Hexahydrocannabinol (HHC) and Δ9-tetrahydrocannabinol (Δ9-THC) driven activation of cannabinoid receptor 1 results in biased intracellular signaling
Oleh Durydivka, Petr Palivec, Matej Gazdarica, Ken Mackie, Jaroslav Blahoš, Martin Kuchař
Scientific Reports April 22, 2024 DOI: 10.1038/s41598-024-58845-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | Δ9-tetrahydrocannabinol (Δ9-THC) |
| Topics | Cannabis |
| Keywords | Cannabinoid receptor Pharmacology Endocannabinoid system Drug Agonist |
| Citations | 7 |
| Key findings | Activation of CB1R by HHC ligands is only broadly comparable to that mediated by Δ9-THC, and both HHC epimers have unique properties. |
Abstract
Abstract 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 Δ 9 -tetrahydrocannabinol (Δ 9 -THC). We provide evidence that activation of CB1R by HHC ligands is only broadly comparable to those mediated by Δ 9 -THC, and that both HHC epimers have unique properties. Together with the greater chemical stability of HHC compared to Δ 9 -THC, these molecules have a potential to become a part of modern medicine.
Comparable studies
Other experimental studies on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Smoked Cannabis' Psychomotor and Neurocognitive Effects in Occasional and Frequent Smokers Occasional (<2x/week) and frequent (≥4x/week) cannabis smokers | 2015 | Controlled within-subjects study | n = 25 |
| Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity Healthy volunteers experienced with cannabis but not regular users | 2019 | Within-subjects experimental design | n = 17 |
| Which biological and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like effects? Young cannabis users | 2018 | Observational study (naturalistic, within-subject counterbalanced design) | n = 410 |
| Cannabis Essential Oil: A Preliminary Study for the Evaluation of the Brain Effects Healthy volunteers | 2018 | Experimental study | n = 5 |
| Coming off cannabis: a cognitive and magnetic resonance imaging study in patients with multiple sclerosis Patients with multiple sclerosis who began using cannabis after disease onset, used it... | 2019 | Quasi-experimental study with odd-even allocation | n = 40 |
Citations in the library
Cited by 3
- Hexahydrocannabinol: pharmacokinetics, systemic toxicity, and acute behavioral effects in Wistar rats. The International Journal of Neuropsychopharmacology August 1, 2025
- Side-Chain Homologs of Δ9-THC, Δ8-THC, and HHC Reveal Pathway Bias at CB1R and CB2R Cannabinoid Receptors. Molecular Neurobiology August 20, 2026
- In vitro activation of the CB1 receptor by the semi‐synthetic cannabinoids hexahydrocannabinol (HHC), hexahydrocannabinol acetate (HHC‐O) and hexahydrocannabiphorol (HHC‐P) Drug Testing and Analysis June 19, 2024