Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review

Since the early 2000s, there has been a turmoil on the global illicit cannabinoid market. Parallel to legislative changes in some jurisdictions regarding herbal cannabis, unregulated and cheap synthetic cannabinoids with astonishing structural diversity have emerged. Recently, semi-synthetic cannabinoids manufactured from hemp extracts by simple chemical transformations have also appeared as recreational drugs. The burst of these semi-synthetic cannabinoids into the market was sparked by legislative changes in the United States, where cultivation of industrial hemp restarted. By now, hemp-derived cannabidiol (CBD), initially a blockbuster product on its own, became a precursor to semi-synthetic cannabinoids such as hexahydrocannabinol (HHC), which appeared on the drug market in 2021. The synthesis and cannabimimetic activity of HHC were first reported eight decades ago in quest for the psychoactive principles of marijuana and hashish. Current large-scale manufacture of HHC is based on hemp-derived CBD extract, which is converted first by cyclization into a Delta(8)/Delta(9)-THC mixture, followed by catalytic hydrogenation to afford a mixture of (9R)-HHC and (9S)-HHC epimers. Preclinical studies indicate that (9R)-HHC has THC-like pharmacological properties. The animal metabolism of HHC is partially clarified. The human pharmacology including metabolism of HHC is yet to be investigated, and (immuno)analytical methods for the rapid detection of HHC or its metabolites in urine are lacking. Herein, the legal background for the revitalization of hemp cultivation, and available information on the chemistry, analysis, and pharmacology of HHC and related analogs, including HHC acetate (HHC-O) is reviewed.

Automated summary

Since the early 2000s, the global illicit cannabinoid market has been in turmoil with the emergence of unregulated synthetic cannabinoids and more recently, semi-synthetic cannabinoids made from hemp extracts. The production of these semi-synthetic cannabinoids, such as hexahydrocannabinol (HHC), was triggered by changes in US legislation regarding hemp cultivation. Current large-scale manufacture of HHC is based on hemp-derived CBD extract and involves cyclization and catalytic hydrogenation processes. While preclinical studies have shown THC-like properties in (9R)-HHC, the human pharmacology and metabolism of HHC are still unknown, and there is a lack of (immuno)analytical methods for rapid detection of HHC or its metabolites in urine. This review provides an overview of the legal background, chemistry, analysis, and pharmacology of HHC and related analogs, including HHC acetate (HHC-O).