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Abstract

Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ(9)-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ(9)-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.

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... Many In the history of the treatment of infectious diseases, cannabis has been used for thousands of years without knowledge of the scientific background of its effects [17,18]. A substantial amount of research has documented that C. sativa possesses hundreds of secondary metabolites including cannabinoids, terpenes and phenolic compounds [19] which have pharmacological properties in anticonvulsant therapy, appetite stimulation, neurodegenerative diseases, pain treatment, skin pathologies and infectious diseases [20]. Cannabinoids and terpenes, or essential oils (EO) enriched with these, are well known to confer anti-inflammatory effects in mammals during infectious diseases [21][22][23]. ...
... In lung injury, cannabinoids are found to be beneficial in vivo since they have a suppressive effect on the cytokine storm. Administration of CBD decreased migration of macrophages, neutrophils, and lymphocytes into the murine lung with acute lung injury (ALI) induced by LPS, followed by significant improvements of lung functions [19]. Crude and fractional extracts of cannabis reduced the level of IL-6, IL-8 in a lung epithelial A459 cell model [175]. ...
... An introduction of 4 and 8 mg ethyl acetate seed and leaf extract showed toxicity to 9-days old chicken embryos [139]. For more detailed information on dose vs toxicity of cannabis, readers are referred to [19,[263][264][265]. ...
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Abstract: Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and antiviral (particularly against SARS-CoV-2) properties of C. sativa with the potential for new antibiotic drug and/or natural antimicrobial agents for industrial or agricultural use, and their therapeutic potential against the newly emerged coron-avirus disease (COVID-19). Cannabis compounds have good potential as drug candidates for new antibiotics, even for some of the WHO's current priority list of resistant pathogens. Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the M pro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19. However, more systemic investigations are warranted to establish the best efficacy and their toxic effects, followed by preclinical trials on a large number of participants.
... Their endogenous ligands are the lipids known as N-arachidonoyl ethanolamine (AEA) and 2-AG (2-arachidonoylglycerol) [24]. The therapeutic effects of agonism and antagonism of both receptors have been found to be clinically useful for a plethora of disorders [24,27]. However, the endocannabinoid system involves many more receptors and ligands and has therefore been termed the "endocannabinoidome." ...
... A 2016 study found that CBD was able to decrease the viability and induce apoptosis of neuroblastoma cells, in addition to decreasing tumor growth with in vivo xenografts [92]. As CBD does not have a particularly high affinity for CB1 [27], this further suggests that anti-cancer effects may be triggered by making use of receptors other than CB1. CBD was also found to affect miRNA expression in neuroblastoma, downregulating hsa-let-7a and upregulating hsa-miRNA-1972. ...
... As discussed earlier, CBD is a popular option for use in children due to its lack of psychoactive side effects, current use in palliation, and low toxicity [27,83,108,109]. However, many CBD products may not be as pure as claimed, nor are they always labeled with the exact amount of CBD present, which may lead to patients unintentionally experiencing undesirable side effects from imprecise doses of CBD [83]. ...
Article
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The antineoplastic effects of cannabis have been known since 1975. Since the identification of the components of the endogenous cannabinoid system (ECS) in the 1990s, research into the potential of cannabinoids as medicine has exploded, including in anti-cancer research. However, nearly all of this research has been on adults. Physicians and governing bodies remain cautious in recommending the use of cannabis in children, since the ECS develops early in life and data about cannabis exposure in utero show negative outcomes. However, there exist many published cases of use of cannabis in children to treat pediatric epilepsy and chemotherapy-induced nausea and vomiting (CINV) that show both the safety and efficacy of cannabis in pediatric populations. Additionally, promising preclinical evidence showing that cannabis has anti-cancer effects on pediatric cancer warrants further investigation of cannabis’ use in pediatric cancer patients, as well as other populations of pediatric patients. This review aims to examine the evidence regarding the potential clinical utility of cannabis as an anti-cancer treatment in children by summarizing what is currently known about uses of medical cannabis in children, particularly regarding its anti-cancer potential.
... 922). Even though it does not have psychoactive properties, it has shown potential for various therapeutic effects and has been extensively investigated for the treatment of various pathologies [25] (pp. [8][9][10][11][12][13]. ...
... All this information is also associated with inflammation with a major role in the progression of the disease. Therefore, the properties that CBD exhibits at the level of neurodegeneration, inflammation, and antioxidation may come to be very important in the treatment and stabilization of these diseases, such as, for example, Alzheimer's, Parkinson and Huntington's [25] (pp. [8][9]. ...
... There is evidence that these compounds mediate antitumor effects by inhibiting cell proliferation, inducing autophagy-mediated apoptosis, and intervening in the migration, invasion, and metastasis of cancer cells. Thus, in the near future, can lead to the development of new drugs based on these cannabinoid structures, for instance, on CBD, which is an antagonist of GPCR 55 in various types of cancer ( [17,25,32] (pp. 11-12), (pp. ...
Article
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Translational research made with Cannabis sativa L. and its biocompounds provides data for some targeted diseases, as also symptoms associated with Autism Spectrum Disorders (ASDs). The main compounds ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are capable of modulating the endocannabinoid system since its dysregulation interferes with the pathophysiology of ASDs there are clinical evidence for its potential use in the treatment of the disease. Conventional therapy still has limitations, as it does not always treat the central symptoms, and there are many patients who do not respond to treatment, which demands more research on new therapies. Through the analysis of published literature on this topic, it is verified that cannabinoids, in particular CBD, improves symptoms associated with common comorbidities in ASDs. Some studies also demonstrate the therapeutic potential of these compounds in the treatment of central symptoms of autism. In addition, cannabinoid therapy to ASDs is associated with low adverse effects and a reduction in concomitant medication. Although it appears to be promising, it is essential to do the translation of this data into clinical research and some of its potential and critical gaps are discussed in this review pointing to large-scale and long-term clinical trials that should include more patients and homogeneous samples.
... As regards the first complexity, it is important to stress that isolated and characterized phytocannabinoids, present in Cannabis sativa L. and a few other plant species (187,188), include about 120 molecules (189), the most studied of which are 9-THC, mainly responsible for cannabis psychoactive effects (55), and cannabidiol (CBD), the major non-psychotropic component (190). ...
... A point to be remembered is that, although cannabis use is associated with an acute antianxiety effect (260), chronic cannabis use may dramatically worsen anxiety (261,262), thus exacerbating tinnitus severity. The anxiety-inducing effect of cannabis is correlated with its 9-THC content, and 9-THC alone may induce anxiety and paranoia (263); on the other hand, CBD appears to have opposite effects on anxiety (264) and is currently under clinical evaluation for the treatment of anxiety, psychosis, and posttraumatic stress disorder (190,265,266). ...
... In general, the pharmacodynamic of CBD appears particularly complex, with over 65 identified molecular targets, and different mechanisms proposed to explain its actions (190,273,274). Here we summarize only the CBD targets which may bear relevance for tinnitus. ...
Chapter
inner ear immunology in vestibular migraine and meniere disease, difrential proinflammatory profile
... Due to their potential medicinal properties, phytocannabinoids have generated considerable interest among researchers and pharmaceutical industries around the globe. 1,2 There are >100 phytocannabinoids reported 3 so far from the Cannabis sativa plant, and three phytocannabinoid-based drugs, namely, Sativex (Nabiximols), 4,5 Nabilone (Cesamet), 6 and Epidiolex, 7,8 have been approved by the global regulatory bodies, USFDA and MHRA (structures of their APIs are provided in Figure 1). ...
... Apart from the CB receptors, CBD is also known to interact with other molecular targets 17 and therefore is being studied for a number of therapeutic areas such as analgesic, anticonvulsant, muscle relaxant, anxiolytic, antipsychotic, neuroprotective, anti-inflammatory, antiseizure, and antioxidant activities. 7,8 Recently, CBD was part of two regulatory approvals: first on its own as an antiepilepsy drug (Epidiolex) and second in a combination with THC (Sativex, THC/CBD; ∼1:∼1 ratio) for pain management. ...
... THC is a psychoactive compound that is very abundant in the Cannabis sativa plant. In addition to THC, CBD and other minor cannabinoids have also been shown to be responsible for many cannabinoid effects, such as euphoria, pain relief, and anti-inflammatory effects [38][39][40]. THC is a nonselective agonist of CBRs and binds with higher affinity to CB1 and lower affinity to CB2 [37,38,41]. CBD has a lower affinity for CBRs and acts as an inverse agonist at CB2 [36,40]. ...
... THC is a nonselective agonist of CBRs and binds with higher affinity to CB1 and lower affinity to CB2 [37,38,41]. CBD has a lower affinity for CBRs and acts as an inverse agonist at CB2 [36,40]. THC, CBD, and other exogenous cannabinoids affect several features of tumor progression, as observed in several cancers, particularly gliomas/glioblastomas [42], followed by carcinomas of the skin, liver, colon, prostate, and breast [43][44][45]. ...
Article
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Breast cancer is the most common malignancy in women worldwide. Sixty-five percent of breast cancers are estrogen and/or progesterone receptor positive. Estrogen receptor expression is a prognostic and predictive biomarker of response to endocrine therapy, which consists of the selective estrogen receptor modulator tamoxifen, aromatase inhibitors, and the selective estrogen receptor degrader fulvestrant. Cannabidiol is a phytocannabinoid that is emerging as a potential therapeutic agent. The aim of this study was to investigate the effect of cannabidiol on estrogen receptor-positive and estrogen receptor-negative representative breast cancer cell lines in combination with standard therapeutic agents used in clinical practice. To compare the effects of cannabidiol on breast cancer cell viability, cancer cell lines were exposed to increasing concentrations of cannabidiol. The effects of cannabidiol in combination with the endocrine therapeutics tamoxifen, fulvestrant, and the cyclin-dependent kinase inhibitor palbociclib on breast cancer cell viability were examined. We demonstrated that cannabidiol dose-dependently decreased the viability of all breast cancer cell lines independent of estrogen expression. The addition of cannabidiol to tamoxifen had an additive negative effect on cell viability in ER + T-47D. Cannabidiol did not attenuate the effect of standard treatment of hormone receptor-positive breast cancer with fulvestrant and palbociclib. In addition, cannabidiol did not attenuate the effect of standard treatment of triple-negative breast cancer and HER2-positive breast cancer cell lines with trastuzumab and cisplatin.
... Cannabidiol (CBD) is a non-psychoactive constituent of phytocannabinoids in industrially used Cannabis sativa [1], which has been studied for its antineoplastic actions, shifting sights towards a new scope of anticancer treatments [2]. CBD has been reported to inhibit angiogenesis related to the proliferation of estrogen receptor-positive breast cancer [3] by inactivating proangiogenic factors such as vascular endothelial growth factor (VEGF), integins or angiopoietins, matrix metalloproteinase-2/9 (MMP-2/9), the urokinase-type plasminogen activator (uPA), endothelin-1 (ET-1), and platelet-derived growth factor-AA (PDGF-AA), or by activating inhibitory effectors such as thrombospondins or interferons [4][5][6]. ...
... Thus, CBD inhibits angiogenesis via interference with pro-angiogenic pathways/signaling, factors, and tumor microenvironments. Moreover, CBD induces the interplay between apoptotic and autophagy-inducing signals, resulting in a non-receptor-mediated programmed cell death of breast cancer [3], whereas it has shown little effect on non-tumorigenic mammary cells [2]. Intratumoral hypoxia is one of the most important tumor microenvironments and causes treatment failure due to reactive oxygen species and DNA damage [10,11]. ...
Article
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To assess the effect of Cannabidiol (CBD) on the angiogenesis and stemness of breast cancer cells as well as proliferation. Methods: mRNA level and the amount of protein of vascular endothelial growth factor (VEGF) were determined by qRT-PCR and ELISA. The angiogenic potential of breast cancer cells under hypoxic conditions was identified by the HUVEC tube formation assay. The degradation of HIF-1α by CBD and the Src/von Hippel–Lindau tumor suppressor protein (VHL) interaction were assessed by a co-immunoprecipitation assay and Western blotting. To identify the stemness of mamospheres, they were evaluated by the sphere-forming assay and flow cytometry. Results: CBD can suppress angiogenesis and stem cell-like properties of breast cancer through Src/VHL/HIF-1α signaling. CBD may potentially be utilized in the treatment of refractory or recurrent breast cancer.
... Unlike delta-9-tetrahydrocannabinol (Δ9-THC), it does not induce psychostimulant effects, nor is associated with an increased risk of abuse and dependence [15]. Due to its non-intoxicating properties and multi-targeted action [16,17], the therapeutic properties of CBD have been investigated in several animal models of neurological and psychiatric disorders, with promising results [18]. The anxiolytic effect of CBD has been shown in different animal models [19][20][21] and clinical trials [19-21]. ...
Preprint
Cannabidiol (CBD) is a non-intoxicating compound extracted from Cannabis sativa, showing antidepressant-like effects in different rodent models. However, inconsistent results have been described depending on the species and the strain used to assess depressive-like behaviour. Moreover, only a few studies have investigated the effect of CBD in female rodents. Therefore, we aimed to i) investigate the effects of CBD in two different strains of mice (Swiss and C57BL/6) and in a rat model of depression based on selective breeding (Flinders Sensitive and Resistant Lines, FSL and FRL) subjected to tests predictive of antidepressant-like effects; and ii) investigate the influence of sex in the effects of CBD in both mice and rats. CBD induced an antidepressant-like effect in male Swiss but not in female Swiss or C57BL/6 mice in the tail suspension test (TST). In male FSL rats, CBD produced an antidepressant-like effect one-hour post-injection. However, in female FSL, CBD induced a bimodal effect, increasing the immobility time at one hour and decreasing it at two hours. Ketamine produced an antidepressant-like effect in male and female FSL rats at different doses. In conclusion, strain, sex, and administration time affect CBD's behavioural response to rodents exposed to tests predictive of antidepressant effects.
... Cannabidiol, a phytocannabinoid derived from Cannabis sativa, with proven antiinflammatory and antioxidant properties, has recently been found to block exosome and microvesicle release, sensitising chemoresistant BC cells to cisplatin [197,198]. Its action is associated with changes in mitochondrial function, including modulation of STAT3 and prohibitin expression, both of which positively regulate cell proliferation [198]. ...
Article
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Resistance to various therapies, including novel immunotherapies, poses a major challenge in the management of breast cancer and is the leading cause of treatment failure. Bidirectional communication between breast cancer cells and the tumour microenvironment is now known to be an important contributor to therapy resistance. Several studies have demonstrated that crosstalk with the tumour microenvironment through extracellular vesicles is an important mechanism employed by cancer cells that leads to drug resistance via changes in protein, lipid and nucleic acid cargoes. Moreover, the cargo content enables extracellular vesicles to be used as effective biomarkers for predicting response to treatments and as potential therapeutic targets. This review summarises the literature to date regarding the role of extracellular vesicles in promoting therapy resistance in breast cancer through communication with the tumour microenvironment.
... Cannabidiol (CBD), a major nonpsychotropic ingredient of phytocannabinoids present in the medical cannabis plant and approved by the FDA for the treatment of Dravet syndrome, has been shown to possess broad-spectrum pharmacological activities in many neurological diseases, such as epilepsy and multiple sclerosis [12,13]. A growing body of evidence suggests that CBD may be an effective and safe antidepressant agent; however, the underlying mechanisms of the antidepressive effect of CBD are unclear [14][15][16]. A recent study revealed that AM251, an antagonist of cannabinoid receptor 1 (CB1R), partly blocks the antidepressant effect of CBD, suggesting that the modulation of the endocannabinoid system may be involved in the antidepressant mechanism of CBD [17]. ...
Article
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Chronic stress impairs radial neural stem cell (rNSC) differentiation and adult hippocampal neurogenesis (AHN), whereas promoting AHN can increase stress resilience against depression. Therefore, investigating the mechanism of neural differentiation and AHN is of great importance for developing antidepressant drugs. The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against depression. However, whether CBD can modulate rNSC differentiation and hippocampal neurogenesis is unknown. Here, by using the chronic restraint stress (CRS) mouse model, we showed that hippocampal rNSCs mostly differentiated into astrocytes under stress conditions. Moreover, transcriptome analysis revealed that the FoxO signaling pathway was involved in the regulation of this process. The administration of CBD rescued depressive-like symptoms in CRS mice and prevented rNSCs overactivation and differentiation into astrocyte, which was partly mediated by the modulation of the FoxO signaling pathway. These results revealed a previously unknown neural mechanism for neural differentiation and AHN in depression and provided mechanistic insights into the antidepressive effects of CBD.
... Although the concentration of CBD does not appear to have changed over the past five decades, there has been a significant increase in THC concentration in international cannabis markets [3]. Unlike THC, CBD has no psychoactive effects and has potential anti-inflammatory, anti-oxidant, anxiolytic and analgesic effects [4,5]. In Switzerland, following a change in the ordinance on illegal drugs by the Swiss Federal administration, use and sales of CBD products containing less than 1% of THC are legal (products with 1% or more THC are still illegal). ...
Article
Aims of the study: In Switzerland, there has been a boom in the market for cannabidiol (CBD) products in recent years. However, little is known on the prevalence, modes of administration and motives for use of CBD products. The aim of the present study was to fill this gap using recent (2019) data from the Cohort Study on Substance Use Risk Factors (C-SURF). Methods: Between April and December 2019, an unselected sample of 5233 Swiss young men from the French- and German-speaking regions (mean age 28.2 years, standard deviation 1.3) completed a self-report questionnaire covering measures of use of CBD products, modes of administration and motives to use of CBD, tetrahydrocannabinol (THC) and cigarettes. Descriptive statistics were used to estimate prevalence of self-reported use, modes of administration and motives to use CBD, whereas logistic regression models were used to test the associations of linguistic region, THC and tobacco use with use of CBD. Results: Lifetime and 12-month prevalence of self-reported use of CBD were 32.4% and 18.5%, respectively. Among past 12-month CBD users, 79.4% used CBD once a month or less often, whereas 20.6% used it more than once a month. The most often reported modes of administration of CBD were in association with tobacco: flowers mixed with tobacco (67.5%), and CBD cigarettes with tobacco (37.1%), while 18.6% used flowers without tobacco. The three most reported reasons for using CBD were: out of curiosity (74.0%), to feel the effects of THC (38.1%) and for well-being and health (37.5%). In multivariable models, CBD use was associated with use of THC (odds ratio [OR] 9.85, 95% confidence interval [CI] 8.28-11.73), cigarettes (OR 2.74, 95% CI 2.28-3.29) or e-cigarettes (OR 1.5795% CI 1.27-1.95), as well as for the linguistic region (French-speaking vs German-speaking region OR 1.3895% CI 1.15-1.65). Conclusions: Self-reported use of CBD is common among young Swiss men: about one third used CBD in their life and about one in five in the previous 12 months. However, the vast majority of CBD users used it infrequently and out of curiosity. CBD use was particularly prevalent among users of THC and cigarette smokers. CBD was most often used in combination with tobacco, thus exposing users to risks associated with smoking tobacco products.
... However, the response of CBD on all these targets is dependent on its concentration and on the cell models [10]. Overall, different studies have attributed several effects to CBD, including anticonvulsive, neuroprotective, antioxidative, anti-inflammatory, analgesic and antiemetic effects [73,74]. ...
Article
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Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment. In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER−) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER+) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2+) and ER+ breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.
... Moreover, it inhibits the cellular uptake of the endogenous CB1 receptor ligand, AEA, directly affecting endocannabinoid tone. Furthermore, CBD shows cytotoxicity in breast tumor cells and is cyto-preservative for normal cells [15]. CBD has many cannabinoid-receptor-independent properties. ...
Article
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Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... It can also suppress aversive memories through extinction facilitation (Bitencourt et al., 2008;Do Monte et al., 2013a;Song et al., 2016) or impair their reconsolidation as demonstrated here and elsewhere (Stern et al., 2012(Stern et al., , 2015Gazarini et al., 2014;Murkar et al., 2019). These properties of the CBD involve multiple mechanisms of action (Campos et al., 2012;Pisanti et al., 2017;Silvestro et al., 2020;Vitale et al., 2021). Regarding its effects on the cognitive domain (aversive learning and memory process), activation of CB1 receptors appears to be indispensable (Stern et al., 2012(Stern et al., , 2017Do Monte et al., 2013a;Raymundi et al., 2020). ...
Article
Growing evidence indicates that cannabidiol (CBD), a substance present in the Cannabis sativa plant, has potential therapeutic value to regulate abnormal emotional memories associated with post-traumatic stress and drug use disorders. CBD can attenuate their valence after retrieval (i.e., during reconsolidation) or potentiate their suppression by extinction. Pharmacological research has now focused on elucidating how it acts. Systemic antagonism of cannabinoid type-1 (CB1) receptors has often prevented the abovementioned effects of CBD. However, it is unknown in which brain regions CBD stimulates CB1 receptors and how it interferes with local activity-related plasticity to produce these effects. The present study addressed these questions considering the reconsolidation of contextual fear memories in rats. We focused on the medial prefrontal cortex (mPFC), which comprises the anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) subregions, as local activity or plasticity has been associated with the process to-be-investigated. Animals that received post-retrieval systemic CBD treatment presented relatively fewer cells expressing Zif268/Egr1 protein, a proxy for synaptic plasticity related to reconsolidation, in the AC and PL. At the same time, there were no significant differences in the IL. Pretreatment with the CB1 receptor antagonist/inverse agonist AM251 into the AC, PL, or IL prevented the impairing effects of systemic CBD treatment on reconsolidation. CBD also caused reconsolidation impairments when injected directly into the AC or PL but not the IL. Together, these findings show complementary mechanisms through which CBD may hinder the reconsolidation of destabilized aversive memories along the dorsoventral axis of the mPFC.
... Moreover, CBD can activate the CB2 receptor to decrease the inflammatory macrophage release mechanism into the lungs (35) and can reduce the immune pathological mechanisms of viral infection (36). The SARS-CoV-2Mpro downregulation is not associated with side effects in humans and remains at this stage as one the best molecular targets for decreasing the coronavirus replication (37,38). ...
Article
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Cannabidiol (CBD) can prevent the inflammatory response of SARS-CoV-2 spike protein in Caco-2-cells. This action is coupled with the inhibition of IL-1beta, IL-6, IL-18, and TNF-alpha, responsible for the inflammatory process during SARS-CoV-2 infection. CBD can act on the different proteins encoded by SARS-CoV-2 and as an antiviral agent to prevent the viral infection. Furthermore, recent studies have shown the possible action of CBD as an antagonist of cytokine release syndromes. In the SARS-CoV-2 pathophysiology, the angiotensin-converting enzyme 2 (ACE2) seems to be the key cell receptor for SARS-CoV-2 infection. The WNT/β-catenin pathway and PPARγ interact in an opposite manner in many diseases, including SARS-CoV-2 infection. CBD exerts its activity through the interaction with PPARγ in SARS-CoV-2 infection. Thus, we can hypothesize that CBD may counteract the inflammatory process of SARS-CoV-2 by its interactions with both ACE2 and the interplay between the WNT/β-catenin pathway and PPARγ. Vaccines are the only way to prevent COVID-19, but it appears important to find therapeutic complements to treat patients already affected by SARS-CoV-2 infection. The possible role of CBD should be investigated by clinical trials to show its effectiveness.
... Interactions between CBD and these drugs may contribute to clinical outcomes specific to the treatment for which they are indicated (9)(10)(11). Therefore, these drugs should be handled safely in recognition of both their beneficial and harmful effects (12). When plasma CRP concentrations were compared before and after CBD use, 2 dogs had decreased concentrations, and 3 dogs had increased concentrations. ...
Article
Objective: We aimed to examine the effects of cannabidiol (CBD)-containing hemp oil without delta-9-tetrahydrocannabinol (THC) as a supplemental treatment for canine atopic dermatitis (CAD), as well as its adverse effects, and effects on concurrent drug use in dogs. Animal: In this retrospective case series, 8 dogs with CAD were diagnosed by veterinary dermatologists certified by the Japanese Society of Veterinary Dermatology. Procedure: The medical records of dogs supplemented with CBD-containing hemp oil were evaluated with respect to signalment, physical examination, plasma C-reactive protein concentrations, pharmacologic management, the CAD Extent and Severity Index (4th iteration), and the Pruritus Visual Analog Scale. Results: Overall, CBD, used as a supplement in combination with other drugs, was well-tolerated over a wide dose range and decreased the occurrence of pruritus in dogs with CAD when ingested twice a day. Conclusion: This study provides the first report of supplementation with CBD without THC that was effective in controlling pruritic behavior in dogs with CAD. Clinical relevance: Further controlled studies are required to investigate the dose range, efficacy, and safety.
... In contrast to THC, CBD is regarded as non-intoxicating [10], while exerting various other effects. CBD is, for example, licensed for the treatment of rare forms of childhood epilepsy [11][12][13][14]. Even though THC and CBD comprised the main focus of cannabis research so far, nearly 150 additional cannabinoids, often referred to as minor cannabinoids, are known today [15]. ...
Article
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Cannabis sativa ( C. sativa ) is commonly chemically classified based on its Δ ⁹ -tetrahydrocannabinol (THC) and cannabidiol (CBD) content ratios. However, the plant contains nearly 150 additional cannabinoids, referred to as minor cannabinoids. Minor cannabinoids are gaining interest for improved plant and product characterization, e.g., for medical use, and bioanalytical questions in the medico-legal field. This study describes the development and validation of an analytical method for the elucidation of minor cannabinoid fingerprints, employing liquid chromatography coupled to high-resolution mass spectrometry. The method was used to characterize inflorescences from 18 different varieties of C. sativa , which were cultivated under the same standardized conditions. Complementing the targeted detection of 15 cannabinoids, untargeted metabolomics employing in silico assisted data analysis was used to detect additional plant ingredients with focus on cannabinoids. Principal component analysis (PCA) was used to evaluate differences between varieties. The overall purpose of this study was to examine the ability of targeted and non-targeted metabolomics using the mentioned techniques to distinguish cannabis varieties from each other by their minor cannabinoid fingerprint. Quantitative determination of targeted cannabinoids already gave valuable information on cannabinoid fingerprints as well as inter- and intra-variety variability of cannabinoid contents. The untargeted workflow led to the detection of 19 additional compounds. PCA of the targeted and untargeted datasets revealed further subgroups extending commonly applied phenotype classification systems of cannabis. This study presents an analytical method for the comprehensive characterization of C. sativa varieties. Graphical abstract
... THC is a partial agonist of the CB1 and CB2 receptors, similar to AEA [18]. However, CBD has a low affinity to the cannabinoid receptors, and is believed to exert its actions predominantly via activating the ECS indirectly, as well as interacting with other targets or receptors [19][20][21][22] 2.5. Therapeutic Actions of CBD CBD has many therapeutic actions, set out in Table 1. ...
Article
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The plant Cannabis sativa has been in use medicinally for several thousand years. It has over 540 metabolites thought to be responsible for its therapeutic effects. Two of the key phytocannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). Unlike THC, CBD does not have potentially intoxicating effects. Preclinical and clinical research indicates that CBD has a wide range of therapeutic effects, and many of them are relevant to the management of cancer. In this article, we explore some of the potential mechanisms of action of CBD in cancer, and evidence of its efficacy in the integrative management of cancer including the side effects associated with its treatment, demonstrating its potential for integration with orthodox cancer care.
... Despite evidence supporting the anxiolytic and antidepressant properties of CBD under certain experimental conditions, the complete characterization of the underlying mechanisms of action is still pending. In this respect, 5-HT1A is one of the main targets studied among the more than 65 targets on which CBD acts [29,65,66], demonstrating the involvement of this receptor in its anxiolytic [32,[67][68][69][70] and antidepressant-like effects [33,36,40]. Here, we aimed to explore further the implication of additional CBD proposed targets, such as CB1r, CB2r and GPR55, given the critical role these receptors play in emotional reactivity, anxiety and mood disorders [14,42,44,48,51,52,[71][72][73]. ...
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The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD’s ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was evaluated at different doses in wild-type (CD1; 10, 20 and 30 mg/kg; i.p.) and knockout (CB1KO, CB2KO; GPR55KO; 20 mg/kg) mice. Moreover, CBD effects (20 mg/kg; i.p.) were evaluated in mice previously treated with the CB1r-antagonist SR141716A (2mg/kg; i.p.). Relative gene expression analyses of Cnr1 and Cnr2, Gpr55 and GABA(A)α2 and γ2 receptor subunits were performed in the amygdala (AMY) and hippocampus (HIPP) of CD1 mice. CBD (10 and 20 mg/kg) showed anxiolytic and antidepressant actions in CD1 mice, being more effective at 20 mg/kg. Its administration did not induce anxiolytic actions in CB1KO mice, contrary to CB2KO and GPR55KO. In all of them, the lack of cannabinoid receptors did not modify the antidepressant activity of CBD. Interestingly, the administration of the CB1r antagonist SR141716A blocked the anxiolytic-like activity of CBD. Real-time PCR studies revealed a significant reduction in Cnr1 and GABA(A)α2 and γ2 gene expression in the HIPP and AMY of CD1 mice treated with CBD. Opposite changes were observed in the Cnr2. Indeed, Gpr55 was increased in the AMY and reduced in the HIPP. CB1r appears to play a relevant role in modulating the anxiolytic actions of CBD. Moreover, this study revealed that CBD also modified the gene expression of GABA(A) subunits α2 and γ2 and CB1r, CB2r and GPR55, in a dose- and brain-region-dependent manner, supporting a multimodal mechanism of action for CBD.
... Preclinical and clinical studies show CBD is anticonvulsant; however, its mechanism of action is unclear and likely involves numerous epilepsy drug targets (Devinsky et al. 2016;Pisanti et al. 2017). Many clinically effective anticonvulsants inhibit Na V channels, and purified CBD non-selectively inhibits these channels (Ghovanloo et al. 2018). ...
Article
Background Purified cannabidiol (CBD), a non-psychoactive phytocannabinoid, has gained regulatory approval to treat intractable childhood epilepsies. Despite this, artisanal and commercial CBD-dominant hemp-based products continue to be used by epilepsy patients. Notably, the CBD doses used in these latter products are much lower than that found to be effective in reducing seizures in clinical trials with purified CBD. This might be because these CBD-dominant hemp products contain other bioactive compounds, including phytocannabinoids and terpenes, which may exert unique effects on epilepsy-relevant drug targets. Voltage-gated sodium (Na V ) channels are vital for initiation of neuronal action potential propagation and genetic mutations in these channels result in epilepsy phenotypes. Recent studies suggest that Na V channels are inhibited by purified CBD. However, the effect of cannabis-based products on the function of Na V channels is unknown. Methods Using automated-planar patch-clamp technology, we profile a hemp-derived nutraceutical product (NP) against human Na V 1.1–Na V 1.8 expressed in mammalian cells to examine effects on the biophysical properties of channel conductance, steady-state fast inactivation and recovery from fast inactivation. Results NP modifies peak current amplitude of the Na V 1.1–Na V 1.7 subtypes and has variable effects on the biophysical properties for all channel subtypes tested. NP potently inhibits Na V channels revealing half-maximal inhibitory concentration (IC 50 ) values of between 1.6 and 4.2 μg NP/mL. Purified CBD inhibits Na V 1.1, Na V 1.2, Na V 1.6 and Na V 1.7 to reveal IC 50 values in the micromolar range. The CBD content of the product equates to IC 50 values (93–245 nM), which are at least an order of magnitude lower than purified CBD. Unlike NP, hemp seed oil vehicle alone did not inhibit Na V channels, suggesting that the inhibitory effects of NP are independent of hemp seed oil. Conclusions This CBD-dominant NP potently inhibits Na V channels. Future study of the individual elements of NP, including phytocannabinoids and terpenes, may reveal a potent individual component or that its components interact to modulate Na V channels.
... Several lines of evidence have supported a therapeutic potential of cannabis derivatives, in particular phytocannabinoids, in human and veterinary medicine (1)(2)(3)(4)(5)(6)(7). Cannabidiol (CBD) and 9tetrahydrocannabinol are the most abundant phytocannabinoids extracted from the Cannabis sativa plant (8)(9)(10), with CBD being the most promising since this molecule is devoid of the psychoactive side effects exhibited by 9-tetrahydrocannabinol (9,11,12). ...
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The therapeutic potential of cannabidiol (CBD), a non-psychtropic component of the Cannabis sativa plant, is substantiated more and more. We aimed to determine the pharmacokinetic behavior of CBD after a single dose via intranasal (IN) and intrarectal (IR) administration in six healthy Beagle dogs age 3-8 years old, and compare to the oral administration route (PO). Standardized dosages applied for IN, IR and PO were 20, 100, and 100 mg, respectively. Each dog underwent the same protocol but received CBD through a different administration route. CBD plasma concentrations were determined by ultra-high performance liquid chromatography-tandem mass spectrometry before and at fixed time points after administration. Non-compartmental analysis was performed on the plasma concentration-time profiles. Plasma CBD concentrations after IR administration were below the limit of quantification. The mean area under the curve (AUC) after IN and PO CBD administration was 61 and 1,376 ng/mL * h, respectively. The maximal plasma CBD concentration (C max) after IN and PO CBD administration was 28 and 217 ng/mL reached after 0.5 and 3.5 h (T max), respectively. Significant differences between IN and PO administration were found in the T max (p = 0.04). Higher AUC and C max were achieved with 100 mg PO compared to 20 mg IN, but no significant differences were found when AUC (p = 0.09) and C max (p = 0.44) were normalized to 1 mg dosages. IN administration of CBD resulted in faster absorption when compared to PO administration. However, PO remains the most favorable route for CBD delivery due to its more feasible administration. The IR administration route is not advised for clinical application.
... Cannabidiol (CBD) is a non-intoxicating and generally safe and well-tolerated ingredient of cannabis that is already on the market, licensed and approved as Epidiolex ® in 2018 by the US Food and Drug Administration for children with severe drug-resistant epilepsy, and internationally approved for the therapy of spasticity in multiple sclerosis. It has also received orphan designation for the treatment of neonatal hypoxia-ischemic encephalopathy [5][6][7][8]. A number of preclinical and clinical studies have also shown it to possess desirable properties, such as antioxidant, anti-inflammatory, immunomodulatory, neuroprotective, procognitive, anti-anxiety, antipsychotic and anti-proliferative effects, which can be used for other clinical conditions, including cardiovascular diseases and hypertension [5][6][7]. ...
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Our study aimed to examine the endothelium (vascular)-protecting effects of chronic cannabidiol (CBD) administration (10 mg/kg once daily for 2 weeks) in aortas and small mesenteric (G3) arteries isolated from deoxycorticosterone-induced hypertensive (DOCA-salt) rats and spontaneously hypertensive rats (SHR). CBD reduced hypertrophy and improved the endothelium-dependent vasodilation in response to acetylcholine in the aortas and G3 of DOCA-salt rats and SHR. The enhancement of vasorelaxation was prevented by the inhibition of nitric oxide (NO) with L-NAME and/or the inhibition of cyclooxygenase (COX) with indomethacin in the aortas and G3 of DOCA-salt and SHR, respectively. The mechanism of the CBD-mediated improvement of endothelial function in hypertensive vessels depends on the vessel diameter and may be associated with its NO-, the intermediate-conductance calcium-activated potassium channel- or NO-, COX-, the intermediate and the small-conductance calcium-activated potassium channels-dependent effect in aortas and G3, respectively. CBD increased the vascular expression of the cannabinoid CB1 and CB2 receptors and aortic levels of endocannabinoids with vasorelaxant properties e.g., anandamide, 2-arachidonoylglycerol and palmitoyl ethanolamide in aortas of DOCA-salt and/or SHR. In conclusion, CBD treatment has vasoprotective effects in hypertensive rats, in a vessel-size- and hypertension-model-independent manner, at least partly via inducing local vascular changes in the endocannabinoid system.
... It is an anticonvulsant used in particular for certain resistant forms of childhood epilepsy [Dravet syndrome and Lennox Gastaut syndrome; (16,17)]. Certain studies have identified possible neuroprotective, analgesic, anti-inflammatory, anti-emetic and even anti-cancer effects (18,19). ...
Article
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Introduction: Cannabidiol (CBD), the second most prevalent cannabinoid found in cannabis, is considered to be safe for use. Studies suggest that CBD may be of benefit in treating cannabis use disorder (CUD). In clinical practice, CBD is already being used by patients who are trying to reduce or stop their cannabis consumption. The aim of this study was to assess the potential of CBD inhaled using a vaping device in CUD. Methods: This was an exploratory, observational, non-randomized, open-label study conducted at an Addiction Support and Prevention Center in Paris. The primary endpoint was a reduction of at least 50% in the reported number of joints consumed daily at 12 weeks. The participants were given an electronic cigarette along with liquid containing CBD. Nicotine at 6 mg/ml could be added in case of co-consumption of tobacco. They were assessed once a week and the CBD liquid dose was adjusted based on withdrawal signs and cravings (33.3, 66.6 or 100 mg/mL). Results: Between November 2020 and May 2021, 20 patients were included and 9 (45%) completed the follow-up. All of the participants used tobacco, and were provided a liquid with nicotine. At 12 weeks, 6 patients (30%) had reduced their daily cannabis consumption by at least 50%. The mean number of joints per day was 3, compared to 6.7 at baseline. The mean amount of CBD inhaled per day was 215.8 mg. No symptomatic treatment for cannabis withdrawal was prescribed. Mild adverse effects attributable to CBD and not requiring the prescription of any medicines were reported in a few patients. Conclusion: This research provides evidence in favor of the use of CBD in CUD. It also highlights the benefits of inhalation as the route of CBD administration in patients who use cannabis: inhalation can allow users to self-titrate CBD based on their withdrawal symptoms and cravings. This study illustrates the interest of proposing an addictological intervention targeting at the same time tobacco and cannabis dependence in users who are co-consumers. A double-blind, randomized, placebo-controlled clinical trial is needed to assess the efficacy of inhaled CBD in CUD.Study registration number (IDRCB) issued by the ANSM (Agence nationale de sécurité du médicament et des produits de santé-French National Agency for Medicines and Health Products Safety): 2018-A03256-49. This study received IEC approval from the CPP Sud-Ouest et Outre-Mer 1 (South-West and Overseas 1 IEC) on 15/06/2020 (CPP 1-19-041/ID 3012).
... indica (marijuana) have become of interest in Thailand and there is a growing body of research on cannabis extract and cannabinoids (Hartsel et al., 2016;Rabgay et al., 2020). Cannabidiol (CBD), a non-euphoric constituent of the cannabis plant, has been demonstrated as an anti-inflammation in both in vivo and in vitro models (Burstein, 2015;Milando & Friedman, 2019;Petrosino et al., 2018;Pisanti et al., 2017). It has been reported that CBD has completely inhibited the production of inducible nitric oxide synthase (iNOS) (Esposito et al., 2007;Rajesh et al., 2007) and nitric oxide (NO) (Borrelli et al., 2009;Costa et al., 2004Costa et al., , 2007, TNF-α (Ben-Shabat et al., 2006;Hammell et al., 2016;Muthumalage & Rahman, 2019;Ribeiro et al., 2015;) and IL-1β (Borrelli et al., 2009;Esposito et al., 2007;Horváth et al., 2012;Kozela et al., 2010;Pan et al., 2009). ...
Article
Objective To evaluate the anti-inflammation and gingival wound healing activities of Cannabis sativa L. subsp. sativa (hemp) extract and cannabidiol (CBD). Design The cellular bioactivities of hemp extract and CBD were determined the inhibition of TNF-α and IL-1β in LPS-induced murine macrophage (RAW 264.7) cells by using ELISA while wound healing activity in human gingival fibroblast (HGF-1) cells was performed by a scratch test assay. The cytotoxicity was also concerned and evaluated by MTT assay. Results The hemp extract and CBD significantly decreased TNF-α releases by up to 91.05 ± 2.91% and 50.78 ± 7.21% of LPS activity respectively in a dose-dependent manner, compared to 10 µg/mL hydrocortisone (61.67 ± 3.79%). The hemp extract and CBD also significantly decreased IL-1β releases, also in dose-dependent response, up to 78.03 ± 3.34% and 85.87 ± 1.11% of LPS activity respectively, compared to 5 µg/mL hydrocortisone (80.81 ± 3.55%). The percentage of wound closure areas were 27.92 ± 1.21% and 33.49 ± 1.67% when exposed to 5 µg/mL hemp extract and 0.5 µg/mL CBD respectively, compared to 24.34 ± 2.29% for non-treated control. Conclusions Our study demonstrates that both hemp extract and CBD can inhibit TNF-α and IL-1β production in LPS-induced RAW 264.7 cells and promote wound healing in HGF-1 cells. This is the first to show that short-term exposure to hemp extract and CBD promoted gingival fibroblast wound healing, demonstrating that hemp extract and CBD have potential benefits in the treatment of oral inflammation and ulcers.
... Several studies are being carried out for possible pharmacological applications involving cannabinoids, especially with CBD due to the absence of psychoactive effects. Conditions such as Alzheimer's disease, anxiety, cancer, chronicle pain, depression, epilepsy, inflammatory diseases, multiple sclerosis, and Parkinson's disease are being investigated with promising results [54]. ...
Article
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The legal cannabis market worldwide is facing new challenges regarding innovation in the production of cannabinoid-based drugs. The usual cannabinoid production involves growing Cannabis sativa L. outdoor or in dedicated indoor growing facilities, followed by isolation and purification steps. This process is limited by the growth cycles of the plant, where the cannabinoid content can deeply vary from each harvest. A game change approach that does not involve growing a single plant has gained the attention of the industry: cannabinoids fermentation. From recombinant yeasts and bacteria, researchers are able to reproduce the biosynthetic pathway to generate cannabinoids, such as (-)-∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), and (-)-∆9-tetrahydrocannabivarin (∆9-THCV). This approach avoids pesticides, and natural resources such as water, land, and energy are reduced. Compared to growing cannabis, fermentation is a much faster process, although its limitation regarding the phytochemical broad range of molecules naturally present in cannabis. So far, there is not a consolidated process for this brand-new approach, being an emerging and promising concept for countries in which cultivation of Cannabis sativa L. is illegal. This survey discusses the techniques and microorganisms already established to accomplish the task and those yet in seeing for the future, exploring upsides and limitations about metabolic pathways, toxicity, and downstream recovery of cannabinoids throughout heterologous production. Therapeutic potential applications of cannabinoids and in silico methodology toward optimization of metabolic pathways are also explored. Moreover, conceptual downstream analysis is proposed to illustrate the recovery and purification of cannabinoids through the fermentation process, and a patent landscape is presented to provide the state-of-the-art of the transfer of knowledge from the scientific sphere to the industrial application.
... CBD has been shown to have anti-inflammatory, antiepileptic, analgesic, anxiolytic, antipsychotic, and immunomodulatory properties. 2 Several studies with cannabinoids have shown effects on various transmembrane ion channels, such as inward sodium and calcium channels and outward potassium channels. 4 In guinea pigs CBD has been shown to be an inhibitor of the cardiac human Ether-a-go-go-Related Gene (hERG) channels at concentrations between 1 and 5 mM. 5 These channels conduct the rapid delayed rectifier potassium currents (I kr ) and play a central role in the third phase of the cardiac repolarization. ...
... cannabidiol, which are partial CNR1 and CNR2 agonists, respectively [20,21]. CNRs' increased expression suggests that they may play a role in immune system functions [22]. ...
Article
Background and aims The COVID-19 pandemic has prompted researchers to look for effective therapeutic targets. The effect of endocannabinoid system against infectious diseases is investigated for several years. In this study, we evaluated the expression level of CNR1 and CNR2 genes in patients with COVID-19 with and without diabetes to provide new insights regarding these receptors and their potential effect in COVID-19 disease. Methods In this study, peripheral blood monocytes cells (PBMCs) were isolated from eight different groups including COVID-19 patients, diabetic patients, and healthy individuals. RNA were extracted to evaluate the expression level of CNR1 and CNR2 genes using real-time PCR. The correlation between the expression levels of these genes in different groups were assessed. Results A total of 80 samples were divided into 8 groups, with each group consisting of ten samples. When comparing severe and moderate COVID-19 groups to healthy control group, the expression levels of the CNR1 and CNR2 genes were significantly higher in the severe and moderate COVID-19 groups. There were no significant differences between the mild COVID-19 group and the healthy control group. It was found that the expression levels of these genes in patients with diabetes who were infected with SARS-COV-2 did not differ across COVID-19 groups with varying severity, but they were significantly higher when compared to healthy controls. Conclusion Our study suggests the possible role of endocannabinoid system during SARS-COV-2 pathogenicity as the expression of CNR1 and CNR2 were elevated during the disease.
... It is found to cause a dose-dependent increase in intoxication, cognitive impairment, anxiety, and psychotic-like symptoms such as delusion, illusion, and euphoria in human laboratory studies (Curran et al. 2002;D'Souza et al. 2004;Freeman et al. 2021). Meanwhile, CBD is non-psychomimetic and is known to reduce the psychoactive effects of Δ 9 -THC by acting as an entourage compound (Pisanti et al. 2017). Additionally, CBD has been gaining much interest over the past few years due to its antioxidative and anti-inflammatory activities as well as its potential as a treatment for generalized anxiety disorders (Blessing et al. 2015;Atalay et al. 2019;Shannon et al. 2019). ...
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A microwave-assisted digestion using only diluted nitric acid for the determination of 14 heavy metals including As, Cd, Hg, and Pb in cannabinoid-based food products using ICP-MS was developed and validated. Cannabinoid-based liquid beverage, powdered beverage, chocolate, and tea samples were digested using different nitric acid concentrations (20, 30, 40, 50, and 100% (v/v) HNO3) and evaluated for digestion efficiency using spike recovery studies. Spike recoveries for As, Cd, Hg, and Pb were all within 81–114% for all acid concentrations; hence, the use of 20% (v/v) HNO3 was selected in view of lower reagent consumption, lower dilution factors, and reduced spectral interferences associated with residual acidity. The developed method was further validated by detection limit, precision, and accuracy. Results showed that the proposed method was highly sensitive with detection limits within parts-per-trillion (ng L–1) levels. Notably, detection limits for Hg were within 2 to 10 ng L–1, making the proposed method comparable to other mercury detection methods. Furthermore, the recovery of majority of the metals analyzed is within 80–120% indicating good accuracy. Finally, the developed method was also applicable to samples with complex matrices such as chocolates. Therefore, it can potentially be used for routine analysis of heavy metals in cannabinoid-based products.
... CBD is a component of cannabis with no psychoactive properties (Vrechi et al., 2021). Using an inverse agonist of CB2 receptors, an agonist of TRPA1, TRPV1, TRPV2, 5HT-1A, and PPARγ receptors, as well as an antagonist of CB1 receptor and GPR55 (Pisanti et al., 2017;Rong et al., 2017;Ferro et al., 2018;Raymundi et al., 2020). CBD also exhibits a wide range of anti-tumor activities, which can induce programmed death of different types of cancer cells according to reports (Olea-Herrero et al., 2009;Aviello et al., 2012;Pacher, 2013;Fonseca et al., 2018;Yang et al., 2020), including human prostate cancer, human breast carcinoma, human glioblastoma, human cervical cancer, human lung cancer, lymphocytic, and monocytic leukemias, endometrial cancer, pancreatic cancer. ...
Article
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Cannabidiol (CBD) is one specific kind of the cannabinoid in Cannabis sativa L with a wide range of pharmacological activities. However, the poor water solubility and specificity of CBD limits its application in pharmaceutical field. For solving these problems, in this work, we successfully prepared a targeted carrier by grafting biotin (BIO) onto ethylenediamine-β-Cyclodextrin (EN-CD) in a single step to generate a functionalized supramolecule, named BIO-CD. Subsequently, an amantadine-conjugated cannabinoids (AD-CBD) was prepared and self-assembled with the BIO-CD. A series of methods were used to characterize the inclusion behavior and physicochemical properties of AD-CBD and BIO-CD. The results showed that AD-CBD entered the cavity of BIO-CD and formed a 1:1 host-guest inclusion complex. MTT assay and confocal laser scanning microscopy (CLSM) revealed that the targeting effect and anticancer activity of AD-CBD/BIO-CD inclusion complex against three human cancer cell lines were higher than BIO-CD, AD-CBD and free CBD. Moreover, the inclusion complex could release drugs under weakly acidic conditions. These results demonstrated that AD-CBD/BIO-CD inclusion complex possess excellent targeted and anticancer activity, which is hopeful to be applied in clinic as a new therapeutic approach.
... CBD has been in the spotlight for its applications in medicine (Pisanti et al., 2017). High levels of CBD are found in trichomes, which are fine hairs with Table 5 Hemp seed oil compositions a . ...
Chapter
Industrial hemp (Cannabis sativa), a member of the family that includes marijuana, has great potentials as a renewable feedstock for a sustainable society. Unlike marijuana, industrial hemp has a high cannabidiol (CBD) content and only < 0.3% tetrahydrocannabinol (THC), the psychoactive compound in marijuana. Moreover, every part of hemp can be used. For instance, hemp bast can be used as a fiber source for textile and paper production. Hemp seeds are a good source of oil, which is rich in omega-3, omega-6, and unsaturated fatty acids for cooking and supplements. Hemp flowering materials (leaves and flowers) are rich in CBD oil, which has medicinal properties for the treatment of Dravet syndrome, Parkinson's disease, schizophrenia, and anxiety disorder. Last but not least, hemp hurd, a soft inner core of hemp stalks and stems, can be used as a starting material for biofuel, bioproducts, and construction materials. Considering the hemp's versatility, the cultivation of industrial hemp and hemp-derived products have increased rapidly. In this chapter, we described selected potential uses of industrial hemp in the following aspects: (1) value-added materials, (2) foods and bioproducts, and (3) biofuels and biochemicals.
Article
Cannabis is one of the oldest cultivated plant, which has been used by humankind for thousands of years due to its biological properties and a wide range of applications. In total, hemp plants contain over 500 different substances while the characteristic components are the cannabinoids. The most important cannabinoids are (-)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD), and cannabinol (CBN – the latter being an oxidation product resulting from Δ⁹-THC). In the course of recent years, a paradigm shift has taken place with regard to the use of products and ingredients derived from hemp, especially CBD. Thus, an ever-increasing number of products containing CBD are on the market; this ranges from classic CBD oil to CBD chewing gum and even CBD shampoo. Despite an increasing presence of these products in the market, the regulation of cannabinoids in these products is very inconsistent in different countries, except for Δ⁹-THC whose limit is 0.2% for many products and many countries. The enormous abundance of CBD-containing products calls for the development of new analytical techniques that allow a reliable and quick determination of the main cannabinoids usually found in hemp. This seems all the more necessary since previous examinations of CBD oils often revealed a difference between the declared amount and the actual content of the ingredients. Many methods usually applied to determine cannabinoids are rather time-consuming and associated with high costs. In this study, we developed and validated a sensitive, simple, reliable as well as fast method for the determination of CBN, CBD and Δ⁹-THC in commercially available CBD oils using high-performance thin-layer chromatography (HPTLC) combined with electrospray ionization mass spectrometry (ESI-MS). Thus, for this method, a recovery rate of ≥90% was determined. This procedure enables both qualitative and quantitative analyses of CBN, CBD and Δ⁹-THC in CBD oils of different matrices such as hempseed oil, olive oil or sunflower oil. Thus, this method is a helpful and fast tool to investigate a broad variety of commercially available CBD oils.
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Cannabidiol (CBD) is a non-intoxicating compound extracted from Cannabis sativa, showing antidepressant-like effects in different rodent models. However, inconsistent results have been described depending on the species and the strain used to assess depressive-like behavior. Moreover, only a few studies investigated the effect of CBD in female rodents. Therefore, we aimed to (i) investigate the effects of CBD in two different strains of mice (Swiss and C57BL/6) and a rat model of depression based on selective breeding (Flinders Sensitive and Resistant Lines, FSL and FRL) subjected to tests predictive of antidepressant-like effects and (ii) investigate the influence of sex in the effects of CBD in both mice and rats. CBD induced an antidepressant-like effect in male Swiss but not in female Swiss or C57BL/6 mice in the tail suspension test (TST). In male FSL rats, CBD produced an antidepressant-like effect 1 h post injection. However, in female FSL, CBD induced a bimodal effect, increasing the immobility time at 1 h and decreasing it at 2 h. In conclusion, strain, sex, and administration time affect CBD’s behavioral response to rodents exposed to tests predictive of antidepressant effects.
Thesis
Water intake is crucial for maintaining body fluid homeostasis and animals’ survival. Complex brain processes trigger thirst, which arises upon losing blood volume (i.e. extracellular dehydration) or increasing blood osmolality (i.e. intracellular dehydration), to replenish water for fluid balance. The brain plays a key role in modulating these processes, but the central mechanisms regulating water intake are not fully understood. Type-1 cannabinoid receptors (CB1) are widely and abundantly expressed in the central nervous system where they modulate a variety of functions, such as memory, anxiety and feeding behavior. However, the role of CB1 receptors in the control of water intake is still a matter of debate, since pharmacological activation or blockade of CB1 receptors produced contradictory results in drinking behavior experiments.My thesis work focuses on the role of CB1 receptors in the control of water intake. By using genetic, pharmacological, anatomical, imaging, and behavioral approaches, I examined the involvement of CB1 receptors in the control of water intake induced by different physiological conditions of extracellular or intracellular dehydration. The results showed that CB1 receptor signaling is required to promote water intake. In particular, global deletion of CB1 receptors does not change plasma osmolality and body water composition, but it decreases water intake induced by water deprivation, systemic or intracerebroventricular (ICV) administration of sodium chloride, or ICV injection of the peptide hormone angiotensin II. In the attempt to better detail the neuronal mechanisms of this function, I discovered that the presence of CB1 receptors in cortical glutamatergic neurons, particularly the ones located in the anterior cingulate cortex (ACC) glutamatergic neurons promote drinking behavior. CB1 receptors are abundantly expressed in axon terminal of ACC glutamatergic neurons projecting to the basolateral amygdala (BLA) and selective expression of CB1 receptors in this circuit is sufficient to guarantee proper drinking behavior in mice. Altogether, these data reveal that CB1 receptors are necessary to promote water intake, and that their presence in the ACC-BLA circuit is sufficient for the top-down control of drinking behavior.Furthermore, I also provided evidence that CB1 controls water intake in different conditions at other levels, e.g. insular cortex, cholinergic cells, and mitochondria.In summary, my thesis work analyzed the role of CB1 receptors in distinct cell populations/neuronal circuits for the control of water intake. These results will help further understanding the functions of the ECS and the brain regulation of thirst.
Article
Parkinson’s disease (PD) is a complex, multifactorial neurodegenerative disease. The main pathological feature of PD is the loss or apoptosis of dopaminergic neurons in the substantia nigra (SN). This study aimed to investigate the protective effect of cannabidiol (CBD) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuronal dopamine injury by inhibiting neuroinflammation, which was one of the factors that cause neuronal apoptosis. Male SPF C57BL/6 mice were used to create a PD model by administering MPTP intraperitoneally for seven days and treated by oral administration of CBD for 14 days. Behaviorally, CBD improved cognitive dysfunction and increased the number of spontaneous locomotion in PD mice. Biochemically, CBD increased the levels of 5-HT, DA and IL-10, and decreased the contents of TNF-α, IL-1β and IL-6. Pathologically, CBD increased the expression of tyrosine hydroxylase (TH). Mechanistically, CBD up-regulated the expression of Bcl-2, down-regulated the levels of Bax and Caspase-3, and repressed the expression of NLRP3/caspase-1/IL-1β inflammasome pathway. In summary, CBD has a therapeutic effect on MPTP-induced PD mice by inhibiting the apoptosis of dopaminergic neurons and neuroinflammation. Therefore, CBD is a potential candidate for PD therapy.
Article
Introduction: Cannabis is the most frequently consumed illegal substance worldwide. More recently, an increasing number of legal cannabis-products low in psychoactive Δ9 -tetrahydrocannabinol (THC), but high in non-intoxicating cannabidiol (CBD) are being more widely consumed. While the detection and quantification of THC and its metabolites in biological matrices is an important forensic-toxicological task, additional detection of CBD is also important, for example when examining the plausibility of consumer's statements. This report describes the method validation for the quantitative determination of THC and its two major metabolites, 11-hydroxy-THC (OH-THC) and 11-nor-9-carboxy-THC (THC-COOH), as well as CBD and cannabinol (CBN) in whole blood and urine. Method: The method employs automated on-line solid phase extraction coupled to gas chromatography tandem mass spectrometry (GC-MS/MS). The method was fully validated according to guidelines of the Swiss Society of Legal Medicine (SGRM) and the Society of Toxicological and Forensic Chemistry (GTFCh). Results: The method fulfilled the validation criteria regarding analytical limits, accuracy and precision, extraction efficacy, and sample stability. Limits of detection (LOD) and quantification (LOQ) in whole blood and urine were 0.15 ng/mL and 0.3 ng/mL, respectively, for THC, OH-THC and CBD, 0.1 ng/mL and 0.2 ng/mL, respectively, for CBN, and 1.0 ng/mL and 3.0 ng/mL, respectively, for THC-COOH. Conclusion: The fully validated and automated method allows sensitive and robust measurement of cannabinoids in whole blood and urine. Detection of CBD provides additional information regarding consumed products.
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As medical cannabis becomes legal in more states, cancer patients are increasingly interested in the potential utility of the ancient botanical in their treatment regimen. Although eager to discuss cannabis use with their oncologist, patients often find that their provider reports that they do not have adequate information to be helpful. Oncologists, so dependent on evidence-based data to guide their treatment plans, are dismayed by the lack of published literature on the benefits of medical cannabis. This results largely from the significant barriers that have existed to effectively thwart the ability to conduct trials investigating the potential therapeutic efficacy of the plant. This is a narrative review aimed at clinicians, summarizing cannabis phytochemistry, trials in the areas of nausea and vomiting, appetite, pain and anticancer activity, including assessment of case reports of antitumor use, with reflective assessments of the quality and quantity of evidence. Despite preclinical evidence and social media claims, the utility of cannabis, cannabinoids or cannabis-based medicines in the treatment of cancer remains to be convincingly demonstrated. With an acceptable safety profile, cannabis and its congeners may be useful in managing symptoms related to cancer or its treatment. Further clinical trials should be conducted to evaluate whether the preclinical antitumor effects translate into benefit for cancer patients. Oncologists should familiarize themselves with the available database to be able to better advise their patients on the potential uses of this complementary botanical therapy.
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Microglia, the dynamic innate immune cells of the central nervous system, become activated in epilepsy. The process of microglial activation in epilepsy results in the creation of an inflammatory environment around the site of seizure onset, which contributes to the epileptogenic process and epilepsy progression. Cannabidiol (CBD) has been effective for use as an adjunctive treatment for two severe pediatric seizure disorders. Newly recognized as an Food and Drug Administration (FDA)-approved drug treatment in epilepsy, it has gained in popularity primarily for pain management. Although CBD is readily available in stores and online retailers, its mechanism of action and specifically its effects on microglia and their functions are yet fully understood. In this study, we examine the effects of commercially available CBD on microglia inflammatory activation and neurogenic response, in the presence and absence of seizures. We use systemic administration of kainate to elicit seizures in mice, which are assessed behaviorally. Artisanal CBD is given in different modes of administration and timing to dissect its effect on seizure intensity, microglial activation and aberrant seizure-related neurogenesis. CBD significantly dampens microglial migration and accumulation to the hippocampus. While long term artisanal CBD use does not prevent or lessen seizure severity, CBD is a promising adjunctive partner for its ability to depress epileptogenic processes. These studies indicate that artisanal CBD is beneficial as it both decreases inflammation in the CNS and reduces the number of ectopic neurons deposited in the hippocampal area post seizure.
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Rationale Cannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces methamphetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is methamphetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH. Objective The aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats. Methods Eighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3–7; i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg; i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg; i.p.) and challenged with acute METH (1 mg/kg; i.p.). Locomotor activity was then measured for 60 min. Results Rats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity. Conclusion These results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.
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Background Our previous studies showed that the non-psychoactive cannabinoid, cannabidiol (CBD), ameliorates the clinical symptoms in mouse myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis model of multiple sclerosis (MS) as well as decreases the memory MOG35-55-specific T cell (TMOG) proliferation and cytokine secretion including IL-17, a key autoimmune factor. The mechanisms of these activities are currently poorly understood. Methods Herein, using microarray-based gene expression profiling, we describe gene networks and intracellular pathways involved in CBD-induced suppression of these activated memory TMOG cells. Encephalitogenic TMOG cells were stimulated with MOG35-55 in the presence of spleen-derived antigen presenting cells (APC) with or without CBD. mRNA of purified TMOG was then subjected to Illumina microarray analysis followed by ingenuity pathway analysis (IPA), weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) elucidation of gene interactions. Results were validated using qPCR and ELISA assays. ResultsGene profiling showed that the CBD treatment suppresses the transcription of a large number of proinflammatory genes in activated TMOG. These include cytokines (Xcl1, Il3, Il12a, Il1b), cytokine receptors (Cxcr1, Ifngr1), transcription factors (Ier3, Atf3, Nr4a3, Crem), and TNF superfamily signaling molecules (Tnfsf11, Tnfsf14, Tnfrsf9, Tnfrsf18). “IL-17 differentiation” and “IL-6 and IL-10-signaling” were identified among the top processes affected by CBD. CBD increases a number of IFN-dependent transcripts (Rgs16, Mx2, Rsad2, Irf4, Ifit2, Ephx1, Ets2) known to execute anti-proliferative activities in T cells. Interestingly, certain MOG35-55 up-regulated transcripts were maintained at high levels in the presence of CBD, including transcription factors (Egr2, Egr1, Tbx21), cytokines (Csf2, Tnf, Ifng), and chemokines (Ccl3, Ccl4, Cxcl10) suggesting that CBD may promote exhaustion of memory TMOG cells. In addition, CBD enhanced the transcription of T cell co-inhibitory molecules (Btla, Lag3, Trat1, and CD69) known to interfere with T/APC interactions. Furthermore, CBD enhanced the transcription of oxidative stress modulators with potent anti-inflammatory activity that are controlled by Nfe2l2/Nrf2 (Mt1, Mt2a, Slc30a1, Hmox1). Conclusions Microarray-based gene expression profiling demonstrated that CBD exerts its immunoregulatory effects in activated memory TMOG cells via (a) suppressing proinflammatory Th17-related transcription, (b) by promoting T cell exhaustion/tolerance, (c) enhancing IFN-dependent anti-proliferative program, (d) hampering antigen presentation, and (d) inducing antioxidant milieu resolving inflammation. These findings put forward mechanism by which CBD exerts its anti-inflammatory effects as well as explain the beneficial role of CBD in pathological memory T cells and in autoimmune diseases.
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Transient receptor potential vanilloid type-2 (TRPV2) is an ion channel that is triggered by agonists like cannabidiol (CBD). Triple negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Chemotherapy is still the first line for the treatment of TNBC patients; however, TNBC usually gains rapid resistance and unresponsiveness to chemotherapeutic drugs. In this study, we found that TRPV2 protein is highly up-regulated in TNBC tissues compared to normal breast tissues. We also observed that TNBC and estrogen receptor alpha negative (ERα-) patients with higher TRPV2 expression have significantly higher recurrence free survival compared to patients with lower TRPV2 expression especially those who were treated with chemotherapy. In addition, we showed that TRPV2 overexpression or activation by CBD significantly increased doxorubicin (DOX) uptake and apoptosis in TNBC cells. The induction of DOX uptake was abrogated by TRPV2 blocking or downregulation. In vivo mouse model studies showed that the TNBC tumors derived from CBD+DOX treated mice have significantly reduced weight and increased apoptosis compared to those treated with CBD or DOX alone. Overall, our studies for the first time revealed that TRPV2 might be a good prognostic marker for TNBC and ERα- breast cancer patient especially for those who are treated with chemotherapy. In addition, TRPV2 activation could be a novel therapeutic strategy to enhance the uptake and efficacy of chemotherapy in TNBC patients.
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Cannabis sativa L. is an important herbaceous species originating from Central Asia, which has been used in folk medicine and as a source of textile fibre since the dawn of times. This fast-growing plant has recently seen a resurgence of interest because of its multi-purpose applications: it is indeed a treasure trove of phytochemicals and a rich source of both cellulosic and woody fibres. Equally highly interested in this plant are the pharmaceutical and construction sectors, since its metabolites show potent bioactivities on human health and its outer and inner stem tissues can be used to make bioplastics and concrete-like material, respectively. In this review, the rich spectrum of hemp phytochemicals is discussed by putting a special emphasis on molecules of industrial interest, including cannabinoids, terpenoids and phenolic compounds, and their biosynthetic routes. Cannabinoids represent the most studied group of compounds, mainly due to their wide range of pharmaceutical effects in humans, including psychotropic activities. The therapeutic and commercial interests of some terpenoids and phenolic compounds, and in particular stilbenoids and lignans, are also highlighted in view of the most recent literature data. Biotechnological avenues to enhance the production and bioactivity of hemp secondary metabolites are proposed by discussing the power of plant genetic engineering and tissue culture. In particular two systems are reviewed, i.e. cell suspension and hairy root cultures. Additionally, an entire section is devoted to hemp trichomes, in the light of their importance as phytochemical factories. Ultimately, prospects on the benefits linked to the use of the -omics technologies, such as metabolomics and transcriptomics to speed up the identification and the large-scale production of lead agents from bioengineered Cannabis cell culture, are presented.
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Objective: Multiple Sclerosis (MS) is a global concern disease leading to a progressive, chronic and demyelinating condition, affecting the central nervous system (CNS). The pathology has an inflammatory/autoimmune origin; nevertheless, neuronal cell death mechanisms are not to be underestimated. The present study was designed to test the effects of intraperitoneal administration of cannabidiol (CBD), the main non-psychotropic cannabinoid of Cannabis sativa (CS), in an experimental model of MS. The aim is to evaluate the capability of CBD administration to thwart the cascade of mediators involved in MS-induced apoptosis. Materials and methods: Experimental Autoimmune Encephalomyelitis (EAE) was induced by immunization with myelin oligodendroglial glycoprotein (MOG)35-55 peptide in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Disease signs were evaluated using a standardized scoring system. Results: Immunohistochemical and Western blot assessments of key apoptotic markers reveal that CBD treatment is able to avoid Fas pathway activation, phospho-ERK p42/44 and cleaved caspase-3 triggering as well as alterations in mitochondrial permeability due to Bax/Bcl-2 unbalance. Moreover, CBD interferes with p53-p21 axis activation. As results, the absence of tissue apobody formation in spinal cord tissues of EAE-mice treated with CBD was established. Most of therapeutic properties of CS are currently ascribed to the psychotropic effects of phenylterpenoid delta-9 tetrahydrocannabinol. Conclusions: We have demonstrated that, alone, purified CBD possesses an anti-apoptotic power against the neurodegenerative processes underlying MS development. This represents an interesting new profile of CBD that could lead to its introduction in the clinical management of MS.
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Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa with potential to treat neurodegenerative diseases. Its neuroprotection has been mainly associated with anti-inflammatory and antioxidant events; however, other mechanisms might be involved. We investigated the involvement of neuritogenesis, NGF receptors (trkA), NGF, and neuronal proteins in the mechanism of neuroprotection of CBD against MPP(+) toxicity in PC12 cells. CBD increased cell viability, differentiation, and the expression of axonal (GAP-43) and synaptic (synaptophysin and synapsin I) proteins. Its neuritogenic effect was not dependent or additive to NGF, but it was inhibited by K252a (trkA inhibitor). CBD did not increase the expression of NGF, but protected against its decrease induced by MPP(+), probably by an indirect mechanism. We also evaluated the neuritogenesis in SH-SY5Y cells, which do not express trkA receptors. CBD did not induce neuritogenesis in this cellular model, which supports the involvement of trkA receptors. This is the first study to report the involvement of neuronal proteins and trkA in the neuroprotection of CBD. Our findings suggest that CBD has a neurorestorative potential independent of NGF that might contribute to its neuroprotection against MPP(+), a neurotoxin relevant to Parkinson's disease.
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Background and purpose: In vivo and in vitro studies have demonstrated a protective effect of cannabidiol (CBD) in reducing infarct size in stroke models, and against epithelial barrier damage in numerous disease models. We aimed to investigate whether CBD also affects blood-brain barrier (BBB) permeability following ischaemia. Experimental approach: Human brain microvascular endothelial cell (HBMEC) and human astrocyte (HA) co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Key results: CBD (10 μM) prevented the increase in permeability caused by 4 h OGD. CBD was most effective when administered pre-OGD, but protective effects were observed up to 2 h into reperfusion. This effect was inhibited by a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, and partially reduced by a serotonin (5-HT1A ) antagonist (but was unaffected by antagonists of CB1 , CB2 , TRPV1 or adenosine A2A ). CBD also reduced cell damage (lactate dehydrogenase) and markers of cellular adhesion (VCAM-1). In HBMEC monocultures, CBD decreased vascular cell adhesion protein 1 (VCAM-1) and increased vascular endothelial growth factor (VEGF), which was inhibited by PPARγ antagonism. Conclusions and implications: These data suggest that activity at the BBB could represent an as yet unrecognised mechanism of CBD-induced neuroprotection in ischaemic stroke, mediated by PPARγ and 5-HT1A . This article is protected by copyright. All rights reserved.
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Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.
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The protective effects of cannabidiol (CBD) have been widely shown in preclinical models and have translated into medicines for the treatment of multiple sclerosis and epilepsy. However, the direct vascular effects of CBD in humans are unknown. Using wire myography, the vascular effects of CBD were assessed in human mesenteric arteries, and the mechanisms of action probed pharmacologically. CBD-induced intracellular signalling was characterised using human aortic endothelial cells (HAECs). CBD caused acute, non-recoverable vasorelaxation of human mesenteric arteries with an Rmax of ∼40%. This was inhibited by cannabinoid receptor 1 (CB1) receptor antagonists, desensitisation of transient receptor potential channels using capsaicin, removal of the endothelium, and inhibition of potassium efflux. There was no role for cannabinoid receptor-2 (CB2) receptor, peroxisome proliferator activated receptor (PPAR)γ, the novel endothelial cannabinoid receptor (CBe), or cyclooxygenase. CBD-induced vasorelaxation was blunted in males, and in patients with type 2 diabetes or hypercholesterolemia. In HAECs, CBD significantly reduced phosphorylated JNK, NFκB, p70s6K and STAT5, and significantly increased phosphorylated CREB, ERK1/2 and Akt levels. CBD also increased phosphorylated eNOS (ser1177), which was correlated with increased levels of ERK1/2 and Akt levels. High glucose prevented the increase in eNOS phosphorylation. This study shows, for the first time, that CBD causes vasorelaxation of human mesenteric arteries via activation of CB1 and TRP channels, and is endothelium- and nitric oxide-dependent. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
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It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumour growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumour angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area. Copyright © 2015. Published by Elsevier Inc.
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Scientific insights into the human immune system have recently led to unprecedented breakthroughs in immunotherapy. In the twenty-first century, drugs and cell-based therapies developed to bolster humoral and T cell immunity represent an established and growing component of cancer therapeutics. Although natural killer (NK) cells have long been known to have advantages over T cells in terms of their capacity to induce antigen-independent host immune responses against malignancies, their therapeutic potential in the clinic has been largely unexplored. A growing number of scientific discoveries into pathways that both activate and suppress NK cell function, as well as methods to sensitize tumours to NK cell cytotoxicity, have led to the development of numerous pharmacological and genetic methods to enhance NK cell antitumour immunity. These findings, as well as advances in our ability to expand NK cells ex vivo and manipulate their capacity to home to the tumour, have now provided investigators with a variety of new methods and strategies to harness the full potential of NK cell-based cancer immunotherapy in the clinic.
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Cannabinoids, the active components of Cannabis sativa Linnaeus, have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, an- ti-inflammatory effects and tumor regression, but their use in chemotherapy is limited by their psychotropic activity. To date, cannabinoids have been successfully used in the treatment of nau- sea and vomiting, two common side effects that accompany chemotherapy in cancer patients. Most non-THC plant cannabinoids e.g. cannabidiol and cannabigerol, seem to be devoid of psychotropic properties. However, the precise pathways through which these molecules produce an antitumor effect have not yet been fully characterized. We therefore investigated the antitumor and anti-in- flammatory activities of cannabidiol (CBD) in human prostate cancer cell lines LNCaP, DU145, PC3, and assessed whether there is any advantage in using cannabis extracts enriched in cannabidiol and low in THC. Results obtained in a panel of prostate cancer cell lines clearly indicate that can- nabidiol is a potent inhibitor of cancer cell growth, with significantly lower potency in non-cancer cells. The mRNA expression level of cannabinoid receptors CB1 and CB2, vascular endothelial growth factor (VEGF), PSA (prostate specific antigen) are significantly higher in human prostate cell lines. Treatment with Cannabis extract containing high CBD down regulates CB1, CB2, VEGF, PSA, pro-inflammatory cytokines/chemokine IL-6/IL-8. Our overall findings support the concept that cannabidiol, which lacks psychotropic activity, may possess anti-inflammatory property and down regulates both cannabinoid receptors, PSA, VEGF, IL-6 and IL-8. High CBD cannabis extracts are cytotoxic to androgen responsive LNCaP cells and may effectively inhibit spheroid formation in cancer stem cells. This activity may contribute to its anticancer and chemosensitizing effect against prostate cancer. Cannabidiol and other non-habit forming cannabinoids could be used as novel therapeutic agents for the treatment of prostate cancer.
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The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPγS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1−/− and GPR55−/−) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPγS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55−/− mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55−/− mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control.
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Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.
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Background Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. Material and methods A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. Results We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2 with nabilone and 1 with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD − 0.10 (95 % CI − 0.20– − 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03–0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8–45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01–0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01–0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13–37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18–0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2–4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06–0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7–12). Conclusion Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.