A new class of synthetic cannabinoids proved exceptionally potent and was linked to deaths | Research

The takeaway

Next-generation synthetic cannabinoids with alkene tail modifications, particularly MDMB-4en-PINACA, showed exceptionally high potency at CB1 receptors and were found in 25 forensic cases including deaths and impaired driving.

Forensic toxicologists, emergency medicine physicians, public health officials, and law enforcement.

MDMB-4en-PINACA: 10x more potent than JWH-018, found in 25 forensic cases

What the researchers found

MDMB-4en-PINACA had a potency of 2.47 nM (compared to JWH-018 at 25.3 nM, making it about 10 times more potent) with 239% efficacy. It was identified in 25 forensic toxicology cases including postmortem and impaired driving investigations. The new class of pent-4en and but-3en analogues retained or exceeded the potency and toxicity of previous generations while evading existing drug scheduling.

Why it matters

Synthetic cannabinoids continue to evolve to evade regulation while maintaining or increasing potency. This new class represents a significant public safety threat because they are being sold without any dosing guidance and are far more potent than natural cannabis.

The numbers in context

MDMB-4en-PINACA: 2.47 nM potency, 239% efficacy. MDMB-4en-PICA: 11.5 nM, 302%. MDMB-3en-BINACA: 14.3 nM, 286%. Reference JWH-018: 25.3 nM, 100%. 25 forensic cases including postmortem investigations. Geographic distribution across Northeast, Midwest, South, and West US.

How the study worked

Combined in vitro CB1 receptor activation assay (beta-arrestin 2 recruitment) for 5 compounds with forensic toxicology case data. Analyzed 25 cases involving MDMB-4en-PINACA across multiple US regions through sample-mining and data-mining.

What this study cannot tell us

In vitro potency does not directly predict human toxicity. Limited case histories available. Cannot determine exact cause of death in postmortem cases. Detection methods may miss some analogues.

How to read the evidence

Strong in vitro pharmacological data combined with real-world forensic cases. Moderate because case histories are limited.

When this study was published

2021 forensic toxicology study.

The bigger picture

The cat-and-mouse game between synthetic cannabinoid manufacturers and regulators continues to produce increasingly dangerous products. These alkene-modified compounds demonstrate that simple chemical modifications can produce substances that evade scheduling while maintaining lethal potency.

Questions still open

How quickly are new alkene analogues entering the market? Can generic scheduling approaches address the entire chemical class? What is the lethal dose range for MDMB-4en-PINACA in humans?

Common questions

How dangerous are these new synthetic cannabinoids?

MDMB-4en-PINACA is about 10 times more potent than JWH-018 at CB1 receptors and was found in forensic cases involving death and impaired driving, indicating real-world lethality.

How are these compounds different from previous synthetic cannabinoids?

They contain alkene modifications to the tail region of the molecule, which maintain or increase potency while creating new chemical entities that may evade existing drug scheduling laws.

Read the original research

The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent-4en and but-3en analogues including MDMB-4en-PINACA.

Drug testing and analysis, 13(2), 427-438

View on PubMed ↗Publisher’s paper ↗

Citation

Krotulski, Alex J; Cannaert, Annelies; Stove, Christophe; Logan, Barry K. (2021). The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent-4en and but-3en analogues including MDMB-4en-PINACA.. Drug testing and analysis, 13(2), 427-438. https://doi.org/10.1002/dta.2935