Synthetic Cannabinoids Research Articles

Development and method validation of a sampling technique for a reproducible detection of synthetic cannabinoids in exhaled breath using an in vitro pig lung model.

Alternative matrices, especially exhaled breath (EB), have gained increasing attention for a few years. To interpret toxicological findings, knowledge on the toxicokinetic (TK) properties of a substance in EB is indispensable. Whilst such data are already accessible for various drugs (e.g. Δ9-tetrahydrocannabinol), they are still not available for new psychoactive substances, particularly synthetic cannabinoids (SCs). As SCs raise a high public health concern, the aim of this study was to assess these data in future TK studies in pigs. For this purpose, an in vitro sampling technique of EB was initially developed, being prospectively applied to anesthetized and ventilated pigs for the detection of SCs in a controlled and reproducible manner as exemplified by cumyl-5F-P7AICA. Furthermore, a method for the qualitative and quantitative detection of cumyl-5F-P7AICA in EB using glass fiber filters (GFF) was established und fully validated. Therefore, cumyl-5F-P7AICA (0.5 mg/mL in ethanol abs.) was initially nebulized using a ventilation machine and a breathing tube, as they are also used in surgeries. The aerosol was delivered into a simulated pig lung. To collect EB, a pump was connected to that part of the breathing tube, that contains EB (expiratory limb), and sampling was performed repeatedly (n=6) for 15 min (2 L EB/min) each using GFF. For extraction of the substance, the GFF were macerated with acetone and the remaining experimental components were rinsed with ethanol. After sample preparation, the extracts were analyzed by LC-MS/MS. In the complete experimental setup, about 40% of the initially nebulized cumyl-5F-P7AICA dose was found with 3.6 ± 1.3% being detected in the GFF. Regarding the comparably high loss of substance, the open ventilation system and a conceivable adsorption of the SC in the ventilator have to be considered. However, the herein introduced approach is promising to determine the TK properties of cumyl-5F-P7AICA in EB.

Exploiting the triple quadrupole mass analyzer for the open detection and tentative identification of synthetic cannabinoid receptor agonists based on common fragmentation pathways

BackgroundThe use of new psychoactive substances (NPS) has emerged as a significant public health concern globally, due to their unknown and unpredictable effects on both physical and mental health. Among them, synthetic cannabinoids receptor agonists (SCRAs) currently stand as the most widely consumed NPS family in Europe. Since the detection of JWH-018 in 2008, the structures of these compounds have evolved to circumvent legislation and/or enhance their effects, consequently increasing the number of reported SCRAs to be monitored. Therefore, new strategies are needed to identify these compounds, whether in seized products or in biological samples. ResultsThis study presents the development of an open method for detecting SCRAs employing a “pseudo-target” screening approach, a strategy previously developed and used in our laboratory for synthetic cathinones identification. The methodology involves monitoring the main product ions and neutral losses derived from 179 SCRAs of the third and fourth generations, based on their fragmentation pathways. This approach allows for the tentative identification of the SCRAs, supported also by the created database. The versatility of the developed methodology is highlighted, extending its utility beyond seizure products or ‘legal highs’, to biological samples. In this sense, it has been successfully applied not only to the detection of SCRAs in research chemicals but also in authentic urine from an anonymous SCRAs consumer, through the identification of a metabolite. SignificanceThis strategy will be particularly useful for the rapid detection of SCRAs in forensic and toxicological laboratories equipped with low-resolution MS/MS instrumentation. This is a valuable tool for the identification and monitoring of SCRAs across various contexts, significantly contributing to public health and forensic security efforts. It is especially beneficial for healthcare providers, enabling them to make informed treatment decisions.

Mechanistic insights into the impact of WIN 55, 212-2, a synthetic cannabinoid, on adhesion molecules PECAM-1 and VE-cadherin in HeLa cells: implications on cancer processes

The endocannabinoid (eCB) system comprises endogenous ligands, cannabinoid receptors (CBRs), and their regulatory proteins; its alteration leads to many diseases including cancer. Thus, becomes a therapeutic target for synthetic cannabinoids aimed to control cancer cell proliferation, migration, adhesion, and invasion. However, little is known about adhesion molecules regulation through CBRs activation. The aim of this study was to evaluate the effects of a CB1/CB2 agonist, WIN-55, 212-2 (WIN), on the regulation of adhesion molecules platelet endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial cadherin (VE-cadherin) in HeLa cells. CBRs expression was evaluated by immunofluorescence staining in HeLa cells and cell viability (thiazolyl blue tetrazolium bromide), cell adhesion (crystal violet), adhesion molecules expression and location (Western blot and immunofluorescence staining assays) were all assessed on cells treated with different WIN concentrations. Receptors CB1, CB2, and G-protein-coupled receptor 55 were expressed in HeLa cells. Additionally, biphasic effects were observed in their metabolic activity and adhesive properties: low WIN concentrations resulted in significant increases whereas, high ones decreased them compared to controls (p < 0.0001), demonstrating that WIN elicits opposite effects depending on the concentration and exposure time. PECAM-1 was detected in HeLa cell’s cytoplasm, membrane, and perinuclear region, whereas VE-cadherin had a nuclear distribution. There were no significant differences in PECAM-1 and VE-cadherin expression and location, suggesting that WIN does not modulate these proteins. These findings support the potential use of WIN due to its anticancer properties without dysregulating adhesion molecules. WIN possible contribution to inhibit cancer progression should be further investigated.

The Impact of Potent Addictive Substances on Angiogenic Behavior: A Comprehensive Review.

Angiogenesis, the formation of new vasculature from preexisting vasculature, is involved in the development of several diseases as well as various physiological processes. Strict cooperation of proangiogenic and antiangiogenic factors mediates the control of angiogenesis. The fundamental steps in angiogenesis include endothelial cell proliferation, migration, and invasion. Addictive substances, which are considered therapeutic candidates in research and medicine, are classified as natural substances, such as nicotine, or synthetic substances, such as synthetic cannabinoids. Addictive substances have been shown to either enhance or suppress angiogenesis. This review article provides an overview of recent studies concerning the effects of several addictive substances on the process of angiogenesis. Google Scholar and PubMed were used to collect the scientific literature used in this review. The addictive substances addressed in this review are nicotine, opioids such as morphine and heroin, alcohol, cocaine, methamphetamine, and cannabinoids. An accurate assessment of the influence of these substances on the angiogenic process may help to construct a potentially effective therapeutic protocol to control and treat several angiogenesis-related diseases.

P03-10 Synthetic cannabinoids & neuronal senescence: distinctive responses of in vitro models to AMB-FUBINACA

P03-10 Synthetic cannabinoids & neuronal senescence: distinctive responses of in vitro models to AMB-FUBINACA

Cannabinoids in the Inflamed Synovium Can Be a Target for the Treatment of Rheumatic Diseases.

The management of rheumatic diseases has noticeably changed in recent years with the development of targeted therapeutic agents, namely, biological disease-modifying antirheumatic drugs. Identifying essential signaling pathways and factors crucial for the development and progression of these diseases remains a significant challenge. Therapy could be used to delay the onset or reduce harm. The endocannabinoid system's presence within the synovium can be identified as a suggested target for therapeutic interventions due to its role in modulating pain, inflammation, and joint metabolism. This review brings together the most pertinent information concerning the actions of the endocannabinoid system present in inflamed synovial tissue and its interaction with phytocannabinoids and synthetic cannabinoids, which can be used from a therapeutic perspective to minimize the inflammatory and pain processes typical of osteoarthritis and rheumatoid arthritis.

New psychoactive substances - 96 cases of deaths related to their use based on the material originating from forensic toxicological practice

Among the emerging investigative fields, forensic medicine and toxicology lead to analyzing fatalities in medico-legal expert opinion formulating. While discussing the problem, the authors have selected 96 fatal cases from their expert practice including the period from 2010 to 2023, in which deaths were connected with taking new psychoactive substances (NPS’s) belonging to various chemical categories, mainly synthetic cathinones (SC), synthetic cannabinoids (SCan) and non-medical synthetic opioids (NSO). In the investigated cases, toxicological analysis revealed 37 NPS’s and their 9 metabolites. The cases involved the use of SC’s (64 cases - 67 %), Scan’s, including their metabolites (10 cases - 10 %) and NSO’s, including their metabolites (6 cases - 6 %). The remaining cases involved the simultaneous use of NSO with SC and/or SCan, including their metabolites (8 cases - 8 %), or SC with SCan (5 cases - 5 %). In three cases (3 %), compounds belonging to other groups were taken. In twenty-five cases, more than one NPS was found. Moreover, in twenty-seven cases, ethyl alcohol was also detected at the concentration range of 0.6–3.6 ‰. The concentration of xenobiotics determined in blood represented extensive ranges of concentration. The victims were at the age of 16–58 years of life. The group included eleven women (11 %). Generally, the deaths related to NPS’s were predominantly of an accidental character (81 %), while the manner of death in sixteen cases (17 %) was suicide, including hanging (5 cases), jumping from a great height (3 cases), self-injury and exsanguination (1 case), as well as acute drug intoxication (6 cases) and intoxication with central nervous system hypoxia after an hanging (1 case). Among the analyzed cases there were two victims of homicide (2 %), in one of which the perpetrator being under the influence of the mixture of the synthetic opioid U-47700 and synthetic cannabinoid AB-FUBINACA. In twenty-eight cases, medications used in psychiatry were found, which suggested that the victims were struggling with mental problems before death. As it was implied by the available information, more than 36 % of the victims had mental problems.

Feature-Based Molecular Network for New Psychoactive Substance Identification: The Case of Synthetic Cannabinoids in a Seized e-Liquid and Biological Samples.

The comprehensive detection of new psychoactive substances, including synthetic cannabinoids along with their associated metabolites in biological samples, remains an analytical challenge. To detect these chemicals, untargeted approaches using appropriate bioinformatic tools such as molecular networks are useful, albeit it necessitates as a prerequisite the identification of a node of interest within the cluster. To illustrate it, we reported in this study the identification of synthetic cannabinoids and some of their metabolites in seized e-liquid, urine, and hair collected from an 18-year-old poisoned patient hospitalized for neuropsychiatric disorders. A comprehensive analysis of the seized e-liquid was performed using gas chromatography coupled with electron ionization mass spectrometry, 1H NMR, and liquid chromatography coupled with high resolution tandem mass spectrometry combined with data processing based on molecular network strategy. It allowed researchers to detect in the e-liquid known synthetic cannabinoids including MDMB-4en-PINACA, EDMB-4en-PINACA, MMB-4en-PINACA, and MDMB-5F-PICA. Compounds corresponding to transesterification of MDMB-4en-PINACA with pentenol, glycerol, and propylene glycol were also identified. Regarding the urine sample of the patient, metabolites of MDMB-4en-PINACA were detected, including MDMB-4en-PINACA butanoic acid, dihydroxylated MDMB-4en-PINACA butanoic acid, and glucurono-conjugated MDMB-4en-PINACA butanoic acid. Hair analysis of the patient allowed the detection of MDMB-4en-PINACA and MDMB-5F-PICA in the two investigated hair segments. This untargeted analysis of seized materials and biological samples demonstrates the utility of the molecular network strategy in identifying closely related compounds and metabolites of synthetic cannabinoids. It also emphasizes the need for developing strategies to anchor molecular networks, especially for new psychoactive substances.

The challenges for psychiatric care posed by synthetic drugs

In addition to the drugs that have been known for decades, several hundred mainly synthetic substances have been identified as drugs for the first time in the last 20years. Presentation of the various groups of substances and their psychotropic effects, the epidemiology of their use and the legal and social background of this development. Narrative literature review. The most important new psychoactive substances (NPS) are synthetic cannabinoids, synthetic stimulants (cathinones), halluginogens and new synthetic opioids (NSO), in particular fentanyl and related substances. The new substances do not have any qualitatively new psychotropic effects. They were brought onto the market in particular as substitutes for substances subject to the Narcotics Act but are often associated with dangerous side effects and even mortality. The increasing availability of these substances has gone hand in hand with the establishment of the Internet as asource of knowledge (e.g. for synthesis routes) and as amarketplace. Substance group-related regulations have also been established in Germany (New Psychoactive Substances Act). In Germany the prevalence of NPS use is significantly lower than that of cannabis; however, there are indications that the production and distribution of synthetic drugs is more profitable for drug dealers than with conventional plant-based drugs, such as heroin. In the USA, for example, NSOs are the primarily drugs used for opioid addiction. It remains to be seen whether NPS and NSOs will replace conventional drugs. The availability of synthetic drugs is more difficult to reduce than that of plant-based drugs. Harm reduction measures should be expanded, e.g., early warning systems for new drugs, drug checking and naloxone programs.

Transition in production and export potential of garlic in India

The present study analyzed the performance of production and export of Indian garlic based on secondary data collected from different governments departmental repositories and websites. Statistical techniques like mean, standard deviation, regression and CAGR was applied for analysis. Garlic held quantity share (29.68 %) of aggregate production of Indian spices. But in export front the share of quantity and value share of garlic estimated only 2.30 % and 1.21 % respectively of total spices export from the country. India ranked 2nd after China possessing 5.85% share of global production and growing with 9.93 % CAGR over last 15 years (2006-2020) which was 3.5 times higher than China. The major destinations for garlic export from India are Malaysia, Thailand, USA, Vietnam (South) and Nepal altogether constituted around 41 % value of average annual export. But out of these countries, negative trend in export was found in three countries makes India searching for new clients. The lower growth rate (CAGR) of productivity (1.91 %) of garlic compared to acreage (5.46 %) over three decades (1990-91 to 2020-21) harnesses for technological breakthrough. Two producing states of India viz., Madhya Pradesh and Rajasthan account around 78.34 % of national production. But in terms of productivity, Punjab (11.39 t/ha), Haryana (10.67 t/ha) and Madhya Pradesh (10.31 t/ha) led the country. Enhancement of productivity through technological development and adequate market infrastructures along with improvement in post harvest management of the crop particularly processing might be given importance to increase production and export potential of garlic.

Evaluation of cannabis product mislabeling: The development of a unified cannabinoid LC-MS/MS method to analyze e-liquids and edible products

The 2018 Agricultural Improvement Act federally legalized the cultivation of hemp and manufacture and sale of cannabidiol (CBD). The overproduction of CBD led to a significant drop in price. To maintain profitability, manufacturers began producing synthetic and semi-synthetic cannabinoids, marketing them as “legal” and “hemp-derived” due to their synthesis from CBD. The cannabis industry is adaptable, and laboratories have struggled to keep up with the rapid emergence of new compounds. This has resulted in products with unlabeled or mislabeled cannabinoids, causing unexpected adverse events. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the separation and quantitation of 21 cannabinoids. The method was applied in the analysis of 55 commercially available products. Results demonstrate significant issues with quality assurance and labeling in the unregulated cannabis market. Many products either did not contain the cannabinoids listed on their labels or contained cannabinoids that were not listed. When cannabinoids were present, their concentrations were often incorrect, with some products showing high concentrations that could pose a potential health risk. Moreover, safety, dosing, and other pharmacological data of these newly proliferated cannabinoids are lacking. Reports of adverse events are increasing to poison controls centers and emergency departments following cannabis product use. Often, the actual cannabinoids involved in the case reprots are not determined. It is critical to develop more comprehensive testing methodologies to determine the content of cannabis products and to implement stronger quality assurance measures and regulations to protect the public from low-quality and potentially dangerous products.

Direct and selective alkylation of indazole-3-carboxylic acid for the preparation of synthetic cannabinoids and metabolites

The most common method for the synthesis of synthetic cannabinoids with an indazole core utilizes methyl indazole-3-carboxylate as a starting material. However, this method commonly suffers from poor selectivity and low yield. In the current work, a method using indazole-3-carboxylic acid as the starting material was developed and successfully applied in the synthesis of nine synthetic cannabinoids and six of their metabolites. The method provided selective alkylation at the N1-position and resulted in overall yields in the range of 51–96 %. Five of the synthetic cannabinoids have not been reported in the literature and were synthesized in a proactive attempt to predict future SCs. All of the synthesized metabolites have previously been encountered in either in vitro studies or authentic urine samples. Hence, the method proved to be useful for production of SC metabolites, which are relevant for forensic toxicology. All synthesized compounds were characterized with NMR and LC-QTOF-HRMS.

Effect of EMB-FUBINACA on brain endothelial cell angiogenesis: Expression analysis of angiogenic markers.

Angiogenesis is the process by which blood vessels are generated from preexisting ones. Synthetic cannabinoids represent new psychoactive substances that bind to the cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) and simulate similar effects of tetrahydrocannabinol, the primary component found in cannabis. In the present study, we used the synthetic cannabinoid EMB-FUBINACA to study its impact on brain angiogenesis. Human brain microvascular endothelial cells (HBMECs) were cultivated in DMEM media before being subjected to different concentrations of EMB-FUBINACA and the control. Cell viability and the migration rates of HBMECs were evaluated using the viability and wound healing assays, respectively. An in vitro Matrigel Tube Formation Assay was carried out to measure the angiogenic capacity of endothelial cells. Angiopoietin-1 (ANG-1), Angiopoietin-2 (ANG-2), and vascular endothelial growth factor (VEGF) mRNA expression were detected using Real-Time PCR. The released VEGF, ANG-1, and ANG-2 concentrations were detected using ELISA. Western blotting was performed to measure the levels of phosphorylated GSK-3β, VEGF, ANG-1, and ANG-2. EMB-FUBINACA stimulated endothelial cell proliferation, migration, and capillary tube-like formation and promoted the expression of proangiogenic factors on RNA and protein levels. This study points out that the synthetic cannabinoid EMB-FUBINACA is a potential candidate for further investigations to confirm its potential as an inducer of brain angiogenesis. This could encourage researchers to create a new therapeutic approach for angiogenesis-related diseases.

Poisoning-Induced Acute Kidney Injury: A Review.

Acute kidney injury (AKI) is a debilitating, multi-etiological disease that is commonly seen in clinical practice and in the emergency department. In this review, we introduce the definition, symptoms, and causes of poisoning-related AKI; we also discuss its mechanisms, risk factors, and epidemiology, as well as elaborate on the relevant laboratory tests. Subsequently, we discuss the treatment strategies for toxin- and substance-related AKI caused by Glafenin, antimicrobial agents, lithium, contrast media, snake venom, herbicides, ethylene glycol, synthetic cannabinoids, cocaine, heroin, and amphetamines. Finally, for a comprehensive overview of poisoning-related AKI, we review the management, prevention, and outcomes of this condition.

O SISTEMA ENDOCANABINOIDE E AS PRINCIPAIS FORMAS DE MANTER SEU EQUILÍBRIO: UMA REVISÃO DE LITERATURA

Considering that the endocannabinoid system (ECS) is an essential ally in the regulation and balance of various physiological processes in the human body and, thus, the negative implications of imbalance in this system, the objective of this study is to analyze the main exogenous substances derived from cannabis sativa , which can help rebalance the SEC. To achieve this purpose, a literature review of scientific articles published in the last five years was carried out in the online databases SciELO and PubMed Central, using the term: Endocannabinoid system AND Cannabis sativa as a search strategy. Therefore, it presents the benefits of the main phytocannabinoids and also their adverse effects, as well as how they interact with each other; The relationship between the endocannabinoid system and the main cannabinoids and brief considerations on synthetic cannabinoids (SCS). It is noteworthy that the prescription of phytocannabinoids requires specific criteria and, therefore, medical caution. This reflects the importance of producing knowledge on this topic that is so important to medicine, society and science in general.

In vivo assessment of the nephrotoxic effects of the synthetic cannabinoid AB-FUBINACA.

The widespread misuse of synthetic cannabinoids (SCs) has led to a notable increase in reported adverse effects, raising significant health concerns. SCs use has been particularly associated with acute kidney injury (AKI). However, the pathogenesis of SCs-induced AKI is not well-understood. We investigated the nephrotoxic effect of acute administration of N-[(1S)- 1-(aminocarbonyl)-2-methylpropyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (AB-FUBINKA) (3mg/kg for 5days) in mice. Various parameters of oxidative stress, inflammation, and apoptosis have been quantified. The expressions of mitochondrial complexes (I-V) in renal tissues were also assessed. Our findings showed that AB-FUBINACA induced substantial impairment in the renal function that is accompanied by elevated expression of renal tubular damage markers; KIM-1 and NGAL. Administration of AB-FUBINACA was found to be associated with a significant increase in the expression of oxidative stress markers (iNOS, NOX4, NOX2, NOS3) and the level of lipid peroxidation in the kidney. The expression of pro-inflammatory markers (IL-6, TNF-alpha, NF-kB) was also enhanced following exposure to AB-FUBINACA. These findings were also correlated with increased expression of major apoptosis regulatory markers (Bax, caspase-9, caspase-3) and reduced expression of mitochondrial complexes I, III, and IV. These results indicate that AB-FUBINACA can trigger oxidative stress and inflammation, and activate caspase-dependent apoptosis in the kidney, with these processes being possibly linked to disruption of mitochondrial complexes and could be an underlying mechanism of SCs-induced nephrotoxicity.

A Comprehensive Exploration of the Multifaceted Neuroprotective Role of Cannabinoids in Alzheimer's Disease across a Decade of Research.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, manifests through dysregulation of brain function and subsequent loss of bodily control, attributed to β-amyloid plaque deposition and TAU protein hyperphosphorylation and aggregation, leading to neuronal death. Concurrently, similar cannabinoids to the ones derived from Cannabis sativa are present in the endocannabinoid system, acting through receptors CB1R and CB2R and other related receptors such as Trpv-1 and GPR-55, and are being extensively investigated for AD therapy. Given the limited efficacy and adverse effects of current available treatments, alternative approaches are crucial. Therefore, this review aims to identify effective natural and synthetic cannabinoids and elucidate their beneficial actions for AD treatment. PubMed and Scopus databases were queried (2014-2024) using keywords such as "Alzheimer's disease" and "cannabinoids". The majority of natural (Δ9-THC, CBD, AEA, etc.) and synthetic (JWH-133, WIN55,212-2, CP55-940, etc.) cannabinoids included showed promise in improving memory, cognition, and behavioral symptoms, potentially via pathways involving antioxidant effects of selective CB1R agonists (such as the BDNF/TrkB/Akt pathway) and immunomodulatory effects of selective CB2R agonists (TLR4/NF-κB p65 pathway). Combining anticholinesterase properties with a cannabinoid moiety may enhance therapeutic responses, addressing cholinergic deficits of AD brains. Thus, the positive outcomes of the vast majority of studies discussed support further advancing cannabinoids in clinical trials for AD treatment.

Comparing CB1 receptor GIRK channel responses to receptor internalization using a kinetic imaging assay

The type 1 cannabinoid receptor (CB1R) mediates neurotransmitter release and synaptic plasticity in the central nervous system. Endogenous, plant-derived, synthetic cannabinoids bind to CB1R, initiating the inhibitory G-protein (Gi) and the β-arrestin signaling pathways. Within the Gi signaling pathway, CB1R activates G protein-gated, inwardly-rectifying potassium (GIRK) channels. The β-arrestin pathway reduces CB1R expression on the cell surface through receptor internalization. Because of their association with analgesia and drug tolerance, GIRK channels and receptor internalization are of interest to the development of pharmaceuticals. This research used immortalized mouse pituitary gland cells transduced with a pH-sensitive, fluorescently-tagged human CB1R (AtT20-SEPCB1) to measure GIRK channel activity and CB1R internalization. Cannabinoid-induced GIRK channel activity is measured by using a fluorescent membrane-potential sensitive dye. We developed a kinetic imaging assay that visualizes and measures CB1R internalization. All cannabinoids stimulated a GIRK channel response with a rank order potency of WIN55,212-2 > (±)CP55,940 > Δ9-THC > AEA. Efficacy was expressed relative to (±)CP55,940 with a rank order efficacy of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. All cannabinoids stimulated CB1R internalization with a rank order potency of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. Internalization efficacy was normalized to (±)CP55,940 with a rank order efficacy of WIN55,212-2 > AEA > (±)CP55,940 > Δ9-THC. (±)CP55,940 was significantly more potent and efficacious than AEA and Δ9-THC at stimulating a GIRK channel response; no significant differences between potency and efficacy were observed with CB1R internalization. No significant differences were found when comparing a cannabinoid’s GIRK channel and CB1R internalization response. In conclusion, AtT20-SEPCB1 cells can be used to assess cannabinoid-induced CB1R internalization. While cannabinoids display differential Gi signaling when compared to each other, this did not extend to CB1R internalization.

Potential Implications of Multi-Drug Exposure with Synthetic Cannabinoids: A Scoping Review of Human Case Studies

Synthetic cannabinoids are a rapidly evolving, diverse class of new psychoactive substances. Synthetic cannabinoid use results in a higher likelihood of adverse events and hospitalization when compared to cannabis use. The mechanisms behind synthetic cannabinoid toxicity remain elusive. Furthermore, poly-substance use may be a significant contributing factor in many cases. This scoping review aimed to identify the key characteristics of synthetic cannabinoid co-exposure cases and discuss the potential implications of poly-substance use in humans. There were 278 human cases involving 64 different synthetic cannabinoids extracted from the databases. Cases involved a total of 840 individual co-exposures, with an average of four substances involved in each case. The most common co-exposures were alcohol (11.4%), opioids (11.2%), and cannabis (11.1%). When analyzed by case outcome, co-exposure to either antipsychotics/antidepressants, alcohol, or tobacco were significantly associated with mortality as an outcome (p &lt; 0.05). Drug-use history (63.4%), mental illness (23.7%), and hypertensive and atherosclerotic cardiovascular disease (20.1%) were prevalent patient histories in the case cohort. There are several potential pharmacodynamic and pharmacokinetic interactions between co-exposure drugs and synthetic cannabinoids that could worsen clinical presentation and toxicity in synthetic cannabinoid users. Individuals with substance-use disorders or psychiatric illness would be especially vulnerable to these multi-drug interactions. Further research into these complex exposures is needed for the successful prevention and treatment of synthetic cannabinoid-related harms.

Qualitative and quantitative analysis of synthetic cannabinoids in e-liquids by pyrolysis–gas chromatography/mass spectrometry

Synthetic cannabinoids (SCs) are a series of synthetic substances that mimic the effects of natural cannabis and cause more serious toxicity and public safety issues. SCs, with a wide variety and fast update rate have become the most abused family of new psychoactive substances. A pyrolysis–gas chromatography/mass spectrometry method has been developed to qualitatively and quantitatively analyze SCs in e-liquids using pyrolysis products as analytical targets, which can effectively expand the detection range of SCs. In qualitative analysis, diluted e-liquids were pyrolyzed in the microfurnace at 800, 600, and 300 ℃, respectively, followed by separation and analysis through gas chromatography/mass spectrometry. SCs in the e-liquids were determined by both shared and characteristic pyrolysis products combined with the EI mass spectrometry of their parent compounds. ADB-BUTINACA and 5F-MDMB-PICA were successfully identified in five e-liquid samples seized by local police. Furthermore, five popular SCs in the illegal market, ADB-BUTINACA, 4F-ABUTINACA, 4CN-CUMYL-BUTINACA, 4F-MDMB-BICA, and 5F-MDMB-PICA, were quantitatively analyzed based on their characteristic pyrolysis products as the analysis targets. The results indicated that the linear range of ADB-BUTINACA was 2–200 μg/mL, while those of 4F-ABUTINACA and 4CN-CUMYL-BUTINACA were 1–200 μg/mL. For 4F-MDMB-BICA and 5F-MDMB-PICA, the linear range was 5–500 μg/mL. The linear correlation coefficients of determination of five SCs were greater than 0.994. The limit of detection (S/N=3) for five SCs was 0.25–2.50 μg/mL, and the limit of quantification (S/N=10) was 0.50–5.00 μg/mL. This quantitative method was applied to five positive samples in real cases. The results showed that the concentrations of ADB-BUTIANCA and 5F-MDMB-PICA in the positive samples were 751.32–4810.10 μg/mL and 1109.41 μg/mL, respectively. The current research provides a validated pyrolysis–gas chromatography/mass spectrometry method, with simple pre-treatment, fast operation and wide screening range, to accurately identify and quantify SCs in e-liquid samples without reference materials.