Synthetic cannabinoid EG-018 showed unusual properties as a weak partial agonist at cannabinoid receptors | Research

The takeaway

Laboratory and animal testing of the synthetic cannabinoid EG-018 revealed it behaves as a weak partial agonist at CB1 receptors with high binding affinity, producing only some cannabinoid-like effects and only through intravenous administration.

Pharmacologists, forensic toxicologists, and researchers studying synthetic cannabinoid receptor mechanisms.

High receptor affinity (21 nM CB1) but weak partial agonist activity

What the researchers found

EG-018 had high affinity for CB1 (21 nM) and CB2 (7 nM) but behaved as a weak partial agonist, unlike typical synthetic cannabinoids. When injected into the abdomen, it produced no effects, but intravenous administration caused reduced movement, catalepsy, and hypothermia, with only catalepsy being CB1-mediated.

Why it matters

EG-018 has been detected in illicit products and human samples, so understanding its pharmacology is important for toxicology and public health. Its unusual partial agonist profile distinguishes it from more dangerous full-agonist synthetic cannabinoids.

The numbers in context

CB1 affinity: 21 nM. CB2 affinity: 7 nM. No effects via i.p. at 100 mg/kg. IV at 56 mg/kg produced hypomotility, catalepsy, hypothermia. Only catalepsy was blocked by rimonabant (CB1 antagonist).

How the study worked

In vitro binding studies at human CB1 and CB2 receptors in HEK293 cells. In vivo testing in mice using the cannabinoid tetrad (hypomotility, catalepsy, hypothermia, analgesia) and THC drug discrimination via both intraperitoneal and intravenous administration.

What this study cannot tell us

The lack of effect via intraperitoneal administration suggests pharmacokinetic issues (possibly rapid metabolism) that complicate interpretation. Only basic behavioral assays were used.

How to read the evidence

Preliminary: in vitro and animal pharmacological characterization of a single compound.

When this study was published

Published in 2020 in Pharmacology, Biochemistry and Behavior.

The bigger picture

The fact that EG-018 has high receptor affinity but low efficacy makes it pharmacologically distinct from full-agonist synthetic cannabinoids like JWH-018, which may have implications for understanding how different cannabinoids produce different effects.

Questions still open

Why does EG-018 not produce effects when injected abdominally despite high receptor affinity? Could partial agonists like EG-018 serve as research tools for studying cannabinoid receptor function?

Common questions

What is EG-018?

EG-018 is a synthetic cannabinoid that has been detected in illicit drug products and human biological samples. Unlike many synthetic cannabinoids that are potent full agonists at CB1 receptors, EG-018 acts as a weak partial agonist despite binding strongly.

Is EG-018 dangerous?

Based on this study, EG-018 appears less potent than full-agonist synthetic cannabinoids because of its partial agonist activity. However, it has been found in unregulated products, and its effects may vary depending on how it is consumed.

Read the original research

In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018.

Pharmacology, biochemistry, and behavior, 193, 172918

View on PubMed ↗Publisher’s paper ↗

Citation

Gamage, Thomas F; Barrus, Daniel G; Kevin, Richard C; Finlay, David B; Lefever, Timothy W; Patel, Purvi R; Grabenauer, Megan A; Glass, Michelle; McGregor, Iain S; Wiley, Jenny L; Thomas, Brian F. (2020). In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018.. Pharmacology, biochemistry, and behavior, 193, 172918. https://doi.org/10.1016/j.pbb.2020.172918