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Chemical structures of (a) hexahydrocannabinol (HHC), (b) cannabigerol (CBG) and (c) cannabichromene (CBC).
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Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant Cannabis sativa L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the counter (OTC) in the form of food supplements, cosmetics a...
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Context 1
... discuss their psychotropic effects, the most common cannabinoids may be divided into two major groups according to the number of rings in the molecule. The first group is composed of tricyclic cannabinols including CBN, and all THC and hexahydrocannabinol (HHC, Figure 3a) isomers. The second group-which will be discussed later in this section-consists of bicyclic cannabinoids with CBD, cannabigerol (CBG, Figure 3b) and cannabichromene (CBC, Figure 3c) being the most prominent representatives. ...
Context 2
... first group is composed of tricyclic cannabinols including CBN, and all THC and hexahydrocannabinol (HHC, Figure 3a) isomers. The second group-which will be discussed later in this section-consists of bicyclic cannabinoids with CBD, cannabigerol (CBG, Figure 3b) and cannabichromene (CBC, Figure 3c) being the most prominent representatives. ...
Context 3
... first group is composed of tricyclic cannabinols including CBN, and all THC and hexahydrocannabinol (HHC, Figure 3a) isomers. The second group-which will be discussed later in this section-consists of bicyclic cannabinoids with CBD, cannabigerol (CBG, Figure 3b) and cannabichromene (CBC, Figure 3c) being the most prominent representatives. ...
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The use of cannabidiol (CBD) in electronic cigarettes is widespread. Previously, it was reported that CBD is partly transformed to THC in case smoking as a cigarette, however, the pyrolysis of this compound has not been assessed extensively. The aim of our study was to investigate the effect of temperature on the composition of pyrolysis products o...
Citations
... In vitro studies conducted in human and animal cell models confirm the conversion of CBD to THC in artificial gastric juice [22,23]. It is unclear how adequate levels of ∆9-THC and ∆8-THC can accumulate in humans after oral ingestion of CBD. ...
Citation: Bartkowiak-Wieczorek, J.; Mądry, E.; Książkiewicz, M.; Winkler-Galicki, J.; Szalata, M.; Szalata, M.; Jiménez, U.E.; Wielgus, K.; Grześkowiak, E.; Słomski, R.; et al. THC-Reduced Cannabis sativa L.-How Does the Solvent Determine the Bioavailability of Cannabinoids Given Orally? Nutrients 2023, 15, 2646. Abstract: The bioavailability levels of cannabidiol (CBD) and tetrahydrocannabinol (THC) determine their pharmacological effects. Therefore, for medical purposes, it is essential to obtain extracts containing the lowest possible content of the psychogenic component THC. In our extract, the CBD/THC ratio was 16:1, which is a high level compared to available medical preparations, where it is, on average, 1:1. This study assessed the bioavailability and stability of CBD and THC derived from Cannabis sativa L. with reduced THC content. The extract was orally administered (30 mg/kg) in two solvents, Rapae oleum and Cremophor, to forty-eight Wistar rats. The whole-blood and brain concentrations of CBD and THC were measured using liquid chromatography coupled with mass spectrometry detection. Much higher concentrations of CBD than THC were observed for both solvents in the whole-blood and brain after oral administration of the Cannabis sativa extract with a decreased THC content. The total bioavailability of both CBD and THC was higher for Rapae oleum compared to Cremophor. Some of the CBD was converted into THC in the body, which should be considered when using Cannabis sativa for medical purposes. The THC-reduced hemp extract in this study is a promising candidate for medical applications.
... In recent years, researchers have reported on the conversion of CBD to 9-THC. CBD has been found in studies to convert to THC under acidic circumstances [22]; also, according to a 2020 assessment of both in vitro and in vivo CBD conversion trials, these conversions did not occur in vivo [35]. Despite this, the possibility of misidentifying whether a sample contains CBD or THC remains, especially given the growing interest in CBD due to its nonpsychoactive qualities and possible medicinal advantages. ...
Citation: Salazar-Bermeo, J.; Moreno-Chamba, B.; Martínez-Madrid, M.C.; Valero, M.; Rodrigo-García, J.; Hosseinian, F.; Martín-Bermudo, F.; Aguado, M.; de la Torre, R.; Martí, N.; et al. Preventing Mislabeling: A Comparative Chromatographic Analysis for Classifying Medical and Industrial Cannabis. Molecules 2023, 28, 3552. https://doi. Abstract: Gas chromatography (GC) techniques for analyzing and determining the cannabinoid profile in cannabis (Cannabis sativa L.) are widely used in standard laboratories; however, these methods may mislabel the profile when used under rapid conditions. Our study aimed to highlight this problem and optimize GC column conditions and mass spectrometry (MS) parameters to accurately identify cannabinoids in both standards and forensic samples. The method was validated for linearity, selectivity, and precision. It was observed that when tetrahydrocannabinol (∆9-THC) and cannabidiolic acid (CBD-A) were examined using rapid GC conditions, the resulting derivatives generated identical retention times. Wider chromatographic conditions were applied. The linear range for each compound ranged from 0.02 µg/mL to 37.50 µg/mL. The R 2 values ranged from 0.996 to 0.999. The LOQ values ranged from 0.33 µg/mL to 5.83 µg/mL, and the LOD values ranged from 0.11 µg/mL to 1.92 µg/mL. The precision values ranged from 0.20% to 8.10% RSD. In addition, forensic samples were analyzed using liquid chromatography (HPLC-DAD) in an interlaboratory comparison test, with higher CBD and THC content than GC-MS determination (p < 0.05) in samples. Overall, this study highlights the importance of optimizing GC techniques to avoid mislabeling cannabinoids in cannabis samples.
... While THC has affinity preferably for the CB1 receptor, resulting in its psychoactive effect, activation of CB2 via CBD results in immune modulation [29]. CBD is not psychoactive but may influence the psychoactive effects elicited by THC [30][31][32]. ...
... Recently, it was reported that CBD in an acidic environment may degrade to yield psychotropic products including THC. This finding may be relevant for the storage stability of cannabis oil [32]. ...
The application of cannabis products in oncology receives interest, especially from patients. Despite the plethora of research data available, the added value in curative or palliative cancer care and the possible risks involved are insufficiently proven and therefore a matter of debate. We aim to give a recommendation on the position of cannabis products in clinical oncology by assessing recent literature. Various types of cannabis products, characteristics, quality and pharmacology are discussed. Standardisation is essential for reliable and reproducible quality. The oromucosal/sublingual route of administration is preferred over inhalation and drinking tea. Cannabinoids may inhibit efflux transporters and drug-metabolising enzymes, possibly inducing pharmacokinetic interactions with anticancer drugs being substrates for these proteins. This may enhance the cytostatic effect and/or drug-related adverse effects. Reversely, it may enable dose reduction. Similar interactions are likely with drugs used for symptom management treating pain, nausea, vomiting and anorexia. Cannabis products are usually well tolerated and may improve the quality of life of patients with cancer (although not unambiguously proven). The combination with immunotherapy seems undesirable because of the immunosuppressive action of cannabinoids. Further clinical research is warranted to scientifically support (refraining from) using cannabis products in patients with cancer.
... Acids can be used to catalyze the reaction converting CBD into psychotropic transformed substances, such as D 9 -THC, D 8 -THC, and hexahydrocannabinols (HHCs) [6]. Other than these major transformed products, hydroxy-CBD derivatives and hydroxy-HHC derivatives are observed under acid treatment of CBD [3,4]. Most of these transformed products are psychotropic substances. ...
Recently, cannabidiol (CBD), one of the major components of the Cannabis species, has been a focus in the cannabis industry due to its various pharmacological effects. Interestingly, CBD can be converted into several psychoactive cannabinoids, such as 9-tetrahydrocannabinol (Δ9-THC) and its structural isomers, under acidic reaction conditions. In this study, chemical transformation of CBD in ethanol solution was conducted with variation in pH at 2.0, 3.5, and 5.0 by addition of 0.1 M hydrochloric acid (HCl). These resulting solutions were derivatized with trimethylsilyl (TMS) reagent and analyzed using GC/MS-scan mode. Time profiles of CBD degradation and transformation of products were examined according to variations in pH and temperature. Several transformed products produced after the acidic reaction of CBD were identified by matching retention times and mass spectra to authentic standards. Regarding the identification of products without authentic standards, the EI-mass spectra of such cannabinoid-OTMS derivatives were interpreted according to structural class, suggesting mass fragmentation pathways. From the GC/MS data, Δ9-THC, CBC, and ethoxy-hexahydrocannabinol (HHC) analogs were shown to be major components, and THC isomers (Δ8- and Δ10-THCs) and 9-hydroxy-HHC were observed as minor components. Using time profile data, the acidity of the reaction solution was an important factor in degradation of CBD. Degradation of CBD and formation of THC rarely occurred at pH 5.0, even at 70 °C with a long process time of 24 h. In contrast, degradation of CBD occurred readily at pH 3.5 and 30 °C over a short process time and was further accelerated by lowering pH, increasing temperature, and lengthening the process time. Based on profile data and identified transformed products, formation pathways from the degradation of CBD under acidic reaction conditions are suggested. Among the transformed products, seven components are known to have psychoactive effects. Thus, industrial CBD manufacturing processes in food and cosmetic products should be carefully controlled. These results will provide important guidelines on the control of manufacturing processes, storage, fermentation processes, and new regulation in industrial applications of CBD.
... This delta-8-THC is then legally (for now) infused in many consumer products. Conversion of CBD to THC in artificial gastric juice (in vitro experiment) and conversion of CBD to THC and gradually to cannabinol (CBN; less psychoactive as compared to THC) in the CBD products stored for a long time are matters of concern [132,133]. However, theoretically, THC is absent in hemp seeds, but during harvesting or seed processing there are potential chances for THC contamination from the part that contains THC [134]. ...
... However, theoretically, THC is absent in hemp seeds, but during harvesting or seed processing there are potential chances for THC contamination from the part that contains THC [134]. Conversion of CBD to THC and CBN needs to be thoroughly examined and earlier research in this aspect has not provided clear conclusions [133]. ...
Hemp (Cannabis sativa L. ssp. sativa) has a long history of domestication due to its versatile uses. Recently, different sectors in the economy are investigating hemp cultivation to increase agro-nomic production and to limit delta-9-tetrahydrocannabinol (THC). Despite the rapid growth of hemp literature in recent years, it is still uncertain whether the knowledge gained from higher latitude regions is applicable to low latitude and tropical regions where hemp has not been grown traditionally. This review provides a comprehensive and updated survey of hemp agronomy, focusing on environmental and management factors influencing the growth, and yield of hemp, methods of cannabinoids detection and quantification, and hemp breeding. The review suggests some previous claims about hemp as a low input crop may not hold true in low-latitude regions. Additional research strategies, such as the integration of experimentation and modeling efforts, are encouraged to hasten new discovery. Furthermore, to effectively increase the outputs of value products (cannabinoids, seeds, fiber and biomass, etc.) while limiting the THC level, new col-laborations between hemp agronomists and economists may streamline the production process by increasing the efficiency of the total production system of hemp as a multifaceted crop.
... Enfin, si les travaux publiés dans la littérature confirment aujourd'hui que l'absorption de CBD pur n'entraîne pas l'apparition de THC dans la salive ou dans d'autres milieux biologiques [17], la consommation ponctuelle ou répétée de CBD contenant moins de 0,3 % de THC entraîne la présence de THC pendant au moins 3 heures après la prise [18,19]. Dans ce cas, les concentrations de CBD sont systématiquement supérieures aux concentrations de THC, permettant de faire la différence entre un usage de CBD et un usage de cannabis récréatif (THC) si on quantifie les deux composés, ce qui n'est pas le cas aujourd'hui avec la loi française qui n'exige que la présence ou l'absence de THC sans aucune quantification. ...
Cannabidiol (CBD) is a phytocannabinoid present in cannabis, obtained either by extraction from the plant or by synthesis. The latter has the advantage of being pure and contains few impurities, unlike CBD of plant origin. It is used by inhalation, ingestion or skin application. In France, the law stipulates that specialties containing CBD may contain up to 0.3% of tetrahydrocannabinol (THC), the psychoactive principle of cannabis. From an analytical point of view, it is therefore important to be able to quantify the two compounds as well as their metabolites in the various matrices that can be used clinically or forensically, in particular saliva and blood. The transformation of CBD into THC, which has long been suggested, appears to be an analytical artifact under certain conditions. CBD is not without toxicity, whether acute or chronic, as seems to attest to the serious adverse effects recorded by pharmacovigilance during the experiment currently being conducted in France by the Agence Nationale de Sécurité du Médicament et des Produits de Santé. Although CBD does not seem to modify driving abilities, driving a vehicle after consuming CBD containing up to 0.3% THC, and sometimes much more in products bought on the internet, can lead to a positive result in screening and confirmation tests by law enforcement agencies, whether salivary or blood tests, and therefore lead to a legal sanction.
... In 2019, the National Laboratory Certification Program (NLCP) [81] stated a potential analytical conversion of CBD to THC-COOH in urine samples (also using GC-MS and acidic derivatization agents). A year later, Golombek et al. [82] concluded that there was in fact a conversion from CBD to THC, but these conversions did not occur in vivo. Likewise, in OF samples CBD can convert to THC and ∆ 8 -THC in strong acidic conditions. ...
Cannabinoids are still the most consumed drugs of abuse worldwide. Despite being considered less harmful to human health, particularly if compared with opiates or cocaine, cannabis consumption has important medico-legal and public health consequences. For this reason, the development and optimization of sensitive analytical methods that allow the determination of these compounds in different biological specimens is important, involving relevant efforts from laboratories. This paper will discuss cannabis consumption; toxicokinetics, the most detected compounds in biological samples; and characteristics of the latter. In addition, a comprehensive review of extraction methods and analytical tools available for cannabinoid detection in selected biological specimens will be reviewed. Important issues such as pitfalls and cut-off values will be considered.
... CBD is a clear crystalline solid at room temperature with a melting point of 62-63 • C [34]. Both pyrolysis and certain acidic conditions may convert CBD to THC, and therefore, if pure CBD is sought, all processes that may heat the compound must be avoided [35]. ...
Dysmenorrhoea effects up to 90% of women of reproductive age, with medical management options including over-the-counter analgesia or hormonal contraception. There has been a recent surge in medicinal cannabis research and its analgesic properties. This paper aims to critically investigate the current research of medicinal cannabis for pain relief and to discuss its potential application to treat dysmenorrhoea. Relevant keywords, including medicinal cannabis, pain, cannabinoids, tetrahydrocannabinol, dysmenorrhoea, and clinical trial, have been searched in the PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library (Wiley) databases and a clinical trial website (clinicaltrials.gov). To identify the relevant studies for this paper, 84 papers were reviewed and 20 were discarded as irrelevant. This review critically evaluated cannabis-based medicines and their mechanism and properties in relation to pain relief. It also tabulated all clinical trials carried out investigating medicinal cannabis for pain relief and highlighted the side effects. In addition, the safety and toxicology of medicinal cannabis and barriers to use are highlighted. Two-thirds of the clinical trials summarised confirmed positive analgesic outcomes, with major side effects reported as nausea, drowsiness, and dry mouth. In conclusion, medicinal cannabis has promising applications in the management of dysmenorrhoea. The global medical cannabis market size was valued at USD 11.0 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 21.06% from 2022 to 2030. This will encourage academic as well as the pharmaceutical and medical device industries to study the application of medical cannabis in unmet clinical disorders.
... CBD is further unstable at room temperature (Jaidee et al., 2021) and undergoes air oxidation to form CBD hydroxyquinone (Pacifici et al., 2017;Watanabe et al., 1991). Isomerization of CBD to tetrahydrocannabinol under aqueous acidic conditions has also been reported (Gaoni and Mechoulam, 1966;Golombek et al., 2020). For these reasons, there remains ongoing interest in developing new compounds to target the cutaneous eCB system (Sheriff et al., 2020). ...
The endocannabinoid (eCB) system plays an active role in epidermal homeostasis. Phytocannabinoids such as CBD modulate this system but also act through eCB-independent mechanisms. This study evaluated effects of CBD, bakuchiol (BAK) and ethyl (linoleate/oleate) (ELN) in keratinocytes (KCs) and reconstituted human epidermis (RHE). Molecular docking simulations showed that each compound binds the active site of the eCB carrier fatty-acid-binding protein 5 (FABP5). However, BAK and ethyl linoleate bound this site with highest affinity when combined 1:1 (w/w) and in vitro assays showed that BAK+ELN most effectively inhibited FABP5 and fatty acid amide hydrolase (FAAH). In TNF-stimulated KCs, BAK+ELN reversed TNF-induced expression shifts and uniquely down-regulated type I interferon genes and PTGS2 (COX-2). BAK+ELN also repressed expression of genes linked to KC differentiation but up-regulated those associated with proliferation. Finally, BAK+ELN inhibited cortisol secretion in RHE skin (not observed with CBD). These results support a model in which BAK and ELN synergistically interact to inhibit eCB degradation, favoring eCB mobilization and inhibition of downstream inflammatory mediators (e.g., TNF, COX-2, type I interferon). Topical combination of these ingredients may thus enhance cutaneous eCB tone or potentiate other modulators, suggesting new ways to modulate the eCB system for innovative skincare product development. [200 words]
... 1 First described by Roger Adams in 1944, 2 HHCs have recently caught the attention of toxicology researchers and analysts since laboratories all over the world started to synthesize them, applying old semisynthetic approaches. 3 Indeed, HHCs can be obtained in two steps, by acidic treatment and successive hydrogenation, starting from cannabidiol (CBD, 1), or by direct reduction of D 9 -tetrahydrocannabinol (D 9 -THC, 2) or D 8 -tetrahydrocannabinol (D 8 -THC, 3) present in hemp, 4 as shown in Figure 1, to add them to hemp-derived products. ...
Introduction: Hexahydrocannabinols (HHCs), referred to as (9R)-HHC and (9S)-HHC diastereoisomers, are poorly studied cannabinoids naturally found in small concentrations in the pollen and the seeds of the hemp plants. Aim: In this study, for the first time, we describe the finding of (9R)-HHC and (9S)-HHC in two commercialized hemp derived products. Methods: The achievement of reference standards by semisynthetic or isolation approach allows us to develop and validate a gas chromatography mass spectrometry method for the identification and quantification of HHCs in hemp-derived resin. Results: The two analyzed samples showed percentage of 42.5 and 41.5 for (9R)-HHC and of 23.6 and 23.6 for (9S)-HHC. Conclusions: Despite the lack of in-depth studies about HHCs activity, potency, toxicity, and safety, these cannabinoids are emerging on the light-cannabis (hemp) market probably because legislations still do not clearly regulate them. Since analytical assay for hemp-derived products usually include only Δ9-THC, THC-A, CBD, and CBD-A, a thorough investigation could be carried out to reveal the possible addition of "new" compounds that might be a matter of safety.
