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

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.

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.

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.

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.