Three new synthetic cannabinoids caused seizures, aggression, and severe toxicity in mice at doses far lower than THC | Research

The takeaway

The synthetic cannabinoids 5F-ADBINACA, AB-FUBINACA, and STS-135 showed nanomolar potency at CB1 and CB2 receptors and caused hypothermia, seizures, aggression, and neurotoxicity in mice through CB1-dependent mechanisms.

Read this if you want to understand why synthetic cannabinoids are far more dangerous than natural cannabis.

Nanomolar potency at CB1/CB2 receptors, with seizures, aggression, and neurotoxicity in mice

What the researchers found

In vitro testing revealed that all three synthetic cannabinoids (5F-ADBINACA, AB-FUBINACA, STS-135) had nanomolar affinity for both mouse and human CB1 and CB2 receptors, making them far more potent than THC. They also induced neurotoxicity in cultured brain cells.

In mice, all three compounds produced a characteristic pattern: hypothermia, increased pain threshold, catalepsy, reduced movement, impaired sensory responses (visual, acoustic, tactile), seizures, myoclonus (involuntary muscle jerks), hyperreflexia, and promoted aggression.

Most effects were fully blocked by the CB1 antagonist AM251, confirming CB1-mediated mechanisms. However, STS-135's visual sensory effects were only partially blocked, suggesting an additional CB1-independent mechanism for that compound.

Why it matters

These third-generation synthetic cannabinoids are sold as "legal" alternatives to cannabis but are orders of magnitude more potent. The seizure and aggression profile seen in this study matches clinical reports of severe reactions in human users. Understanding their pharmacology is essential for emergency medicine and toxicology.

The numbers in context

All three compounds: nanomolar affinity at CB1 and CB2 receptors. Effects: hypothermia, analgesia, catalepsy, motor suppression, sensory impairment, seizures, myoclonus, hyperreflexia, aggression. All effects (except partial for STS-135 visual) blocked by AM251.

How the study worked

Combined in vitro and in vivo study. In vitro: competition binding experiments for CB1/CB2 affinity and potency; neurotoxicity testing in mouse neuro-2a cells. In vivo: behavioral and neurological assessment in male CD-1 mice comparing the three synthetics with THC and JWH-018, with CB1 antagonist (AM251) challenge to confirm receptor mechanisms.

What this study cannot tell us

Animal study using injected synthetic cannabinoids at controlled doses. Human users often smoke these compounds with unknown purity and dosing. The mouse model may not capture all human-relevant effects. Only male mice were tested. Long-term effects were not assessed.

How to read the evidence

Controlled animal toxicology study with receptor binding confirmation. Provides important safety data but uses controlled conditions different from human use patterns.

When this study was published

Published in 2017. New synthetic cannabinoids continue to emerge, and each requires individual toxicological characterization.

The bigger picture

The synthetic cannabinoid market continuously produces new compounds designed to evade drug scheduling. Each generation tends to be more potent and less predictable than the last. This study documents the toxicological profile of three such compounds, providing reference data for clinicians and regulators. The seizure and aggression findings explain why synthetic cannabinoid emergencies often look nothing like natural cannabis intoxication.

Questions still open

Do these compounds have different toxicity profiles at sub-seizure doses? Are there biomarkers that can identify which synthetic cannabinoid a patient has taken? Could the CB1-independent mechanism of STS-135 explain atypical clinical presentations?

Common questions

Why are synthetic cannabinoids more dangerous than marijuana?

These compounds are designed to be much more potent than THC, with nanomolar affinity at cannabinoid receptors. While THC produces its effects at relatively high concentrations, synthetic cannabinoids overwhelm the same receptors at much lower doses, causing seizures, aggression, and toxicity that natural cannabis does not produce.

Are synthetic cannabinoids "legal weed"?

They are sometimes marketed that way, but they are pharmacologically very different from cannabis. They are typically sold as incense or research chemicals to circumvent drug laws. Their extreme potency and unpredictable effects make them far more dangerous than cannabis.

Read the original research

Pharmaco-toxicological effects of the novel third-generation fluorinate synthetic cannabinoids, 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice. In vitro and in vivo studies.

Human psychopharmacology, 32(3)

View on PubMed ↗Publisher’s paper ↗

Citation

Canazza, Isabella; Ossato, Andrea; Vincenzi, Fabrizio; Gregori, Adolfo; Di Rosa, Fabiana; Nigro, Federica; Rimessi, Alessandro; Pinton, Paolo; Varani, Katia; Borea, Pier Andrea; Marti, Matteo. (2017). Pharmaco-toxicological effects of the novel third-generation fluorinate synthetic cannabinoids, 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice. In vitro and in vivo studies.. Human psychopharmacology, 32(3). https://doi.org/10.1002/hup.2601