Modulation of type 1 cannabinoid receptor activity by cannabinoid by-products from and non-cannabis phytomolecules.

contains more than 120 cannabinoids and 400 terpene compounds (i.e., phytomolecules) present in varying amounts. 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 is the type 1 cannabinoid receptor (CB1R). ∆-tetrahydrocannabinolic acid (∆-THCa) is often the most abundant cannabinoid present in many cultivars of . Decarboxylation converts ∆-THCa to ∆-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- phytomolecules, as the diversity of available products grows. Here, we chose to focus on whether 10 phytomolecules (∆-THC, ∆-THC, 11-OH-∆-THC, cannabinol, curcumin, epigallocatechin gallate, olivetol, palmitoylethanolamide, piperine, and quercetin) alter CB1R-dependent signaling with or without a co-treatment of ∆-THC. Phytomolecules were screened for their binding to CB1R, inhibition of forskolin-stimulated cAMP accumulation, and βarrestin2 recruitment in Chinese hamster ovary cells stably expressing human CB1R. Select compounds were assessed further for cataleptic, hypothermic, and anti-nociceptive effects on male mice. Our data revealed partial agonist activity for the cannabinoids tested, as well as modulation of ∆-THC-dependent binding and signaling properties of phytomolecules and . These data represent a first step in understanding the complex pharmacology of - and non-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 compounds.