benzodiazepine Boom: Tracking Etizolam, Pyrazolam, and Flubromazepam from Pre-UK Psychoactive Act 2016 to Present Using Analytical and Social Listening Techniques

Anthony Mullin et al. Pharmacy (Basel). .

Abstract

Introduction: The designer benzodiazepine (DBZD) market continues to expand whilst evading regulatory controls. The widespread adoption of social media by pro-drug use communities encourages positive discussions around DBZD use/misuse, driving demand. This research addresses the evolution of three popular DBZDs, etizolam (E), flubromazepam (F), and pyrazolam (P), available on the drug market for over a decade, comparing the quantitative chemical analyses of tablet samples, purchased from the internet prior to the implementation of the Psychoactive Substances Act UK 2016, with the thematic netnographic analyses of social media content.

Method: Drug samples were purchased from the internet in early 2016. The characterisation of all drug batches were performed using UHPLC-MS and supported with 1H NMR. In addition, netnographic studies across the platforms X (formerly Twitter) and Reddit, between 2016-2023, were conducted. The latter was supported by both manual and artificial intelligence (AI)-driven thematic analyses, using numerous.ai and ChatGPT, of social media threads and discussions.

Results: UHPLC-MS confirmed the expected drug in every sample, showing remarkable inter/intra batch variability across all batches (E = 13.8 ± 0.6 to 24.7 ± 0.9 mg; F = 4.0 ± 0.2 to 23.5 ± 0.8 mg; P = 5.2 ± 0.2 to 11.5 ± 0.4 mg). 1H NMR could not confirm etizolam as a lone compound in any etizolam batch. Thematic analyses showed etizolam dominated social media discussions (59% of all posts), with 24.2% of posts involving sale/purchase and 17.8% detailing new administration trends/poly-drug use scenarios. Artificial intelligence confirmed three of the top five trends identified manually.

Conclusions: Purity variability identified across all tested samples emphasises the increased potential health risks associated with DBZD consumption. We propose the global DBZD market is exacerbated by surface web social media discussions, recorded across X and Reddit. Despite the appearance of newer analogues, these three DBZDs remain prevalent and popularised. Reporting themes on harm/effects and new developments in poly-drug use trends, demand for DBZDs continues to grow, despite their potent nature and potential risk to life. It is proposed that greater controls and constant live monitoring of social media user content is warranted to drive active regulation strategies and targeted, effective, harm reduction strategies.

Keywords: analytical characterisation; designer benzodiazepines; poly-drug use; social media.

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Conflict of interest statement

F.S. was a member of the UK Advisory Council on the Misuse of Drugs (ACMD; 2011–2019) and is currently a member of the EMA Advisory Board (Psychiatry). J.M.C. is a co-opted member of the ACMD’s Technical and Novel Psychoactive Substances Committees. A.M., A.G., G.V., D.A., G.F., V.C., J.L.S. and M.S. declare no conflicts of interest. None of the views or opinions expressed here are necessarily those of the contributors’ employers, the ACMD or the EMA.

Figures

Figure 1
Figure 1
Tablet samples included in the study. NB: Each batch and tablet sample were coded for simplicity (etizolam tablets, ET1, ET2, ET3, ET4, ET5, ET6; flubromazepam tablets, FT1, FT2, FT3, FT4 and FT5; pyrazolam tablets, PT1, PT2, PT3 and PT4).
Figure 2
Figure 2
Etizolam UHPLC-MS analysis: peak elution for all etizolam tablet samples (ET) and etizolam reference standard (ERS). Chromatogram (left) shows etizolam mass elution at ca 2.45 min, with diazepam internal standard at ca 2.73 min; image shows sample descriptors. Reference standard mass spectra inlayed (middle), tablet sample ET1 mass spectra (right), and target molecule etizolam (inset). Corresponding to the average molecular mass for etizolam, accounting for Cl-35 and Cl-37 isotopes, we report a mass at 343.80 g/mol−1 [37]. Thus, protonated isotopic variants report parent ions for etizolam at m/z 343 and 345, respectively, which are identified in all spectra. Accounting for the presence of a sodium adducts MH+, a byproduct of the UHPLC-MS process, we identified a parent ion at 265 m/z, as expected [38].
Figure 3
Figure 3
Flubromazepam UHPLC-MS analysis: peak elution for all flubromazepam tablet samples (FT) and flubromazepam reference standard (FRS). Chromatogram (left) show flubromazepam mass elution at ca. 2.45 min, with diazepam internal standard at ca. 2.68 min; image shows sample descriptors. Reference standard mass spectra inlayed (middle left (FRS), tablet sample FT1 mass spectra inlayed (middle right), and target molecule flubromazepam (inset). Flubromazepam molecular mass 333.150 g/mol−1 [39], with UHPLC-MS showing typical protonated ions in flubromazepam at m/z 333 and 335 [40].
Figure 4
Figure 4
Pyrazolam UHPLC-MS analysis: peak elution for all pyrazolam tablet samples (PT) and pyrazolam reference standard (PRS). Chromatogram (left) show pyrazolam mass elution at ca. 1.02 min, with diazepam internal standard at ca. 2.68 min; image shows sample descriptors. Reference standard mass spectra inlayed (middle), tablet sample PT1 mass spectra (right), and target molecule pyrazolam (inset). Pyrazolam molecular mass 354.20 g/mol−1 [41]. MS shows a nominal mass of m/z 356, indicating the presence of Br-81 isotope protonated molecular ion.
Figure 5
Figure 5
The 600 MHz 1H NMR comparison of pyrazolam tablet samples against pyrazolam reference standard, showing comparable spectral profiles, with sample P1 and P3 showing reduced profile definition attributable to drug concentration.
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