Synthetic Cannabinoid Abuse Research Articles

Incomplete autophagy and increased cholesterol synthesis during neuronal cell death caused by a synthetic cannabinoid, CP-55,940

There is a propensity for synthetic cannabinoid abuse to spread worldwide. CP-55,940, a synthetic cannabinoid having the ability to activate both CB1 and CB2 receptors, has been shown to induce cell death in neurons as well as other cells. Here we investigate molecular events underling the adverse effects of CP-55,940 on neuronal cells. Exposure of mouse neuroblastoma Neuro2a cells to 10–50 µM CP-55,940 results in concentration-dependent cell death that is not accompanied by an induction of apoptosis. CP-55,940 also stimulates autophagy, but the stimulation is not followed by an increase in autophagic degradation. Transcriptome analysis using DNA microarray revealed the increased expression of genes for the cholesterol biosynthesis pathway that is associated with the activation of SREBP-2, the master transcriptional regulator of cholesterol biosynthesis. However, free cholesterol is localized mainly to cytoplasmic structures, although it is localized to the plasma membrane in healthy cells. Thus, cellular trafficking of cholesterol seems to be somewhat disrupted in CP-55,940 stimulated cells. These results show for the first time that CP-55,940 stimulates autophagy as well as cholesterol biosynthesis, although not all the processes involved in the cellular response to CP-55,940 seem to be complete in these cells.

The Rise of the inadvertently called Adolescent 'Zombie' Behavior: A Spotlight on Synthetic Cannabinoid Abuse.

The Rise of the inadvertently called Adolescent 'Zombie' Behavior: A Spotlight on Synthetic Cannabinoid Abuse.

Comorbidity of mental disorders in synthetic cannabinoids abuse: clinical dynamics, behavior, adaptation

IntroductionThe study of the phenomenon of deformation of mental disorders, clinical dynamics, behaviors, and adaptations in case of abuse of synthetic cannabinoids is of relevance.ObjectivesTo study the phenomenon of deformation of mental disorders, clinical dynamics, behaviors, and adaptations in case of abuse of synthetic cannabinoidsMethodsCatamnestic, clinical-psychopathological methods (PANS, SANS, CGI, MMPI, CGI, STAI, LSI, TPA, ICD-10), statistical (Python 3.11.0).Results291 men (age from 18 to 35 years) were examined: 240 - F12.2xx, of which 98 - F60.xx-F62.xx, 142 - F20.xx and 51 - F20.xx without substance abuse. The study took place from 2018 to 2023 based on psychiatric institutions of the Russia, Tomsk region, St. Petersburg, Noyabrsk and Nizhnevartovsk.ConclusionsThe phenomenon of abuse of synthetic cannabinoids is a factor in the deformation of mental disorders. Persistent exogenous visual and delusional disorders contribute to the symptoms of exacerbations of schizophrenia; schizophrenic symptoms are included in psychotic episodes in personality disorders. In remission of schizophrenia, there is a quasi-adaptation from socio-professional environments, mostly addictive and criminalized, a pronounced smoothing of emotional impoverishment, a stigmatizing symptom is mainly a volitional defect, as well as frequent rehospitalizations not indirectly related to drugs. In remissions of drug use in patients with personality disorder, persistent schizophrenia of behavior. In patients with schizophrenia and patients with personality disorders, there is a distortion of behavior with a predominance in patterns of inclinations to delict, nonconformity, isolation in an addictive environment, suspiciousness. Drug abuse may initiate auto-aggression predominantly in individuals with personality disorders and to a lesser extent in patients with schizophrenia. True suicides in drug users include only episodes with depressive symptoms.Disclosure of InterestNone Declared

A comprehensive LC-MS/MS method for simultaneous analysis of 65 synthetic cannabinoids in human hair samples and application to forensic investigations

Synthetic cannabinoids (SCs) represent a diverse class of new psychoactive substances characterized by extensive substance variety and severe abuse implications. The current situation of synthetic cannabinoid abuse in China is getting worse, with an increasing number of SC variants emerging. Therefore, it is imperative to improve synthetic cannabinoid detecting methods to align with the prevalent abuse situation in the region. In this study, a reliable and validated liquid chromatography-tandem mass spectrometry method was developed for the qualitative and quantitative analysis of 65 SC analogues in human hair samples. The validation results demonstrated satisfactory linearity (r ≥ 0.99) within the range of 25–2500 pg/mg for each SC analogue. The method exhibited limits of detection ranging from 10 to 15 pg/mg and limits of quantification ranging from 25 to 40 pg/mg. The relative standard deviations of intra-day precision and inter-day precision were below 15 %. Furthermore, negligible matrix effects were observed, with recovery rates ranging from 85.70 % to 119.43 %. Analysis of abuser demographics revealed that the primary group engaged in SC analogue abuse consisted of adolescents, predominantly males, accounting for 79.5 % of cases. Among the suspected individuals, ADB-BUTINACA and MDMB-4en-PINACA were the most frequently detected substances. The present study develops a highly sensitive analytical method and provides a comprehensive overview of the prevalence of SC abuse in the eastern region of China.

Synthetic Cannabinoids-Related Cardiovascular Emergencies: A Review of the Literature.

Synthetic cannabinoids (SCBs) are a group of psychoactive compounds, known to cause a range of multisystem adverse events, including the cardiovascular system. The aim of this review is to provide an overview of the literature on cardiovascular emergencies associated with SCBs. A systematic search of electronic databases was conducted to identify relevant studies published between January 2010 and September 2022. Inclusion criteria were studies reporting on cardiovascular emergencies in individuals with SCB abuse. The search yielded a total of 43 studies, including case reports, case series, and meta-analyses.This review indicates that SCB abuse can lead to a range of cardiovascular emergencies, including acute coronary syndrome, arrhythmias, and hypertension. The onset of these emergencies is often sudden and may occur in previously healthy individuals. The severity of these complications can vary widely, with some cases resulting in cardiac arrest or death.Management strategies for SCB-related cardiovascular emergencies include supportive care, pharmacological interventions, and, sometimes, invasive procedures. There is no specific antidote against SCBto date. In conclusion, SCB abuse is associated with various cardiovascular emergencies, which can be life-threatening in some cases. Early recognition and management of these emergencies are critical for improving outcomes. Further research is needed to better understand the underlying mechanisms of SCB-related cardiovascular complications and to develop effective prevention and management strategies.

Acute toxic effects of new synthetic cannabinoid on brain: Neurobehavioral and Histological: Preclinical studies

The psychoactive effects of new synthetic cannabinoids (SCs), MDMB-4en-PINACA, are being marketed as a blend of herbs and spices. This study aims to determine the behavioral, neurochemical, histopathological, and immunohistochemical alterations associated with the acute toxicity of MDMB-4en-PINACA compounds. MethodsAdult male albino rats were administered various toxic doses of the drug (1.5, 3, and 6 mg/kg), and behavioral studies were conducted 2 and 24 h later; animals were then sacrificed. Histopathological and neurochemical examinations were performed. Two hours after intraperitoneal. ResultsIntraperitoneal injection of MDMB-4en-PINACA, horizontal movement, the number of stops, and mobility ratio were significantly impaired, along with coordination and balance. In addition, it led to a decline in spatial learning and memory, and neurotransmitter concentrations decreased significantly in a dose-dependent manner. Further examination of the cerebral cortex and hippocampus histopathology revealed pathological degeneration of small pyramidal cells. ConclusionThus, these findings revealed that MDMB-4en-PINACA interferes with hippocampal function and impairs cognitive performance, highlighting the cognitive risk associated with SC abuse.

Study on the metabolic process of synthetic cannabinoids 4F-MDMB-BINACA and 4F-MDMB-BICA in human liver microsome and zebrafish model via UHPLC-QE Orbitrap MS

In order to address the increasing abuse of synthetic cannabinoids, on July 1, 2021, China listed the whole category of synthetic cannabinoids in the Supplementary Catalog for the Control of Non-medicinal Narcotic Drugs and Psychotropic Substances. Because synthetic cannabinoids metabolize rapidly, techniques are urgently needed to identify the phase I metabolites of new synthetic cannabinoids, as well as the symbol metabolites, which can be used for detection in real cases. In this study, we used pooled human liver microsome (pHLM) and zebrafish combined with ultra-high-performance liquid chromatography (UHPLC) Q Exactive Orbitrap MS to identify the phase Imetabolites of two new synthetic cannabinoids 4F-MDMB-BICA and 4F-MDMB-BINACA in vitro and in vivo, respectively. We studied the toxicokinetics of 4F-MDMB-BICA and 4F-MDMB-BINACA by sampling from a pHLM incubation system at different time points to study the change in metabolites over time. We detected a total of 14 metabolites of 4F-MDMB-BINACA and 16 metabolites of 4F-MDMB-BICA in this study. Metabolites of 4F-MDMB-BICA were detected in vitro for the first time. One metabolite of 4F-MDMB-BINACA, M05, was discovered for the first time. Based on the toxicokinetics results, we recommend three metabolites (M03, M11, M12) of 4F-MDMB-BINACA and three metabolites (M10, M12, M14) of 4F-MDMB-BICA as their symbol metabolites. The results showed that these two structurally similar synthetic cannabinoids 4F-MDMB-BINACA and 4F-MDMB-BICA had similar metabolic processes, as well as similar structures of their main symbol metabolites.

Spice, vulnerability, and victimization: Synthetic cannabinoids and interpersonal crime victimization among homeless adults

Background Although the physiologic and psychological harms associated with the use of synthetic cannabinoids, such as spice, are well-described, researchers have yet to examine how spice abuse affects exposure to crime. This paper describes the dangerous social environment where spice is used and delineates how synthetic cannabinoid abuse increases the risk of victimization. Methods: This qualitative study used semi-structured interviews to examine crime- and victimization-related experiences of 22 homeless adults. Transcripts were analyzed for emergent themes using a two-tiered qualitative coding process. Results: Those experiencing homelessness describe synthetic cannabinoids as powerful intoxicants. Substances such as spice are sought for their ability to detach those under the drug’s influence from reality. Participants illustrated their understanding of how synthetic cannabinoids affect the health and safety of unsheltered persons. Spice use frequently results in rapid intoxication; individuals under the influence of spice are thereby physically vulnerable to crime, particularly theft and robbery. Conclusion: Findings add to previous research on the harms of synthetic cannabinoid abuse. This study suggests a victimization process common among homeless persons who use spice: Incapacitation often rapidly follows use, which in turn precipitates victimization.

Simultaneous screening of 239 synthetic cannabinoids and metabolites in blood and urine samples using liquid chromatography–high resolution mass spectrometry

Synthetic cannabinoids (SCs) are new psychoactive substances that function as endocannabinoid CB1 and CB2 receptor agonists. Abuse of SCs can lead to symptoms such as confusion, dizziness, and even death. At present, Synthetic cannabinoids constitute one of the largest groups of new psychoactive substances and become popular recreational drugs of abuse for their psychoactive properties. The continuous transformation of SCs also leads to an endless emergence of new types. An efficient, high-throughput screening method is therefore very important for their identification. This paper describes a liquid chromatography–high resolution mass spectrometry (LC-HRMS) method for simultaneously screening 179 SCs and 80 SC metabolites in blood and urine. Simple acetonitrile was used to precipitate the blood and urine proteins, and the supernatants obtained after centrifugation were analyzed. The LC-HRMS run time was 20 min. The mass spectrometer used an ESI source with a scanning range of m/z 100–1000. LC-HRMS provided accurate mass, retention time, and fragment ions for qualitative analysis. The method validation results showed that the limits of detection (LODs) for over 80% compounds were 5 ng/mL in blood and urine samples. At low concentrations (50 ng/mL), 229 compounds (95.8%) in the blood showed recoveries of more than 50%, and 232 compounds (97.1%) had matrix effects greater than 80%. In the urine, 219 compounds (91.6%) had recoveries above 50%, and the matrix effects of 234 compounds (97.9%) were greater than 80%. This method was successfully applied to actual forensic cases.

Identification of AD-18, 5F-MDA-19, and pentyl MDA-19 in seized materials after the class-wide ban of synthetic cannabinoids in China.

To curb the manufacturing, trafficking, and abuse of synthetic cannabinoids, China implemented a class-wide regulation on synthetic cannabinoids in July 2021. Recently, three different types of synthetic cannabinoid analogs that were not covered by the generic definitions were detected in seized powdered and e-liquid materials. These derivatives included 2-(2-(1-(4-fluorobenzyl)-1H-indol-3-yl)acetamido)-3,3-dimethylbutanamide (AD-18), N'-(1-(5-fluoropentyl)-2-oxoindolin-3-ylidene)benzohydrazide (5F-MDA-19), and N'-(2-oxo-1-pentylindolin-3-ylidene)benzohydrazide (pentyl MDA-19). Identification was based on ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UHPLC-QTOF-MS), gas chromatography-mass spectrometry (GC-MS), nuclear magnetic resonance spectroscopy (NMR), and Fourier transform infrared spectroscopy (FT-IR). AD-18 is a methylene analog of ADB-FUBICA. No chemical or pharmacological data about AD-18 and 5F-MDA-19 have appeared until now, making this the first report on these two compounds. Pentyl MDA-19 has previously been reported to have high affinity for cannabinoid CB1 and CB2 receptors, but this is the first report of its presence in the recreational drug market. Moreover, the collision-induced dissociation (CID) and electron ionization (EI) characteristic fragmentation routes of AD-18 and the other two MDA-19 derivatives were also discussed to facilitate forensic laboratories in their identification of other substances with a similar structure in their case work.

Relation Between Acute Administration of Synthetic Cannabinoids and Induction of Epileptic Seizures

Objectives: Recently, there has been an obvious increase in the synthetic cannabinoid abuse that can cause severe toxicity and major physical and psychological consequences. Here we have assessed the impacts of synthetic cannabinoids intake on induction of seizures and on electroencephalographic activity, allowing for exploration of one of the physical hazards that might associate synthetic cannabinoids use helping for better management. Methods: Forty male patients using synthetic cannabinoids and 40 nonusing males were registered in this work. All individuals were determined via a detailed history of substance use and diagnosed according to International Classification of Diseases version 11 as synthetic cannabinoid use disorders, detailed history of seizures from close relatives who witnessed seizure occurrence and its correlation with the last dose of synthetic cannabinoid use and then investigated by long-term electroencephalograph. Results: Seizures were considerably more common in the synthetic cannabinoid using group than in the nonusing group, with the main presenting event in the form of the generalized tonic-clonic seizure. Seizures occurred within 15 minutes of intake in 81.8% of patients. Long-term electroencephalography showed electroencephalographic changes in 45% of cases using synthetic cannabinoids that were statistically more significant than in the nonusing group (2.5%), with the most prominent electroencephalographic change in the form of left frontal focus in 22.5% of cases. Conclusion: Synthetic cannabinoid usage has been linked to seizure induction and has been shown to alter electroencephalographic activity.

Mental Disorders Associated with the Abuse of Synthetic Cannabinoids (Spices)

Introduction: the abuse of synthetic cannabinoids may trigger the development of mental disorders characterized by distortions of disease processes that can cause incorrect diagnosis.Objective: to study the phenomenon of the abuse of synthetic cannabinoids (Spice) as a trigger psychotic episode in psychiatric patients (with schizophrenia and personality disorders) and risk factors for developing paranoid schizophrenia.Patients and research methods: 291 men were examined: 241 with dependence on synthetic cannabinoids — 101 of them were diagnosed with personality and behavior disorders in adulthood, 140 with a diagnosis of paranoid schizophrenia and 50 with a diagnosis of paranoid schizophrenia without drug dependence.Research methods: clinicalpsychopathological, psychometric (SANS, CGI, MMPI), follow-up, statistical R (R version 3.2.4).Results: intoxication conditions caused by synthetic cannabinoids can provoke the development of psychotic episodes and be a trigger for the manifestation of schizophrenia. There are four variants of narcotic intoxication: delirious, schizophrenic, with pseudo-hallucinations, with delirium. The personalities of patients addicted to synthetic cannabinoids are similar in the prevalence of emotionally unstable, rigid, introverted, deviant traits. Patients with personality disorders, dependent on synthetic cannabinoids, differed from typical drug addicts in such patterns of behavior as disorganization, conflict, unpredictability, spontaneity, thoughtlessness of actions, impulsivity, and nonconformity. The stigmatizing signs of the schizophrenic process in patients who are dependent on synthetic cannabinoids are the symptoms of abulia–apathy of mild severity. Patients with schizophrenia, dependent on synthetic cannabinoids, differed from patients without dependence on drugs by the phenomenon of the absence of an emotional defect expressed in the expressiveness of emotions, the desire for communication.Conclusion: the phenomenon of synthetic cannabinoid abuse is a trigger of a psychotic episode in both schizophrenic patients and those with personality disorders in whom antisocial, schizoid and paranoid personality traits prevail. The abuse of synthetic cannabinoids is a risk factor for the development of paranoid schizophrenia, which differs from schizophrenia without drug dependence by a mild degree of stigmatizing symptoms of abulia–apathy and social activity during periods of short-term remissions.

Abuse Potential of Synthetic Cannabinoids: AM-1248, CB-13, and PB-22.

Currently, the expanding recreational use of synthetic cannabinoids (SCBs) threatens public health. SCBs produce psychoactive effects similar to those of tetrahydrocannabinol, the main component of cannabis, and additionally induce unexpected pharmacological side effects. SCBs are falsely advertised as legal and safe, but in reality, SCB abuse has been reported to cause acute intoxication and addictive disorders. However, because of the lack of scientific evidence to elucidate their dangerous pharmacological effects, SCBs are weakly regulated and continue to circulate in illegal drug markets. In the present study, the intravenous self-administration (IVSA) paradigm was used to evaluate the abuse potential of three SCBs (AM-1248, CB-13, and PB-22) in rats. All three SCBs maintained IVSA with a large number of infusions and active lever presses, demonstrating their reinforcing effects. The increase of active lever presses was particularly significant during the early IVSA sessions, indicating the reinforcement-enhancing effects of the SCBs (AM-1248 and CB-13). The number of inactive lever presses was significantly higher in the SCB groups (AM-1248 and CB-13) than that in the vehicle group, indicating their impulsive effects. In summary, these results demonstrated that SCBs have distinct pharmacological properties and abuse potential.

QSAR Model for Predicting the Cannabinoid Receptor 1 Binding Affinity and Dependence Potential of Synthetic Cannabinoids.

In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure–activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared tetrahydrocannabinol (THC) and 14 SCs and their derivatives (naphthoylindoles, naphthoylnaphthalenes, benzoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established, and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via Y-randomization test and external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

Therapeutic Potential of Cannabidiol (CBD) for Skin Health and Disorders.

Though there is limited research confirming the purported topical benefits of cannabinoids, it is certain that cutaneous biology is modulated by the human endocannabinoid system (ECS). Receptors from the ECS have been identified in the skin and systemic abuse of synthetic cannabinoids, and their analogs, have also been associated with the manifestation of dermatological disorders, indicating the effects of the ECS on cutaneous biology. In particular, cannabidiol (CBD), a non-psychoactive compound from the cannabis plant, has garnered significant attention in recent years for its anecdotal therapeutic potential for various pathologies, including skin and cosmetic disorders. Though a body of preclinical evidence suggests topical application of CBD may be efficacious for some skin disorders, such as eczema, psoriasis, pruritis, and inflammatory conditions, confirmed clinical efficacy and elucidation of underlying molecular mechanisms have yet to be fully identified. This article provides an update on the advances in CBD research to date and the potential areas of future exploration.

Diagnosing intake and rationalizing toxicities associated with 5F-MDMB-PINACA and 4F-MDMB-BINACA abuse.

5F-MDMB-PINACA and 4F-MDMB-BINACA are synthetic cannabinoids (SCs) that elicit cannabinoid psychoactive effects. Defining pharmacokinetic-pharmacodynamic (PK-PD) relationships governing SCs and their metabolites are paramount to investigating their in vivo toxicological outcomes. However, the disposition kinetics and cannabinoid receptor (CB) activities of the primary metabolites of SCs are largely unknown. Additionally, reasons underlying the selection of ester hydrolysis metabolites (EHMs) as urinary biomarkers are often unclear. Here, metabolic reaction phenotyping was performed to identify key metabolizing enzymes of the parent SCs. Hepatic clearances of parent SCs and their EHMs were estimated from microsomal metabolic stability studies. Renal clearances were simulated using a mechanistic kidney model incorporating in vitro permeability and organic anionic transporter 3 (OAT3)-mediated uptake data. Overall clearances were considered in tandem with estimated volumes of distribution for in vivo biological half-lives (t1/2) predictions. Interactions of the compounds with CB1 and CB2 were investigated using a G-protein coupled receptor activation assay. We demonstrated that similar enzymatic isoforms were implicated in the metabolism of 5F-MDMB-PINACA and 4F-MDMB-BINACA. Our in vivo t1/2 determinations verified the rapid elimination of parent SCs and suggest prolonged circulation of their EHMs. The pronounced attenuation of the potencies and efficacies of the metabolites against CB1 and CB2 further suggests how toxic manifestations of SC abuse are likely precipitated by augmented exposure to parent SCs. Notably, basolateral OAT3-mediated uptake of the EHMs substantiates their higher urinary abundance. These novel insights underscore the importance of mechanistic, quantitative and systematic characterization of PK-PD relationships in rationalizing the toxicities of SCs.

Clinical and Forensic Toxicological Aspects of Synthetic Cannabinoids: A Review and Update

Abstract Background: Synthetic cannabinoids (SCs) are highly abused of New Psychoactive Substances (NPS). SCs has known under street names such as “Spice”, “herbal incense” and “K2”, act as endocannabinoids (CB) receptor full agonists and have unpredictable toxicity and abuse potential. This narrative review was conducted to update the present evidence about the clinical and forensic toxicological aspects of SCs. Methods: PubMed, Scopus and Google Scholar databases from 2015 to 2020 (up to 1st May) were searched using the terms “synthetic cannabinoids”, “synthetic cannabimimetics”, “ K2”, “Spice”, “clinical toxicology”, “forensic toxicology”, “poisoning”, “toxicity”, “abuse” , “addiction “analysis” and “determination” to identify the relevant articles. In addition, a manual search of reference lists of the retrieved articles was conducted. Results: ADB-FUBINACA , XRL-11, 5F-ADB, 5F-PB-22, MDMB-CHMICA and MMB-2201 are the commonly reported SCs analogues among acute toxicities and fatalities cases. Adverse reactions and toxic effects of SCs includes psychoneurological, cardiovascular, renal and gastrointestinal involvements. Deaths related to SCs have been reported due to stroke and cardiac dysrhythmia. Analysis of SCs in biological samples in the clinical and postmortem setting needs sophisticated analytical instruments. Liquid gas chromatography tandem mass spectrometry (LC-MS/MS) has a crucial role for detection of SCs and their metabolites in biological samples. Conclusion: Unlike natural cannabinoids, the SCs abuse/poisoning has serious and life-threatening effects in abuser. Also, analysis of SCs is not included in the routine forensic urine drug testing. Therefore, suitable measures of informing the public and health care professionals for prevention of SCs abuse are recommended.

Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity

AKB48 and its fluorinated derivative 5F-AKB48 are synthetic cannabinoids (SCs) which have caused hospitalizations and deaths in human users. Abuse of SCs is dangerous because users may mistake them for natural cannabis, which is generally considered to be unlikely to elicit adverse effects. The present studies were designed to investigate the in vitro oxidative metabolism of 5F-AKB48 by human microsomal fractions from different organs and sexes as well as recombinant human cytochrome P450s (P450s). Mass spectrometry data tentatively provides evidence for the existence of mono-, di-, and trihydroxylated metabolites in a successive metabolism. Experiments utilizing P450s revealed that the most active enzymes (CYP2D6, CYP2J2, CYP3A4, and CYP3A5) effectively produced mono- and dihydroxylated metabolites, while CYP3A4/5 also produced significant amounts of the trihydroxylated metabolite. Moreover, although the affinity and potency of Phase I metabolite 4OH-5F-AKB48 is reduced when compared to that of the parent drug, this metabolite nevertheless retains similar high affinity for CB1 receptors, and greater efficacy for G protein activation, when compared to THC. Finally, 5F-AKB48 produced time- and dose-dependent cannabimimetic effects in mice which were more potent, but shorter acting, than those of Δ9-THC, and were attenuated by prior treatment with the CB1 antagonist rimonabant. Based on our data, we hypothesize that while many cases of toxicity result from genetic mutations, which can lead to a decrease or even absence of activity for Phase I drug-metabolizing enzymes, other P450s could potentially increase their role in the metabolism of these SCs. Because many metabolites of SCs remain biologically active, they could contribute to the deleterious effects of these substances.

Discriminative Stimulus Effects of (R)(−)‐DOI and AM8936, a Synthetic Cannabinoid

Increased abuse of synthetic cannabinoids (SCBs) continues to be a public health concern. Preclinical studies have identified SCBs as being THC‐like; however, occurrences of emesis, hallucinations, and seizures have been reported with their usage. These studies examined the premise that the hallucinogenic effects of AM8936, a highly potent synthetic CB1 agonist, resemble the discriminative stimulus effects of another hallucinogen, the 5HT2A agonist (R)(−)2,5‐dimethoxy‐4‐iodoamphetamine (DOI). Male and female Sprague‐Dawley rats (n=6/group) were trained to discriminate either 0.18 mg/kg AM8936 or 0.56 mg/kg DOI from saline under a shock avoidance schedule of reinforcement. In both DOI and AM8936 trained subjects, their respective training dose produced full (>80%) substitution. In the DOI trained subjects, AM8936 (0.032 – 0.18 mg/kg), delta‐9‐tetrahydrocannabinol (Δ9‐THC) (1 – 10 mg/kg), and JWH‐018 (0.1 – 3.2 mg/kg) produced dose‐dependent increases in DOI‐lever responding, but only JWH‐018 and AM8936 produced full substitution. In the AM8936 trained subjects, DOI (0.56 – 3.2 m/k), Δ9‐THC (1 – 10 mg/kg), and JWH‐018 (0.1 – 10 mg/kg) produced dose‐dependent increases in AM8936‐lever responding, but only JWH‐018 produced full (>80%) substitution. Doses of DOI that produced AM8936‐appropriate responding (0.56 – 3.2 mg/kg) were higher than those that resulted in DOI‐appropriate responding (0.1 – 0.8 mg/kg). In addition, the mu‐opioid receptor agonist morphine (1 – 10 mg/kg) (negative control) engendered less than 20% DOI‐lever responding or AM8936‐lever responding up to doses that produced behavioral disruption. These studies indicate that there is bi‐directional overlap in the discriminative stimulus effects of SCBs and a 5‐HT2A agonist, suggesting similarities in their subjective effects.Support or Funding InformationAcknowledgementsFunded by NIH/NIDA: DA043700

The Assessment of in Vitro Cardiotoxic Potentials for Synthetic Cannabinoid, AM-2201

Synthetic cannabinoid abuse has become more common in recent years, although knowledge about the risk of the relatively new synthetic cannabinoid molecules is not adequate. Data is limited and analytical methods and case reports related to the clinical effects of this substance are recent and new. The studies are generally related to the cardiac effects of first defined molecules rather than every molecule in the group. The cardiac clinical effects of synthetic cannabinoid abuse and its underlying mechanisms are not certain. In this regard, this study aims to investigate AM-2201, one of synthetic cannabinoids, because knowledge related to AM-2201 is less than the others in this group. The cardiotoxicity and underlying mechanisms of AM-2201 were assessed on cardiac cell culture. The half-maximal inhibition concentration (IC50) values were 101.49 and 63.33 µM by WST-1 and LDH assays. AM-2201 did not induced the reactive oxygen species (ROS) levels. Correlatively, no change was observed in total antioxidant capacity (TAC) levels. As to the measurements, Annexin V-FITC and acridine orange dye, AM-2201 did not induce apoptosis and the primary cell death was necrosis. According to our results, further studies such as mechanism on cell death and cancer pathways should be investigated.