2026/06/25 by Noa Raz, Aharon M. Eyal, Nardine Fahoum-Khalefa +3
Medicine · Pharmacology, Toxicology and Pharmaceutics · Psychology · #Cannabis and Cannabinoid Research #Forensic Toxicology and Drug Analysis #Psychedelics and Drug Studies
paper · doi:10.1016/j.bcp.2026.118185
Cannabis terpenes are widely recognized for shaping the plant’s aromatic and sensory profiles. Yet, their pharmacological role in cannabis is less established. Recent work demonstrated that several cannabis terpenes can activate cannabinoid receptors type 1 and 2 (CB 1 R and CB 2 R) as low-efficacy agonists, raising the possibility that they may also modulate the activation at these receptors by Δ 9 -tetrahydrocannabinol (THC), through orthosteric or allosteric mechanisms. Here, we systematically investigated the effects of individual terpenes and of terpene mixtures on THC-evoked activation at CB 1 R and CB 2 R, expressed in Xenopus laevis oocytes. Using G protein–gated inwardly rectifying potassium (GIRK) channel activation as a functional readout, we quantified concentration–response relationships for THC alone and in combination with terpenes, and applied isobolographic analysis to distinguish additive, synergistic, and antagonistic interactions. We found that several terpenes selectively potentiated THC activation at CB 1 R and CB 2 R. Isobolographic analysis suggested additive THC–terpene interactions for some terpenes, and synergistic interactions for others, including borneol, limonene, sabinene, terpineol, α-pinene and ocimene at CB 1 R, and β-caryophyllene and linalool at CB 2 R. Terpene mixtures displayed dose-dependent CB 1 R activation, and several mixtures synergistically enhanced THC responses. Together, our findings suggest that cannabis terpenes may act as both partial orthosteric agonists and allosteric modulators at CB 1 R and CB 2 R. These results provide a mechanistic framework for cannabinoid–terpene synergy and highlight the importance of receptor specificity and of formulation design in shaping terpene mediated activation. These findings stress the need for terpenes selection for formulations tailor for specified medicinal needs.