Plasma cannabidiolic acid (CBDA) concentrations are 14-times higher following administration of CBD in the cannabis extract than when administered as a single molecule, shows a new mice study from the University of Sydney. The likely reason for this high increase is cannabinoid-cannabinoid interactions at the breast cancer resistance protein (BCRP).
The newest study on the interaction of cannabis molecules published in Nature found that cannabis extracts provide a natural vehicle for enhancing plasma CBDA concentrations. It also found that CBDA might have a more significant contribution to the pharmacological effects of orally administered cannabis extracts than it was previously thought, which brings more light to this so far overlooked molecule.
What is CBDA?
CBDA is the main phytocannabinoid in the fiber and seed-oil hemp varieties. It is most abundant in female seedless flowers. Being its chemical precursor, the decarboxylation of CBDA induced by light or heat leads to the creation of CBD. It could be recovered by industrial hemp processing and the huge amount of its by-products and wastes.
In preclinical studies, CBDA has demonstrated an ability to reduce vomiting in rats, and the main focus of scientists is its anti-inflammatory activity. The CBDA anticancer activity was also preliminarily investigated on acute lymphocytic leukemia and promyelocytic leukemia cells. Data from those experiments, as well as on human prostate carcinoma cells, showed that CBDA was less active than CBD. Therefore, no further attention was given to the potential anticancer activity of CBDA. Only when CBDA was tested towards a highly aggressive triple-negative breast cancer cell line, it expressed its full potential. A 2012 study led by Dr. Shuso Takeda from the Department of Molecular Biology of the Daiichi University of Pharmacy was the first to suggest that CBDA can be used as a potential therapy for the abrogation of aggressive breast cancers cells.
The newest research
In the newest study, the cannabinoids were administered orally as either a full-spectrum cannabis extract or individually at equivalent doses to those in the full-spectrum extract. Conducting the pharmacokinetic analysis of mouse plasma after the administration of the extract, the scientists found that there were no traces of Cannabichromene (CBC), cannabidivarin (CBDV), cannabigerol (CBG), cannabinol (CBN), and Δ9-tetrahydrocannabivarin (Δ9-THCV). The analysis detected six cannabinoids – CBD, CBDA, cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA), Δ9-THC, and Δ9-THCA. Each of these cannabinoids was then administered orally as an individual compound at an equivalent dose to that found in the full-spectrum extract.
To their astonishment, the scientists found that CBDA concentration in mice plasma was 14 times higher than when CBDA was administered as a single molecule. On the other hand, the plasma concentrations of CBD, CBDVA, CBGA, Δ9-THC, and Δ9-THCA following administration of the full-spectrum extract were lower than when they were administered as single molecules at equivalent doses. The total plasma exposure of each of these cannabinoids was nearly two to four times lower with the full-spectrum extract than when the molecules were administered individually.
The absorption time of the cannabinoids with the full-spectrum extract was slow, with maximum absorption in 45 to 60 minutes. While CBD, CBDA, CBGA, and Δ9-THC were all maximally absorbed by 60 min when administered as a full-spectrum extract, maximal plasma values were delayed (90–120 min) when each of them was administered individually. In contrast, absorption of CBDVA (15 min) and Δ9-THCA (30 min) was more rapid as individual cannabinoids compared to within the full-spectrum extract (maximum values 60 and 45 min, respectively).
The half-lives of the cannabinoids were another interesting point in this study. When administered in the full-spectrum extract, the cannabinoids had relatively long half-lives, 484 min (CBD), 310 min (CBDA), 120 min (CBDVA), 298 min (CBGA), and 330 min (Δ9-THC), with the exception of Δ9-THCA (t1/2 46 min) and were, for the most part, longer than those when the cannabinoids were administered individually, 217 min (CBD), 198 min (CBDA), 210 min (Δ9-THC) and 37 min (Δ9-THCA). The half-life of CBDVA, however, was slightly longer when administered as a single compound (150 min vs. 120 min).
Intestine protein interactions
Since the drug transporters like P-glycoprotein and breast cancer resistance protein (BCRP) limit the absorption, and cannabinoids are both substrates and/or inhibitors of these drug transporters, the scientists examined whether the converging action of the cannabinoids on these transporters might provide a mechanism for the pharmacokinetic interaction.
CBD, CBG, CBDA, CBDVA, and Δ9-THC are all BCRP substrates. While BCRP inhibitor elacridar significantly inhibits the transport of CBD, CBDA, and CBDVA substrates and causes weakness of CBG and Δ9-THC substrates, CBDV transport is not inhibited by elacridar.
Since CBDA was identified as a BCRP substrate, the scientists found it possible that cannabinoids within the full-spectrum extract inhibited BCRP-mediated efflux of CBDA in the intestinal lumen, which would enhance plasma CBDA exposure following oral dosing with the full-spectrum extract.
They investigated whether the cannabinoids identified as BCRP substrates (CBD, CBDVA, CBG, and Δ9-THC) inhibited BCRP-mediated transport of CBDA, as substrates may inhibit the transport of other substrates competitively.
As a result, the rates of CBDA transport were significantly inhibited by 10 µM CBG and Δ9-THC, while neither CBD nor CBDVA affected CBDA transport via BCRP.
They also found that CBD but not the other phytocannabinoids modestly inhibited BCRP-mediated transport of the established BCRP substrate prazosin, primarily used to treat high blood pressure, symptoms of an enlarged prostate, and posttraumatic stress disorder.
When examining the effect of the five BCRP substrates on P-glycoprotein function, the scientists found that CBDA was not a substrate of P-glycoprotein but was an inhibitor as it was the only cannabinoid to significantly reduce the permeability of digoxin, a medication used to treat various heart conditions.
Pharmacokinetic entourage effect
After the study published in April in Nature confirmed the entourage effect, this is a new step forward in the discovery of the mechanisms that could explain the efficiency of orally consumed CBD products in lower concentrations.
The newest research from the Lambert Initiative for Cannabinoid Therapeutics compares the pharmacokinetic parameters of cannabinoids administered as an extract to those when administered as an individual compound at equivalent doses, with the results showing a substantial difference.
The study shows that different cannabinoids interact to alter plasma levels of cannabinoids themselves due to what the scientists named a ‘pharmacokinetic entourage effect’.
“Our results suggest CBDA might play a greater role in the effects of these low-dose CBD products than previously thought. Our own preclinical studies show CBDA reduces anxiety and seizures. This result provides us with a pathway to explore why some cannabis extracts yield pharmacological effects in humans at lower doses.”, said the lead author of the study, Dr. Lyndsey Anderson in a press release.
The scientists will continue to work on how this pharmacokinetic entourage effect might lead to observed therapeutic outcomes for cannabinoids in people.