Updated: Nov 21
Welcome to Cannabis Conclusions, a unique educational series from Higher Learning LV that is targeted at hemp and cannabis industry professionals. This series provides readers with the conclusion section from important modern peer-reviewed research studies.
An August 2022 research study entitled "Pharmacology of Minor Cannabinoids at the Cannabinoid CB1 Receptor: Isomer- and Ligand-Dependent Antagonism by Tetrahydrocannabivarin" that was published in the journal Receptors investigated "the agonist effects of a group of minor cannabinoids on the CB1 receptor by measuring the activation of GIRK channels in pituitary ATt20 cells. In addition, we sought to characterize the CB1 receptor antagonist properties of THCV using the isomers Δ9-THCV and Δ8-THCV."
"Recent advances in the bioengineering of microbial systems to synthesize cannabinoids, along with improvements in the cannabis extraction methods, have provided a greater availability of minor cannabinoids. As such, cannabinoids including CBN, CBG, CBC and THCV are now being introduced into topical creams, beverages and edibles for consumer use. Preclinical and clinical studies suggest that some minor cannabinoids may possess neuroprotective and anti-epileptic properties.
"CBDA and CBDV display efficacy in reducing both the number and severity of seizures in animal and human studies. Despite these findings, the molecular pharmacology of the minor cannabinoids remains largely unknown."
"For example, CBDA and CBDV display efficacy in reducing both the number and severity of seizures in animal and human studies. Despite these findings, the molecular pharmacology of the minor cannabinoids remains largely unknown. While these compounds were first hypothesized to act via the endogenous cannabinoid system (i.e., CB1 and CB2 receptors, endocannabinoid synthesis and reuptake pathways, etc.), they are now known to act at numerous "off targets" including TRP channels, 5-HT1a receptors, PPARs, orphan receptors, and others.
"In the present study, we evaluated CB1 receptor agonist activity of a group of minor cannabinoids that consisted of CBN, CBG, CBC, CBT, CBDV and THCV. When compared with the full CB1 receptor agonist WIN 55-212-2 and the partial agonist Δ9-THC, none of these minor cannabinoids caused any stimulation of the CB1 receptor/Gi/GIRK channel signaling pathway. While previous studies have examined the effects of select minor cannabinoids on the CB1 receptor, there are limited data comparing groups of cannabinoids under the same experimental conditions.
THCV molecular structure
"Husni et al., 2014, reported that Δ9-THCA, Δ9-THCV, CBG and CBDV display almost no functional activity when assayed using GTPγS binding in HEK293 cells expressing the CB1 receptor. In contrast, CBGA and CBN possess CB1 receptor activity (EC50 = 100 to 300 nM) comparable to Δ9-THC. The finding with CBN is consistent with other reports showing that this cannabinoid weakly inhibits adenylyl cyclase in CB1 receptor-expressing COS cells. Zagzoog et al., 2020, compared the functional activity of a series of minor cannabinoids by measuring CB1 receptor-mediated inhibition of forskolin-stimulated cAMP accumulation in CHO cells. While CBG, CBC and THCV showed partial agonist activity (compared with full agonist CP 55,940) at high nanomolar concentrations, no activity was measured with Δ9-THCA and CBDV.
"These results were consistent with the anti-nociceptive effects of Δ9-THC, CBG, CBC and THCV measured in the same study with C57Bl/6 mice. It should be noted that for their experiments, forskolin-stimulated cAMP accumulation was measured in the cells following 90 min of treatment with the cannabinoid ligands. In contrast, we measured GIRK channel activation during a 2 min exposure to the cannabinoids.
"Several studies have established that THCV acts as a neutral antagonist at the CB1 receptor."
"This may account for the different normalized responses of Δ9-THC in our assay (20% of the maximum WIN 55,212-2 fluorescent signal compared to their assay (56% of the maximum CP 55,940-induced inhibition) and might explain why we observed no effects of CBG, CBC and THCV. Alternatively, CBG and CBC might display ligand-biased signaling toward inhibiting adenylyl cyclase versus GIRK channel activation. For example, anandamide (an endocannabinoid) is about seven times more biased toward inhibiting cAMP formation than stimulating pERK1/2 activity.
"Several studies have established that THCV acts as a neutral antagonist at the CB1 receptor. Pertwee and colleagues found that 1 µM THCV produces a rightward shift in the concentration versus the response curve for CP 55,940- and WIN 55,212-2- stimulated [35S]GTPγS binding to mouse brain membranes. The apparent dissociation constant (KB) for this antagonism, calculated using Schild analysis, was 93 nM (CP 55,940) and 85 nM (WIN 55,212-2). In another study, Δ9-THCV at concentrations of 100 nM to 1 µM also antagonized WIN 55,212-2-stimulated GTPγS binding to mouse brain membranes.
"However, AM-251, a selective CB1 receptor antagonist, was over 200-fold more potent as an antagonist of GTPγS binding when compared with Δ9-THCV. In addition to the antagonism of ligand-induced GTPγS binding, THCV also prevented cannabinoid agonist inhibition of electrically-evoked contractions of the mouse isolated vas deferens. Consistent with our results this antagonist effect was "ligand-dependent." THCV was more potent in antagonizing the contractile effects of WIN 55,212-2 and anandamide than the activity of Δ9-THC.
"Obesity is a growing worldwide health issue that is associated with an increased risk of cardiovascular disease and type 2 diabetes."
Obesity is a growing worldwide health issue that is associated with an increased risk of cardiovascular disease and type 2 diabetes. Clinical trials conducted in the United States and Europe in the early 2000s showed that the drug rimonabant (SR141716) decreases bodyweight and waist circumference in obese patients. Unfortunately, rimonabant has adverse effects including anxiety, depression and an increase in suicidal thoughts. For this reason, rimonabant was withdrawn from the market in Europe and was never approved for use in the United States.
In animal studies, THCV decreases food intake and body weight, but without the adverse psychological effects of rimonabant. In one clinical study, THCV decreased glucose levels and improved pancreatic insulin production in patients with type 2 diabetes. Thus, further investigation of the in vitro and in vivo effects of THCV and related minor cannabinoids is certainly warranted.
View the original study.
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