Repeated exposure to a synthetic cannabinoid caused lasting cognitive and brain changes in mice | Research

The takeaway

Seven days of JWH-018 exposure in mice produced psychotic-like symptoms and lasting impairments in memory, social behavior, and brain plasticity that persisted for at least 15 days after the drug was stopped.

Toxicology researchers, addiction specialists, harm reduction professionals

Cognitive and brain changes persisted 15+ days after stopping the drug

What the researchers found

Repeated JWH-018 treatment (6 mg/kg daily for 7 days) induced psychomotor agitation, reduced social dominance and recognition memory, impaired prepulse inhibition, disrupted hippocampal long-term potentiation, decreased BDNF expression, and altered endocannabinoid system components in the striatum and hippocampus, all persisting 15+ days after last exposure.

Why it matters

Synthetic cannabinoids are far more potent than plant cannabis and are associated with severe psychiatric outcomes in humans. This study provides mechanistic evidence for how repeated exposure produces lasting brain changes.

The numbers in context

6 mg/kg JWH-018 daily for 7 days; 15-16 day washout; reduced hippocampal CB1 receptor density; altered AEA and 2-AG levels; decreased BDNF, PSD95, and NMDA receptor subunit expression

How the study worked

Male CD-1 mice received daily injections of vehicle, JWH-018 (6 mg/kg), CB1 antagonist NESS-0327 (1 mg/kg), or co-administration for 7 days. After 15-16 days washout, behavioral, neurochemical, electrophysiological, and molecular assessments were performed.

What this study cannot tell us

Used a single high dose in male mice only. JWH-018 is one of many synthetic cannabinoids with varying potency. Route of administration (injection) differs from typical human use (smoking). No female mice included.

How to read the evidence

Well-designed animal study with multiple outcome measures and CB1 antagonist control, but single dose level in male mice only limits generalizability.

When this study was published

Published 2023

The bigger picture

The persistence of cognitive and neuroplasticity deficits well after drug cessation raises concerns about lasting brain damage from synthetic cannabinoid use, which is particularly relevant given the prevalence of these substances in unregulated markets.

Questions still open

Are these neuroplasticity changes reversible with longer washout periods? Do lower doses or intermittent exposure produce similar lasting effects?

Common questions

How do synthetic cannabinoids affect the brain differently than plant cannabis?

This study found that repeated JWH-018 (a synthetic cannabinoid) exposure caused lasting changes to memory, social behavior, brain plasticity, and the endocannabinoid system itself. These effects persisted at least 15 days after the drug was stopped.

Were the cognitive effects reversible?

After 15-16 days without the drug, mice still showed impaired memory, reduced social dominance, disrupted brain plasticity, and altered endocannabinoid signaling. Whether longer recovery periods would allow reversal was not tested.

Read the original research

Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH-018 in male mice.

British journal of pharmacology, 180(21), 2777-2801

View on PubMed ↗Publisher’s paper ↗

Citation

Bilel, Sabrine; Zamberletti, Erica; Caffino, Lucia; Tirri, Micaela; Mottarlini, Francesca; Arfè, Raffaella; Barbieri, Mario; Beggiato, Sarah; Boccuto, Federica; Bernardi, Tatiana; Casati, Sara; Brini, Anna T; Parolaro, Daniela; Rubino, Tiziana; Ferraro, Luca; Fumagalli, Fabio; Marti, Matteo. (2023). Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH-018 in male mice.. British journal of pharmacology, 180(21), 2777-2801. https://doi.org/10.1111/bph.16164