Of 11 DEA-flagged synthetic cannabinoids tested in rodents, most were significantly more potent than natural THC — some producing equivalent effects at a fraction of the dose.
Toxicologists treating synthetic cannabinoid exposures, DEA and public health officials monitoring drug supply, forensic chemists identifying novel substances.
What the researchers found
The DEA identified 11 synthetic cannabinoids of concern, and researchers tested each one in rodent models for two key properties: how strongly they suppressed movement (locomotor depression) and whether rats trained to recognize THC also recognized these compounds (drug discrimination).
In locomotor tests, most of the 11 compounds were more potent than THC (which had an ED50 of 3.3 mg/kg). Three compounds — FUB-144, 5Cl-AKB-48, and ADB-FUBIATA — were exceptions, producing only weak locomotor effects at tested doses.
In the drug discrimination assay (where rats are trained to distinguish THC from placebo), most compounds fully substituted for THC with greater potency (THC ED50 = 0.55 mg/kg). FUB-144 was less potent, 5Cl-AKB-48 was substantially less potent, and ADB-FUBIATA and MDA-19 failed to fully substitute for THC even at doses up to 100 mg/kg — suggesting these two may not produce classical cannabinoid effects.
The indazole and indole structural classes generally showed the highest potency, while benzimidazole compounds were more variable.
Why it matters
Synthetic cannabinoids continue to cause hospitalizations and deaths because users cannot predict their potency. This study provides the first systematic potency comparison for 11 specific compounds the DEA has flagged as concerning — giving clinicians, toxicologists, and poison control centers reference data for treating exposures.
The numbers in context
11 compounds tested. THC ED50 (reference): 3.3 mg/kg (locomotor), 0.55 mg/kg (discrimination). Most compounds more potent than THC in both assays. Exceptions: FUB-144, 5Cl-AKB-48 (lower potency), ADB-FUBIATA and MDA-19 (failed to fully substitute for THC at 100 mg/kg). Structural classes: indazole, indole, benzimidazole.
How the study worked
Behavioral pharmacology study testing 11 DEA-identified synthetic cannabinoids. Locomotor activity measured in Swiss-Webster mice. Drug discrimination conducted in Sprague-Dawley rats trained to discriminate THC. ED50 values calculated for each compound relative to THC in both assays.
Who was studied
Swiss-Webster mice and Sprague-Dawley rats were used for testing.
What this study cannot tell us
Rodent behavioral models may not perfectly predict human pharmacological responses. Only two behavioral measures tested — other important properties (duration of action, receptor binding profiles, toxicity) were not assessed. The ED50 comparisons provide relative potency but don't directly translate to human dosing. New synthetic cannabinoids appear faster than they can be characterized.
How to read the evidence
Controlled preclinical pharmacology study — rigorous for establishing relative potency in animal models but translation to human clinical effects requires caution.
When this study was published
Published in 2026, characterizing synthetic cannabinoids currently in circulation as identified by the DEA.
The bigger picture
This adds to the semi-synthetic cannabinoid picture (RTHC-00234) by characterizing a different class — fully synthetic cannabinoids with novel chemical scaffolds. While RTHC-00234 focused on HHC and hemp-derived semi-synthetics in Europe, this study addresses the more dangerous fully synthetic compounds that continue to appear in the US drug supply. The finding that most are more potent than THC explains why synthetic cannabinoid exposures produce more severe clinical presentations than natural cannabis.
Replication
Not stated in abstract.
Funding
Supported by NIDA contract N01DA-18-8936; N01DA-23-8936.
Conflicts of interest
Not reported in abstract.
Questions still open
- Why did ADB-FUBIATA and MDA-19 fail to substitute for THC — do they work through non-cannabinoid mechanisms? Can these potency data help predict which compounds pose the greatest overdose risk? Would faster characterization pipelines help public health responses to newly emerging synthetics?
Read the original research
Behavioral pharmacology of novel synthetic indazole, indole, and benzimidazole cannabinoids in rodents.
Journal of cannabis research, 8(1), 22
The Journal of Cannabis Research is a peer-reviewed publication focusing on cannabis-related studies.
Citation
Shetty, Ritu A; Hill, Rebecca D; McDonald, Jared A; Sumien, Nathalie; Forster, Michael J; Gatch, Michael B. (2026). Behavioral pharmacology of novel synthetic indazole, indole, and benzimidazole cannabinoids in rodents.. Journal of cannabis research, 8(1), 22. https://doi.org/10.1186/s42238-026-00390-3
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