28 Synthetic Cannabinoids Tested Show Full Agonism and Unpredictable Activity | Research

The takeaway

Lab testing of 28 synthetic cannabinoids revealed they are mostly potent full agonists at cannabinoid receptors, unlike THC, with no clear structure-activity patterns explaining their behavior.

Toxicologists, drug safety researchers, harm reduction workers

28 synthetic cannabinoids showed full agonism with no predictable structure-activity patterns

What the researchers found

Twenty-eight synthetic cannabinoid receptor agonists were evaluated for receptor binding and signaling. Most displayed full agonism with low nanomolar potency at both CB1 and CB2 receptors, unlike THC's partial agonism. Many showed bias toward cAMP inhibition over beta-arrestin2 recruitment, but no clear structure-activity relationship emerged.

Why it matters

The full agonism and high potency of synthetic cannabinoids drive their toxicity. Understanding their pharmacology is essential for predicting harm from new compounds entering illegal markets.

The numbers in context

28 compounds tested including reference ligands CP55,940 and THC. Most showed low nanomolar potency. Many displayed signaling bias, especially at CB2R where several were inactive in beta-arrestin2 recruitment.

How the study worked

In vitro pharmacological characterization using radioligand binding and two signaling assays (cAMP inhibition and beta-arrestin2 recruitment) in CHO-K1 cells expressing CB1R or CB2R.

What this study cannot tell us

In vitro assays in cell lines may not reflect in vivo behavior. Only two signaling pathways were measured; other pathways may be relevant. Clinical effects depend on pharmacokinetics not captured in these assays.

How to read the evidence

Rigorous in vitro characterization with multiple assays, though cell-based results need in vivo validation.

When this study was published

2025 study characterizing synthetic cannabinoids currently in circulation.

The bigger picture

Synthetic cannabinoids keep evolving to evade regulation. The lack of predictable structure-activity relationships means each new compound is essentially a pharmacological unknown, making harm prediction extremely difficult.

Questions still open

Can signaling bias explain differences in toxicity between synthetic cannabinoids? What unmeasured factors determine the clinical danger of each compound? Could binding kinetics better predict harm than steady-state assays?

Common questions

Why are synthetic cannabinoids more dangerous than cannabis?

Unlike THC, which is a partial agonist, most synthetic cannabinoids are full agonists with much higher potency at cannabinoid receptors. This stronger receptor activation is thought to drive their toxicity, including psychosis, severe vomiting, and heart problems.

Can scientists predict how dangerous a new synthetic cannabinoid will be?

This study found no clear relationship between chemical structure and pharmacological behavior, meaning each new compound is essentially unpredictable without direct testing.

Read the original research

In vitro pharmacological activity of twenty-eight synthetic cannabinoid receptor agonists at the type 1 and 2 cannabinoid receptors.

Neurochemistry international, 190, 106039

View on PubMed ↗Publisher’s paper ↗

Citation

Mercier, Gabrielle; Mohamed, Kawthar A; Zagzoog, Ayat; Cropper, Laura; Ritchie, Brendan; Jin, Zhiyun; Patel, Mikin; Laprairie, Robert B. (2025). In vitro pharmacological activity of twenty-eight synthetic cannabinoid receptor agonists at the type 1 and 2 cannabinoid receptors.. Neurochemistry international, 190, 106039. https://doi.org/10.1016/j.neuint.2025.106039