Fourth generation of synthetic cannabinoid receptor agonists: a summary on the latest insights

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Sara Malaca
Anastasio Tini
Federica Umani Ronchi


synthetic cannabinoids, new psychoactive substances, receptor agonists, toxicology


Background and aim: From few years, an emerging number of new psychoactive substances (NPS) entered the illicit market. NPS are designed to be similar to the effects of classical drugs of abuse, with increased effects and duration. Synthetic cannabinoids are cannabinoid receptor agonists (SCRAs), some of the most abused NPS.
Methods: We have herein briefly highlighted current relevant available information on the newest SCRAs generation, with relevant structural remarks as to the distinctive traits of such substances.
Results: Compared to the previous SCRAs generations, the structures of the last generation result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be mainly responsible for the psychoactive effects of THC and its analogues. Accordingly, these more potent cannabimimetic effects may increase the number of adverse reactions such as neurological disorders, psychiatric episodes and deaths. In the last decade, more than a hundred SCRAs from different chemical classes emerged on the illicit web market. SCRAs have been thoroughly studied and the last generations include increasingly potent and toxic compounds, posing a potentially daunting health threat to consumers.
Conclusions: From November 2017 to February 2021, at least 20 new “fourth-generation” SCRAs were formally reported to international drug agencies. Our understanding about the neurotoxicity of these compounds is still limited, due to the lack of global data, but their potency and their toxicity are likely higher than those of the previous generations.


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1.Malaca S, Carlier J, Busardò FP. Advances in Forensic Toxicology. Curr Pharm Des 2020; 26: 3779-3780.
2.Giorgetti A, Busardò FP, Tittarelli R, Auwärter V, Giorgetti R. Post-Mortem Toxicology: A Systematic Review of Death Cases Involving Synthetic Cannabinoid Receptor Agonists. Front Psychiatry 2020; 11: 464.
3.Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R. “Zombie” Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York. N Engl J Med 2017; 376: 235-42.
4.Rosado T, Gonçalves J, Luís Â, Malaca S, Soares S, Vieira DN, et al. Synthetic cannabinoids in biological specimens: A review of current analytical methods and sample preparation techniques. Bioanalysis 2018; 10: 1609-23.
5.Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, Huestis MA. Synthetic cannabinoids: Epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend 2014; 144: 12-41.
6.Debruyne D, Le Boisselier R. Emerging drugs of abuse: current perspectives on synthetic cannabinoids. Subst Abuse Rehabil 2015; 6: 113-29.
7.Busardo 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.
Zaami S, Busardò FP, Pichini S, Pacifici R, Marinelli E. The value of toxicological and forensic analyses in the global challenge to health risks caused by new psychoactive substances. Eur Rev Med Pharmacol Sci 2019; 23: 6008-10.

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