Dependence Potential of the Synthetic Cannabinoids JWH-073, JWH-081, and JWH-210: In Vivo and In Vitro Approaches

Cannabis has been used in pain management since 2900 BC. In the 20th century, synthetic cannabinoids began to emerge, thus opening the way for improved efficacy. The search for new forms of synthetic cannabinoids continues and, as such, the aim of this review is to provide a comprehensive tool for the research and development of this promising class of drugs. Methods for the in vitro assessment of cytotoxic, mutagenic or developmental effects are presented, followed by the main in vivo pain models used in cannabis research and the results yielded by different types of administration (systemic versus intrathecal versus inhalation). Animal models designed for assessing side-effects and long-term uses are also discussed. In the second part of this review, pharmacokinetic and pharmacodynamic studies of synthetic cannabinoid biodistribution, together with liquid chromatography–mass spectrometric identification of synthetic cannabinoids in biological fluids from rodents to humans are presented. Last, but not least, different strategies for improving the solubility and physicochemical stability of synthetic cannabinoids and their potential impact on pain management are discussed. In conclusion, synthetic cannabinoids are one of the most promising classes of drugs in pain medicine, and preclinical research should focus on identifying new and improved alternatives for a better clinical and preclinical outcome.

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Comparison of in vitro and in vivo models for the elucidation of metabolic patterns of 7‐azaindole‐derived synthetic cannabinoids exemplified using cumyl‐5F‐P7AICA

Drug Testing and Analysis ◽

10.1002/dta.2899 ◽

2020 ◽

Author(s):

Nadja Walle ◽

Frederike Nordmeier ◽

Adrian A. Doerr ◽

Benjamin Peters ◽

Matthias W. Laschke ◽

...

Keyword(s):

Synthetic Cannabinoids ◽

In Vivo Models

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Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model

Molecules ◽

10.3390/molecules25194474 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4474

Author(s):

Yu Mi Park ◽

Markus R. Meyer ◽

Rolf Müller ◽

Jennifer Herrmann

Keyword(s):

Drug Metabolism ◽

Human Urine ◽

Parent Compound ◽

Synthetic Cannabinoids ◽

Drug Distribution ◽

Early Developmental Stage ◽

Administration Routes ◽

Zebrafish Larvae

Zebrafish (Danio rerio) larvae have gained attention as a valid model to study in vivo drug metabolism and to predict human metabolism. The microinjection of compounds, oligonucleotides, or pathogens into zebrafish embryos at an early developmental stage is a well-established technique. Here, we investigated the metabolism of zebrafish larvae after microinjection of methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′N-5F-ADB) as a representative of recently introduced synthetic cannabinoids. Results were compared to human urine data and data from the in vitro HepaRG model and the metabolic pathway of 7′N-5F-ADB were reconstructed. Out of 27 metabolites detected in human urine samples, 19 and 15 metabolites were present in zebrafish larvae and HepaRG cells, respectively. The route of administration to zebrafish larvae had a major impact and we found a high number of metabolites when 7′N-5F-ADB was microinjected into the caudal vein, heart ventricle, or hindbrain. We further studied the spatial distribution of the parent compound and its metabolites by mass spectrometry imaging (MSI) of treated zebrafish larvae to demonstrate the discrepancy in metabolite profiles among larvae exposed through different administration routes. In conclusion, zebrafish larvae represent a superb model for studying drug metabolism, and when combined with MSI, the optimal administration route can be determined based on in vivo drug distribution.

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Recent trends in drugs of abuse metabolism studies for mass spectrometry–based analytical screening procedures

Analytical and Bioanalytical Chemistry ◽

10.1007/s00216-021-03311-w ◽

2021 ◽

Author(s):

Lea Wagmann ◽

Tanja M. Gampfer ◽

Markus R. Meyer

Keyword(s):

Drugs Of Abuse ◽

Synthetic Cannabinoids ◽

New Psychoactive Substances ◽

In Vivo Models ◽

Mass Spectral ◽

Recent Developments ◽

Recent Trends ◽

Spectral Libraries

AbstractThe still increasing number of drugs of abuse, particularly the so-called new psychoactive substances (NPS), poses an analytical challenge for clinical and forensic toxicologists but also for doping control. NPS usually belong to various classes such as synthetic cannabinoids, phenethylamines, opioids, or benzodiazepines. Like other xenobiotics, NPS undergo absorption, distribution, metabolism, and excretion processes after consumption, but only very limited data concerning their toxicokinetics and safety properties is available once they appear on the market. The inclusion of metabolites in mass spectral libraries is often crucial for the detection of NPS especially in urine screening approaches. Authentic human samples may represent the gold standard for identification of metabolites but are often not available and clinical studies cannot be performed due to ethical concerns. However, numerous alternative in vitro and in vivo models are available. This trends article will give an overview on selected models, discuss current studies, and highlight recent developments.

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Cannabinoids and Neurogenesis: The Promised Solution for Neurodegeneration?

Molecules ◽

10.3390/molecules26206313 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6313

Author(s):

Andrea Valeri ◽

Emanuela Mazzon

Keyword(s):

Nervous System ◽

Experimental Evidence ◽

Neuronal Death ◽

Synthetic Cannabinoids ◽

Neuronal Population ◽

Adult Brain ◽

Analgesic Action ◽

Beneficial Effects

The concept of neurons as irreplaceable cells does not hold true today. Experiments and evidence of neurogenesis, also, in the adult brain give hope that some compounds or drugs can enhance this process, helping to reverse the outcomes of diseases or traumas that once were thought to be everlasting. Cannabinoids, both from natural and artificial origins, already proved to have several beneficial effects (e.g., anti-inflammatory, anti-oxidants and analgesic action), but also capacity to increase neuronal population, by replacing the cells that were lost and/or regenerate a damaged nerve cell. Neurogenesis is a process which is not highly represented in literature as neuroprotection, though it is as important as prevention of nervous system damage, because it can represent a possible solution when neuronal death is already present, such as in neurodegenerative diseases. The aim of this review is to resume the experimental evidence of phyto- and synthetic cannabinoids effects on neurogenesis, both in vitro and in vivo, in order to elucidate if they possess also neurogenetic and neurorepairing properties.

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Erratum to: In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

Forensic Toxicology ◽

10.1007/s11419-017-0380-y ◽

2017 ◽

Vol 36 (1) ◽

pp. 229-229

Author(s):

Richard C. Kevin ◽

Timothy W. Lefever ◽

Rodney W. Snyder ◽

Purvi R. Patel ◽

Timothy R. Fennell ◽

...

Keyword(s):

Synthetic Cannabinoids ◽

In Vivo Pharmacokinetics

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Synthetic Cannabinoids JWH-122 and THJ-2201 Disrupt Endocannabinoid-Regulated Mitochondrial Function and Activate Apoptotic Pathways as a Primary Mechanism of In Vitro Nephrotoxicity at In Vivo Relevant Concentrations

Toxicological Sciences ◽

10.1093/toxsci/kfz050 ◽

2019 ◽

Vol 169 (2) ◽

pp. 422-435 ◽

Cited By ~ 6

Author(s):

João P Silva ◽

Ana Margarida Araújo ◽

Paula Guedes de Pinho ◽

Helena Carmo ◽

Félix Carvalho

Keyword(s):

Mitochondrial Function ◽

Synthetic Cannabinoids ◽

Primary Mechanism ◽

Apoptotic Pathways

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Cannabinoids in the landscape of cancer

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03710-7 ◽

2021 ◽

Author(s):

Nagina Mangal ◽

Simon Erridge ◽

Nagy Habib ◽

Anguraj Sadanandam ◽

Vikash Reebye ◽

...

Keyword(s):

Animal Studies ◽

Cannabinoid Receptors ◽

Cannabis Sativa ◽

Relevant Literature ◽

Single Agent ◽

Synthetic Cannabinoids ◽

Cancer Type ◽

Anticancer Properties

Abstract Introduction Cannabinoids are a group of terpenophenolic compounds derived from the Cannabis sativa L. plant. There is a growing body of evidence from cell culture and animal studies in support of cannabinoids possessing anticancer properties. Method A database search of peer reviewed articles published in English as full texts between January 1970 and April 2021 in Google Scholar, MEDLINE, PubMed and Web of Science was undertaken. References of relevant literature were searched to identify additional studies to construct a narrative literature review of oncological effects of cannabinoids in pre-clinical and clinical studies in various cancer types. Results Phyto-, endogenous and synthetic cannabinoids demonstrated antitumour effects both in vitro and in vivo. However, these effects are dependent on cancer type, the concentration and preparation of the cannabinoid and the abundance of receptor targets. The mechanism of action of synthetic cannabinoids, (−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) has mainly been described via the traditional cannabinoid receptors; CB1 and CB2, but reports have also indicated evidence of activity through GPR55, TRPM8 and other ion channels including TRPA1, TRPV1 and TRPV2. Conclusion Cannabinoids have shown to be efficacious both as a single agent and in combination with antineoplastic drugs. These effects have occurred through various receptors and ligands and modulation of signalling pathways involved in hallmarks of cancer pathology. There is a need for further studies to characterise its mode of action at the molecular level and to delineate efficacious dosage and route of administration in addition to synergistic regimes.

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