HHC

The main cannabinoid receptor in the brain, responsible for THC’s intoxicating effects. HHC acts as a partial CB1 agonist, with most activity coming from the 9R epimer. 9R-HHC binds CB1 with a Ki of about 15 nM, essentially equal to Delta-9-THC at 15 nM in the same study, while 9S-HHC binds much more weakly at approximately 176 nM.

Functional research shows the same strong difference between the epimers. In one CB1 signalling pathway, 9R-HHC had an EC50 of 3.4 nM compared with approximately 3.9 nM for Delta-9-THC, while 9S-HHC required about 57 nM. A separate study found 9R-HHC less potent than THC in another signalling pathway, with 9.39 nM versus 4.79 nM, while 9S-HHC was much weaker at 68.3 nM. This shows that 9R-HHC can approach THC-like CB1 potency, while 9S-HHC contributes considerably less.

Commercial HHC normally contains both epimers, with one study finding an average 9R:9S ratio of approximately 2:1. Considering the THC-like binding and functional activity of 9R-HHC, the much weaker activity of 9S-HHC, and their typical mixture, HHC is theoretically estimated at around 0.7x the psychoactive potency of Delta-9-THC. The exact potency can vary substantially with epimer composition and has not been verified in a controlled human HHC-versus-THC comparison.

The main cannabinoid receptor in the immune system, involved in regulating immune cell activity and inflammatory responses. The same receptor studies report CB2 affinity for 9R-HHC (Ki about 13 nM) and lower affinity for 9S-HHC (Ki roughly 105 nM), values again comparable to or somewhat weaker than Delta-9-THC. In CB2 functional assays, both epimers show activity as partial agonists, with 9R-HHC activating CB2 around 6.2 nM and 9S-HHC at about 56 nM. These CB2 actions suggest that HHC can modulate immune signalling and inflammatory pathways in a THC-like manner, although specific effects have not yet been established in dedicated animal or human studies.

TRPA1 is a sensory ion channel involved in pain, irritation and inflammatory signalling. Both HHC epimers can activate human TRPA1, but (9R)-HHC is considerably more active than (9S)-HHC. Based on concentration-response data, (9R)-HHC shows approximately 0.85x the TRPA1 activity of Delta-9-THC, while (9S)-HHC has less than half of Delta-9-THC’s activity.

TRPA1 activation can initially increase sensory nerve signalling, but continued activation can desensitise the channel and reduce further pain signalling. HHC could therefore potentially influence both irritation and pain sensitivity, although the importance of this mechanism in humans has not been established.

The mu-opioid receptor is involved in pain control, reward and several other nervous-system functions. Research using rat brain membranes found that HHC inhibited binding at the mu-opioid receptor with an IC50 of approximately 10 µM, compared with approximately 7 µM for Delta-9-THC, corresponding to around 0.7x THC’s potency in this binding assay. The interaction was suggested to be allosteric, meaning HHC may alter receptor behaviour by binding outside the main opioid binding site.

This could potentially modify opioid-related pain and reward signalling, but HHC has not been shown to act as a conventional mu-opioid agonist and the importance of this interaction in humans remains unknown.

HHC is extensively metabolised into several hydroxylated and carboxylated metabolites, including 11-OH-HHC, 8-OH-HHC and HHC-COOH.

11-OH-HHC is pharmacologically active, with the 9R form showing much stronger THC-like activity than the 9S form. In animal discrimination studies, 11-OH-9R-HHC was approximately 3.5x as potent as Delta-9-THC in rats and 8x in pigeons, while the 9S form was much weaker. This suggests that 11-OH-9R-HHC may contribute substantially to HHC’s psychoactive effects, although its potency has not been directly measured in humans.