Key Insights from What's New on the Designer Drug Scene: Synthetic Cannabinoids, Precursors, and More

Holly Pierzynski, manager of Forensic Novel Psychoactive Substance Research at Cayman Chemical, discussed recent developments among several popular drug classes in a recent webinar presented as part of the 2024 Current Trends in Seized Drug Analysis Symposium. Featured topics included new analogs that have appeared recently on the grey marketplace and a review of the emergence of synthetic precursors being sold for the non-legitimate production of synthetic cannabinoids, benzodiazepines, and opioids. We have summarized the top three insights from this webinar below.

Synthetic Cannabinoids (1m 30s)

Class-wide bans in China have prompted the emergence of DIY semi-finished kits that provide precursors for the synthesis of synthetic cannabinoids, enabling the user to finish the synthesis themselves, dodging these regulations. These precursors may appear in forensic and/or toxicological casework and are critical for understanding the production and distribution of illicit synthetic cannabinoids and the efficacy of diversion measures.

There are several synthetic pathways to obtain synthetic cannabinoids. The most common two may follow Route A or Route B (see below). Both routes produce the final product either with the addition of the tail piece for route A or the addition of the amine head group for route B.

Route A (Figure 1) starts with the indole or indazole carboxylic acid and with the addition of the amine head group yields the following precursor I. These types of precursors appear to be the most popular showing up in casework.

Figure 1. Route A for the synthetic cannabinoid synthesis.

Route A: Indole Precursors to Watch (3m 20s)

Route A: Indazole Precursors to Watch (4m 13s)

Route B (Figure 2) starts with the indole or indazole carboxylic acid and with the addition of the tail piece, precursor II is obtained. Importantly, these precursors may also be produced as metabolites during synthetic cannabinoid metabolism and may be encountered in toxicological casework.

Figure 2. Route B for synthetic cannabinoid synthesis.

Route B: Carboxylic Acid Precursors to Watch (5m 13s)

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NMDMSB – A Synthetic Cannabinoid to Watch (5m 30s)

The emergence of novel synthetic cannabinoids with alternative core structures presents a challenge for researchers and scientists tasked with the identification of these emerging substances in forensic and toxicological casework. The identification of emerging drugs of abuse is critically dependent on the availability of analytical standards for which to compare unknown spectra to reference library mass spectra.

Cayman was asked to assist in the identification of unknown substances appearing in GC-MS spectra from Turkey and the United States. Backed by a global collaboration network and extensive knowledge of how to interpret synthetic cannabinoid mass spectra, we used the known mass spectra of QMiPSB to presumptively identify and name the unknown compound as NMDMSB, a sulfamoyl synthetic cannabinoid. Cayman responded by rapidly producing an analytical reference standard for NMDMSB, allowing for the confirmed positive identification of NMDMSB as the unknown substance.

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Other Synthetic Cannabinoids to Watch

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Benzodiazepines (11:00)

Although bromazolam only recently appeared in the NPS scene, its popularity on social media forums and illicit websites has exploded, making bromazolam the most common benzodiazepine identified in casework. Benzodiazepine prodrugs such as clonazafone and rilmazafone are also increasingly popular. Some of these prodrugs are simple, uncyclized versions of their corresponding benzodiazepine, whereas others have an amino acid attached to the primary amine. In both cases, stomach acid will either cyclize or cleave the prodrug to form the desired active product.

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Benzodiazepines to Watch

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Fentanyls (12m 36s)

Though there have been fewer new fentanyl analogs entering the market, precursors and byproducts of fentanyl analog synthesis have been emerging in the recent NPS scene. These include Boc-protected anilino piperidines along with their fluorinated or methylated counterparts as well as Boc-protected norfentanyl (N-Boc norfentanyl) and para-fluoro norfentanyl. The Boc-protected piperidone undergoes a reductive amination with the corresponding aniline to form a Boc-protected anilino piperidine in this first step (Figure 3). The Boc group prevents the piperidine nitrogen from reacting with itself, allowing for the synthesis of fentanyl analogs.

Figure 3. Precursors in the synthesis of fentanyl analogs.

Fentanyl Precursors to Watch

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Other products to watch are synthetic byproducts, including N-propionyl para-fluoro norfentanyl. Considering one possible synthesis route, when propionyl chloride is added in the absence of a Boc-protecting group or benzyl to protect the piperidine nitrogen, a double addition may occur, leading to the production of N-propionyl norfentanyl or its fluoro counterpart (Figure 4).

Figure 4. Byproducts produced during the synthesis of fentanyl analogs.

Other byproducts that may be encountered include N-phenethyl-N-phenylpropionamide, a byproduct of the Valdez method, and ethyl 4-ANPP, which has been found in samples throughout the United States.

Fentanyl Byproducts to Watch (13m 23s)

Download or request a physical copy of the Laboratory Guide for Fentanyl Identification, Naming, and Metabolism