Abstract
Cultivation of industrial low-Δ9-tetrahydrocannabinol (Δ9-THC) hemp has created an oversupply of cannabidiol (CBD)-rich products. The fact that phytocannabinoids, including CBD, can be used as precursors to synthetically produce a range of THC variants—potentially located in a legal loophole—has led to a diversification of cannabis recreational drug markets. ‘Hemp-compliant’, ‘hemp-derived’ and ‘semisynthetic’ cannabinoid products are emerging and being advertised as (legal) alternatives for Δ9-THC. This study included a large panel (n = 30) of THC isomers, homologs, and analogs that might be derived via semisynthetic procedures. As a proxy for the abuse potential of these compounds, we assessed their potential to activate the CB1 cannabinoid receptor with a β-arrestin2 recruitment bioassay (picomolar–micromolar concentrations). Multiple THC homologs (tetrahydrocannabihexol, THCH; tetrahydrocannabiphorol, THCP; tetrahydrocannabinol-C8, THC-C8) and THC analogs (hexahydrocannabinol, HHC; hexahydrocannabiphorol, HHCP) were identified that showed higher potential for CB1 activation than Δ9-THC, based on either higher efficacy (Emax) or higher potency (EC50). Structure–activity relationships were assessed for Δ9-THC and Δ8-THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB1 activity were established for various THC isomers (Δ7-THC, Δ10-THC) and analogs (HHC, HHCP). Evaluation of the relative abundance of 9(S)-HHC and 9(R)-HHC epimers in seized drug material revealed varying epimeric compositions between batches. Increased abundance of the less active 9(S)-HHC epimer empirically resulted in decreased potency, but sustained efficacy for the resulting diastereomeric mixture. In conclusion, monitoring of semisynthetic cannabinoids is encouraged as the dosing and the relative composition of stereoisomers can impact the harm potential of these drugs, relative to Δ9-THC products.
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Acknowledgements
The authors acknowledge The Special Research Fund (BOF) of Ghent University for supporting L.K.J. (grant number BOF20/DOC/051). Ann Houvenaghel, Goedele Van Nuffel and Valerie De Muyt are acknowledged for their support in the LC–QTOF analysis.
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Conceptualization: LKJ and CPS; methodology: LKJ, KVU and CS; investigation: LKJ and KVU; Resources: JBW, KWH, and DMI; CS; writing—original draft: LKJ; writing—review and editing: LKJ, KVU, JBW, KWH, DMI and CPS.
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The authors declare the following competing financial interest(s): None of the authors have personal financial conflicts of interest. Jeffrey B. Williams, Kirk W. Hering and Donna M. Iula are employees of Cayman Chemical Company, which commercially supplies products that were provided for this study.
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Janssens, L.K., Van Uytfanghe, K., Williams, J.B. et al. Investigation of the intrinsic cannabinoid activity of hemp-derived and semisynthetic cannabinoids with β-arrestin2 recruitment assays—and how this matters for the harm potential of seized drugs. Arch Toxicol (2024). https://doi.org/10.1007/s00204-024-03769-4
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DOI: https://doi.org/10.1007/s00204-024-03769-4