Cis-Δ9-tetrahydrocannabinolic acid occurrence in Cannabis sativa L.

Tolomeo, Francesco; Russo, Fabiana; Kaczorová, Dominika; Vandelli, Maria Angela; Biagini, Giuseppe; Laganà, Aldo; Capriotti, Anna Laura; Paris, Roberta; Fulvio, Flavia; Carbone, Luigi; Perrone, Elisabetta; Gigli, Giuseppe; Cannazza, Giuseppe; Citti, Cinzia

doi:10.1016/j.jpba.2022.114958

Cited by 14 publications

(16 citation statements)

References 23 publications

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“…The method was applied to analyze all phytocannabinoids and HHC epimers in ethanolic extracts of two hemp biomass samples (HHC-1 and HHC-2), one HHC hashish sample (HHC-3), and a pure HHC sample (HHC-4) (Figure S5, Supporting Information). Extraction of the analytes was performed using ethanol, as previous studies have demonstrated its superior ability to extract this class of compounds 2 – 4 , 24 – 26 . The chromatograms of the extracts were examined for interfering compounds using HRMS, which confirmed the absence of other cannabinoids at the retention time of the analytes.…”

Section: Resultsmentioning

confidence: 99%

“…The HESI parameters were optimized in previous works for cannabinoids: spray voltage 4200 kV and 3800 kV for HESI + and HESI- mode respectively, sheath gas 70 au, auxiliary gas 5 au, sweep gas 0.5 au, ion transfer tube temperature 390 °C and vaporizer temperature 150°C 26 , 29 . The mass analyzer was operated in both full scan (FS) and data-dependent acquisition (DDA) mode.…”

Section: Methodsmentioning

confidence: 99%

“…In FS mode the resolution was set at 60,000 FWHM (full width at half maximum), the RF lens level at 70%, the maximum injection time 54 ms, the m/z range at 150–750, and the isolation window at m/z 1.2. In DDA mode the resolution was set at 30,000 FWHM, the maximum injection time at 22 ms, the m/z range at 50–750, the isolation window at m/z 1.2, and the stepped normalized collision energy (NCE) at 20–40-100 26 , 29 . The injection volume was 5 µL.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and pharmacological activity of the epimers of hexahydrocannabinol (HHC)

Russo

Vandelli

Biagini

et al. 2023

Sci Rep

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Cannabis is a multifaceted plant with numerous therapeutic properties on one hand, and controversial psychotropic activities on the other hand, which are modulated by CB1 endocannabinoid receptors. Δ9-Tetrahydrocannabinol (Δ9-THC) has been identified as the main component responsible for the psychotropic effects, while its constitutional isomer cannabidiol (CBD) has shown completely different pharmacological properties. Due to its reported beneficial effects, Cannabis has gained global popularity and is openly sold in shops and online. To circumvent legal restrictions, semi-synthetic derivatives of CBD are now frequently added to cannabis products, producing "high" effects similar to those induced by Δ9-THC. The first semi-synthetic cannabinoid to appear in the EU was obtained through cyclization and hydrogenation of CBD, and is known as hexahydrocannabinol (HHC). Currently, there is limited knowledge regarding HHC, its pharmacological properties, and its prevalence, as it is not commonly investigated in routine toxicological assays. In this study, synthetic strategies were explored to obtain an excess of the active epimer of HHC. Furthermore, the two epimers were purified and individually tested for their cannabinomimetic activity. Lastly, a simple and rapid chromatographic method employing a UV detector and a high-resolution mass spectrometer was applied to identify and quantify up to ten major phytocannabinoids, as well as the HHC epimers, in commercial cannabis samples.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis and pharmacological activity of the epimers of hexahydrocannabinol (HHC)

Russo

Vandelli

Biagini

et al. 2023

Sci Rep

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“…Area of the peaks for each analyte was plotted against nominal concentration and the back-calculated concentration was checked to be within 15% of the nominal value. Samples of hemp in orescence and HHC hashish were extracted using the method reported in the German Pharmacopoeia for the extraction of phytocannabinoids from cannabis in orescence 21 . The extracts HHC-1 and HHC-2 from hemp in orescence were analysed after 100× dilution with mobile phase, while the extract HHC-3 from HHC hashish was 1000× diluted.…”

Section: Methodsmentioning

confidence: 99%

The semisynthetic cannabinoid Hexahydrocannabinol (HHC)

Russo

Vandelli

Biagini

et al. 2023

Preprint

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Cannabis is a double-faced plant with uncountable therapeutic properties, on one side, and controversial psychotropic activities, on the other side, modulated by CB1 endocannabinoid receptors. Δ9-Tetrahydrocannabinol (Δ9-THC) has been identified as the main component responsible for the psychotropic effects, while its isomer cannabidiol (CBD) has shown completely different pharmacological properties. Based on the remarkable beneficial effects, Cannabis has spread worldwide and it is openly sold in shops and online. In order to overcome restrictions due to legal issues, nowadays semi-synthetic derivatives of CBD are often added to cannabis products, obtaining “high” effects similar to those given by Δ9-THC. The first semi-synthetic cannabinoid appeared in the EU was obtained by cyclization and hydrogenation of CBD, and known as hexahydrocannabinol (HHC). At present, very little is known about HHC, its pharmacological properties, and diffusion, since it is not commonly investigated in routine toxicological assays. In the present work, the synthetic strategies aimed to obtain an excess of the active epimer of HHC were investigated and the two epimers were purified and individually tested for their cannabinomimetic activity. Lastly, a simple and fast chromatographic method with a UV detector and a high-resolution mass spectrometer was applied to identify and quantify up to ten major phytocannabinoids, as well as the HHC epimers in commercial cannabis samples.

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“…This is for a few potential reasons: (1) the compounds often do not have the possibility of forming chiral centers; this is typically because there are chemical bonds that are not saturated, i.e., the compound contains double bonds; (2) the compounds only have atomic centers with duplicate substituents, for instance, two hydrogens or two carbons; (3) the plant preferentially only synthesizes one of the enantiomers as a requirement for downstream processes. Because most of the compounds of interest (namely cannabidiol (CBD) and tetrahydrocannabinol (THC)) exist naturally as only a single isomer (with some low levels of other isomers having been reported recently [ 13 , 14 , 15 ]), the literature contains hundreds of examples of separations on classical achiral phases such as silica or octadecyl silane (ODS or C 18 ) [ 16 , 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Chiral Separation of Cannabichromene, Cannabicyclol, and Their Acidic Analogs on Polysaccharide Chiral Stationary Phases

Ferraro¹,

Umstead²

2023

Molecules

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Until recently, chirality has not been a major focus in the study of cannabinoids, as most cannabinoids of interest, such as cannabidiol and tetrahydrocannabinol, exist as a single isomer from natural sources. However, this is changing as more cannabinoids are identified, and compounds such as cannabichromene and cannabicyclol are emerging as potential investigatory candidates for varying indications. Because these molecules are chiral, the separation and study of the individual enantiomers’ biological and physiological effects should therefore be of interest. The purpose of this study was to identify analytical separation conditions and then adapt those conditions to preparative separation. This was accomplished with a column-screening approach on Daicel’s immobilized polysaccharide chiral stationary phases using non-traditional mobile phases, which included dichloromethane, ethyl acetate, and methyl tert-butyl ether under high-performance liquid chromatography conditions. CHIRALPAK® IK was found to separate all four compounds well with mobile phases containing hexane-dichloromethane (with or without an acidic additive). From these methods, the separation productivities were calculated to better visualize the separation scalability, which shows that the kilogram-scale separations of each are feasible.

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Cis-Δ9-tetrahydrocannabinolic acid occurrence in Cannabis sativa L.

Cited by 14 publications

References 23 publications

Synthesis and pharmacological activity of the epimers of hexahydrocannabinol (HHC)

Synthesis and pharmacological activity of the epimers of hexahydrocannabinol (HHC)

The semisynthetic cannabinoid Hexahydrocannabinol (HHC)

Chiral Separation of Cannabichromene, Cannabicyclol, and Their Acidic Analogs on Polysaccharide Chiral Stationary Phases

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