Cannabis and Cannabinoid Research最新文献

Introduction: The endocannabinoid system (ECS) is a widespread neurotransmitter system. A key characteristic of the ECS is that there are multiple endogenous ligands (endocannabinoids). Of these, the most extensively studied are arachidonoyl ethanolamide (AEA) and 2-arachidonoyl-glycerol (2-AG), both act as agonists at the cannabinoid CB₁ receptor. In humans, three CB₁ variants have been identified: hCB₁, considered the most abundant G protein-coupled receptor in the brain, alongside the less abundant and studied variants, hCB_1a and hCB_1b. CB₁ exhibits a preference for coupling with inhibitory G_i/o proteins, although its interactions with specific members of the G_i/o family remain poorly characterized. This study aimed to compare the AEA and 2-AG-induced activation of various G protein subtypes at CB₁. Furthermore, we compared the response of human CB₁ (hCB₁, hCB_1a, hCB_1b) and explored species differences by examining rodent receptors (mCB₁, rCB₁). Materials and Methods: Activation of individual G protein subtypes in HEK293 cells transiently expressing CB₁ was measured with G protein dissociation assay utilizing TRUPATH biosensors. The performance of the TRUPATH biosensors was evaluated using Z-factor analysis. Pathway potencies and efficacies were analyzed using the operational analysis of bias to determine G protein subtype selectivity for AEA and 2-AG. Results: Initial screening of TRUPATH biosensors performance revealed variable sensitivities within our system. Based on the biosensor performance, the G protein subtypes pursued for further characterization were G_i1, G_i3, G_oA, G_oB, G_Z, G₁₂, and G₁₃. Across all pathways, AEA demonstrated partial agonism, whereas 2-AG exhibited full or high-efficacy agonism. Notably, we provide direct evidence that the hCB₁ receptor couples to G₁₂ and G₁₃ proteins. Our findings do not indicate any evidence of G protein subtype selectivity. Similar observations were made across the human receptor variants (hCB₁, hCB_1a, hCB_1b), as well as at mCB₁ and rCB₁. Discussion: There was no evidence suggesting G protein subtype selectivity for AEA and 2-AG at CB₁, and this finding remained consistent across human receptor variants and different species.

Since ancient times, humanity has been exploring natural substances with the aim of increasing stress resistance, enhancing biochemical homeostasis, and treating different diseases. In this way, the objective of the present review is to compare the biological effects of cannabinoids (CNBs) with adaptogens, this exploration allows us to consider the controversy if they can be classified together considering the effects on the body. First, the work revises different features of adaptogens such as their chemical structure, ligand-receptors properties, and homeostasis-stress capabilities. Also, this review includes an overview of preclinical and clinical studies of the effect of adaptogens considering a broad spectrum of adverse biological, chemical, and physical factors. Then, the work does a review of the CNBs effects on the body including the principal uses for the treatment of several diseases as neurodegenerative disorders, arthritis, cancer, cardiovascular affections, diabetes, anxiety, chronic pain, among others. In addition, the different characteristics of the specific endocannabinoid system are described explaining the wide CNBs body effects. Finally, this review presents a comparative analysis between CNBs and adaptogens properties, expecting to contribute to understanding if CNBs can be classified as adaptogens.

Aim: Few studies have directly compared the bioavailability of different cannabinoid formulations. Our goal was to assess the pharmacokinetic parameters and relative bioavailability of two Δ9-tetrahydrocannabinol:cannabidiol (THC:CBD) formulations: orally administered THC:CBD extract and oromucosally administered nabiximols. Methods: This pilot crossover study counterbalanced (1) 1 mL of orally administered THC:CBD extract (10 mg/mL each of THC and CBD in grapeseed oil) and (2) oromucosally administered nabiximols (four sprays of 2.7 mg THC and 2.5 mg CBD per spray, for a total dose of 10.8 mg THC and 10 mg CBD). Blood samples were obtained pre-dose and at 16 post-dose timepoints over 24 h. Pharmacokinetic parameters were calculated for THC, 11-hydroxy-tetrahydrocannabinol (11-OH-THC), and CBD. Results: Twelve occasional cannabis users (6 male, 6 female) were tested under fasting conditions. C_max for THC and CBD was significantly higher with significantly shorter half-lives for THC:CBD extract versus nabiximols. C_max for nabiximols was significantly higher in males compared with females. Under both treatment conditions, THC and CBD were undetectable by 24 h post-dose, and 11-OH-THC was markedly reduced from its peak. No serious adverse events were reported. Conclusions: Little is known about the comparative pharmacokinetics of commercially available cannabis products. This pilot study shows that the extract formulation achieved higher THC and CBD concentrations within a shorter time frame than nabiximols. These findings may have implications for clinical populations using these formulations therapeutically. Future studies should examine multiple doses in the context of therapeutic outcomes to characterize the relative clinical utility of these formulations.

Background: Over the last decade, there has been a significant increase in the production of multiple tetrahydrocannabidiol (THC) related products via the acid catalysis of cannabidiol (CBD). The widespread availability of CBD and the unregulated or poorly regulated nature of its use have flooded the market with THC-containing products of unverifiable provenance and frequently contaminated by trace metals and residual solvents. Under non-optimized, poorly controlled, or harsh reaction conditions, these acid-catalyzed transformations yield multiple cannabinoids including Δ⁹-THC and Δ⁸-THC, along with numerous side products. These side products are rarely identified or quantified accurately, and their safety and pharmacology remain largely unknown. Aims: This review aims to present an up-to-date understanding of one of the fundamental transformations in cannabinoid chemistry: the cyclization of CBD to THC. This knowledge will facilitate the development of safer, cleaner, more affordable, and accessible cannabinoid products while guiding medical practitioners and regulators. Materials and Methods: We conducted a literature review of studies published over the last 5-6 years on the interconversion of CBD to THC. Our review focused on the following key aspects: (1) advances in understanding reaction mechanisms and optimizing desirable reaction outcomes; (2) development of new catalysts, including "green chemistry" approaches such as solid-supported acids; and (3) implementation of fit-for-purpose analytical methods to better characterize reaction outcomes and reassess the accuracy of cannabis and hemp product labeling. Results: Provided strict quality controls of materials, reaction conditions, and related isolation techniques, the latest research of the acid-catalyzed CBD cyclization shows that it is feasible to access products with elevated and consistently high quality, enriched with either CBD or THC fractions, in a cost-effective manner. Among a spectrum of possible products, easy access to low-potency THC compositions may be particularly relevant for serving the needs of medical patients consuming cannabis and hemp-derived cannabinoids including dose titration as well as to supporting safe and responsible use in recreational markets now saturated with overly potent products.

Background: Activation of cannabinoid receptor 1 (CB1R) in the nervous system modulates the processing of acute and chronic pain. CB1R activity is regulated by desensitization and internalization. SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1) inhibits the internalization of CB1R. This causes increased and prolonged association of the desensitized receptor with G protein-coupled receptor kinase 3 (GRK3) and beta-arrestin on the cell membrane and results in decreased activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Genetic deletion of SGIP1 in mice leads to altered CB1R-related functions, such as decreased anxiety-like behaviors, modified cannabinoid tetrad behaviors, reduced acute nociception, and increased sensitivity to analgesics. In this work, we asked if deletion of SGIP1 affects chronic nociception and analgesic effect of Δ⁹-tetrahydrocannabinol (THC) and WIN 55,212-2 (WIN) in mice. Methods: We measured tactile responses of hind paws to increasing pressure in wild-type and SGIP1 knock-out mice. Inflammation in the paw was induced by local injection of carrageenan. To determine the mechanical sensitivity, the paw withdrawal threshold (PWT) was measured using an electronic von Frey instrument with the progression of the applied force. Results: The responses to mechanical stimuli varied depending on the sex, genotype, and treatment. SGIP1 knock-out male mice exhibited lower PWT than wild-type males. On the contrary, the female mice exhibited comparable PWT. Following THC or WIN treatment in male mice, SGIP1 knock-out males exhibited PWT lower than wild-type males. THC treatment in SGIP1 knock-out females resulted in PWT higher than after THC treatment of wild-type females. However, SGIP1 knock-out and wild-type female mice exhibited similar PWT after WIN treatment. Conclusions: We provide evidence that SGIP1, possibly by interacting with CB1R, is involved in processing the responses to chronic pain. The absence of SGIP1 results in enhanced sensitivity to mechanical stimuli in males, but not females. The antinociceptive effect of THC is superior to that of WIN in SGIP1 knock-out mice in the carrageenan-induced model of chronic pain.

Introduction: This research investigated the impact of Cannabistilbene I on Angiotensin II (Ang II)-induced cardiac hypertrophy and its potential role in cytochrome P450 (CYP) enzymes and arachidonic acid (AA) metabolic pathways. Cardiac hypertrophy, a response to increased stress on the heart, can lead to severe cardiovascular diseases if not managed effectively. CYP enzymes and AA metabolites play critical roles in cardiac function and hypertrophy, making them important targets for therapeutic intervention. Methods: Adult human ventricular cardiomyocyte cell line (AC16) was cultured and treated with Cannabistilbene I in the presence and absence of Ang II. The effects on mRNA expression related to cardiac hypertrophic markers and CYP were analyzed using real-time polymerase chain reaction, while CYP protein levels were measured by Western blot analysis. AA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Results showed that Ang II triggered hypertrophy, as evidenced by the increase in hypertrophic marker expression, and enlarged the cell surface area, effects that were alleviated by Cannabistilbene I. Gene expression analysis indicated that Cannabistilbene I upregulated CYP1A1, leading to increased enzymatic activity, as evidenced by 7-ethoxyresorufin-O-deethylase assay. Furthermore, LC-MS/MS analysis of AA metabolites revealed that Ang II elevated midchain (R/S)-hydroxyeicosatetraenoic acid (HETE) concentrations, which were reduced by Cannabistilbene I. Notably, Cannabistilbene I selectively increased 19(S)-HETE concentration and reversed the Ang II-induced decline in 19(S)-HETE, suggesting a unique protective role. Conclusion: This study provides new insights into the potential of Cannabistilbene I in modulating AA metabolites and reducing Ang II-induced cardiac hypertrophy, revealing a new candidate as a therapeutic agent for cardiac hypertrophy.

Introduction: Ultra-endurance exercise events result in central fatigue, impacting on mental alertness and decision making. Endocannabinoids are typically elevated during endurance exercise and have been implicated in central processes such as learning and memory, but their role in central fatigue has never been studied. Materials and Methods: Twenty-four recreational male ultrarunners participated in a 100-km trail run, and 18 of them completed at least 60 km and were included in the analyses. A cognitive test battery to assess median reaction time (MRT) and median movement time during a reaction time task and median response latency during a rapid visual information processing task was completed prior to and immediately after the trail. Blood serum samples pre- and postexercise were analyzed for endocannabinoids and related lipids (anadamide: AEA; 2-arachidonoylglycerol: 2-AG; palmitoylethanolamide: PEA; oleoylethanolamide: OEA; stearoylethanolamine: SEA) via liquid chromatography-mass spectrometry. Results: Ultra-endurance exercise worsened all cognitive parameters and increased abundance of AEA, PEA, OEA, and SEA but not 2-AG. Interestingly, the exercise-induced change in MRT showed moderate, positive correlations with the change in different endocannabinoids, that is, AEA (r = 0.5164, p = 0.0338), PEA (r = 0.5466, p = 0.0251), and OEA (r = 0.5442, p = 0.0239). Conclusion: These results indicate a potential role of endocannabinoids on mental alertness following ultra-endurance exercise.

Background: In 2020, the Lebanese parliament legalized cannabis for medical and industrial use, sparking diverse reactions among health care professionals (HCP). Few studies have been conducted to reflect the position of HCP on the topic, and no previous studies targeted all physicians with relevant specialties or had a large sample size. The current study aimed to assess the knowledge, attitude, and practice of the Lebanese medical community toward medicinal cannabis (MC). Methods: A cross-sectional study was conducted targeting HCP from different backgrounds and specialties. The survey questionnaire was disseminated through different scientific societies in the Lebanese Order of Physicians and other professional bodies. An online survey was shared with oncologists, rheumatologists, psychiatrists, neurologists, pharmacists, and psychotherapists across different geographic regions. It covered questions about sociodemographic details, knowledge, attitude, and practice related to MC. Descriptive and bivariate analyses were performed. A total of 202 HCP responded to the survey, yielding a response rate of 34%. Results: Eighteen percent of the participants described their level of knowledge about the indications of MC as good. Twenty-five percent of the respondents are willing to prescribe, and 30% "may consider" it. Among those willing to prescribe, the majority may consider MC to treat chronic pain, palliative care, post-traumatic stress disorder, epilepsy, and anxiety. Respondents' knowledge about the side effects of MC is as follows: driving difficulties (82%), addiction (69%), drug interactions (65%), and weight gain (43%). Willingness to prescribe varies by medical specialty, previous clinical experience with MC, and gender. The majority of the participants expressed concerns about the potential harm of using MC and indicated that legalization would negatively impact society. Sixty-nine percent of the respondents reported not receiving any formal education about MC and agreed on the need to expand knowledge about its indications and side effects. The majority agreed that MC should be dispensed based on a prescription from a physician with special training and recognized the importance of establishing a national registry for patients undergoing MC treatment, as well as the necessity of guidelines for approval. Conclusion: The current data indicate that attitudes toward prescribing MC vary by medical specialty, gender, and clinical experience. Implementation of effective educational strategies in Lebanon to enhance HCP knowledge about MC and promote its proper use is crucial.