Repeated doses of the synthetic cannabinoid JWH-018 progressively increased hyperactivity and aggression in mice | Research

The takeaway

Repeated high-dose injections of the synthetic cannabinoid JWH-018 in mice caused escalating locomotor activity and aggressive behavior through both CB1 receptor and dopamine-dependent mechanisms.

Toxicologists, emergency physicians treating synthetic cannabinoid cases, and neuropharmacology researchers.

Progressive escalation of aggression

What the researchers found

Repeated JWH-018 (6 mg/kg) treatment progressively increased spontaneous locomotion and aggressiveness in mice. The CB1 antagonist AM-251 prevented effects across all injections. Dopamine D1 antagonist SCH23390 and D2 antagonist haloperidol attenuated and prevented seventh-injection effects, respectively, especially in combination. Behavioral changes were accompanied by alterations in cortical, hippocampal, striatal, and cerebellar dopamine receptor and tyrosine hydroxylase gene expression.

Why it matters

Synthetic cannabinoids are linked to unpredictable psychiatric symptoms including agitation and aggression. This study identifies specific neurobiological mechanisms through which repeated exposure may produce escalating behavioral effects.

The numbers in context

JWH-018 dose: 6 mg/kg i.p. AM-251 (CB1 antagonist): 6 mg/kg. SCH23390 (D1 antagonist): 0.1 mg/kg. Haloperidol (D2 antagonist): 0.05 mg/kg. Progressive increases in locomotion and aggression observed across repeated injections.

How the study worked

Adult male ICR-CD1 mice received repeated JWH-018 injections (6 mg/kg, i.p.) with pharmacological challenges using CB1 antagonist AM-251, D1 antagonist SCH23390, and D2 antagonist haloperidol. Behavior was assessed by locomotor activity and aggression. Brain immunohistochemistry examined D1, D2 receptor and tyrosine hydroxylase expression.

What this study cannot tell us

Animal study using a single high dose that may not reflect human use patterns. Only male mice were studied. JWH-018 is one of many synthetic cannabinoids with varying pharmacology. Behavioral tests in mice have limited translational value for human aggression.

How to read the evidence

Well-designed pharmacological animal study with multiple antagonist challenges and neurobiological confirmation, but limited by single dose, male-only design, and animal-to-human translation constraints.

When this study was published

2025 publication

The bigger picture

The dual CB1 and dopamine mechanism identified here helps explain why synthetic cannabinoid users sometimes present with symptoms resembling stimulant psychosis rather than typical cannabis intoxication.

Questions still open

Do other synthetic cannabinoids produce similar progressive behavioral escalation? Would lower doses produce the same pattern over longer timeframes? Can dopamine antagonists be useful in treating synthetic cannabinoid-induced agitation in clinical settings?

Common questions

Why did JWH-018 cause increasing aggression with repeated use?

The study found two mechanisms: CB1 receptor activation (blocked entirely by the CB1 antagonist AM-251) and dopamine signaling changes (attenuated by D1 and D2 antagonists). Brain tissue showed altered dopamine receptor and tyrosine hydroxylase expression.

Could this explain aggressive behavior in synthetic cannabinoid users?

It provides a plausible biological mechanism. The progressive escalation of stimulant-like effects and aggression through dopamine pathways mirrors clinical reports of agitation and psychosis in synthetic cannabinoid users.

Read the original research

Repeated treatment with JWH-018 progressively increases motor activity and aggressiveness in male mice: involvement of CB1 cannabinoid and D1/D2 dopaminergic receptors.

European journal of pharmacology, 998, 177633

View on PubMed ↗Publisher’s paper ↗

Citation

Corli, Giorgia; De Luca, Fabrizio; Bilel, Sabrine; Bassi, Marta; Roda, Elisa; Rossi, Paola; Fattore, Liana; Locatelli, Carlo Alessandro; Marti, Matteo. (2025). Repeated treatment with JWH-018 progressively increases motor activity and aggressiveness in male mice: involvement of CB1 cannabinoid and D1/D2 dopaminergic receptors.. European journal of pharmacology, 998, 177633. https://doi.org/10.1016/j.ejphar.2025.177633