Synthetic Cannabinoids Research Articles

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 < 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.

Synthetic cannabinoid identification in cases associated with blue lotus and valerian root vaping products.

Synthetic cannabinoids emerged in the early 21st century and have continued to evolve and flourish to present day. Like other novel psychoactive substances (NPS), synthetic cannabinoids have been sold under the guise of legitimate products. Some examples include "potpourri," "incense," and herbal material. Between May 2020 and December 2023, the United States Army Criminal Investigation Laboratory, Drug Chemistry Division (USACIL) received 29 seized drug cases mentioning "blue lotus" or "valerian root." In 90% of these cases, at least one exhibit contained one or more synthetic cannabinoids. During the same timeframe, the Armed Forces Medical Examiner System, Division of Forensic Toxicology received 65 toxicology cases that contained synthetic cannabinoids and/or their corresponding metabolites where case history mentioned "blue lotus." The most frequently observed synthetic cannabinoids between laboratories were 5F-MDMB-PICA, ADB-BUTINACA, and MDMB-4en-PINACA. Innocuous branding and marketing may deceive law enforcement, investigators, and healthcare providers into believing that the adverse effects of erratic behavior, sedation, slurred speech, and hallucinations are a result of toxicity from botanical extracts (e.g. apomorphine and nuciferine in blue lotus). Due to the dangerous nature of these NPS, synthetic cannabinoid screening is recommended for all cases where there is suspected use of vaping products suggested to contain "blue lotus" or "valerian root" as vendors continue to conceal the presence of these compounds.

Metabolic characteristic profiling of 1-amino-3,3-dimethyl-1-oxobutan-2-yl-derived indole and indazole synthetic cannabinoids in vitro

Characterizing the metabolic profiles of synthetic cannabinoids (SCs), a type of new psychoactive substances, is of particular importance for forensic detection and analysis. Although the metabolism of individual SCs derived from 1-amino-3,3-dimethyl-1-oxobutan-2-yl (ADB-SCs) has been reported, their metabolites also undergo a continuous change and combination of their tail and core regions. Therefore, elucidating the metabolic characteristics and effects of these structures is essential to enhance our understanding. In this study, the human liver microsome was used as the model for studying the in vitro phase I metabolism of 12 ADB-SCs, and the metabolites obtained were analyzed using ultra-high performance liquid chromatography–tandem four-level rod-electrostatic field orbital ion trap mass spectrometry to determine type, structure, and relative contents. The results indicated that hydroxylation and N-dealkylation were the major metabolic pathways in 12 ADB-SCs. The effects of the core and tail on the metabolism of these ADB-SCs were studied using theoretical calculations. For N-dealkylation metabolism, the strong electron-withdrawing conjugative effect of the –N= moiety in the pyrazole ring, steric hindrance of the tail, and electronic effect of substituents on the tail significantly affected metabolism. Further, it changed the relative contents of N-dealkylation metabolites. For hydroxylation, the reaction types were inconsistent at different parts. For instance, the phenyl group of the core is electrophilic, and its electron cloud density determines whether the phenyl group can be hydroxylated at the specific metabolic sites. Meanwhile, hydroxylation of the neopentyl moiety of the linked group involves the oxidation of aliphatic C–H bonds, whereas amide–hydroxylamine tautomerism affects hydroxylation metabolism. When the alkyl chain in the tail contains functional groups (such as –F and >CC<), oxidative defluorination or dihydrodiol metabolites are produced. Taken together, we systematically determined d the effect of functional groups in the core and tail of ADB-SCs on their metabolism, validating confirmed the feasibility of ADB-SC metabolism prediction based on their structural characteristics.

In vitro metabolism study of ADB-P-5Br-INACA and ADB-4en-P-5Br-INACA using human hepatocytes, liver microsomes, and in-house synthesized references.

Synthetic cannabinoids (SCs) remain a major public health concern, as they continuously are linked to severe intoxications and drug-related deaths worldwide. As new SCs continue to emerge on the illicit drug market, an understanding of SC metabolism is needed to identify formed metabolites that may serve as biomarkers in forensic toxicology screening and for understanding the pharmacokinetics of the drugs. In this work, the metabolism of ADB-4en-P-5Br-INACA and ADB-P-5Br-INACA ((S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-5-bromo-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-5-bromo-1-pentyl-1H-indazole-3-carboxamide respectively) were investigated using human hepatocytes in vitro and in-house synthesized references. Both SCs were incubated with pooled human hepatocytes over 3h, with the aim to identify unique and abundant metabolites using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In total nine metabolites were identified for ADB-4en-P-5Br-INACA and 10 metabolites for ADB-P-5Br-INACA. The observed biotransformations included dihydrodiol formation, terminal amide hydrolysis, hydroxylation, dehydrogenation, carbonyl formation, glucuronidation, and combinations thereof. The major metabolites were confirmed by in-house synthesized references. Recommended biomarkers for ADB-P-5Br-INACA and ADB-4en-P-5Br-INACA are the terminal hydroxy and dihydrodiol metabolite respectively.

Capture and analysis of MDMB-4en-PINACA and ADB-4en-PINACA in exhaled breath using functionalized cotton fiber: A novel approach to noninvasive drug abuse detection

Breath analysis has emerged as a promising noninvasive method for detecting drug abuse, offering potential advantages over traditional blood or urine samples. However, the capture and analysis of trace analytes in exhaled breath (EB) remains a challenge for practical applications. In this study, we explore the utilization of poly (methacrylic anhydride-co-ethylene glycol dimethacrylate)-functionalized cotton fiber (poly (MAA-co-EGDMA)-functionalized cotton fiber) for the capture of MDMB-4en-PINACA and ADB-4en-PINACA, two popular synthetic cannabinoids, from exhaled breath. Capture efficiencies of 92 % and 88 % for MDMB-4en-PINACA and ADB-4en-PINACA were achieved demonstrating robust performance across batches and excellent stability. Animal experiments were conducted and exhaled breath samples were collected and analyzed. Shorter half-lives were shown for MDMB-4en-PINACA and ADB-4en-PINACA in EB than in plasma. The detection window for MDMB-4en-PINACA was 210 min, while 150 min for ADB-4en-PINACA. This pilot study presents a novel approach for the capture of MDMB-4en-PINACA and ADB-4en-PINACA in exhaled breath using functionalized cotton fiber. The demonstrated efficacy in capturing MDMB-4en-PINACA and ADB-4en-PINACA highlights the potential of this low-cost and stable platform for noninvasive drug abuse detection. By offering a viable alternative to invasive methods, our findings demonstrate a new noninvasive method of drug abuse detection using exhaled breath holds great promise for enhancing public health efforts to combat drug abuse.

Rapid Nuclease-Assisted Selection of High-Affinity Small-Molecule Aptamers.

Aptamers are nucleic acid bioreceptors that have been widely utilized for a variety of biosensing applications, including in vivo detection methods that would not be possible with antibody-based systems. However, it remains challenging to generate high-quality aptamers for small molecule targets, particularly for use under physiological conditions. We present a highly effective aptamer selection technology for small-molecule targets that utilizes the nuclease EcoRI to remove nonspecific or weakly binding sequences in solution phase, rapidly enriching high-affinity target binders within just a few rounds of selection. As proof-of-concept, we used our nuclease-assisted SELEX (NA-SELEX) method to isolate aptamers for a synthetic cannabinoid, AB-FUBINACA. Within five rounds, we identified two highly specific aptamers that exhibit nanomolar affinity at physiological temperature. We also demonstrate the robustness and reproducibility of NA-SELEX by performing the same selection experiment with fresh reagents and libraries, obtaining the same two aptamers as well as two other high-quality aptamer candidates. Finally, we compare NA-SELEX against a conventional library-immobilized SELEX screen for AB-FUBINACA using the same screening conditions, identifying aptamers with 25-100-fold weaker affinity after 11 rounds of selection. NA-SELEX therefore could be an effective selection method for the isolation of high-quality aptamers for small-molecule targets.

Discrepancies between the stated contents and analytical findings for electronic cigarette liquid products: Identification of the new cannabinoid, Δ9-tetrahydrocannabihexol acetate.

A number of synthetic cannabinoids have been appearing in the recreational drug market for more than a decade. Recent additions are so-called semi-synthetic cannabinoids, and they structurally closely resemble the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol. Knowledge of new (semi-)synthetic cannabinoids is essential to help identify them in authentic forensic case samples. Therefore, the aim of the study was to examine two commercially available electronic cigarette liquid products claiming to contain cannabinoids and characterize the structures of the main compounds. The liquid products were analyzed by gas chromatography-mass spectrometry (GC-MS), GC-quadrupole time-of-flight mass spectrometry (GC-QTOF-MS), and liquid chromatography-high-resolution mass spectrometry (LC-HRMS). In product A, typical cannabinoids (cannabidiol, cannabigerol, and cannabinol) and terpenes (α-caryophyllene and β-caryophyllene) were identified by comparison with reference materials. An unknown peak was isolated by semi-preparative high-performance LC, analyzed by nuclear magnetic resonance (NMR) spectroscopy, and identified to be Δ9-tetrahydrocannabihexol acetate (Δ9-THCH-O). To the authors' knowledge, this is the first report of the identification of Δ9-THCH-O in commercially available products. Another compound estimated as cannabihexol acetate was also detected. In product B, cannabidiol, cannabinol, α-caryophyllene, and β-caryophyllene were identified, while two unknown peaks were estimated as tetrahydrocannabidiol isomers. Despite products A and B being labeled to contain "60% HHCPM" and "80% 10-OH-HHC," respectively, no such compounds were detected. The findings of this study could help detect Δ9-THCH-O in case samples and highlight the need to keep monitoring commercial products to identify new drugs, while warning that the package labels cannot be trusted.

Current options for cannabinoids in the treatment of Parkinson's disease

The utility of cannabinoids as agents used to treat diseases is a popular topic of discussion these days. The approval of medical marijuana continues to stir up controversy. As far back as ancient times, hemp was used for medicinal purposes. These plants have the ability to produce phytochemicals and other compounds such as flavonoids and terpenes. Respective species of hemp differ in the content of particular chemical compounds and therefore have different possible uses. Among the best-known phytocannabinoids found in hemp are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). They have partially opposing effects and interact with the corresponding receptors of the endocannabinoid system in the body's tissues. We also distinguish between cannabinoids of endogenous origin - endocannabinoids (EC) and synthetic cannabinoids (SC). The effects of THC and CBD on the human body are still being studied. Information about them that appears in the media, is often reported inaccurately or incompletely. There is now a growing body of research into the use of cannabinoids to treat and alleviate the symptoms of many diseases. Due to the neuroprotective effects of THC and CBD, researchers' work has focused on using them to treat neurodegenerative diseases, which include Parkinson's disease (PD).

Long-term effects on cardiorespiratory and behavioral responses in male and female rats prenatally exposed to cannabinoid.

Development of the respiratory system can be affected by the use of drugs during pregnancy, as the prenatal phase is highly sensitive to pharmacological interventions, resulting in long-term consequences. The deleterious effects of external cannabinoids during gestation may be related to negative interference in central nervous system formation, cardiorespiratory system function, and behavioral disorders. Nevertheless, the impact of external cannabinoids on cardiorespiratory network development, chemosensitivity, and its future consequences in adulthood is still unclear. We evaluated the effects of prenatal exposure to a synthetic cannabinoid (WIN 55,212-2, 0.5 mg·kg-1·day-1) on the cardiorespiratory control and panic-like behavior of male and female rats in adulthood. Exogenous cannabinoid exposure during pregnancy resulted in a sex-dependent difference in breathing control. Specifically, males showed increased chemosensitivity to CO2 and O2, whereas females exhibited decreased sensitivity. Altered cardiovascular control was evident, with prenatally treated males and females being more susceptible to hypertension and tachycardia under adverse environmental conditions. Moreover, WIN-treated males exhibited higher fragmentation of sleep episodes, whereas females displayed anxiolytic and panicolytic behavioral responses to CO2. However, no changes were observed in the mechanical component of the respiratory system, and there were no neuroanatomical alterations, such as changes in the expression of CB1 receptors in the brainstem or in the quantification of catecholaminergic and serotonergic neurons. These findings highlight that external interference in cannabinoid signaling during fetal development causes sex-specific, long-lasting effects for the cardiorespiratory system and behavioral responses in adulthood.NEW & NOTEWORTHY The surge in recreational cannabis use and cannabinoid-based medication prescription among pregnant women has been notable in recent years, fueled by the misconception that natural products are inherently safe. Significant gaps persist regarding the potential risks of maternal consumption of cannabinoids and the long-term effects on the cardiorespiratory system of their offspring, which may be determined by sex. Accordingly, this research aims to diminish this lack of information and raise a note of caution.

Comparative analysis of addiction severity and renal functions in patients with synthetic cannabinoid use disorder versus cannabis use disorder

BackgroundThe use of synthetic cannabinoids (SC) has become a concerning public health issue due to their potential adverse effects on both physical and mental health. Understanding the effect of cannabis and synthetic cannabinoids use on kidney functions and creatinine phosphokinase-total (CPK) levels is essential for targeted intervention and patient care.MethodsThis cross-sectional study aimed to assess addiction severity using the Addiction Severity Index (ASI) and kidney functions in 45 patients with SC use disorder and compare them to 45 patients with cannabis use disorder (CUD). Participants were recruited from the addiction outpatient clinics and inpatient ward of the addiction psychiatry unit at “Kasr Al Aini Hospital,” Cairo University.ResultsThere was a statistically significant difference between the 2 groups regarding the Addiction Severity Index domains, where patients with SC use disorder had higher scores in all domains of the ASI.Regarding kidney functions and CPK-total levels, there was a significant difference in the serum CPK-total level (p < 0.05) between the 2 groups; however, there was no significant difference regarding the other kidney function tests (serum creatinine, urea, blood urea nitrogen, and estimated glomerular filtration rate).As for the correlative analysis, there was a significant correlation between some domains of the ASI and the kidney function tests in both patient groups.ConclusionOur results strongly suggest that SC may have a more hazardous and detrimental impact on individuals, encompassing various aspects of addiction severity such as physical health, psychological well-being, social functioning, and overall quality of life. Our findings also highlight the potential risk of elevated CPK-total levels in patients with SC use disorder; therefore, regular monitoring of kidney function in patients with synthetic cannabinoid use disorder is crucial for guiding appropriate treatment interventions and mitigating adverse health outcomes.

JWH-182: a safe and effective synthetic cannabinoid for chemotherapy-induced neuropathic pain in preclinical models

Chemotherapy-induced neuropathic pain (CINP), a condition with unmet treatment needs, affects over half of cancer patients treated with chemotherapeutics. Researchers have recently focused on the endocannabinoid system because of its critical role in regulating our bodies' most important functions, including pain. We used in vitro and in vivo methods to determine the toxicity profile of a synthetic cannabinoid, JWH-182, and whether it could be potentially effective for CINP alleviation. In vitro, we evaluated JWH-182 general toxicity, measuring fibroblast viability treated with various concentrations of compound, and its neuroprotection on dorsal root ganglion neurons treated with paclitaxel. In vivo, we performed an evaluation of acute and 28-day repeated dose toxicity in mice, with monitoring of health status and a complete histopathological examination. Finally, we evaluated the efficacy of JWH-182 on a CINP model in mice using specific pain assessment tests. JWH-182 has an acceptable toxicity profile, in both, in vitro and in vivo studies and it was able to significantly reduce pain perception in a CINP model in mice. However, the translation of these results to the clinic needs further investigation.

Respiratory Depressant Effects of Fentanyl in Combination With Synthetic Cannabinoid Receptor Agonists: A Potential Mechanism for “Narcan-Resistant” Overdose

Respiratory Depressant Effects of Fentanyl in Combination With Synthetic Cannabinoid Receptor Agonists: A Potential Mechanism for “Narcan-Resistant” Overdose

Stability of new psychoactive substances in crude wastewater.

Those involved in drug testing continue to grapple with the dynamic nature of emerging psychoactive substances (NPS) and their rapid infiltration into society. The challenge extends beyond merely detecting and measuring NPS using analytical tools; it also encompasses the complexities arising from the formation and presence of metabolites and degradation products. This study utilises liquid chromatography time-of-flight mass spectrometry to investigate the stability of new psychoactive substances in wastewater. Seven NPS compounds including 25C-NBOMe, 5F-APINACA 4-hydroxyphenyl, AB-PINACA, APINACA 4-hydroxyphenyl, fentanyl, norfentanyl and MDPV, along with their corresponding internal standard, were examined. Reference material for each NPS compound was introduced into a wastewater sample from a Wessex water treatment plant. The sample was then exposed to four different environments: room temperature, refrigerator temperature, acidification to pH 2, and the introduction of sodium metabisulfite. The findings highlight the critical dependence of storage conditions on target analytes, emphasizing the paramount importance of the time elapsed between collection and analysis for NPS wastewater analysis. Notably, synthetic cannabinoids exhibit limited stability in wastewater whereas cathinone-like substances demonstrate greater stability. Furthermore, metabolites prove to be more stable in wastewater than the parent drug, suggesting that focusing on metabolite detection may be more favourable for future analysis.

Local activation of CB1 receptors by synthetic and endogenous cannabinoids dampens burst firing mode of reticular thalamic nucleus neurons in rats under ketamine anesthesia.

The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.

Generation of High-Affinity Aptamers for Indazole Synthetic Cannabinoids.

Synthetic cannabinoids are a widely abused class of dangerous psychoactive substances, especially among youths and young adults. Dozens of such drugs have been identified to date, and new ones continue to emerge. The ability to detect these drugs is important for interdiction efforts and the diagnosis of drug overdose, but existing analytical methods lack broad cross-reactivity to diverse members of this drug family. Here, we have utilized library-immobilized SELEX to generate DNA aptamers that can broadly recognize various members of the indazole-3-carboxamide synthetic cannabinoid family. Using two representatives of this family, AB-FUBINACA and 5F-AMB, we identify two aptamers FUB4 and AMB2F with respective dissociation constants (KDs) of 138 ± 15 and 411 ± 20 nM for their targets. These aptamers can recognize many indazole-based synthetic cannabinoids with high affinity and excellent specificity against natural cannabinoids as well as other structurally similar interferents like serotonin and tryptophan. We use these two aptamers to develop fluorescence strand-displacement sensors that successfully detect these synthetic cannabinoids at concentrations as low as 50 nM in human serum. The sensors can also detect up to 14 different drugs from this family─a major improvement over the six recognized by an existing commercial immunoassay.

Retrospective screening of new psychoactive substances (NPS) in post mortem samples from 2014 to 2021

Systematic retrospective processing of previously analysed biological samples has been proven to be a valuable tool in the search for new drugs (e.g. new psychoactive substances (NPS)) and for quality assessment in clinical and forensic toxicology. In a previous study, we developed a strategy for retrospective data-analysis using a personalized library of synthetic cannabinoids, designer benzodiazepines and synthetic opioids obtained from the crowdsourced database HighResNPS (https://highresnps.com). In this study, the same strategy was employed for the compounds within the groups of NPS that were not previously included such as synthetic cathinones, phenethylamines, aminoindanes, arylalkylamines, piperazine derivates, piperidines, pyrrolidines, indolalkylamines and arylcyclohexylamines. Synthetic opioids and designer benzodiazepines, which were not part of the previous study, were also included. To enhance the effectiveness of the retrospective analysis, a predicted retention time was included for all entries. Data files from the analysis of 2186 forensic post mortem samples with an Agilent Technologies 6540 ultra-high pressure liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) performed in the laboratory from January 2014 to December 2021 were retrospectively processed with the up-to-date library. Tentative findings were classified in two groups: The findings where MS/MS data was acquired for library match (category 1) and the less certain findings where such data lacked (category 2). Five compounds of category 1 (three synthetic cathinones and two indolalkylamines) were identified in 12 samples. Only one of the findings, 4-MEAPP (4-methyl-α-ethylaminopentiophenone), was deemed plausible after reviewing case information. As many as 501 presumably positive category 2 findings were detected. Using the predicted retention time as an additional criterion the number was significantly reduced but still too high for a manual review. This work has demonstrated that the strategy developed in the previous study can be applied to other NPS groups. However, it is important to note the limitations such a method may have in detecting compounds at very low concentrations.

Impulsivity and self-harm behavior in patients with synthetic cannabinoids dependence

Background Synthetic cannabinoids (SCs) dependence is increasingly prevalent among young individuals globally, with limited understanding of their potential detrimental effects. Therefore, we conducted this comparative study to assess impulsivity and non-suicidal self-harm behavior in patients with SCs dependence. Subjects and method We conducted this comparative, case-control study in the outpatient clinics of (Beni-suef University Hospital). We recruited 30 patients with SCs dependence and the 30 healthy subjects as a control group. Psychometric scales, including Addiction Severity Index (ASI), Barratt Impulsivity Scale-11 (BIS-11), Deliberate Self-harm Inventory-Short Version (DSHI), SCID I, SCID II, and drug urine screen, were applied to compare the two study arms. Results DSHI-s scores were significantly higher between the two study arms (3.23 ± 4.97 vs. 0.0 ± 0.0, p < 0.001, for cases and controls, respectively). Similarly, the mean ± SD score of the BIS scale was significantly higher in cases 68.13 ± 9.75 compared to the control group (45.67 ± 5.12) with a statistically significant difference (p < 0.001). Using the regression analysis, we observed a significant positive linkage between age, duration of substance use, DSHI-s, and the Barratt scale. Conclusion Patients with synthetic cannabis addiction exhibited more impulsivity and self-harm behaviors compared to healthy controls. The adverse effects of substance use disorder escalated, notably in individuals classified as having severe addiction based on the Addiction Severity Index. Age and length of substance use were found to be potential factors influencing the level of impulsivity and self-harm actions.