Drug misuse in prisons contributes to increased disruption and violence and negatively impacts prisoner safety, rehabilitation, and recovery. Synthetic cannabinoid receptor agonists (SCRAs), colloquially known as “spice”, are infused into papers and are of particular concern in a prison setting where they are commonly vaped. Methods for the qualitative and quantitative analysis of SCRA infused papers, including impurity profiling, were developed using gas chromatography–mass spectrometry (GC–MS) with qualitative confirmation by ultra high pressure liquid chromatography with photodiode array and quadrupole time of flight mass spectrometry detection (UPLC‐PDA‐QToF‐MS) and applied to 354 individual seized paper samples originating from 168 seizures from three Scottish prisons. Of these samples, 41% (146 samples from 101 seizures) contained at least one SCRA and multiple SCRAs were detected on 23% of these papers. Concentrations ranged from < 0.05–1.17 mg/cm2 paper, representing the first reported quantitative data for SCRA infused papers. An evolution in the SCRAs detected was demonstrated; 5F‐MDMB‐PINACA (5F‐ADB) predominated until late 2018, after which time 5F‐MDMB‐PICA and 4F‐MDMB‐BINACA became increasingly more prevalent, followed by the arrival of MDMB‐4en‐PINACA in June 2019. Concentration mapping data from two seized paper samples demonstrated that SCRA concentrations across larger papers were highly variable (0.47–2.38 mg/cm2 paper) making consistent dosing by users, and representative sampling by laboratory analysts, difficult. Near real‐time qualitative and quantitative information on SCRAs circulating in prisons acts as an early warning system for SCRAs emerging on the wider illicit market, inform the methods used to detect them and limit supply, and provide information to support harm reduction measures.

Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB 1 and CB 2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC 50 (a measure of potency) and E max (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB 2 receptor than at the CB 1 receptor and ( S )-enantiomers had an enhanced potency to both receptors over the ( R )-enantiomers. The relative potency of the enantiomers to the CB 2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of ( R )-enantiomers in seized samples. Lux® Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux® i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) ≥ 1.99. Achiral GC-MS analysis of seized herbal materials ( n = 16), found 5F-MDMB-PINACA (<1.0–91.5 mg/g herbal material) and AMB-FUBINACA (15.5–58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the ( S )-enantiomer predominated in all samples (93.6–99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the “intrinsic” potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.

The synthetic cannabinoid receptor agonist (SCRA) market is transnational, and the availability of individual SCRAs changes regularly in response to national and international legislative controls. This generates a cyclic pattern and near constant evolution of SCRA compounds. This study reports toxicology-based and/or seized samplebased prevalence data relating to SCRA use in prisons from Germany, the United Kingdom (UK; Scotland and Wales), and the United States (US), representing 4427 individual test results. The study examines SCRA detections in prisons from July 2018 to September 2020, and where possible, prison-based data are compared with SCRA prevalence data in the wider population. The relative influence of Chinese, other international, and national drug legislation on the prevalence of individual SCRAs in prisons is also considered. tert-Leucinate-and valinate-indole-and indazole-3-carboxamides were the most common SCRA detections, and MDMB-4en-PINACA was one of the most commonly detected SCRAs in all jurisdictions by September 2020. However, despite there being a global production and supply market, there were notable regional differences. Analog controls in German and US legislation may have led to increased compound diversity that is not reflected in the UK which has both analog controls and a blanket ban on psychoactive substances.While there were regional differences, SCRA prevalence in prisons closely aligned with the SCRAs detected on the local market, demonstrating that SCRA (and possibly other NPS) monitoring programs in prisons can act as early warning systems for the wider population in that given jurisdiction.

Synthetic cannabinoid receptor agonists (SCRAs), colloquially known as “spice,” are commonly used in prisons and enter establishments via the mail in the form of infused papers. Many prisons use benchtop ion mobility spectroscopy (IMS) instruments to screen mail and seized materials for the presence of SCRAs and other controlled substances. The selectivity and sensitivity of Rapiscan Itemiser® 3E and Itemiser® 4DN Ion Trap Mobility Spectroscopy™ (ITMS™) systems were evaluated using 21 SCRA reference standards. Some differences in the SCRA reduced mobility (K0) values were observed between this study and those reported previously using IMS detection systems, particularly for cumyl and quinolinyl SCRAs (e.g., 5F‐PB‐22, Cumyl‐4CN‐BINACA, and 5F‐Cumyl‐PEGACLONE), although this was found to have little effect at an operational level. Operational reliability of the systems was evaluated by analyzing 392 paper and card samples with known drug content. ITMS™ system results (e.g., detect or nondetect) were in agreement with gas chromatography–mass spectrometry (GC–MS) analysis in up to 95% of samples tested. Overall, this study found the ITMS™ systems tested to be effective instruments when deployed for the rapid detection of SCRA‐infused papers. Used effectively and with up‐to‐date substance libraries, they will help reduce the supply of SCRAs into prisons and identify emerging threats as they arise. Several emerging SCRAs (5F‐MPP‐PICA, 5F‐EMB‐PICA, and 4F‐MDMB‐BICA) were detected for the first time in Scottish prisons between May and August 2020 as a result of routine monitoring, and all were detected using the ITMS™ systems tested.

Synthetic cannabinoid receptor agonists (SCRAs) elicit many of their psychoactive effects via type‐1 human cannabinoid (CB1) receptors. Enantiomer pairs of eight tert‐leucinate or valinate indole‐ and indazole‐3‐carboxamide SCRAs were synthesized and their CB1 potency and efficacy assessed using an in vitro β‐arrestin recruitment assay in a HEK239T stable cell system. A chiral high‐performance liquid chromatography method with photodiode array and/or quadrupole time‐of‐flight‐mass spectrometry detection (HPLC‐PDA and HPLC‐PDA‐QToF‐MS) was applied to 177 SCRA‐infused paper samples seized in Scottish prisons between 2018 and 2020. In most samples, SCRAs were almost enantiopure (S)‐enantiomer (>98% of total chromatographic peak area), although in some (n = 18), 2% to 16% of the (R)‐enantiomer was detected. (S)‐enantiomers are consistently more potent than (R)‐enantiomers and often more efficacious. The importance of SCRA‐CB1 receptor interactions in the “head” or “linked group” moiety is demonstrated, with the conformation of the “bulky” tert‐leucinate group greatly affecting potency (by up to a factor of 374), significantly greater than the difference observed between valinate SCRA enantiomers. (S)‐MDMB‐4en‐PINACA, (S)‐4F‐MDMB‐BINACA, and (S)‐5F‐MDMB‐PICA are currently the most prevalent SCRAs in Scottish prisons, and all have similar high potency (EC50, 1–5 nM) and efficacy. Infused paper samples were compared using estimated intrinsic efficacy at the CB1 receptor (EIECB1) to evaluate samples with variable SCRA content. Given their similar potency and efficacy, any variation in CB1 receptor‐mediated psychoactive effects are likely to derive from variation in dose, mode of use, pharmacokinetic differences, and individual factors affecting the user, rather than differences in the specific SCRA present.