Abstract
Cannabis is a complex mixture of hundreds of bioactive molecules. This provides the potential for pharmacological interactions between cannabis constituents, a phenomenon referred to as “the entourage effect” by the medicinal cannabis community. We hypothesize that pharmacokinetic interactions between cannabis constituents could substantially alter systemic cannabinoid concentrations. To address this hypothesis we compared pharmacokinetic parameters of cannabinoids administered orally in a cannabis extract to those administered as individual cannabinoids at equivalent doses in mice. Astonishingly, plasma cannabidiolic acid (CBDA) concentrations were 14-times higher following administration in the cannabis extract than when administered as a single molecule. In vitro transwell assays identified CBDA as a substrate of the drug efflux transporter breast cancer resistance protein (BCRP), and that cannabigerol and Δ9-tetrahydrocannabinol inhibited the BCRP-mediated transport of CBDA. Such a cannabinoid-cannabinoid interaction at BCRP transporters located in the intestine would inhibit efflux of CBDA, thus resulting in increased plasma concentrations. Our results suggest that cannabis extracts provide a natural vehicle to substantially enhance plasma CBDA concentrations. Moreover, CBDA might have a more significant contribution to the pharmacological effects of orally administered cannabis extracts than previously thought.
Highlights
Cannabis is a complex mixture of bioactive molecules including cannabinoids, terpenoids and flavonoids
The pharmacokinetic profiles of various cannabinoids administered in a full‐spectrum cannabis extract differ substantially from cannabinoids administered as single molecules at equivalent doses
To infer whether compound-compound interactions alter the pharmacokinetic profile of the cannabinoids in the full-spectrum extract, we compared the profiles of the cannabinoids administered in a full-spectrum extract to those of the cannabinoids administered as individual components (Fig. 1)
Summary
Cannabis is a complex mixture of bioactive molecules including cannabinoids, terpenoids and flavonoids. Medicinal cannabis products contain a multitude of both acidic and neutral cannabinoids amongst other phytochemicals, each with a complex pharmacology, so there is the potential for interactions between cannabis constituents. Few studies have addressed the "entourage effect" hypothesis; there is growing evidence that the effects of full-spectrum cannabis extracts may not be attributed to an individual constituent. More recently there has been a "CBD craze", with a substantial increase in demand for cannabisbased products which are perceived to treat a myriad of health conditions[11] These products, which contain a multitude of cannabinoids, are administered at much lower doses than purified forms of CBD and Δ9-THC that have been shown to be effective in clinical trials[10, 11]. We compared the pharmacokinetic parameters of cannabinoids administered as an extract to those when administered as an individual compound at equivalent doses
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