The entourage effect sparks controversy. Despite many proponents [1], critics claim a scarcity of hard evidence [2]. Recently, a group of researchers [3] investigated the “cannabimimetic” activity of terpenes; in other words, they studied if and how terpenes behave like cannabinoids. They employed a synthetic cannabinoid agonist and antagonist to define this behavior. The results illustrate that terpenes enhance or affect cannabinoid activity, strongly supporting the entourage effect.
The study began in vivo with terpenes α-humulene, β-pinene, linalool, geraniol, and β-caryophyllene. The researchers administered terpenes (50–200 mg/kg) to measure responses associated with the cannabinoid type 1 (CB1) receptor, namely pain blocking, slower motion, decreased sensitivity (catalepsy), and low body temperature (hypothermia). The cannabinoid agonist WIN55,212-2 was used as a control. Each terpene other than β-caryophyllene demonstrated at least three of the four effects, confirming cannabimimetic activity.
When a terpene was added together with a low dose of WIN55,212-2, the pain-blocking effects became more pronounced than either substance alone. This illustrates synergism—the cannabinoid agonist and terpene were more potent together. To determine the site of this action, the researchers added a cannabinoid antagonist, rimonabant, which efficaciously reversed this effect for the terpenes and WIN55,212-2.
Not all of the four effects could be pinpointed to the endocannabinoid system. For example, rimonabant partially reversed hypothermia only for α-humulene and the control, WIN55,212-2. The catalepsy response was also mostly independent of CB1 receptors. The researchers identified involvement of adenosine A2a receptors for these effects. For example, an A2a antagonist completely blocked catalepsy for α-humulene and β-pinene. Linalool appeared to slow motion via CB1 in males and A2a in females.
The researchers further confirmed that the terpenes activate cellular signaling dependent on CB1 receptors in vitro. Some of the terpenes (i.e., α-humulene, β-pinene and β-caryophyllene) activated non-cannabinoid targets. All terpenes also interacted with CB2 receptors, supporting “terpene poly-pharmacology.”
Thus, they present three possibilities: 1) terpenes are weak CB1 agonists; 2) terpenes modulate membranes positively toward CB1 activation; and/or 3) terpenes modulate endocannabinoids (e.g., anandamide), which in turn activate receptors.
The study concludes, “Our findings suggest that these Cannabis terpenes are multifunctional cannabimimetic ligands that provide conceptual support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids.” [3]
References
1- Russo EB. The case for the entourage effect and conventional breeding of clinical cannabis: No “strain,” no gain. Front Plant Sci. 2019;9:1969. doi:10.3389/fpls.2018.01969. [Impact Factor: 4.407; Times Cited: 75 (Semantic Scholar)]
2- Cogan PS. The ‘entourage effect’ or ‘hodge-podge hashish’: the questionable rebranding, marketing, and expectations of cannabis polypharmacy. Expert Rev Clin Pharmacol. 2020;13(8):835-845. doi:10.1080/17512433.2020.1721281. [Impact Factor: 3.481; Times Cited: 9 (Semantic Scholar)]
3- LaVigne JE, et al. Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Scientific Reports. 2021;11(8232). [Impact Factor: 3.998; Times Cited: 1 (Semantic Scholar)]
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