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In this work, a low-cost and eco-friendly paper-based analytical device (PAD) method is described for the determination of phyto-cannabinoids in cannabis and oral fluids based on a simple colorimetric reaction. The PAD was able to distinguish tetrahydrocannabinol (THC)- and cannabidiol (CBD)-rich plant samples by using 4-aminophenol (4-AP) and later on to quantify total phyto-cannabinoid content (THC + CBD + CBN) in plant and oral fluids by using the Fast Corinth V reagent. The chemical and physical properties regarding paper type and reagent concentration in the PAD were optimized to achieve the best analytical performance. After that, analytical features were obtained, including a linear range of 0.01-0.1 mg mL -1 , a limit of detection (LOD) of 0.003 mg mL -1 , and a suitable precision, expressed as relative standard deviation (RSD) lower than 10%. Furthermore, no significant interferences were observed in colorimetric reactions when tea, herbs, and drug samples were analyzed. Additionally, the PAD proved color stability up to 1 month after the sampling at 25 °C. The developed PAD was suitable for determining total phyto-cannabinoid content in plants and oral fluids, obtaining good results compared to GC-MS. Overall, this method showed good reliability resulting in an operational on-site device for drug monitoring., (© 2023. The Author(s).)

A new concept of paper-based device has been developed combining the advantages of cellulose supports and the rich surface chemistry of metal-organic frameworks (MOFs). The composite, named as NH 2 -UiO-66@paper, has been developed for the isolation of synthetic cannabinoid receptor agonists (SCRAs) in oral fluids, trying to mimic the interactions of those compounds with the human CB1R and CB2R receptors, mainly governed by hydrogen bonding and π-interactions with serine and histidine residues. MOF selection (UiO-66) and functionalization of the ligand (2-aminoterephthalic acid) has been done according to the following criteria: (i) water stability of the selected MOF, and (ii) promoting appropriate interactions with SCRAs due to the MOF nature. NH 2 -UiO-66@paper composite has been characterized in depth and the results confirmed that the material is stable at the temperature selected for thermal desorption (230 °C). Furthermore, the developed method provided appropriate precision values (RSD < 12%) and a limit of detection as low as 10 ng using ion mobility spectrometry as analytical technique. Lastly, the method has been successfully applied to the isolation of several synthetic cannabinoids from oral fluids. This method claims to be an interesting approach for expanding the combination of MOFs with sustainable support and represents a promising alternative to sophisticated and non-portable systems due to the negligible sample treatment required and the simplicity of the operation, which can be applied with screening purposes., (© 2023. The Author(s).)

Synthetic cannabinoids are one of the many substances of abuse widely spreading in modern society. Medical practitioners and law enforcement alike highly seek portable, efficient, and reliable tools for on-site detection and diagnostics. Here, we propose a colorimetric lateral flow assay (LFA) combined with dye-loaded polymersome to detect the synthetic cannabinoid JWH-073 efficiently. Rhodamine B-loaded polymersome was conjugated to antibodies and fully characterized. Two LFA were proposed (sandwich and competitive), showing a high level of sensitivity with a limit of detection (LOD) reaching 0.53 and 0.31 ng/mL, respectively. The competitive assay was further analyzed by fluorescence, where the LOD reached 0.16 ng/mL. The application of the LFA over spiked synthetic saliva or real human saliva demonstrated an overall response of 94% for the sandwich assay and 97% for the competitive LFA. The selectivity of the system was assessed in the presence of various interferents. The analytical performance of the LFA system showed a coefficient of variation below 6%. The current LFA system appears as a plausible system for non-invasive detection of substance abuse and shows promise for synthetic cannabinoid on-site sensing., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objectives: The liberalisation of cannabis laws, the increasing availability and potency of cannabis has renewed concern about the risk of psychosis with cannabis., Methods: The objective of the WFSBP task force was to review the literature about this relationship., Results: Converging lines of evidence suggest that exposure to cannabis increases the risk for psychoses ranging from transient psychotic states to chronic recurrent psychosis. The greater the dose, and the earlier the age of exposure, the greater the risk. For some psychosis outcomes, the evidence supports some of the criteria of causality. However, alternate explanations including reverse causality and confounders cannot be conclusively excluded. Furthermore, cannabis is neither necessary nor sufficient to cause psychosis. More likely it is one of the multiple causal components. In those with established psychosis, cannabis has a negative impact on the course and expression of the illness. Emerging evidence also suggests alterations in the endocannabinoid system in psychotic disorders., Conclusions: Given that exposure to cannabis and cannabinoids is modifiable, delaying or eliminating exposure to cannabis or cannabinoids, could potentially impact the rates of psychosis related to cannabis, especially in those who are at high risk for developing the disorder.

Early warning systems detect new psychoactive substances (NPS), while dedicated monitoring programs and routine drug and toxicology testing identify fluctuations in prevalence. We report the increasing prevalence of the synthetic cannabinoid receptor agonist (SCRA) ADB-BUTINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-butyl-1H-indazole-3-carbox-amide). ADB-BUTINACA was first detected in a seizure in Sweden in 2019, and we report its detection in 13 routine Swedish forensic toxicology cases soon after. In January 2021, ADB-BUTINACA was detected in SCRA-infused papers seized in Scottish prisons and has rapidly increased in prevalence, being detected in 60.4% of the SCRA-infused papers tested between January and July 2021. In this work, ADB-BUTINACA was incubated with human hepatocytes (HHeps), and 21 metabolites were identified in vitro, 14 being detected in authentic case samples. The parent drug and metabolites B9 (mono-hydroxylation on the n-butyl tail) and B16 (mono-hydroxylation on the indazole ring) are recommended biomarkers in blood, while metabolites B4 (dihydrodiol formation on the indazole core), B9, and B16 are suitable biomarkers in urine. ADB-4en-PINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[pent-4-en-1-yl]-1H-indazole-3-carboxamide) was detected in Scottish prisons in December 2020, but, unlike ADB-BUTINACA, prevalence has remained low. ADB-4en-PINACA was incubated with HHeps, and 11 metabolites were identified. Metabolites E3 (dihydrodiol formed in the tail moiety) and E7 (hydroxylation on the linked/head group) are the most abundant metabolites in vitro and are suggested as urinary biomarkers. The in vitro potencies of ADB-BUTINACA (EC 50 , 11.5 nM and ADB-4en-PINACA (EC 50 , 11.6 nM) are similar to that of MDMB-4en-PINACA (EC 50 , 4.3 nM). A third tert-leucinamide SCRA, ADB-HEXINACA was also detected in prison samples and warrants further investigation., (© 2021 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Cannabinoids present a unique set of analytical challenges. An increasing number of states have voted to decriminalize recreational marijuana use, creating a need for new kinds of rapid testing. At the same time, synthetic compounds with activity similar to THC, termed synthetic cannabinoids, have become more prevalent and pose significant health risks. A rapid method capable of detecting both natural and synthetic cannabinoids would be useful in cases of driving under the influence of drugs, where it might not be obvious whether the suspect consumed marijuana, a synthetic cannabinoid, or both. Paper spray mass spectrometry is an ambient ionization technique which allows for the direct ionization of analyte from a biofluid spot on a piece of paper. Natural cannabinoids like THC, however, are labile and rapidly disappear from dried sample spots, making it difficult to detect them at clinically relevant levels. Presented here is a method to concentrate and preserve THC and synthetic cannabinoids in urine and oral fluid on paper for analysis by paper spray mass spectrometry. Sesame seed oil was investigated both as a means of preserving THC and as part of a technique, termed paper strip extraction, wherein urine or oral fluid is flowed through an oil spot on a strip of paper to preconcentrate cannabinoids. This technique preserved THC in dried biofluid samples for at least 27 days at room temperature; paper spray MS/MS analysis of these preserved dried spots was capable of detecting THC and synthetic cannabinoids at low ng/mL concentrations, making it suitable as a rapid screening technique. The technique was adapted to be used with a commercially available autosampler.

A direct mass spectrometry method utilizing reactive paper spray ionization was developed for sensitive cannabinoid quantitation in biofluid matrices. The ca. 2-minute sample measurements used on-paper derivatization to significantly increase paper spray mass spectrometry (PS-MS) positive ion mode sensitivity while minimizing sample preparation steps. Calibrations demonstrate high linearity, with R 2 > 0.99 for (-)- trans -Δ 9 -tetrahydrocannabinol (THC) in oral fluid and 11-nor-9-carboxy-Δ 9 -tetrahydrocannabinol (THC-COOH) in urine. The limit of detection and lower limit of quantitation were 0.78 and 10 ng mL -1 for THC in oral fluid and 1.3 and 10 ng mL -1 for THC-COOH in urine, respectively. THC-COOH levels measured by reactive PS-MS in seven spiked human urine samples showed bias of -9.4 to 5.9%, and percent difference values of -16.8 to 9.8% in comparison with a reference LC-MS method. Based upon the method simplicity, validation experiments, sensitivity, and rapidity, we conclude that reactive PS-MS has potential applications for rapid cannabinoid drug testing in urine and oral fluid.

Cannabinoids comprehend endocannabinoids, phytocannabinoids, and synthetic cannabinoids, with actions both in the central and peripherical nervous systems. A considerable amount of publications have been made in recent years, although cannabis has been known for over a thousand years. Scientific Departments from the Brazilian Academy of Neurology described evidence for medical use in their areas. Literature is constantly changing, and possible new evidence can emerge in the next days or months. Prescription of these substances must be discussed with patients and their families, with knowledge about adverse events and their efficacy.

The last few years have witnessed the change in the modalities of smuggling of synthetic cannabinoid receptor agonists (SCRAs) by impregnating them in mail envelopes and fast parcels. Considering the aforementioned scenario, it is important to develop a portable technique to identifying SCRAs through packages. The purpose of this research was to detect SCRAs impregnated into substrates of paper using attenuated total reflectance Fourier transform infrared (ATR‐FTIR) spectroscopy. Three SCRAs that included 5F‐PB‐22, AB‐FUBINACA and AKB‐48 were purchased from Sigma Aldrich. The three SCRAs and four cutting agents were impregnated into paper of variable thickness at four concentrations (10, 15, 20, and 25 mg/mL). Spectra were collected over the wavenumber range of 650–4000 cm−1 using ATR‐FTIR spectroscopy and were exported to Matlab 2020b where data analysis was applied. The FTIR spectral data was able to show the three SCRAs could be detected on paper using ATR‐FTIR spectroscopy and quantitatively modeled using the partial least squares regression algorithm. Principal component analysis showed separate clustering for the compounds that crystallized (5F‐PB‐22, AB‐FUBINACA and caffeine) onto the papers surface from those impregnated into the bulk of the paper (AKB‐48 and procaine) with the latter situated near blank papers in score plots. In summary, ATR‐FTIR spectroscopy has proven to be a successful non‐destructive technique in detecting and quantifying a selection of SCRAs impregnated into paper. [ABSTRACT FROM AUTHOR]

Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5'Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5'Br-INACA (ADMB-5Br-INACA), MDMB-5'Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (S)-enantiomers of these substances, as well as of two predicted analogs MDMB-5'Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5'F-BUTINACA (ADMB-B-5F-INACA), using CB 1 and CB 2 β-arrestin 2 recruitment assays and a CB 1 intracellular calcium release assay. Surprisingly, the tail-less (S)-ADB-5'Br-INACA and (S)-MDMB-5'Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (S)-ADB-5'Br-BUTINACA and (S)-MDMB-5'Br-BUTINACA, respectively, which were potent and efficacious CB 1 agonists. Also, at CB 2 , tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((S)-ADB-INACA) resulted in a reduced activity at CB 1 ; however, this effect was less prominent at CB 2 . Looking at tailed analogs, replacing the bromine with a fluorine substitution ((S)-ADB-5'F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5'Br-INACA and MDMB-5'Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB 1 receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5'Br-INACA and MDMB-5'Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected., (© 2023 John Wiley & Sons Ltd.)

The rapidly evolving synthetic cannabinoid receptor agonist (SCRA) market poses significant challenges for forensic scientists. Since the enactment of a generic ban in China, a variety of new compounds have emerged capable of evading the legislation by carrying new structural features. One recent example of a SCRA with new linker and head moieties is CH-PIATA (CH-PIACA, CHX-PIATA, CHX-PIACA). CH-PIATA bears an additional methylene spacer in the linker moiety between the indole core and the traditional carbonyl component of the linker. This study describes detections in 2022 of this new SCRA in the United States, Belgium, and Scottish prisons. CH-PIATA was detected once in a seized powder by Belgian customs and 12 times in Scottish prisons in infused papers or resin. The metabolites of CH-PIATA were investigated via in vitro human liver microsome (HLM) incubations and eight metabolites were identified, dominated by oxidative biotransformations. A blood sample from the United States was confirmed to contain a mixture of SCRAs including CH-PIATA via presence of the parent and at least five of the metabolites identified from HLM incubations. Furthermore, this paper evaluates the intrinsic in vitro cannabinoid 1 and 2 (CB 1 and CB 2 ) receptor activation potential of CH-PIATA reference material and the powder seized by Belgian customs by means of β-arrestin 2 recruitment assays. Both the reference and the seized powder showed a weak activity at both CB receptors with signs of antagonism found. Based on these results, the expected harm potential of this newly emerging substance remains limited., (© 2023 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

ABSTRACT Cannabinoids comprehend endocannabinoids, phytocannabinoids, and synthetic cannabinoids, with actions both in the central and peripherical nervous systems. A considerable amount of publications have been made in recent years, although cannabis has been known for over a thousand years. Scientific Departments from the Brazilian Academy of Neurology described evidence for medical use in their areas. Literature is constantly changing, and possible new evidence can emerge in the next days or months. Prescription of these substances must be discussed with patients and their families, with knowledge about adverse events and their efficacy.

Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest groups of new psychoactive substances (NPS). Yet, another novel analog started spreading on the NPS market around 2021. Soon after, the substance could be analytically characterized in herbal material as ADB-HEXINACA, an SCRA containing a hexyl-substituted tail on the indazole core. Here, we present suitable urinary markers to prove the consumption of this analog, a case report of acute polydrug intoxication and data on its prevalence in Germany. Anticipated phase I metabolites were detected in 12 authentic urine samples that were collected for abstinence control and analyzed by ultra-performance liquid chromatography coupled to a time-of-flight mass spectrometer (UPLC-qToF-MS). The results of in vivo samples were confirmed by analysis of in vitro incubates with pooled human liver microsomes (pHLMs). Forensic samples were used to assess the prevalence of ADB-HEXINACA. Thirty-two phase I metabolites were detected in the authentic urine samples. The main metabolites resulted from amide hydrolysis in combination with either monohydroxylation or ketone formation at the hexyl moiety (M15 and M26), the monitoring of which is recommended as a proof of consumption. ADB-HEXINACA was detected in 3.5% of SCRA positive urine samples collected for abstinence control in Freiburg up to December 2022 and in 5.5% of the SCRA positive blood/serum samples. The hexyl substituent of ADB-HEXINACA allows for the detection of specific urinary biomarkers suggested as analytical targets to confirm its prior intake. ADB-HEXINACA had a rather low prevalence in Germany, alternating months of higher prevalence with periods of total absence., (© 2024 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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Abstract: We define narrative bias as a tendency to interpret information as part of a larger story or pattern, regardless of whether the facts support the full narrative. Narrative bias in title and abstract means that results reported in the title and abstract of an article are done so in a way that could distort their interpretation and mislead readers who had not read the whole article. Narrative bias is often referred to as "spin." It is prevalent in abstracts of scientific papers and is impactful because abstracts are often the only part of an article read. We found no extant narrative bias instrument suitable for exploring both efficacy and safety statements in randomized trials and systematic reviews of pain. We constructed a 6-point instrument with clear instructions and tested it on randomised trials and systematic reviews of cannabinoids and cannabis-based medicines for pain, with updated searches to April 2021. The instrument detected moderate or severe narrative bias in the title and abstract of 24% (8 of 34) of randomised controlled trials and 17% (11 of 64) of systematic reviews; narrative bias for efficacy and safety occurred equally. There was no significant or meaningful association between narrative bias and study characteristics in correlation or cluster analyses. Bias was always in favour of the experimental cannabinoid or cannabis-based medicine. Put simply, reading title and abstract only could give an incorrect impression of efficacy or safety in about 1 in 5 papers reporting on these products., (Copyright © 2024 International Association for the Study of Pain.)

Rationale: ADB-FUBIATA is one of the most recently identified new psychoactive substance (NPS) of synthetic cannabinoids. The co-use of in vitro (human liver microsomes) and in vivo (zebrafish) models offers abundant metabolites and may give a deep insight into the metabolism of NPS., Methods: In vivo and in vitro metabolic studies of new synthetic cannabinoid ADB-FUBIATA were carried out using zebrafish and pooled human liver microsome models. Metabilites were structurally characterized by liquid chromatography-high-resolution mass spectrometry., Results: In total, 18 metabolites were discovered and identified in the pooled human liver microsomes and zebrafish, including seventeen phase I metabolites and one phase II metabolite. The main metabolic pathways of ADB-FUBIATA were hydroxylation, dehydrogenation, N-dealkylation, amide hydrolysis, glucuronidation, and combination thereof., Conclusion: Hydroxylated metabolites can be recommended as metabolic markers for ADB-FUBIATA because of the structural characteristics and high intensity. These metabolism characteristics of ADB-FUBIATA were useful for its further forensic or clinical related investigations., (© 2024 John Wiley & Sons Ltd.)

Although the use, structural variety, and prevalence of synthetic cannabinoids (SCs) have steadily increased on the drug market, they are rarely analyzed in abstinence control programs for driver's license regranting. The aim of this study was to determine the SC prevalence in these programs by analyzing hair samples collected between March 2020 and March 2021 from various regions in Germany, mainly Bavaria (40%). Specimens were analyzed quantitatively for drugs of abuse and qualitatively for 107 SCs. Hair samples were screened by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and to search for unknown SC analogs, positive samples were additionally screened by liquid chromatography-high resolution time of flight mass spectrometry (LC-qTOF/MS). The analysis of 5097 hair samples resulted in 181 SC detections (3.6%), showing a wide range of 44 SCs, with up to 13 different compounds found in a single sample. The most prevalent compounds were 5F-MDMB-PICA and MDMB-4en-PINACA; furthermore, 10 new substances not initially covered by LC-MS/MS analysis were detected by LC-qTOF/MS. The SC positivity rate was comparable to cocaine (5.4%) and amphetamine (2.6%). Only in 35 cases (0.7%), SC analysis was requested by the clients, highlighting the insufficient coverage of SC consumption in the studied collective. In summary, hair sample analysis proved to be a valuable tool to monitor the use of SCs. In order to keep pace with newly emerging SC analogs, an up-to-date analytical method is essential. Prospectively, SCs should be more routinely screened in hair analysis for abstinence control to avoid cannabis substitution by SCs., (© 2023 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Background and Purpose: AKB48 is a synthetic cannabinoid illegally sold for its psychoactive cannabis-like effects that have been associated with acute intoxication and whose effects are poorly known., Experimental Approach: Using a behavioural, neurochemical, and immunohistochemical approach, we investigated the pharmaco-toxicological effects, pharmacokinetics, and neuroplasticity at cannabinoid CB 1 receptors in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice., Key Results: The effects of AKB48 varied significantly depending on sex and treatment duration. The first injection impaired sensorimotor responses and reduced body temperature, analgesia, and breath rate to a greater extent in females than in males; the second injection induced stronger effects in males while the third injection of AKB48 induced weaker responses in both sexes, suggesting emergence of tolerance. The CB 1 receptor antagonist NESS-0327 prevented the effects induced by repeated AKB48, confirming a CB 1 receptor-mediated action. Blood AKB48 levels were higher in females than in males and repeated administration caused a progressive rise of AKB48 levels in both sexes, suggesting an inhibitory effect on cytochrome activity. Finally, immunohistochemical analysis revealed higher expression of CB 1 receptors in the cerebellum and cortex of females, and a rapid CB 1 receptor down-regulation in cerebellar and cortical areas following repeated AKB48 injections, with neuroadaptation occurring generally more rapidly in females than in males., Conclusion and Implications: We have shown for the first time that AKB48 effects significantly vary with prolonged use and that sex affects the pharmacodynamic/pharmacokinetic responses to repeated administration, suggesting a sex-tailored approach in managing AKB48-induced intoxication., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Synthetic cannabinoids, a type of new psychoactive substances, are likely to be rapidly metabolized; thus, the detection of their metabolites, rather than the parent compound, is a common method used to prove drug consumption. Although the analysis of metabolites is generally performed by mass spectrometry, it is limited to structural estimation because of few commercially available standards. In particular, distinguishing between positional isomers is difficult. Synthetic cannabinoids with a cumyl moiety can be hydroxylated at the cumyl moiety during metabolism, but it remains unclear whether the hydroxylation occurs at the ortho, meta, or para position. This study determined the structures of a metabolite formed by mono-hydroxylation at the cumyl moiety of the synthetic cannabinoid CUMYL-THPINACA, used as a model compound. Chemical synthesis was performed to create possible metabolites with one hydroxyl group at the ortho, meta, or para positions of the cumyl moiety. Using the synthesized metabolites and liquid chromatography-quadrupole time-of-flight mass spectrometry, the metabolite detected in the microsomal reaction of CUMYL-THPINACA was identified as a compound mono-hydroxylated at the para position based on retention time and product ion spectra. Moreover, the rapid metabolism of CUMYL-THPINACA was demonstrated with an in vitro half-life of 4.9 min and the identified metabolite could be detected for a relatively long time in vitro. The synthesized metabolite may be utilized as a good reference standard for proof of CUMYL-THPINACA consumption. These findings have potential applications in the synthesis of metabolites of other synthetic cannabinoids bearing a cumyl moiety., (© 2023 John Wiley & Sons, Ltd.)

A simple, rapid, accurate, and non-destructive method was developed for the determination of cannabinoids, combining principal component analysis and multi-layer perceptron neural network to classify indole and indazole amide synthetic cannabinoids. Under the experimental conditions of this study, 25 experimental samples were successfully classified into two categories as the final classification, which guaranteed 96% correct rate. First, the samples were manually classified and divided into two categories according to the difference in peak position and peak intensity of the differential Raman characteristic peaks at 650-540 cm -1 , etc. Fisher's discriminant method (FDA) and principal component analysis (PCA) were used to analyze the experimental data. Fisher's discriminant analysis was used to formulate two classification functions to discriminate the results of manual classification, and the overall accuracy rate of classification reached 88%. Principal component analysis was used to reduce the dimensionality of the data, which could reduce the influence of redundant data on the experimental results. The original data, FDA-processed data and PCA-processed data, and artificial neural network algorithm (ANN-MLP/RBF) were combined to build a classification model. In the MLP model, the classification accuracy of the original data, FDA-processed data, and PCA-processed data was 80%, 92%, and 96% respectively, and the overall accuracy of the sample classification was 89.33%. In the RBF model, the accuracy of sample classification was 76%, 84%, and 92% respectively, and the overall accuracy of sample classification was 84%. Differential Raman spectroscopy could be used to distinguish 25 kinds of synthetic cannabinoids, and finally, the samples were divided into two categories. The PCA + MLP model was the best for processing spectral data. Based on the perspective of multivariate data, this study demonstrated that the method could be used for rapid and non-destructive testing of indole and indazole amide synthetic cannabinoids and that an efficient and non-destructive classification model was obtained. This method could be used for rapid detection and inspection of drugs in the field of forensic science., (© 2022 American Academy of Forensic Sciences.)

In recent years, N-methoxybenzyl-methoxyphenylethylamine (NBOMe) derivatives, a class of designer hallucinogenic drugs, have become popular drugs of abuse. These drugs have been the cause of severe intoxications and even deaths. They act as 5-HT2A receptors agonists and have been reported to produce serotonin-like syndrome with bizarre behavior, severe agitation and seizures persisting for as long as 3 days. The most commonly reported derivatives are 25I-NBOMe, 25B-NBOMe and 25C-NBOMe, respectively 2-(4-iodo-2,5-dimethoxyphenyl)- N-[(2-methoxyphenyl) methyl]ethanamine, N-(2-methoxybenzyl)- 2,5-dimethoxy-4-bromophenethylamine and N-(2-methoxybenzyl)- 2,5-dimethoxy-4-chlorophenethylamine. Like many low dose hallucinogenic drugs these compounds are often sold on blotter paper. Three different types of commercially available blotter papers reported to contain NBOMe derivatives were obtained. These blotter papers were screened using Direct Analysis in Real Time AccuTOFTM mass spectrometry followed by confirmation and quantification by high-performance liquid chromatography triple quadrapole mass spectrometry. The major drug present on each of the three blotter products was different, 25I-NBOMe, 25C-NBOMe or 25B-NBOMe. The blotter papers were also found to have minute amounts of two or three NBOMe derivative impurities of 25H-NBOMe, 25I-NBOMe, 25C-NBOMe, 25B-NBOMe and/or 25D-NBOMe. [ABSTRACT FROM AUTHOR]

Hemp-based materials have gained interest as alternative feed ingredients for livestock. However, safety concerns arise regarding the transfer of cannabinoids from the plant to the animals. Addressing these concerns requires the use of methods capable of detecting and quantifying cannabinoids in livestock. In this study, a fast and sensitive method was developed for quantification of cannabinoids and cannabinoid metabolites in cattle plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The extraction of cannabinoids from the plasma matrix was achieved by combining the Captiva Enhanced Matrix Removal-Lipid clean-up and salting-out assisted liquid-liquid extraction procedure. The developed method underwent validation using various analytical parameters, and the results demonstrated good accuracy, precision, specificity, and high sensitivity. The method was applied to real plasma samples obtained from cattle fed hemp for 2 weeks, and successfully detected various cannabinoids, including delta-9-tetrahydrocannabinol. Furthermore, the study revealed that 7-carboxy cannabidiol, a metabolite of cannabidiol, was the predominant cannabinoid present in the cattle plasma throughout the feeding period, which could remain detectable for weeks after the hemp feeding had ended., (© 2023 Wiley-VCH GmbH.)

Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances found on recreational drug markets worldwide. The indole-containing compound, 5F-MDMB-PICA, is a popular SCRA associated with serious medical consequences, including overdose and hospitalizations. In vitro studies reveal that 5F-MDMB-PICA is a potent agonist at cannabinoid type 1 receptors (CB 1 ), but little information exists regarding in vivo pharmacology of the drug. To this end, we examined the in vitro and in vivo cannabinoid-like effects produced by 5F-MDMB-PICA and related 5F-pentylindole analogs with differing composition of the head group moiety (i.e., 5F-NNEI, 5F-SDB-006, 5F-CUMYL-PICA, 5F-MMB-PICA). In mouse brain membranes, 5F-MDMB-PICA and its analogs inhibited binding to [ 3 H]rimonabant-labeled CB 1 and displayed agonist actions in [ 35 S]GTPγS functional assays. 5F-MDMB-PICA exhibited the highest CB 1 affinity (K i = 1.24 nM) and functional potency (EC 50  = 1.46 nM), but head group composition markedly influenced activity in both assays. For example, the 3,3-dimethylbutanoate (5F-MDMB-PICA) and cumyl (5F-CUMYL-PICA) head groups engendered high CB 1 affinity and potency, whereas a benzyl (5F-SDB-006) head group did not. In C57BL/6J mice, all 5F-pentylindole SCRAs produced dose- and time-dependent hypothermia, catalepsy, and analgesia that were reversed by rimonabant, indicating CB 1 involvement. In vitro K i and EC 50 values were positively correlated with in vivo ED 50 potency estimates. Our findings demonstrate that 5F-MDMB-PICA is a potent SCRA, and subtle alterations to head group composition can have profound influence on pharmacological effects at CB 1 . Importantly, measures of CB 1 binding and efficacy in mouse brain tissue seem to accurately predict in vivo drug potency in this species., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Since the Act on the medical use of cannabis, at which cannabis-based medicines and cannabinoids became law, there has been an exponential increase in prescriptions for the acquisition of cannabis for medical purposes. The aim of this leading article is to compile and assess the currently available relevant clinical evidence for the use of cannabis and cannabinoids for treatment of acute and chronic pain. Based on the systematic literature review "Cannabis-Potential and risks (CAPRIS)" commissioned by the German Federal Ministry of Health and the recently published recommendations of the European Pain Federation EFIC, this article aims to give an orientation aid for the decision-making process in the clinical routine.

Synthetic cannabinoids (SC) are extremely prevalent within the prison system and cause problems for prisoners, law enforcement and health services. SC are often soaked into paper then posted into prisons therefore one of the aims of this research is to collaborate with Rapiscan Systems Ltd. and local prisons in England to measure the effectiveness of trace detection methods for the indication of SC in prison post using the Itemiser 3E®. To ensure compounds did not go undetected, samples with Ion Trap Mobility Spectrometry™ peaks indicative of synthetic cannabinoids on the Itemiser 3E® were analysed using Gas Chromatography-Mass Spectrometry, Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy to identify chemical characteristics which allowed comparison to reference spectra. Sample data spanning three years from one prison's Itemiser 3E® were collated to identify trends in drug prevalence and the influence of library updates. To date, the method has identified four compounds: 5F-MDMB-PICA, MMB-4en-PICA, 4F-MDMB-BUTINACA and MDMB-4en-PINACA on prison post which were not already included on, or needed confirmatory analysis to update, the Itemiser 3E® library. As a result, the libraries on prison Itemiser 3E®s have been updated to ensure future detection of such compounds. Trends and influences from the processed Itemiser 3E® data were also reported back to the West Midlands Prison Group. This research directly benefitted both the West Midlands Prison Group and Rapiscan Systems Ltd. and it is anticipated that the continuation of this research could be expanded to a national scale., Competing Interests: Conflict of interest The Itemiser 3E® instruments used in this study were owned by the West Midlands Prison Group, His Majesty's Prison and Probation Service (HMPPS) and used with their permission. Although technical and operational matters were discussed, Rapiscan Systems Ltd. staff were not involved in the preparation of this manuscript., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: For centuries, cannabinoids are known to be effective in pain relief. Itch is an unpleasant sensation that provokes a desire to scratch. Since itch and pain are two sensations sharing a lot in common, we aimed to investigate whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behavior and also observe whether modulation of Nitric Oxide (NO) production mediates the antipruritic effect of WIN 55,212-2. Methods: Scratching behavior is induced by intradermal injection of serotonin (50 µg/50 µL/mouse) to BALB/c mice. The cannabinoid agonist WIN 55,212-2 (1, 3, 10 mg/kg, IP) was given 30 min before serotonin injection. To observe the effect of NO modulation on the antipruritic effect of cannabinoids, the endothelial nitric oxide synthase (NOS) inhibitor L-NAME (3 mg/kg, IP), the neuronal NOS inhibitor 7-nitroindazole (3 mg/kg, IP), and the NO precursor L-arginine (100 mg/kg, IP) were administered together with WIN 55,212-2. Results: WIN 55,212-2 reduced serotonin-induced scratches at higher doses (3, 10 mg/kg; P<0.0001). The endothelial NOS inhibitor L-NAME, the neuronal NOS inhibitor 7-nitroindazole, and the nitric oxide precursor L-arginine did not influence the antipruritic action of WIN 55,212-2. When NO modulators were used alone, only the neuronal NOS inhibitor 7-nitroindazole attenuated serotonin-induced scratches (P<0.0001). Conclusion: Our findings indicate that exogenous cannabinoids may attenuate serotonininduced scratches and NO does not mediate the antipruritic effect of WIN 55,212-2. On the other hand, neuronal NOS inhibition may play a role in the production of serotonin-induced scratches. [ABSTRACT FROM AUTHOR]

With new synthetic cannabinoids (SCs) appearing on the European drug market every year, early warning systems are key to detect, monitor, and respond to threats posed by them. The European Union Early Warning System (EU EWS) implemented by the European Monitoring Centre for Drugs and Drug Addiction has monitored these substances since their first European detection in 2008. Since then, national and international responses have been implemented, aimed at tackling risks posed by SCs. Throughout this time, new SCs have emerged on the European market containing diverse structural moieties, appearing to be designed in a way that circumvents existing legal controls, contributing to a complex public health scenario. This study provides an inventory of the SCs detected in the EU from 2008 to 2022, describing their structural evolution by analysing separately four structural features: their core, tail, linker, and linked groups. The range of structural changes is analysed considering key milestones, including the year of first report by the European Union Early Warning System to the key legislative changes that have occurred since. The analysis shows that from June 2021 to July 2022, 20 out of 23 newly emerged SCs evade the generic SC legislation introduced in China in May 2021. This supports the hypothesis that the protection of public health benefits from timely information exchange and careful assessment of the risks associated with these substances. Additionally, the introduction of legal responses, albeit an important instrument to reduce the availability of dangerous substances on the market, may also be accompanied by unintended consequences., (© 2022 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Synthetic cannabinoids (SCs) remain one of the largest groups of new psychoactive substances. Recently, new synthetic cannabinoids 5F-MDMB-PICA and 4F-MDMB-BINACA are increasing in popularity. A 33-year-old man lost consciousness after smoking an unknown substance. A glass pipe and two lumps of substance that turned out to contain 5F-MDMB-PICA and 4F-MDMB-BINACA were found at the scene. Blood, urine and cerebrospinal fluid were collected during the examination of the body. The synthetic cannabinoids were isolated from autopsy materials by precipitation with acetonitrile and extraction with ethyl acetate. The screening and quantitative analyses were performed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The liquid chromatography-quadrupole/time of flight mass spectrometry (LC-Q/TOF) technique was used for metabolite identification. 5F-MDMB-PICA was detected and quantified in all analysed materials, whereas 4F-MDMB-BINACA was found only in cerebrospinal fluid. The determined concentrations of 5F-MDMB-PICA were 0.9 (blood), 0.1 (urine) and 3.2 ng/mL (cerebrospinal fluid). The concentration of 4F-MDMB-BINACA in cerebrospinal fluid was 0.1 ng/mL. The main metabolites of both compounds (hydrolysis and oxidative defluorination) were found in all analysed body fluids. Cerebrospinal fluid may be important alternative material in autopsy cases. Rapid elimination of 5F-MDMB-PICA and 4F-MDMB-BINACA compounds also means that the metabolite analysis can be crucial for the investigation. Laboratories must be made aware of their presence and incorporate these SCs and their metabolites into workflows for detection and confirmation. Ester hydrolysis and oxidative defluorination products can be found in blood, urine and cerebrospinal fluid making them useful biomarkers of intake., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: The current article examines recent publications regarding ongoing clinical and ethical challenges and opportunities related to substance use disorders (SUD) in solid organ transplantation (SOT) utilizing a lens of interprofessional clinical models and care delivery., Recent Findings: Innovative interprofessional clinician skillsets and care models are increasingly emphasized in the SOT literature as the standard of care for common, complex psychosocial problems like substance use and SUD. Cannabinoids are common among candidates and recipients and present several unique quandaries to SOT teams. Opioid use disorder treatment can often be definitively treated with medications that SOT teams may find unfamiliar, controversial, or aversive. Arguably the quintessential example of SUD in SOT, early liver transplantation for patients with alcohol-related liver disease and short periods of sobriety has become increasingly common and accepted in recent years requiring liver teams to rapidly acquire significant interprofessional psychiatric awareness and expertise. The question of retransplantation in patients who have experienced recurrent SUD remains unsettled., Summary: Regardless of substances used or organs transplanted, interprofessional care continues to emerge as a foundational aspect of clinical care and research in SOT., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Antiepileptic drugs have been successfully treating epilepsy and providing individuals sustained seizure freedom. However, about 30% of the patients with epilepsy present drug resistance, which means they are not responsive to the pharmacological treatment. Considering this, it becomes extremely relevant to pursue alternative therapeutic approaches, in order to provide appropriate treatment for those patients and also improve their quality of life. In the light of that, this review aims to discuss some innovative options for the treatment of epilepsy, which are currently under investigation, addressing strategies that go from therapeutic compounds to clinical procedures. For instance, peptides derived from animal venoms, such as wasps, spiders, and scorpions, demonstrate to be promising antiepileptic molecules, acting on a variety of targets. Other options are cannabinoids and compounds that modulate the endocannabinoid system, since it is now known that this network is involved in the pathophysiology of epilepsy. Furthermore, neurostimulation is another strategy, being an alternative clinical procedure for drug-resistant patients who are not eligible for palliative surgeries., (© 2022 Wiley Periodicals LLC.)

In the past years, new psychoactive substances (NPS) started circulating in prisons, leading to health risks and challenges for the criminal justice system. Seizures of papers and cards impregnated with synthetic cannabinoid (SCs) have been reported. In November 2021, a letter suspected to be drug-infused was sent from a German prison to this laboratory. Toxicological analyses were performed by means of gas chromatography-mass spectrometry (GC-MS) for drug screening and liquid chromatography-tandem mass spectrometry (LC-MS/MS) as well as high-performance (HP) LC with diode-array detection (DAD) for semi-quantification of the compounds. The novel synthetic opioid (NSO) AP-237 was detected on the letter, with an estimated concentration of 1.2 μg/cm 2 , together with the SCs MDMB-4en-PINACA (77 μg/cm 2 ) and 5F-ADB (6.5 μg/cm 2 ). To the best of the authors' knowledge, this is the first time an NSO was detected on a drug-infused paper seized in a prison. Highly potent NSOs could easily be dissolved in organic solvents to produce impregnated papers and textiles, and this might represent a serious threat to the health of people in prison. Given the inhomogeneity in drug concentrations, health risks might in particular arise from the consumption of highly concentrated areas of the paper-so-called "hot spots"-especially when highly potent NSOs are used for infusion. Laboratories engaged in analyzing such impregnated papers should be aware of the potential presence of NSOs and adapt the respective methods accordingly., (© 2022 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

In recent years, several nations have implemented various measures to control the surge of new synthetic cannabinoid receptor agonists (SCRAs) entering the recreational drug market. In July 2021, China put into effect a new generic legislation, banning SCRAs containing one of seven general core scaffolds. However, this has driven manufacturers towards the synthesis of SCRAs with alternative core structures, exemplified by the recent emergence of "OXIZID SCRAs." Here, using in vitro β-arrestin2 recruitment assays, we report on the CB 1 and CB 2 potency and efficacy of five members of this new class of SCRAs: BZO-HEXOXIZID, BZO-POXIZID, 5-fluoro BZO-POXIZID, BZO-4en-POXIZID, and BZO-CHMOXIZID. All compounds behaved as full agonists at CB 1 and partial agonists at CB 2 . Potencies ranged from 84.6 to 721 nM at CB 1 and 2.21 to 25.9 nM at CB 2 . Shortening the n-hexyl tail to a pentyl tail enhanced activity at both receptors. Fluorination of this pentyl analog did not yield a higher receptor activation potential, whereas an unsaturated tail resulted in decreased potency and efficacy at CB 1 . The cyclohexyl methyl analog BZO-CHMOXIZID was the most potent compound at both receptors, with EC 50 values of 84.6 and 2.21 nM at CB 1 and CB 2 , respectively. Evaluation of the activity of a seized powder containing BZO-4en-POXIZID suggested a high purity, in line with high-performance liquid chromatography coupled to diode-array detection (HPLC-DAD), gas chromatography coupled to mass spectrometry (GC-MS), liquid chromatography coupled to time-of-flight mass spectrometry (LC-QTOF-MS), and Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) analysis. Furthermore, all tested compounds showed a preference for CB 2 , except for BZO-POXIZID. Overall, these findings inform public health officials, law enforcement agencies, and clinicians on these newly emerging SCRAs., (© 2022 John Wiley & Sons Ltd.)

New chemical moieties continue to appear in synthetic cannabimimetics (SC), the largest group of new psychoactive substances in the EU. We describe the first comprehensive characterisation of the novel SC Cumyl-Tosyl-Indazole-3-Carboxamide (Cumyl-TsINACA) (N-[2-phenylpropan-2-yl]-1-tosyl-1H-indazole-3-carboxamide) from seized case samples. Structure elucidation was performed within the EU-project ADEBAR plus to facilitate confident identification by other researchers and practitioners worldwide. Characteristic MS fragmentations include the cleavage of the sulfonamide bond (S-N), the aryl sulfone bond (C-S) and the elimination rearrangement of SO 2 in the side chain. Cumyl-TsINACA is a full receptor agonist at hCB 1 (E max  = 228%) with very weak binding affinity (K i  = 292 nm) and low functional activity (EC 50  = 31 μm). Thermal degradation of Cumyl-TsINACA was observed under GC conditions. The degree to which the tosyl side chain is cleaved due to pyrolysis primarily depends on solvent, the use of glass wool in the liner and injector temperature. The determination of the constitution by NMR spectroscopy was ambiguous due to the high number of neighbouring, non-proton-bearing atoms. Therefore, other possible structures compatible with the NMR correlations were generated using the WebCocon software. The unambiguous structural evidence was finally obtained by spectra comparison after the synthesis of Cumyl-TsINACA. The low thermal stability, as well as the low affinity and potency, renders this compound unfavourable for the use as a psychoactive substance. Thus, we do not expect widespread adoption of this SC., (© 2022 John Wiley & Sons, Ltd.)

Drugs that target the endocannabinoid system are of interest as pharmacological options to combat cancer and to improve the life quality of cancer patients. From this perspective, cannabinoid compounds have been successfully tested as a systemic therapeutic option in a number of preclinical models over the past decades. As a result of these efforts, a large body of data suggests that the anticancer effects of cannabinoids are exerted at multiple levels of tumour progression via different signal transduction mechanisms. Accordingly, there is considerable evidence for cannabinoid-mediated inhibition of tumour cell proliferation, tumour invasion and metastasis, angiogenesis and chemoresistance, as well as induction of apoptosis and autophagy. Further studies showed that cannabinoids could be potential combination partners for established chemotherapeutic agents or other therapeutic interventions in cancer treatment. Research in recent years has yielded several compounds that exert promising effects on tumour cells and tissues in addition to the psychoactive Δ 9 -tetrahydrocannabinol, such as the non-psychoactive phytocannabinoid cannabidiol and inhibitors of endocannabinoid degradation. This review provides an up-to-date overview of the potential of cannabinoids as inhibitors of tumour growth and spread as demonstrated in preclinical studies., (© 2022. The Author(s).)