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de Oliveira MC, Vides MC, Lassi DLS, Torales J, Ventriglio A, Bombana HS, Leyton V, Périco CDAM, Negrão AB, Malbergier A, Castaldelli-Maia JM. Toxicity of Synthetic Cannabinoids in K2/Spice: A Systematic Review. Brain Sci 2023; 13:990. [PMID: 37508922 PMCID: PMC10377539 DOI: 10.3390/brainsci13070990] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/19/2023] [Accepted: 06/22/2023] [Indexed: 07/30/2023] Open
Abstract
(1) Background: Synthetic cannabinoids (SCs) are emerging drugs of abuse sold as 'K2', 'K9' or 'Spice'. Evidence shows that using SCs products leads to greater health risks than cannabis. They have been associated with greater toxicity and higher addiction potential unrelated to the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). Moreover, early cases of intoxication and death related to SCs highlight the inherent danger that may accompany the use of these substances. However, there is limited knowledge of the toxicology of Spice ingredients. This systematic review intends to analyze the toxicity of SCs compounds in Spice/K2 drugs. (2) Methods: Studies analyzing synthetic cannabinoid toxicity and dependence were included in the present review. We searched the PubMed database of the US National Library of Medicine, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. (3) Results: Sixty-four articles reporting the effects of synthetic cannabinoids in humans were included in our review. Ten original papers and fifty-four case studies were also included. Fourteen studies reported death associated with synthetic cannabinoid use, with AB-CHMINACA and MDMB-CHMICA being the main reported SCs. Tachycardia and seizures were the most common toxicity symptoms. The prevalence of neuropsychiatric symptoms was higher in third-generation SCs. (4) Conclusion: SCs may exhibit higher toxicity than THC and longer-lasting effects. Their use may be harmful, especially in people with epilepsy and schizophrenia, because of the increased risk of the precipitation of psychiatric and neurologic disorders. Compared to other drugs, SCs have a higher potential to trigger a convulsive crisis, a decline in consciousness, and hemodynamic changes. Therefore, it is crucial to clarify their potential harms and increase the availability of toxicology data in both clinical and research settings.
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Affiliation(s)
- Mariana Campello de Oliveira
- Interdisciplinary Group of Alcohol and Drug Studies (GREA), Institute Perdizes, Department of Psychiatry Medical School, São Paulo University, São Paulo 05403-903, SP, Brazil
| | - Mariana Capelo Vides
- Interdisciplinary Group of Alcohol and Drug Studies (GREA), Institute Perdizes, Department of Psychiatry Medical School, São Paulo University, São Paulo 05403-903, SP, Brazil
| | - Dângela Layne Silva Lassi
- Interdisciplinary Group of Alcohol and Drug Studies (GREA), Institute Perdizes, Department of Psychiatry Medical School, São Paulo University, São Paulo 05403-903, SP, Brazil
| | - Julio Torales
- Department of Psychological Medicine, School of Medical Sciences, National University of Asuncion, San Lorenzo 111421, Paraguay
| | - Antonio Ventriglio
- Department of Experimental Medicine, Medical School, University of Foggia, 71122 Foggia, Italy
| | - Henrique Silva Bombana
- Department of Legal Medicine, Medical School, São Paulo University, São Paulo 05508-090, SP, Brazil
| | - Vilma Leyton
- Department of Legal Medicine, Medical School, São Paulo University, São Paulo 05508-090, SP, Brazil
| | | | - André Brooking Negrão
- Interdisciplinary Group of Alcohol and Drug Studies (GREA), Institute Perdizes, Department of Psychiatry Medical School, São Paulo University, São Paulo 05403-903, SP, Brazil
| | - André Malbergier
- Interdisciplinary Group of Alcohol and Drug Studies (GREA), Institute Perdizes, Department of Psychiatry Medical School, São Paulo University, São Paulo 05403-903, SP, Brazil
| | - João Maurício Castaldelli-Maia
- Interdisciplinary Group of Alcohol and Drug Studies (GREA), Institute Perdizes, Department of Psychiatry Medical School, São Paulo University, São Paulo 05403-903, SP, Brazil
- Department of Neuroscience, Medical School, FMABC University Center, Santo André 09060-870, SP, Brazil
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
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Corli G, Tirri M, Bilel S, Arfè R, Coccini T, Roda E, Marchetti B, Vincenzi F, Zauli G, Borea PA, Locatelli CA, Varani K, Marti M. MAM-2201 acute administration impairs motor, sensorimotor, prepulse inhibition, and memory functions in mice: a comparison with its analogue AM-2201. Psychopharmacology (Berl) 2023:10.1007/s00213-023-06378-8. [PMID: 37233813 DOI: 10.1007/s00213-023-06378-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 05/02/2023] [Indexed: 05/27/2023]
Abstract
RATIONALE 1-[(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl) methanone (MAM-2201) is a potent synthetic cannabinoid receptor agonist illegally marketed in "spice" products and as "synthacaine" for its psychoactive effects. It is a naphthoyl-indole derivative which differs from its analogue 1-[(5-Fluoropentyl)-1H-indol-3-yl](1-naphthylenyl) methanone (AM-2201) by the presence of a methyl substituent on carbon 4 (C-4) of the naphthoyl moiety. Multiple cases of intoxication and impaired driving have been linked to AM-2201 and MAM-2201 consumption. OBJECTIVES This study aims to investigate the in vitro (murine and human cannabinoid receptors) and in vivo (CD-1 male mice) pharmacodynamic activity of MAM-2201 and compare its effects with those induced by its desmethylated analogue, AM-2201. RESULTS In vitro competition binding studies confirmed that MAM-2201 and AM-2201 possess nanomolar affinity for both CD-1 murine and human CB1 and CB2 receptors, with preference for the CB1 receptor. In agreement with the in vitro binding data, in vivo studies showed that MAM-2201 induces visual, acoustic, and tactile impairments that were fully prevented by pretreatment with CB1 receptor antagonist/partial agonist AM-251, indicating a CB1 receptor mediated mechanism of action. Administration of MAM-2201 also altered locomotor activity and PPI responses of mice, pointing out its detrimental effect on motor and sensory gating functions and confirming its potential use liability. MAM-2201 and AM-2201 also caused deficits in short- and long-term working memory. CONCLUSION These findings point to the potential public health burden that these synthetic cannabinoids may pose, with particular emphasis on impaired driving and workplace performance.
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Affiliation(s)
- Giorgia Corli
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Via Fossato Di Mortara 17-19, 44121, Ferrara, Italy
| | - Micaela Tirri
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Via Fossato Di Mortara 17-19, 44121, Ferrara, Italy
| | - Sabrine Bilel
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Via Fossato Di Mortara 17-19, 44121, Ferrara, Italy
| | - Raffaella Arfè
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Via Fossato Di Mortara 17-19, 44121, Ferrara, Italy
| | - Teresa Coccini
- Laboratory of Clinical and Experimental Toxicology, and Poison Control Centre and National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 10, 27100, Pavia, Italy
| | - Elisa Roda
- Laboratory of Clinical and Experimental Toxicology, and Poison Control Centre and National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 10, 27100, Pavia, Italy
| | - Beatrice Marchetti
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Via Fossato Di Mortara 17-19, 44121, Ferrara, Italy
| | - Fabrizio Vincenzi
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Giorgio Zauli
- Research Department, King Khaled Eye Specialistic Hospital, Riyadh, Saudi Arabia
| | | | - Carlo Alessandro Locatelli
- Laboratory of Clinical and Experimental Toxicology, and Poison Control Centre and National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 10, 27100, Pavia, Italy
| | - Katia Varani
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Matteo Marti
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Via Fossato Di Mortara 17-19, 44121, Ferrara, Italy.
- Department of Anti-Drug Policies, Collaborative Center for the Italian National Early Warning System, Presidency of the Council of Ministers, Ferrara, Italy.
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Corli G, Tirri M, Bilel S, Giorgetti A, Bernardi T, Boccuto F, Borsari M, Giorgetti R, Marti M. Ethanol enhances JWH-018-induced impairment of sensorimotor and memory functions in mice: From preclinical evidence to forensic implication in Driving Under the Influence of Drugs. Drug Alcohol Depend 2023; 247:109888. [PMID: 37120918 DOI: 10.1016/j.drugalcdep.2023.109888] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/03/2023] [Accepted: 04/14/2023] [Indexed: 05/02/2023]
Abstract
BACKGROUND Several new Synthetic Cannabinoids have appeared each year since their introduction into the illicit drug market as recreational drugs. Among these, naphtalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) is one of the most detected compounds in biological samples from patients involved in intoxication or death cases. Furthermore, consumption of JWH-018 has been linked to several cases of Driving Under the Influence of Drugs (DUID) suggesting that effects induced by this compound can affect individuals' ability to drive. METHODS Given the high spread of polydrug consumption and the wide number of alcohol-related traffic accidents, this study aims to investigate the acute effects induced by co-administration of JWH-018 with ethanol on sensorimotor and motor responses, grip strength and memory functions in CD-1 male mice. Acute impairments induced by JWH-018 and ethanol alone have also been investigated, in order to compare their effects with that induced by their concurrent administration. RESULTS In vivo behavioral experiments revealed a worsening of the cognitive and sensorimotor disruption after the co-administration of JWH-018 with ethanol compared to single compounds. CONCLUSIONS These animal-based findings suggest a potential increased impairment on psychomotor performances which could be related to driving abilities posed by poly-drug consumption involving SCs and ethanol.
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Affiliation(s)
- Giorgia Corli
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Ferrara, Italy
| | - Micaela Tirri
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Ferrara, Italy
| | - Sabrine Bilel
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Ferrara, Italy
| | - Arianna Giorgetti
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, Bologna, 40126, Italy
| | - Tatiana Bernardi
- Department of Environmental Sciences and Prevention, University of Ferrara, Ferrara, 44121, Italy
| | - Federica Boccuto
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Ferrara, Italy
| | - Martina Borsari
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Ferrara, Italy
| | - Raffaele Giorgetti
- Department of Excellence of Biomedical Science and Public Health, Faculty of Medicine, Polytechnic University of Marche, Ancona, Italy
| | - Matteo Marti
- Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Ferrara, Italy; Collaborative Center for the Italian National Early Warning System, Department of Anti-Drug Policies, Presidency of the Council of Ministers, Italy.
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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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Barbieri M, Tirri M, Bilel S, Arfè R, Corli G, Marchetti B, Caruso L, Soukupova M, Cristofori V, Serpelloni G, Marti M. Synthetic cannabinoid JWH-073 alters both acute behavior and in vivo/vitro electrophysiological responses in mice. Front Psychiatry 2022; 13:953909. [PMID: 36339851 PMCID: PMC9634257 DOI: 10.3389/fpsyt.2022.953909] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 10/04/2022] [Indexed: 11/30/2022] Open
Abstract
JWH-073 is a synthetic cannabinoid (SCB) that is illegally marketed within an "herbal blend", causing psychoactive effects more intense than those produced by Cannabis. Users report that JWH-073 causes less harmful effects than other SCBs, misrepresenting it as a "safe JWH-018 alternative", which in turn prompts its recreational use. The present study is aimed to investigate the in vivo pharmacological activity on physiological and neurobehavioral parameters in male CD-1 mice after acute 1 mg/kg JWH-073 administration. To this aim we investigate its effect on sensorimotor (visual, acoustic, and tactile), motor (spontaneous motor activity and catalepsy), and memory functions (novel object recognition; NOR) in mice coupling behavioral and EEG data. Moreover, to clarify how memory function is affected by JWH-073, we performed in vitro electrophysiological studies in hippocampal preparations using a Long-Term Potentiation (LTP) stimulation paradigm. We demonstrated that acute administration of JWH-073 transiently decreased motor activity for up to 25 min and visual sensorimotor responses for up to 105 min, with the highest effects at 25 min (~48 and ~38%, respectively), while the memory function was altered up to 24 h (~33%) in treated-mice as compared to the vehicle. EEG in the somatosensory cortex showed a maximal decrease of α (~23%) and γ (~26%) bands at 15 min, β (~26%) band at 25 min, a maximal increase of θ (~14%) band at 25 min and δ (~35%) band at 2 h, and a significant decrease of θ (~18%), α (~26%), and β (~10%) bands during 24 h. On the other hand, EEG in the hippocampus showed a significant decrease of all bands from 10 min to 2 h, with the maximal effect at 30 min for θ (~34%) and γ (~26%) bands and 2 h for α (~36%), β (~29%), and δ (~15%) bands. Notably, the δ band significant increase both at 5 min (~12%) and 24 h (~19%). Moreover, in vitro results support cognitive function impairment (~60% of decrease) by interfering with hippocampal synaptic transmission and LTP generation. Our results suggest that JWH-073 deeply alters brain electrical responsiveness with minor behavioral symptoms. Thus, it poses a subtle threat to consumers who mistakenly consider it safer than other SCBs.
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Affiliation(s)
- Mario Barbieri
- Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Micaela Tirri
- Department of Translational Medicine, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy
| | - Sabrine Bilel
- Department of Translational Medicine, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy
| | - Raffaella Arfè
- Department of Translational Medicine, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy
| | - Giorgia Corli
- Department of Translational Medicine, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy
| | - Beatrice Marchetti
- Department of Translational Medicine, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy
| | - Lorenzo Caruso
- Department of Environment and Prevention Sciences, University of Ferrara, Ferrara, Italy
| | - Marie Soukupova
- Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Virginia Cristofori
- Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
| | - Giovanni Serpelloni
- Neuroscience Clinical Center and Transcranial Magnetic Stimulation (TMS) Unit, Verona, Italy
| | - Matteo Marti
- Department of Translational Medicine, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy.,Department for Anti-Drug Policies, Collaborative Center of the National Early Warning System, Presidency of the Council of Ministers, Rome, Italy
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Lappas NT, Lappas CM. Cannabinoids. Forensic Toxicol 2022. [DOI: 10.1016/b978-0-12-819286-3.00026-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Orazietti V, Basile G, Giorgetti R, Giorgetti A. Effects of synthetic cannabinoids on psychomotor, sensory and cognitive functions relevant for safe driving. Front Psychiatry 2022; 13:998828. [PMID: 36226105 PMCID: PMC9548613 DOI: 10.3389/fpsyt.2022.998828] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/07/2022] [Indexed: 11/24/2022] Open
Abstract
Recreational use of Synthetic Cannabinoids (SCs), one of the largest groups of New Psychoactive Substances (NPS), has increased globally over the past few years. Driving is a structured process requiring the cooperation of several cognitive and psychomotor functions, organized in different levels of complexity. Each of these functions can be affected when Driving Under the Influence (DUI) of SCs. In order to reduce the likelihood of SC-related road accidents, it is essential to understand which areas of psychomotor performance are most affected by these substances, as well as the severity of impairment. For this purpose, a multiple database- literature review of recent experimental studies in humans and animals regarding the psychomotor effects of SCs has been performed. Despite the many limitations connected to experimental studies on humans, results showed a consistency between animal and human data. SCs appear to impair psychomotor performance in humans, affecting different domains related to safe driving even at low doses. Cases of DUI of SC have been repeatedly reported, although the exact prevalence is likely to be underestimated due to current analytical and interpretative issues. For this reason, an accurate physical examination performed by trained and experienced personnel has a primary role in recognizing signs of impairment in case of strong suspicion of SC consumption. The identification of a suspected case should be followed by reliable laboratory examination.
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Affiliation(s)
- Vasco Orazietti
- Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University of Ancona, Ancona, Italy
| | - Giuseppe Basile
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Galeazzi Orthopedics Institute, Milan, Italy
| | - Raffaele Giorgetti
- Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University of Ancona, Ancona, Italy
| | - Arianna Giorgetti
- Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University of Ancona, Ancona, Italy.,Unit of Legal Medicine, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Burt TS, Brown TL, Milavetz G, McGehee DV. Mechanisms of cannabis impairment: Implications for modeling driving performance. Forensic Sci Int 2021; 328:110902. [PMID: 34634690 DOI: 10.1016/j.forsciint.2021.110902] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/30/2021] [Accepted: 07/02/2021] [Indexed: 10/20/2022]
Abstract
Past research on cannabis has been limited in scope to THC potencies lower than legally available and efforts to integrate the effects into models of driving performance have not been attempted to date. The purpose of this systematic review is to understand the implications for modeling driving performance and describe future research needs. The risk of motor vehicle crashes increases 2-fold after smoking marijuana. Driving during acute cannabis intoxication impairs concentration, reaction time, along with a variety of other necessary driving-related skills. Changes to legislation in North America and abroad have led to an increase in cannabis' popularity. This has given rise to more potent strains, with higher THC concentrations than ever before. There is also rising usage of novel ingestion methods other than smoking, such as oral cannabis products (e.g., brownies, infused drinks, candies), vaping, and topicals. The PRISMA guidelines were followed to perform a systematic search of the PubMed database for peer-reviewed literature. Search terms were combined with keywords for driving performance: driving, performance, impairment. Grey literature was also reviewed, including congressional reports, committee reports, and roadside surveys. There is a large discrepancy between the types of cannabis products sold and what is researched. Almost all studies that used inhalation as the mode of ingestion with cannabis that is around 6% THC. This pales in comparison to the more potent strains being sold today which can exceed 20%. Which is to say nothing of extracts, which can contain 60% or more THC. Experimental protocol is another gap in research that needs to be filled. Methodologies that involve naturalistic (real world) driving environments, smoked rather than vaporized cannabis, and non-lab certified products introduce uncontrollable variables. When considering the available literature and the implications of modeling the impacts of cannabis on driving performance, two critical areas emerge that require additional research: The first is the role of cannabis potency. Second is the route of administration. Does the lower peak THC level result in smaller impacts on performance? How long does potential impairment last along the longer time-course associated with different pharmacokinetic profiles. It is critical for modeling efforts to understand the answers to these questions, accurately model the effects on driver performance, and by extension understand the risk to the public.
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Affiliation(s)
- Thomas S Burt
- National Advanced Driving Simulator, University of Iowa, Iowa City, IA, USA; Department of Industrial and Systems Engineering, University of Iowa, Iowa City, IA, USA.
| | - Timothy L Brown
- National Advanced Driving Simulator, University of Iowa, Iowa City, IA, USA; Department of Industrial and Systems Engineering, University of Iowa, Iowa City, IA, USA
| | - Gary Milavetz
- National Advanced Driving Simulator, University of Iowa, Iowa City, IA, USA; College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | - Daniel V McGehee
- National Advanced Driving Simulator, University of Iowa, Iowa City, IA, USA; Department of Industrial and Systems Engineering, University of Iowa, Iowa City, IA, USA; Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Public Policy Center, University of Iowa, Iowa City, IA, USA
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9
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Martínez L, La Maida N, Papaseit E, Pérez-Mañá C, Poyatos L, Pellegrini M, Pichini S, Ventura M, Galindo L, Busardò FP, Farré M. Acute Pharmacological Effects and Oral Fluid Concentrations of the Synthetic Cannabinoids JWH-122 and JWH-210 in Humans After Self-Administration: An Observational Study. Front Pharmacol 2021; 12:705643. [PMID: 34489699 PMCID: PMC8417402 DOI: 10.3389/fphar.2021.705643] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/15/2021] [Indexed: 11/13/2022] Open
Abstract
Synthetic cannabinoids (SCs) are a group of new psychoactive drugs used recreationally with potential health risks. They are monitored by the EU Early Warning System since 2010 due to severe adverse effects on consumers. JWH-122 and JWH-210 are naphthoylindole SCs and potent cannabinoid receptor CB1 and CB2 agonists. Information about the effects of SCs usually is available from intoxication cases and surveys, and few studies on humans after controlled administration or observational/naturalistic studies using standardized measures of cardiovascular and subjective effects are available. The aim of this study was to evaluate the acute pharmacological effects of JWH-122 and JWH-210 recreational consumption in a 4 h observational study and assess their disposition in oral fluid (OF). Sixteen volunteers self-administered 1 mg dose of JWH-122 (n = 8) or 2.25 mg mean dose of JWH-210 (range 2–3 mg, n = 8) by inhalation (smoking). Physiological parameters including blood pressure (systolic and diastolic), heart rate (HR), and cutaneous temperature were measured. A set of visual analog scales, the 49-item short-form version of the Addiction Research Center Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) were used for the evaluation of subjective effects. OF was collected at baseline and at 10, 20, and 40 min and 1, 2, 3, and 4 h after self-administration. Statistically significant increases in systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR were observed after JWH-122 self-administration but not after JWH-210 self-administration. JWH-210 self-administration produced significant changes in subjective drug effects, similar to those induced by THC (intensity, high, good effects, and hunger). The subjective effects following JWH-122 consumption were minimal. The maximal effects were mostly observed 20 min after intake. JWH-122 and JWH 210 OF concentration reached a peak 20 min after administration and could not be detected after 3 h. The results demonstrated a different pattern of effects of these two SCs. Due to the limitations of our observational study, further research with a larger sample and controlled studies are needed to better define the acute pharmacological effect and health risk profile of JWH-122 and JWH-210.
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Affiliation(s)
- Lucia Martínez
- Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), Barcelona, Spain.,Clinical Pharmacology Department, Hospital Universitario La Paz, Madrid, Spain
| | - Nunzia La Maida
- Department of Excellence of Biomedical Science and Public Health, University "Politecnica delle Marche", Ancona, Italy
| | - Esther Papaseit
- Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), Barcelona, Spain.,Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Spain
| | - Clara Pérez-Mañá
- Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), Barcelona, Spain.,Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Spain
| | - Lourdes Poyatos
- Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), Barcelona, Spain.,Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Spain
| | - Manuela Pellegrini
- National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy
| | - Simona Pichini
- National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy
| | - Mireia Ventura
- Energy Control, Associació Benestar i Desenvolupament, Barcelona, Spain
| | - Liliana Galindo
- Energy Control, Associació Benestar i Desenvolupament, Barcelona, Spain.,Department of Psychiatry, University of Cambridge/Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, United Kingdom
| | - Francesco Paolo Busardò
- Department of Excellence of Biomedical Science and Public Health, University "Politecnica delle Marche", Ancona, Italy
| | - Magí Farré
- Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), Barcelona, Spain.,Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Spain
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10
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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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11
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Theunissen EL, Reckweg JT, Hutten NRPW, Kuypers KPC, Toennes SW, Neukamm MA, Halter S, Ramaekers JG. Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users. Pharmacol Biochem Behav 2021; 202:173118. [PMID: 33497715 DOI: 10.1016/j.pbb.2021.173118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND Smoking mixtures containing synthetic cannabinoids (SCs) have become very popular over the last years but pose a serious risk for public health. Limited knowledge is, however, available regarding the acute effects of SCs on cognition and psychomotor performance. Earlier we demonstrated signs of impairment in healthy volunteers after administering one of the first SCs, JWH-018, even though subjective intoxication was low. In the current study, we aimed to investigate the acute effects of JWH-018 on several cognitive and psychomotor tasks in participants who are demonstrating representative levels of acute intoxication. METHODS 24 healthy cannabis-experienced participants took part in this placebo-controlled, cross-over study. Participants inhaled the vapor of 75 μg JWH-018/kg body weight and were given a booster dose if needed to induce a minimum level of subjective high. They were subsequently monitored for 4 h, during which psychomotor and cognitive performance, vital signs, and subjective experience were measured, and serum concentrations were determined. RESULTS Maximum subjective high (average 64%) was reached 30 min after administration of JWH-018, while the maximum blood concentration was shown after 5 min (8 ng/mL). JWH-018 impaired motor coordination (CTT), attention (DAT and SST), memory (SMT), it lowered speed-accuracy efficiency (MFFT) and slowed down response speed (DAT). CONCLUSION In accordance with our previous studies, we demonstrated acute psychomotor and cognitive effects of a relatively low dose of JWH-018.
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Affiliation(s)
- Eef L Theunissen
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands.
| | - Johannes T Reckweg
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Nadia R P W Hutten
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Kim P C Kuypers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, 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 - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Sebastian Halter
- Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Hermann Staudinger Graduate School, University of Freiburg, Hebelstr. 27, 79104 Freiburg, Germany
| | - Johannes G Ramaekers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands
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12
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Trexler KR, Vanegas SO, Poklis JL, Kinsey SG. The short-acting synthetic cannabinoid AB-FUBINACA induces physical dependence in mice. Drug Alcohol Depend 2020; 214:108179. [PMID: 32688070 PMCID: PMC7461724 DOI: 10.1016/j.drugalcdep.2020.108179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Recent years have seen a rise in the diversity and use of synthetic cannabinoids. The present study evaluated the behavioral effects of the third-generation indazole-3-carboxamide-type synthetic cannabinoid, AB-FUBINACA. METHODS Adult male and female C57BL/6J mice were treated with AB-FUBINACA (0-3 mg/kg, i.p.) and tested repeatedly in the tetrad battery measuring catalepsy, antinociception, hypothermia, and locomotor activity. Mice treated with AB-FUBINACA (≥2 mg/kg, i.p.) displayed classic cannabinoid effects in the tetrad that were blocked by the CB1 receptor selective antagonist rimonabant. To address tolerance and withdrawal effects, a second group of mice was injected with AB-FUBINACA (3 mg/kg, s.c.) or vehicle consisting of 5% ethanol, 5% Kolliphor EL, and 90 % saline every 12 h and tested daily in modified tetrad over the course of 5 days. On the 6th day, withdrawal was precipitated using rimonabant (3 mg/kg, s.c.), and somatic signs of withdrawal (i.e., head twitches and paw tremors) were quantified. RESULTS Although mice did not develop tolerance to AB-FUBINACA or cross-tolerance to Δ9-tetrahydrocannabinol (THC; 50 mg/kg, i.p.), somatic precipitated withdrawal signs were observed. Repeated tetrad testing up to 48 h post injection indicated that AB-FUBINACA effects are relatively short-lived, as compared with THC. Brain levels of AB-FUBINACA, as quantified by UHPLC-MS/MS, were undetectable 4 h post injection. CONCLUSIONS These data indicate that the cannabinoid effects of AB-FUBINACA are relatively short-lived, yet sufficient to induce dependence in mice.
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Affiliation(s)
- Kristen R. Trexler
- Department of Psychology, West Virginia University, Morgantown, WV, United States
| | - S. Olivia Vanegas
- Department of Psychology, West Virginia University, Morgantown, WV, United States,Department of Psychological Sciences, University of Connecticut, Storrs, CT, United States,School of Nursing, University of Connecticut, Storrs, CT, United States
| | - Justin L. Poklis
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Steven G. Kinsey
- Department of Psychology, West Virginia University, Morgantown, WV, United States,School of Nursing, University of Connecticut, Storrs, CT, United States,Corresponding author at: 231 Glenbrook Rd., Unit 4026, University of Connecticut, Storrs, CT, 06269-3237, United States. (S.G. Kinsey)
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13
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Fels H, Herzog J, Skopp G, Holzer A, Paul LD, Graw M, Musshoff F. Retrospective analysis of new psychoactive substances in blood samples of German drivers suspected of driving under the influence of drugs. Drug Test Anal 2020; 12:1470-1476. [DOI: 10.1002/dta.2897] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/26/2020] [Accepted: 07/07/2020] [Indexed: 11/08/2022]
Affiliation(s)
- Helena Fels
- Forensic Toxicological Centre (FTC) Munich Munich Germany
| | | | - Gisela Skopp
- Forensic Toxicological Centre (FTC) Munich Munich Germany
| | - Anna Holzer
- Institute of Forensic Medicine Ludwig‐Maximilians‐University Munich Munich Germany
| | - Liane D. Paul
- Institute of Forensic Medicine Ludwig‐Maximilians‐University Munich Munich Germany
| | - Matthias Graw
- Institute of Forensic Medicine Ludwig‐Maximilians‐University Munich Munich Germany
| | - Frank Musshoff
- Forensic Toxicological Centre (FTC) Munich Munich Germany
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14
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The synthetic cannabinoid 5F-MDMB-PICA: A case series. Forensic Sci Int 2020; 314:110410. [PMID: 32683270 DOI: 10.1016/j.forsciint.2020.110410] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 12/23/2022]
Abstract
5F-MDMB-PICA has been detected in products sold on the internet as well as in biological samples since 2016. It is associated with serious adverse health and behavioral effects and even death. Herein we report on twelve cases with proven 5F-MDMB-PICA consumption, including three fatalities, four cases of driving under the influence of drugs and five other criminal acts. In these cases, 5F-MDMB-PICA was detected in postmortem blood or serum. Concentrations ranged from 0.1-16ng/mL. In some blood (serum) and urine samples, the hydrolysis metabolite of 5F-MDMB-PICA (M12) could also be detected. In this case series, co-consumption with other drugs occurred in 9 of 12 cases, most commonly alcohol, cannabis and other contemporary SCs. In five cases, 4F-MDMB-BINACA was also detected. The described cases demonstrate various adverse effects that might be associated with 5F-MDMB-PICA. Observed physical adverse effects were mainly balance deficiencies and ocular effects such as reddened conjunctivae, glassy eyes and delayed or unresponsive pupil light reactions. Observed mental and behavioral effects were mainly changing moods, aggression, confusion, erratic behavior, mental leaps, disorientation, slowed reaction, logorrhea and slurred speech. Due to the fast changing market of synthetic cannabinoids, data on such new appearing substances are basically scarce. Because of the limited number of studies on pharmacological properties of synthetic cannabinoids, reports of findings in human samples along with corresponding case history descriptions can be valuable for the interpretation of upcoming routine cases.
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15
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Affiliation(s)
- Piotr Adamowicz
- Department of Forensic Toxicology, Institute of Forensic Research, Kraków, Poland
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16
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Umut G, Evren C, Atagun MI, Hisim O, Yilmaz Cengel H, Bozkurt M, Keskinkilic C. Impact of At Least 2 Years of Synthetic Cannabinoid Use on Cognitive and Psychomotor Functions Among Treatment-Seeking Male Outpatients. Cannabis Cannabinoid Res 2020; 5:164-171. [PMID: 32656348 DOI: 10.1089/can.2019.0017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Introduction: Synthetic cannabinoid (SC) use, an important public health problem, is becoming increasingly widespread and leads to many medical and psychiatric problems. This study aimed to evaluate the impact of SC use on cognitive and psychomotor functions of patients. Materials and Methods: The participants (30 outpatients with SC use disorder and 33 healthy controls) were administered the Montreal Cognitive Assessment (MOCA) test, the Edinburgh Handedness Inventory (EHI), the Finger-Tapping Test (FTT), and the Adult Memory and Information Processing Battery-B form (AMIPB-B). Results: The SC users scored lower in AMIPB-B, MOCA. and FTT compared to the healthy controls. Conclusion: These findings suggest that SC might impair both cognitive and psychomotor functions. Therefore, outpatients with SC use disorder should be carefully evaluated for cognitive and psychomotor functions since neurological examinations and interventions may also be required in treatment programs for these cases.
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Affiliation(s)
- Gokhan Umut
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Istanbul, Turkey
| | - Cuneyt Evren
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Istanbul, Turkey
| | - Murat Ilhan Atagun
- Department of Psychiatry, Medicine Faculty, Yildirim Beyazit University, Ankara, Turkey
| | - Ozge Hisim
- Department of Psychiatry, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey
| | - Hanife Yilmaz Cengel
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Istanbul, Turkey
| | - Muge Bozkurt
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Istanbul, Turkey
| | - Cahit Keskinkilic
- Deparment of Psychology, Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Istanbul, Turkey
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17
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Luethi D, Liechti ME. Designer drugs: mechanism of action and adverse effects. Arch Toxicol 2020; 94:1085-1133. [PMID: 32249347 PMCID: PMC7225206 DOI: 10.1007/s00204-020-02693-7] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 02/25/2020] [Indexed: 12/18/2022]
Abstract
Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at μ-opioid receptors and γ-aminobutyric acid-A (GABAA) or GABAB receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-D-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.
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Affiliation(s)
- Dino Luethi
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Währinger Strasse 13a, 1090, Vienna, Austria.
- Institute of Applied Physics, Vienna University of Technology, Getreidemarkt 9, 1060, Vienna, Austria.
- Division of Clinical Pharmacology and Toxicology, University Hospital Basel and University of Basel, Schanzenstrasse 55, 4056, Basel, Switzerland.
| | - Matthias E Liechti
- Division of Clinical Pharmacology and Toxicology, University Hospital Basel and University of Basel, Schanzenstrasse 55, 4056, Basel, Switzerland.
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18
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Kakehashi H, Shima N, Ishikawa A, Nitta A, Asai R, Wada M, Nakano S, Matsuta S, Sasaki K, Kamata H, Kamata T, Nishioka H, Miki A, Katagi M. Effects of lipophilicity and functional groups of synthetic cannabinoids on their blood concentrations and urinary excretion. Forensic Sci Int 2019; 307:110106. [PMID: 31902661 DOI: 10.1016/j.forsciint.2019.110106] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 11/28/2019] [Accepted: 12/01/2019] [Indexed: 01/16/2023]
Abstract
The influence of lipophilicity and functional groups of synthetic cannabinoids (SCs) on their blood concentrations and urinary excretion has been studied by analyzing blood and urine specimens sampled from drivers who were involved in a car crashes under the influence of SCs. A total of 58 specimens (26 urine and 31 blood specimens), sampled within 13h of the occurrence, were analyzed by liquid chromatography-tandem mass spectrometry. Fifteen SCs were detected in those specimens; the SCs detected were categorized as follows: Class 1, Naphthoyl/Benzoyl indole (EAM2201 and three other analogs); Class 2, Indole-3-carboxylate/carboxamide containing naphthol/quinol (5F-PB-22 and four other analogs); and Class 3, Indazole-3-carboxamide containing valine/tert-leucine derivative (5F-AMB and five other analogs). The calculated lipophilicity index log P, the octanol/water participation coefficient, of those SCs in Classes 1, 2, and 3 ranged between 5.01-8.14, 5.80-6.74 and 2.29-3.81, respectively. Class 3 SCs were detectable in 12 out of 13 urine specimens, but those in Classes 1 and 2 were not detected in urine. Our analytical results indicated that the boundary line for their detectability in urine lies between log P 4 and 5. The blood concentrations of Class 3 SCs varied widely (0.0036-31ng/ml) depending on their log P, while much smaller variation was observed among those in Class 2 (0.10-5.0ng/ml).
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Affiliation(s)
- Hidenao Kakehashi
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan.
| | - Noriaki Shima
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Akari Ishikawa
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Atsushi Nitta
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Ryutaro Asai
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Misato Wada
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Shihoko Nakano
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Shuntaro Matsuta
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Keiko Sasaki
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Hiroe Kamata
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Tooru Kamata
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Hiroshi Nishioka
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Akihiro Miki
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
| | - Munehiro Katagi
- Forensic Science Laboratory, Osaka Prefectural Police Headquarters, 1-3-18 Hommachi, Chuo-ku, Osaka 541-0053, Japan
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Bilel S, Tirri M, Arfè R, Ossato A, Trapella C, Serpelloni G, Neri M, Fattore L, Marti M. Novel halogenated synthetic cannabinoids impair sensorimotor functions in mice. Neurotoxicology 2019; 76:17-32. [PMID: 31610187 DOI: 10.1016/j.neuro.2019.10.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 09/18/2019] [Accepted: 10/07/2019] [Indexed: 02/06/2023]
Abstract
JWH-018-Cl, JWH-018-Br and AM-2201 (JWH-018 halogenated-derivatives; JWH-018-R compounds) are synthetic cannabinoid agonists illegally marketed as "Spice", "K2", "herbal blend" and research chemicals for their cannabis-like psychoactive effects. In rodents, JWH-018 and its halogenated derivatives reproduce the typical effects of Δ9-tetrahydrocannabinol (Δ9-THC), i.e. hypothermia, analgesia, hypolocomotion and akinesia. Yet, the effects of JWH-018-R compounds on sensorimotor functions are still unknown. This study was designed to investigate the effect of an acute intraperitoneal (i.p.) administration of JWH-018-R compounds (0.01-6 mg/kg) on sensorimotor functions in mice and to compare them to those caused by the reference compound JWH-018 and Δ9-THC. A well validated battery of behavioral tests was used to investigate the effects of these synthetic cannabinoids on the visual, auditory and tactile responses in mice, while the pre-pulse inhibition (PPI) test was used to investigate their effect on sensorimotor gating. The effect of the synthetic cannabinoids on spontaneous locomotion was also measured by a video tracking analysis to assess potential cannabinoid-induced motor impairment. Results showed that, similarly to JWH-018, systemic administration of JWH-018-R compounds inhibits sensorimotor and PPI responses at lower doses (0.01-0.1 mg/kg) and reduced spontaneous locomotion at intermediate/high doses (1-6 mg/kg). All effects were prevented by the administration of the selective cannabinoid CB1 receptor antagonist/inverse agonist AM-251 thus confirming a CB1 receptor-mediated action. Finding that lower doses of JWH-018-R compounds selectively impair sensorimotor and PPI responses without affecting locomotion should be carefully considered to better understand the potential danger that halogenated-derivatives of JWH-018 may pose to public health, with particular reference to decreased performance in driving and hazardous works.
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Affiliation(s)
- Sabrine Bilel
- Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy
| | - Micaela Tirri
- Department of Morphology, Experimental Medicine and Surgery, Section of Legal Medicine, University of Ferrara, Ferrara, Italy
| | - Raffaella Arfè
- Institute of Public Health, Section of Legal Medicine, Catholic University of Rome, Rome, Italy
| | - Andrea Ossato
- Institute of Public Health, Section of Legal Medicine, Catholic University of Rome, Rome, Italy
| | - Claudio Trapella
- Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Italy
| | - Giovanni Serpelloni
- Drug Policy Institute, Department of Psychiatry in the College of Medicine, University of Florida, USA
| | - Margherita Neri
- Department of Morphology, Experimental Medicine and Surgery, Section of Legal Medicine, University of Ferrara, Ferrara, Italy
| | - Liana Fattore
- Institute of Neuroscience-Cagliari, National Research Council, Italy.
| | - Matteo Marti
- Department of Morphology, Experimental Medicine and Surgery, Section of Legal Medicine, University of Ferrara, Ferrara, Italy; Center for Neuroscience and National Institute of Neuroscience, Italy; Collaborative Center for the Italian National Early Warning System, Department of Anti-Drug Policies, Presidency of the Council of Ministers, Italy
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20
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Higgins K, O’Neill N, O’Hara L, Jordan JA, McCann M, O’Neill T, Clarke M, O’Neill T, Campbell A. Evidence for public health on novel psychoactive substance use: a mixed-methods study. PUBLIC HEALTH RESEARCH 2019. [DOI: 10.3310/phr07140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background
Novel psychoactive substances (NPSs) contribute to the public health impact of substance misuse. This report provides research evidence addressing 11 research questions related to NPSs, covering types, patterns and settings of use; supply sources; and implications for policy and practice.
Methods
The study used a conceptually linked three-phase mixed-methods design with a shared conceptual framework based on multiple-context risk and protective factors. Phase 1 was a quantitative phase involving secondary data analysis of the longitudinal Belfast Youth Development Study (BYDS), a latent class analysis using the 2039 BYDS participants. Phase 2 was an extensive qualitative analysis via narrative interviews with participants, sampled from BYDS, drug/alcohol services and prisons, to explore NPS use trajectories. Phase 3 was the final quantitative phase; generalisability of the shared risk factor part of the model was tested using the manual three-step approach to examine risk factors associated with latent class membership. The quantitative and qualitative analyses were integrated, thus allowing emerging findings to be further explored.
Results
The data suggest that NPSs have a place within a range of polydrug use trajectories. Models showed no distinctive NPS class, with no clear evidence of differential risks for NPS use compared with the use of other substances. From the qualitative analysis, a taxonomy of groups was derived that explored how and where NPSs featured in a range of trajectories. This taxonomy was used to structure the analysis of factors linked to use within a risk and protective framework. Drivers for use were considered alongside knowledge, perceptions and experience of harms. Suggestions about how interventions could best respond to the various patterns of use – with special consideration of synthetic cannabinoids (SCs), including how they relate to the use of heroin and the potential for NPSs to operate as a ‘snare’ to more problem use – were also presented.
Limitations
The study was conducted during 2016/17; generalisability beyond this sample and time point is limited. The level of missing data for some of the BYDS analysis was a limitation, as was the fact that the BYDS data were collected in 2011, so in a different context from the data collected during the narrative interviews. The Psychoactive Substances Act 2016 (Great Britain. Psychoactive Substances Act 2016. London: The Stationery Office; 2016) came into force during qualitative fieldwork and, although not particularly influential in this study, may be influential in future work. It is acknowledged that many of the data related to SCs and mephedrone. Although drug use was measured by self-report, the strength of rapport within interviews, reflective diaries and methodological acceptability checks helped to mitigate self-report bias.
Conclusions
NPSs continue to present significant challenges for legislation and monitoring, researching and developing interventions. Understanding of usage patterns remains poor, with most information based on populations and settings where problems have already occurred. This research contributes to the evidence base by providing much needed further empirical data on the lived experiences of NPS users across a range of settings. In the light of these data, implications for policy and practice are discussed.
Future work
Future research must generate improved epidemiological data on the extent, patterns and motivations for use longitudinally. The uniqueness of the information concerning SC use points to a specific set of findings not evidenced in other literature (e.g. intensity of SC withdrawal). Future research should focus on the symbiotic link between SC and heroin use.
Funding
The National Institute for Health Research Public Health Research programme.
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Affiliation(s)
- Kathryn Higgins
- Centre for Evidence and Social Innovation, Queen’s University Belfast, Belfast, UK
- School of Social Sciences, Education and Social Work, Queen’s University Belfast, Belfast, UK
| | - Nina O’Neill
- Centre for Evidence and Social Innovation, Queen’s University Belfast, Belfast, UK
- School of Social Sciences, Education and Social Work, Queen’s University Belfast, Belfast, UK
| | - Leeanne O’Hara
- Centre for Evidence and Social Innovation, Queen’s University Belfast, Belfast, UK
- School of Social Sciences, Education and Social Work, Queen’s University Belfast, Belfast, UK
| | - Julie-Ann Jordan
- Centre for Evidence and Social Innovation, Queen’s University Belfast, Belfast, UK
- School of Social Sciences, Education and Social Work, Queen’s University Belfast, Belfast, UK
| | - Mark McCann
- MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Glasgow, UK
| | - Tara O’Neill
- Centre for Evidence and Social Innovation, Queen’s University Belfast, Belfast, UK
- School of Psychology, Queen’s University Belfast, Belfast, UK
| | - Mike Clarke
- School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
| | - Tony O’Neill
- Centre for Evidence and Social Innovation, Queen’s University Belfast, Belfast, UK
- School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
| | - Anne Campbell
- Centre for Evidence and Social Innovation, Queen’s University Belfast, Belfast, UK
- School of Social Sciences, Education and Social Work, Queen’s University Belfast, Belfast, UK
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Understanding and managing the new psychoactive substances phenomenon: a holistic approach. J Public Health Policy 2019; 40:217-235. [PMID: 30504846 DOI: 10.1057/s41271-018-0156-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The new psychoactive substances (NPS) phenomenon has emerged as a global threat that challenges public health and institutions. There are important qualitative differences between the NPS and traditional drugs phenomena. We discuss these differences and explore the complex structure of the NPS phenomenon. We analyse the entire phenomenon with a global, holistic approach. We present an original framework to help policy makers, healthcare practitioners, and community workers understand the NPS phenomenon's structure and to plan comprehensive policy responses and prevention strategies. We discuss fundamental characteristics, driving forces, routes of information, and social and individual health risks of the phenomenon. We conclude that a holistic approach integrating all aspects of the framework is essential for addressing this emerging threat. We give practical examples of interventions likely to be effective.
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Akram H, Mokrysz C, Curran HV. What are the psychological effects of using synthetic cannabinoids? A systematic review. J Psychopharmacol 2019; 33:271-283. [PMID: 30789300 DOI: 10.1177/0269881119826592] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Synthetic cannabinoids are, typically, full agonists at the cannabinoid CB1 receptor, and therefore considerably more potent than natural cannabis and may have correspondingly more serious psychological effects. Despite government sanctions against their production they continue to be available in ever-increasing varieties over the Internet. The psychological consequences of synthetic cannabinoid use are relatively unknown. AIM The purpose of this study was to synthesise the available research on the psychological consequences of synthetic cannabinoid use. METHOD A literature search of three databases was conducted in February 2018, including the following keywords: Spice, synthetic cannabis, cognition, affect, behaviour, psychosis, depression and anxiety. RESULTS Seventeen studies involving a variety of participants were eligible for inclusion: one controlled administration study, seven cross-sectional studies, five Internet surveys and four qualitative studies. The controlled administration study showed that, compared to placebo, synthetic cannabinoids acutely affected some aspects of cognitive functioning and subjective psychological ratings. Non-controlled, cross-sectional studies generally showed that synthetic cannabinoid users had lower performance on cognitive tasks and showed elevated symptomatology (e.g. paranoia) compared to both natural cannabis and non-cannabis users. Methodological limitations were noted across different study designs. There is limited research on how doses, frequency or type of synthetic cannabinoid influence outcomes. CONCLUSIONS Acute synthetic cannabinoid use can result in a range of psychological outcomes and, when non-intoxicated, synthetic cannabinoid users appear to differ from natural cannabis and non-users on various affective and cognitive domains. As synthetic cannabinoid use is increasing in at-risk populations there is an urgent need for more and better research to inform users, professionals and policymakers.
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Affiliation(s)
- Hina Akram
- 1 Department of Clinical, Educational and Health Psychology, University College London, London, UK.,2 UCL Clinical Psychopharmacology Unit, University College London, London, UK
| | - Claire Mokrysz
- 2 UCL Clinical Psychopharmacology Unit, University College London, London, UK
| | - H Valerie Curran
- 2 UCL Clinical Psychopharmacology Unit, University College London, London, UK
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Mensen VT, Vreeker A, Nordgren J, Atkinson A, de la Torre R, Farré M, Ramaekers JG, Brunt TM. Psychopathological symptoms associated with synthetic cannabinoid use: a comparison with natural cannabis. Psychopharmacology (Berl) 2019; 236:2677-2685. [PMID: 30968175 PMCID: PMC6695363 DOI: 10.1007/s00213-019-05238-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 03/22/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Synthetic cannabinoids (SCs) are a class of new psychoactive substances that have been rapidly evolving around the world throughout recent years. Many different synthetic cannabinoid analogues are on the consumer market and sold under misleading names, like "spice" or "incense." A limited number of studies have reported serious health effects associated with SC use. In this study, we compared clinical and subclinical psychopathological symptoms associated with SC use and natural cannabis (NC) use. METHODS A convenience sample of 367 NC and SC users was recruited online, including four validated psychometric questionnaires: The Drug Use Disorders Identification Test (DUDIT), Insomnia Severity Index (ISI), Altman Mania Scale (Altman), and Brief Symptom Inventory (BSI). The two groups were compared with analysis of variance (ANOVA) and covariance (ANCOVA), chi2 tests, and logistic regression when appropriate. RESULTS The SC user group did not differ in age from the NC user group (27.7 years), but contained less females (21% and 30%, respectively). SC users scored higher than NC users on all used psychometric measures, indicating a higher likelihood of drug abuse, sleep problems, (hypo)manic symptoms, and the nine dimensions comprising the BSI, somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Odds ratios (95% CI) for the SC user group vs NC user group were, respectively, drug dependence 3.56 (1.77-7.16), (severe) insomnia 5.01 (2.10-11.92), (hypo-)mania 5.18 (2.04-13.14), and BSI psychopathology 5.21 (2.96-9.17). DISCUSSION This study shows that SC use is associated with increased mental health symptomatology compared to NC use.
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Affiliation(s)
| | - Annabel Vreeker
- University Medical Center Utrecht, Department of Psychiatry, University of Utrecht, Utrecht, The Netherlands
| | - Johan Nordgren
- Department of Social Work, Malmö University, Malmö, Sweden
| | - Amanda Atkinson
- Public Health Institute, Liverpool John Moores University, Liverpool, UK
| | - Rafael de la Torre
- Integrative Pharmacology and Systems Neurosciences, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Magi Farré
- Integrative Pharmacology and Systems Neurosciences, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
- Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Johannes G Ramaekers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Tibor M Brunt
- Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
- Department of Developmental Psychopathology, Radboud University, Nijmegen, The Netherlands.
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Carlier J, Wohlfarth A, Salmeron BD, Scheidweiler KB, Huestis MA, Baumann MH. Pharmacodynamic Effects, Pharmacokinetics, and Metabolism of the Synthetic Cannabinoid AM-2201 in Male Rats. J Pharmacol Exp Ther 2018; 367:543-550. [PMID: 30266766 PMCID: PMC6246978 DOI: 10.1124/jpet.118.250530] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 09/06/2018] [Indexed: 12/20/2022] Open
Abstract
Novel synthetic cannabinoids are appearing in recreational drug markets worldwide. Pharmacological characterization of these new drugs is needed to inform clinicians, toxicologists, and policy makers who monitor public health. [1-(5-Fluoropentyl)-1H-indol-3-yl](1-naphthyl)methanone (AM-2201) is an abused synthetic cannabinoid that was initially created as a research tool for investigating the endocannabinoid system. Here we measured the pharmacodynamic effects of AM-2201 in rats, and simultaneously determined plasma pharmacokinetics for the parent drug and its metabolites. Male Sprague-Dawley rats were fitted with surgically implanted temperature transponders and indwelling jugular catheters under pentobarbital anesthesia. One week later, rats received subcutaneous injection of AM-2201 (0.1, 0.3, and 1.0 mg/kg) or its vehicle, and serial blood specimens were withdrawn via catheters. Core temperatures and catalepsy were measured just prior to each blood withdrawal, and plasma was assayed for drug and metabolites using liquid chromatography-tandem mass spectrometry. We found that AM-2201 produced dose-related hypothermia and catalepsy that peaked at 2 hours and lasted up to 8 hours. AM-2201 plasma concentrations rose linearly with increasing dose and ranged from 0.14 to 67.9 µg/l. Concentrations of three metabolites, AM-2201 N-(4-hydroxypentyl) (≤0.17 µg/l), naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) N-(5-hydroxypentyl) (≤1.14 µg/l), and JWH-018 N-pentanoic acid (≤0.88 µg/l) were detectable but much lower. Peak AM-2201, JWH-018 N-(5-hydroxypentyl), and JWH-018 N-pentanoic acid concentrations occurred at 1.3, 2.4, and 6.5 hours, respectively. Concentrations of AM-2201, JWH-018 N-(5-hydroxypentyl), and JWH-018 N-pentanoic acid were negatively correlated with body temperature, but, given the low concentrations of metabolites detected, AM-2201 is likely the major contributor to pharmacodynamic effects under our experimental conditions.
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Affiliation(s)
- Jeremy Carlier
- Chemistry and Drug Metabolism (J.C., A.W., K.B.S., M.A.H.) and Designer Drug Research Unit (B.D.S., M.H.B.), Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, Maryland
| | - Ariane Wohlfarth
- Chemistry and Drug Metabolism (J.C., A.W., K.B.S., M.A.H.) and Designer Drug Research Unit (B.D.S., M.H.B.), Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, Maryland
| | - Bonita D Salmeron
- Chemistry and Drug Metabolism (J.C., A.W., K.B.S., M.A.H.) and Designer Drug Research Unit (B.D.S., M.H.B.), Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, Maryland
| | - Karl B Scheidweiler
- Chemistry and Drug Metabolism (J.C., A.W., K.B.S., M.A.H.) and Designer Drug Research Unit (B.D.S., M.H.B.), Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, Maryland
| | - Marilyn A Huestis
- Chemistry and Drug Metabolism (J.C., A.W., K.B.S., M.A.H.) and Designer Drug Research Unit (B.D.S., M.H.B.), Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, Maryland
| | - Michael H Baumann
- Chemistry and Drug Metabolism (J.C., A.W., K.B.S., M.A.H.) and Designer Drug Research Unit (B.D.S., M.H.B.), Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, Maryland
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Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes. Arch Pharm Res 2018; 41:691-710. [PMID: 30039377 DOI: 10.1007/s12272-018-1055-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 07/11/2018] [Indexed: 01/06/2023]
Abstract
Synthetic cannabinoids, a new class of psychoactive substances, are potent agonists of cannabinoid receptors, which mimic the psychoactive effects of the principal psychoactive component of cannabis, ∆9-tetrahydrocannabinol. Despite governmental scheduling as illicit drugs, new synthetic cannabinoids are being produced. The abuse of synthetic cannabinoids with several drugs containing different chemical groups has resulted in large numbers of poisonings. This has increased the urgency for forensic and public health laboratories to identify the metabolites of synthetic cannabinoids and apply this knowledge to the development of analytical methods and for toxicity prediction. It is necessary to determine whether synthetic cannabinoids are involved in drug-metabolizing enzyme-mediated drug-drug interactions. This review describes the metabolic pathways of 13 prevalent synthetic cannabinoids and various drug-metabolizing enzymes responsible for their metabolism, including cytochrome P450 (CYP), UDP-glucuronosyltransferases (UGTs), and carboxylesterases. The inhibitory effects of synthetic cannabinoids on CYP and UGT activities are also reviewed to predict the potential of synthetic cannabinoids for drug-drug interactions. The drug-metabolizing enzymes responsible for metabolism of synthetic cannabinoids should be characterized and the effects of synthetic cannabinoids on CYP and UGT activities should be determined to predict the pharmacokinetics of synthetic cannabinoids and synthetic cannabinoid-induced drug-drug interactions in the clinic.
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Cohen K, Weinstein AM. Synthetic and Non-synthetic Cannabinoid Drugs and Their Adverse Effects-A Review From Public Health Prospective. Front Public Health 2018; 6:162. [PMID: 29930934 PMCID: PMC5999798 DOI: 10.3389/fpubh.2018.00162] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 05/14/2018] [Indexed: 01/01/2023] Open
Abstract
There is a growing use of novel psychoactive substances containing synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis, yet, these drugs are more potent and dangerous, and have been associated with dangerous adverse effects. Here, we review current literature on the epidemiology, acute, and chronic effects of synthetic and natural cannabinoid-based drugs. Synthetic drugs contain a mixture of psychoactive compounds that mostly bind cannabinoid receptors with high potency. These synthetic drugs replicate the effects of natural cannabis and Δ9-tetrahydrocannabinol but they induce more severe adverse effects including respiratory difficulties, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Chronic use of synthetic cannabinoids has been associated with serious psychiatric and medical conditions and even death. Given the growing popularity in the use of cannabinoid-based drugs and their harmful potential, there is a need for further research in this field.
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Affiliation(s)
- Koby Cohen
- Behavioral Science, Ariel University, Science Park, Ariel, Israel
| | - Aviv M Weinstein
- Behavioral Science, Ariel University, Science Park, Ariel, Israel
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27
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Wacht O, Melech-Shalom S, Grinstein-Cohen O. Synthetic Cannabis Use in Israel: “Nice or Bad Guy—Spice”. Int J Ment Health Addict 2018. [DOI: 10.1007/s11469-018-9907-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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Cengel HY, Bozkurt M, Evren C, Umut G, Keskinkilic C, Agachanli R. Evaluation of cognitive functions in individuals with synthetic cannabinoid use disorder and comparison to individuals with cannabis use disorder. Psychiatry Res 2018; 262:46-54. [PMID: 29407568 DOI: 10.1016/j.psychres.2018.01.046] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 11/26/2017] [Accepted: 01/24/2018] [Indexed: 02/05/2023]
Abstract
The use of synthetic cannabinoid has been increasing throughout the world and has become a major public health problem. The present study aims to investigate the attention, memory, visuospatial and executive functions in individuals with synthetic cannabinoid use disorder and compare the results with findings obtained from individuals with cannabis use disorder and healthy volunteers with no substance use. Fifty-two patients with synthetic cannabinoid use disorder, 45 patients with cannabis use disorder and 48 healthy control group males were included in the study. The neuropsychological test battery was designed to involve ten studies evaluating a large series of cognitive functions. Impairments in attention, memory, executive and visuospatial functions were identified in individuals with synthetic cannabinoid use disorder and these impairments were found to be significantly greater than in individuals with cannabis use disorder and healthy controls. In line with the data obtained from this study; the evaluation of each cognitive function with more comprehensive test batteries and supporting these evaluations with sensitive brain imaging studies are important topics for future research.
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Affiliation(s)
- Hanife Yilmaz Cengel
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey.
| | - Muge Bozkurt
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
| | - Cuneyt Evren
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
| | - Gokhan Umut
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
| | - Cahit Keskinkilic
- Department of Neuropsychology, Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Istanbul, Turkey
| | - Ruken Agachanli
- Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Bakirkoy Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
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29
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Busardò FP, Pichini S, Pellegrini M, Montana A, Lo Faro AF, Zaami S, Graziano S. Correlation between Blood and Oral Fluid Psychoactive Drug Concentrations and Cognitive Impairment in Driving under the Influence of Drugs. Curr Neuropharmacol 2018; 16:84-96. [PMID: 28847293 PMCID: PMC5771389 DOI: 10.2174/1570159x15666170828162057] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Revised: 08/09/2017] [Accepted: 08/24/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The effects of drugs on driving performance should be checked with drug concentration in the brain and at the same time with the evaluation of both the behavioural and neurophysiological effects. The best accessible indicator of this information is the concentration of the drug and/or metabolites in blood and, to a certain extent, oral fluid. We sought to review international studies on correlation between blood and oral fluid drug concentrations, neurological correlates and cognitive impairment in driving under the influence of drugs. METHODS Relevant scientific articles were identified from PubMed, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE up to April 2017. RESULTS Up to 2010, no epidemiological studies were available on this matter and International scientists suggested that even minimal amounts of parent drugs in blood and oral fluid could affect driving impairment. More recently, epidemiological data, systematic reviews and meta-analysis on drugged drivers allowed the suggestion of impairment concentration limits for the most common illicit drugs. These values were obtained comparing driving disability induced by psychotropic drugs with that of established blood alcohol limits. Differently from ethyl alcohol where both detection methods and concentration limits have been well established even with inhomogeneity of ranges within different countries, in case of drugs of abuse no official cut-offs have yet been established, nor any standardized analytical protocols. CONCLUSION Multiple aspects of driving performance can be differently affected by illicit drugs, and even if for few of them some dose/concentration dependent impairment has been reported, a wider knowledge on concentration/impairment relationship is still missing.
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Affiliation(s)
- Francesco Paolo Busardò
- Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Italy
| | - Simona Pichini
- National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy
| | - Manuela Pellegrini
- National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy
| | - Angelo Montana
- Department “G.F. Ingrassia” – University of Catania, Catania, Italy
| | | | - Simona Zaami
- Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Italy
| | - Silvia Graziano
- National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy
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30
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Paul ABM, Simms L, Amini S, Paul AE. Teens and Spice: A Review of Adolescent Fatalities Associated with Synthetic Cannabinoid Use. J Forensic Sci 2017; 63:1321-1324. [DOI: 10.1111/1556-4029.13704] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 10/12/2017] [Accepted: 11/01/2017] [Indexed: 01/01/2023]
Affiliation(s)
- Anthea B. Mahesan Paul
- Office of the Medical Examiner; Clark County Coroner; 1704 Pinto Lane, Las Vegas NV 89106
- University of Oxford; Oxford OX3 9DU UK
- Department of Pathology; The Ottawa Hospital; University of Ottawa; Ottawa Ontario Canada
| | - Lary Simms
- Office of the Medical Examiner; Clark County Coroner; 1704 Pinto Lane, Las Vegas NV 89106
| | | | - Abraham Ebenezer Paul
- Office of the Medical Examiner; Clark County Coroner; 1704 Pinto Lane, Las Vegas NV 89106
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Theunissen EL, Hutten NRPW, Mason NL, Toennes SW, Kuypers KPC, de Sousa Fernandes Perna EB, Ramaekers JG. Neurocognition and subjective experience following acute doses of the synthetic cannabinoid JWH-018: a phase 1, placebo-controlled, pilot study. Br J Pharmacol 2017; 175:18-28. [PMID: 29164599 DOI: 10.1111/bph.14066] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 08/28/2017] [Accepted: 09/27/2017] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND AND PURPOSE Synthetic cannabinoids (often sold as Spice or K2) have become a very popular alternative to cannabis due to their easy access and portrayed safety. Controlled studies on the behavioural effects of synthetic cannabinoids are currently lacking, which hampers risk assessments of these compounds. EXPERIMENTAL APPROACH This is a first attempt to assess the influence of a synthetic cannabinoid, JWH-018, on neurocognition and subjective experience in humans after controlled administration. JWH-018, 2 and 3 mg, was administered to six healthy cannabis-experienced volunteers in a placebo-controlled, cross-over study following an escalating dosing schedule. Participants were monitored for 12 h after drug administration, and several neurocognitive measures and subjective questionnaires were taken. KEY RESULTS Serum concentrations of JWH-018 were highest after the 2 mg dose but generally low after administration of both doses. Both doses of JWH-018 were well tolerated, and no serious side effects were reported. Participants reported feeling more 'high' at 1 and 2 h after administration, particularly after the 2 mg dose. Behavioural impairments also emerged despite the low serum concentrations of JWH-018. The low dose of JWH-018 impaired performance on the tracking, divided attention and stop signal task. CONCLUSION AND IMPLICATIONS JWH-018 dosing in the present study resulted in drug concentrations that were generally low and not fully representative of common use. Yet initial impairments of neurocognitive function and subjective feelings of high did emerge despite low levels of JWH-018 in serum. Higher doses are needed to obtain a more representative risk profile of JWH-018.
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Affiliation(s)
- Eef L Theunissen
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Nadia R P W Hutten
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Natasha L Mason
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Stefan W Toennes
- Department of Forensic Toxicology, Institute of Legal Medicine, Goethe University of Frankfurt, Frankfurt, Germany
| | - Kim P C Kuypers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Eliza B de Sousa Fernandes Perna
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Johannes G Ramaekers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
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Three fatalities associated with the synthetic cannabinoids 5F-ADB, 5F-PB-22, and AB-CHMINACA. Forensic Sci Int 2017; 281:e9-e15. [PMID: 29133010 DOI: 10.1016/j.forsciint.2017.10.042] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 10/28/2017] [Accepted: 10/30/2017] [Indexed: 11/24/2022]
Abstract
The use of synthetic cannabinoids (SC) has been widespread in certain groups of drug users for many years. In the scientific literature many intoxication cases and a number of fatalities after the use of synthetic cannabinoids were reported. In this paper three death cases are described with involvement of the synthetic cannabinoids 5F-PB-22, AB-CHMINACA, and 5F-ADB. The three cases occurred in the eastern region of Germany, which is known as a region of high methamphetamine abuse. All decedents were male, between 25 and 41 years old, and had a known history of drug use. Femoral blood concentrations of the synthetic cannabinoids were measured using a validated LC-MS/MS method. The concentration of 5F-PB-22 in the first case was 0.37ng/mL, the concentration of AB-CHMINACA in the second case was approximately 4.1ng/mL (extrapolated) and the 5F-ADB concentration in the third case was 0.38ng/mL. Compared to other published cases the concentrations in the here presented cases seem to be in the lower range. However, taking into account the scene of death, the results of the forensic autopsy and the full toxicological analysis, the deaths can be explained as a direct consequence of consumption of synthetic cannabinoids, although in case one and two relevant amounts of ethanol were found, and in case three trimipramine and olanzapine were present in non-toxic concentrations. It has to be noted that concentrations of synthetic cannabinoids in femoral blood cannot directly be judged as toxic or lethal due to the possibility of postmortem redistribution and the development of tolerance after frequent use. Therefore, all available information has to be considered carefully before stating SC use as the cause of death.
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Hondebrink L, Zwartsen A, Westerink RHS. Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data? Pharmacol Ther 2017; 182:193-224. [PMID: 29097307 DOI: 10.1016/j.pharmthera.2017.10.022] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The use of new psychoactive substances (NPS) is increasing and currently >600 NPS have been reported. However, limited information on neuropharmacological and toxicological effects of NPS is available, hampering risk characterization. We reviewed the literature on the in vitro neuronal modes of action to obtain effect fingerprints of different classes of illicit drugs and NPS. The most frequently reported NPS were selected for review: cathinones (MDPV, α-PVP, mephedrone, 4-MEC, pentedrone, methylone), cannabinoids (JWH-018), (hallucinogenic) phenethylamines (4-fluoroamphetamine, benzofurans (5-APB, 6-APB), 2C-B, NBOMes (25B-NBOMe, 25C-NBOMe, 25I-NBOMe)), arylcyclohexylamines (methoxetamine) and piperazine derivatives (mCPP, TFMPP, BZP). Our effect fingerprints highlight the main modes of action for the different NPS studied, including inhibition and/or reversal of monoamine reuptake transporters (cathinones and non-hallucinogenic phenethylamines), activation of 5-HT2receptors (hallucinogenic phenethylamines and piperazines), activation of cannabinoid receptors (cannabinoids) and inhibition of NDMA receptors (arylcyclohexylamines). Importantly, we identified additional targets by relating reported effect concentrations to the estimated human brain concentrations during recreational use. These additional targets include dopamine receptors, α- and β-adrenergic receptors, GABAAreceptors and acetylcholine receptors, which may all contribute to the observed clinical symptoms following exposure. Additional data is needed as the number of NPS continues to increase. Also, the effect fingerprints we have obtained are still incomplete and suffer from a large variation in the reported effects and effect sizes. Dedicated in vitro screening batteries will aid in complementing specific effect fingerprints of NPS. These fingerprints can be implemented in the risk assessments of NPS that are necessary for eventual control measures to reduce Public Health risks.
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Affiliation(s)
- Laura Hondebrink
- Dutch Poisons Information Center (DPIC), University Medical Center Utrecht, Utrecht University, The Netherlands
| | - Anne Zwartsen
- Dutch Poisons Information Center (DPIC), University Medical Center Utrecht, Utrecht University, The Netherlands; Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, The Netherlands
| | - Remco H S Westerink
- Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, The Netherlands.
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Funada M, Takebayashi-Ohsawa M. Synthetic cannabinoid AM2201 induces seizures: Involvement of cannabinoid CB 1 receptors and glutamatergic transmission. Toxicol Appl Pharmacol 2017; 338:1-8. [PMID: 29042214 DOI: 10.1016/j.taap.2017.10.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 10/11/2017] [Accepted: 10/13/2017] [Indexed: 12/01/2022]
Abstract
Abuse of synthetic cannabinoids is a serious social problem worldwide. Intentional ingestion of synthetic cannabinoids can cause severe toxicity, including seizures. Here we investigated the effects of acute administration of synthetic cannabinoids on the induction of epileptic seizures by monitoring electroencephalographic activity in freely moving mice. The synthetic cannabinoid, AM2201, induced abnormal, high-amplitude (>2-fold baseline amplitude), sharp-wave activity. The abnormal spike-wave discharges were accompanied by epileptiform behavior: rigid posture, tail extension, rearing with forepaws extended, jumping, and intermittent tonic-clonic jerking movements. The abnormal spike-wave discharges and behavioral changes were suppressed by pretreatment with the selective CB1 receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630 or the vanilloid receptor antagonist, capsazepine. Furthermore, the group 1 metabotropic glutamate receptor antagonist SIB1757 eliminated AM2201-induced spike-wave discharges and episodes of epileptiform behavior. AM2201 markedly increased the extracellular glutamate concentration in the hippocampus during periods of AM2201-induced abnormal spike-wave discharges and behavioral changes. These findings are the first evidence that AM2201 induces epileptic seizures by enhancing glutamatergic transmission in the hippocampus. Our findings demonstrate that induction of epileptic seizures by synthetic cannabinoids is mediated by CB1 receptors, but not by CB2 receptors, and further suggest that rapid elevation of glutamatergic transmission may play an important role in the induction of seizures following intentional ingestion of 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
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Kevin RC, Wood KE, Stuart J, Mitchell AJ, Moir M, Banister SD, Kassiou M, McGregor IS. Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA. J Psychopharmacol 2017; 31:757-769. [PMID: 28093016 DOI: 10.1177/0269881116684336] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆9-tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 × 1 mg/kg and 6 × 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.
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Affiliation(s)
- Richard C Kevin
- 1 School of Psychology, The University of Sydney, NSW, Australia
| | - Katie E Wood
- 1 School of Psychology, The University of Sydney, NSW, Australia
| | - Jordyn Stuart
- 1 School of Psychology, The University of Sydney, NSW, Australia
| | - Andrew J Mitchell
- 2 Centenary Institute of Cancer Medicine and Cell Biology, Sydney, NSW, Australia
| | - Michael Moir
- 3 School of Chemistry, The University of Sydney, NSW, Australia
| | | | - Michael Kassiou
- 3 School of Chemistry, The University of Sydney, NSW, Australia
| | - Iain S McGregor
- 1 School of Psychology, The University of Sydney, NSW, Australia
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36
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Mdege ND, Meader N, Lloyd C, Parrott S, McCambridge J. The Novel Psychoactive Substances in the UK Project: empirical and conceptual review work to produce research recommendations. PUBLIC HEALTH RESEARCH 2017. [DOI: 10.3310/phr05040] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BackgroundAlthough illegal drug use has largely been declining in the UK over the past decade, this period has witnessed the emergence of a range of novel psychoactive substances (NPS) (‘legal highs’). These are new, mostly synthetic, substances that mimic the effects of existing drugs). Despite there being many causes for concern in relation to NPS, there has been little prior study of the burden associated with their use in public health terms. Clarity is lacking on research priorities in this rapidly developing literature.ObjectivesTo inform the development of public health intervention research on NPS by reviewing existing data on their use, associated problems and potential responses to such problems.DesignA scoping review and narrative synthesis of selected bodies of evidence was undertaken to summarise and evaluate what is known about NPS use and the related harms of, and responses to, such use. Relevant literature was identified from electronic databases (covering January 2006 to June 2016 inclusive), Google (Google Inc., Mountain View, CA, USA), relevant websites and online drug forums and by contacting experts. Articles were included if they were primary studies, secondary studies involving the analysis and interpretation of primary research or discussion papers. A conceptual framework postulating an evidence-informed public health approach to NPS use in the UK was developed through a pragmatic literature review, the iterative development of concepts and finalisation in light of the results from the empirical review work. The process also involved feedback from various stakeholders. Research recommendations were developed from both strands of work.ResultsA total of 995 articles were included in the scoping review, the majority of which related to individual-level health-related adverse effects attributable to NPS use. The prevalence of lifetime NPS use varied widely between (e.g. with higher prevalence in young males) and within population subgroups. The most commonly reported adverse effects were psychiatric/other neurological, cardiovascular, renal and gastrointestinal manifestations, and there is limited evidence available on responses. In these and other respects, available evidence is at an early stage of development. Initial evidence challenges the view that NPS should be treated differently from other illicit drugs. The conceptual framework indicated that much of the evidence that would be useful to inform public health responses does not yet exist. We propose a systems-based prevention approach that develops existing responses, is multilevel and life course informed in character, and emphasises commonalities between NPS and other legal and illegal drug use. We make 20 recommendations for research, including nine key recommendations.LimitationsScoping reviews do not interrogate evidence in depth, and the disjunction between the scoping review and the conceptual framework findings is worthy of careful attention.ConclusionsKey research recommendations build on those that have previously been made and offer more evidence-based justification and detail, as previous recommendations have not yet been acted on. The case for decision-making on commissioning new research based on these recommendations is both strong and urgent.Future workThe validity of recommendations generated through this project could be enhanced via further work with research commissioners, policy-makers, researchers and the public.Study registrationThe systematic review element of this study is registered as PROSPERO CRD42016026415.FundingThe National Institute for Health Research Public Health Research programme.
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Affiliation(s)
- Noreen D Mdege
- Department of Health Sciences, University of York, York, UK
| | - Nick Meader
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Charlie Lloyd
- Department of Health Sciences, University of York, York, UK
| | - Steve Parrott
- Department of Health Sciences, University of York, York, UK
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Niaz K, Khan F, Maqbool F, Momtaz S, Ismail Hassan F, Nobakht-Haghighi N, Rahimifard M, Abdollahi M. Endo-cannabinoids system and the toxicity of cannabinoids with a biotechnological approach. EXCLI JOURNAL 2017; 16:688-711. [PMID: 28827985 PMCID: PMC5547394 DOI: 10.17179/excli2017-257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 04/29/2017] [Indexed: 01/06/2023]
Abstract
Cannabinoids have shown diverse and critical effects on the body systems, which alter the physiological functions. Synthetic cannabinoids are comparatively innovative misuse drugs with respect to their nature of synthesis. Synthetic cannabinoids therapy in healthy, chain smokers, and alcoholic individuals cause damage to the immune and nervous system, eventually leading to intoxication throughout the body. Relevant studies were retrieved using major electronic databases such as PubMed, EMBASE, Medline, Scopus, and Google Scholar. The extensive use of Cannabis Sativa L. (C. Sativa) and its derivatives/analogues such as the nonpsychoactive dimethyl heptyl homolog (CBG-DMH), and tetrahydrocannabivarin (THCV) amongst juveniles and adults have been enhanced in recent years. Cannabinoids play a crucial role in the induction of respiratory, reproductive, immune and carcinogenic effects; however, potential data about mutagenic and developmental effects are still insufficient. The possible toxicity associated with the prolong use of cannabinoids acts as a tumor promoter in animal models and humans. Particular synthetic cannabinoids and analogues have low affinity for CB1 or CB2 receptors, while some synthetic members like Δ9-THC have high affinity towards these receptors. Cannabinoids and their derivatives have a direct or indirect association with acute and long-term toxicity. To reduce/attenuate cannabinoids toxicity, pharmaceutical biotechnology and cloning methods have opened a new window to develop cannabinoids encoding the gene tetrahydrocannabinolic acid (THCA) synthase. Plant revolution and regeneration hindered genetic engineering in C. Sativa. The genetic culture suspension of C. Sativa can be transmuted by the use of Agrobacterium tumefaciens to overcome its toxicity. The main aim of the present review was to collect evidence of the endo-cannabinoid system (ECS), cannabinoids toxicity, and the potential biotechnological approach of cannabinoids synthesis.
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Affiliation(s)
- Kamal Niaz
- International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran.,Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fazlullah Khan
- International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran.,Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Faheem Maqbool
- International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran.,Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeideh Momtaz
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
| | - Fatima Ismail Hassan
- International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran.,Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Navid Nobakht-Haghighi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, North Cyprus Mersin 10, Turkey
| | - Mahban Rahimifard
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran.,Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Inhibition of cytochrome P450 and uridine 5'-diphospho-glucuronosyltransferases by MAM-2201 in human liver microsomes. Arch Pharm Res 2017; 40:727-735. [PMID: 28484907 DOI: 10.1007/s12272-017-0917-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 04/30/2017] [Indexed: 02/03/2023]
Abstract
MAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors and is increasingly used as an illicit recreational drug. The inhibitory effects of MAM-2201 on major drug-metabolizing enzymes such as cytochrome P450s (CYPs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) have not yet been investigated although it is widely abused, sometimes in combination with other drugs. We evaluated the inhibitory effects of MAM-2201 on eight major human CYPs (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six UGTs (UGTs 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) of pooled human liver microsomes; we thus explored potential MAM-2201-induced drug interactions. MAM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4'-hydroxylation, CYP3A4-catalyzed midazolam 1'-hydroxylation, and UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, with K i values of 5.6, 5.4 and 5.0 µM, respectively. MAM-2201 exhibited mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-de-ethylation with K i and k inact values of 1.0 µM and 0.0738 min-1, respectively. In human liver microsomes, MAM-2201 (50 µM) negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7. Based on these in vitro results, we conclude that MAM-2201 has the potential to trigger in vivo pharmacokinetic drug interactions when co-administered with substrates of CYP2C8, CYP2C9, CYP3A4, and UGT1A3.
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Kim JH, Kwon SS, Kong TY, Cheong JC, Kim HS, In MK, Lee HS. AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5'-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes. Molecules 2017; 22:molecules22030443. [PMID: 28287454 PMCID: PMC6155437 DOI: 10.3390/molecules22030443] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 03/08/2017] [Indexed: 01/07/2023] Open
Abstract
AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry to investigate drug interaction potentials of AM-2201. AM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP3A4-catalyzed midazolam 1′-hydroxylation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, and UGT2B7-catalyzed naloxone 3-glucuronidation with IC50 values of 3.9, 4.0, 4.3, and 10.0 µM, respectively, and showed mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-deethylation with a Ki value of 2.1 µM. It negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, and UGT1A9 activities at 50 μM in human liver microsomes. These in vitro results indicate that AM-2201 needs to be examined for potential pharmacokinetic drug interactions in vivo due to its potent inhibition of CYP2C8, CYP2C9, CYP3A4, UGT1A3, and UGT2B7 enzyme activities.
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Affiliation(s)
- Ju-Hyun Kim
- Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea.
| | - Soon-Sang Kwon
- Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea.
| | - Tae Yeon Kong
- Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea.
| | - Jae Chul Cheong
- Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, Korea.
| | - Hee Seung Kim
- Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, Korea.
| | - Moon Kyo In
- Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, Korea.
| | - Hye Suk Lee
- Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea.
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40
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Nachon-Phanithavong M, Wille S, Richeval C, Di Fazio V, Samyn N, Humbert L, Gaulier JM, Allorge D. New psychoactive substances in a drugged driving population: Preliminary results. TOXICOLOGIE ANALYTIQUE ET CLINIQUE 2017. [DOI: 10.1016/j.toxac.2016.12.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Weinstein AM, Rosca P, Fattore L, London ED. Synthetic Cathinone and Cannabinoid Designer Drugs Pose a Major Risk for Public Health. Front Psychiatry 2017; 8:156. [PMID: 28878698 PMCID: PMC5572353 DOI: 10.3389/fpsyt.2017.00156] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 08/08/2017] [Indexed: 12/16/2022] Open
Abstract
As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here, we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects, and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system and can induce acute psychosis, hypomania, paranoid ideation, and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania, and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment.
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Affiliation(s)
- Aviv M Weinstein
- Department of Behavioral Science, Ariel University, Ariel, Israel
| | - Paola Rosca
- Department for the Treatment of Substance Abuse, Ministry of Health, Jerusalem, Israel
| | - Liana Fattore
- Institute of Neuroscience-Cagliari, National Research Council of Italy, Cagliari, Italy
| | - Edythe D London
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, United States.,Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, United States.,Brain Research Institute, University of California Los Angeles, Los Angeles, CA, United States
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Abstract
Novel psychoactive drugs (NPDs), an emerging class of dangerous substances, generally mimic the actions of commonly abused substances such as marijuana, stimulants, hallucinogens, and opiates, but are formulated, marketed, and used either to sidestep legal restrictions or to avoid positive drug screens. Synthetic cannabinoids such as Spice and K2 along with synthetic stimulants often referred to as “bath salts” have recently entered U.S. markets. The current study explores the relationship between being arrested and using NPDs per self-report survey data obtained from 2,349 students at a large university in the Southeastern United States. Respondents indicated whether they had used synthetic psychoactive drugs, reported demographic characteristics, and whether they had been arrested for a number of offenses. Results from logistic regression and propensity score matching models indicate that those who have been arrested are also more likely to use NPDs.
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43
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Kong TY, Kim JH, Choi WG, Lee JY, Kim HS, Kim JY, In MK, Lee HS. Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes. Anal Bioanal Chem 2016; 409:1667-1680. [PMID: 27924364 DOI: 10.1007/s00216-016-0113-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Revised: 11/14/2016] [Accepted: 11/23/2016] [Indexed: 12/16/2022]
Abstract
MAM-2201 is a synthetic cannabinoid that is increasingly found in recreational drug abusers and cases of severe intoxication. Thus, characterization of the metabolic pathways of MAM-2201 is necessary to predict individual pharmacokinetics and toxicity differences, and to avoid toxic drug-drug interactions. Collectively, 19 phase 1 metabolites of MAM-2201 were identified using liquid chromatography-Orbitrap mass spectrometry following human liver microsomal incubations in the presence of NADPH: 7 hydroxy-MAM-2201 (M1-M7), 4 dihydroxy-MAM-2201 (M8-M11), dihydrodiol-MAM-2201 (M12), N-(5-hydroxypentyl)-MAM-2201 (M13), hydroxy-M13 (M14), N-dealkyl-MAM-2201 (M15), 2 hydroxy-M15 (M16, M17), MAM-2201 N-pentanoic acid (M18), and hydroxy-M18 (M19). On the basis of intrinsic clearance values in human liver microsomes, hydroxy-MAM-2201 (M1), N-(5-hydroxypentyl)-MAM-2201 (M13), and hydroxy-M13 (M14) were the major metabolites. Based on an enzyme kinetics study using human cDNA-expressed cytochrome P450 (CYP) enzymes and an immunoinhibition study using selective CYP antibodies in human liver microsomes, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were responsible for MAM-2201 metabolism. The CYP3A4 enzyme played a prominent role in MAM-2201 metabolism, and CYP1A2, CYP2B6, CYP2C8, and CYP2C9 enzymes played major roles in the formation of some metabolites. MAM-2201 is extensively metabolized by multiple CYP enzymes, indicating that MAM-2201 and its metabolites should be used as markers of MAM-2201 abuse and toxicity. Graphical abstract In vitro metabolic pathways of MAM-2201 were characterized in human liver microsomes and recombinant CYPs using LC-HRMS analysis. Total 19 phase I metabolites were identified with predominant contribution of CYP3A4.
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Affiliation(s)
- Tae Yeon Kong
- College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Ju-Hyun Kim
- College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Won Gu Choi
- College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Joo Young Lee
- College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Hee Seung Kim
- Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Jin Young Kim
- Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Moon Kyo In
- Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Hye Suk Lee
- College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
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Borg D, Tverdovsky A, Stripp R. A Fast and Comprehensive Analysis of 32 Synthetic Cannabinoids Using Agilent Triple Quadrupole LC–MS-MS. J Anal Toxicol 2016; 41:6-16. [DOI: 10.1093/jat/bkw104] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 06/24/2016] [Accepted: 07/03/2016] [Indexed: 11/14/2022] Open
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Affiliation(s)
- Juliana Tournebize
- CEIP-Addictovigilance, Nancy University Medical Center, Nancy, France
- French Addictovigilance Network (FAN), Nancy, France
| | - Valérie Gibaja
- CEIP-Addictovigilance, Nancy University Medical Center, Nancy, France
- French Addictovigilance Network (FAN), Nancy, France
| | - Jean-Pierre Kahn
- CEIP-Addictovigilance, Nancy University Medical Center, Nancy, France
- French Addictovigilance Network (FAN), Nancy, France
- Department of Psychiatry and Clinical Psychology, Centre Psychothérapique de Nancy, Nancy, France
- Université de Lorraine, Nancy, France
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46
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Simultaneous detection of 93 synthetic cannabinoids by liquid chromatography-tandem mass spectrometry and retrospective application to real forensic samples. Drug Test Anal 2016; 9:721-733. [DOI: 10.1002/dta.2030] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 06/13/2016] [Accepted: 06/13/2016] [Indexed: 11/07/2022]
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Carlier J, Scheidweiler KB, Wohlfarth A, Salmeron BD, Baumann MH, Huestis MA. Quantification of [1-(5-fluoropentyl)-1H-indol-3-yl](naphthalene-1-yl)methanone (AM-2201) and 13 metabolites in human and rat plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr A 2016; 1451:97-106. [PMID: 27208987 PMCID: PMC4886661 DOI: 10.1016/j.chroma.2016.05.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 05/02/2016] [Accepted: 05/04/2016] [Indexed: 11/24/2022]
Abstract
AM-2201 is a popular synthetic cannabinoid first synthesized in 2000. AM-2201 pharmacokinetic and pharmacodynamic data are scarce, requiring further investigation. We developed a sensitive method for quantifying AM-2201 and 13 metabolites in plasma to provide a tool to further metabolic, pharmacokinetic and pharmacodynamic studies. Analysis was performed by liquid chromatography-tandem mass spectrometry. Chromatographic separation was performed by gradient elution on a biphenyl column with 0.1% formic acid in water/0.1% formic acid in acetonitrile:methanol 50:50 (v/v) mobile phase. Sample preparation (75μL) consisted of an enzymatic hydrolysis and a supported liquid extraction. The method was validated with human plasma with a 0.025 or 0.050-50μg/L working range, and cross-validated for rat plasma. Analytical recovery was 88.8-110.1% of target concentration, and intra- (n=30) and inter-day (n=30) imprecision<11.9% coefficient of variation. Method recoveries and matrix effects ranged from 58.4-84.4% and -62.1 to -15.6%, respectively. AM-2201 and metabolites were stable (±20%) at room temperature for 24h, at 4°C for 72h, and after three freeze-thaw cycles, and for 72h in the autosampler after extraction. The method was developed for pharmacodynamic and pharmacokinetic studies with controlled administration in rats but is applicable for pre-clinical and clinical research and forensic investigations. Rat plasma specimen analysis following subcutaneous AM-2201 administration demonstrated the suitability of the method. AM-2201, JWH-018 N-(5-hydroxypentyl), and JWH-018 N-pentanoic acid concentrations were 4.8±1.0, 0.15±0.03, and 0.34±0.07μg/L, respectively, 8h after AM-2201 administration at 0.3mg/kg (n=5).
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Affiliation(s)
- Jeremy Carlier
- Clinical Pharmacology & Therapeutics Research Branch, Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), 251 Bayview Boulevard Suite 200, Baltimore, MD 21224, USA
| | - Karl B Scheidweiler
- Clinical Pharmacology & Therapeutics Research Branch, Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), 251 Bayview Boulevard Suite 200, Baltimore, MD 21224, USA.
| | - Ariane Wohlfarth
- Clinical Pharmacology & Therapeutics Research Branch, Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), 251 Bayview Boulevard Suite 200, Baltimore, MD 21224, USA
| | - Bonita D Salmeron
- Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), 333 Cassell Drive Suite 4400, Baltimore, MD 21224, USA
| | - Michael H Baumann
- Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), 333 Cassell Drive Suite 4400, Baltimore, MD 21224, USA
| | - Marilyn A Huestis
- Clinical Pharmacology & Therapeutics Research Branch, Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), 251 Bayview Boulevard Suite 200, Baltimore, MD 21224, USA
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Chase PB, Hawkins J, Mosier J, Jimenez E, Boesen K, Logan BK, Walter FG. Differential physiological and behavioral cues observed in individuals smoking botanical marijuana versus synthetic cannabinoid drugs. Clin Toxicol (Phila) 2016; 54:14-9. [PMID: 26653952 DOI: 10.3109/15563650.2015.1101769] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
CONTEXT Synthetic cannabinoid use has increased in many states, and medicinal and/or recreational marijuana use has been legalized in some states. These changes present challenges to law enforcement drug recognition experts (DREs) who determine whether drivers are impaired by synthetic cannabinoids or marijuana, as well as to clinical toxicologists who care for patients with complications from synthetic cannabinoids and marijuana. Our goal was to compare what effects synthetic cannabinoids and marijuana had on performance and behavior, including driving impairment, by reviewing records generated by law enforcement DREs who evaluated motorists arrested for impaired driving. METHODS Data were from a retrospective, convenience sample of de-identified arrest reports from impaired drivers suspected of using synthetic cannabinoids (n = 100) or marijuana (n = 33). Inclusion criteria were arrested drivers who admitted to using either synthetic cannabinoids or marijuana, or who possessed either synthetic cannabinoids or marijuana; who also had a DRE evaluation at the scene; and whose blood screens were negative for alcohol and other drugs. Exclusion criteria were impaired drivers arrested with other intoxicants found in their drug or alcohol blood screens. Blood samples were analyzed for 20 popular synthetic cannabinoids by using liquid chromatography-tandem mass spectrometry. Delta-9-tetrahydrocannabinol (THC) and THC-COOH were quantified by gas chromatography-mass spectrometry. Statistical significance was determined by using Fisher's exact test or Student's t-test, where appropriate, to compare the frequency of characteristics of those in the synthetic cannabinoid group versus those in the marijuana group. RESULTS 16 synthetic cannabinoid and 25 marijuana records met selection criteria; the drivers of these records were arrested for moving violations. Median age for the synthetic cannabinoid group (n = 16, 15 males) was 20 years (IQR 19-23 years). Median age for the marijuana group (n = 25, 21 males) was 20 years (IQR 19-24 years) (p = 0.46). In the synthetic cannabinoid group, 94% (15/16) admitted to using synthetic cannabinoids. In the marijuana group, 96% (24/25) admitted to using marijuana. Blood was available for testing in 96% (24/25) of the marijuana group; 21 of these 24 had quantitative levels of THC (mean + SD = 10.7 + 5 ng/mL) and THC-COOH (mean + SD = 57.8 + 3 ng/mL). Blood was available for testing in 63% (10/16) of the synthetic cannabinoid group, with 80% (8/10) of these positive for synthetic cannabinoids. Those in the synthetic cannabinoid group were more frequently confused (7/16 [44%] vs. 0/25 [0%], p ≤ 0.003) and disoriented (5/16 [31%] vs. 0/25 [0%], p ≤ 0.003), and more frequently had incoherent, slurred speech (10/16 [63%] vs. 3/25 [12%], p = 0.0014) and horizontal gaze nystagmus (8/16 [50%] vs. 3/25 [12%], p = 0.01) than those in the marijuana group. CONCLUSION Drivers under the influence of synthetic cannabinoids were more frequently impaired with confusion, disorientation, and incoherent, slurred speech than drivers under the influence of marijuana in this population evaluated by DREs.
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Affiliation(s)
- Peter B Chase
- a Arizona Poison and Drug Information Center, The University of Arizona College of Pharmacy , Tucson , AZ , USA
| | | | - Jarrod Mosier
- c Department of Emergency Medicine , The University of Arizona College of Medicine , Tucson , AZ , USA
| | | | - Keith Boesen
- a Arizona Poison and Drug Information Center, The University of Arizona College of Pharmacy , Tucson , AZ , USA
| | | | - Frank G Walter
- a Arizona Poison and Drug Information Center, The University of Arizona College of Pharmacy , Tucson , AZ , USA ;,c Department of Emergency Medicine , The University of Arizona College of Medicine , Tucson , AZ , USA
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New psychoactive substance α-PVP in a traffic accident case. Forensic Toxicol 2016; 34:403-410. [PMID: 27429656 PMCID: PMC4929156 DOI: 10.1007/s11419-016-0309-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 02/18/2016] [Indexed: 01/06/2023]
Abstract
The problems of new psychoactive substances (NPSs), especially related to drivers, constitute an open research area. In this case report, we present a traffic accident case, in which two passengers of five individuals died instantly, while the other three persons survived the accident with minor injuries only. From the blood samples of the driver and the passengers, α-pyrrolidinovalerophenone (α-PVP), an NPS belonging to the category of cathinone derivatives, was disclosed. Therefore, we established a detailed procedure for analysis of α-PVP in blood samples by liquid chromatography–tandem mass spectrometry. After careful validation tests of this method, α-PVP concentration in blood samples from the surviving driver and passengers, and from the two deceased, were measured. The concentrations varied from 20 to 650 ng/mL. Access to detailed information originating from the court files and from explanations provided by the driver and eye witnesses revealed extremely valuable illustrative details addressing the symptoms and pharmacological effects of α-PVP on the human organism, thus contributing to enriching the body of knowledge of α-PVP abuse.
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Lorenzetti V, Solowij N, Yücel M. The Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users. Biol Psychiatry 2016; 79:e17-31. [PMID: 26858212 DOI: 10.1016/j.biopsych.2015.11.013] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 10/28/2015] [Accepted: 11/01/2015] [Indexed: 01/18/2023]
Abstract
The past few decades have seen a marked change in the composition of commonly smoked cannabis. These changes primarily involve an increase of the psychoactive compound ∆(9)-tetrahydrocannabinol (THC) and a decrease of the potentially therapeutic compound cannabidiol (CBD). This altered composition of cannabis may be linked to persistent neuroanatomic alterations typically seen in regular cannabis users. In this review, we summarize recent findings from human structural neuroimaging investigations. We examine whether neuroanatomic alterations are 1) consistently observed in samples of regular cannabis users, particularly in cannabinoid receptor-high areas, which are vulnerable to the effects of high circulating levels of THC, and 2) associated either with greater levels of cannabis use (e.g., higher dosage, longer duration, and earlier age of onset) or with distinct cannabinoid compounds (i.e., THC and CBD). Across the 31 studies selected for inclusion in this review, neuroanatomic alterations emerged across regions that are high in cannabinoid receptors (i.e., hippocampus, prefrontal cortex, amygdala, cerebellum). Greater dose and earlier age of onset were associated with these alterations. Preliminary evidence shows that THC exacerbates, whereas CBD protects from, such harmful effects. Methodologic differences in the quantification of levels of cannabis use prevent accurate assessment of cannabis exposure and direct comparison of findings across studies. Consequently, the field lacks large "consortium-style" data sets that can be used to develop reliable neurobiological models of cannabis-related harm, recovery, and protection. To move the field forward, we encourage a coordinated approach and suggest the urgent development of consensus-based guidelines to accurately and comprehensively quantify cannabis use and exposure in human studies.
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Affiliation(s)
- Valentina Lorenzetti
- Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Melbourne; Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Melbourne
| | - Nadia Solowij
- School of Psychology, Centre for Health Initiatives and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia
| | - Murat Yücel
- Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Melbourne; Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Melbourne.
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