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
- Author
- Liesl Janssens (UGent) , Katleen Van Uytfanghe (UGent) , Jeffrey B. Williams, Kirk W. Hering, Donna M. Iula and Christophe Stove (UGent)
- Organization
- Project
- Abstract
- Cultivation of industrial low-Delta 9-tetrahydrocannabinol (Delta 9-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 Delta 9-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 beta-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 Delta 9-THC, based on either higher efficacy (Emax) or higher potency (EC50). Structure-activity relationships were assessed for Delta 9-THC and Delta 8-THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB1 activity were established for various THC isomers (Delta 7-THC, Delta 10-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 Delta 9-THC products.
- Keywords
- Semisynthetic cannabinoids, Phytocannabinoids, Pharmacological characterization, Toxicology, HHC, Bioassay, SAMPLES, CB1, AGONISTS, RAT
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01J1S7QP0RE4MGPY900R66YVK6
- MLA
- Janssens, Liesl, 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.” ARCHIVES OF TOXICOLOGY, vol. 98, no. 8, 2024, pp. 2619–30, doi:10.1007/s00204-024-03769-4.
- APA
- Janssens, L., Van Uytfanghe, K., Williams, J. B., Hering, K. W., Iula, D. M., & Stove, C. (2024). 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. ARCHIVES OF TOXICOLOGY, 98(8), 2619–2630. https://doi.org/10.1007/s00204-024-03769-4
- Chicago author-date
- Janssens, Liesl, Katleen Van Uytfanghe, Jeffrey B. Williams, Kirk W. Hering, Donna M. Iula, and Christophe Stove. 2024. “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.” ARCHIVES OF TOXICOLOGY 98 (8): 2619–30. https://doi.org/10.1007/s00204-024-03769-4.
- Chicago author-date (all authors)
- Janssens, Liesl, Katleen Van Uytfanghe, Jeffrey B. Williams, Kirk W. Hering, Donna M. Iula, and Christophe Stove. 2024. “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.” ARCHIVES OF TOXICOLOGY 98 (8): 2619–2630. doi:10.1007/s00204-024-03769-4.
- Vancouver
- 1.Janssens L, Van Uytfanghe K, Williams JB, Hering KW, Iula DM, Stove C. 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. ARCHIVES OF TOXICOLOGY. 2024;98(8):2619–30.
- IEEE
- [1]L. Janssens, K. Van Uytfanghe, J. B. Williams, K. W. Hering, D. M. Iula, and C. Stove, “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,” ARCHIVES OF TOXICOLOGY, vol. 98, no. 8, pp. 2619–2630, 2024.
@article{01J1S7QP0RE4MGPY900R66YVK6,
abstract = {{Cultivation of industrial low-Delta 9-tetrahydrocannabinol (Delta 9-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 Delta 9-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 beta-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 Delta 9-THC, based on either higher efficacy (Emax) or higher potency (EC50). Structure-activity relationships were assessed for Delta 9-THC and Delta 8-THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB1 activity were established for various THC isomers (Delta 7-THC, Delta 10-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 Delta 9-THC products.}},
author = {{Janssens, Liesl and Van Uytfanghe, Katleen and Williams, Jeffrey B. and Hering, Kirk W. and Iula, Donna M. and Stove, Christophe}},
issn = {{0340-5761}},
journal = {{ARCHIVES OF TOXICOLOGY}},
keywords = {{Semisynthetic cannabinoids,Phytocannabinoids,Pharmacological characterization,Toxicology,HHC,Bioassay,SAMPLES,CB1,AGONISTS,RAT}},
language = {{eng}},
number = {{8}},
pages = {{2619--2630}},
title = {{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}},
url = {{http://doi.org/10.1007/s00204-024-03769-4}},
volume = {{98}},
year = {{2024}},
}
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