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Ozhan O, Ermis N, Celbis O, Samdanci E, Petekkaya S, Oruc M, Soylu O, Koparir P, Acet A, Parlakpinar H. Acute and subacute cardiovascular effects of synthetic cannabinoid JWH-018 in rat. Forensic Toxicol 2025:10.1007/s11419-025-00720-9. [PMID: 40240703 DOI: 10.1007/s11419-025-00720-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025]
Abstract
PURPOSE This study investigates the cardiovascular effects of the synthetic cannabinoid naphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-018) in rats. The research aims to evaluate the pharmacologic, cardiologic, biochemical, and histopathological effects of acute and subacute administration at low and high doses. The primary research question is how JWH-018 impacts heart function, blood pressure, ECG patterns, and cardiac tissue integrity. METHODS Wistar albino rats were divided into five groups: control, acute low-dose (ALD, 0.5 mg/kg), acute high-dose (AHD, 5 mg/kg), subacute low-dose (SALD, 0.5 mg/kg for 14 days), and subacute high-dose (SAHD, 5 mg/kg for 14 days). Cardiovascular effects were assessed using echocardiography, hemodynamic and ECG analysis, histopathology, biochemical markers, and LC-MS/MS quantification of JWH-018 and its metabolites in heart tissue. RESULTS Acute high-dose JWH-018 caused bradycardia and hypotension, while subacute high-dose increased heart rate but continued to lower blood pressure. JWH-018 induced cardiac arrhythmias, conduction blocks, and ischemic ECG changes, with prolonged QT intervals in subacute high-dose rats. Histopathological findings revealed myocardial infarction-like features, including contraction bands and ischemic damage, particularly in subacute groups. Elevated pro-BNP and triglycerides indicated cardiac stress and metabolic effects. JWH-018 and its metabolites were detected in heart tissue, primarily in high-dose groups. CONCLUSIONS JWH-018 has significant cardiovascular risks, causing heart rate dysregulation, hypotension, arrhythmias, and ischemic damage. These effects depend on dose and duration. The study highlights the potential dangers of synthetic cannabinoids, emphasizing that they should not be considered safe alternatives to natural cannabis.
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Affiliation(s)
- Onural Ozhan
- Department of Pharmacology, Faculty of Medicine, Inonu University, 44280, Malatya, Türkiye.
| | - Necip Ermis
- Department of Cardiology, Faculty of Medicine, Inonu University, Malatya, Türkiye
| | - Osman Celbis
- Department of Forensic Medicine, Faculty of Medicine, Inonu University, Malatya, Türkiye
| | - Emine Samdanci
- Department of Pathology, Faculty of Medicine, Inonu University, Malatya, Türkiye
| | - Semih Petekkaya
- Department of Forensic Medicine, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, Türkiye
| | - Mucahit Oruc
- Department of Forensic Medicine, Faculty of Medicine, Inonu University, Malatya, Türkiye
| | - Ozcan Soylu
- Department of Chemistry, Forensic Medicine Institute, Malatya, Türkiye
| | - Pelin Koparir
- Department of Chemistry, Forensic Medicine Institute, Malatya, Türkiye
| | - Ahmet Acet
- Department of Pharmacology, Faculty of Medicine, Inonu University, 44280, Malatya, Türkiye
| | - Hakan Parlakpinar
- Department of Pharmacology, Faculty of Medicine, Inonu University, 44280, Malatya, Türkiye
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Jones AT, Marwan Abu Taha A, Miller GP. The resurgence of synthetic cannabinoid receptor agonists as adulterants in the Era of Cannabis legalization: Lessons from prior epidemics and clinical implications. Neurosci Biobehav Rev 2025; 170:106043. [PMID: 39922438 PMCID: PMC11870277 DOI: 10.1016/j.neubiorev.2025.106043] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
Momentum towards legalization of medical and recreational cannabis drives a convergence between natural cannabinoids and their synthetic counterparts, creating new clinical challenges in a second wave of exposures. This review critically examines the emerging challenges posed by synthetic cannabinoid receptor agonists (SCRAs) and semi-synthetic cannabinoids, emphasizing their clinical implications. SCRAs are potent full agonist activity that have been identified as adulterants in several recreational substances, including cannabis and opioids. Adulteration often leads to unpredictable clinical outcomes and exacerbates the potential for drug interactions. Drawing parallels with other drug epidemics, this paper highlights the urgent need for clinical preparedness to address the nuanced presentations of cannabinoid toxicity, stressing the importance of patient history, physical examination, and judicious use of supportive laboratory tests. This review serves as a cautionary tale and call to action for researchers and policymakers. There is a clear need for robust quality control measures, enhanced public awareness campaigns, and development of evidence-based clinical guidelines to mitigate the health risks associated with intentional and unintentional use of synthetic cannabinoids.
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Affiliation(s)
- Austin T Jones
- College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
| | - Alaa Marwan Abu Taha
- Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
| | - Grover P Miller
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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Janssens LK, Sommer MJ, Grafinger KE, Hermanns-Clausen M, Auwärter V, Stove CP. Interpreting mono- and poly-SCRA intoxications from an activity-based point of view: JWH-018 equivalents in serum as a comparative measure. Arch Toxicol 2024; 98:3337-3350. [PMID: 39115690 DOI: 10.1007/s00204-024-03830-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 07/25/2024] [Indexed: 09/17/2024]
Abstract
Synthetic cannabinoid receptor agonists (SCRAs) are a class of synthetic drugs that mimic and greatly surpass the effect of recreational cannabis. Acute SCRA intoxications are in general difficult to assess due to the large number of compounds involved, differing widely in both chemical structure and pharmacological properties. The rapid pace of emergence of unknown SCRAs hampers on one hand the timely availability of methods for identification and quantification to confirm and estimate the extent of the SCRA intoxication. On the other hand, lack of knowledge about the harm potential of emerging SCRAs hampers adequate interpretation of serum concentrations in intoxication cases. In the present study, a novel comparative measure for SCRA intoxications was evaluated, focusing on the cannabinoid activity (versus serum concentrations), which can be measured in serum extracts with an untargeted bioassay assessing ex vivo CB1 activity. Application of this principle to a series of SCRA intoxication cases (n = 48) allowed for the determination of activity equivalents, practically entailing a conversion from different SCRA serum concentrations to a JWH-018 equivalent. This allowed for the interpretation of both mono- (n = 34) and poly-SCRA (n = 14) intoxications, based on the intrinsic potential of the present serum levels to exert cannabinoid activity (cf. pharmacological/toxicological properties). A non-distinctive toxidrome was confirmed, showing no relation to CB1 activity. The JWH-018 equivalent was partly related to the poison severity score (PSS) and causality of the clinical intoxication elicited by the SCRA. Altogether, this equivalent concept allows to comparatively and timely interpret (poly-)SCRA intoxications based on CB1 activity.
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Affiliation(s)
- Liesl K Janssens
- Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - Michaela J Sommer
- Institute of Forensic Medicine, Forensic Toxicology, Medical Center, University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Hermann Staudinger Graduate School, University of Freiburg, Freiburg, Germany
| | - Katharina Elisabeth Grafinger
- Institute of Forensic Medicine, Forensic Toxicology, Medical Center, University of Freiburg, Freiburg, Germany
- Institute of Chemistry and Bioanalytics, University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland
| | - Maren Hermanns-Clausen
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Poisons Information Center, Center for Pediatrics, Medical Center, University of Freiburg, Freiburg, Germany
| | - Volker Auwärter
- Institute of Forensic Medicine, Forensic Toxicology, Medical Center, University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christophe P Stove
- Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
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Thomsen LR, Glass M, Rosengren RJ. The impact of piperazine and antipsychotic co-exposures and CB1 blockade on the effects elicited by AMB-FUBINACA, a synthetic cannabinoid, in mice. Eur J Pharmacol 2024; 979:176844. [PMID: 39053868 DOI: 10.1016/j.ejphar.2024.176844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 07/10/2024] [Accepted: 07/23/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND & PURPOSE The constant emergence and broad toxicological effects of synthetic cannabinoids create a discernible public health threat. The synthetic cannabinoid AMB-FUBINACA (AMB-FUB) is a potent agonist at the CB1 receptor and has been associated with numerous fatalities. Synthetic cannabinoids are commonly abused alongside other drugs and medications, including a "party pill" drug, para-fluorophenylpiperazine (pFPP), and the antipsychotic risperidone. This research aimed to investigate the mechanisms underpinning AMB-FUB toxicity and the impact of clinically relevant co-exposures in vivo. EXPERIMENTAL APPROACH Male and female C57Bl/6 mice received a single dose of AMB-FUB (3 or 6 mg kg-1), pFPP (10 or 20 mg kg-1) or vehicle intraperitoneally. Mice were co-exposed to AMB-FUB (3 mg kg-1) and pFPP (10 mg kg-1) or risperidone (0.5 mg kg-1) to investigate these drug combinations. To study receptor-dependency and potential rescue of AMB-FUB toxicity, rimonabant (3 mg kg-1) was administered both pre- and post-AMB-FUB. Adverse effects caused by drug administration, including hypothermia and convulsions, were recorded. KEY RESULTS AMB-FUB induced CB1-dependent hypothermia and convulsions in mice. The combination of AMB-FUB and pFPP significantly potentiated hypothermia, as did risperidone pre-treatment. Interestingly, risperidone provided significant protection from AMB-FUB-induced convulsions in female mice. Pre- and post-treatment with rimonabant was able to significantly attenuate both hypothermia and convulsions in mice administered AMB-FUB. CONCLUSION & IMPLICATIONS Factors such as dose, CB1 signalling, and substance co-exposure significantly contribute to the toxicity of AMB-FUBINACA. Mechanistic understanding of synthetic cannabinoid toxicity and fatality can help inform overdose treatment strategies and identify vulnerable populations of synthetic cannabinoid users.
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Affiliation(s)
- Lucy R Thomsen
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
| | - Michelle Glass
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
| | - Rhonda J Rosengren
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
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Kew ME, Dave U, Marmor W, Olsen R, Jivanelli B, Tsai SHL, Kuo LT, Ling DI. Sex Differences in Mental Health Symptoms in Elite Athletes: A Systematic Review and Meta-analysis. Sports Health 2024:19417381241264491. [PMID: 39129353 PMCID: PMC11569523 DOI: 10.1177/19417381241264491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2024] Open
Abstract
CONTEXT Mental health is a growing area of concern for elite athletes. OBJECTIVE To determine the sex differences in mental health symptoms in elite athletes. DATA SOURCES PubMed, EMBASE, and Cochrane Library databases were used. STUDY SELECTION Included studies included comparisons of mental health symptoms of athletes by sex. STUDY DESIGN Systematic review and meta-analysis were conducted following the PRISMA guidelines. LEVEL OF EVIDENCE Level 2a. DATA EXTRACTION The rate ratio (RR) was calculated as the rates in female and male athletes. Data were pooled using a random-effects model. RESULTS Of 1945 articles identified, 60 articles were included. Male athletes reported higher alcohol misuse (RR, 0.74; CI, 0.68-0.80), illicit drug abuse (RR, 0.82; CI, 0.75-0.89), and gambling problems (RR, 0.14; CI, 0.08-0.25). Female athletes reported higher overall anxiety (RR, 1.17; CI, 1.08-1.27), depression (RR, 1.42; CI, 1.31-1.54), distress (RR, 1.98; CI, 1.40-2.81), and disordered eating (RR, 2.19; CI, 1.58-3.02). Sleep disturbances were reported at similar rates in male and female athletes (RR, 1.13; CI, 0.98-1.30). CONCLUSION Female and male athletes have significant differences in reported mental health symptoms. Female athletes are more likely to report anxiety, depression, distress, and disordered eating, while male athletes report more alcohol misuse, illicit drug abuse, and gambling. Monitoring and evaluation of mental health is a necessary part of any sport, including access to resources. Longitudinal studies following athletes over time to determine the development and causation for mental health symptoms should be included in future research directions.
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Affiliation(s)
- Michelle E. Kew
- Sports Medicine Institute, Hospital for Special Surgery, New York, New York
| | - Udit Dave
- Tulane University School of Medicine, New Orleans, Louisiana
| | - William Marmor
- University of Miami, Department of Orthopaedics, Miami, Florida
| | - Reena Olsen
- Sports Medicine Institute, Hospital for Special Surgery, New York, New York
| | - Bridget Jivanelli
- Kim Barrett Memorial Library, HSS Education Institute, Hospital for Special Surgery, New York, New York
| | - Sung Huang Laurent Tsai
- Division of Sports Medicine, Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Chiayi, Chiayi County, Taiwan and School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Liang-Tseng Kuo
- School of Medicine, Chang Gung University, Taoyuan, Taiwan and Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
| | - Daphne I. Ling
- Sports Medicine Institute, Hospital for Special Surgery, New York, New York, Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan, and Department of Population Health Sciences, Weill Cornell Medical College, New York, New York
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Smith KE, Feldman JD, Dunn KE, McCurdy CR, Grundmann O, Garcia-Romeu A, Panlilio LV, Rogers JM, Sharma A, Fernandez SP, Kheyfets M, Epstein DH. Novel methods for the remote investigation of emerging substances: Application to kratom. Exp Clin Psychopharmacol 2024; 32:215-227. [PMID: 37213182 PMCID: PMC10663387 DOI: 10.1037/pha0000656] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
The botanical product commonly called "kratom" is still relatively novel to the United States. Like other natural products marketed as supplements, kratom is highly variable, both in terms of the alkaloids naturally occurring in kratom leaves and in terms of processing and formulation. Kratom products sold in the United States are not well-characterized, nor are daily use patterns among regular users. Surveys and case reports have comprised most of the literature on kratom use among humans. To advance our understanding of real-world kratom use, we developed a protocol for the remote study of regular kratom-using adults in the United States. Our study had three aspects implemented in one pool of participants nationwide: an in-depth online survey, 15 days of ecological momentary assessment (EMA) via smartphone app, and the collection and assay of the kratom products used by participants during EMA. Here, we describe these methods, which can be used to investigate myriad drugs or supplements. Recruiting, screening, and data collection occurred between July 20, 2022 and October 18, 2022. During this time, we demonstrated that these methods, while challenging from a logistical and staffing standpoint, are feasible and can produce high-quality data. The study achieved high rates of enrollment, compliance, and completion. Substances that are emerging or novel, but still largely legal, can be productively studied via nationwide EMA combined with assays of shipped product samples from participants. We discuss challenges and lessons learned so other investigators can adapt these methods. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Affiliation(s)
- Kirsten E. Smith
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
| | - Jeffrey D. Feldman
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
| | - Kelly E. Dunn
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Christopher R. McCurdy
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Oliver Grundmann
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Albert Garcia-Romeu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Leigh V. Panlilio
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
| | - Jeffrey M. Rogers
- San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology, San Diego, CA, United States
| | - Abhisheak Sharma
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Salma-Pont Fernandez
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
| | - Marina Kheyfets
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
| | - David H. Epstein
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
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Stogner J, Baldwin JM, Wiercioch A. 'Spice' Use Motivations, Experiences, and Repercussions among Veterans of the United States Armed Forces. Subst Use Misuse 2024; 59:1182-1189. [PMID: 38548662 DOI: 10.1080/10826084.2024.2330900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
BACKGROUND AND OBJECTIVES The potential for synthetic cannabinoids (SCs) to function as an alternative to marijuana without the same risk of a positive urinalyses led to claims of pervasive military SC use. Case studies confirm use among veterans, but no study has adequately explored SC use in the military using detailed interview data. METHODS Interviews (1-2 h) were conducted with 318 justice-involved veterans. Recruitment was attempted with all participants in eight veterans treatment courts in three U.S. states (54.9% of 579 eligible veterans). Interviews were transcribed and thematic analyses completed. RESULTS SC use was reported by 65 participants (21.3%). Major emergent themes indicated SCs were perceived as unpleasant, overly powerful, and a poor substitute for marijuana. Further, habitual use was rare as many chose not to reuse after initial negative experiences. Few indicated that the perception that SCs would not appear on routine military urinalyses enabled their use. Veterans were aware of the changing drug composition and feared "bad batches." CONCLUSIONS SCs were explicitly disliked both independently and relative to marijuana. Nine discussed avoiding positive military drug screens as a consideration, but negative initial experiences generally prevented progression to habitual use. Veterans did not view SCs as a suitable marijuana replacement. Fears that SCs are being used as a marijuana alternative among veterans subject to frequent drug testing appear unfounded. These interviews suggest that routine military drug testing did not motivate individuals to use SCs habitually as a marijuana replacement; however, veterans' negative interpretation of SC effects contributed to this outcome.
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Affiliation(s)
- John Stogner
- Department of Criminal Justice and Criminology, University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, North Carolina
| | - Julie Marie Baldwin
- Department of Justice, Law & Criminology, American University, Washington, DC
| | - Amelia Wiercioch
- Department of Criminal Justice, University of Central Florida, 12494 University Blvd, Orlando, FL
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Merli D, Lio E, Protti S, Coccia R, Profumo A, Alberti G. Molecularly Imprinted Polymer-based voltammetric sensor for amino acids/indazole derivatives synthetic cannabinoids detection. Anal Chim Acta 2024; 1288:342151. [PMID: 38220285 DOI: 10.1016/j.aca.2023.342151] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/07/2023] [Accepted: 12/15/2023] [Indexed: 01/16/2024]
Abstract
BACKGROUND Synthetic cannabinoids (SCs) are a broad class of illicit drugs that are classified according to the chemical structure of the aromatic core that they present (i.e., indole, imidazole, pyrrole) and their detection is still a challenge, despite their widespread diffusion. The identification of a specific class of SC in complex matrices, such as real samples with a rapid, economic analytical device useable directly in the field, is highly desirable, as it can provide immediate and reliable information that eventually addresses more targeted analyses. RESULTS The present paper proposes a Molecularly Imprinted Polymer (MIP)-based voltammetric sensor for the rapid and selective detection of indazole-type SCs. In this context, a polyacrylate-based MIP was used to functionalize a Pt electrode. The MIP composition was optimized through a Design of Experiments approach, and for the sake of safety, a non-psychotropic compound structurally related to the selected SCs was employed as the template in the MIP formulation. A complete characterization of the electrochemical behavior of the selected SCs was performed, and differential pulse voltammetry (DPV) in acetonitrile/lithium perchlorate 0.1 M was the technique applied for their quantification. LOD around 0.01 mM and linearity up to 0.8 mM were found. Comparison with the non-imprinted (NIP) modified and bare electrodes showed better selectivity and reproducibility of the MIP-based sensor. Recovery tests (in the 70-115 % range) were performed on simulated pills and smoking mixtures to test the reliability of the proposed method. SIGNIFICANCE The method proposed allows the identification and quantification of indazole-based SCs as a class in complex matrices. Due to the selectivity of the obtained device, no clean-up of the sample before analyses is needed. For the same reason, the interference of cutting substances and natural cannabinoids was negligible.
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Affiliation(s)
- Daniele Merli
- Dipartimento di Chimica, Università di Pavia, via Taramelli 12, 27100, Pavia, Italy
| | - Erika Lio
- Dipartimento di Chimica, Università di Pavia, via Taramelli 12, 27100, Pavia, Italy
| | - Stefano Protti
- Dipartimento di Chimica, Università di Pavia, via Taramelli 12, 27100, Pavia, Italy
| | - Roberta Coccia
- Dipartimento di Chimica, Università di Pavia, via Taramelli 12, 27100, Pavia, Italy; Dipartimento di Scienze Biomolecolari, Università di Urbino "Carlo Bo", via Maggetti 26, 61029, Urbino, PU, Italy
| | - Antonella Profumo
- Dipartimento di Chimica, Università di Pavia, via Taramelli 12, 27100, Pavia, Italy
| | - Giancarla Alberti
- Dipartimento di Chimica, Università di Pavia, via Taramelli 12, 27100, Pavia, Italy.
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Lea Houston M, Morgan J, Kelso C. Narrative Review of the Pharmacodynamics, Pharmacokinetics, and Toxicities of Illicit Synthetic Cannabinoid Receptor Agonists. Mini Rev Med Chem 2024; 24:92-109. [PMID: 37190813 DOI: 10.2174/1389557523666230515163107] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/20/2023] [Accepted: 04/03/2023] [Indexed: 05/17/2023]
Abstract
BACKGROUND Synthetic cannabinoid receptor agonists (SCRAs) are the most diverse class of new psychoactive substances worldwide, with approximately 300 unique SCRAs identified to date. While the use of this class of drug is not particularly prevalent, SCRAs are associated with several deaths every year due to their severe toxicity. METHODS A thorough examination of the literature identified 15 new SCRAs with a significant clinical impact between 2015 and 2021. RESULTS These 15 SCRAs have been implicated in 154 hospitalizations and 209 deaths across the US, Europe, Asia, and Australasia during this time period. CONCLUSION This narrative review provides pharmacodynamic, pharmacokinetic, and toxicologic data for SCRAs as a drug class, including an in-depth review of known pharmacological properties of 15 recently identified and emerging SCRAs for the benefit of researchers, policy makers, and clinicians who wish to be informed of developments in this field.
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Affiliation(s)
- Matilda Lea Houston
- Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia
| | - Jody Morgan
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales, Australia
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia
| | - Celine Kelso
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales, Australia
- Molecular Horizons Institute, University of Wollongong, Wollongong, New South Wales, Australia
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia
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Wang Z, Leow EYQ, Moy HY, Chan ECY. Advances in urinary biomarker research of synthetic cannabinoids. Adv Clin Chem 2023; 115:1-32. [PMID: 37673518 DOI: 10.1016/bs.acc.2023.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
New psychoactive substances (NPS) are chemical compounds designed to mimic the action of existing illicit recreational drugs. Synthetic cannabinoids (SCs) are a subclass of NPS which bind to the cannabinoid receptors, CB1 and CB2, and mimic the action of cannabis. SCs have dominated recent NPS seizure reports worldwide. While urine is the most common matrix for drug-of-abuse testing, SCs undergo extensive Phase I and Phase II metabolism, resulting in almost undetectable parent compounds in urine samples. Therefore, the major urinary metabolites of SCs are usually investigated as surrogate biomarkers to identify their consumption. Since seized urine samples after consuming novel SCs may be unavailable in a timely manner, human hepatocytes, human liver microsomes and human transporter overexpressed cell lines are physiologically-relevant in vitro systems for performing metabolite identification, metabolic stability, reaction phenotyping and transporter experiments to establish the disposition of SC and its metabolites. Coupling these in vitro experiments with in vivo verification using limited authentic urine samples, such a two-pronged approach has proven to be effective in establishing urinary metabolites as biomarkers for rapidly emerging SCs.
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Affiliation(s)
- Ziteng Wang
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Eric Yu Quan Leow
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Hooi Yan Moy
- Analytical Toxicology Laboratory, Applied Sciences Group, Health Sciences Authority, Singapore, Singapore
| | - Eric Chun Yong Chan
- Department of Pharmacy, National University of Singapore, Singapore, Singapore.
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Celeste-Villalvir A, Crouch C, Witte L, Heads AM, Weaver M, Schmitz JM, Isbell F, Schick V. Assessing Stage of Change and Harm Reduction Strategies for Synthetic Cannabinoid Use Among Individuals Experiencing Homelessness in Houston, Texas. JOURNAL OF DRUG ISSUES 2023. [DOI: 10.1177/00220426231161284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
Synthetic cannabinoids (SCs) are low-cost substances that have been associated with adverse health outcomes and an increase in emergency department visits over recent years, particularly among people experiencing homelessness. This mixed methods study explored the connection between homelessness, SC use, and readiness to quit in order to inform the development of harm reduction strategies. Individuals (18+) residing in homeless encampments in Houston, TX with experiences of SC use were eligible to participate. Participants ( N = 65) completed an interviewer-administered survey about their SC use. Most participants were Black/African American (65.7%), male (82.9%), and most (75.4%) reported using SCs to avoid positive drug tests. Many wanted to quit using SCs (69.2%) and already employed harm reduction strategies while using SCs. Organizations supporting individuals experiencing homelessness who use SCs should focus on reducing barriers to stopping SC use and increasing the availability of housing and supportive services.
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Affiliation(s)
- Alane Celeste-Villalvir
- Department of Management, Policy & Community Health, University of Texas Health Science Center at Houston, Houston, TX, USA
| | | | - Laura Witte
- Department of Management, Policy & Community Health, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Angela M. Heads
- Department of Psychiatry and Behavioral Health, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Michael Weaver
- Department of Psychiatry and Behavioral Health, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
- Center for Neurobehavioral Research on Addiction, Houston, TX, USA
| | - Joy M. Schmitz
- Department of Psychiatry and Behavioral Health, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
- Center for Neurobehavioral Research on Addiction, Houston, TX, USA
| | | | - Vanessa Schick
- Department of Management, Policy & Community Health, University of Texas Health Science Center at Houston, Houston, TX, USA
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12
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Al-Eitan L, Alkhawaldeh M. MDMB-FUBINACA Influences Brain Angiogenesis and the Expression of VEGF, ANG-1, and ANG-2. Curr Vasc Pharmacol 2023; 21:356-365. [PMID: 37711102 DOI: 10.2174/1570161121666230913093441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 09/16/2023]
Abstract
AIM This study aims to explore the impact of the synthetic cannabinoid methyl 2-(1-(4- fluorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (MDMB-FUBINACA) on the angiogenesis process in human brain microvascular endothelial cells. BACKGROUND Synthetic cannabinoids (SCs) are substances that mimic the natural components found in the cannabis plant. SCs are considered prohibited substances that have a clear impact on the central nervous system (CNS). OBJECTIVES The purpose of this study is to explore how MDMB-FUBINACA influences angiogenesis in human brain microvascular endothelial cells and to clarify the pathways related to the cannabinoid receptors. METHODS Human brain microvascular endothelial cells (hBMECs) were grown in the medium containing Dulbecco Modified Eagle Medium (DMEM/F12) using an endothelial cell growth kit. Endothelial cell viability was evaluated using the MTT test. Migration ability was measured using the Wound healing test. The angiogenic capability was measured using a Tube Formation assay. Real-time polymerase chain reaction (RT-PCR) was utilized to explore the mRNA concentrations following MDMBFUBINACA treatment. ELISA and Western blotting were also employed to measure the protein levels. RESULTS MDMB-FUBINACA greatly increases tube formation, endothelial cell proliferation, and migration. Pro-angiogenic factors such as angiopoietins 1 and 2 (ANG-1 and 2) and vascular endothelial growth factor (VEGF) were shown to be increased at both the RNA and protein levels. CONCLUSION MDMB-FUBINACA induces the progression of the angiogenesis process by inducing the expression of pro-angiogenic factors. These findings aim toward developing novel treatments for angiogenesis- related disorders.
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Affiliation(s)
- Laith Al-Eitan
- Biotechnology and Genetic Engineering Department, Jordan University of Science and Technology, Irbid, 22110, Jordan
| | - Mishael Alkhawaldeh
- Biotechnology and Genetic Engineering Department, Jordan University of Science and Technology, Irbid, 22110, Jordan
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13
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Giorgetti A, Orazietti V, Busardò FP, Giorgetti R. Psychomotor performances relevant for driving under the combined effect of ethanol and synthetic cannabinoids: A systematic review. Front Psychiatry 2023; 14:1131335. [PMID: 36911125 PMCID: PMC9998479 DOI: 10.3389/fpsyt.2023.1131335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 02/08/2023] [Indexed: 02/26/2023] Open
Abstract
OBJECTIVE To determine whether the acute co-consumption of ethanol and synthetic cannabinoids (SCs) increases the risk of a motor vehicle collision and affects the psychomotor performances relevant for driving. DESIGN Systematic review of the literature. DATA SOURCES Electronic searches were performed in two databases, unrestricted by year, with previously set method and criteria. Search, inclusion and data extraction were performed by two blind authors. RESULTS Twenty articles were included, amounting to 31 cases of SCs-ethanol co-consumption. The impairment of psychomotor functions varied widely between studies, ranging from no reported disabilities to severe unconsciousness. Overall, a dose-effect relationship could not be observed. CONCLUSION Despite the biases and limitations of the literature studies, it seems likely that the co-consumption poses an increased risk for driving. The drugs might exert a synergistic effect on the central nervous system depression, as well as on aggressiveness and mood alterations. However, more research is needed on the topic.
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Affiliation(s)
- Arianna Giorgetti
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Bologna, Italy
| | - Vasco Orazietti
- Department of Excellence of Biomedical Science and Public Health, University "Politecnica delle Marche" of Ancona, Ancona, Italy
| | - Francesco Paolo Busardò
- Department of Excellence of Biomedical Science and Public Health, University "Politecnica delle Marche" of Ancona, Ancona, Italy
| | - Raffaele Giorgetti
- Department of Excellence of Biomedical Science and Public Health, University "Politecnica delle Marche" of Ancona, Ancona, Italy
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14
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Methyl (S)-2-(1-7 (5-fluoropentyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate (5F-MDMB-PICA) intoxication in a child with identification of two new metabolites (ultra-high-performance liquid chromatography-tandem mass spectrometry). Forensic Toxicol 2023; 41:47-58. [PMID: 36652054 DOI: 10.1007/s11419-022-00629-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 05/12/2022] [Indexed: 01/21/2023]
Abstract
PURPOSE Methyl (S)-2-(1-7 (5-fluoropentyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate (5F-MDMA-PICA) intoxication in 1.5-year-old child was presented, together with diagnostic parameters discussion and 5F-MDMB-PICA determination in biological material. Furthermore, 5F-MDMB-PICA metabolites were identified in a urine sample as markers of exposure in situation when a parent compound is not present in specimens. METHODS Drugs and metabolites were extracted from serum and urine with ethyl acetate both under alkaline (pH 9) and acidic (pH 3) conditions. Hair, after decontamination and pulverization, were incubated with methanol (16 h, 60 °C). The analysis was carried out using ultra-high-performance liquid chromatography-tandem mass spectrometry. For the identification of 5F-MDMB-PICA metabolites, an urine sample was precipitated with cold acetonitrile. Analysis was performed using ultra-high-performance liquid chromatograph with quadrupole time-of-flight mass spectrometer. RESULTS 5F-MDMB-PICA was determined only in serum sample at concentration of 298 ng/mL. After 1 year, when analysis was repeated, concentration of synthetic cannabinoid in the same sample was only 17.6 ng/mL which revealed high instability of 5F-MDMB-PICA in serum sample. Eight 5F-MDMB-PICA metabolites were identified in urine sample, including two potentially new ones with m/z 391.18964 and m/z 275.14016. CONCLUSIONS Toxicological analysis confirmed a 1.5-year-old boy intoxication with 5F-MDMB-PICA. Besides the parent drug, metabolites of 5F-MDMB-PICA were identified, including two potentially new ones, together with possible metabolic reactions which they resulted from. Metabolites determination could serve as a marker of 5F-MDMB-PICA exposure when no parent drug is present in biological material.
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15
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Wilson CD, Hiranita T, Fantegrossi WE. Cannabimimetic effects of abused indazole-carboxamide synthetic cannabinoid receptor agonists AB-PINACA, 5F-AB-PINACA and 5F-ADB-PINACA in mice: Tolerance, dependence and withdrawal. Drug Alcohol Depend 2022; 236:109468. [PMID: 35643039 DOI: 10.1016/j.drugalcdep.2022.109468] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 04/16/2022] [Accepted: 04/16/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Chronic abuse of synthetic cannabinoid receptor agonists (SCRAs), known as "K2″ or "Spice", threatens public health and safety. Recently, SCRAs of the indazole-carboxamide structural class have become more prevalent. Preclinical studies investigating the tolerance and dependence potentially involved in chronic SCRA abuse is limited. The present study determined the in vivo effects of chronic exposure to indazole-carboxamide SCRAs, AB-PINACA, 5F-AB-PINACA and 5F-ADB-PINACA compared to the first-generation SCRA, JWH-018. METHODS Adult male C57Bl/6 mice were used for dose-effect determinations of hypothermic effects. Adult male NIH Swiss mice were used in biotelemetry studies to assess tolerance to hypothermic effects following repeated SCRA administration over 5 consecutive days, and to determine the role of Phase I drug metabolism via acute CYP450 inhibition in the presence of 1-ABT, a nonspecific CYP450 inhibitor. SCRA dependence was determined in adult male NIH Swiss mice via assessment of rimonabant-precipitated observable sign of withdrawal (i.e., front paw tremors). RESULTS All SCRAs elicited dose-dependent hypothermia mediated through cannabinoid CB1 receptors (CB1Rs). 1-ABT increased duration of hypothermia for all SCRAs tested, and increased the magnitude of hypothermia for all SCRAs except 5F-ADB-PINACA. Upon repeated administration, tolerance to hypothermic effects of AB-PINACA, 5F-AB-PINACA and 5F-ADB-PINACA was much less than that of JWH-018. Similarly, rimonabant-precipitated front paw tremors were much less frequent in mice treated with 5F-AB-PINACA and 5F-ADB-PINACA than in mice treated with JWH-018. CONCLUSIONS These findings suggest a decreased potential for tolerance and withdrawal among indazole-carboxamide SCRAs, and may imply structural class-dependent profiles of in vivo effects among SCRAs.
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Affiliation(s)
- Catheryn D Wilson
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA
| | - Takato Hiranita
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - William E Fantegrossi
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
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16
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Theunissen EL, Reckweg JT, Hutten NRPW, Kuypers KPC, Toennes SW, Neukamm MA, Halter S, Ramaekers JG. Psychotomimetic symptoms after a moderate dose of a synthetic cannabinoid (JWH-018): implications for psychosis. Psychopharmacology (Berl) 2022; 239:1251-1261. [PMID: 33501595 PMCID: PMC9110546 DOI: 10.1007/s00213-021-05768-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/14/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Synthetic cannabinoids (SCs) are the largest class of novel psychoactive substances (NPS) and are associated with an increased risk of overdosing and adverse events such as psychosis. JWH-018 is one of the earliest SCs and still widely available in large parts of the world. Controlled studies to assess the safety and behavioural profiles of SCs are extremely scarce. AIM The current study was designed to assess the psychotomimetic effects of a moderate dose of JWH-018. METHODS Twenty-four healthy participants (10 males, 14 females) entered a placebo-controlled, double blind, within-subjects trial and inhaled vapour of placebo or 75μg/kg bodyweight JWH-018. To ascertain a minimum level of intoxication, a booster dose of JWH-018 was administered on an as-needed basis. The average dose of JWH-018 administered was 5.52 mg. Subjective high, dissociative states (CADSS), psychedelic symptoms (Bowdle), mood (POMS) and cannabis reinforcement (SCRQ) were assessed within a 4.5-h time window after drug administration. RESULTS JWH-018 caused psychedelic effects, such as altered internal and external perception, and dissociative effects, such as amnesia, derealisation and depersonalisation and induced feelings of confusion. CONCLUSION Overall, these findings suggest that a moderate dose of JWH-018 induces pronounced psychotomimetic symptoms in healthy participants with no history of mental illness, which confirms that SCs pose a serious risk for public health.
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Affiliation(s)
- Eef L Theunissen
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200, MD, Maastricht, The Netherlands.
| | - Johannes T Reckweg
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200, MD, Maastricht, The Netherlands
| | - Nadia R P W Hutten
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200, MD, Maastricht, The Netherlands
| | - Kim P C Kuypers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200, MD, Maastricht, The Netherlands
| | - Stefan W Toennes
- Department of Forensic Toxicology, Institute of Legal Medicine, Goethe University of Frankfurt, Frankfurt, Germany
| | - Merja A Neukamm
- Institute of Forensic Medicine, Forensic Toxicology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sebastian Halter
- Institute of Forensic Medicine, Forensic Toxicology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Hermann Staudinger Graduate School, University of Freiburg, Freiburg, Germany
| | - Johannes G Ramaekers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200, MD, Maastricht, The Netherlands
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17
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Moore CF, Stiltner JW, Davis CM, Weerts EM. Translational models of cannabinoid vapor exposure in laboratory animals. Behav Pharmacol 2022; 33:63-89. [PMID: 33136615 PMCID: PMC8079522 DOI: 10.1097/fbp.0000000000000592] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Cannabis is one of the most frequently used psychoactive substances in the world. The most common route of administration for cannabis and cannabinoid constituents such as Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is via smoking or vapor inhalation. Preclinical vapor models have been developed, although the vaporization devices and delivery methods vary widely across laboratories. This review examines the emerging field of preclinical vapor models with a focus on cannabinoid exposure in order to (1) summarize vapor exposure parameters and other methodological details across studies; (2) discuss the pharmacological and behavioral effects produced by exposure to vaporized cannabinoids; and (3) compare behavioral effects of cannabinoid vapor administration with those of other routes of administration. This review will serve as a guide for past and current vapor delivery methods in animals, synergize findings across studies, and propose future directions for this area of research.
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Affiliation(s)
- Catherine F. Moore
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jeffrey W. Stiltner
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Catherine M. Davis
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Elise M. Weerts
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
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18
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Abdelmoneim WM, Ghandour NM, Fawzy M, Mohammed MK, Ramadan AG, Abdellah NZ. Clinical pattern of synthetic cannabinoids users in Upper Egypt: cross-sectional study. MIDDLE EAST CURRENT PSYCHIATRY 2022. [PMCID: PMC8964025 DOI: 10.1186/s43045-022-00188-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background There is an expanding use of new psychoactive substances containing synthetic cannabinoids in the last years. This study was conducted to identify the epidemiologic data of acute and chronic toxicity by synthetic cannabinoids in Upper Egypt patients. Results All cases included in the presenting study were fifty males. Most users of synthetic cannabinoids were in the adolescence and middle age group (15–< 35) representing 68%. Curiosity was the most common motivator for using synthetic cannabinoids. Alteration of perception was reported in 68% of subjects after synthetic cannabinoids use. Additionally, dizziness, loss of consciousness, convulsion, and panic attacks were also reported. Cardiovascular adverse effects experienced by users were palpitations (76%) and chest pain (12%). Half of included subjects (50%) reported financial problems and about one-third (32%) got involved in domestic violence. Abnormal routine laboratory findings that were found in included cases were in the form of 12% anemia, 10% leukocytosis, and 6% leucopenia. Also, liver and kidney functions were elevated in 8% and 4% of the cases, respectively. While 22% and 4% of cases were positive for hepatitis C and HIV respectively. Conclusions This study can be concluded that adolescence are the most common users of SCs; neuro-psychiatric and cardiovascular side effects were the most experienced by subjects. Violence in many forms, especially domestic violence, was associated with synthetic cannabinoids abuse. Trial registration Registered in clinical trial under name syntheticcannabinoidsAssiut and ID NCT03866941 and URL.
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19
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Curtis B, Mahat B, Macklin M, Mihalo J, Dakroub AH. Acute Kidney Injury Related to Intoxication From Synthetic Cannabis: Don’t You Know That You’re Toxic? Cureus 2022; 14:e23427. [PMID: 35481311 PMCID: PMC9033635 DOI: 10.7759/cureus.23427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2022] [Indexed: 11/16/2022] Open
Abstract
Acute kidney injury (AKI) occurs infrequently in young patients and often raises concern for irreversible or deadly etiologies. However, AKI related to synthetic marijuana, colloquially known as K2, is an increasingly common phenomenon in the United States and resolves quickly with fluid resuscitation. Here, we present a case of a young male who presented with severe AKI that initially raised concern for the need to start renal replacement therapy. Laboratory testing revealed an elevated osmolar gap and negative urine drug screen, while urinalysis demonstrated acanthocytes, raising concern for toxic alcohol ingestion or vasculitis. Following fluid resuscitation, his renal function improved dramatically, and he was discharged home within days of presentation. K2-related AKI most frequently occurs in young men, mirroring the population that most frequently uses synthetic marijuana. Its exact etiology remains unknown, but direct nephrotoxicity appears to be the most plausible mechanism. No other known case has reported acanthocytes. Although objective data indicates severe illness on presentation, patients often recover rapidly to baseline and often do not suffer long-term renal impairment following conservative management.
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20
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Ameen A, Brown K, Dennany L. Can synthetic cannabinoids be reliably screened with electrochemistry? An assessment of the ability to screen for synthetic cannabinoids STS-135 and BB-22 within a single sample matrix. J Electroanal Chem (Lausanne) 2022. [DOI: 10.1016/j.jelechem.2022.116141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Shi Y, Liu M, Li X, Xu N, Yuan S, Yu Z, Xiang P, Wu H. Simultaneous screening of 239 synthetic cannabinoids and metabolites in blood and urine samples using liquid chromatography-high resolution mass spectrometry. J Chromatogr A 2022; 1663:462743. [PMID: 34974369 DOI: 10.1016/j.chroma.2021.462743] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/26/2021] [Accepted: 12/09/2021] [Indexed: 11/24/2022]
Abstract
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.
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Affiliation(s)
- Yan Shi
- Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai Key Laboratory of forensic medicine, Shanghai Forensic Science Platform, China
| | - Mengxi Liu
- Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai Key Laboratory of forensic medicine, Shanghai Forensic Science Platform, China; School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenhe District, Shenyang 110016, China
| | - Xiangjun Li
- Thermo Fisher Scientific, Xinjinqiao Road 27, Pudong New District, Shanghai 201206, China
| | - Niusheng Xu
- Thermo Fisher Scientific, Xinjinqiao Road 27, Pudong New District, Shanghai 201206, China
| | - Shuai Yuan
- Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai Key Laboratory of forensic medicine, Shanghai Forensic Science Platform, China
| | - Zhiguo Yu
- School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenhe District, Shenyang 110016, China
| | - Ping Xiang
- Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai Key Laboratory of forensic medicine, Shanghai Forensic Science Platform, China.
| | - Hejian Wu
- Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai Key Laboratory of forensic medicine, Shanghai Forensic Science Platform, China.
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22
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Theunissen EL, Kuypers KPC, Mason NL, Ramaekers JG. A Comparison of Acute Neurocognitive and Psychotomimetic Effects of a Synthetic Cannabinoid and Natural Cannabis at Psychotropic Dose Equivalence. Front Psychiatry 2022; 13:891811. [PMID: 35664482 PMCID: PMC9160432 DOI: 10.3389/fpsyt.2022.891811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/26/2022] [Indexed: 01/12/2023] Open
Abstract
Due to differences in potency, efficacy, and affinity for CB1 receptors, similarities and differences in psychoactive effect profiles of natural cannabis and synthetic cannabinoids (SCs) cannot reliably be derived from equipotent dose comparisons. Instead, the current study proposes to compare the intrinsic psychoactive effects of natural cannabis (THC) and an SC, JWH-018, at psychotropic dose equivalence. Participants from two placebo-controlled studies were matched for their levels of subjective high to compare neurocognitive and psychotomimetic effects of THC and JWH-018. At equal subjective intoxication levels, both drugs impaired psychomotor, divided attention, and impulse control, with no significant difference between the two drugs. Both drugs also caused significant psychotomimetic effects, but dissociative effects were considerably more pronounced for JWH-018 than THC. We conclude that psychotropic dose equivalence provides a uniform approach for comparing the neurocognitive and psychotomimetic profiles of CB1 agonists, which can also be applied to other drug classes.
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Affiliation(s)
- Eef Lien Theunissen
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Kim Paula Colette Kuypers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Natasha Leigh Mason
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Johannes Gerardus Ramaekers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands
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23
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Craft S, Ferris JA, Barratt MJ, Maier LJ, Lynskey MT, Winstock AR, Freeman TP. Clinical withdrawal symptom profile of synthetic cannabinoid receptor agonists and comparison of effects with high potency cannabis. Psychopharmacology (Berl) 2022; 239:1349-1357. [PMID: 34533608 PMCID: PMC9110517 DOI: 10.1007/s00213-021-05945-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 07/25/2021] [Indexed: 11/02/2022]
Abstract
Synthetic cannabinoid receptor agonists (SCRAs) may be used as an alternative to natural cannabis; however, they may carry a greater risk of problematic use and withdrawal. This study aimed to characterise the withdrawal symptom profile of SCRAs and compare their profile of effect with high-potency herbal cannabis. Global Drug Survey data (2015 and 2016) were used to access a clinically relevant sample of people reporting use of SCRAs >10 times in the past 12-months, a previous SCRA quit attempt, and lifetime use of high-potency herbal cannabis. Participants completed an 11-item SCRA withdrawal symptom checklist and compared SCRAs and high-potency herbal cannabis on their onset and duration of effects, speed of the development of tolerance, severity of withdrawal, and difficulty with dose titration. Participants (n = 284) reported experiencing a mean of 4.4 (95% CI: 4.1, 4.8) withdrawal symptoms after not using SCRAs for >1 day; most frequently reported were sleep issues (59.2%), irritability (55.6%), and low mood (54.2%). Withdrawal symptoms were significantly associated with frequency (>51 vs. 11-50 times per year: IRR = 1.43, 95% CI: 1.16, 1.77, p = 0.005) and quantity (grams per session: IRR = 1.13, 95% CI: 1.05, 1.22, p = 0.001) of SCRA use. Compared to high-potency herbal cannabis, SCRAs were rated as having a faster onset and shorter duration of effects, faster development of tolerance, and more severe withdrawal (p's < 0.001). In conclusion, SCRA withdrawal symptoms are more likely to occur after greater SCRA exposure. The effects of SCRA indicate a more severe withdrawal syndrome and a greater risk of problematic use than natural cannabis.
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Affiliation(s)
- Sam Craft
- Addiction and Mental Health Group (AIM), Department of Psychology, University of Bath, Bath, UK. .,National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
| | - Jason A. Ferris
- grid.1003.20000 0000 9320 7537Centre for Health Services Research, University of Queensland, QLD, Queensland Brisbane, Australia
| | - Monica J. Barratt
- grid.1017.70000 0001 2163 3550Social and Global Studies Centre and Digital Ethnography Research Centre, RMIT University, Victoria Melbourne, Australia ,grid.1005.40000 0004 4902 0432National Drug and Alcohol Research Centre, University of New South Wales Sydney, New South Wales Sydney, Australia
| | - Larissa J. Maier
- grid.266102.10000 0001 2297 6811Department of Clinical Pharmacy, University of California San Francisco, San Francisco, USA
| | - Michael T. Lynskey
- grid.13097.3c0000 0001 2322 6764National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Adam R. Winstock
- Global Drug Survey Ltd, London, UK ,grid.83440.3b0000000121901201Institute of Epidemiology and Health Care, University College London, London, UK
| | - Tom P. Freeman
- grid.7340.00000 0001 2162 1699Addiction and Mental Health Group (AIM), Department of Psychology, University of Bath, Bath, UK ,grid.13097.3c0000 0001 2322 6764National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Bukke VN, Archana M, Villani R, Serviddio G, Cassano T. Pharmacological and Toxicological Effects of Phytocannabinoids and Recreational Synthetic Cannabinoids: Increasing Risk of Public Health. Pharmaceuticals (Basel) 2021; 14:ph14100965. [PMID: 34681189 PMCID: PMC8541640 DOI: 10.3390/ph14100965] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 01/01/2023] Open
Abstract
Synthetic Cannabinoids (CBs) are a novel class of psychoactive substances that have rapidly evolved around the world with the addition of diverse structural modifications to existing molecules which produce new structural analogues that can be associated with serious adverse health effects. Synthetic CBs represent the largest class of drugs detected by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) with a total of 207 substances identified from 2008 to October 2020, and 9 compounds being reported for the first time. Synthetic CBs are sprayed on natural harmless herbs with an aim to mimic the euphoric effect of Cannabis. They are sold under different brand names including Black mamba, spice, K2, Bombay Blue, etc. As these synthetic CBs act as full agonists at the CB receptors, they are much more potent than natural Cannabis and have been increasingly associated with acute to chronic intoxications and death. Due to their potential toxicity and abuse, the US government has listed some synthetic CBs under schedule 1 classification. The present review aims to provide a focused overview of the literature concerning the development of synthetic CBs, their abuse, and potential toxicological effects including renal toxicity, respiratory depression, hyperemesis syndrome, cardiovascular effects, and a range of effects on brain function.
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Yüncü Z, Cakmak Celik Z, Colak C, Thapa T, Fornito A, Bora E, Kitis O, Zorlu N. Resting state functional connectivity in adolescent synthetic cannabinoid users with and without attention-deficit/hyperactivity disorder. Hum Psychopharmacol 2021; 36:e2781. [PMID: 33675677 DOI: 10.1002/hup.2781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 02/11/2021] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Synthetic cannabinoids (SCs) have become increasingly popular in recent years, especially among adolescents. The first aim of the current study was to examine resting-state functional connectivity (rsFC) in SC users compared to controls. Our second aim was to examine the influence of comorbid attention-deficit/hyperactivity disorder (ADHD) symptomatology on rsFC changes in SC users compared to controls. METHODS Resting-state functional magnetic resonance imaging (fMRI) analysis included 25 SC users (14 without ADHD and 11 with ADHD combined type) and 12 control subjects. RESULTS We found (i) higher rsFC between the default mode network (DMN) and salience network, dorsal attention network and cingulo-opercular network, and (ii) lower rsFC within the DMN and between the DMN and visual network in SC users compared to controls. There were no significant differences between SC users with ADHD and controls, nor were there any significant differences between SC users with and without ADHD. CONCLUSIONS We found the first evidence of abnormalities within and between resting state networks in adolescent SC users without ADHD. In contrast, SC users with ADHD showed no differences compared to controls. These results suggest that comorbidity of ADHD and substance dependence may show different rsFC alterations than substance use alone.
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Affiliation(s)
- Zeki Yüncü
- Department of Child Psychiatry, Ege University School of Medicine, Izmir, Turkey
| | | | - Ciğdem Colak
- Department of Psychiatry, Cigli Regional Training Hospital, Izmir, Turkey
| | - Tribikram Thapa
- Brain & Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences and School of Psychological Sciences, Monash University, Victoria, Australia
| | - Alex Fornito
- Brain & Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences and School of Psychological Sciences, Monash University, Victoria, Australia
| | - Emre Bora
- Department of Psychiatry, Dokuz Eylül University Medical School, Izmir, Turkey
| | - Omer Kitis
- Department of Radiodiagnostics, Ege University School of Medicine, Izmir, Turkey
| | - Nabi Zorlu
- Department of Psychiatry, Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey
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26
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'Synthetic cannabis': A dangerous misnomer. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2021; 98:103396. [PMID: 34343944 DOI: 10.1016/j.drugpo.2021.103396] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 11/23/2022]
Abstract
The term 'synthetic cannabis' has been widely used in public discourse to refer to a group of cannabinoid receptor agonists. In this paper we detail the characteristics of these drugs, and present the case that the term is a misnomer. We describe the pharmacodynamics of these drugs, their epidemiology, mechanisms of action, physiological effects and how these differ substantially from delta-9-tetrahydrocannabinol (THC). We argue that not only is the term a misnomer, but it is one with negative clinical and public health implications. Rather, the substances referred to as 'synthetic cannabis' in public discourse should instead be referred to consistently as synthetic cannabinoid receptor agonists (SCRAs), a drug class distinct from plant-derived cannabinoids. SCRAs have greater potency and efficacy, and psychostimulant-like properties. While such terminology may be used in the scientific community, it is not widely used amongst the media, general public, people who use these drugs or may potentially do so. A new terminology has the potential to reduce the confusion and harms that result from the misnomer 'synthetic cannabis'. The constant evolution of this distinct drug class necessitates a range of distinct policy responses relating to terminology, harm reduction, epidemiology, treatment, and legal status.
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27
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Jackson MA, Brown AL, Johnston J, Clancy R, McGregor I, Bruno R, Lintzeris N, Montebello M, Luksza J, Bowman J, Phung N, Allsop D, Dunlop AJ. The use and effects of synthetic cannabinoid receptor agonists by New South Wales cannabis treatment clients. J Cannabis Res 2021; 3:33. [PMID: 34311790 PMCID: PMC8314558 DOI: 10.1186/s42238-021-00091-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 07/09/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction Despite decreasing consumption by general populations, use of synthetic cannabinoid receptor agonists (SCRAs) persists in some marginalised groups, including those who use other substances. This article explores SCRA consumption in an Australian cannabis treatment sample, comparing those who report ever using SCRAs with those who have never used SCRAs. Methods A questionnaire orally administered in person to a convenience sample of 154 cannabis treatment service clients from New South Wales, Australia (71% male, median age 35) collected information regarding cannabis and SCRA use including motivations, effects and health-related consequences of use, demographics, other substance use and overall health. Demographic profiles and between-group differences were explored. McNemar tests compared effects of SCRA and cannabis. Logistic regression analysis determined predictors of SCRA use. Results Half (53%) reported lifetime SCRA use; 20% reported previous-month use. The SCRA + cannabis group displayed greater polysubstance use and psychological distress. Reduced dependence on cannabis but higher levels of other substance use may predict SCRA use. Although curiosity motivated initial SCRA consumption, perceived psychoactive strength drove continued use. SCRAs appear to induce more negative side-effects than cannabis. Of the SCRA + cannabis group, 27% sought medical assistance for SCRA use. Most (90%) preferred cannabis to SCRAs, citing superior safety, effects and consistency of cannabis. Conclusions Among clients seeking treatment for cannabis use, SCRA use was relatively common, although not a preferred substance. Hazardous substance use and poor mental health characterised SCRA consumers, highlighting the need for continued monitoring by researchers and treatment providers of SCRA consumption in populations who use substances. Supplementary Information The online version contains supplementary material available at 10.1186/s42238-021-00091-z.
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Affiliation(s)
- Melissa A Jackson
- Drug and Alcohol Clinical Services, Hunter New England Local Health District, Level 3, 670 Hunter Street, Newcastle, NSW, 2290, Australia.
| | - Amanda L Brown
- Drug and Alcohol Clinical Services, Hunter New England Local Health District, Level 3, 670 Hunter Street, Newcastle, NSW, 2290, Australia
| | - Jennifer Johnston
- University Centre for Rural Health, University of Sydney, Lismore, NSW, Australia
| | - Richard Clancy
- Centre for Brain and Mental Health Research, Hunter New England Local Health District, Newcastle, NSW, Australia
| | - Iain McGregor
- The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
| | - Raimondo Bruno
- School of Health, University of Tasmania, Hobart, TAS, Australia
| | - Nick Lintzeris
- Drug and Alcohol Services, South East Sydney Local Health District, Sydney, NSW, Australia
| | - Mark Montebello
- Drug and Alcohol Services, Northern Sydney Local Health District, Sydney, NSW, Australia
| | - Jennifer Luksza
- Drug Health, Western Sydney Local Health District, Sydney, NSW, Australia
| | - Jenny Bowman
- Faculty of Science and Information Technology, University of Newcastle, Newcastle, NSW, Australia
| | - Nghi Phung
- Drug Health, Western Sydney Local Health District, Parramatta, NSW, Australia
| | - Dave Allsop
- The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
| | - Adrian J Dunlop
- Drug and Alcohol Clinical Services, Hunter New England Local Health District, Level 3, 670 Hunter Street, Newcastle, NSW, 2290, Australia
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28
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Relation Between Acute Administration of Synthetic Cannabinoids and Induction of Epileptic Seizures. ADDICTIVE DISORDERS & THEIR TREATMENT 2021. [DOI: 10.1097/adt.0000000000000286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Efeoglu Ozseker P, Daglioglu N, Gulmen MK, Tolunay I, Efeoglu F. Determination of AB-FUBINACA and 5F-NPB-22 in rats exposed to "Bonsai" via inhalation and analysis of seized product. Leg Med (Tokyo) 2021; 50:101869. [PMID: 33713938 DOI: 10.1016/j.legalmed.2021.101869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/05/2021] [Accepted: 02/27/2021] [Indexed: 10/22/2022]
Abstract
Synthetic cannabinoids (SCs) are the most rapidly growing class of recreational designer drugs. Illicit drug manufacturers began to produce herbal smoking materials under a variety of brands names, e.g. "Spice, K2, Bonsai, Yucatan Fire". They were appeared on the European market in 2008. In this study, types of SCs in the herbal product sold as "Bonsai" in Turkey were determined and the identification of these substances in biological samples collected from rats depending on the inhalation of different amounts of plant material were aimed. To determine the SC species in the content of the plant product, analysis was performed via gas chromatography-mass spectrometry. Liquid-liquid extraction methods were utilized for blood and organ samples, while solid-phase extraction with β-glucuronidase enzyme treatment was applied for urine sample preparation. The relationship between the amount of burned plant and the amount of SCs accumulated in the blood, urine and organ samples of rats exposed to the plant product by inhalation was examined by liquid chromatography-tandem mass spectrometry. AB-FUBINACA and 5F-NPB-22 were detected in the herbal product. A significant correlation was found between the amount of herbal product inhaled and the prevalence of SCs, especially in lung tissues while no SCs were detected in the blood and urine samples of rats. There is currently no study on biological samples of individuals exposed to herbal products containing SCs by inhalation. Regarding the findings obtained in this study, the overall increase in the amounts of herbal product inhaled was demonstrated to pose a potential risk to humans.
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Affiliation(s)
- Pinar Efeoglu Ozseker
- Department of Forensic Medicine, Faculty of Medicine, Cukurova University, Adana, Turkey.
| | - Nebile Daglioglu
- Department of Forensic Medicine, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Mete Korkut Gulmen
- Department of Forensic Medicine, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Ilknur Tolunay
- Adana City Education & Research Hospital, Child Intensive Care Department, Adana, Turkey
| | - Fehiman Efeoglu
- Department of Forensic Medicine, Faculty of Medicine, Cukurova University, Adana, Turkey
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30
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Lowe CC, Stogner JM, Miller BL. Spice Use among Adolescents in the United States: A National Profile of Synthetic Cannabinoid Users. JOURNAL OF CHILD & ADOLESCENT SUBSTANCE ABUSE 2021. [DOI: 10.1080/1067828x.2021.1873880] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- C. Cory Lowe
- University of Florida, Gainesville, FL, USA
- Loss Prevention Research Council, Gainesville, FL, USA
| | - John M. Stogner
- University of North Carolina at Charlotte, Charlotte, NC, USA
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31
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Li J, Zhang Y, Zhou Y, Feng XS. Cannabinoids: Recent Updates on Public Perception, Adverse Reactions, Pharmacokinetics, Pretreatment Methods and Their Analysis Methods. Crit Rev Anal Chem 2021; 52:1197-1222. [PMID: 33557608 DOI: 10.1080/10408347.2020.1864718] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Cannabinoids (CBDs) have been traditionally used as a folk medicine. Recently, they have been found to exhibit a high pharmacological potential. However, they are addicted and are often abused by drug users, thereby, becoming a threat to public safety. CBDs and their metabolites are usually found in trace levels in plants or in biological matrices and, are therefore not easy to be detected. Advances have been made toward accurately analyzing CBDs in plants or in biological matrices. This review aims at elucidating on the consumption of CBDs as well as its adverse effects and to provide a comprehensive overview of CBD pretreatment and detection methods. Moreover, novel pretreatment methods such as microextraction, Quick Easy Cheap Effective Rugged Safe and online technology as well as novel analytic methods such as ion-mobility mass spectrometry, application of high resolution mass spectrometry in nontarget screening are summarized. In addition, we discuss and compare the strengths and weaknesses of different methods and suggest their future prospect.
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Affiliation(s)
- Jie Li
- School of Pharmacy, China Medical University, Shenyang, China
| | - Yuan Zhang
- School of Pharmacy, China Medical University, Shenyang, China
| | - Yu Zhou
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xue-Song Feng
- School of Pharmacy, China Medical University, Shenyang, China
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32
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Shafi A, Berry AJ, Sumnall H, Wood DM, Tracy DK. New psychoactive substances: a review and updates. Ther Adv Psychopharmacol 2020; 10:2045125320967197. [PMID: 33414905 PMCID: PMC7750892 DOI: 10.1177/2045125320967197] [Citation(s) in RCA: 149] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/26/2020] [Indexed: 12/19/2022] Open
Abstract
New psychoactive substances (NPS) are a heterogeneous group of substances. They are associated with a number of health and social harms on an individual and societal level. NPS toxicity and dependence syndromes are recognised in primary care, emergency departments, psychiatric inpatient and community care settings. One pragmatic classification system is to divide NPS into one of four groups: synthetic stimulants, synthetic cannabinoids, synthetic hallucinogens and synthetic depressants (which include synthetic opioids and benzodiazepines). We review these four classes of NPS, including their chemical structures, mechanism of action, modes of use, intended intoxicant effects, and their associated physical and mental health harms. The current challenges faced by laboratory testing for NPS are also explored, in the context of the diverse range of NPS currently available, rate of production and emergence of new substances, the different formulations, and methods of acquisition and distribution.
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Affiliation(s)
- Abu Shafi
- East London Foundation Trust, London, UK
| | - Alex J. Berry
- Division of Psychiatry, University College London, UK
| | | | - David M. Wood
- Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
- Clinical Toxicology, Faculty of Life Sciences and Medicine, King’s College London, London, UK
| | - Derek K. Tracy
- Consultant Psychiatrist, Oxleas NHS Foundation Trust, London, UK
- Department of Psychosis Studies, the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, DeCrespigny Park, London, SE5 8AF, UK
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33
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DeVuono MV, Hrelja KM, Petrie GN, Limebeer CL, Rock EM, Hill MN, Parker LA. Nausea-Induced Conditioned Gaping Reactions in Rats Produced by High-Dose Synthetic Cannabinoid, JWH-018. Cannabis Cannabinoid Res 2020; 5:298-304. [PMID: 33381644 DOI: 10.1089/can.2019.0103] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Introduction: Cannabinoid hyperemesis syndrome is becoming a more prominently reported side effect of cannabis containing high-dose Δ9-tetrahydrocannabinol (THC) and designer cannabinoid drugs such as "Spice." One active ingredient that has been found in "Spice" is 1-pentyl-3-(1-naphthoyl)indole (JWH-018), a synthetic full agonist of the cannabinoid 1 (CB1) receptor. In this study, we evaluated the potential of different doses of JWH-018 to produce conditioned gaping in rats, an index of nausea. Materials and Methods: Rats received 3 daily conditioning trials in which saccharin was paired with JWH-018 (0.0, 0.1, 1, and 3 mg/kg, intraperitoneal [i.p.]). Then the potential of pretreatment with the CB1 antagonist, rimonabant (SR), to prevent JWH-018-induced conditioned gaping was determined. To begin to understand the potential mechanism underlying JWH-018-induced nausea, serum collected from trunk blood was subjected to a corticosterone (CORT) analysis in rats receiving three daily injections with vehicle (VEH) or JWH-018 (3 mg/kg). Results: At doses of 1 and 3 mg/kg (i.p.), JWH-018 produced nausea-like conditioned gaping reactions. The conditioned gaping produced by 3 mg/kg JWH-018 was reversed by pretreatment with rimonabant, which did not modify gaping on its own. Treatment with JWH-018 elevated serum CORT levels compared to vehicle-treated rats. Conclusions: As we have previously reported with high-dose THC, JWH-018 produced conditioned gaping in rats, reflective of a nausea effect mediated by its action on CB1 receptors and accompanied by elevated CORT, reflective of hypothalamic-pituitary-adrenal (HPA) activation.
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Affiliation(s)
- Marieka V DeVuono
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
| | - Kelly M Hrelja
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
| | - Gavin N Petrie
- Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.,Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
| | - Cheryl L Limebeer
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
| | - Erin M Rock
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
| | - Matthew N Hill
- Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.,Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
| | - Linda A Parker
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
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34
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Sholler DJ, Huestis MA, Amendolara B, Vandrey R, Cooper ZD. Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids. Pharmacol Biochem Behav 2020; 199:173059. [PMID: 33086126 PMCID: PMC7725960 DOI: 10.1016/j.pbb.2020.173059] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/22/2020] [Accepted: 10/09/2020] [Indexed: 02/07/2023]
Abstract
The phytocannabinoid Δ9-tetrahydrocannabinol (THC) was isolated and synthesized in the 1960s. Since then, two synthetic cannabinoids (SCBs) targeting the cannabinoid 1 (CB1R) and 2 (CB2R) receptors were approved for medical use based on clinical safety and efficacy data: dronabinol (synthetic THC) and nabilone (synthetic THC analog). To probe the function of the endocannabinoid system further, hundreds of investigational compounds were developed; in particular, agonists with (1) greater CB1/2R affinity relative to THC and (2) full CB1/2R agonist activity. This pharmacological profile may pose greater risks for misuse and adverse effects relative to THC, and these SCBs proliferated in retail markets as legal alternatives to cannabis (e.g., novel psychoactive substances [NPS], "Spice," "K2"). These SCBs were largely outlawed in the U.S., but blanket policies that placed all SCB chemicals into restrictive control categories impeded research progress into novel mechanisms for SCB therapeutic development. There is a concerted effort to develop new, therapeutically useful SCBs that target novel pharmacological mechanisms. This review highlights the potential therapeutic efficacy and safety considerations for unique SCBs, including CB1R partial and full agonists, peripherally-restricted CB1R agonists, selective CB2R agonists, selective CB1R antagonists/inverse agonists, CB1R allosteric modulators, endocannabinoid-degrading enzyme inhibitors, and cannabidiol. We propose promising directions for SCB research that may optimize therapeutic efficacy and diminish potential for adverse events, for example, peripherally-restricted CB1R antagonists/inverse agonists and biased CB1/2R agonists. Together, these strategies could lead to the discovery of new, therapeutically useful SCBs with reduced negative public health impact.
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Affiliation(s)
- Dennis J Sholler
- Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Marilyn A Huestis
- Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA, USA
| | - Benjamin Amendolara
- UCLA Cannabis Research Initiative, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA
| | - Ryan Vandrey
- Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ziva D Cooper
- UCLA Cannabis Research Initiative, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA
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35
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Robson H, Braund R, Glass M, Ashton J, Tatley M. Synthetic cannabis: adverse events reported to the New Zealand Pharmacovigilance Centre. Clin Toxicol (Phila) 2020; 59:472-479. [DOI: 10.1080/15563650.2020.1828592] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Hunter Robson
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Rhiannon Braund
- New Zealand Pharmacovigilance Centre, University of Otago, Dunedin, New Zealand
| | - Michelle Glass
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Janelle Ashton
- New Zealand Pharmacovigilance Centre, University of Otago, Dunedin, New Zealand
| | - Michael Tatley
- New Zealand Pharmacovigilance Centre, University of Otago, Dunedin, New Zealand
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36
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Funada M, Takebayashi-Ohsawa M, Tomiyama KI. Synthetic cannabinoids enhanced ethanol-induced motor impairments through reduction of central glutamate neurotransmission. Toxicol Appl Pharmacol 2020; 408:115283. [PMID: 33068620 DOI: 10.1016/j.taap.2020.115283] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/29/2020] [Accepted: 10/11/2020] [Indexed: 01/05/2023]
Abstract
Marijuana or synthetic cannabinoids and alcohol are often used together, with these combinations causing motor impairments that can subsequently lead to motor vehicle accidents. This study investigated the combined use of both synthetic cannabinoids and ethanol and their effect on motor coordination in mice in addition to examining the neurochemical changes in the cerebellum. Ethanol (2 g/kg, i.p.) significantly induced motor impairment in the accelerating rotarod test in mice. Furthermore, ethanol-induced motor impairments were further accentuated when combined with the synthetic cannabinoid, JWH-018 or AB-CHMINACA. The enhancement effects of the synthetic cannabinoids were completely antagonized by pretreatment with the selective CB1 receptor antagonist AM251, but not by the selective CB2 receptor antagonist AM630. Neurochemical study results showed that ethanol caused a reduction in the extracellular glutamate levels in the cerebellum during periods of ethanol-induced motor impairment. In addition to the enhanced motor impairment seen when ethanol was combined with JWH-018, these combinations also enhanced the reduction of the extracellular glutamate levels in the cerebellum. We additionally used microelectrode array recordings to examine the effects of ethanol and/or JWH-018 on the spontaneous network activity in primary cultures from mouse cerebellum. Results showed that ethanol combined with JWH-018 significantly reduced spontaneous neuronal network activity in the primary cerebellar culture. Our findings demonstrate that ethanol-induced motor impairments are enhanced by synthetic cannabinoids, with these effects potentially mediated by CB1 receptors. An accentuated reduction of neurotransmissions in the cerebellum may play an important role in motor impairments caused by ethanol combined with synthetic cannabinoids.
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Affiliation(s)
- Masahiko Funada
- Department of Drug Dependence Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8553, Japan.
| | - Mika Takebayashi-Ohsawa
- Department of Drug Dependence Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8553, Japan
| | - Ken-Ich Tomiyama
- Department of Drug Dependence Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8553, Japan
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37
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Fattore L, Marti M, Mostallino R, Castelli MP. Sex and Gender Differences in the Effects of Novel Psychoactive Substances. Brain Sci 2020; 10:brainsci10090606. [PMID: 32899299 PMCID: PMC7564810 DOI: 10.3390/brainsci10090606] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 12/12/2022] Open
Abstract
Sex and gender deeply affect the subjective effects and pharmaco-toxicological responses to drugs. Men are more likely than women to use almost all types of illicit drugs and to present to emergency departments for serious or fatal intoxications. However, women are just as likely as men to develop substance use disorders, and may be more susceptible to craving and relapse. Clinical and preclinical studies have shown important differences between males and females after administration of “classic” drugs of abuse (e.g., Δ9-tetrahydrocannabinol (THC), morphine, cocaine). This scenario has become enormously complicated in the last decade with the overbearing appearance of the new psychoactive substances (NPS) that have emerged as alternatives to regulated drugs. To date, more than 900 NPS have been identified, and can be catalogued in different pharmacological categories including synthetic cannabinoids, synthetic stimulants (cathinones and amphetamine-like), hallucinogenic phenethylamines, synthetic opioids (fentanyls and non-fentanyls), new benzodiazepines and dissociative anesthetics (i.e., methoxetamine and phencyclidine-derivatives). This work collects the little knowledge reached so far on the effects of NPS in male and female animal and human subjects, highlighting how much sex and gender differences in the effects of NPS has yet to be studied and understood.
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Affiliation(s)
- Liana Fattore
- Institute of Neuroscience-Cagliari, National Research Council (CNR), Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy
- Correspondence:
| | - Matteo Marti
- Department of Morphology, Surgery and Experimental Medicine, Section of Legal Medicine and LTTA Center, University of Ferrara, 44121 Ferrara, Italy;
- Department of Anti-Drug Policies, Collaborative Center for the Italian National Early Warning System, Presidency of the Council of Ministers, 00187 Rome, Italy
| | - Rafaela Mostallino
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy; (R.M.); (M.P.C.)
| | - Maria Paola Castelli
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy; (R.M.); (M.P.C.)
- National Institute of Neuroscience (INN), University of Cagliari, 09124 Cagliari, Italy
- Center of Excellence “Neurobiology of Addiction”, University of Cagliari, 09124 Cagliari, Italy
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38
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An Investigation of the COMT Gene Val158Met Polymorphism in Patients Admitted to the Emergency Department Because of Synthetic Cannabinoid Use. Balkan J Med Genet 2020; 23:63-68. [PMID: 32953411 PMCID: PMC7474226 DOI: 10.2478/bjmg-2020-0010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Catechol-O-methyl transferase (COMT) enzyme has a role in the inactivation of catecholamine neurotransmitters. Functional polymorphism in the COMT gene has been reported to play an important role in schizophrenia, bipolar affective disorder, aggressive and antisocial behavior, suicide attempts and the pathogenesis of Parkinson's disease. In this study, we aimed to investigate the effect of the Vall58Met polymorphism of the COMT gene on substance use, and treatment history in patients with synthetic cannabinoid (SC) intoxication. The COMT enzyme Val158Met polymorphisms from DNA of 49 patients who were evaluated in the Emergency Department after SC use and 50 healthy control groups aged 18-45 years, were identified by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses as reported in the literature. Information regarding recurrent intake or hospitalization due to substance use was obtained from hospital records. Wild-type (WT) genotypes in 14 (28.6%) patients, heterozygous genotypes in 25 (51.0%) and homozygous genotypes in 10 (20.4%) patients were detected. Wild-type genotypes The homozygous genotype was found to be significantly higher in patients hospitalized due to drug addiction and substance use (p 0.008). The Vall58 Met polymorphism of the COMT gene was not found to be significant in the first use after substance intake, while a significant relationship was found in terms of this polymorphism in patients with substance addiction diagnosis and treatment history.
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39
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Shapira B, Rosca P, Berkovitz R, Gorjaltsan I, Neumark Y. The switch from one substance-of-abuse to another: illicit drug substitution behaviors in a sample of high-risk drug users. PeerJ 2020; 8:e9461. [PMID: 32742781 PMCID: PMC7370931 DOI: 10.7717/peerj.9461] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 06/10/2020] [Indexed: 01/07/2023] Open
Abstract
Background Substitution can be defined as the consciously motivated choice to use one drug, either licit or illicit, instead of another, due to perceptions of cost, availability, safety, legality, substance characteristics, and substance attributions. Substitution represents a potential risk to drug users, mainly when substitutes are of higher potency and toxicity. This study offers a basic conceptualization of illicit substitution behavior and describes substitution patterns among users of two highly prevalent drugs of abuse-heroin and cannabis. Methods Here, 592 high-risk drug users undergoing pharmacological and psycho-social treatment were interviewed. Patients were asked questions about current drug use, lifetime substitution, and substitution patterns. Descriptive statistics, chi-square tests of independence, and multinomial logistic regressions were used to identify and test correlates of substitution patterns for heroin and cannabis. Results Of the 592 drug users interviewed, 448 subjects (75.7%) reported having substituted their preferred drug for another illicit substance. Interviews yielded a total of 275 substitution events reported by users of cannabis, and 351 substitution events reported by users of heroin. The most frequently reported substitution substances for responders who preferred heroin were illicit non-prescribed "street" methadone (35.9%), followed by oral and transdermal prescription opioids (17.7%). For responders who preferred cannabis, substitution for synthetic cannabinoid receptor agonists (33.5%) followed by alcohol (16.0%) were the most commonly reported. Age at onset-of-use (p < 0.005), population group (p = 0.008), and attending treatment for the first time (p = 0.026) were significantly associated with reported lifetime substitution. Past-year use of stimulants, heroin, hallucinogens, methylenedioxymethamphetamine (MDMA), and novel psychoactive substances were-at the 95% confidence level-also significantly associated with reported lifetime substitution. In multivariate analysis, the odds for methadone substitution among heroin users were significantly affected by age at onset-of-use, type of treatment center, and education. Odds for substitution for synthetic cannabinoid receptor agonists among cannabis users were significantly affected by age, population group, type of treatment center, and education. Conclusion Self-substitution behavior should be considered by clinicians and policymakers as a common practice among most drugusers. Substitution for street methadone provides evidence for the ongoing diversion of this substance from Opioid Maintenance Treatment Centers, while the prominence of substitution of synthetic cannabinoids among dual-diagnosis patients should be regarded as an ongoing risk to patients that needs to be addressed by clinicians. Analysis of additional substitution patterns should provide further valuable insights into the behavior of drugusers.
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Affiliation(s)
- Barak Shapira
- Braun School of Public Health and Community Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.,Division of Enforcement and Inspection, Israel Ministry of Health, Jerusalem, Israel
| | - Paola Rosca
- Department for the Treatment of Substance Abuse, Israel Ministry of Health, Jerusalem, Israel
| | - Ronny Berkovitz
- Division of Enforcement and Inspection, Israel Ministry of Health, Jerusalem, Israel
| | | | - Yehuda Neumark
- Braun School of Public Health and Community Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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40
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Fleisch SB, Walker JN. Surreptitious Opioid Misuse in the General Hospital via Rectal Administration: A Case Report. PSYCHOSOMATICS 2020; 61:405-407. [PMID: 31980212 DOI: 10.1016/j.psym.2019.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 11/16/2022]
Affiliation(s)
- Sheryl B Fleisch
- Assistant Professor of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN.
| | - Jessica N Walker
- Assistant in Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN
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41
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Gamage TF, Barrus DG, Kevin RC, Finlay DB, Lefever TW, Patel PR, Grabenauer MA, Glass M, McGregor IS, Wiley JL, Thomas BF. In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018. Pharmacol Biochem Behav 2020. [PMID: 32247816 DOI: 10.1016/j.pbb.2020.172918.in] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
Synthetic cannabinoid receptor agonists (SCRAs) possess high abuse liability and complex toxicological profiles, making them serious threats to public health. EG-018 is a SCRA that has been detected in both illicit products and human samples, but it has received little attention to date. The current studies investigated EG-018 at human CB1 and CB2 receptors expressed in HEK293 cells in [3H]CP55,940 competition binding, [35S]GTPγS binding and forskolin-stimulated cAMP production. EG-018 was also tested in vivo for its ability to produce cannabimimetic and abuse-related effects in the cannabinoid tetrad and THC drug discrimination, respectively. EG-018 exhibited high affinity at CB1 (21 nM) and at CB2 (7 nM), but in contrast to typical SCRAs, behaved as a weak partial agonist in [35S]GTPγS binding, exhibiting lower efficacy but greater potency, than that of THC at CB1 and similar potency and efficacy at CB2. EG-018 inhibited forskolin-stimulated cAMP with similar efficacy but lower potency, compared to THC, which was likely due to high receptor density facilitating saturation of this signaling pathway. In mice, EG-018 (100 mg/kg, 30 min) administered intraperitoneally (i.p.) did not produce effects in the tetrad or drug discrimination nor did it shift THC's ED50 value in drug discrimination when administered before THC, suggesting EG-018 has negligible occupancy of brain CB1 receptors following i.p. administration. Following intravenous (i.v.) administration, EG-018 (56 mg/kg) produced hypomotility, catalepsy, and hypothermia, but only catalepsy was blocked by the selective CB1 antagonist rimonabant (3 mg/kg, i.v.). Additional studies of EG-018 and its structural analogues could provide further insight into how cannabinoids exert efficacy through the cannabinoid receptors.
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MESH Headings
- Animals
- Behavior, Animal/drug effects
- Body Temperature/drug effects
- Cannabinoid Receptor Agonists/pharmacokinetics
- Cannabinoid Receptor Agonists/pharmacology
- Carbazoles/pharmacokinetics
- Carbazoles/pharmacology
- Cyclic AMP/metabolism
- Dronabinol/pharmacology
- HEK293 Cells
- Humans
- Liver/cytology
- Locomotion/drug effects
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred ICR
- Microsomes/drug effects
- Naphthalenes/pharmacokinetics
- Naphthalenes/pharmacology
- Rats
- Rats, Long-Evans
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/metabolism
- Signal Transduction/drug effects
- Synthetic Drugs/metabolism
- Synthetic Drugs/pharmacokinetics
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Affiliation(s)
- Thomas F Gamage
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Daniel G Barrus
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Richard C Kevin
- The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia; Faculty of Science, School of Psychology, The University of Sydney, Sydney, NSW 2006, Australia
| | - David B Finlay
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Timothy W Lefever
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Purvi R Patel
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Megan A Grabenauer
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Michelle Glass
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Iain S McGregor
- The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia; Faculty of Science, School of Psychology, The University of Sydney, Sydney, NSW 2006, Australia
| | - Jenny L Wiley
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA.
| | - Brian F Thomas
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
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42
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DeVuono MV, Parker LA. Cannabinoid Hyperemesis Syndrome: A Review of Potential Mechanisms. Cannabis Cannabinoid Res 2020; 5:132-144. [PMID: 32656345 PMCID: PMC7347072 DOI: 10.1089/can.2019.0059] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Introduction: Cannabinoids have long been known for their ability to treat nausea and vomiting. Recent reports, however, have highlighted the paradoxical proemetic effects of cannabinoids. Cannabinoid hyperemesis syndrome (CHS) is characterized by cyclical episodes of nausea and vomiting, accompanied by abdominal pain following prolonged, high-dose cannabis use, which is alleviated by hot baths and showers. Little is known about the cause of this syndrome. Discussion: Cannabinoids produce a biphasic effect on nausea and vomiting, with low doses having an antiemetic effect and high doses producing emesis. Presentation and treatment of CHS are similar to cyclical vomiting syndrome as well as chemotherapy-related anticipatory nausea and vomiting, suggesting that these phenomena may share mechanisms. The prevalence of CHS is not known because of the symptomatic overlap with other disorders and the lack of knowledge of the syndrome by the public and physicians. Treatment with typical antiemetic drugs is ineffective for CHS, but anxiolytic and sedative drugs, along with hot showers, seem to be consistently effective at reducing symptoms. The only known way to permanently end CHS, however, is abstinence from cannabinoids. Case studies and limited pre-clinical data on CHS indicate that prolonged high doses of the main psychotropic compound in cannabis, Δ9-tetrahydrocannabinol (THC), result in changes to the endocannabinoid system by acting on the cannabinoid 1 (CB1) receptor. These endocannabinoid system changes can dysregulate stress and anxiety responses, thermoregulation, the transient receptor potential vanilloid system, and several neurotransmitters systems, and are thus potential candidates for mediating the pathophysiology of CHS. Conclusions: Excessive cannabinoid administration disrupts the normal functioning of the endocannabinoid system, which may cause CHS. More clinical and pre-clinical research is needed to fully understand the underlying pathophysiology of this disorder and the negative consequences of prolonged high-dose cannabis use.
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Affiliation(s)
- Marieka V. DeVuono
- Department of Psychology and Collabortive Neuroscience Program, University of Guelph, Guelph, Canada
| | - Linda A. Parker
- Department of Psychology and Collabortive Neuroscience Program, University of Guelph, Guelph, Canada
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43
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Hobbs M, Patel R, Morrison PD, Kalk N, Stone JM. Synthetic cannabinoid use in psychiatric patients and relationship to hospitalisation: A retrospective electronic case register study. J Psychopharmacol 2020; 34:648-653. [PMID: 32108548 PMCID: PMC7249610 DOI: 10.1177/0269881120907973] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
INTRODUCTION AND OBJECTIVES Cannabis use has been associated with psychosis and with poor outcome in patients with mental illness. Synthetic cannabinoids (SCs) have been suggested to pose an even greater risk to mental health, but the effect on clinical outcome has not been directly measured. In this study, we aimed to investigate the demographics and hospitalisation of psychiatric patients who were SC users. METHODS We searched the Biomedical Research Centre Clinical Record Interactive Search register for SC users and age- and sex-matched SC non-users who had been psychiatric patients under the South London and Maudsley NHS Trust. We recorded diagnosis, homelessness, cannabis use and the total number of days admitted as an inpatient to secondary and tertiary mental-health services. RESULTS We identified 635 SC users and 635 age- and sex-matched SC non-users. SC users were significantly more likely to be homeless (χ2=138.0; p<0.0001) and to use cannabis (χ2=257.3; p<0.0001) than SC non-users. SC users had significantly more inpatient days after their first recorded use of SCs than controls (M (SD)=85.5 (199.7) vs. 25.4 (92.32); p<0.0001). Post hoc tests revealed that SC non-users who used cannabis had fewer inpatient days than SC users (p<0.0001), and that non-users of both SC and cannabis had fewer inpatient days than SC non-using cannabis users (p=0.02). CONCLUSIONS SC use may lead to an increase in the number of days spent in hospital in patients with psychiatric illness. This highlights the need for clinicians to ask specifically about SC use.
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Affiliation(s)
- Melissa Hobbs
- Institute of Psychiatry Psychology and
Neuroscience, King’s College London, London, UK
| | - Rashmi Patel
- Institute of Psychiatry Psychology and
Neuroscience, King’s College London, London, UK,South London and Maudsley NHS Foundation
Trust, Bethlem Royal Hospital, Beckenham, UK
| | - Paul D Morrison
- Institute of Psychiatry Psychology and
Neuroscience, King’s College London, London, UK,South London and Maudsley NHS Foundation
Trust, Bethlem Royal Hospital, Beckenham, UK
| | - Nicola Kalk
- Institute of Psychiatry Psychology and
Neuroscience, King’s College London, London, UK,South London and Maudsley NHS Foundation
Trust, Bethlem Royal Hospital, Beckenham, UK
| | - James M Stone
- Institute of Psychiatry Psychology and
Neuroscience, King’s College London, London, UK,South London and Maudsley NHS Foundation
Trust, Bethlem Royal Hospital, Beckenham, UK,James M Stone, Centre for Neuroimaging Sciences,
Institute of Psychiatry Psychology and Neuroscience, De Crespigny Park, London, SE5 8AF,
UK.
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44
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Cohen K, Rosenzweig S, Rosca P, Pinhasov A, Weizman A, Weinstein A. Personality Traits and Psychotic Proneness Among Chronic Synthetic Cannabinoid Users. Front Psychiatry 2020; 11:355. [PMID: 32477173 PMCID: PMC7242629 DOI: 10.3389/fpsyt.2020.00355] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 04/07/2020] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Chronic use of synthetic cannabinoids (SCs) has been associated with a wide range of negative consequences for health including psychotic and affective disturbances. Accumulating evidence indicates that cannabinoids use may be a risk factor for schizophrenia, and chronic natural cannabis users score higher than non-users on measures of schizotypal personality traits. However, little is known regarding the personality characteristics of SC users, especially in comparison with recreational cannabis users and healthy individuals. This study aimed to examine the differences in personality characteristics and schizotypy between SC users, regular cannabis users, and non-users and to compare these measures between groups. METHODS Forty-two chronic SC users, 39 natural cannabis users, and 47 non-using control participants, without history of mental disorder, or current substance use diagnosis (mean age 26± 4.47 years; 23 females, 105 males), completed the Big-Five Factor Inventory (BFI), the Schizotypal Personality Questionnaire-Brief (SPQ-B), substance use history, rating scales of depression and anxiety, and a demographic questionnaire. RESULTS On the BFI, SC users scored higher than natural cannabis users and non-users on neuroticism, but lower on agreeableness and extraversion, and endorsed greater schizotypal symptoms on the SPQ-B. In addition, SC users had lower scores on conscientiousness than non-users, and natural cannabis users were more extroverted than non-users. Higher openness and lower conscientiousness predicted schizotypy for both SC and natural cannabis users. Finally, greater neuroticism predicted schizotypy for natural cannabis users, and introversion predicted schizotypy for non-users. CONCLUSIONS These results show that chronic SC users differ from natural cannabis users and non-users on dimensions of specific personality traits and schizotypy that may indicate psychotic proneness.
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Affiliation(s)
- Koby Cohen
- Department of Behavioral Science, Ariel University, Ariel, Israel
| | - Shiri Rosenzweig
- Department of Behavioral Science, Ariel University, Ariel, Israel
| | - Paola Rosca
- Ministry of Health (Israel), Jerusalem, Israel
| | - Albert Pinhasov
- Adelson School of Medicine, Ariel University, Ariel, Israel
- Department of Molecular Biology, Ariel University, Ariel, Israel
| | | | - Aviv Weinstein
- Department of Behavioral Science, Ariel University, Ariel, Israel
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45
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Shapira B, Berkovitz R, Rosca P, Neumark Y. Recent Use of Synthetic Cannabinoids, Synthetic Opioids, and Other Psychoactive Drug Groups among High-risk Drug Users. J Psychoactive Drugs 2020; 52:334-343. [DOI: 10.1080/02791072.2020.1754534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Barak Shapira
- Hebrew University-Hadassah Braun School of Public Health and Community Medicine, Jerusalem, Israel
| | - Ronny Berkovitz
- Division of Enforcement and Inspection, Israel Ministry of Health, Jerusalem, Israel
| | - Paola Rosca
- Department for the Treatment of Substance Abuse, Israel Ministry of Health, Jerusalem, Israel
| | - Yehuda Neumark
- Hebrew University-Hadassah Braun School of Public Health and Community Medicine, Jerusalem, Israel
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46
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Grigg J, Killian JJ, Matthews S, Scott D, Arunogiri S, Manning V, Taylor DA, Crossin R, Smith K, Lubman DI. The impact of legislation on acute synthetic cannabinoid harms resulting in ambulance attendance. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2020; 79:102720. [PMID: 32279004 DOI: 10.1016/j.drugpo.2020.102720] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 02/28/2020] [Accepted: 03/04/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Synthetic cannabinoid receptor agonists (SCRAs) have been challenging current drug policy due to the rapid emergence of new variants, and their propensity for acute harm. In Australia, as in other parts of the world, multiple regulatory changes have occurred in response to these new psychoactive compounds, and population surveys indicate use is declining. This suggests that related harms would also be declining. We examined the impact of drug legislative changes on acute SCRA-related harms resulting in ambulance attendance. Secondary aims were to describe patient and attendance characteristics. METHODS A retrospective analysis of coded ambulance attendance data from Victoria, Australia (January 2014-December 2018). Interrupted time-series was used to analyse the trajectories of SCRA-related attendances relative to legislative changes. RESULTS During the study period, 3727 SCRA-related ambulance attendances were identified. There was an upward trend in attendances following legislation scheduling specific SCRAs in Victoria in October 2016 (slope = 1.31, 95% CI 1.17, 1.45). A downward trend in attendances followed 'blanket' legislation targeting all new psychoactive substances, implemented in Victoria in November 2017 (slope = -1.87, 95% CI -2.27, -1.46). Patient median age was 33 years, 80.5% were male, co-occurring substance use was identified in 30.4% cases, and 15.2% had >1 SCRA-related attendance. Overall, 69.4% cases were transported to hospital, with the odds of transport to hospital increasing each year from 2016. CONCLUSION This study represents a population-level examination of the impact of drug policy on acute SCRA-related harms resulting in ambulance attendance. Scheduling of specific SCRAs was associated with a spike in attendances, likely due to the introduction of more harmful variants in the drug market. Blanket legislation was associated with a reduction in SCRA-related attendances, however, a corresponding increase in cases transported to hospital indicates a greater severity of harm that may have been inadvertently promoted by this policy.
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Affiliation(s)
- Jasmin Grigg
- Turning Point, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia; Monash Addiction Research Centre, Monash University, Melbourne, Australia.
| | - Jessica J Killian
- Turning Point, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia
| | - Sharon Matthews
- Turning Point, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia
| | - Debbie Scott
- Turning Point, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia; Monash Addiction Research Centre, Monash University, Melbourne, Australia
| | - Shalini Arunogiri
- Turning Point, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia; Monash Addiction Research Centre, Monash University, Melbourne, Australia
| | - Victoria Manning
- Turning Point, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia; Monash Addiction Research Centre, Monash University, Melbourne, Australia
| | | | - Rose Crossin
- Turning Point, Eastern Health, Melbourne, Australia
| | - Karen Smith
- Centre for Research and Evaluation, Ambulance Victoria, Melbourne, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia; Department of Community Emergency Health and Paramedic Practice, Monash University, Melbourne, Australia
| | - Dan I Lubman
- Turning Point, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia; Monash Addiction Research Centre, Monash University, Melbourne, Australia
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47
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Gamage TF, Barrus DG, Kevin RC, Finlay DB, Lefever TW, Patel PR, Grabenauer MA, Glass M, McGregor IS, Wiley JL, Thomas BF. In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018. Pharmacol Biochem Behav 2020; 193:172918. [PMID: 32247816 DOI: 10.1016/j.pbb.2020.172918] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 03/26/2020] [Indexed: 01/08/2023]
Abstract
Synthetic cannabinoid receptor agonists (SCRAs) possess high abuse liability and complex toxicological profiles, making them serious threats to public health. EG-018 is a SCRA that has been detected in both illicit products and human samples, but it has received little attention to date. The current studies investigated EG-018 at human CB1 and CB2 receptors expressed in HEK293 cells in [3H]CP55,940 competition binding, [35S]GTPγS binding and forskolin-stimulated cAMP production. EG-018 was also tested in vivo for its ability to produce cannabimimetic and abuse-related effects in the cannabinoid tetrad and THC drug discrimination, respectively. EG-018 exhibited high affinity at CB1 (21 nM) and at CB2 (7 nM), but in contrast to typical SCRAs, behaved as a weak partial agonist in [35S]GTPγS binding, exhibiting lower efficacy but greater potency, than that of THC at CB1 and similar potency and efficacy at CB2. EG-018 inhibited forskolin-stimulated cAMP with similar efficacy but lower potency, compared to THC, which was likely due to high receptor density facilitating saturation of this signaling pathway. In mice, EG-018 (100 mg/kg, 30 min) administered intraperitoneally (i.p.) did not produce effects in the tetrad or drug discrimination nor did it shift THC's ED50 value in drug discrimination when administered before THC, suggesting EG-018 has negligible occupancy of brain CB1 receptors following i.p. administration. Following intravenous (i.v.) administration, EG-018 (56 mg/kg) produced hypomotility, catalepsy, and hypothermia, but only catalepsy was blocked by the selective CB1 antagonist rimonabant (3 mg/kg, i.v.). Additional studies of EG-018 and its structural analogues could provide further insight into how cannabinoids exert efficacy through the cannabinoid receptors.
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Affiliation(s)
- Thomas F Gamage
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Daniel G Barrus
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Richard C Kevin
- The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia; Faculty of Science, School of Psychology, The University of Sydney, Sydney, NSW 2006, Australia
| | - David B Finlay
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Timothy W Lefever
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Purvi R Patel
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Megan A Grabenauer
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
| | - Michelle Glass
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Iain S McGregor
- The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia; Faculty of Science, School of Psychology, The University of Sydney, Sydney, NSW 2006, Australia
| | - Jenny L Wiley
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA.
| | - Brian F Thomas
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA
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Aykut Kul, Cucu AK, Ahmad S. Determination of XLR-11 Metabolites in Urine by Ultrahigh-performance Liquid Chromatography-tandem Mass Spectrometry. JOURNAL OF ANALYTICAL CHEMISTRY 2020. [DOI: 10.1134/s1061934820030107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Fagiola M, Hahn T, Avella J. Evaluation of Acetylfentanyl Following Suspected Heroin Overdose When Complicated by the Presence of Toxic Fentanyl and Alprazolam Concentrations. Acad Forensic Pathol 2020; 9:191-199. [PMID: 32110254 DOI: 10.1177/1925362119892005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/11/2019] [Indexed: 12/30/2022]
Abstract
A 34-year-old male was reported to be snorting a white powder that was believed to contain heroin. Toxicological analysis revealed free morphine (356 μg/L), fentanyl (34.7 μg/L), alprazolam (64.9 μg/L), and acetylfentanyl (32.9 μg/L) in femoral blood and 6-monoacetylmorphine (6-MAM, <10.0 μg/L) in vitreous fluid. Norfentanyl was only detected in stomach contents (<1.00 μg/total). Heroin, fentanyl, and acetylfentanyl were also detected in solid dose evidence submitted by law enforcement. The fentanyl and alprazolam concentrations might normally be associated with a fatal outcome and are supported with the distribution of fentanyl and alprazolam being consistent with an acute intoxication. In addition, the presence of 6-MAM and a free versus total morphine ratio of 67.9% provide supporting evidence of a rapid death following intranasal (IN) administration. However, the presence of illicit acetylfentanyl complicates toxicologic interpretation due to overlapping recreational and fatal concentrations of this compound reported in the literature as well as a potential for postmortem redistribution (PMR). Reported acetylfentanyl concentrations have also varied when presented with significant fentanyl concentrations and underscore the need to consider a wide range of illicit opioid compounds when investigating drug-related deaths. Based on our comprehensive toxicologic analysis, the results suggest an acute intoxication primarily by IN administration of acetylfentanyl and fentanyl. In addition, we suggest the presence of alprazolam, 6-MAM, and a percentage free morphine is also consistent with rapid death. The cause of death was officially attributed to an acute combined intoxication of acetylfentanyl, fentanyl, alprazolam, and heroin, with the manner of death as accidental.
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Devgun JM, Rasin A, Kim T, Mycyk MB, Bryant SM, Wahl MS, DesLauriers C, Navon L, Moritz ED, Thompson TM, Swoboda HD, Lu J, Aks SE. An outbreak of severe coagulopathy from synthetic cannabinoids tainted with Long-Acting anticoagulant rodenticides. Clin Toxicol (Phila) 2019; 58:821-828. [DOI: 10.1080/15563650.2019.1690149] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
| | | | | | - Mark B. Mycyk
- Toxikon Consortium, Chicago, IL, USA
- Department of Emergency Medicine, Division of Medical Toxicology, Cook County Health, Chicago, IL, USA
| | - Sean M. Bryant
- Toxikon Consortium, Chicago, IL, USA
- Department of Emergency Medicine, Division of Medical Toxicology, Cook County Health, Chicago, IL, USA
- Illinois Poison Center, Chicago, IL, USA
| | | | | | - Livia Navon
- Illinois Department of Public Health, Springfield, IL, USA
| | - Erin D. Moritz
- Illinois Department of Public Health, Springfield, IL, USA
| | - Trevonne M. Thompson
- Toxikon Consortium, Chicago, IL, USA
- Department of Emergency Medicine, Division of Medical Toxicology, UI Health, Chicago, IL, USA
| | - Henry D. Swoboda
- Department of Emergency Medicine, Division of Medical Toxicology, Rush University Medical Center, Chicago, IL, USA
- Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA
| | - Jenny Lu
- Toxikon Consortium, Chicago, IL, USA
- Department of Emergency Medicine, Division of Medical Toxicology, Cook County Health, Chicago, IL, USA
| | - Steven E. Aks
- Toxikon Consortium, Chicago, IL, USA
- Department of Emergency Medicine, Division of Medical Toxicology, Cook County Health, Chicago, IL, USA
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