Abstract
Limited evidence has suggested that terpenes found in Cannabis sativa are analgesic, and could produce an “entourage effect” whereby they modulate cannabinoids to result in improved outcomes. However this hypothesis is controversial, with limited evidence. We thus investigated Cannabis sativa terpenes alone and with the cannabinoid agonist WIN55,212 using in vitro and in vivo approaches. We found that the terpenes α-humulene, geraniol, linalool, and β-pinene produced cannabinoid tetrad behaviors in mice, suggesting cannabimimetic activity. Some behaviors could be blocked by cannabinoid or adenosine receptor antagonists, suggesting a mixed mechanism of action. These behavioral effects were additive with WIN55,212, providing support for a terpene “entourage effect.” In vitro experiments showed that all terpenes activated the CB1R, while some activated other targets. Our findings suggest that these Cannabis terpenes are multifunctional cannabimimetic ligands that provide support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids.
Competing Interest Statement
This study was funded by institutional funds from the University of Arizona. JMS has an equity stake in Botanical Results, LLC, a local cannabidiol company; no company products or interests were tested in this study. The authors have no other relevant conflicts of interest to declare.
Abbreviations
- 2-AG
- 2-Arachidonoylglycerol
- A2a
- Adenosine A2a Receptor
- CBD
- Cannabidiol
- CB1/2
- Cannabinoid Receptor Type 1/2
- ERK
- Extracellular Signal-Regulated Kinase
- FBS
- Fetal Bovine Serum
- NAM
- Negative Allosteric Modulator
- THC
- Δ9-Tetrahydrocannabinol
- TBST
- Tris-Buffered Saline with Tween