Synthetic cannabinoids produce their main effects through CB1 receptors, just like THC, according to quantitative pharmacological analysis | Research

The takeaway

Quantitative analysis using rimonabant to shift dose-response curves of five synthetic cannabinoids and THC confirmed that CB1 receptors largely mediate the central pharmacological effects of synthetic cannabinoids, not other receptor targets.

Read this if you want to understand whether synthetic cannabinoids work through the same receptor as THC.

Similar rimonabant affinity estimates across all compounds confirm CB1-mediated effects

What the researchers found

Using pA2 and pKB analyses (quantitative pharmacological methods), researchers determined that the CB1 receptor antagonist rimonabant produced consistent rightward shifts in the dose-response curves of five synthetic cannabinoids (A-834,735D, WIN55,212-2, CP55,950, JWH-073, CP47,497) and THC.

The similarity of the rimonabant affinity estimates across all compounds indicates that CB1 receptors, and not other pharmacological targets, largely mediate the central effects of these synthetic cannabinoids (catalepsy, pain relief, and temperature reduction).

This is important because some researchers have speculated that the increased dangers of synthetic cannabinoids might be due to non-CB1 targets, but this quantitative analysis suggests their core pharmacological effects operate through the same receptor as THC.

Why it matters

Understanding whether synthetic cannabinoids work through CB1 or other targets has implications for both treatment and regulation. This study shows that their core effects are CB1-mediated, meaning their increased danger likely comes from higher potency and efficacy at CB1, not from activating different receptors.

The numbers in context

5 synthetic cannabinoids tested: A-834,735D, WIN55,212-2, CP55,950, JWH-073, CP47,497. Plus THC. All showed similar pA2/pKB values with rimonabant, indicating CB1 mediation. Triad endpoints: catalepsy, antinociception, hypothermia.

How the study worked

In vivo pharmacological analysis in mice using the cannabinoid triad (catalepsy, antinociception, hypothermia). The CB1 antagonist rimonabant was used to generate rightward shifts in dose-response curves for each compound. pA2 and pKB values were calculated to estimate apparent CB1 receptor affinity.

What this study cannot tell us

Only tested three pharmacological endpoints (the classic triad). Synthetic cannabinoids may have non-CB1 effects on other systems (e.g., seizures, psychosis) not captured by this analysis. The analysis focuses on central effects; peripheral effects may involve other targets. Only five of the many synthetic cannabinoids in circulation were tested.

How to read the evidence

Controlled in vivo pharmacological study using rigorous quantitative methods. Strong methodology for the specific question addressed.

When this study was published

Published in 2017. The quantitative pharmacological approach continues to be applied to newer synthetic cannabinoids.

The bigger picture

If synthetic cannabinoids worked through non-CB1 targets, they would require different clinical management than THC intoxication. The confirmation that CB1 mediates their core effects means that CB1-based approaches to treating overdose or adverse reactions should be applicable to synthetic cannabinoid emergencies as well.

Questions still open

Do the seizures and psychosis caused by synthetic cannabinoids involve non-CB1 mechanisms not captured by this analysis? Would CB1 antagonists be effective emergency treatments for synthetic cannabinoid toxicity? Do newer-generation synthetic cannabinoids maintain the same CB1-mediated profile?

Common questions

If synthetic cannabinoids work through the same receptor as THC, why are they more dangerous?

The analysis shows they work through CB1, but they bind more tightly and activate the receptor more fully than THC. It is their higher potency and efficacy at CB1, not activation of different receptors, that makes them more dangerous. A small dose can overwhelm the receptor system.

Could a CB1 blocker treat synthetic cannabinoid overdose?

The finding that effects are CB1-mediated suggests that CB1 antagonists could theoretically counteract synthetic cannabinoid toxicity. However, this has not been tested clinically, and any such treatment would need to account for potential rebound effects.

Read the original research

Apparent CB1 Receptor Rimonabant Affinity Estimates: Combination with THC and Synthetic Cannabinoids in the Mouse In Vivo Triad Model.

The Journal of pharmacology and experimental therapeutics, 362(1), 210-218

View on PubMed ↗Publisher’s paper ↗

Citation

Grim, T W; Morales, A J; Thomas, B F; Wiley, J L; Endres, G W; Negus, S S; Lichtman, A H. (2017). Apparent CB1 Receptor Rimonabant Affinity Estimates: Combination with THC and Synthetic Cannabinoids in the Mouse In Vivo Triad Model.. The Journal of pharmacology and experimental therapeutics, 362(1), 210-218. https://doi.org/10.1124/jpet.117.240192