Hexahydrocannabinol (HHC) and Δ 9 -tetrahydrocannabinol (Δ 9 -THC) driven activation of cannabinoid receptor 1 results in biased intracellular signaling.

The Cannabis sativa plant has been used for centuries as a recreational drug and more recently in the treatment of patients with neurological or psychiatric disorders. In many instances, treatment goals include relief from posttraumatic disorders, anxiety, or to support treatment of chronic pain. Ligands acting on cannabinoid receptor 1 (CB1R) are also potential targets for the treatment of other health conditions. Using an evidence-based approach, pharmacological investigation of CB1R agonists is timely, with the aim to provide chronically ill patients relief using well-defined and characterized compounds from cannabis. Hexahydrocannabinol (HHC), currently available over the counter in many countries to adults and even children, is of great interests to policy makers, legal administrators, and healthcare regulators, as well as pharmacologists. Herein, we studied the pharmacodynamics of HHC epimers, which activate CB1R. We compared their key CB1R-mediated signaling pathway activities and compared them to the pathways activated by Δ9 -tetrahydrocannabinol (Δ9 -THC). We provide evidence that activation of CB1R by HHC ligands is only broadly comparable to those mediated by Δ9 -THC, and that both HHC epimers have unique properties. Together with the greater chemical stability of HHC compared to Δ9 -THC, these molecules have a potential to become a part of modern medicine.