Cannabis Sativa L. is one of the of the most controversial plants in the world. The most studied class of compounds produced by the plant is that of cannabinoids, which are responsible for both the therapeutic and psychotropic effects.
Although some cannabinoids are achiral (e.g., cannabigerol, CBG and cannabinol, CBN), many others (such as Delta9-tetrahydrocannabinol, Delta9-THC and cannabidiol, CBD) contain one or more asymmetric carbons. Production of cannabinoids by the plant has thought to be stereoselective for a long time, with (-)-trans forms preferentially synthesized. As a result, analytical methods employed to characterize cannabis products have been usually based only on achiral determination, irrespective of stereochemistry.
However, since the number of discovered cannabinoids exceeds 100, the biological activity of each single chiral cannabinoid is still largely unknown. Only recently, due to the increasing popularity of cannabis products and recent legalization, there is a growing interest towards the characterization of cannabis samples also in terms of enantiomeric purity and stereostability.
The lack of studies on chirality of cannabinoids is also due to the fact that reference standards are not available for every single chiral cannabinoid. A quick search in literature databases shows that there are only few peer-reviewed papers available where chiral LC has been applied to the separation of chiral cannabinoids. These works date back to the beginning of nineties, and they report the separation of enantiomers of CBD and Delta8-THC, together with other synthetic cannabinoids, on an amylose-based chiral stationary phase (CSP) under normal-phase (NP) conditions. More recently, different companies have published technical notes showing the separation of Delta8-THC and Delta9-THC again on polysaccharide CSPs under NP conditions. However, there is a lack of fundamental studies on retention properties of cannabinoids on CSPs and they have never been tested under reversed-phase (RP) conditions.
This work reports about recent studies made by our research group aimed at characterizing retention behavior of natural cannabinoids on different chiral stationary phases (CSPs). These CSPs have been operated under different chromatographic conditions (including NP and RP) and the influence of stationary phase chemistry on enantio- and chemo-selectivity has been explored. Future challenges and pitfalls in this field will be also discussed.

Alberto Cavazzini

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