Biochem Pharmacol 2025 Oct 30;243Pt 1:117498. doi: 10.1016/j.bcp.2025.117498.

Selective activation of cannabinoid receptors by cannabis terpenes.

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Terpenes are aromatic compounds abundantly present in plants, including cannabis. Emerging preclinical and clinical evidence indicates that certain terpenes exhibit pharmacological effects in various physiological and psychological conditions. Yet, their molecular mechanisms of action, particularly in cannabis preparations remain poorly understood. We have previously reported results of activating cannabinoid receptor type 1 (CB1R) by several terpenes that are most common in cannabis. Here we employed the same Xenopus oocytes functional heterologous expression system to complement the CB1R data and to study the activation of the cannabinoid receptor type 2 (CB2R) by sixteen individual cannabis terpenes and by terpene mixtures. Employing receptor- induced GIRK currents as a measure for receptor activation, dose-dependent responses were found for many of these terpenes, reaching a maximal response of about 10-60 % the activation elicited by THC. Terpenes' apparent EC50 at CB1R and CB2R were similar to, or lower than those obtained for THC at the same apparatus, suggesting lower efficacy but equivalent or even improved potency. At CB2R, multiple terpenes reach 'clinical effect level' at concentration equivalent or lower than those of THC (≥ 0.1 µM). Per a given receptor, terpenes differ in their activation level. Additionally, terpenes act differently at the two receptors, giving room for receptor selectivity. Our results support the role of cannabis terpenes as partial agonists at CB1R and CB2R and provide the basis for selecting terpenes or terpene mixture for affecting physiological functions involving these receptors. These results may further contribute to our understanding of terpenes' medicinal effects.

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