Δ⁹-cis-Tetrahydrocannabinol: Natural Occurrence, Chirality, and Pharmacology

Thecis-stereoisomers of Δ⁹-THC [(−)- 3 and (+)- 3 ] were identified and quantified in a series of low-THC-containing varieties ofCannabis sativaregistered in Europe as fiber hemp and in research accessions of cannabis. While Δ⁹-cis-THC ( 3 ) occurs in cannabis fiber hemp in the concentration range of (−)-Δ⁹-trans-THC [(−)- 1 ], it was undetectable in a sample of high-THC-containing medicinal cannabis. Natural Δ⁹-cis-THC ( 3 ) is scalemic (ca. 80-90% enantiomeric purity), and the absolute configuration of the major enantiomer was established as 6aS,10aR[(−)- 3 ] by chiral chromatographic comparison with a sample available by asymmetric synthesis. The major enantiomer, (−)-Δ⁹-cis-THC [(−)- 3 ], was characterized as a partial cannabinoid agonist in vitro and elicited a full tetrad response in mice at 50 mg/kg doses. The current legal discrimination between narcotic and non-narcotic cannabis varieties centers on the contents of “Δ⁹-THC and isomers” and needs therefore revision, or at least a more specific wording, to account for the presence of Δ⁹-cis-THCs [(+)- 3 and (−)- 3 ] in cannabis fiber hemp varieties.