Third-Generation Synthetic Cannabinoids Were Up to 30 Times More Potent Than Earlier Versions | Research

The takeaway

Four third-generation Spice/K2 compounds showed CB1 receptor binding affinities up to 30 times higher than JWH-018, with greater dopamine-stimulating properties in the brain's reward center.

Toxicologists, emergency clinicians, and anyone tracking the evolving danger of synthetic cannabinoids.

BB-22 had 30x higher CB1 receptor affinity than the earlier synthetic cannabinoid JWH-018

What the researchers found

Researchers characterized four third-generation synthetic cannabinoids (BB-22, 5F-PB-22, 5F-AKB-48, STS-135) and compared them to the earlier compound JWH-018.

BB-22 and 5F-PB-22 had CB1 receptor binding affinities 30 and 26 times higher than JWH-018 respectively, with higher potency and efficacy as CB1 agonists. All four compounds stimulated dopamine release specifically in the nucleus accumbens shell (the brain's reward center) but not in other nearby regions.

The dopamine-stimulating effect was completely blocked by the CB1 antagonist AM251 and showed a bell-shaped dose-response curve. The compounds did not activate G-proteins in CB1 knockout mice, confirming CB1 receptor specificity.

Why it matters

The escalating potency of successive synthetic cannabinoid generations helps explain the increasing severity of clinical toxicity reports. Compounds 30 times more potent than earlier versions pose correspondingly greater risks of overdose and adverse effects.

The numbers in context

BB-22 Ki: 0.11 nM (vs. JWH-018: 3.38 nM). 5F-PB-22 Ki: 0.13 nM. BB-22 Emax: 217% (vs. JWH-018: 163%). All four stimulated nucleus accumbens shell dopamine release at doses consistent with their CB1 affinity.

How the study worked

In vitro receptor binding and GTPgammaS assays on rat and mouse CB1/CB2 receptors. In vivo brain microdialysis in freely moving mice measuring dopamine release in nucleus accumbens shell, core, and medial prefrontal cortex. CB1 knockout mice used for specificity.

What this study cannot tell us

In vitro binding does not perfectly predict in vivo effects. Mouse dopamine studies may not directly translate to human reward processing. Only acute effects were studied. The specific compounds may have been replaced by even newer variants in the illicit market.

How to read the evidence

This is a well-designed pharmacological study combining in vitro and in vivo approaches with appropriate controls, providing strong preclinical characterization.

When this study was published

Published in 2016. The synthetic cannabinoid market has continued to evolve with potentially even more potent compounds.

The bigger picture

This study documents a dangerous trend in the synthetic cannabinoid market: each generation of compounds is more potent than the last. The selective dopamine release in the reward center, combined with super-high potency, helps explain both the addictive potential and the severe toxicity of these substances.

Questions still open

Is there a ceiling to how potent synthetic cannabinoids can become? Does the bell-shaped dose-response curve for dopamine explain some of the paradoxical effects reported by users?

Common questions

Why are newer synthetic cannabinoids more dangerous?

Each generation has been designed with higher potency at CB1 receptors. This study showed third-generation compounds with up to 30x higher receptor binding than earlier versions, meaning less material is needed for an effect, which makes overdose more likely and effects less predictable.

Why do synthetic cannabinoids release dopamine in the reward center?

All cannabinoid CB1 agonists, including THC, can stimulate dopamine release in reward circuits. However, the super-high potency of these synthetic compounds means they produce much stronger dopamine signals, which may contribute to both their addictive potential and acute toxicity.

Read the original research

Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135.

Neuropharmacology, 105, 630-638

View on PubMed ↗Publisher’s paper ↗

Citation

De Luca, Maria Antonietta; Castelli, M Paola; Loi, Barbara; Porcu, Alessandra; Martorelli, Mariella; Miliano, Cristina; Kellett, Kathryn; Davidson, Colin; Stair, Jacqueline L; Schifano, Fabrizio; Di Chiara, Gaetano. (2016). Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135.. Neuropharmacology, 105, 630-638. https://doi.org/10.1016/j.neuropharm.2015.11.017