Synthetic cannabinoid JWH-018 produced nausea-like behavior in rats via CB1 receptors with stress hormone activation | Research

The takeaway

The synthetic cannabinoid JWH-018 (found in "Spice" products) produced conditioned gaping, a nausea indicator, in rats at doses of 1 and 3 mg/kg, an effect reversed by the CB1 antagonist rimonabant and accompanied by elevated stress hormones.

CHS researchers, toxicologists, emergency physicians treating synthetic cannabinoid exposures

JWH-018 nausea was CB1-mediated and accompanied by elevated corticosterone

What the researchers found

JWH-018 at 1 and 3 mg/kg produced conditioned gaping (nausea). The 3 mg/kg effect was reversed by rimonabant, confirming CB1 mediation. JWH-018 elevated serum corticosterone levels, indicating HPA axis activation. This parallels previous findings with high-dose THC.

Why it matters

JWH-018 has been found in "Spice" products linked to cannabinoid hyperemesis syndrome. This study provides mechanistic evidence that synthetic cannabinoids produce nausea through CB1-mediated stress response activation.

The numbers in context

JWH-018 at 1 and 3 mg/kg induced conditioned gaping. Rimonabant reversed 3 mg/kg effect. Corticosterone elevated at 3 mg/kg vs. vehicle.

How the study worked

Rats received 3 daily conditioning trials pairing saccharin with JWH-018 (0, 0.1, 1, 3 mg/kg). Rimonabant pretreatment tested for CB1 involvement. Serum corticosterone analyzed after 3 daily JWH-018 injections.

What this study cannot tell us

Animal model; conditioned gaping is a proxy for nausea; JWH-018 doses may not match human recreational exposure; only one synthetic cannabinoid tested.

How to read the evidence

Single animal study with mechanistic detail but limited to one synthetic compound.

When this study was published

Published in 2020.

The bigger picture

This supports the hypothesis that cannabinoid hyperemesis syndrome results from CB1-mediated HPA axis dysregulation, explaining why both high-dose THC and synthetic cannabinoids can produce paradoxical nausea.

Questions still open

Would other synthetic cannabinoids found in "Spice" produce similar nausea effects? Could CRH antagonists prevent CHS symptoms in humans?

Common questions

Why would a cannabinoid cause nausea when cannabis is used to treat nausea?

At low doses, cannabinoids reduce nausea. At high doses or with potent full agonists like JWH-018, they can paradoxically induce nausea through overstimulation of CB1 receptors and activation of the stress response. This is thought to underlie cannabinoid hyperemesis syndrome.

What is the connection to "Spice" products?

JWH-018 is one of the active ingredients found in synthetic cannabis products sold as "Spice." Unlike THC (a partial CB1 agonist), JWH-018 is a full agonist, making it more likely to produce severe effects including nausea and vomiting.

Read the original research

Nausea-Induced Conditioned Gaping Reactions in Rats Produced by High-Dose Synthetic Cannabinoid, JWH-018.

Cannabis and cannabinoid research, 5(4), 298-304

View on PubMed ↗Publisher’s paper ↗

Citation

DeVuono, Marieka V; Hrelja, Kelly M; Petrie, Gavin N; Limebeer, Cheryl L; Rock, Erin M; Hill, Matthew N; Parker, Linda A. (2020). Nausea-Induced Conditioned Gaping Reactions in Rats Produced by High-Dose Synthetic Cannabinoid, JWH-018.. Cannabis and cannabinoid research, 5(4), 298-304. https://doi.org/10.1089/can.2019.0103