The synthetic enantiomer (+)-CBD was roughly 10 times more potent than natural (-)-CBD at inhibiting endocannabinoid signaling at CB1 receptors and also activated sphingosine-1-phosphate receptors, revealing a distinct pharmacological profile.
Pharmacology researchers, drug developers, and advanced readers interested in cannabinoid chemistry.
(+)-CBD is 10x more potent at CB1 than natural (-)-CBD
What the researchers found
(+)-CBD had a 5-fold lower inhibition constant for displacing a CB1 agonist and was approximately 10 times more potent at inhibiting depolarization-induced suppression of excitation (DSE), a form of endocannabinoid-mediated synaptic plasticity. (+)-CBD also stereoselectively activated sphingosine-1-phosphate receptors S1P1 and S1P3, a completely different signaling pathway.
Why it matters
Natural cannabis only produces (-)-CBD, but the synthetic mirror image (+)-CBD has dramatically different pharmacology, suggesting that CBD's 3D shape matters enormously for its biological effects and opening new drug development possibilities.
The numbers in context
(+)-CBD was ~5x more potent at displacing CP55,940 at CB1 and ~10x more potent at inhibiting DSE compared to (-)-CBD.
How the study worked
Enantioselective synthesis of both CBD enantiomers, with a new NMR-based method for confirming enantiomeric purity. Pharmacological testing in autaptic hippocampal neurons (a model of endocannabinoid signaling) and CHO-K1 cells. Binding, signaling, and functional assays performed.
What this study cannot tell us
In vitro and cell-based studies only. (+)-CBD does not occur naturally and its in vivo effects are unknown. The clinical significance of S1P receptor activation by (+)-CBD is unclear. No behavioral or therapeutic testing performed.
How to read the evidence
Rigorous in vitro pharmacology with novel synthetic compounds, but no in vivo or clinical data.
When this study was published
Published in 2022.
The bigger picture
The discovery that CBD enantiomers have distinct signaling profiles, including activation of sphingosine-1-phosphate receptors by (+)-CBD, expands the potential therapeutic toolkit derived from cannabis chemistry beyond what the plant naturally produces.
Questions still open
- Could (+)-CBD be a more effective CB1 modulator than natural CBD? What therapeutic applications might arise from its S1P receptor activation? Would it have the same safety profile as natural CBD?
Common questions
What is an enantiomer?
Why is (+)-CBD more potent than natural CBD?
Read the original research
Differential Enantiomer-Specific Signaling of Cannabidiol at CB1 Receptors.
Molecular pharmacology, 102(6), 259-268
Citation
Bosquez-Berger, Taryn; Wilson, Sierra; Iliopoulos-Tsoutsouvas, Christos; Jiang, Shan; Wager-Miller, Jim; Nikas, Spyros P; Mackie, Ken P; Makriyannis, Alexandros; Straiker, Alex. (2022). Differential Enantiomer-Specific Signaling of Cannabidiol at CB1 Receptors.. Molecular pharmacology, 102(6), 259-268. https://doi.org/10.1124/molpharm.121.000305
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