ArticleLiterature Review

Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress

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Abstract

Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB₁ and CB₂ G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.

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... For example, CBD has been proved to be specifically effective in dealing with several types of pain. This activity is also effective as an anti-inflammatory, much as an over-the-counter anti-inflammatory drug is used for typical aches and pains [9]. Recent studies have also proven a significant anti-inflammatory response from synthetic cannabinoids (212-2, 940, WIN55, and CP55). ...
... In this way, inflammation is reduced with the help of CBD, CBG, and THCV-containing fractions. Indeed, they confirmed the ACE2-reducing activity of cannabis-derived products [9]. ...
... Preclinical data showed that cannabinoids could attenuate the autoimmune inflammatory response. In an animal model of multiple sclerosis, CBD reduced transcription of genes that promote inflammation [2,6,9]. ...
Article
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This article reviews recent research on cannabinoids that mediate anti-inflammatory effects through cannabinoid receptors. Inflammation is involved in many of the diseases. Chronic inflammation can be caused by cancer, autoimmune disorders, and untreated infections. Some factors like smoking, obesity, or stress may also be caused by chronic inflammation. Early researchers show that Cannabidiol (CBD) has a significant role in reducing inflammation. Cannabis sativa is most commonly used for its medicinal and anti-inflammatory properties. This article focuses primarily on using cannabinoids as a new class of anti-inflammatory agents against specific autoimmune diseases and inflammatory responses caused by cell-mediated immune compounds or activated T cells.
... This statement is based on evidence suggesting that CBD could induce changes in cortisol release, regulating inflammatory response to injury Yeager et al., 2010). This mediation is due to the interaction between CBD CB 1 , and CB 2 cannabinoids and adenosine receptors, leading to reduced cytokine levels and downregulating overreactive immune cells (Booz, 2011;Hill et al., 2012;Burstein, 2015). Also, CBD intake seems to mediate processes associated with gastrointestinal damage protection, due to inflammation, and promote healing of skeletal injuries . ...
... This is supported by a recent narrative review in sports, suggesting the potential anti-inflammatory effect in humans and the possible role in the performance of the athletes . This affirmation is theoretically based on the suggested CBD capacity to interact with receptors involved in controlling inflammation as CB1 cannabinoid, CB2 cannabinoid, adenosine A2A, and also in reducing the levels of some cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor α (TNFα), and downregulating overreactive immune cells reducing the impact of collateral inflammatory damage of tissues (Booz, 2011;Hill et al., 2012;Burstein, 2015). There is also evidence suggesting the CBD potential to promote the release of arachidonic acid, leading to greater healing capacity as a result of core regulation of growth signals mediated by proresolving substances, such as lipoxin A4 and 15d-PGJ2 (Burstein, 2015). ...
... CBD consumption could exhibit a beneficial effect over edema and hyperalgesia (Burstein, 2015;Hill et al., 2017), acting directly on the central nervous system and leading to sedative effects (Zuardi A. W. et al., 1993). The idea of considering CBD as an antinociceptive agent is based on the efficiency of treating the pain associated with proinflammatory cytokine release due to the activation of Vanilloid receptors, provoking antinociceptive effects and reducing the perception of pain (Booz, 2011). CBD could inhibit presynaptic neurotransmitters and neuropeptide release, modulate postsynaptic neuronal excitability, activate the descending inhibitory pain pathway, and reduce neuroinflammatory signaling (Starowicz and Finn, 2017). ...
Article
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The use of cannabidiol (CBD) among athletes is becoming extensive and frequent. This could be due to its elimination of CBD from the list of prohibited substances by federations and international institutions of sport. Also, CBD legalization, and production and commercialization allowance could rise it intake. This situation, despite the fact that the use and commercialization of cannabinoids has not ceased, has fueled the race to study their properties, benefits and risks for health and performance in athletes. Although there is evidence that suggests some beneficial properties such as anxiolytics, antidepressants, anti-inflammatory, antioxidants among others, the evidence presented so far is neither clear nor conclusive. In fact, there is a great gap in knowledge regarding the physiological pathways that explain the role of CBD in sports performance. This mini-review aims to expose the evidence suggesting that CBD has the potential to be used as part of strategies to recover from fatigue and muscle damage related to physical and cognitive exertion in sport.
... mRNA and protein expression (in beta-amyloid) were inhibited dose-dependently. Additionally, the expression of inducible nitric oxide synthase (iNOS) and IL-1β protein and release of NO and IL-1β are also reduced by CBD (Booz 2011;. It is reported that CBD reduced phosphorylation of the stress-activated protein kinase and P38 mitogen-activated protein kinase (MAPK), which results in preventing the transfer of nuclear factor-kappa β (NF-kβ) into the nucleus and the successive pro-inflammatory genes transcription and also which encoded for iNOS protein ). ...
... The CBD has antagonistic effect on these receptors. Treatment with CBD may reduce the progression of atherosclerosis along with reduction in inflammation and oxidative stress (Booz 2011;Rajesh et al. 2010). ...
... In addition, CBD acts via many other molecular targets including G-protein-coupled receptors (GPCRs; for example, activation of the peroxisome proliferator-activated γ (PPARγ) receptor and serotonin 5-HT1A and 5-HT2A receptors) and ionotropic receptors (e.g., activation of vanilloid TRPV1 but inhibition of serotonin 5-HT3 receptors). Moreover, it inhibits various transporters (e.g., adenosine uptake) and enzyme activities (e.g., fatty acid amide hydrolase (FAAH), an enzyme responsible for the degradation of the endocannabinoid anandamide) (for details and other molecular targets, see reviews [51,66]). In order to explain its effect against oxidative/nitrative stress, direct effects on the mitochondria and nuclei have been taken into consideration as additional molecular mechanisms [66]. ...
... Moreover, it inhibits various transporters (e.g., adenosine uptake) and enzyme activities (e.g., fatty acid amide hydrolase (FAAH), an enzyme responsible for the degradation of the endocannabinoid anandamide) (for details and other molecular targets, see reviews [51,66]). In order to explain its effect against oxidative/nitrative stress, direct effects on the mitochondria and nuclei have been taken into consideration as additional molecular mechanisms [66]. ...
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ9-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.
... CBD is characterized by a wide spectrum of biological activity, including antioxidant and anti-inflammatory properties, so it is often studied for use in the prevention and treatment of diseases whose development is associated with redox imbalance and inflammation [43]. CBD can regulate redox state directly by affecting elements of the redox system and/or indirectly by interacting with other molecular targets associated with redox system, e.g., G protein-bound receptors [44]. CBD reduces oxidative conditions by preventing the formation of superoxide radicals, generated by xanthine oxidase and NADPH oxidase and by chelating transition metal ions involved in the Fenton reaction to form extremely reactive hydroxyl radicals [45]. ...
... Moreover, CBD inhibits, at least in part, LPS-dependent alterations in the production of pro-oxidative enzymes, and consequently NETosis, as evidenced by lower levels of cfDNA and the percentage of NETotic cells. This direct action of CBD is supported by the known modulation of cellular antioxidant activity [44]. The antioxidant effect of CBD is also associated with the activation of the redox-sensitive transcription factor Nrf2, which is responsible for the biosynthesis of cytoprotective proteins, including antioxidants, as well as the protection of both non-enzymatic and enzymatic cellular antioxidants [47]. ...
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Psoriasis is associated with increased production of reactive oxygen species which leads to oxidative stress. As antioxidants can provide protection, the aim of this study was to evaluate the effects of cannabidiol (CBD) on neutrophil extracellular trap (NET) formation in psoriatic and healthy neutrophils. Important markers of NETosis were measured in healthy and psoriatic neutrophils after incubation with CBD, lipopolysaccharide (LPS), and LPS + CBD). The percentage of neutrophils undergoing NETosis and the level of NETosis markers (cfDNA, MPO, elastase) were higher in the neutrophils and blood plasma of psoriatic patients, compared to controls. After LPS treatment, all of the markers of NETosis, except elastase, and p47 and citrullinated histones, were increased in samples from healthy subjects and psoriasis patients. CBD reduced the concentrations of NETosis markers. This led to a reduction in NETosis, which was more pronounced in psoriatic neutrophils and neutrophils treated with LPS in both psoriatic and healthy participants. These results suggest that psoriatic patients neutrophils are at a higher risk of NETosis both in vitro and in vivo. CBD reduces NETosis, mainly in psoriatic neutrophils, possibly due to its antioxidant properties. The anti-NET properties of CBD suggest the positive effect of CBD in the treatment of autoimmune diseases.
... mRNA and protein expression (in beta-amyloid) were inhibited dose-dependently. Additionally, the expression of inducible nitric oxide synthase (iNOS) and IL-1β protein and release of NO and IL-1β are also reduced by CBD (Booz 2011;Pisanti et al. 2017). It is reported that CBD reduced phosphorylation of the stress-activated protein kinase and P38 mitogen-activated protein kinase (MAPK), which results in preventing the transfer of nuclear factor-kappa β (NF-kβ) into the nucleus and the successive pro-inflammatory genes transcription and also which encoded for iNOS protein (Iuvone et al. 2009). ...
... The CBD has antagonistic effect on these receptors. Treatment with CBD may reduce the progression of atherosclerosis along with reduction in inflammation and oxidative stress (Booz 2011;Rajesh et al. 2010). ...
Chapter
Inflammation is a reaction of immune system to external stress conditions or any microbial attack on body, or it may be followed by autoimmune reaction. Different treatment strategies have been utilized to manage with this situation including use of different nonsteroidal anti-inflammatory drugs (NSAIDs) and other disease-modifying agents. In recent years, different newer natural agents have been screened for their anti-inflammatory activity, and one such agent is cannabidiol (CBD), which has significant activity against inflammation. CBD is an active constituent of Cannabis sativa and other species of Cannabis. Besides, anti-inflammatory activity, this plant species also possess different activities like neuroprotective, antiepileptic, hypoxia-ischemia, anxiolytic, antipsychotic, analgesic , anti-asthmatic, and antitumor properties. In this communication, anti-inflammatory effects of CBD are described along with its mechanism of action and pharmacokinetic studies.
... mRNA and protein expression (in beta-amyloid) were inhibited dose-dependently. Additionally, the expression of inducible nitric oxide synthase (iNOS) and IL-1β protein and release of NO and IL-1β are also reduced by CBD (Booz 2011;. It is reported that CBD reduced phosphorylation of the stress-activated protein kinase and P38 mitogen-activated protein kinase (MAPK), which results in preventing the transfer of nuclear factor-kappa β (NF-kβ) into the nucleus and the successive pro-inflammatory genes transcription and also which encoded for iNOS protein ). ...
... The CBD has antagonistic effect on these receptors. Treatment with CBD may reduce the progression of atherosclerosis along with reduction in inflammation and oxidative stress (Booz 2011;Rajesh et al. 2010). ...
Chapter
Sickle cell anemia (SCA) is an inherited disorder in the β-globin chain of hemoglobin that affects millions of people around the world, especially children. This disease prevalently occurs in some Mediterranean and Saharan Africa. For the treatment of SCA patients, a wide range of drugs have been explored by targeting antisickling activity, γ-globulin induction, antiplatelet effect, etc., but hardly a few drugs have shown potential to combat with this complex disease phenomenon. In spite of unprecedented advances in modern system of medicine, people in the disease-prone area have been taking traditional medicinal plants or plant-derived products to increase the life span of patients. Moreover, numerous clinical trials have been going on for the use of natural products under the purview of symptomatic management of SCA. This chapter is focused on the effect of natural products in pure form or characterized phytoconstituents on particularly inhibition of hemoglobin polymerization. This summarized information will be beneficial for further exploration of new therapeutics in the treatment arena of SCA.
... The antioxidant effect of CBD has been reported in a model of nephropathy induced by cisplatin, reducing ROS and generating NAPDH oxidases, iNOS and NT-3, which reduce cell death and improve kidney function (Pan et al., 2009). Therefore, it is suggested that the antioxidant effect of CBD acts at the mitochondrial level (Booz, 2011). Additionally, CBD has been reported to act as an antagonist of the GPR55 receptor, which decreases intracellular Ca 2+ flux and modulates neuronal hyperexcitability (Rosenberg et al., 2017). ...
Article
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Neural hyperexcitability in the event of damage during early life, such as hyperthermia, hypoxia, traumatic brain injury, status epilepticus, or a pre-existing neuroinflammatory condition, can promote the process of epileptogenesis, which is defined as the sequence of events that converts a normal circuit into a hyperexcitable circuit and represents the time that occurs between the damaging event and the development of spontaneous seizure activity or the establishment of epilepsy. Epilepsy is the most common neurological disease in the world, characterized by the presence of seizures recurring without apparent provocation. Cannabidiol (CBD), a phytocannabinoid derived from the subspecies Cannabis sativa (CS), is the most studied active ingredient and is currently studied as a therapeutic strategy: it is an anticonvulsant mainly used in children with catastrophic epileptic syndromes and has also been reported to have anti-inflammatory and antioxidant effects, supporting it as a therapeutic strategy with neuroprotective potential. However, the mechanisms by which CBD exerts these effects are not entirely known, and the few studies on acute and chronic models in immature animals have provided contradictory results. Thus, it is difficult to evaluate the therapeutic profile of CBD, as well as the involvement of the endocannabinoid system in epileptogenesis in the immature brain. Therefore, this review focuses on the collection of scientific data in animal models, as well as information from clinical studies on the effects of cannabinoids on epileptogenesis and their anticonvulsant and adverse effects in early life.
... More recently, it has also been proposed that CBD action involves non-canonical targets such as the transient receptor potential (TRP) channel [43,44], the adenosine receptor A2A (A2AAR) [45], and the orphan receptor (GPR55) [46] in addition to its known activity on CB1. Furthermore, CBD has also been reported to elicit anti-inflammatory effects [47,48] that may decrease the glial response after seizures. Besides, CBD activates the microglia promoting their phagocytic activity [43]. ...
... More recently, it has also been proposed that CBD action involves non-canonical targets such as the transient receptor potential (TRP) channel [43,44], the adenosine receptor A2A (A2AAR) [45], and the orphan receptor (GPR55) [46] in addition to its known activity on CB1. Furthermore, CBD has also been reported to elicit anti-inflammatory effects [47,48] that may decrease the glial response after seizures. Besides, CBD activates the microglia promoting their phagocytic activity [43]. ...
... In this sense, the most abundant non-psychotomimetic compound found in the Cannabis sativa plant, the cannabidiol (CBD) has gained great prominence. This recognition is due to its potential therapeutic in several disorders such as anxiety, epilepsy, schizophrenia, chronic pain, depression and also diabetes (Booz 2011;Campos et al. 2012;Chaves et al. 2020;Crippa et al. 2011;de Gregorio et al. 2019;de Mello Schier et al. 2014;de Morais et al. 2016;Devinsky et al. 2014;Freitas et al. 2017;Gaetani et al. 2009;Gobbi et al. 2005;Hill et al. 2009;Horváth et al. 2012;Izzo et al. 2009;Lehmann et al. 2016;Lutz et al. 2015;Patel et al. 2017;Réus et al. 2011;Zhou et al. 2017;Zuardi et al. 2017). Studies show that CBD was able to reduce the incidence of DM1 in mice and early pancreatic inflammation in this type of diabetes, and may also delay the damage caused by diabetes in pancreatic-β cells (Di Marzo et al. 2011;Lehmann et al. 2016;Weiss et al. 2006). ...
Article
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Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists − 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.
... Besides this, it is important to note that there is limited number of highly valuable mechanistic, pharmacological and clinical studies. As for the pleiotropic and biphasic mode of action and frequently discussed entourage effect of cannabinoids, the involvement of them in oxidative stress and cannabinoid-based antioxidant effects have recently begun to be discussed [12]. It was demonstrated that CBD protects the liver by inhibiting oxidative and nitrative stress [13] and attenuating inflammatory response [14]. ...
Article
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In this contribution, a comprehensive study of the redox transformation, electronic structure, stability and photoprotective properties of phytocannabinoids is presented. The non-psychotropic cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and psychotropic tetrahydrocannabinol (THC) isomers and iso-THC were included in the study. The results show that under aqueous ambient conditions at pH 7.4, non-psychotropic cannabinoids are slight or moderate electron-donors and they are relatively stable, in the following order: CBD>CBG≥CBN>CBC. In contrast, psychotropic Δ9-THC degrades approximately one order of magnitude faster than CBD. The degradation (oxidation) is associated with the transformation of OH groups and changes in the double-bond system of the investigated molecules. The satisfactory stability of cannabinoids is associated with the fact that their OH groups are fully protonated at pH 7.4 (pKa is ≥ 9). The instability of CBN and CBC was accelerated after exposure to UVA radiation, with CBD (or CBG) being stable for up to 24 h. To support their topical applications, an in vitro dermatological comparative study of cytotoxic, phototoxic and UVA or UVB photoprotective effects using normal human dermal fibroblasts (NHDF) and keratinocytes (HaCaT) was done. NHDF are approx. twice as sensitive to the cannabinoids’ toxicity as HaCaT. Specifically, toxicity IC50 values for CBD after 24 h of incubation are 7.1 and 12.8 μM for NHDF and HaCaT, respectively. None of the studied cannabinoids were phototoxic. Extensive testing has shown that CBD is the most effective protectant against UVA radiation of the studied cannabinoids. For UVB radiation, CBN was the most effective. The results acquired could be used for further redox biology studies on phytocannabinoids and evaluations of their mechanism of action at the molecular level. Furthermore, the UVA and UVB photoprotectivity of phytocannabinoids could also be utilized in the development of new cannabinoid-based topical preparations.
... While the mechanism of how CBD targets the inflammatory response is still unknown, it is known that CBD decreases microglial and macrophage migration, which may play a role for the treatment of inflammatory diseases, such as multiple sclerosis, cancer, diabetes, and neuropathic pain (62)(63)(64). ...
Article
Chronic pain can be recurrent or constant pain that lasts for longer than three months and can result in disability, suffering, and a physical disturbance. Related to the complex nature of chronic pain, treatments have a pharmacological and non-pharmacological approach. Due to the opioid epidemic, alternative therapies have been introduced, and components of the cannabis Sativa, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have gained recent interest as a choice of treatment. The exact mechanism for cannabidiol is currently unknown, but unlike the CBD's psychoactive counterpart, THC, the side effects of CBD itself have been shown to be overall much more benign. The current pharmaceutical products for the treatment of chronic pain are known as nabiximols, and they contain a ratio of THC combined with CBD, which has been promising. This review focuses on the treatment efficacy of CBD, THC: CBD based treatments for chronic pain and adverse events with each.
... CB2 receptors are primarily located on immune system cells and serve as immune system modulators (Cabral and Griffin-Thomas, 2009), while CB1 receptors are located in the CNS (particularly in the hippocampus, cerebral cortex, basal ganglia, and cerebellum), peripheral nervous system (PNS) and peripheral organs (Zou and Kumar, 2018). Interestingly, cannabidiol (CBD), an abundant bioactive but non-psychotomimetic constituent of the plant Cannabis sativa, has emerged as a promising strategy to treat inflammation induced by microglial hyperactivation (Martin-Moreno et al., 2011;Mechoulam et al., 2007;Saito et al., 2012) and to attenuate oxidative and nitrosative stress in different animal models of neuroinflammatory diseases (Booz, 2011;Cassol et al., 2010;Ligresti et al., 2016;Mukhopadhyay et al., 2011;Ruiz-Valdepenas et al., 2011), thus opening a novel window of opportunity to treat inflammatory and autoimmune disorders with cannabinoids. ...
Article
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a multifactorial etiology. Latest researches are raising the hypothesis of a link between the onset of the main behavioral symptoms of ASD and the chronic neuroinflammatory condition of the autistic brain; increasing evidence of this connection is shedding light on new possible players in the pathogenesis of ASD. The endocannabinoid system (ECS) has a key role in neurodevelopment as well as in normal inflammatory responses and it is not surprising that many preclinical and clinical studies account for alterations of the endocannabinoid signaling in ASD. These findings lay the foundation for a better understanding of the neurochemical mechanisms underlying ASD and for new therapeutic attempts aimed at exploiting the renowned anti-inflammatory properties of cannabinoids to treat pathologies encompassed in the autistic spectrum. This review discusses the current preclinical and clinical evidence supporting a key role of the ECS in the neuroinflammatory state that characterizes ASD, providing hints to identify new biomarkers in ASD and promising therapies for the future.
... In adolescent humans, prenatal cannabinoid exposure is linked to reduced left cerebellar activity (Smith et al., 2004). Although there are studies that explored the effect of cannabinoids on oxidative stress (Booz, 2011), inflammation, and apoptosis (Pozzoli et al., 2006), to date, few studies have examined the effects of prenatal cannabinoid exposure on the above mentioned parameters in the cerebellum. However, it is important to understand how prenatal cannabinoid exposure alters cerebellar functions since the cerebellum plays an essential role in learning and motor function. ...
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Cannabis is the most commonly used illicit drug worldwide. Recently, cannabis use among young pregnant women has greatly increased. However, prenatal cannabinoid exposure leads to long-lasting cognitive, motor, and behavioral deficits in the offspring and alterations in neural circuitry through various mechanisms. Although these effects have been studied in the hippocampus, the effects of prenatal cannabinoid exposure on the cerebellum are not well elucidated. The cerebellum plays an important role in balance and motor control, as well as cognitive functions such as attention, language, and procedural memories. The aim of this study was to investigate the effects of prenatal cannabinoid exposure on the cerebellum of adolescent offspring. Pregnant rats were treated with synthetic cannabinoid agonist WIN55,212-2, and the offspring were evaluated for various cerebellar markers of oxidative stress, mitochondrial function, and apoptosis. Additionally, signaling proteins associated with glutamate dependent synaptic plasticity were examined. Administration of WIN55,212-2 during pregnancy altered markers of oxidative stress by significantly reducing oxidative stress and nitrite content. Mitochondrial Complex I and Complex IV activities were also enhanced following prenatal cannabinoid exposure. With regard to apoptosis, pP38 levels were significantly increased, and proapoptotic factor caspase-3 activity, pERK, and pJNK levels were significantly decreased. CB1R and GluA1 levels remained unchanged; however, GluN2A was significantly reduced. There was a significant decrease in MAO activity although tyrosine hydroxylase activity was unaltered. Our study indicates that the effects of prenatal cannabinoid exposure on the cerebellum are unique compared to other brain regions by enhancing mitochondrial function and promoting neuronal survival. Further studies are required to evaluate the mechanisms by which prenatal cannabinoid exposure alters cerebellar processes and the impact of these alterations on behavior.
... Based on this, we can hypothesize that, in our study, the low levels of oxidative stress on exercised mice ameliorated the PGE 2 -induced chronic pain, also triggering a protective physiological environment which prevented the PGE 2 -induced chronic pain. In this context, it is interesting to mention the role of the cannabinoid system, and its ligands, on reducing oxidative stress parameters [51]. In fact, the direct effect of physical exercise on the endocannabinoid system can also explain the exercise-induced analgesia observed in the present study, once the endocannabinoid system has emerged as the main mechanisms for how exercise benefits the whole organism and how it reduces and controls pain [52]. ...
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Chronic pain affects significant portion of the world's population and physical exercise has been extensively indicated as non-pharmacological clinical intervention to relieve symptoms in chronic pain conditions. In general, studies on pain chronification and physical exercise intervention have focused on neuropathic pain, although chronic pain commonly results from an original inflammatory episode. Based on this, the objective of the present study was to investigate the therapeutic and preventive effect of the running wheel exercise on the persistent hyperalgesia induced by repetitive inflammatory stimulus, a rodent model that simulates clinical conditions of chronic pain that persist even with no more inflammatory stimulus present. To evaluate the therapeutic effect of physical exercise, we first induced persistent hyperalgesia through 14 days of PGE2 hind paw injections and, after that, mice have access to the regular voluntary running wheel. To evaluate the preventive effect of physical exercise , we first left the mice with access to the regular voluntary running wheel and, after that, we performed 14 days of PGE2 hind paw injection. Our results showed that voluntary running wheel exercise reduced persistent mechanical and chemical hyperalgesia intensity induced by repetitive inflammatory stimulus. In addition, we showed that this therapeutic effect is long-lasting and is observed even if started belatedly, i.e. two weeks after the development of hyperalgesia. Also, our results showed that voluntary running wheel exercise absolutely prevented persistent mechanical and chemical hyperalgesia induction. We can conclude that physical exercise has therapeutic and preventive effect on inflammatory stimulus induced persistent hyperalgesia. Our data from animal experiments bypass placebo effects bias of the human studies and reinforce physical exercise clinical recommendations to treat and prevent chronic pain.
... CBD has suppressive effects on the immune system, including inflammatory response reduction, cellular and humoral immunity suppression, and induction of apoptosis in some lymphocytes; these effects are beneficial for treating inflammatory diseases [113,114]. Type 1 diabetes is an example of an inflammatory-based disease that can benefit from CBD preemptive treatment; non-obese diabetic mice receiving CBD had delayed development of diabetes, and had significantly lower activation of leukocytes than mice receiving control vehicle [115]. Zhou, Wang, Ji, Lou, and Fan [116] demonstrated anti-neuroinflammatory properties of hemp seed using an experimental mouse model. ...
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Industrial hemp (Cannabis sativa L., Cannabaceae) is an ancient cultivated plant originating from Central Asia and historically has been a multi-use crop valued for its fiber, food, and medicinal uses. Various oriental and Asian cultures kept records of its production and numerous uses. Due to the similarities between industrial hemp (fiber and grain) and the narcotic/medical type of Cannabis, the production of industrial hemp was prohibited in most countries, wiping out centuries of learning and genetic resources. In the past two decades, most countries have legalized industrial hemp production, prompting a significant amount of research on the health benefits of hemp and hemp products. Current research is yet to verify the various health claims of the numerous commercially available hemp products. Hence, this review aims to compile recent advances in the science of industrial hemp, with respect to its use as value-added functional food ingredients/nutraceuticals and health benefits, while also highlighting gaps in our current knowledge and avenues of future research on this high-value multi-use plant for the global food chain.
... Cannabis is known to work on the body's endocannabinoid system, which is known to regulate functions such as sleep, immune system, and pain perception. 17,18 Cannabis is shown as an effective antiemetic agent among cancer patients with chemotherapy-induced nausea/vomiting. 19 Last, CBD has Food Drug Administration approval in the form of a drug named Epidiolex, to treat seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. ...
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The use of cannabis for recreational as well as medicinal use is on the rise recently with more states legalizing it. We conducted a review analysis of the literature published on acute respiratory failure from vaping cannabis oil. We have also summarized the clinical details (age, length of stay, mode of ventilation, common clinical findings, and steroid use) along with common laboratory abnormalities. This article aims to educate health care providers on the clinical manifestations and management strategies for vaping-induced acute respiratory failure. We also discussed the different available formulations of cannabis oil and key ingredients responsible for the vaping-associated lung injury.
... We note that we did not measure any mediators of inflammation, nor did we measure the cannabinoid content of the cannabis used by participants. As cannabinoids, and specifically cannabidiol, is believed to be responsible anti-inflammatory properties of marijuana (Booz, 2011), future research is needed to empirically test the anti-inflammatory hypotheses about our results. ...
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HIV is associated with disruptions in cognition and brain function. Marijuana use is highly prevalent in HIV but its effects on resting brain function in HIV are unknown. Brain function can be characterized by brain activity that is correlated between regions over time, called functional connectivity. Neuropsychiatric disorders are increasingly being characterized by disruptions in such connectivity. We examined the synergistic effects of HIV and marijuana use on functional whole-brain network organization during resting state. Our sample included 78 adults who differed on HIV and marijuana status (19 with co-occurring HIV and marijuana use, 20 HIV-only, 17 marijuana-only, and 22 controls). We examined differences in local and long-range brain network organization using eight graph theoretical metrics: transitivity, local efficiency, within-module degree, modularity, global efficiency, strength, betweenness, and participation coefficient. Local and long-range connectivity were similar between the co-occurring HIV and marijuana use and control groups. In contrast, the HIV-only and marijuana-only groups were both associated with disruptions in brain network organization. These results suggest that marijuana use in HIV may normalize disruptions in brain network organization observed in persons with HIV. However, future work is needed to determine whether this normalization is suggestive of a beneficial or detrimental effect of marijuana on cognitive functioning in HIV.
... CBD modulates inflammatory processes [21]. In preclinical models of acute inflammation, CBD has been reported to attenuate immune cell accumulation (e.g. ...
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Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.
... Cannabidiol (CBD) is currently the best studied nonpsychotropic cannabinoid with multiple targets. Based on extensive pharmacological effects, CBD functions as a potent antioxidant and anti-inflammatory agent in various diseases, including Parkinson's disease, Alzheimer's disease, epilepsy, dermatitis, and ischemiareperfusion injury [13,14]. In skin keratinocytes, CBD can reduce the expression levels of proinflammatory cytokines and protect against ultraviolet-related oxidative stress injury [15]. ...
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Oral mucositis (OM) is a common complication during chemotherapy characterized by ulceration, mucosa atrophy, and necrosis, which seriously interferes with nutritional intake and oncotherapy procedures among patients. However, the efficacy of current treatments for OM remains limited. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including antioxidant and anti-inflammatory potential. In this study, we aimed to investigate the chemopreventive effects and mechanisms of CBD in protecting C57BL/6N mice and human oral keratinocytes (HOK) from 5-fluorouracil- (5-FU-) induced OM. Here, we found that CBD alleviated the severity of 5-FU-induced OM in mice, including improved survival, decreased body weight loss, reduced ulcer sizes, and improved clinical scores. Histologically, CBD restored epithelial thickness and normal structure in tongue tissues. Meanwhile, CBD attenuated reactive oxygen species (ROS) overproduction and improved the antioxidant response, suppressed the inflammatory response, promoted the proliferation of epithelial cells, and inhibited 5-FU-induced apoptosis. In vitro, consistent outcomes showed that CBD suppressed cellular ROS levels, enhanced antioxidant ability, reduced inflammatory response, promoted proliferation, and inhibited apoptosis in 5-FU-treated HOK cells. In particular, CBD upregulated the expression levels of antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO1), by increasing the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreasing Kelch-like ECH-associated protein 1 (Keap1). Notably, the Nrf2 inhibitor ML385 reversed the protective effect of CBD. Nrf2-siRNA transfection also significantly blunted the antioxidant effect of CBD in in vitro OM model. Collectively, our findings suggested that CBD protected against 5-FU-induced OM injury at least partially via the Nrf2/Keap1/ARE signaling pathways, highlighting the therapeutic prospects of CBD as a novel strategy for chemotherapy-induced OM.
... However, the psychoactive effects of THC and other compounds with CB1 or CB1/CB2 activity limit their possible therapeutic applications. Interestingly, despite negligible affinity toward the CB2 receptor, CBD has been shown to exert very potent anti-inflammatory activities in various models of peripheral and CNS inflammation (9,10). Therefore, there is considerable interest in the development of either CB2 ligands or CBD-like compounds that lack psychoactive properties while exerting potent immunoregulatory effects. ...
... CBD also has the capacity to down-regulate the release of anti-inflammatory or proinflammatory mediators [104]. Due to the agonistic activity of CBD on serotonin 5-HT1 receptors, TRPV1 and the glycine signaling pathway [50,61,123], the generation of ROS and the release of pro-inflammatory chemokines and cytokines can be inhibited, along with T cell proliferation [124,125]. Repeated injections of CBD (1.5 mg/kg IP) into animals for 10 weeks lead to reduced T cell differentiation and invasion, which is accompanied by a decrease in the release of pro-inflammatory cytokines and chemokines [126]. Another study has shown that CBD causes the suppression of NFAT, in addition to common proinflammatory cytokines such as IL-2 and IFN-γ, suggesting an inhibition of the activity of NK cells and/or T cells [106][107][108]127] (Table 2). ...
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In recent years, evidence has accumulated that cannabinoids—especially the non-psychoactive compound, cannabidiol (CBD)—possess promising medical and pharmacological activities that might qualify them as potential anti-tumor drugs. This review is based on multiple studies summarizing different mechanisms for how CBD can target tumor cells including cannabinoid receptors or other constituents of the endocannabinoid system, and their complex activation of biological systems that results in the inhibition of tumor growth. CBD also participates in anti-inflammatory activities which are related to tumor progression, as demonstrated in preclinical models. Although the numbers of clinical trials and tested tumor entities are limited, there is clear evidence that CBD has anti-tumor efficacy and is well tolerated in human cancer patients. In summary, it appears that CBD has potential as a neoadjuvant and/or adjuvant drug in therapy for cancer.
... [45] Exacerbation of the AD process is also linked to neuroinflammatory processes and oxidative stress, both of which are well-known. [46] The oxidative stress that occurs in the condition is a significant element in the pathophysiology of AD. [47] There is a growing body of data indicating oxidative stress and AD are associated with progressive cerebrovascular abnormalities. Cerebrovascular dysfunction and neurodegeneration are not mutually exclusive. ...
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Cannabis sativa L. subspecies sativa is a subspecies of the genus Cannabis (Cannabaceae), also known as industrial hemp. It is a herbaceous and double-jawed plant. Tetrahydrocannabinol (THC), a psychoactive compound found in cannabis plants, and the non-psychoactive cannabidiol (CBD) are essential compounds in industry and medicine. These compounds are very similar to endocannabinoids, which are found in the human body. As a result, both compounds have the potential to interact with the body's endocannabinoid system. They exhibit chemical activity in areas affected by oxidative stress, such as the cardiovascular system, muscle development, liver and lung function, reproductive function, metabolism, neurological activities, and cell aging. Since the human body's free radical and antioxidant levels are destabilized, antioxidants fail to neutralize free radicals, resulting in oxidative damage, i.e. a stress effect. This balance in the body can be influenced by compounds like THC and CBD acting on cellular receptors. Thus, the occurrence of various diseases is observed. This review examined the effect of the active substances in the cannabis plant on oxidative stress and the diseases that develop as a result of this stressful situation.
... The effects of CBD on oxidative stress and ROS production in neuronal cells are well documented [41,49,50,79,80]. Treatment with 5 µM CBD has been shown to attenuate the OGD/R-induced damage of HT22 hippocampal cells, in part, due to the reduction in oxidative stress [41]. ...
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Cannabidiol (CBD) is part of a group of phytocannabinoids derived from Cannabissativa. Initial work on CBD presumed the compound was inactive, but it was later found to exhibit antipsychotic, anti-depressive, anxiolytic, and antiepileptic effects. In recent decades, evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation. Despite these advances, current data demonstrate contradictory findings with regard to not only the magnitude of effects mediated by CBD, but also to the direction of effects. For example, there are data indicating that CBD treatment can increase, decrease, or have no significant effect on intrinsic apoptosis. Differences between studies in cell type, cell-specific response to CBD, and, in some cases, dose of CBD may help to explain differences in outcomes. Most studies on CBD and mitochondria have utilized treatment concentrations that exceed the highest recorded plasma concentrations in humans, suggesting that future studies should focus on CBD treatments within a range observed in pharmacokinetic studies. This review focuses on understanding the mechanisms of CBD-mediated regulation of mitochondrial functions, with an emphasis on findings in neural cells and tissues and therapeutic relevance based on human pharmacokinetics.
... Moreover, CBD contains immunomodulatory properties, such as reducing inflammatory responses, suppressing cellular and humoral immunity, and inducing the death of specific lymphocytes. Therefore, these properties are helpful in the treatment of inflammatory disorders (Booz 2011). Diabetes mellitus is primarily an endocrine disorder. ...
Chapter
Bhanga (Cannabis) has been reported with numerous therapeutic, traditional, commercial, and sacred uses in India and across the globe. Its uses are deeply rooted in the cultural, social, and economic lives of the people. The inclusion of Cannabis under ‘Scheduled E1’ drugs in India restricts its use. However, being a crop of economic and medicinal importance, the pharmaceutical and various other sectors are showing much interest in the plant. The present review article delineates traditional, culinary, cosmetic, ritual, social, spiritual, recreational, economic, and therapeutic uses of Cannabis. The review illustrates various uses of Cannabis across the globe; noted from articles, publications, and books providing description of various parts, viz. leaves and seeds (Bhanga), flowering and fruiting tops (Ganja), resin (Charas), extract, tincture, and whole plant, stalks (Fibers). The review may be helpful to researchers, clinicians, and pharmaceutical companies to carry out further research for developing cost-effective healthcare options.
... [30][31][32][33][34] Interestingly, there is significant overlap with mechanisms controlling pain when CBD and THC are compared. CBD has been shown to inhibit pain through modulation of calcium and TRP channels, serotonin receptors, glycine receptors, and modulation of the immune system 6 microglia and macrophage function, 35 leading to anti-inflammatory activity. ...
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Background Chemotherapy-induced peripheral neuropathy is a common and often severe side effect from many chemotherapeutic agents, with limited treatment options. There is no literature on the use of topical cannabinoids for chemotherapy-induced neuropathy. Case Presentations The current manuscript presents a case series of patients presenting in oncology clinics at Sutter Health, CA and Mayo Clinic, Rochester, MN from April 2019 to December 2020 with chemotherapy-induced peripheral neuropathy who used topical creams containing the cannabinoids delta-nine-tetrahydrocannabinol (THC) and/or cannabidiol (CBD). Conclusions This case series suggests that topical cannabinoids may be helpful for patients with chemotherapy-induced peripheral neuropathy. This paper also discusses the potential mechanisms of action by which topical cannabinoids might alleviate established CIPN symptoms. A randomized placebo-controlled trial using a standardized product is planned to study the actual efficacy of such treatment.
... Moreover, CBD contains immunomodulatory properties, such as reducing inflammatory responses, suppressing cellular and humoral immunity, and inducing the death of specific lymphocytes. Therefore, these properties are helpful in the treatment of inflammatory disorders (Booz 2011). Diabetes mellitus is primarily an endocrine disorder. ...
... It is not fully understood how this CBD product exerts its anticonvulsant effect in humans, however researchers do not believe that it is due to an interaction with cannabinoid receptors [6]. CBD also has the potential for alleviating pain and has various applications in other areas such as sports enhancement due to its anxiolytic effects and anti-inflammatory properties [10] [11]. ...
... For example, cannabidiol (CBD) is an exogenous cannabinoid receptor agonist currently being evaluated in a number of clinical trials for multiple medical conditions [14][15][16][17]. CBD has been shown to reduce reactive oxygen and nitrogen species production, chemokine and cytokine release, microglial and astrocyte activation, as well as T cell proliferation [18,19]. In addition, WIN 55,212-2, a non-selective CB receptor agonist, downregulates central nervous systems neutrophil infiltration and apoptosis in multiple sclerosis [20], promotes neural remyelination in neonatal rats experiencing hypoxia-ischaemia [21] and relieves neuropathic pain following peripheral nerve injury in mice [22]. ...
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Study design Systematic review. Objectives To evaluate the impact of cannabinoids on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI), with the aim of determining suitability for clinical trials involving SCI patients. Methods A systematic search was performed in MEDLINE and Embase databases, following registration with PROPSERO (CRD42019149671). Studies evaluating the impact of cannabinoids (agonists or antagonists) on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic SCI were included. Data extracted from relevant studies, included sample characteristics, injury model, neurobehavioural outcomes assessed and study results. PRISMA guidelines were followed and the SYRCLE checklist was used to assess risk of bias. Results The search returned 8714 studies, 19 of which met our inclusion criteria. Sample sizes ranged from 23 to 390 animals. WIN 55,212-2 ( n = 6) and AM 630 ( n = 8) were the most used cannabinoid receptor agonist and antagonist respectively. Acute SCI models included traumatic injury ( n = 16), ischaemia/reperfusion injury ( n = 2), spinal cord cryoinjury ( n = 1) and spinal cord ischaemia ( n = 1). Assessment tools used assessed locomotor function, pain and anxiety. Cannabinoid receptor agonists resulted in statistically significant improvement in locomotor function in 9 out of 10 studies and pain outcomes in 6 out of 6 studies. Conclusion Modulation of the endo-cannabinoid system has demonstrated significant improvement in both pain and locomotor function in pre-clinical SCI models; however, the risk of bias is unclear in all studies. These results may help to contextualise future translational clinical trials investigating whether cannabinoids can improve pain and locomotor function in SCI patients.
... A THC/CBD ratio of 247:1 in THC dominant strains matched with those in "Sativa" and "Indica" strains that were almost devoid of CBD (Fischedick et al., 2010;Hazekamp and Fischedick, 2012;Fischedick, 2015Fischedick, , 2017Hazekamp et al., 2016;Jin et al., 2020). Due to CBD's therapeutic potential without psychoactive effects (Booz, 2011;Couch et al., 2017;Vallée et al., 2017;Callejas et al., 2018;Mallada Frechín, 2018), breeding for high CBD concentrations began only recently by integrating hemp-type CBD acid synthase gene clusters into a background of drug-type cannabis to elevate CBDA production (Clarke and Merlin, 2016;Grassa et al., 2018). The CBD to THC ratios in intermediate trains were similar to 1.8:1 in our previously reported values (Jin et al., 2020), and also matched with the reported cannabinoid profile of intermediate strains available in the database. ...
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Previous chemotaxonomic studies of cannabis only focused on tetrahydrocannabinol (THC) dominant strains while excluded the cannabidiol (CBD) dominant strains and intermediate strains (THC ≈ CBD). This study investigated the utility of the full spectrum of secondary metabolites in different plant parts in three cannabis chemotypes (THC dominant, intermediate, and CBD dominant) for chemotaxonomic discrimination. Hierarchical clustering, principal component analysis (PCA), and canonical correlation analysis assigned 21 cannabis varieties into three chemotypes using the content and ratio of cannabinoids, terpenoids, flavonoids, sterols, and triterpenoids across inflorescences, leaves, stem bark, and roots. The same clustering results were obtained using secondary metabolites, omitting THC and CBD. Significant chemical differences were identified in these three chemotypes. Cannabinoids, terpenoids, flavonoids had differentiation power while sterols and triterpenoids had none. CBD dominant strains had higher amounts of total CBD, cannabidivarin (CBDV), cannabichromene (CBC), α-pinene, β-myrcene, (-)-guaiol, β-eudesmol, α-eudesmol, α-bisabolol, orientin, vitexin, and isovitexin, while THC dominant strains had higher total THC, total tetrahydrocannabivarin (THCV), total cannabigerol (CBG), camphene, limonene, ocimene, sabinene hydrate, terpinolene, linalool, fenchol, α-terpineol, β-caryophyllene, trans-β-farnesene, α-humulene, trans-nerolidol, quercetin, and kaempferol. Compound levels in intermediate strains were generally equal to or in between those in CBD dominant and THC dominant strains. Overall, with higher amounts of β-myrcene, (-)-guaiol, β-eudesmol, α-eudesmol, and α-bisabolol, intermediate strains more resemble CBD dominant strains than THC dominant strains. The results of this study provide a comprehensive profile of bioactive compounds in three chemotypes for medical purposes. The simultaneous presence of a predominant number of identified chemotype markers (with or without THC and CBD) could be used as chemical fingerprints for quality standardization or strain identification for research, clinical studies, and cannabis product manufacturing.
... Cannabidiol (CBD) is an exogenous cannabinoid that has direct and indirect antioxidative effects [60,61] and targets a variety of receptors [62,63], including CB1 and CB2 receptors [64,65]. Although CBD has a low affinity for these receptors, it appears to act as a negative allosteric modulator of CB1 and a partial agonist of CB2 receptors [66][67][68]. ...
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Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.
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Oral mucositis is a painful and distressing complication of chemotherapy‐induced toxicity in cancer patients that can develop early during the treatment regimen. Previous studies have demonstrated that both oxidative stress and inflammation play a role in the development of the ulceration that is a characteristic of oral mucositis. To date, a few studies have investigated the effect of this complication on the well‐being of patients, demonstrating its negative impact on patients’ functional ability and quality of life. This effect may entail chemotherapeutic drug dose reduction among patients, in turn reducing their cancer survival rates. Therefore, interventions to address the detrimental effects of oral mucositis on the well‐being of cancer patients are required. This review provides an overview of the studies that have examined the negative effects of oral mucositis on Chinese cancer patients undergoing chemotherapy, as well as the interventions shown to be effective in treating this complication, with a focus on interventions utilizing traditional Chinese medicine. Overall, both traditional Chinese medicine‐based interventions and interventions involving patient education about effective oral care led by trained nurses were found to be useful in reducing the incidence and severity of oral mucositis among Chinese patients undergoing chemotherapy. Future oral mucositis management plans aiming at effective oral care among cancer patients undergoing chemotherapy should incorporate these types of interventions as integral components to enhance the well‐being of these patients.
Chapter
Nutraceuticals are a type of nutritional supplement used for healthcare in addition to nourishment. They can be used to maintain the body’s structure and function to promote health, slow down the aging process, prevent chronic diseases, and extend life. Echinacea, ginseng, green tea, glucosamine, omega-3, lutein, folic acid, and cod liver oil have been popular global nutraceuticals in the past few decades. The majority of nutraceutical products are regulated like pharmaceuticals, food additives, and dietary supplements. Nutraceuticals can be classified based on the source, methods of action, chemical structure, composition, etc. In addition to the recreational and medicinal value, Cannabis has been widely established globally as a primordial source of fiber, protein, and fat with great nutritional value. Cannabis has been legally utilized as human food in the United States for the past 10 years. The hemp seed oil is an excellent prophylactic and therapeutic potential to prevent and treat various human-related health ailments. Cannabis contains active bioactive ingredients and oils with polyunsaturated fatty acids, which can be a potent nutraceutical for the current and future generations. Cannabis alone or in combination with the other existing nutraceutical (s) can provide additive or synergistic protective effects to improve human healthcare. It is estimated that by 2028, the worldwide cannabis nutraceuticals market is projected to be worth 19.25 billion USD. The present chapter dwells on the concept of nutraceuticals, the classification of nutraceuticals, their health benefits, and the potential of cannabis as a nutraceutical source.
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Chronic hepatitis C virus (HCV) infection is a risk factor of insulin resistance, and HCV‐infected patients are at a high risk of developing diabetes. In the general population, research has shown the potential benefit of cannabis use for the prevention of diabetes and related metabolic disorders. We aimed to test whether cannabis use is associated with a lower risk of diabetes in chronic HCV‐infected patients.Chronic HCV‐infected patients (n=10,445) were selected from the French national, multicenter, observational ANRS CO22 Hepather cohort. Cross‐sectional data collected at cohort enrolment were used to assess the association between patients’ clinical and behavioral characteristics and the risk of diabetes. Logistic regression model was performed with cannabis use as the main independent variable and a significance level set at 5%. A similar model stratified by the presence of advanced liver fibrosis (FIB‐4>3.25) was also run. After multivariable adjustment, current (AOR [95%CI]: 0.49 [0.38‐0.63]) and former (0.81 [0.67‐0.98], p<.001) cannabis use were both associated with a reduced odds of diabetes. Conversely, male gender, tobacco use, elevated BMI, poverty, being a migrant and advanced fibrosis were associated with increased odds of diabetes. The association between cannabis use and diabetes was maintained in the stratified analysis. In this large cross‐sectional study of chronic HCV‐infected patients, cannabis use was associated with a lower risk of diabetes independently of clinical and socio‐behavioral factors. Further studies are needed to elucidate a potential causal link and shed light on cannabis compounds and mechanisms involved in this relationship.
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Cannabis is an annual plant with a long history of use as food, feed, fiber, oil, medicine, and narcotics. Despite realizing its true value, it has not yet found its true place. Cannabis has had a long history with many ups and downs, and now it is our turn to promote it. Cannabis contains approximately 600 identified and many yet unidentified potentially useful compounds. Cannabinoids, phenolic compounds, terpenoids, and alkaloids are some of the secondary metabolites present in cannabis. However, among a plethora of unique chemical compounds found in this plant, the most important ones are phytocannabinoids (PCs). Over hundreds of 21-22-carbon compounds exclusively produce in cannabis glandular hairs through either polyketide and or deoxyxylulose phosphate/methylerythritol phosphate (DOXP/MEP) pathways. Trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are those that first come to mind while talking about cannabis. Nevertheless, despite the low concentration, cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinodiol (CBND), and cannabinidiol (CBDL) may have potentially some medical effects. PCs and endocannabinoids (ECs) mediate their effects mainly through CB1 and CB2 receptors. Despite all concerns regarding cannabis, nobody can ignore the use of cannabinoids as promising tonic, analgesic, antipyretic, antiemetic, anti-inflammatory, anti-epileptic, anticancer agents, which are effective for pain relief, depression, anxiety, sleep disorders, nausea and vomiting, multiple sclerosis, cardiovascular disorders, and appetite stimulation. The scientific community and public society have now increasingly accepted cannabis specifically hemp as much more than a recreational drug. There are growing demands for cannabinoids, mainly CBD, with many diverse therapeutic and nutritional properties in veterinary or human medicine. The main objective of this review article is to historically summarize findings concerning cannabinoids, mainly THC and CBD, towards putting these valuable compounds into food, feed and health baskets and current and future trends in the consumption of products derived from cannabis.
Article
Context: With increased use of cannabis-based products by the public for both recreational and medical use, sports medicine clinicians should be informed of historical context, current legal considerations, and existing evidence with regard to efficacy, safety, and risks in the athletic community. Evidence acquisition: A review of ClinicalTrials.gov, MEDLINE, and CINAHL from 2015 to present was conducted with emphasis on the most recent literature using search terms, cannabis, nabiximols, cannabinoids, pain management, THC, CBD, and marijuana. Bibliographies based on original search were utilized to pursue further literature search. Study design: Clinical review. Level of evidence: Level 3. Results: At present, limited high-quality studies exist for use of cannabinoids for acute pain, chronic pain, or concussion. None of the trials involving cannabinoids included the athletic population. Thus, results from this clinical review are extrapolated to conditions of the sports medicine population. For acute pain, 2 small-randomized double-blinded crossover trials concluded no immediate effect of cannabinoid therapy. More robust evidence exists for treatment of chronic pain conditions through meta-analysis and systemic reviews. Cannabinoid therapy exhibits moderate efficacy as a treatment for some chronic pain conditions. Investigations included a broad spectrum of chronic pain conditions, including neuropathic, musculoskeletal, inflammatory, and central pain conditions, and reveal reduction in pain and improvement of quality of life with limited adverse effects. For concussion, evidence is based on preclinical in vitro and animal models revealing possible neuroprotective effects as well as 2 clinical studies involving the presence of cannabinoids for concussion (some sports-related), but there are no high-quality trials evaluating efficacy for treatment with cannabinoids at this time. Conclusion: Although various biochemical explanations exist on the use of cannabinoid therapy through modulation of the endocannabinoid system for several medical issues affecting athletes, recommendations from clinicians must be extrapolated from a majority of research done in the nonathletic population. Lack of strong-quality clinical evidence, coupled with inconsistent federal and state law as well as purity issues with cannabis-based products, make it difficult for the sports medicine clinician to widely recommend cannabinoid therapeutics at present. Future larger, higher quality clinical research studies with standardized pure extracts will better guide appropriate medical use going forward. At present, evidence for a multitude of therapeutic applications is emerging for cannabinoid treatment approaches. With emphasis placed on patient-centered clinical decisions, cannabinoids hold promise of treatment for athletes with chronic pain conditions. Clinicians who treat the athletic community must consider legal and ethical issues when discussing and recommending the use of cannabinoids, with acknowledgment of inconsistencies in purity of various formulations and concerns of drug testing.
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With growing scientific interest in cannabinoids, a number of studies have focused on biological activities of cannabidiol and its major source, inflorescence and leaf of Cannabis sativa plant. However, recent analytical chemistry studies have reported the pharmacological significance of non-cannabinoid phytochemicals that are rich in other parts of the plant. Thus, the objective of this study was to investigate the anti-inflammatory effects of Cannabis extracts from plant parts of shelled seeds, roots, and stems containing no or trace amounts of cannabinoids. Among water and ethanol extracts from three plant parts, Cannabis stem ethanol extract (CSE) had the most potent free radical scavenging activities and suppressive effects on the production of nitric oxide from macrophages. In further studies using macrophages, CSE effectively inhibited lipopolysaccharide (LPS)-induced inflammatory responses by suppressing proinflammatory cytokines, nuclear factor-κB and mitogen-activated protein kinase phosphorylations, and cellular accumulation of reactive oxygen species. Moreover, in mice exposed to LPS, CSE reduced tumor necrosis factor-α production and normalized activations of proapoptotic proteins in the liver, kidney, and spleen. Gas chromatography/mass spectrometry analyses of CSE showed several active compounds that might be associated with its antioxidant and anti-inflammatory effects. Collectively, these findings indicate that CSE counteracts LPS-induced acute inflammation and apoptosis, suggesting pharmaceutical applications for the stem part of C. sativa.
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One of the main non-psychoactive phytocannabinoids of cannabis is cannabidiol (CBD), which has attracted much attention for its neuroprotective roles. The present study was designed to assess whether pretreatment of CBD can attenuate two of the destructive processes of cerebral ischemia, including oxidative stress and cell death. The male rats were randomly divided into 6 main groups (control, MCAO, vehicle, and CBD-treated groups). Using stereotaxic surgery, a cannula was inserted into the right lateral ventricle of the rat brain. CBD was injected at doses of 50, 100 and 200 ng/rat for five consecutive days. After pretreatment, middle cerebral artery (MCA) was blocked for 60 min using the intraluminal filament technique. 24 h after reperfusion, each main group was considered for measurement of infarct volume, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), p53 gene expression, pathological alterations, and expression of Bax, Bcl-2, cytochrome C, and caspase-3 proteins. The results revealed that CBD at dose of 100 ng/rat reduced the infarction volume and MDA level in cortical and striatal areas of rat brain compared with vehicle group. In addition, the CBD at dose of 100 ng/rat elevated the activity of SOD enzyme in cortex and striatum. The increase in the activity of CAT was also seen at dose of 100 ng/rat in cortex. Furthermore, the Bcl-2/Bax ratio was significantly diminished by the dose of 100 ng/rat CBD in cortex. Moreover, a decrease in expression of cytosolic cytochrome C was observed by CBD at doses of 100 and 200 ng/rat in cortex. CBD at doses 100 and 200 ng/rat also reduced the expression of caspase-3 in cortical and striatal areas, respectively. P53 was downregulated following administration of CBD at dose of 100 ng/rat. Moreover, histological analysis showed the decrease in the percentage of pyknotic neurons in 100 and 200 ng/rat CBD-received groups. CBD played the anti-apoptosis and anti-oxidant roles in cerebral ischemia by affecting the pathways of intrinsic apoptosis, endogenous antioxidant enzymes, and lipid peroxidation.
Thesis
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In this thesis a process for the efficient production of (−)-trans-cannabidiol (CBD, 10), (−)-trans-Δ9-tetrahydrocannabinol (dronabinol, 21) und (−)-trans-cannabidivarin (CBDV, 30) by means of continuous synthesis was researched and developed. CBD was synthesized in three steps using a continuous synthesis process from olivetol-carboxylic acid methyl ester (OM, 6) and Menthadienol G (3) with a yield of 41%. With optimized conditions, the purity after crystallization was >99%. The stereochemistry was distinctly determined as 1R,6R by X-ray crystal analysis. Beneficial was the fact that toluene was used instead of a chlorinated solvent. Further advantages comprised a short reaction time and the fact that the synthesis can be carried out at room temperature. Five by-products were detected and identified, one of them being dronabinol. With optimized reaction parameters, a yield of up to 64.5% of dronabinol was achieved. By simulated moving bed (SMB) chromatography, dronabinol was produced repeatedly with a purity of >95%. After the synthesis process, four impurities were detectable, namely olivetol (17), CBD, exo-tetrahydrocannabinol (exo-THC, 23) and Δ8-tetrahydrocannabinol (Δ8-THC, 22). All impurities were depleted to a monograph (USP 37) conforming level through SMB purification. After the final distillation, one further unidentified impurity occurred with a content of about 0.4 area%. CBDV was synthesized through continuous synthesis in three steps from divarin-carboxylic acid methyl ester (DM, 25) und Menthadienol G. The yield was approximately 30%, the purity after crystallization >99%. Five by-products were detected which were not further characterized within the scope of this thesis. Through modification of the side groups at position 6 (R1) and position 5 (R2) of the alkyl benzene moiety, the synthesis route offers access to synthetic cannabinoids with a CBD or CBDV scaffold. Nine new cannabinoids have been produced: 2-hydroxyethyl cannabidiolate (2-HEC, 31), 2-hydroxypentyl cannabidiolate (2-HPC, 32), glyceryl cannabidiolate (GCBD, 33), cyclohexyl cannabidiolate (CHC, 34), hexyl cannabidiolate (HC, 35), N-methyl-sulfonyl cannabidiolate (NMSC, 36), 2-hydroxyethyl cannabidivarinolate (2-HECBDV, 37), cyclohexyl cannabidivarinolate (CHCBDV, 38), hexyl cannabidivarinolate (HCBDV, 39). Binding affinity was studied in CB receptor-transfected HEK293EBNA cells, the intrinsic activity in CHO cells, the induction of nuclear factor kappa B (NF-κB) and nuclear factor of activated T cells (NFAT) in Jurkat T cells, the induction of pro-inflammatory cytokines and chemokines (interleukin (IL)-6, IL 1β, CC chemokine ligand 2 (CCL2) and tumor necrosis factor (TNF)-α) on the mRNA level in RAW264.7 macrophages and the expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and prostaglandin E2 (PGE2) on the protein level in primary human monocytes. The CBD derivatives showed higher selectivity for CB2. The CBDV derivatives HCBDV and CHCBDV showed specific binding at CB1 and CB2 receptors in the nanomolar range. 2-HEC, 2-HPC, GCBD and NMSC acted as agonists at CB2 and as antagonists at CB1 receptors. CHC bound CB1 and CB2 at the submicromolar range, and acted as an agonist for both receptors. 2-HECBDV was demonstrated to be an agonist at CB2 and an agonist at CB1. In Jurkat T cells, NMSC inhibited both NF-κB and NFAT activity in a dose-dependent fashion. 2-HEC, 2-HPC and GCBD inhibited the expression of NFAT, also in a dose-dependent manner. CHC and HC dose-dependently reduced the expression of IL-1β and CCL2 mRNA in RAW264.7 macrophages. NMSC inhibited at lower doses IL-1β, CCL2 and TNF-α and at higher doses induced a pronounced increase in IL-6 mRNA. In human primary monocytes, 2-HEC and GCBD inhibited IL-1β, IL-6 and TNF-α synthesis in a dose-dependent fashion. 2-HPC dose-dependently prevented the expression of TNF-α and IL-6 in high concentrations. HC decreased TNF-α and IL-6 release in a dose-dependent fashion. NMSC further increased LPS-elevated IL-1β release but inhibited TNF-α, IL-8 und PGE2. The CBD and CBDV derivatives studied here are suitable for targeting CB receptors. Some of the derivatives might be used as selective CB2 agonists. The length of the aliphatic rest at R2 of CBD (pentyl) and CBDV (propyl) did not correlate with binding affinity. Higher polarity at R1 (2-HECBDV > NMSC > GCBD > 2 HEC) however appeared to favor the agonistic activity at CB2 receptors. To give the results on the relationship between structure and effect more significance, further synthetic derivatives and their testing would be necessary.
Chapter
The endocannabinoid system consists of cannabinoid receptors (which mediate the actions of cannabis), their endogenous ligands (endocannabinoids), and the enzymes and proteins associated with their regulation. In brain, the endocannabinoid system, in part, functions to modulate the release of other neurotransmitters via the subtype 1 (CB1) receptor. Abnormalities of CB1 receptor expression or endocannabinoid transmission have been associated with several neuropsychiatric diseases. Subtype 2 (CB2) receptors are found primarily on immune and neuroimmune cells, and are overexpressed in activated microglia and neuroinflammation. Both receptors are of particular interest for biomarker development and therapeutic targets. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are responsible for the breakdown of endocannabinoids. Growing evidence supports the regulation of endocannabinoids as involved in neuropsychiatric and neuroinflammatory diseases. However, the function of endocannabinoid system components in vivo remains difficult to assess. Therefore, the use of functional imaging techniques, such as positron-emission tomography (PET), may be particularly useful in the assessment and quantification of the endocannabinoid system. This review covers the current understanding of PET imaging that directly targets the endocannabinoid system.
Conference Paper
Microcystin-LR is a hepatotoxic cyclic heptapeptide produced by some species of bloom forming aquatic cyanobacteria. The liver is the main target of this toxin however it has been shown that MC-LR can also cause damages to the other tissues. Several episodes of human and livestock poisoning have been reported after drinking contaminated fresh water. The toxicity is associated with the inhibition of serine-threonine phosphatases 1 and 2A and also to the generation of intracellular reactive oxygen species leading to oxidative stress triggering apoptosis, disrupting the cytoskeleton, damaging DNA and leading to development of degenerative diseases. In order to counteract the damaging effects of such toxic agents, the use of exogenous antioxidants may constitute an effective protection and therapy for the body tissues. In this study, we focused on melatonin and N-acetyl-L-cysteine (NAC) as antioxidant agents; where the former is a hormone synthesized in the pineal gland and plays an important role in the regulation of circadian rhythms and the latter is the acetylated form of the amino acid Lcysteine and plays an important role as a glutathione precursor; a key cellular antioxidant and detoxifier. BalbC mice were used to assess the protective effect of melatonin (20 mg/ kg body weight) and N-acetylcysteine (10 mM/ kg body weight) against an acute dose of MC-LR (LD50= 34.5 mg/kg body weight) injected intraperitoneally after 10 days of supplementation with the antioxidants orally. Biomarkers of toxicity were assayed; that is lipid peroxidation (LPO), protein carbonyl content (PCC), reduced glutathione (GSH) and serum lactate dehydrogenase (LDH) and sorbitol dehydrogenase (SDH). Results demonstrated that the liver of mice treated only with the toxin suffers significant oxidative damages while antioxidant treated mice were significantly less affected. Melatonin was found to have a better protective effect than N-acetylcysteine against MC LR-induced toxicity. These results may suggest a therapeutic use of these substances against oxidative damages caused by different toxins.
Article
Low tetrahydrocannabinol Cannabis sativa products, also known as hemp products, have become widely available and their use in veterinary patients has become increasingly popular. Despite prevalence of use, the veterinary literature is lacking and evidence‐based resource for cannabinoid efficacy. The most prevailing cannabinoid found in hemp is cannabidiolic acid (CBDA) and becomes cannabidiol (CBD) during heat extraction; CBD has been studied for its direct anti‐neoplastic properties alone and in combination with standard cancer therapies, yielding encouraging results. The objectives of our study were to explore the anti‐proliferative and cell death response associated with in vitro treatment of canine cancer cell lines with CBD alone and combination with common chemotherapeutics, as well as investigation into major proliferative pathways (e.g. p38, JNK, AKT, mTOR) potentially involved in the response to treatment with CBD. CBD significantly reduced canine cancer cell proliferation far better than cannabidiolic acid (CBDA) across five canine neoplastic cell lines when treated with concentrations ranging from 2.5‐10 μg/mL. Combinatory treatment with CBD and vincristine reduced cell proliferation in a synergistic or additive manner at anti‐proliferative concentrations with less clear results using doxorubicin in combination with CBD. The cellular signaling effects of CBD treatment, showed that autophagy supervened induction of apoptosis and may be related to prompt induction of ERK and JNK phosphorylation prior to autophagy. In conclusion, CBD is effective at hindering cell proliferation and induction of autophagy and apoptosis rapidly across neoplastic cell lines and further clinical trials are needed to understand its efficacy and interactions with traditional chemotherapy. This article is protected by copyright. All rights reserved.
Conference Paper
Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is one of the principal causes of death in the world. The drug resistance mechanisms developed by the bacterium against the limited number of antibiotics leads to multi- or ultra-drug-resistant tuberculosis. Plant compounds may eventually augment the current therapeutic options or become an alternative since they are considered safe with little or no side effects. The present work consists of a search for active molecules derived from some selected medicinal plants, used traditionally by local populations, that can constitute potential inhibitors of β-lactamase (BlaC) enzymes responsible for bacterial resistance to antibiotic in M. tuberculosis via a computational approach. In the search for new β-lactamase inhibitors we employed the online server Pharmit to discover new 3-D pharmacophores and search different databases of chemical libraries, and commercial compounds. Autodock Vina was employed to perform molecular docking of selected compounds from ChEMBL/MolPort/ZINC databases using the M. tuberculosis β-lactamase 3NC8.pdb as the target protein. This combination of 3-D pharmacophore screening and molecular docking lead to the discovery of natural products, and novel, small molecules inhibitors. The obtained results were able to highlight the feasibility of research and use of active phytocompounds to counteract bacterial antibiotic resistance. Ceftazidime has been shown to be the beta-lactam antibiotic with the highest binding affinity for beta-lactamase (BlaC) compared to the other nine recognized antibiotics. However, among the ten tested phytocompounds that could exert a potential inhibition of the enzyme BlaC, diosgenin exhibited a better affinity for the active site of BlaC compared to the reference antibiotic ceftazidime. In addition, carpain, catechin and berberine showed also potential inhibition of this enzyme, but to a lesser degree. The bioactive phyto-molecules identified in the present study have shown very interesting in silico results as potential inhibitors of BlaC. It is therefore expected that the identified inhibitors will serve as a starting point for experimental studies aimed at the design and discovery of BlaC inhibitors.
Article
The popularity of cannabidiol (CBD) in consumer products is soaring as consumers are using CBD for general health and well-being as well as to seek relief from ailments especially pain, inflammation, anxiety, depression, and sleep disorders. However, there is limited data currently in the public domain that provide support for these benefits. By contrast, a significant amount of safety evaluation data for CBD has been obtained recently from pre-clinical and clinical studies of the CBD therapeutic Epidiolex®. Yet some key data gaps concerning the safe use of CBD still remain. Furthermore, current regulations on CBD use in consumer products remain uncertain and often conflict between the state and federal level. In light of the rapidly expanding popularity of CBD-related products in the marketplace, here we review the current understanding of the benefits, safety, and regulations surrounding CBD in consumer products. This review does not advocate for or against the use of CBD in consumer products. Rather this review seeks to assess the state-of-the-science on the health effects and safety of CBD, to identify critical knowledge gaps for future studies, and to raise the awareness of the current regulations that govern CBD use in consumer products.
Article
Background: Cannabis use and elevated fatty liver index (FLI≥ 60) (a biomarker of hepatic steatosis in the general population) have been identified as predictors of HCV-related and overall mortality, respectively, in HIV-HCV co-infected patients. However, the relationship between cannabis use and the risk of elevated FLI has never been explored. Methods: Using five-year follow-up data from 997 HIV-HCV co-infected patients (ANRS CO13 HEPAVIH cohort), we analyzed the relationship between cannabis use and FLI using mixed-effects multivariable logistic (outcome: elevated FLI yes/no) and linear (outcome: continuous FLI) regression models. Results: At the last follow-up visit, 27.4% of patients reported regular or daily cannabis use and 27.8% had elevated FLI. After multivariable adjustment, regular or daily cannabis use was associated with a 55% lower risk of elevated FLI (adjusted odds ratio [95% confidence interval]: 0.45 [0.22; 0.94]; p = 0.033) and lower FLI values (adjusted model coefficient: -4.24 [-6.57; -1.91], p<0.0001). Conclusions: Cannabis use is associated with a reduced risk of elevated fatty liver index in HIV-HCV co-infected patients. Further research is needed to confirm whether and how cannabinoids may inhibit the development of hepatic steatosis or other metabolic disorders in high-risk populations.
Thesis
Cannabis sativa L. eignet sich aufgrund der Möglichkeit, die ganze Pflanze zu nutzen, hervorragend für die Kreislaufwirtschaft und ist daher ein Paradebeispiel für eine multifunktionale Nutzpflanze. Die Cannabispflanze erlebt derzeit einen Boom aufgrund ihres reichhaltigen Repertoires an sekundären Pflanzeninhaltsstoffen, ihrer Fasern und ihres wertvollen Öls in zahlreichen Industriezweigen sowie ihrer positiven landwirtschaftlichen Eigenschaften. Das Hauptaugenmerk liegt dabei im medizinischen Nutzen, basierend auf den in Blüten und Blättern vorhandenen Phytocannabinoiden. Es ist wichtig, zwischen Nutzhanf Genotypen und phytocannabinoid-reichen (PCR) Genotypen zu unterscheiden. Nutzhanf erfüllt den von der EU-Gesetzgebung vorgeschriebenen THC-Grenzwert von 0,2% und kann daher im Feldmaßstab legal angebaut werden. PCR Genotypen, enthalten hohe Mengen an nicht-psychoaktiven Cannabinoiden, wie CBD und Cannabigerol (CBG), in einem Bereich von 10–30%, während ihr THC-Gehalt unter 0,2% liegt. Diese Genotypen werden derzeit gezüchtet und sind noch kaum auf dem Markt erhältlich. Die Cannabinoid-Extraktion von aus Nutzhanf gewonnenen Rohstoffen, könnte einen entscheidenden Wettbewerbsvorteil bieten, da die geerntete Biomasse durch eine bessere Flächennutzung und mehr Kosteneffizienz im Vergleich zu einem Indoor-Produktionssystem deutlich erhöht werden könnte. Darüber hinaus kann die Multifunktionalität der Nutzhanfpflanze einen wirtschaftlichen Mehrwert bieten. Bestehende Anbausysteme für die Faser- und Ölsaatenproduktion müssen neu entwickelt werden, da sich der Erntezeitpunkt und Ernteorgan stark von den bisherigen Systemen unterscheiden dürften. Um dies zu erreichen, befasst sich Publikation I mit folgenden Zielen: Ermittlung des Ertragspotenzials verschiedener Nutzhanf Genotypen hinsichtlich Blütenstand- und Biomasseertrag sowie Cannabinoidgehalt in Abhängigkeit von Genotyp, Wachstumsstadium und Biomassefraktion in einem Freilandanbausystem. In einem zweijährigen Feldversuch wurden sieben Nutzhanf Genotypen (Finola, Fédora17, Ferimon, Félina32, Futura75, USO31 und Santhica27) angebaut. Die Beprobung von Blättern und Blütenständen erfolgte zu vier spezifischen Wachstumsstadien: vegetatives Blattstadium, Knospenstadium, Vollblütestadium und zur Samenreife. Die Trockensubstanz wurde erfasst sowie der Cannabinoidgehalt analysiert. Die Ergebnisse zeigten, dass der Gehalt an Cannabinoiden stark vom Genotyp und dem Wachstumsstadium abhängt. Daher müssen für ein optimales Ernteergebnis die Biomasse und der Ertrag der Blütenstände berücksichtigt werden. Der Genotyp Santhica27 wies den höchsten Gehalt an CBG/A auf. Die Genotypen Futura75, Fédora17, Félina32, Ferimon, Finola und Santhica27, welche die höchsten CBD/A- bzw. CBG/A Gehalte aufwiesen hatten zur Samenreife die höchsten Biomasseerträge an Druschrückständen und somit einen höheren CBD/A- und CBG/A-Ertrag pro Fläche. Folglich ist eine Ernte nach der Samenreife wirtschaftlich vorteilhaft. Diese Ergebnisse machen ausgewählte Nutzhanf Genotypen zu idealen Kandidaten für den Mehrzweckanbau in Bezug auf Biomasseproduktion und CBD/A- bzw. CBG/A-Gewinnung, um das volle Potenzial der Hanfpflanze auszuschöpfen. Zusätzlich befasste sich die Arbeit mit einer weiteren Standardisierung von PCR Genotypen in Indoor-Anbausystemen. Aufgrund der vorgeschriebenen hohen Qualitätsanforderungen für medizinisches Cannabismaterial rückt der Indoor-Anbau immer mehr in den Fokus, da alle Produktionsparameter standardisiert werden können. Die Produktion von Cannabinoiden unter Indoor-Bedingungen ist aufgrund von Verarbeitungskosten und regulatorischen Einschränkungen teur. Daher wird eine kosteneffektive Produktionskette angestrebt. In Publikation II wurde die Anpassung der Pflanzenarchitektur durch den gezielten Einsatz von synthetischen Phytohormonen evaluiert. Mit dem Ziel eine kleine und kompakte Pflanzenmorphologie mit hohen Blütenerträgen zu generieren. Dies umfasste folgende Zielsetzungen: den Einfluss exogen applizierter Pflanzenwachstumsregulatoren (PGRs), wie NAA, BAP und einer Mischung (NAA/BAP-Mix) aus beiden auf die Pflanzenarchitektur verschiedener PCR Genotypen zu prüfen. Darüber hinaus den Biomasseertrag sowie den CBD/A Gehalt zu bestimmen. In einem Gewächshausexperiment wurden die Genotypen mit synthetischen Phytohormonen in verschiedenen Konzentrationen behandelt. Als Ergebnis wurde ein genotyp-spezifischer Einfluss der applizierten PGRs auf die Pflanzenarchitektur festgestellt. NAA führte beim Genotyp KANADA zu einer kompakteren Pflanzenmorphologie mit einem konstant hohen Blütenertrag, während der CBD/A-Gehalt nicht beeinflusst wurde. Die Genotypen 0.2x und FED zeigten durch die Anwendungen reduzierte Blütenerträge. Publikation III befasste sich mit der Bewertung von Ertragsparametern und CBD Gehalt von PCR Genotypen, welche in verschiedenen Substratzusammensetzungen in einem Indoor-Topfanbausystem kultiviert wurden. In einem Gewächshausexperiment wurde der Einfluss folgender Substratzusammensetzungen: Torf-Mix (PM); Torf-Mix, substituiert mit 30% Grünfasern (G30), und Kokosfaser (CC), auf Wachstumsleistung, N-Gehalt, Wurzelwachstum sowie CBD/A-Gehalt untersucht. Die verschiedenen Substrate zeigten signifikante Auswirkungen auf die Wachstumsleistung und die Wurzelentwicklung der getesteten Genotypen. Es wurde eine genotyp-spezifische Reaktion auf den Blütenertrag untersucht wobei kein limitierender Effekt auf den CBD/A-Gehalt festgestellt wurde. Es lässt sich schlussfolgern, dass organische Torfalternativen wie Grünfasern, die Torf in Standardtopfsubstraten teilweise ersetzen, eine genotyp-spezifische Option bieten.
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This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines (CBM) for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are: 1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; 2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and 3) to identify important directions for future research. In service of these goals, this review a) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; b) describes pharmacokinetics of cannabinoids in rodents and humans; and c) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.
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The major non-psychoactive compound of cannabis plant, cannabidiol, has been reported to be a promising therapeutic agent for many inflammatory, autoimmune and neurodegenerative diseases. In spite of growing interest in therapeutic use of cannabidiol very little is known about its influence on the immune system. Present study aimed to evaluate lymphocyte subsets distribution in peripheral blood after repeated, systemic administration of cannabidiol. Adult male Wistar rats received intraperitoneal injections of vehicle or cannabidiol at dose of 2.5 or 5 mg/kg/day, for 14 consecutive days. Blood samples were collected one hour after the last injection. Three-color immunofluorescent antibody staining procedure (CD3-FITC/CD45RA-PC7/CD161A-APC and CD3-FITC/CD4-PC7/CD8-APC) was used for determination of T, B, NK, NKT, T helper, and T cytotoxic lymphocyte subsets. Total leukocyte number and percentage numbers of leukocyte subpopulations were also assessed. Administration of cannabidiol at dose of 5 mg/kg caused a significant decrease in total leukocyte number and a significant fall in total numbers of T, B, and both T helper and T cytotoxic lymphocyte subsets. This immunosuppressive effect did not affect the total numbers of NK and NKT cells that are responsible for the primary, nonspecific antiviral and antitumor immune response. In contrast, administration of cannabidiol at dose of 2.5 mg/kg increased the total and percentage NKT cells numbers, and the percentage number of NK cells. The results suggest that repeated treatment with cannabidiol inhibits specific immunity by reduction of T, B, T cytotoxic, and T helper cell numbers, and may enhance nonspecific antiviral and antitumor immune response related to NK and NKT cells.
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Cannabidiol (CBD), a nonpsychotropic, nontoxic compound has been shown to block diabetes- and endotoxin-induced retinal damage. However, the protective mechanism of this anti-inflammatory cannabinoid is not completely understood. The goal of this study is to determine the role of adenosine signaling in retinal inflammation and its potential modulation by CBD. The adenosine receptor (AR) subtypes expressed in rat retinal microglial cells were assessed by quantitative real-time RT-PCR. AR function was determined via in vitro and in vivo inflammatory models. Microglial cells or rats were treated with or without lipopolysaccharide (LPS) in the presence or absence of adenosine, adenosine receptor agonists/antagonists, or CBD. Adenosine uptake and tumor necrosis factor (TNF)-alpha release in cells or in retinas were determined. The results showed that A(2A)ARs are abundantly expressed in rat retinal microglial cells. When the cells or rats were treated with LPS, activation of the A(2A)AR was the most efficient in mediating AR agonist- or CBD-induced TNF-alpha inhibition. CBD inhibited adenosine uptake via equilibrative nucleoside transporter 1 and synergistically enhanced adenosine's TNF-alpha suppression after treatment with LPS. These results suggest that the activated A(2A)AR in the retinal microglial cells plays a major anti-inflammatory role in the retina and that CBD's anti-inflammatory effects are linked to the inhibition of adenosine uptake.
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Increasing evidence supports the notion that spinal cord microglia activation plays a causal role in the development of neuropathic pain after peripheral nerve injury; yet the mechanisms for microglia activation remain elusive. Here, we provide evidence that NADPH oxidase 2 (Nox2)-derived ROS production plays a critical role in nerve injury-induced spinal cord microglia activation and subsequent pain hypersensitivity. Nox2 expression was induced in dorsal horn microglia immediately after L5 spinal nerve transection (SNT). Studies using Nox2-deficient mice show that Nox2 is required for SNT-induced ROS generation, microglia activation, and proinflammatory cytokine expression in the spinal cord. SNT-induced mechanical allodynia and thermal hyperalgesia were similarly attenuated in Nox2-deficient mice. In addition, reducing microglial ROS level via intrathecal sulforaphane administration attenuated mechanical allodynia and thermal hyperalgesia in SNT-injured mice. Sulforaphane also inhibited SNT-induced proinflammatory gene expression in microglia, and studies using primary microglia indicate that ROS generation is required for proinflammatory gene expression in microglia. These studies delineate a pathway involving nerve damage leading to microglial Nox2-generated ROS, resulting in the expression of proinflammatory cytokines that are involved in the initiation of neuropathic pain.
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Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Examples of neuropathic pain include painful polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-stroke pain. Clinically, neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Methods such as questionnaires for screening and assessment focus on the presence and quality of neuropathic pain. Basic research is enabling the identification of different pathophysiological mechanisms, and clinical assessment of symptoms and signs can help to determine which mechanisms are involved in specific neuropathic pain disorders. Management of neuropathic pain requires an interdisciplinary approach, centred around pharmacological treatment. A better understanding of neuropathic pain and, in particular, of the translation of pathophysiological mechanisms into sensory signs will lead to a more effective and specific mechanism-based treatment approach.
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In patients with major depression or in animal models of depression, significantly increases in the concentrations of pro-inflammatory cytokines have been consistently reported. Proinflammatory cytokines can stimulate the hypothalamic-pituitary-adrenal (HPA) axis to release stress hormone, glucocorticoids. As a consequence of excessive inflammatory response triggered by pro-inflammatory cytokines in the periphery, free radicals, oxidants and glucocorticoids are over-produced, which can affect glial cell functions and damage neurons in the brain. Indeed, decreased neurogenesis and the dysfunction of neurotrophic system (up- or down-regulations of neurotrophins and their receptors) have been recently found. Effective treatments for depressive symptoms, such as antidepressants and omega-3 fatty acids can increase or modulate neurotrophic system and enhance neurogenesis. However, the relationship between glial cells; microglia (mostly involved in neuroinflammation) and astrocytes (producing neurotrophins), and the contribution of inflammation to decreased neurogenesis and dysfunction of neurotrophic system are almost unknown. This review first introduces changes in behavior, neurotransmitter, cytokine and neurogenesis aspects in depressed patients and several animal models of depression, secondly explores the possible relationship between pro- and anti-inflammatory cytokines and neurogenesis in these models, then discusses the effects of current treatments on inflammation, neurotrophic system and neurogenesis, and finally pointes out the limitations and future research directions.
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Accumulating recent evidence suggests that cannabinoid-1 (CB(1)) receptor activation may promote inflammation and cell death and its pharmacological inhibition is associated with anti-inflammatory and tissue-protective effects in various preclinical disease models, as well as in humans. In this study, using molecular biology and biochemistry methods, we have investigated the effects of genetic deletion or pharmacological inhibition of CB(1) receptors on inflammation, oxidative/nitrosative stress and cell death pathways associated with a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin. Cisplatin significantly increased endocannabinoid anandamide content, activation of p38 and JNK mitogen-activated protein kinases (MAPKs), apoptotic and poly (ADP-ribose)polymerase-dependent cell death, enhanced inflammation (leucocyte infiltration, tumour necrosis factor-alpha and interleukin-1beta) and promoted oxidative/nitrosative stress [increased expressions of superoxide-generating enzymes (NOX2(gp91phox), NOX4), inducible nitric oxide synthase and tissue 4-hydroxynonenal and nitrotyrosine levels] in the kidneys of mice, accompanied by marked histopathological damage and impaired renal function (elevated creatinine and serum blood urea nitrogen) 3 days following its administration. Both genetic deletion and pharmacological inhibition of CB(1) receptors with AM281 or SR141716 markedly attenuated the cisplatin-induced renal dysfunction and interrelated oxidative/nitrosative stress, p38 and JNK MAPK activation, cell death and inflammatory response in the kidney. The endocannabinoid system through CB(1) receptors promotes cisplatin-induced tissue injury by amplifying MAPK activation, cell death and interrelated inflammation and oxidative/nitrosative stress. These results also suggest that inhibition of CB(1) receptors may exert beneficial effects in renal (and most likely other) diseases associated with enhanced inflammation, oxidative/nitrosative stress and cell death.