Cytogenotoxicity and inflammatory response in liver of rats exposed to different doses of cannabis nano emulsions.

Cannabis is the most used illicit substance for recreational purposes around the world. However, it has become increasingly common to witness the use of approved cannabis preparations for symptoms management in various diseases. The aim of this study was to investigate the effects of cannabis nano emulsion in the liver of Wistar rats, with different proportions of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). For this, a total of 40 male Wistar rats were distributed into 5 groups, as follows (n = 8 per group): Control: G1, Experimental group (G2): treated with cannabis nano emulsion (THC and CBD) at a dose of 2.5 mg/kg, Experimental group (G3): treated with cannabis nano emulsion (THC and CBD) at a dose of 5 mg/kg, Experimental group (G4): treated with cannabis nano emulsion (CBD) at a dose of 2.5 mg/kg; Experimental group (G5): treated with cannabis nano emulsion (CBD) at a dose of 5 mg/kg. Exposure to the nano emulsion was carried out for 21 days, once a day, orally (gavage). Our results showed that cannabis nano emulsions at higher doses (5 mg/kg), regardless of the composition, induced histopathologic changes in the liver (G3 and G5) in comparison with the control group. In line with that, placental glutathione S-transferase (GST-P) positive foci increased in both G3 and G5 (p < 0.05), as well as the immune expression of Ki-67, vascular endothelial growth factor (VEGF) and p53 (p < 0.05). Also, the nano emulsion intake induced an increase in the number of micronucleated hepatocytes in G5 (p < 0.05) whereas G3 showed an increase in binucleated cells (p < 0.05). As for metanuclear alterations, karyolysis and pyknosis had an increased frequency in G3 (p < 0.05). Taken together, the results show that intake of cannabis nano emulsion may induce degenerative changes and genotoxicity in the liver in higher doses, demonstrating a clear dose-response relationship.

Cannabidiol Exposure During Gestation Leads to Adverse Cardiac Outcomes Early in Postnatal Life in Male Rat Offspring.

Introduction: Studies indicate that ∼7% of pregnant individuals in North America consume cannabis in pregnancy. Pre-clinical studies have established that maternal exposure to Δ9-tetrahydrocannabinol (THC; major psychoactive component in cannabis) leads to fetal growth restriction and impaired cardiac function in offspring. However, the effects of maternal exposure to cannabidiol (CBD; major non-euphoric constituent) on cardiac outcomes in offspring remain unknown. Therefore, our objective is to investigate the functional and underlying molecular impacts in the hearts of offspring exposed to CBD in pregnancy. Methods: Pregnant Wistar rats were exposed to either 3 or 30 mg/kg CBD or vehicle control i.p. daily from gestational day 6 to term. Echocardiography was used to assess cardiac function in male and female offspring at postnatal day (PND) 21. Furthermore, quantitative polymerase chain reaction (qPCR), immunoblotting, and bulk RNA-sequencing (RNA-seq) were performed on PND21 offspring hearts. Results: Despite no differences in the heart-to-body weight ratio, both doses of CBD led to reduced cardiac function exclusively in male offspring at 3 weeks of age. Underlying this, significant alterations in the expression of the endocannabinoid system (ECS; e.g., decreased cannabinoid receptor 2) were observed. In addition, bulk RNA-seq data demonstrated transcriptional pathways significantly enriched in mitochondrial function/metabolism as well as development. Conclusion: Collectively, we demonstrated for the first time that gestational exposure to CBD, a constituent perceived as safe, leads to early sex-specific postnatal cardiac deficits and alterations in the cardiac ECS in offspring.

Cannabidiol Exposure During Rat Pregnancy Leads to Labyrinth-Specific Vascular Defects in the Placenta and Reduced Fetal Growth.

Introduction: Cannabis use is increasing among pregnant people, and cannabidiol (CBD), a constituent of cannabis, is often perceived as "natural" and "safe" as it is non-intoxicating. In utero, cannabis exposure is associated with negative health outcomes, including fetal growth restriction (FGR). The placenta supplies oxygen and nutrients to the fetus, and alterations in placental development can lead to FGR. While there has been some investigation into the effects of Δ9-THC, there has been limited investigation into the impacts of in utero gestational CBD exposure on the placenta. Methods: This study used histological and transcriptomic analysis of embryonic day (E)19.5 rat placentas from vehicle and CBD (3 mg/kg intraperitoneal injection) exposed pregnancies (E6.5-18.5). Results: The study revealed that pups from CBD-exposed pregnancies were 10% smaller, with the placentae displaying a decreased fetal blood space perimeter-to-area ratio. The transcriptomic analysis supported compromised angiogenesis and blood vessel formation with downregulated biological processes, including tube morphogenesis, angiogenesis, blood vessel morphogenesis, blood vessel development and vasculature development. Further, the CBD-exposed placentas displayed changed expression of glucose transporters (decreased GLUT1 and GR expression and increased GLUT3 expression). Transcriptomic analysis further revealed upregulated biological processes associated with metabolism. Finally, histological and transcriptomic analysis revealed altered cell populations within the placenta, specifically to syncytiotrophoblast layer II and endothelial cells. Conclusion: Together these results suggest that the structural changes in CDB-exposed placentae, including the altered expression of nutrient transporters and the changes to the placental fetal vasculature, may underlie the reduced fetal growth.

High Concentrations of Cannabidiol Induce Neurotoxicity in Neurosphere Culture System.

Recent studies have demonstrated that cannabinoids are potentially effective in the treatment of various neurological conditions, and cannabidiol (CBD), one of the most studied compounds, has been proposed as a non-toxic option. However, the adverse effects of CBD on neurodevelopmental processes have rarely been studied in cell culture systems. To better understand CBD's influence on neurodevelopment, we exposed neural progenitor cells (NPCs) to different concentrations of CBD (1 µM, 5 µM, and 10 µM). We assessed the morphology, migration, differentiation, cell death, and gene expression in 2D and 3D bioprinted models to stimulate physiological conditions more effectively. Our results showed that CBD was more toxic at higher concentrations (5 µM and 10 µM) and affected the viability of NPCs than at lower concentrations (1 µM), in both 2D and 3D models. Moreover, our study revealed that higher concentrations of CBD drastically reduced the size of neurospheres and the number of NPCs within neurospheres, impaired the morphology and mobility of neurons and astrocytes after differentiation, and reduced neurite sprouting. Interestingly, we also found that CBD alters cellular metabolism by influencing the expression of glycolytic and ß-oxidative enzymes in the early and late stages of metabolic pathways. Therefore, our study demonstrated that higher concentrations of CBD promote important changes in cellular functions that are crucial during CNS development.

Acute and chronic cannabidiol treatment: In vitro toxicological aspects on human oral cells.

Cannabidiol is gaining increasing interest for its potential anti-inflammatory, immunomodulatory, and antineoplastic effects. The purpose of this study is to investigate the biological effects of acute and chronic CBD administration on gingival fibroblasts and oral keratinocytes. Viability, morphology, migration, apoptosis and cell cycle, and expression of related genes (p53, BCL2, p21, and BAX) and of endocannabinoid system receptors (CB1, CB2 and GPR55) with real-time PCR and DNA damage with phospho-γ-H2AX immunofluorescence detection were analyzed. Concentrations between 100 µM and 0.001 µM were used: 50 µM (toxic dose), 25 µM (viability promoter), and 1 µM (nontoxic), were selected for subsequent chronic analysis. Acute treatment reveals significant effects than chronic, in particular in fibroblasts: concentrations ≥50 µM are highly cytotoxic, with increased apoptosis and reduced migration. Cell death correlates with increased p53 and BAX, followed by arrest in G0/G1 phase, with elevated p21 levels, suggesting a time- and dose-dependent damage. An increase in H2AX phosphorylation was observed with 25 µM and 50 µM, while 1 µM was biocompatible. Keratinocytes showed less cytotoxic effect than fibroblasts. Induced cell damage was dose- and time-related, with less damage after chronic treatment. Further investigations are needed with longer time frames to evaluate CBD dose- and time-dependent effects to identify an effective therapeutic dose.

Evaluation of the effect of cannabidiol on the THLE-2 liver cell line exposed to lead.

Environmental and soil pollution increase the likelihood of human exposure to toxic metals. Therefore, there is a need for new methods and substances to protect individuals against the harmful effects caused by toxic metals. The study is the first to aim at determining the protective effect of cannabidiol (CBD) against oxidative stress and inflammation induced by toxic metal exposure in Transformed Human Liver Epithelial-2 (THLE-2) cell lines representing healthy liver cells. The IC50 value was determined by exposing THLE-2 human liver healthy cell line to different molarities of lead (Pb) using the XTT kit. The protective efficacy of CBD was assessed by adding 5 µM CBD in addition to the Pb doses determined at IC50 levels to the Pb groups created in cell lines. The levels of GSH, MDA, MPO, CAT, TNF-α, IL-1ß, and IL-6 in cell lines were determined using ELISA kits. The inhibition of toxic metal entry into the cells by CBD was assessed through ICP-MS analysis. The IC50 value for Pb was determined as 10 µM in 2D cell lines and 25 µM in 3D cell lines. It was observed that the application of 5 µM concentration of CBD, along with the determined IC50 doses for Pb, increased the cell proliferation rate. Furthermore, the decrease in GSH and CAT levels and the increase in MDA, MPO, TNF-α, IL-1ß, and IL-6 levels observed in cell lines treated only with Pb were reversed with the application of CBD. The ICP-MS analysis revealed that CBD reduced the cellular uptake of Pb. The reversal of oxidative stress and inflammation induced by Pb, the increase in cell proliferation, and the reduction in the cellular uptake of toxic metals by CBD can be considered as strong evidence for the protective use of CBD in Pb exposures.

Gestational exposure to cannabidiol leads to glucose intolerance in 3-month-old male offspring.

Reports in North America suggest that up to 20% of young women (18-24 years) use cannabis during pregnancy. This is concerning given clinical studies indicate that maternal cannabis use is associated with fetal growth restriction and dysglycemia in the offspring. Preclinical studies demonstrated that prenatal exposure to Δ9-tetrahydrocannabinol, the main psychoactive component of cannabis, in rat dams led to female-specific deficits in ß-cell mass and glucose intolerance/insulin resistance. Yet to date, the contributions of cannabidiol (CBD), the primary nonpsychoactive compound in cannabis, remain elusive. This study aimed to define the effects of in utero cannabidiol (CBD) exposure on postnatal glucose regulation. Pregnant Wistar rat dams received daily intraperitoneal injections of either a vehicle solution or 3 mg/kg of CBD from gestational day (GD) 6 to parturition. CBD exposure did not lead to observable changes in maternal or neonatal outcomes; however, by 3 months of age male CBD-exposed offspring exhibited glucose intolerance despite no changes in pancreatic ß/α-cell mass. Transcriptomic analysis on the livers of these CBD-exposed males revealed altered gene expression of circadian rhythm clock machinery, which is linked to systemic glucose intolerance. Furthermore, alterations in hepatic developmental and metabolic processes were also observed, suggesting gestational CBD exposure has a long-lasting detrimental effect on liver health throughout life. Collectively, these results indicate that exposure to CBD alone in pregnancy may be detrimental to the metabolic health of the offspring later in life.

Induction of apoptosis by cannabidiol and its main metabolites in human Leydig cells.

Cannabidiol (CBD) is one of the most prevalent and abundant cannabinoids extracted from the plant Cannabis sativa. CBD has been reported to induce male reproductive toxicity in animal models. In this study, we examined the effects of CBD and its main metabolites, 7-carboxy-CBD and 7-hydroxy-CBD, on primary human Leydig cells, which play a crucial role in male reproductive health. Our results showed that CBD, at concentrations below the Bayesian benchmark dose (BMD)50, inhibited the growth of human Leydig cells by arresting the cell cycle at G1/S transition, disrupting cell cycle regulators, and decreasing DNA synthesis. Concentration-response transcriptomic profiling identified that apoptosis was one of the top biological processes significantly affected by treatment with CBD for 24 h. The occurrence of apoptosis was confirmed by increased activation of caspase-3/7 and an increased proportion of annexin V and propidium iodide (PI)-positive cells. Similar to CBD, both 7-carboxy-CBD and 7-hydroxy-CBD decreased cell viability and induced apoptosis after treatment for 24 h. 7-Hydroxy-CBD and 7-carboxy-CBD showed lower cytotoxicity than CBD, and 7-carboxy-CBD had the lowest cytotoxicity among the three compounds. Our findings revealed that CBD and its main metabolites can cause adverse effects on primary human Leydig cells.

Can cannabidiol (CBD) help with low back pain?

INTRODUCTION AND OBJECTIVE: Low back pain (LBP) is a major cause of disability and the main reason why individual patients need medical attention. Pharmacological treatment options for LBP are limited and are often associated with serious side-effects. This makes it necessary to search for new painkillers. One potential therapeutic agent is cannabidiol (CDB). Cannabidiol and tetrahydrocannabinol are the most researched components of cannabis, the plant more commonly known as marijuana or hemp. To the best of our knowledge, this is the first narrative review of the effects of CBD alone on acute and chronic back pain. REVIEW METHODS: Based on the guidelines provided by the Primary Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA), the PubMed/ MEDLINE database was used to identify articles for analysis from the last 30 years. Due to the limited number of studies on this topic, all types of studies that met the inclusion criteria were included. After analysis, 10 studies were included in this review. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: Currently, the use of medical marijuana continues to increase and the Food and Drug Administration (FDA) has already approved four cannabis-based drugs. Cannabidiol (CBD) is a relatively safe substance for humans and generally well tolerated. It is a substance that is easily available and often taken by patients with LBP. SUMMARY: Evidence for the effectiveness of CBD in the treatment of acute low back pain is lacking. There was only one clinical trial conducted in the Emergency Department that showed no superiority of CBD over placebo in acute LBP. The majority of studies concern chronic rather than acute LBP. Although most of the results suggest a beneficial effect of cannabinoids in relieving chronic LBP, hard evidence is lacking. Rigorous randomized controlled trials are needed.

Effects of a combination of cannabidiol and delta-9-tetrahydrocannabinol on key biological functions of HTR-8/SVneo extravillous trophoblast cells.

In recent years, cannabis use has increased among pregnant women. In addition, the phytocannabinoids cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) alone or in combination are being used for therapeutical applications. THC and CBD are able to cross the placenta and a lot remains unknown concerning their impact on angiogenesis and extravillous trophoblasts' (EVTs) migration and invasion, which are essential processes for placentation. Thus, in this study, the HTR-8/SVneo cell line was employed to evaluate the effects of CBD, THC and of their combination (1:1, 2 µM). Cannabinoids affected epithelial-mesenchymal transition, as showed by increased expression of the epithelial protein marker E-cadherin for CBD and CBD plus THC treatments, and decrease of mesenchymal intermediate filament vimentin for all treatments. The gene expression of the metalloproteinases MMP2 and MMP9, and of their inhibitors TIMP1 and TIMP2 was increased, except the latter for THC treatment. Moreover, CBD reduced cell migration and invasion, an effect that was enhanced by its combination with THC. CBD with or without THC also upregulated the gene expression of PGF, while the anti-angiogenic factor sFLT1 was increased for all treatments. VEGFA and FLT1 were not affected. Alone or combined CBD and THC also decreased tube segments' length. Additionally, ERK1/2 and STAT3 phosphorylation was increased in the CBD and CBD plus THC-treated cells, while THC only activated STAT3. AKT activation was only affected by CBD. This work demonstrates that the exposure to cannabinoid-based products containing CBD and/or THC, may interfere with key processes of EVTs differentiation. Therefore, crucial phases of placental development can be affected, compromising pregnancy success.

Genotoxicity evaluation of cannabidiol.

Consumer use of cannabidiol (CBD) for personal wellness purposes has garnered much public interest. However, safety-related data on CBD in the public domain are limited, including a lack of quality studies evaluating its genotoxic potential. The quality of available studies is limited due to the test material used (e.g., low CBD purity) and/or study design, leading some global regulatory agencies to highlight genotoxicity as an important data gap for CBD. To address this gap, the genotoxic potential of a pure CBD isolate was investigated in a battery of three genotoxicity assays conducted according to OECD testing guidelines. In an in vitro microbial reverse mutation assay, CBD up to 5000 µg/plate was negative in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, and Escherichia coli strain WP2 uvrA, with and without metabolic activation. Testing in an in vitro micronucleus assay was negative in human TK6 cells up to 10-11 µg/mL, with and without metabolic activation. Finally, an in vivo micronucleus assay conducted in male and female rats was negative for genotoxicity up to 1000 mg/kg-bw/d. Bioanalysis of CBD and its primary metabolite, 7-carboxy CBD, confirmed a dose-related increase in plasma exposure. Together, these assays indicate that CBD is unlikely to pose a genotoxic hazard.

Short-term exposure of Cannabidiol on Zebrafish (Danio Rerio): Reproductive Toxicity.

Cannabidiol (CBD), a medically active component of hemp, is a popular ingredient in healthcare and personal-care products. The increasing demand for CBD and the legalization of hemp growth may promote chronic exposure of non-target organisms to CBD. In this study, the reproductive toxicity of CBD was investigated on adult zebrafish. With CBD treatment, female zebrafish spawned less with higher natural mortality and malformation rates. Both female and male zebrafish showed a decreased gonadosomatic index with an increased percentage of pre-mature oocytes and sperm and had an increased hepatosomatic index with decreased content of vitellogenin. The value of estrogen/testosterone (E2/T) decreased in female zebrafish and increased in male zebrafish. Sex hormone synthesis genes were downregulated in ovaries and upregulated in testicles, except for cyp11a, in contrast to the other genes. Apoptosis-related genes were upregulated in the zebrafish brain, gonad, and liver. These results show that CBD might damage the reproductive function by inducing an apoptotic response, further inhibiting zebrafish reproductive ability.

Differential inflammatory profile in the lungs of mice exposed to cannabis smoke with varying THC:CBD ratio.

Cannabis contains cannabinoids including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC causes the psychoactive effects of cannabis, and both THC and CBD are thought to be anti-inflammatory. Cannabis is typically consumed by inhaling smoke that contains thousands of combustion products that may damage the lungs. However, the relationship between cannabis smoke exposure and alterations in respiratory health is poorly defined. To address this gap in knowledge, we first developed a mouse model of cannabis smoke exposure using a nose-only rodent inhalation exposure system. We then tested the acute effects of two dried cannabis products that differ substantially in their THC-CBD ratio: Indica-THC dominant (I-THC; 16-22% THC) and Sativa-CBD dominant (S-CBD; 13-19% CBD). We demonstrate that this smoke exposure regime not only delivers physiologically relevant levels of THC to the bloodstream, but that acute inhalation of cannabis smoke modulates the pulmonary immune response. Cannabis smoke decreased the percentage of lung alveolar macrophages but increased lung interstitial macrophages (IMs). There was also a decrease in lung dendritic cells as well as Ly6Cintermediate and Ly6Clow monocytes, but an increase in lung neutrophils and CD8+ T cells. These immune cell changes were paralleled with changes in several immune mediators. These immunological modifications were more pronounced when mice were exposed to S-CBD compared to the I-THC variety. Thus, we show that acute cannabis smoke differentially affects lung immunity based on the THC:CBD ratio, thereby providing a foundation to further explore the effect of chronic cannabis smoke exposures on pulmonary health.

Review of the oral toxicity of cannabidiol (CBD).

Information in the published literature indicates that consumption of CBD can result in developmental and reproductive toxicity and hepatotoxicity outcomes in animal models. The trend of CBD-induced male reproductive toxicity has been observed in phylogenetically disparate organisms, from invertebrates to non-human primates. CBD has also been shown to inhibit various cytochrome P450 enzymes and certain efflux transporters, resulting in the potential for drug-drug interactions and cellular accumulation of xenobiotics that are normally transported out of the cell. The mechanisms of CBD-mediated toxicity are not fully understood, but they may involve disruption of critical metabolic pathways and liver enzyme functions, receptor-specific binding activity, disruption of testosterone steroidogenesis, inhibition of reuptake and degradation of endocannabinoids, and the triggering of oxidative stress. The toxicological profile of CBD raises safety concerns, especially for long term consumption by the general population.

Reproductive and developmental toxicity evaluation of cannabidiol.

An important data gap in determining a safe level of cannabidiol (CBD) intake for consumer use is determination of CBD's potential to cause reproductive or developmental toxicity. We conducted an OECD Test Guideline 421 GLP-compliant study in rats, with extended postnatal dosing and hormone analysis, where hemp-derived CBD isolate (0, 30, 100, or 300 mg/kg-bw/d) was administered orally. Treatment-related mortality, moribundity, and decreased body weight and food consumption were observed in high-dose F0 adult animals, consistent with severe maternal toxicity. No effects were observed on testosterone concentrations, F0 reproductive performance, or reproductive organs. Hepatocellular hypertrophy in the 100- and 300 mg/kg-bw/day groups correlated with hypertrophy/hyperplasia in the thyroid gland and changes in mean thyroid hormone concentrations in F0 animals. Mean gestation length was unaffected; however, total litter loss for two females and dystocia for two additional females in the high-dose group occurred. Other developmental effects were limited to lower mean pup weights in the 300 mg/kg-bw/d group compared to those of concurrent controls. The following NOAELs were identified for CBD isolate based on this study: 100 mg/kg-bw/d for F0 systemic toxicity and female reproductive toxicity, 300 mg/kg-bw/d for F0 male reproductive toxicity, and 100 mg/kg-bw/d for F1 neonatal and F1 generation toxicity.

Oral toxicity evaluation of cannabidiol.

Use of cannabidiol (CBD) in humans has increased considerably in recent years. While currently available studies suggest that CBD is relatively safe for human consumption, data from publicly available studies on CBD conducted according to modern testing guidelines are lacking. In the current study, the potential for toxicity following repeated oral exposure to hemp-derived CBD isolate was evaluated in male and female Sprague Dawley rats. No adverse treatment-related effects were observed following administration of CBD via oral gavage for 14 and 90 days at concentrations up to 150 and 140 mg/kg-bw/d, respectively. Microscopic liver and adrenal gland changes observed in the 90-day study were determined to be resolved after a 28-day recovery period. CBD was well tolerated at these dose levels, and the results of this study are comparable to findings reported in unpublished studies conducted with other CBD isolates. The current studies were conducted as part of a broader research program to examine the safety of CBD.

Establishment of a point of departure for CBD hepatotoxicity employing human HepaRG spheroids.

The United States Food and Drug Administration recently approved the use of Cannabis sativa derived cannabidiol (CBD) in the treatment of Dravet Syndrome and Lennox-Gastaut Syndrome, under the trade name, Epidiolex. In double-blinded, placebo-controlled clinical trials, elevated ALT levels were observed in some patients, but these findings could not be uncoupled from the confounds of potential drug-drug interactions with co-administration of valproate and clobazam. Given the uncertainty of the potential hepatatoxic effects of CBD, the objective of the present study was to determine a point of departure for CBD, using human HepaRG spheroid cultures, followed by transcriptomic benchmark dose analysis. Treatment of HepaRG spheroids with CBD for 24 and 72 h, resulted in EC50 concentrations for cytotoxicity of 86.27 µM and 58.04 µM, respectively. Subsequent transcriptomic analysis at these timepoints demonstrated little alteration of gene and pathway data sets at a CBD concentration at or below 10 µM. Although this current analysis was conducted using liver cells, interestingly the findings at 72 h post CBD treatment showed suppression of many genes more commonly associated with immune regulation. Indeed, the immune system is a well-established target for CBD based on immune function assays. Collectively, in the present studies a point of departure was derived using transcriptomic changes produced by CBD in a human cell-based model system, which has been shown to accurately translate to human hepatotoxicity modeling.

Safety assessment and redox status in rats after chronic exposure to cannabidiol and cannabigerol.

Cannabidiol (CBD) and cannabigerol (CBG) are the two main non-psychotropic phytocannabinoids with high application potential in drug development. Both substances are redox-active and are intensively investigated for their cytoprotective and antioxidant action in vitro. In this study, we focused on an in vivo safety evaluation and the effect of CBD and CBG on the redox status in rats in a 90-d experiment. The substances were administered orogastrically in a dose of 0.66 mg synthetic CBD or 0.66 mg/1.33 mg CBG/kg/day. CBD produced no changes in the red or white blood count or biochemical blood parameters in comparison to the control. No deviations in the morphology or histology of the gastrointestinal tract and liver were observed. After 90 d of CBD exposure, a significant improvement in redox status was found in the blood plasma and liver. The concentration of malondialdehyde and carbonylated proteins was reduced compared to the control. In contrast to CBD, total oxidative stress was significantly increased and this was accompanied by an elevated level of malondialdehyde and carbonylated proteins in CBG-treated animals. Hepatotoxic (regressive changes) manifestations, disruption in white cell count, and alterations in the ALT activity, level of creatinine and ionized calcium were also found in CBG-treated animals. Based on liquid chromatography-mass spectrometry analysis, CBD/CBG accumulated in rat tissues (in the liver, brain, muscle, heart, kidney and skin) at a low ng level per gram. Both CBD and CBG molecular structures include a resorcinol moiety. In CBG, there is an extra dimethyloctadienyl structural pattern, which is most likely responsible for the disruption to the redox status and hepatic environment. The results are valuable to further investigation of the effects of CBD on redox status and should contribute towards opening up critical discussion on the applicability of other non-psychotropic cannabinoids.

Benefits, toxicity and current market of cannabidiol in edibles.

The commercialization of products with cannabidiol (CBD) has undergone a significant increase. These products can be presented in different forms such as baked goods, gummies or beverages (such as kombucha, beer or teas, among others) using wide concentrations ranges. The use of CBD in edibles favors its consumption, for medicinal users, during the work week, avoid its possible social stigma and facilitates its transport. These products can be purchased on store shelves and online. There is a large number of specialized studies, in which the possible advantages of CBD consumption are described in the preclinical and clinical trials. It is also necessary to recognize the existence of other works revealing that the excessive consumption of CBD could have some repercussions on health. In this review, it is analyzed the composition and properties of Cannabis sativa L., the health benefits of cannabinoids (focusing on CBD), its consumption, its possible toxicological effects, a brief exposition of the extraction process, and a collection of different products that contain CBD in its composition.

Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells.

Cannabidiol (CBD), one of the major cannabinoids in the plant Cannabis sativa L., is the active ingredient in a drug approved for the treatment of seizures associated with certain childhood-onset epileptic disorders. CBD has been shown to induce male reproductive toxicity in multiple animal models. We previously reported that CBD inhibits cellular proliferation in the mouse Sertoli cell line TM4 and in primary human Sertoli cells. In this study, using a transcriptomic approach with mRNA-sequencing analysis, we identified molecular mechanisms underlying CBD-induced cytotoxicity in primary human Sertoli cells. Analysis of differentially expressed genes demonstrated that DNA replication, cell cycle, and DNA repair were the most significantly affected pathways. We confirmed the concentration-dependent changes in the expression of key genes in these pathways using real-time PCR. mRNA sequencing showed upregulation of a group of genes tightly associated with the senescence-associated secretory phenotype (SASP) and with the activation of the p53 signaling pathway, a key upstream event in cellular senescence. Prolonged treatment of 10 µM CBD-induced cellular senescence, as evidenced by the stable cessation of proliferation and the activation of senescence-associated ß-galactosidase (SA-ß-gal), 2 hallmarks of senescence. Additionally, using real-time PCR and Western blotting assays, we observed that CBD treatment increased the expression of p16, an important marker of cellular senescence. Taken together, our results show that CBD exposure disturbs various interrelated signaling pathways and induces cellular senescence in primary human Sertoli cells.