Two Novel Synthetic Cannabinoids Caused Seizures, Aggression, and Dopamine Release in Mice | Research

The takeaway

The synthetic cannabinoids AKB48 and 5F-AKB48 produced hypothermia, pain insensitivity, catalepsy, impaired senses, seizures, and aggression in mice, with the fluorinated version (5F-AKB48) being more potent.

Anyone interested in why synthetic cannabinoids are more dangerous than natural cannabis.

Fluorination increased potency of the synthetic cannabinoid, amplifying dangerous effects

What the researchers found

Researchers conducted the first comprehensive pharmacological characterization of AKB48 and its fluorinated derivative 5F-AKB48, two synthetic cannabinoids sold as "Spice" products.

Both compounds showed nanomolar affinity for CB1 and CB2 receptors in binding experiments. In mice, they produced the classic cannabinoid "tetrad" effects (hypothermia, pain insensitivity, catalepsy, reduced movement) plus additional concerning effects: impaired visual, acoustic, and tactile senses; seizures; myoclonia (involuntary muscle jerks); hyperreflexia; and promoted aggression.

Brain microdialysis showed both compounds stimulated dopamine release in the nucleus accumbens, a key reward center. All behavioral and neurochemical effects were blocked by the CB1 antagonist AM251. The fluorinated derivative (5F-AKB48) was generally more potent, suggesting that adding a fluorine atom increases the drug's effectiveness.

Why it matters

These findings explain why synthetic cannabinoid users report more severe and dangerous effects than cannabis users. The seizures, aggression, and sensory impairment produced by these compounds go well beyond what THC typically causes, and the fluorinated variant's increased potency shows how chemical modifications can amplify danger.

The numbers in context

Nanomolar affinity for CB1 and CB2 receptors. Both compounds increased dopamine in nucleus accumbens. Fluorinated 5F-AKB48 showed greater potency than AKB48. All effects blocked by CB1 antagonist AM251.

How the study worked

In vitro receptor binding on mouse and human CB1/CB2 receptors. In vivo studies in male CD-1 mice included tetrad testing, sensorimotor assessment, neurological evaluation, brain microdialysis for dopamine measurement, and comparison with THC and JWH-018.

What this study cannot tell us

This was an animal study in mice. The doses used may not precisely reflect human exposure from synthetic cannabinoid products. Some effects (seizures, aggression) may not translate directly to human use patterns. Only acute effects were studied.

How to read the evidence

This is a comprehensive in vitro and in vivo animal study providing first-time characterization of these compounds. Results are preclinical.

When this study was published

Published in 2016. AKB48 and 5F-AKB48 may have been supplanted by newer synthetic compounds in the illicit market.

The bigger picture

The practice of fluorinating synthetic cannabinoids to increase potency is a concerning trend in the illicit drug market. This study demonstrates that such modifications can increase both the pharmacological activity and the risk of dangerous effects including seizures and aggression.

Questions still open

Why do synthetic cannabinoids produce seizures while natural cannabis generally does not? Could the aggression-promoting effects contribute to violent behavior in human synthetic cannabinoid users?

Common questions

Why are synthetic cannabinoids more dangerous than marijuana?

Synthetic cannabinoids are full agonists at CB1 receptors (THC is a partial agonist), meaning they activate the receptor more strongly. This study also showed they cause effects not typical of THC, including seizures and aggression. Their potency is amplified by chemical modifications like fluorination.

What does fluorination do to the drug?

Adding a fluorine atom to the synthetic cannabinoid molecule increased its potency and effectiveness. This is a common modification in illicit drug manufacturing that allows producers to use less material while achieving stronger effects, but also increases the risk of dangerous reactions.

Read the original research

Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on "tetrad", sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies.

Psychopharmacology, 233(21-22), 3685-3709

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Citation

Canazza, Isabella; Ossato, Andrea; Trapella, Claudio; Fantinati, Anna; De Luca, Maria Antonietta; Margiani, Giulia; Vincenzi, Fabrizio; Rimondo, Claudia; Di Rosa, Fabiana; Gregori, Adolfo; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; Marti, Matteo. (2016). Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on "tetrad", sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies.. Psychopharmacology, 233(21-22), 3685-3709.