Fourth-Generation Synthetic Cannabinoids Are More Potent and Toxic Than Ever | Research

The takeaway

At least 20 new "fourth-generation" synthetic cannabinoids emerged between 2017 and 2021, with higher potency and likely greater toxicity than previous generations.

Emergency medicine providers, toxicologists, drug policy researchers, harm reduction workers

20+ new compounds in just over 3 years

What the researchers 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.

Why it 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 numbers in context

At least 20 new fourth-generation SCRAs reported from November 2017 to February 2021; over 100 total SCRAs emerged in the last decade

How the study worked

Review of international literature on the newest generation of synthetic cannabinoids, covering chemical structures, pharmacological properties, and toxicological profiles reported to international drug agencies.

What this study cannot tell us

Limited global data on fourth-generation SCRA toxicity. Understanding of neurotoxicity is incomplete due to the rapid pace of new compound emergence.

How to read the evidence

Review of pharmacological and toxicological data reported to international agencies, but limited by the rapid emergence of new compounds outpacing research.

When this study was published

Published in 2022

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.

Questions still open

Can regulation keep pace with the rate of new SCRA development? What emergency treatments are most effective for fourth-generation SCRA poisoning?

Common 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.

Read the original research

Fourth Generation of Synthetic Cannabinoid Receptor Agonists: A Review on the Latest Insights.

Current pharmaceutical design, 28(32), 2603-2617

View on PubMed ↗Publisher’s paper ↗

Citation

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