Studies Pertaining to the Emerging Cannabinoid Hexahydrocannabinol (HHC)

Abstract

We report studies pertaining to two isomeric hexahydrocannabinols (HHCs), (9R)-HHC and (9S)-HHC, which are derivatives of the psychoactive cannabinoids Δ9- and Δ8-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 Δ9-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.

Comprehensive Safety Assessment of Diverse Cannabinoids: A Scientific Inquiry

“…13 Crude D8 THC: HPLC (C18): 9.729 min, 1 H NMR (400 MHz, CDCl 3 ) δ 6.32 (d, J = 1.6 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 5.50-5.27 (m, 2H), 3.32-3.18 (m, 1H), 2.82-2.67 (m, 1H), 2.44 (td, J = 7.4, 2.0 Hz, 2H), 2.26-2.06 (m, 1H), 2.02-1.76 (m, 3H), 1.72 (d, J = 1.7 Hz, 3H), 1.56 (s, 2H), 1.49-1.23 (m, 7H), 1.13 (s, 3H), 1.02-0.83 (m, 3H).) 13…”

“…Crude HHC: HPLC (C18): 7.112, 7.261 min, 1 H NMR (400 MHz, CDCl 3 ) δ 6.27 (d, J = 1.6 Hz, 1H), 6.08 (t, J = 1.7 Hz, 1H), 5.06 (s, 1H), 3.15-3.05 (m, 1H), 2.54-2.36 (m, 3H), 1.91-1.77 (m, 1H), 1.66 (td, J = 8.5, 3.5 Hz, 1H), 1.65-1.48 (m, 1H), 1.51-1.37 (m, 3H), 1.39-1.29 (m, 3H), 1.32-1.23 (m, 2H), 1.21-1.07 (m, 3H), 1.09 (s, 2H), 1.00-0.73 (m, 5H). 13…”

“…Distilled D8-THC: HPLC (C18): 10.005 min, 1 H NMR (400 MHz, CDCl 3 ) δ 6.33 (d, J = 1.6 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 5.47 (d, J = 12.4 Hz, 2H), 3.32-3.22 (m, 1H), 2.75 (td, J = 10.9, 4.5 Hz, 1H), 2.44 (td, J = 7.4, 1.9 Hz, 2H), 2.23-2.10 (m, 1H), 1.94-1.83 (m, 2H), 1.83 (s, 1H), 1.57 (p, J = 7.2 Hz, 2H), 1.43 (s, 3H), 1.38-1.24 (m, 4H), 1.14 (s, 3H), 0.91 (t, J = 6.8 Hz, 3H). 13 Crude D8 THC: HPLC (C18): 9.729 min, 1 H NMR (400 MHz, CDCl 3 ) δ 6.32 (d, J = 1.6 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 5.50-5.27 (m, 2H), 3.32-3.18 (m, 1H), 2.82-2.67 (m, 1H), 2.44 (td, J = 7.4, 2.0 Hz, 2H), 2.26-2.06 (m, 1H), 2.02-1.76 (m, 3H), 1.72 (d, J = 1.7 Hz, 3H), 1.56 (s, 2H), 1.49-1.23 (m, 7H), 1.13 (s, 3H), 1.02-0.83 (m, 3H).) 13…”

“…Distilled THCP: HPLC (C18): 8.531 min, 1 H NMR (400 MHz, CDCl 3 ) δ 6.35 (p, J = 1.7 Hz, 1H), 6.33-6.23 (m, 1H), 6.15 (d, J = 1.7 Hz, 1H), 5.23 (s, 1H), 3.23 (dp, J = 10.6, 2.5 Hz, 1H), 2.44 (tt, J = 7.2, 3.7 Hz, 2H), 2.22-2.13 (m, 2H), 2.01-1.87 (m, 1H), 1.79-1.63 (m, 4H), 1.61-1.49 (m, 1H), 1.43 (s, 3H), 1.44-1.32 (m, 1H), 1.35-1.21 (m, 10H), 1.11 (s, 2H), 0.95-0.85 (m, 3H). 13…”

“…Positioned as a cost-effective alternative to controlled D9-THC, monitoring HHC poses a critical challenge for toxicological and forensic purposes. Addressing this concern underscores the necessity for continued research on HHC to assist health providers in identifying and managing related intoxications [13].…”