Studies Pertaining to the Emerging Cannabinoid Hexahydrocannabinol (HHC).

We report studies pertaining to two isomeric hexahydrocannabinols (HHCs), ( 9R )-HHC and ( 9S )-HHC, which are derivatives of the psychoactive cannabinoids Δ 9 - and Δ 8 -THC. HHCs have been known since the 1940s, but have become increasingly available to the public in the United States and are typically sold as a mixture of isomers. We show that ( 9R )-HHC and ( 9S )-HHC can be prepared using hydrogen-atom transfer reduction, with ( 9R )-HHC being accessed as the major diastereomer. In addition, we report the results of cannabinoid receptor studies for ( 9R )-HHC and ( 9S )-HHC. The binding affinity and activity of isomer ( 9R )-HHC are similar to that of Δ 9 -THC, whereas ( 9S )-HHC binds strongly in cannabinoid receptor studies but displays diminished activity in functional assays. This is notable, as our examination of the certificates of analysis for >60 commercially available HHC products show wide variability in HHC isomer ratios (from 0.2:1 to 2.4:1 of ( 9R )-HHC to ( 9S )-HHC). These studies suggest the need for greater research and systematic testing of new cannabinoids. Such efforts would help inform cannabis-based policies, ensure the safety of cannabinoids, and potentially lead to the discovery of new medicines.