Search Results (8)

Hexahydrocannabinol (HHC), a hydrogenated derivative of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), is a semi-synthetic cannabinoid marketed as an alternative to Δ⁹-THC. Its hydroxylated metabolite, 8-hydroxyhexahydrocannabinol (8-OH-HHC), exists as four stereoisomers: (6aR,8R,9R,10aR), (6aR,8S,9S,10aR), (6aR,8S,9R,10aR), and (6aR,8R,9S,10aR). However, the lack of reference standards has hindered pharmacokinetic and forensic studies. This work reports the first stereoselective synthesis and structural confirmation of all four 8-OH-HHC stereoisomers. Two strategies were employed: hydroboration–oxidation and epoxidation–reduction. Hydroboration of Δ⁸-THC with BH₃·THF followed by oxidation predominantly produced anti-isomers (6aR,8R,9R,10aR) and (6aR,8S,9S,10aR) in moderate yields, along with small amounts of syn-isomer (6aR,8S,9R,10aR), suggesting an atypical mechanistic pathway. In contrast, syn-isomers (6aR,8S,9R,10aR) and (6aR,8R,9S,10aR) were accessed via epoxidation of Δ⁸-THC acetate using mCPBA and subsequent reduction with NaBH₃CN/BF₃·OEt₂, affording the desired products with moderate selectivity. Absolute configurations were confirmed by nuclear Overhauser effect spectroscopy (NOESY). These methods will facilitate future pharmacokinetic and forensic research and support the development of improved detection strategies. Full article

Cannabis and its derivatives are increasingly popular. The public perception of “cannabis” is commonly related to abuse potential with no sharp distinction to “marijuana”, “cannabinoids”, “hemp”, and cannabis derivatives. Delta 9-tetrahydrocannabinol (THC)—rich cannabis (“marijuana”), needs to be distinguished from hemp and cannabidiol (CBD)—rich; the former is psychotomimetic, while the latter is not, and it is increasingly used as a “health product”; the phytochemical composition makes the difference. However, this is still inadequately addressed. Without a detailed characterization of the components and effects conclusions cannot be generalized and are only applicable to the product used. Cannabis varieties have a highly variable phytochemical composition; the effects cannot always be attributed solely to the “main cannabinoids.” Growth conditions and processing methods also have a significant influence on the properties of the final product, even when the same cannabis variety is used. Therefore, the few comparative studies between extracts and the corresponding pure cannabinoids often produce conflicting results, as numerous preclinical and clinical examples demonstrate. They also show how little attention is paid to the phytochemical profile, even in scientific publications. Both in scientific research and consumer products, the phytochemical profile beyond the main cannabinoids should be disclosed in detail, especially since new cannabis products containing semi-synthetic CBD derivatives have recently entered the market. Full article

Background and Clinical Significance: The recreational use of semisynthetic cannabinoids (SSCs) is increasing, and SSCs account for more than 40% of all new substances reported at the European level. Although designed to mimic the effects of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, evidence suggests that certain SSCs may elicit stronger, prolonged and unintended pharmacological effects. SSCs are easily accessible, particularly via online retailers, but in some countries, SSCs are also sold in convenience stores or specialty stores selling legal low-THC or cannabidiol (CBD) products. Often, SSCs are sold as “legal highs” and are found in various forms, including herbal mixtures (spice), vape products, and edibles such as cookies and candies, specifically targeting young users, including children. The products are frequently mislabeled and sold as souvenirs or aromatic potpourri to bypass regulations. Case Presentation: We present a case of a male in his early forties who was admitted to the Emergency Department due to noticeable deficits in alertness and responsiveness after recreational ingestion of two cannabis cookies labeled to contain 40 mg “CC9” and a bite of a gummy with unknown contents. The patient experienced vomiting and visual problems, and suffered from nine days of cognitive and physical impairment. HHC-C9, a novel SSC, was detected in blood through forensic toxicological analysis. Conclusions: Recreational use of HHC-C9 can cause vomiting, visual disturbances, and drowsiness, potentially requiring hospital treatment. Potency, clinical effects, and toxicity of SSCs can vary significantly, and in combination with easy accessibility, SSCs pose a potential risk of intoxication to unaware consumers. Full article

Since the 2018 Farm Bill legalized hemp, semi-synthetic cannabinoids, typically derived from hemp-extracted CBD, have been marketed as offering a “legal high”, raising concerns about consumer safety, labeling, and regulation. Consequently, the potency analysis of these compounds has become increasingly important. To address this need, an LC-DAD method was developed for the quantification of seventeen cannabinoids, selected based on the synthetic pathways of semi-synthetic cannabinoids. These included naturally occurring compounds, semi-synthetic derivatives, and byproducts (CBC, CBD, CBDV, CBG, CBN, CBN-O-acetate, CBT, 9(R)-HHC, 9(S)-HHC, 9(R)-HHC-O-acetate, 9(S)-HHC-O-acetate, Δ⁸-THC, Δ⁹-THC, Δ^9,11-THC, Δ⁸-THC-O-acetate, Δ⁹-THC-O-acetate, and Δ⁹-THCV), using abnormal CBD as an internal standard. The method was validated according to ISO 17025 guidelines, demonstrating a linear calibration range from 0.1 to 50 µg/mL. The method was further applied to the potency analysis of one Δ⁸-THC, two THC-O-acetate, two HHC, and one HHC-O-acetate vaping oil sample. Using an innovative method to recover the contents of vaping cartridges, cannabinoids were extracted using methanol, diluted to a concentration of 50 µg/mL, and analyzed using the validated LC-DAD method, which provided a quantifiable range of 0.1 to 100% (w/w). Method specificity was evaluated using ESI/TOFMS and showed minimal interference, despite the presence of other isomers of the semi-synthetic cannabinoids in the samples. Full article

Δ⁹-Tetrahydrocannabiphorol (Δ⁹-THCP, THCP) a psychoactive cannabinoid recently found in Cannabis sativa L., is widely used as a legal marijuana substitute. THCP is encountered in sprayed Cannabis, edibles, and vape liquids. The distributors of such products claim that the THCP in use originates from a natural source. The legal status of this substance varies from country to country. THCP and similar cannabinoids with a dibenzoyprane structure have been banned in Switzerland since October 2023. A vape liquid, which contains 90% THCP and 10% terpenes according to the distributor, was analyzed by gas chromatography coupled with mass spectrometry (GC-MS). Besides CBP, CBDP, Δ⁹-THCP and Δ⁸-THCP and some terpenes, other compounds were found which probably result from a synthetic procedure. This sample contained 5-heptylresorcinol, the heptyl homologue of olivetol, a common precursor for the synthesis of tetrahydrocannabinol (THC). Bisalkylated compounds (m/z 476) were found as a result of the reaction of one equivalent of 5-heptylresorcinol with two equivalents of (+)-p-mentha-1,8-dien-4-ol or another precursor. Similar bisalkylated compounds are known as undesired side products of the synthesis of THC. The sample contained unidentified isomers of Δ⁹-THCP, presumably abnormal cannabinoids (abn-Δ⁹-THCP; abn-Δ⁸-THCP) and iso-cannabinoids (iso-THCP). Chiral derivatization with Mosher acid chlorides revealed that the Δ⁹-THCP in the sample was enantiopure. Full article

The aim of this research was to develop and deploy efficient deep convolutional neural network (DCNN) frameworks for detecting and discriminating between various categories of designer drugs. These are of particular relevance in forensic contexts, aiding efforts to prevent and counter drug use and trafficking and supporting associated legal investigations. Our multinomial classification architectures, based on Attenuated Total Reflectance Fourier-Transform Infrared (ATR-FTIR) spectra, are primarily tailored to accurately identify synthetic cannabinoids. Within the scope of our dataset, they also adeptly detect other forensically significant drugs and misused prescription medications. The artificial intelligence (AI) models we developed use two platforms: our custom-designed, pre-trained Convolutional Autoencoder (CAE) and a structure derived from the Vision Transformer Trained on ImageNet Competition Data (ViT-B/32) model. In order to compare and refine our models, various loss functions (cross-entropy and focal loss) and optimization algorithms (Adaptive Moment Estimation, Stochastic Gradient Descent, Sign Stochastic Gradient Descent, and Root Mean Square Propagation) were tested and evaluated at differing learning rates. This study shows that innovative transfer learning methods, which integrate both unsupervised and supervised techniques with spectroscopic data pre-processing (ATR correction, normalization, smoothing) and present significant benefits. Their effectiveness in training AI systems on limited, imbalanced datasets is particularly notable. The strategic deployment of CAEs, complemented by data augmentation and synthetic sample generation using the Synthetic Minority Oversampling Technique (SMOTE) and class weights, effectively address the challenges posed by such datasets. The robustness and adaptability of our DCNN models are discussed, emphasizing their reliability and portability for real-world applications. Beyond their primary forensic utility, these systems demonstrate versatility, making them suitable for broader computer vision tasks, notably image classification and object detection. Full article

Dronabinol, a natural cannabinoid, and its semi-synthetic derivative, nabilone, are marketed as medicines in several countries. The aim of our work was to systematically evaluate the frequency of adverse events related to dronabinol or nabilone treatment compared to placebo. Scientific databases were searched for placebo-controlled clinical studies of patients receiving either dronabinol or nabilone therapy with placebo control groups. This meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register. There were 16 trials included in the meta-analysis. In the nabilone studies, drowsiness was more than 7 times as frequent in patients treated with nabilone than in the placebo group (OR: 7.25; 95% CI: 1.64–31.95), and the risk of dizziness (OR: 21.14; 95% CI: 2.92–152.75) and dry mouth was also higher (OR: 17.23; 95% CI: 4.33–68.55). The frequency of headache was not different in the two groups. In case of dronabinol, the frequency of dry mouth (OR: 5.58; 95% CI: 3.19–9.78), dizziness (OR: 4.60 95% CI: 2.39–8.83) and headache (OR: 2.90; 95% CI: 1.07–7.85) was significantly higher in the dronabinol groups, whereas in case of nausea, drowsiness and fatigue there was no difference. The severity of adverse events was typically mild-to-moderate and transient. In a risk-benefit assessment, these adverse effects are acceptable compared to the achievable benefit. However, considering the diversity of the adverse effects, more studies are needed to provide a more accurate assessment on the side effect profiles of these two compounds. Full article

In 2020, nearly one-third of new drugs on the global market were synthetic cannabinoids including the drug of abuse N-(1-adamantyl)-1-(5-pentyl)-1H-indazole-3-carboxamide (5F-APINACA, 5F-AKB48). Knowledge of 5F-APINACA metabolism provides a critical mechanistic basis to interpret and predict abuser outcomes. Prior qualitative studies identified which metabolic processes occur but not the order and extent of them and often relied on problematic “semi-quantitative” mass spectroscopic (MS) approaches. We capitalized on 5F-APINACA absorbance for quantitation while leveraging MS to characterize metabolite structures for measuring 5F-APINACA steady-state kinetics. We demonstrated the reliability of absorbance and not MS for inferring metabolite levels. Human liver microsomal reactions yielded eight metabolites by MS but only five by absorbance. Subsequent kinetic studies on primary and secondary metabolites revealed highly efficient mono- and dihydroxylation of the adamantyl group and much less efficient oxidative defluorination at the N-pentyl terminus. Based on regiospecificity and kinetics, we constructed pathways for competing and intersecting steps in 5F-APINACA metabolism. Overall efficiency for adamantyl oxidation was 17-fold higher than that for oxidative defluorination, showing significant bias in metabolic flux and subsequent metabolite profile compositions. Lastly, our analytical approach provides a powerful new strategy to more accurately assess metabolic kinetics for other understudied synthetic cannabinoids possessing the indazole chromophore. Full article