Studies Pertaining to the Emerging Cannabinoid Hexahydrocannabinol (HHC)

Area of Science:

• Cannabinoid science
• Organic chemistry
• Pharmacology

Background:

• Hexahydrocannabinols (HHCs) are THC derivatives increasingly available in the US, often as isomer mixtures.
• HHCs have been known since the 1940s but lack comprehensive scientific investigation.
• Commercial HHC products display significant variability in isomer ratios.

Purpose of the Study:

• To synthesize and characterize two HHC isomers: (9R)-HHC and (9S)-HHC.
• To evaluate the cannabinoid receptor binding affinity and activity of these isomers.
• To assess the implications of variable isomer ratios in commercially available HHC products.

Main Methods:

• Synthesis of (9R)-HHC and (9S)-HHC via hydrogen-atom transfer reduction.
• Cannabinoid receptor binding assays to determine affinity.
• Functional assays to assess receptor activity.
• Analysis of certificates of analysis for over 60 commercial HHC products.

Main Results:

• (9R)-HHC was synthesized as the major diastereomer.
• (9R)-HHC demonstrated binding affinity and activity comparable to Δ9-THC.
• (9S)-HHC exhibited strong binding but reduced activity in functional assays.
• Commercial HHC products showed wide isomer ratio variations (0.2:1 to 2.4:1 for (9R): (9S)).

Conclusions:

• The differing pharmacological profiles of (9R)-HHC and (9S)-HHC are significant.
• Variability in commercial HHC products necessitates further research and standardized testing.
• These findings support informed cannabis policy, enhanced cannabinoid safety, and potential therapeutic discoveries.