AUTHOR=Zagzoog Ayat , Cabecinha Ashley , Abramovici Hanan , Laprairie Robert B. 

TITLE=Modulation of type 1 cannabinoid receptor activity by cannabinoid by-products from Cannabis sativa and non-cannabis phytomolecules

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.956030

DOI=10.3389/fphar.2022.956030

ISSN=1663-9812

ABSTRACT=Cannabis sativa contains more than 120 cannabinoids and 400 terpene compounds (i.e. phytomolecules) present in varying amounts. Cannabis is increasingly available for legal medicinal and non-medicinal use globally, and with increased access comes the need for a more comprehensive understanding of the pharmacology of phytomolecules. The main transducer of the intoxicating effects of Cannabis is the type 1 cannabinoid receptor (CB1R). ∆9-tetrahydrocannabinolic acid (∆9-THCa) is often the most-abundant cannabinoid present in many cultivars of Cannabis. Decarboxylation converts ∆9-THCa to ∆9-THC, which is a CB1R partial agonist. Understanding the complex interplay of phytomolecules – often referred to as ‘the entourage effect’ – has become a recent and major line of inquiry in cannabinoid research. Additionally, this interest is extending to other non-Cannabis phytomolecules, as the diversity of available Cannabis products grows. Here, we chose to focus on whether ten phytomolecules (∆8-THC, ∆6a,10a-THC, 11-OH-∆9-THC, cannabinol, curcumin, epigallocatechin gallate, olivetol, palmitoylethanolamide, piperine, and quercetin) alter CB1R-dependent signaling with or without a co-treatment of ∆9-THC. Phytomolecules were screened for their binding to CB1R, inhibition of forskolin-stimulated cAMP accumulation and arrestin2 recruitment in Chinese hamster ovary cells stably-expressing human CB1R. Select compounds were assessed further for cataleptic, hypothermic, and anti-nociceptive effects in male mice. Our data reveal partial agonist activity for the cannabinoids tested, as well as modulation of ∆9-THC-dependent binding and signaling properties of phytomolecules in vitro and in vivo. These data represent a first step in understanding the complex pharmacology of Cannabis and non-Cannabis derived phytomolecules at CB1R and determining whether these interactions may affect the physiological outcomes, adverse effects and abuse liabilities associated with the use of these many compounds.