Fourth-Generation Synthetic Cannabinoids Are More Potent and Toxic Than Ever
At least 20 new "fourth-generation" synthetic cannabinoids emerged between 2017 and 2021, with higher potency and likely greater toxicity than previous generations.
Quick Facts
What This Study Found
Fourth-generation synthetic cannabinoid receptor agonists have increased CB1 receptor affinity and efficacy compared to previous generations, leading to more potent psychoactive effects and increased adverse reactions including psychosis, hallucinations, self-harm, tachycardia, and deaths.
Key Numbers
At least 20 new fourth-generation SCRAs reported from November 2017 to February 2021; over 100 total SCRAs emerged in the last decade
How They Did This
Review of international literature on the newest generation of synthetic cannabinoids, covering chemical structures, pharmacological properties, and toxicological profiles reported to international drug agencies.
Why This Research Matters
Synthetic cannabinoids remain among the most abused new psychoactive substances globally. Each new generation has been more potent and dangerous, and the fourth generation represents the most concerning iteration yet.
The Bigger Picture
The arms race between drug designers and regulators continues to produce increasingly dangerous compounds. As each chemical class gets banned, newer, more potent alternatives appear on the illicit market.
What This Study Doesn't Tell Us
Limited global data on fourth-generation SCRA toxicity. Understanding of neurotoxicity is incomplete due to the rapid pace of new compound emergence.
Questions This Raises
- ?Can regulation keep pace with the rate of new SCRA development?
- ?What emergency treatments are most effective for fourth-generation SCRA poisoning?
Trust & Context
- Key Stat:
- 20+ new compounds in just over 3 years
- Evidence Grade:
- Review of pharmacological and toxicological data reported to international agencies, but limited by the rapid emergence of new compounds outpacing research.
- Study Age:
- Published in 2022
- Original Title:
- Fourth Generation of Synthetic Cannabinoid Receptor Agonists: A Review on the Latest Insights.
- Published In:
- Current pharmaceutical design, 28(32), 2603-2617 (2022)
- Authors:
- Malaca, Sara, Busardò, Francesco P(2), Nittari, Giulio, Sirignano, Ascanio, Ricci, Giovanna
- Database ID:
- RTHC-04031
Evidence Hierarchy
Summarizes existing research on a topic.
What do these levels mean? →Frequently Asked Questions
What are fourth-generation synthetic cannabinoids?
They are the newest wave of lab-made chemicals designed to activate cannabinoid receptors more potently than THC. At least 20 new compounds emerged between 2017 and 2021, with higher CB1 receptor binding and more severe side effects than previous generations.
Why are synthetic cannabinoids so dangerous?
Each new generation has increased potency at CB1 receptors, leading to more intense psychoactive effects and more severe adverse reactions including psychosis, hallucinations, cardiac events, and deaths.
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Cite This Study
https://rethinkthc.com/research/RTHC-04031APA
Malaca, Sara; Busardò, Francesco P; Nittari, Giulio; Sirignano, Ascanio; Ricci, Giovanna. (2022). Fourth Generation of Synthetic Cannabinoid Receptor Agonists: A Review on the Latest Insights.. Current pharmaceutical design, 28(32), 2603-2617. https://doi.org/10.2174/1381612827666211115170521
MLA
Malaca, Sara, et al. "Fourth Generation of Synthetic Cannabinoid Receptor Agonists: A Review on the Latest Insights.." Current pharmaceutical design, 2022. https://doi.org/10.2174/1381612827666211115170521
RethinkTHC
RethinkTHC Research Database. "Fourth Generation of Synthetic Cannabinoid Receptor Agonists..." RTHC-04031. Retrieved from https://rethinkthc.com/research/malaca-2022-fourth-generation-of-synthetic
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.