Title:Fourth Generation of Synthetic Cannabinoid Receptor Agonists: A Review on
the Latest Insights
Volume: 28
Issue: 32
Author(s): Sara Malaca, Francesco P. Busardò*, Giulio Nittari, Ascanio Sirignano and Giovanna Ricci
Affiliation:
- Department of Excellence of Biomedical Sciences and Public Health, University “Politecnica delle Marche” of Ancona, Ancona,
Italy
Keywords:
Synthetic cannabinoids, new psychoactive substances, receptor agonists, toxicology, THC, fourth generation.
Abstract:
Background: Over the past few years, an emerging number of new psychoactive substances (NPSs)
entered the illicit market. NPSs are designed to resemble the effects of classical drugs of abuse, reinforcing
their effects and duration. Among the most abused NPS, synthetic cannabinoids are cannabinoid receptor agonists
(SCRAs) that mimic the effect of the main psychotropic phytocannabinoid Δ9-tetrahydrocannabinol (THC).
Methods: We herein reviewed the international literature to provide available information on the newest
SCRAs generation.
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 (e.g., psychosis, agitation, irritability,
paranoia, confusion, and anxiety), psychiatric episodes (e.g., hallucinations, delusions, self-harm), other physical
conditions (e.g., tachycardia, hypertension, arrhythmia, chest pain, nausea, vomiting, and fever) 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: they were physico-chemically characterized, and pharmaco-toxicological
characteristics were investigated. The last SCRAs generations include increasingly potent and toxic compounds,
posing a potential health threat to consumers.
Conclusion: From November 2017 to February 2021, at least 20 new “fourth-generation” SCRAs were formally
reported to international drug agencies. Our understanding of 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.
