Study Provides Clues to How Minor Cannabinoids Work in the Body
We are learning a lot about how THC and CBD interact with the endocannabinoid system (ECS) to stimulate appetite and help treat pain, anxiety and seizures. But cannabis also contains a huge range of minor cannabinoids. What is their therapeutic potential and how do they work in the body?
Pharmacological activity in vitro and in vivo of isolated minor cannabinoids
These are questions to which a study from Robert Laprairie's lab at the University of Saskatchewan sought to answer. They found that THC, CBD, and six minor cannabinoids, tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG) and cannabichromene (CBC), interacted with cannabinoid receptors and that many had positive effects in mice.
THC is known to exert its impact in part through the activation of the most studied cannabinoid receptors, CB1 and CB2. THC is therefore a partial CB1R and CB2R agonist, however, the pharmacology of CBD is far from clear. CBD has been described as a CB1R negative allosteric modulator, CB2R antagonist, GPR18 agonist, GPR55 antagonist, among other effects.
Beyond ∆9-THC and CBD, it is believed that there are at least 120 other phytocannabinoids found in cannabis whose receptor-mediated mechanisms are still actively studied. Among these less well-known phytocannabinoids, we can mention ∆9-tetrahydrocannabidiolic acid (∆9-THCa), tetrahydrocannabivarin (THCV), cannabigerol (CBG), cannabichromene (CBC) and cannabidivarin (CBDV).
CB1R and CB2R, their endogenous agonists 2-arachidonoylglycerol (2-AG) and anandamide (AEA), as well as the associated anabolic and catabolic enzymes constitute the endocannabinoid system.
Activation of CB1R inhibits nociception and locomotor activity, activates reward pathways, and regulates mood, memory and cognition, as well as central hormone homeostasis.
Potential interactive effects of complex cannabinoid mixtures
The eight cannabinoids tested all had some level of binding to CB1 but, with the exception of THC, this binding was weak. Most cannabinoids have bound themselves to CB2 as well, including THC, THCV, and CBDA. As expected, CBD bound little to this receptor.
We observed that all the compounds tested exhibited some degree of activity at the level of CB1R or CB2R, several of them being weak partial agonists. This research sheds critical light on the therapeutic potential and usefulness of phytocannabinoids.
Our data, as well as previous studies, indicate that ∆ 9 -THCa may mediate neuroprotective and anti-inflammatory actions via CB1R, CB2R, and PPARγ when administered in high enough concentrations and in the absence of other cannabinoids. .
In mice, THC, THCA, and THCV but not CBD were found to reduce pain, while THC, CBD, THCA, THCV, and CBG all had a positive impact on anxiety. The authors concluded that THCA and THCV, which binds CB1 and CB2, may be able to reduce pain, inflammation, and anxiety when either is used in the absence of other cannabinoids. This conclusion is important because there is growing interest in clinical applications of monocannabinoid preparations.
Given the number of companies that have reported synthetic production of cannabinoids Using cell culture techniques, pharmacological studies like this will play a key role in assessing the behavior of each cannabinoid in the body.
Poly-pharmacology of cannabinoid receptors
This work represents a first step in the evaluation of the pharmacology of a subset of phytomolecules derived from cannabis at the level of the most studied cannabinoid receptors, CB1R and CB2R. It is possible that if the phytocannabinoids tested here which exhibited a CB1R agonist and in vivo activity were present at sufficiently high concentrations in cannabis products; they can produce intoxicating effects similar to those of ∆ 9 -THC.
Therefore, in order to fully understand the poly-pharmacology of cannabinoid receptors in vivo, other target receptors must be considered. Finally, cannabis products contain many phytomolecules which are co-administered during cannabis consumption. This study represents a first foray into the potential interactions between and among phytomolecules which can be developed gradually. Pharmacology is a reductionist approach to biochemical interactions that cannot always model the complex interactions occurring in nature. As the initial characterizations of single ligands are performed, more complex combinatorial pharmacology assays may be performed. Ultimately, we hope to assess the potential interactive effects of complex mixtures of cannabinoids and to assess the pharmacodynamic and pharmacokinetic differences that arise from chemically distinct ligands.