ArticleLiterature Review

Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases?

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Abstract

Since the discovery of the cannabinoid receptors and their endogenous ligands, significant advances have been made in studying the physiological function of the endocannabinoid system. The presence of cannabinoid receptors on cells of the immune system and anecdotal and historical evidence suggesting that cannabis use has potent immuno-modulatory effects, has led to research directed at understanding the function and role of these receptors within the context of immunological cellular function. Studies from chronic cannabis smokers have provided much of the evidence for immunomodulatory effects of cannabis in humans, and animal and in vitro studies of immune cells such as T cells and macrophages have also provided important evidence. Cannabinoids can modulate both the function and secretion of cytokines from immune cells. Therefore, cannabinoids may be considered for treatment of inflammatory disease. This review article will highlight recent research on cannabinoids and how they interact with the immune system and also their potential use as therapeutic agents for a number of inflammatory disorders.

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... This type of medication regulates overactive immune response and can alter long-term outcomes by minimizing disease activity. New trends that are being discussed and not yet introduced in the guidelines include cannabinoid treatment [9]. A large number of studies show that cannabinoids can be used as a potential therapeutic agents in autoimmune diseases to reduce inflammation, modulate the immune system, and restore intestinal homeostasis [9]. ...
... New trends that are being discussed and not yet introduced in the guidelines include cannabinoid treatment [9]. A large number of studies show that cannabinoids can be used as a potential therapeutic agents in autoimmune diseases to reduce inflammation, modulate the immune system, and restore intestinal homeostasis [9]. ...
... Cannabis is known for its analgesic effect due to the ingredient THC. The expanding legalization of medical cannabis and its therapeutic potential could be assessed as a safe opportunity [9,10]. ...
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Терапевтичният потенциал на канабиноидите е обект на засилен научен интерес през последните десетилетия. От дълбока древност се използват лечебните им свойства, но непознаването на механизмите, по които въздействат на органите и системите в човешкото тяло и наблюдаваните странични ефекти, ограничават навлизането им в клиничната практика. Все още остават неизяснени патогенетичните механизми, чрез които канабиноидите повлияват на толкова голям спектър от различни по своята същност заболявания. Натрупват се все повече доказателства за тяхното противовъзпалително и антифибротично действие, участват в регулацията на свръхактивирания имунен отговор и могат да се използват като симптоматично средство за лечение на хронична болка. В настоящия обзор се разглежда физиологичната и патофизиологична роля на ендоканабиноидната система, терапевтичните възможности на канабиса и синтетичните канабиноидни аналози, приложението им при различни ревматологични и автоимунни заболявания и потенциалните рискове от провеждането на такъв тип лечение.
... One of the findings in the field of immune-regulatory factors is identifying the endocannabinoid (EC) system, which could modulate the immune responses, particularly T-and B-lymphocytes migration, proliferation, and proliferation cytokine production (Braile et al., 2021;Cencioni et al., 2010;Klein et al., 2003). The previously studied results on the EC system brought them to the attention of researchers as potential medications for introducing a novel target for many hypersensitivity diseases (Croxford & Yamamura, 2005;Tanasescu & Constantinescu, 2010) such as multiple sclerosis (MS; ...
... Moreover, they might have modulatory effects on the immune system and control various activities in the brain such as learning and memory, mood, pain perception, and healing events in neural damages (Reggio, 2010). However, the CB1 and CB2 activities have been introduced in many immune tissues and cells (Bab et al., 2008;Croxford & Yamamura, 2005). ...
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Background: As effective immune modulators, Endocannabinoids may suppress the inflammatory responses in periodontitis. This study assessed the expression of cannabinoid receptors in gingiva and the impact on periodontitis. Methods: A cross-sectional study on 20 patients with more than stage II and Grade A periodontitis and a control group consisting of 19 healthy individuals was performed. The gingival biopsies were assessed for the expression of CB1 and CB2 using the quantitative reverse transcription polymerase chain reaction, TaqMan method. Results: The study sample consisted of 39 subjects, 31 females (79.5%) and 8 males (20.5%), including 20 periodontitis subjects (80% female and 20% male), and control groups (78.9% female and 21.1% male). The mean ages of cases and controls were 33.3 ± 4.7 and 35.7 ± 5.1 years, respectively. The gene expression of CB2 in periodontitis was 27.62 ± 7.96 and in healthy subjects was 78.15 ± 23.07. The CB2 was significantly lower than the control group (p = .008). In comparison, the gene expression index of CB1 in the periodontal group (9.42 ± 3.03) was higher than the control group (6.62 ± 1.13) but did not meet a significant value (p = .671). Conclusion: The lower expression of CB2 receptors in the periodontitis group may be due to the reduced protective effect of anti-inflammatory agents. These elements include cannabinoids and the imbalance leading to the predominance of pro-inflammatory effects. Therefore, the local effects of cannabinoids as an immunomodulator could be useful for oral inflammatory diseases such as periodontitis.
... The CB2 receptor is highly expressed in immune cells, B-cells, natural killer cells, macrophage, monocytes, polymorphonucleate neutrophils, T8 and T4 cells, and brain and it's involved in inflammatory reactions, immune response and modulation of cytokine expression [10,[14][15][16][17]. ...
... According to their findings, the 1-[(2E,4E,8Z)-tetradecatrienoyl] piperidine (11) and two alkylamides (12 and 13) were the most potent binders of CB1 and CB2 receptors with a K i value of 0.8 μM and 0.16 μM respectively for 1-[(2E,4E,8Z)-tetradecatrienoyl]piperidine (11) and a good binding affinity of 0.9 µM to CB2, 2.6 µM to CB1 and 0.55 µM to CB2 and 102 µM to CB1 for compounds 12 and 13 respectively (Fig. 3). The authors also identified a series of thienylheptatrienamides (14)(15)(16)(17)(18), among them compound piperidinyl-amide 16 contributed moderately to CB2 binding affinity of the extract, whereas all others were able to bind cannabinoid and opioid receptors with low affinity [39,40]. ...
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Nowadays cardiovascular diseases (CVDs) are the major causes for the reduction of the quality of life. The endocannabinoid system is an attractive therapeutic target for the treatment of cardiovascular disorders due to its involvement in vasomotor control, cardiac contractility, blood pressure and vascular inflammation. Alteration in cannabinoid signalling can be often related to cardiotoxicity, circulatory shock, hypertension, and atherosclerosis. Plants have been the major sources of medicines until modern eras in which researchers are experiencing a rediscovery of natural compounds as novel therapeutics. One of the most versatile plant is Cannabis sativa L., containing phytocannabinoids that may play a role in the treatment of CVDs. The aim of this review is to collect and investigate several less studied plants rich in cannabinoid-like active compounds able to interact with cannabinoid system; these plants may play a pivotal role in the treatment of disorders related to the cardiovascular system.
... Furthermore, it was described that CBD can induce apoptosis in human monocytes by mitochondrial oxidative stress [39]. In the same way, similar effects on microglia proliferation, migration and inflammatory response were elicited by CBD [40][41][42]. In light of these evidences, we hypothesized that CBD treatment could alter the activity of PMNs in a similar way that it does with microglia/macrophages and others circulating leukocytes leading to reduce the immunocompetence of PMNs, by producing functional alterations and/or affecting their viability. ...
... This would possibly contribute to reducing the clearance of AEDs and also make their access to the brain parenchyma more effective, bypassing the excretory activity of P-gp in the blood-brain barrier. Several reports show that CBD has an anti-inflammatory effect by reducing the secretion of pro-inflammatory mediators and that it can produce an immunoparalysis acting on lymphocytes, monocytes, macrophages and even microglia [37][38][39][40][41][42]. However, the role of CBD on the activity of PMNs has been little investigated. ...
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Cannabidiol (CBD), a lipophilic cannabinoid compound without psychoactive effects, has emerged as adjuvant of anti-epileptic drugs (AEDs) in the treatment of refractory epilepsy (RE), decreasing the severity and/or frequency of seizures. CBD is considered a multitarget drug that could act throughout the canonical endocannabinoid receptors (CB1-CB2) or multiple non-canonical pathways. Despite the fact that the CBD mechanism in RE is still unknown, experiments carried out in our laboratory showed that CBD has an inhibitory role on P-glycoprotein excretory function, highly related to RE. Since CB2 is expressed mainly in the immune cells, we hypothesized that CBD treatment could alter the activity of polymorphonuclear neutrophils (PMNs) in a similar way that it does with microglia/macrophages and others circulating leukocytes. In vitro, CBD induced PMN cytoplasmatic vacuolization and proapoptotic nuclear condensation, associated with a significantly decreased viability in a concentration-dependent manner, while low CBD concentration decreased PMN viability in a time-dependent manner. At a functional level, CBD reduced the chemotaxis and oxygen consumption of PMNs related with superoxide anion production, while the singlet oxygen level was increased suggesting oxidative stress damage. These results are in line with the well-known CBD anti-inflammatory effect and support a potential immunosuppressor role on PMNs that could promote an eventual defenseless state during chronic treatment with CBD in RE.
... From in vitro/vivo experiments with exogenous cannabinoids, there is solid evidence that cannabinoids influence key functions of immune cells, such as proliferation, migration, antibody formation, cytolytic activity, differentiation and apoptosis (rev in [146,147,151,[205][206][207]. All of these functions are relevant for the immune cell composition of the TME and tumor growth. ...
... Since ECS components are expressed in innate immune cells (see Table 1), endocannabinoid signaling in these cells may influence functions relevant for tumor growth. Macrophages are highly responsive to cannabinoids in terms of cytokine secretion, migration, phagocytosis and antigen presentation (rev. in [151]). They express cannabinoid receptors [35, 181,183] and MGL [35,223], and a CB 2 dependent pro-tumorigenic role of macrophage-expressed MGL has been recently described [35]. ...
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Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.
... The main findings were as follows: (i) among healthy volunteers and among cannabis users, cannabinoids seemed to decrease the inflammatory response, thus decreasing the immune response leading in turn to a higher risk of infections; (ii) among patients with MS, cannabinoids seemed to have little impact on the inflammatory markers' levels. A review published in 2005 analyzed the immune system impacts of the cannabis extracts [29]. They demonstrated an apparent contradiction about the immune reactions; although the majority of studies showed that the administration of cannabinoids has inhibitory effects on immune cells, a number of recent studies have demonstrated that the endocannabinoids may have some stimulatory impact on the immune system. ...
... In spite of that, the articles analyzed in this study, which used only human volunteers, reveal that among healthy volunteers and cannabis users, exogenous cannabinoids seemed to decrease the inflammatory response, thus decreasing immune response and leading to a higher risk of infections. Thus, on in vivo research, the contradiction about the cannabis use on inflammatory effects is smaller than that on in vitro experiments [29]. ...
Article
Introduction: Although the recreational cannabis use is expressive worldwide, the literature about medical potential of cannabis extracts, including its anti-inflammatory properties, remains inconclusive. Methods: We screened all articles, published on the PubMed database, on inflammatory mediators and any information about cannabis use from 1980 to March 2019. Results: Six studies were included, and the main findings were as follows: (i) among healthy volunteers and cannabis users, cannabinoids seemed to decrease the inflammatory response, thus decreasing the immune response, which led to a higher risk of infections; (ii) among patients with multiple sclerosis, cannabinoids seemed to have little impact on the inflammatory markers' levels. Discussion: Although cannabis use can produce immune inflammatory suppression in healthy people, this effect is not robust enough to change inflammatory mediators' levels in situations of highly dysfunctional inflammatory activation. Nevertheless, the impact of cannabinoids in clinical outcomes of these conditions remains to be determined.
... 17 Endocannabinoids have been shown to have anti-inflammatory and antioxidant properties. 18,19 While fatty acid amide hydrolase is the primary enzyme involved in the catabolism of AEA, 20 monoacylglycerol lipase (MAGL) is the enzyme predominantly responsible for the breakdown of 2-AG. 21 JZL184 is a selective and potent MAGL inhibitor. ...
... In addition to the ischemia-reperfusion group, 4 mg/kg and 16 mg/kg JZL184 (Cayman Chemical) was administered intraperitoneally 30 min before reperfusion. Rahmani et al. 18 showed that 4 mg/kg JZL184 reduced inflammation and improved neurological functions after stroke treatment, while in another study, 22 16 mg/kg dose improved histopathology and renal function in renal IRI. That is why we chose to use these two doses in our study. ...
Article
Aim: Ovarian torsion is a gynecopathology that requires emergency surgery in women. However, ischemia reperfusion injury (IRI) occurs after treatment with detorsion. This study aimed to evaluate the effects of monoacylglycerol lipase inhibitor JZL184 on ovarian IRI and ovarian reserve. Methods: Forty-eight female Wistar albino rats were divided into six groups. Group 1: Sham, Group 2: Ischemia, Group 3: ischemia/reperfusion (IR), Group 4: IR + JZL184 4 mg/kg, Group 5: IR + JZL184 16 mg/kg, Group 6: IR + vehicle (dimethyl sulfoxide). Three hours of ischemia followed by 3 h of reperfusion. Two different doses of JZL184 (4 and 16 mg/kg) were administered intraperitoneally in Group 4 and 5, 30 min before reperfusion. Ovarian IRI and ovarian reserve were evaluated in serum and tissue by using histopathological and biochemical parameters. Results: Treatment with JZL184 was associated with a significant increase in ovarian 2-arachidonoylglycerol and improved serum anti-Mullerian hormone, İnhibin B, primordial follicle count, and ovarian histopathological damage score (p < 0.05). JZL184 treatment significantly decreased the level of malondialdehyde, and increased superoxide dismutase enzyme activity and glutathione (GSH) levels (p < 0.05). The increased phosphorile nuclear factor-κB (Phospho-NF-κB-p65), tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), transforming growth factor beta 1 (TGF-β1), and TUNEL assay immunopositivity scores in ovarian I/R injury were decreased after treatment with JZL184 (p < 0.05). Conclusions: JZL184 showed significant ameliorative effects on ovarian IRI and ovarian reserve caused by IR through acting as an antioxidant, anti-inflammatory, and antiapoptotic agent. Thus, JZL184 may be a novel therapeutic agent for ovarian IRI.
... The endocannabinoid system as an important regulator is thus a relatively new target in pharmaceutical development to combat numerous diseases. Primarily inflammatory and immunological disorders such as rheumatoid arthritis and multiple sclerosis (Croxford & Yamamura 2005), but also neuronal and neuro-endocrine indications such as stress and anxiety (Viveros et al. 2005), obesity (e.g. C Bl antagonist Rimonabant®) (Fagotto et al. 2005), Huntington's disease (Consroe et al. 1991) or neuroprotection (Fowler 2003) are promising fields for new drugs acting within the endocannabinoid system. ...
... Among the historic indications o f cannabis appear frequently inflammatory diseases (Li 1974a/b Mecboulam 1986, which gained further support by observations o f impaired immune and inflammatory response both in human cannabis users and cannabis treated animals (Nahas et al. 1973a/b, Sofia et al. 1973. Thereafter, tests o f cannabis and phytocannabinoids in various in vitro and in vivo models confirmed immunomodulatory and anti-inflammatory effects, which is increasingly focused on endo-and synthetic cannabinoids and has been frequently reviewed for its potential in drug development (Klein -2 9 -et al. 1999, 2003, Berdyshev 2000, Mbvundula et al. 2004, Croxford & Yamamura 2005, Lu et al. 2006, Ashton 2007 receptor involvement (Barrett et al. 1985, Verhoeckx et al. 2005, Gertsch et al. 2008). ...
Thesis
Cannabis is used as a co-medication by patients with cancer or chronic inflammatory diseases. Anti-inflammatory effects of Δ9-tetrahydrocannabinol (THC) and other cannabinoids are frequently linked to the modulation of the Nuclear Factor kappaB (NF-KB). Advantages of using whole plant preparations have also been reported. The composition of preparations such as traditional hydroethanolic cannabis extracts (CE) varies due to the type of plant and preparation. This dissertation aimed to contribute insights into chemical standardisation and pharmacological profiling as part of a European Project developing CE medicines. The chemical profile of CE from different starting materials was determined using HPLC and 1H-NMR. Their pharmacological properties were measured as the ability to modulate the activation of NF-KB in IL-6 reporter gene stably transfected HeLa cells, to induce in vitro cytotoxicity in cancer cell lines (MTT-assay) and to activate caspase 3/7. The effect of pure cannabinoids and their combinations with plant phenolics and classical anti-inflammatory/cytotoxic drugs was also investigated. The HPLC/NMR profiles showed cannabinoid dominance even in polar extracts and a substantial portion of cannabinoid acids depending on CE age and storage. Markers for standardisation indicating plant type, solvent and stability -such as the ratio between neutral and carboxylated cannabinoids- are proposed. CE toxicity correlated with the total cannabinoid but not necessarily the THC content. Also all main pure phytocannabinoids proved to be equally toxic. Some CE were more toxic than pure phytocannabinoids, other CE reduced the effects of the compounds alone. In most cases toxicity correlated with the effect on NF-KB activation and also with the caspase 3/7 activation indicating apoptotic signalling. It appears also that the NF-KB activity of cannabinoids/CE is neither CB1 nor CB2 receptor dependent. The results show that there is a strong link between NF-KB and the toxic effect of cannabis in cancer cell lines. The in vitro effect of CE can differ from that of pure cannabinoids and is more influenced by factors other than the chemotype. Thus standardised CE of plants with predominantly non-psychotropic cannabinoids such as cannabidiol or cannabigerol may be as useful as traditional THC-type derived CE for the co-treatment in cancer and inflammatory diseases.
... Phytocannabinoids with a high affinity for the CBR2 exhibit immunomodulatory properties both in terms of the cellular and of the humoral response. An association has been reported between CBR2 expression level, cell activation, and the presence of immune modulators [85]. Inhibition of CBR2 with JTE907 acting as a selective CBR2 inverse agonist with combined CBR1/CBR2 gene silencing, showed that CBR2 (not CBR1) is responsible for phytocannabinoid-mediated immune suppression [86]. ...
... Other concerns are related to the concentrations of cannabinoids produced in the body, and the relationship between these concentrations and the resulting response. In vitro, cannabinoids have been shown to stimulate cell proliferation at nanomolar concentrations and inhibit it at micromolar concentrations (biphasic response); notably, the latter considerably exceed concentrations found in the blood of cannabis smokers [85]. Additionally, sub-micromolar concentrations of CB receptor agonists have been reported to stimulate the proliferation of some cancer cell lines (glioma-U373-MG, lung cancer-NCI-H292). ...
Article
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Recently, there has been a growing interest in the medical applications of Cannabis plants. They owe their unique properties to a group of secondary metabolites known as phytocannabinoids, which are specific for this genus. Phytocannabinoids, and cannabinoids generally, can interact with cannabinoid receptors being part of the endocannabinoid system present in animals. Over the years a growing body of scientific evidence has been gathered, suggesting that these compounds have therapeutic potential. In this article, we review the classification of cannabinoids, the molecular mechanisms of their interaction with animal cells as well as their potential application in the treatment of human diseases. Specifically, we focus on the research concerning the anticancer potential of cannabinoids in preclinical studies, their possible use in cancer treatment and palliative medicine, as well as their influence on the immune system. We also discuss their potential as therapeutic agents in infectious, autoimmune, and gastrointestinal inflammatory diseases. We postulate that the currently ongoing and future clinical trials should be accompanied by research focused on the cellular and molecular response to cannabinoids and Cannabis extracts, which will ultimately allow us to fully understand the mechanism, potency, and safety profile of cannabinoids as single agents and as complementary drugs.
... The CB 1 receptors are typically coupled with ion channels to reduce neuronal firing and inhibit neurotransmitter release. The activation of CB 1 receptors triggers the A-type, inward potassium ion currents and suppresses N, P/Q-type calcium ion currents [39]. The activation of CB 2 receptors does not influence potassium and calcium ions. ...
... Therefore, the consequent expression of CB 2 receptors on immune cells relates to their neuroinflammation and neuroprotective roles in the body's physiological system. The discovery of the presence of CB 2 receptors in the brain microglia and astrocyte following injury suggests that cannabinoids also act on these receptors to exert more substantial immunomodulatory effects [39]. ...
Article
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Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.
... One more consideration in the overlap between AD treatment and cannabis use is in their rich cross-talk with the immune system. While accumulating evidence indicates immunomodulatory and anti-inflammatory effects of cannabinoids [220][221][222][223][224], the connection of stress, depression, and anxiety with the immune system is well established [225][226][227][228][229][230][231][232]. The meaning of this interaction is that depressed and anxious patients may already have immune disruption [225,226,[228][229][230][231][232], and that use of AD normalizes it [232]. ...
... The meaning of this interaction is that depressed and anxious patients may already have immune disruption [225,226,[228][229][230][231][232], and that use of AD normalizes it [232]. Due to the fact that the precise mechanisms whereby antidepressants cause these changes are uncertain, it is unclear whether additional cannabis use, which affects the immune system as well [220][221][222][223][224], may affect AD treatment's efficiency. ...
Article
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Depression and anxiety disorders are two of the most common and growing mental health concerns in adolescents. Consequently, antidepressant medication (AD) use has increased widely during the last decades. Several classes of antidepressants are used mainly to treat depression, anxiety, and obsessive-compulsive disorders by targeting relevant brain neurochemical pathways. Almost all randomized clinical trials of antidepressants examined patients with no concomitant medications or drugs. This does not address the expected course of therapy and outcome in cannabis users. Cannabis is the most commonly used illicit substance globally. Substantial changes in its regulation are recently taking place. Many countries and US states are becoming more permissive towards its medical and recreational use. The psychological and physiological effects of cannabis (mainly of its major components, tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been extensively characterized. Cannabis use can be a risk factor for depressive and anxiety symptoms, but some constituents or mixtures may have antidepressant and/or anxiolytic potential. The aim of this literature review is to explore whether simultaneous use of AD and cannabis in adolescence can affect AD treatment outcomes. Based on the current literature, it is reasonable to assume that antidepressants are less effective for adolescents with depression/anxiety who frequently use cannabis. The mechanisms of action of antidepressants and cannabis point to several similarities and conjunctions that merit future investigation regarding the potential effectiveness of antidepressants among adolescents who consume cannabis regularly.
... The adaptive immune system will also be activated by the dendritic cells (DC) through T-cell modulation and through antigen presentation by the macrophages. This process will lead to T cell differentiation followed by the biosynthesis of specific pro-and anti-inflammatory cytokines and the augmentation of the inflammatory and oxidative cascades (Figure 3) [170][171][172][173][174][175][176][177][178][179][180]. Together with the development of more and more studies in the area of cannabinoids and on their impact on the immune system a series of effects (both of stimulation and inhibition) have been reported. ...
... B cells have an increased expression of CB2 receptor this impacting on the number of B lymphocytes, as well as on the expressions of IgG, IgM, C3 and C4 complement. [172]. Macrophages play an important role in the modulation of the innate immune system and adaptive immune system. ...
Article
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Critically ill patients with sepsis require a multidisciplinary approach, as this situation implies multiorgan distress, with most of the bodily biochemical and cellular systems being affected by the condition. Moreover, sepsis is characterized by a multitude of biochemical interactions and by dynamic changes of the immune system. At the moment, there is a gap in our understanding of the cellular, genetic, and molecular mechanisms involved in sepsis. One of the systems intensely studied in recent years is the endocannabinoid signaling pathway, as light was shed over a series of important interactions of cannabinoid receptors with biochemical pathways, specifically for sepsis. Furthermore, a series of important implications on inflammation and the immune system that are induced by the activity of cannabinoid receptors stimulated by the delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been noticed. One of the most important is their ability to reduce the biosynthesis of pro-inflammatory mediators and the modulation of immune mechanisms. Different studies have reported that cannabinoids can reduce oxidative stress at mitochondrial and cellular levels. The aim of this review paper was to present, in detail, the important mechanisms modulated by the endocannabinoid signaling pathway, as well as of the molecular and cellular links it has with sepsis. At the same time, we wish to present the possible implications of cannabinoids in the most important biological pathways involved in sepsis, such as inflammation, redox activity, immune system, and epigenetic expression.
... inflammatory cytokines, chemokines, and cell migration (Croxford & Yamamura, 2005;Klein et al., 2003;Tanasescu & Constantinescu, 2010). The current shortcomings in our clinical understanding of marijuana exist largely due to incomplete knowledge of the complex biological activities of the phytocannabinoids and limited clinical studies. ...
... A clinical study reported that among patients using opioids for pain management, CBD hemp extract significantly provided chronic pain relief along with the reduction of opioid use and improved sleep quality among CBD-treated patients (Capano et al., 2020). The hemp/CBD oils affect the body by modulating receptor systems specifically targeting the ECS (Croxford & Yamamura, 2005;Jean-Gilles et al., 2015;Klein et al., 2003). The main ingredients found in hemp oils are CBD along with other cannabinoids, terpenoids, and polyphenolics (flavonoids) that exhibit a synergistic effect on the body termed the "Entourage Effect." ...
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Introduction: In the last two decades, our understanding of the therapeutic utility and medicinal properties of cannabis has greatly changed. This change has been accompanied by widespread cannabis use in various communities and different age groups, especially within the United States. With this increase, we should consider the potential effects of cannabis-hemp on general public health and how they could alter therapeutic outcomes. Material and methods: The present investigation examined cannabis use for recreational and therapeutic use and a review of pertinent indexed literature was performed. The focused question evaluates "how cannabis or hemp products impact health parameters and do they provide potential therapeutic value in dentistry, and how do they interact with conventional medicines (drugs)." Indexed databases (PubMed/Medline, EMBASE) were searched without any time restrictions but language was restricted to English. Results: The review highlights dental concerns of cannabis usage, the need to understand the endocannabinoid system (ECS), cannabinoid receptor system, its endogenous ligands, pharmacology, metabolism, current oral health, and medical dilemma to ascertain the detrimental or beneficial effects of using cannabis-hemp products. The pharmacological effects of pure cannabidiol (CBD) have been studied extensively while cannabis extracts can vary significantly and lack empirical studies. Several metabolic pathways are affected by cannabis use and could pose a potential drug interaction. The chronic use of cannabis is associated with health issues, but the therapeutic potential is multifold since there is a regulatory role of ECS in many pathologies. Conclusion: Current shortcomings in understanding the benefits of cannabis or hemp products are limited due to pharmacological and clinical effects not being predictable, while marketed products vary greatly in phytocompounds warrant further empirical investigation. Given the healthcare challenges to manage acute and chronic pain, this review highlights both cannabis and CBD-hemp extracts to help identify the therapeutic application for patient populations suffering from anxiety, inflammation, and dental pain.
... THC is the main psychotropic component of cannabis, as it crosses the blood-brain barrier (BBB) to alter cognition including short-term memory (Atakan, 2012). Furthermore, THC is immunomodulatory, with the majority of literature demonstrating immune suppressive and anti-inflammatory activity in vivo and in vitro (Croxford and Yamamura, 2005;Karmaus et al., 2011;Karmaus et al., 2013;Katchan et al., 2016). THC modulates the activity of almost every immune cell type including T cells, B cells, monocyte/macrophages, natural killer cells and dendritic cells, and suppresses a range of inflammatory functions including proliferation, chemotaxis, phagocytosis and cytokine production (Croxford and Yamamura, 2005;Turcotte et al., 2015;Katchan et al., 2016). ...
... Furthermore, THC is immunomodulatory, with the majority of literature demonstrating immune suppressive and anti-inflammatory activity in vivo and in vitro (Croxford and Yamamura, 2005;Karmaus et al., 2011;Karmaus et al., 2013;Katchan et al., 2016). THC modulates the activity of almost every immune cell type including T cells, B cells, monocyte/macrophages, natural killer cells and dendritic cells, and suppresses a range of inflammatory functions including proliferation, chemotaxis, phagocytosis and cytokine production (Croxford and Yamamura, 2005;Turcotte et al., 2015;Katchan et al., 2016). Immune cell modulation by THC occurs primarily through the binding of specific G-protein coupled receptors, termed cannabinoid receptor 1 and 2 (CB1 and CB2) (Pertwee, 1997); however, CBindependent effects have been observed (Brown, 2007;Karmaus et al., 2012). ...
... They can affect T cell number and proliferation, but may also have important effects on T helper1 and 2 specific cytokines and TGF-b (transforming growth factor beta) secretion [54], as well as T cells response to viral infections. When an individual has low T cells the individual becomes more susceptible to viral infection. ...
... Cannabinoid compounds present in marijuana affects number of B cells, proliferation of B cells, their migration, and Immunoglobulin (Ig) production or isotype switching [54]. B cells are responsible for fighting bacterial infection; hence low B cell count makes an individual to be immune compromised. ...
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A review on reported effects of illicit drugs (Cocaine, Opioids and Marijuana) on the immune cell function in human.
... Cannabinoids can modulate immune cell function, activity, and secretion of cytokines [10,11]. Compounds that activate CB2R are of particular interest for their immunomodulatory activity because these receptors are predominantly expressed in the immune system. ...
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Aromatic compounds have a long history of use as medicines in most recorded cultures. An increasing interest in these therapeutic volatile molecules in both scientific and lay communities has led to the advancement of essential oils as phytomedicines. Recent discoveries suggest essential oils augment the endocannabinoid system in a positive manner to mitigate various pathologies. However, the exact mechanisms whereby essential oils influence endocannabinoid system activity are not fully known, these studies provide a glimpse into their involvement and warrant further evaluation. Additional study of the interaction between essential oils and the endocannabinoid system may lead to promising phytomedicines for the treatment of diseases and conditions involving dysregulation or activation of the endocannabinoid system.
... An emerging target for the regulation of inflammation and the immune response is the endocannabinoid system (ECS). [21][22][23] Activation of the ECS occurs via ligand binding to the cannabinoid receptors 1 and 2 (CB1R, CB2R), and both receptors subtypes are present in periodontal tissues. 24 CB2R, in particular, has a key regulatory role in inflammation and modulating immune responses. ...
Article
Objective The aim of this study is to understand the role of cannabinoid type 2 receptor (CB2R) during periodontal inflammation and to identify anti‐inflammatory agents for the development of drugs to treat periodontitis (PD). Background Cannabinoid type 2 receptor is found in periodontal tissue at sites of inflammation/infection. Our previous study demonstrated anti‐inflammatory responses in human periodontal ligament fibroblasts (hPDLFs) via CB2R ligands. Methods Anandamide (AEA), HU‐308 (agonist), and SMM‐189 (inverse agonist) were tested for effects on IL‐1β‐stimulated cytokines, chemokines, and angiogenic and vascular markers expressed by hPDLFs using Mesoscale Discovery V‐Plex Kits. Signal transduction pathways (p‐c‐Jun, p‐ERK, p‐p‐38, p‐JNK, p‐CREB, and p‐NF‐kB) were investigated using Cisbio HTRF kits. ACTOne and Tango™ ‐BLA functional assays were used to measure cyclic AMP (cAMP) and β‐arrestin activity. Results IL‐1β stimulated hPDLF production of 18/39 analytes, which were downregulated by the CB2R agonist and the inverse agonist. AEA exhibited pro‐inflammatory and anti‐inflammatory effects. IL‐1β increased phosphoproteins within the first hour except p‐JNK. CB2R ligands attenuated p‐p38 and p‐NFĸB, but a late rise in p‐38 was seen with HU‐308. As p‐ERK levels declined, a significant increase in p‐ERK was observed later in the time course by synthetic CB2R ligands. P‐JNK was significantly affected by SMM‐189 only, while p‐CREB was elevated significantly by CB2R ligands at 180 minutes. HU‐308 affected both cAMP and β‐arrestin pathway. SMM‐189 only stimulated cAMP. Conclusion The findings that CB2R agonist and inverse agonist may potentially regulate inflammation suggest that development of CB2R therapeutics could improve on current treatments for PD and other oral inflammatory pathologies.
... Cannabis use is common amongst HIV-infected individuals in the United States, with an estimated prevalence of 23-56% (Ware et al. 2003;Okafor et al. 2017;Pacek et al. 2018). Constituents of cannabis (e.g., Δ 9 -tetrahydrocannabinol (THC)) have been shown to exhibit immune suppressive and anti-inflammatory activity (Croxford and Yamamura 2005;Turcotte et al. 2015). Recent evidence has emerged that HIV+ marijuana-users (MJ+) have fewer circulating CD16 + monocytes and activated CD8 + T cells compared to HIV + MJ- (Manuzak et al. 2018;Rizzo et al. 2018). ...
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HIV infection affects an estimated 38 million people. Approximately 50% of HIV patients exhibit neurocognitive dysfunction termed HIV-Associated Neurocognitive Disorder (HAND). HAND is a consequence of chronic low-level neuroinflammation due to HIV entry into the brain. Initially, monocytes become activated in circulation and traffic to the brain. Monocytes, when activated, become susceptible to infection by HIV and can then carry the virus across the blood brain barrier. Once in the brain, activated monocytes secrete chemokines, which recruit virus-specific CD8⁺ T cells into the brain to further promote neuroinflammation. HAND is closely linked to systemic inflammation driven, in part, by HIV but is also due to persistent translocation of microorganisms across the GI tract. Persistent anti-viral responses in the GI tract compromise microbial barrier integrity. Indeed, HIV patients can exhibit remarkably high levels of activated (CD16⁺) monocytes in circulation. Recent studies, including our own, show that HIV patients using medical marijuana exhibit lower levels of circulating CD16⁺ monocytes than non-cannabis using HIV patients. Cannabis is a known immune modulator, including anti-inflammatory properties, mediated, in part, by ∆⁹-tetrahydrocannabinol (THC), as well as less characterized minor cannabinoids, such as cannabidiol (CBD), terpenes and presumably other cannabis constituents. The immune modulating activity of THC is largely mediated through cannabinoid receptors (CB) 1 and 2, with CB1 also responsible for the psychotropic properties of cannabis. Here we discuss the anti-inflammatory properties of cannabinoids in the context of HIV and propose CB2 as a putative therapeutic target for the treatment of neuroinflammation. [Figure not available: see fulltext.]. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
... A number of immune cell subsets express CBRs, and cannabinoids have been reported to affect cytokine production in immune cells. However, the vast majority of these publications studied cells in vitro or ex vivo (13), and there is little information on the effects of cannabinoids in vivo in acute inflammation or on the regulation of the endocannabinoid system during inflammatory illnesses such as sepsis. ...
Article
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Cannabis sativa and its principal components, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol, are increasingly being used to treat a variety of medical problems, including inflammatory conditions. Although studies suggest that the endocannabinoid system has immunomodulatory properties, there remains a paucity of information on the effects of cannabinoids on immunity and on outcomes of infection and injury. We investigated the effects and mechanism(s) of action of cannabinoid receptor agonists, including Δ9-THC, on inflammation and organ injury in endotoxemic mice. Administration of Δ9-THC caused a dramatic early upregulation of plasma IL-10 levels, reduced plasma IL-6 and CCL-2 levels, led to better clinical status, and attenuated organ injury in endotoxemic mice. The anti-inflammatory effects of Δ9-THC in endotoxemic mice were reversed by a cannabinoid receptor type 1 (CB1R) inverse agonist (SR141716), and by clodronate-induced myeloid-cell depletion, but not by genetic invalidation or blockade of other putative Δ9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although Δ9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of Δ9-THC were preserved in splenectomized endotoxemic mice. Finally, using IL-10-GFP reporter mice, we showed that blood monocytic myeloid-derived suppressive cells mediate the Δ9-THC-induced early rise in circulating IL-10. These results indicate that Δ9-THC potently induces IL-10, while reducing proinflammatory cytokines, chemokines, and related organ injury in endotoxemic mice via the activation of CB1R. These data have implications for acute and chronic conditions that are driven by dysregulated inflammation, such as sepsis, and raise the possibility that CB1R-signaling may constitute a novel target for inflammatory disorders.
... Secondly, cannabionoids stimulate the immunologic immune system mediated by T helper Type 2 whilst inhibiting the cellular defense immune responses mediated by T helper Type 1 [24]. This is re lected by changes in their respective cytokines levels [39]. ...
... In fact, CB2 levels in microglia are phenotype-dependent, being principally expressed in activated and primed microglia (Stella, 2010). The activation of CB2 is related to decreases in pro-inflammatory cytokines (TNF-α, interferon gamma (IFN-ɣ), IL-1, IL-2, IL-6 or IL-12) (Croxford and Yamamura, 2005;Mecha et al., 2016;Yuan et al., 2002), chemokines (Bátkai et al., 2012;Sheng et al., 2005) and iNOS (Wen et al., 2015;Zarruk et al., 2012) via inhibition of the NF-κB pathway (Fakhfouri et al., 2012;Jeon et al., 1996). Hence, CB2 would act as a homeostatic regulator, bringing the system back to physiological states. ...
Article
Alcohol is a psychoactive substance highly used worldwide, whose harmful use might cause a broad range of mental and behavioural disorders. Underlying brain impact, the neuroinflammatory response induced by alcohol is recognised as a key contributing factor in the progression of other neuropathological processes, such as neurodegeneration. These sequels are determined by multiple factors, including age of exposure. Strikingly, it seems that the endocannabinoid system modulation could regulate the alcohol-induced neuroinflammation. Although direct CB1 activation can worsen alcohol consequences, targeting other components of the expanded endocannabinoid system may counterbalance the pro-inflammatory response. Indeed, specific modulations of the expanded endocannabinoid system have been proved to exert anti-inflammatory effects, primarily through the CB2 and PPARγ signalling. Among them, some endo- and exogeneous cannabinoids can block certain pro-inflammatory mediators, such as NF-κB, thereby neutralizing the neuroinflammatory intracellular cascades. Furthermore, a number of cannabinoids are able to activate complementary anti-inflammatory pathways, which are necessary for the transition from chronically overactivated microglia to a regenerative microglial phenotype. Thus, cannabinoid modulation provides cooperative anti-inflammatory mechanisms that may be advantageous to resolve a pathological neuroinflammation in an alcohol-dependent context.
... In animal models, cannabis has been regarded as anti-inflammatory and immunomodulatory (Croxford and Yamamura, 2005). The impact of cannabis use on inflammatory markers has been studied in different cohorts with mixed results; cannabis use was associated with lower Creactive protein (CRP) levels in the National Health and Nutrition Examination Surveys (NHANES) cohort (Alshaarawy and Anthony, 2015), but not in the Coronary Artery Risk Development in Young Adults (CARDIA) study cohort (Alshaarawy et al., 2019). ...
Article
Background The effect of concomitant cocaine and cannabis use on monocyte activation and inflammation in patients with alcohol use disorder (AUD) is unknown. Methods To analyze the impact of cocaine and cannabis use on levels of markers of monocyte activation (sCD163 and soluble [sCD14]) and systemic inflammation (interleukin-6 [IL-6]) in AUD patients with admitted for hospital treatment between 2013 and 2018. Clinical and laboratory parameters were obtained upon admission. IL-6, sCD163, and sCD14 were measured in frozen plasma samples. We performed logistic regression to detect associations between cocaine and cannabis use and markers of monocyte activation and inflammation and in the highest quartile. Results A total of 289 patients (77.5 % male) were included (median age = 50 years). The median alcohol intake upon admission was 142 g/day. The median duration of AUD was 20 years. Of the 289 patients with AUD, 76 % were active smokers, 23.1 % and 22.1 % concomitantly used cocaine and cannabis, respectively The median levels of IL-6, sCD163, and sCD14 were 4.37 pg/mL, 759 ng/mL, and 1.68 × 10⁶ pg/mL, respectively. We did not detect associations between cocaine use and inflammation, monocyte activation, or microbial translocation. Cannabis use was associated with a higher odds of having sCD163 levels in the highest quartile (adjusted odds ratio = 2.34, 95 % confidence interval = 1.07–5.15, p = 0.03). Cannabis use was not associated with inflammation. Conclusion In this series of AUD patients the concomitant use of cannabis use was associated with sCD163 levels that were in the highest quartile, consistent with monocyte activation.
... Cannabinoids and, particularly, various phytocannabinoids have been shown to affect the functional activities of immune cells [7,[30][31][32][33][34], while the inhibitory effect of cannabis on lymphocytes has been widely observed before [35]. For example, phytocannabinoids have the potential to modulate the activation and balance of human T-helper 1 (Th1)/T-helper 2 (Th2) cells, lymphocytes, and killer cells [36,37]. ...
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Cannabis or its derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects. However, cannabis has potent immunomodulatory properties. To determine if cannabis consumption during immunotherapy affects therapy outcomes, we conducted a prospective observatory study including 102 (68 immunotherapy and 34 immunotherapy plus cannabis) consecutive patients with advanced cancers who initiated immunotherapy. Cannabis consumption correlated with a significant decrease in time to tumor progression and overall survival. On the other hand, the use of cannabis reduced therapy-related immune-related adverse events. We also tested the possibility that cannabis may affect the immune system or the tumor microenvironment through the alteration of the endocannabinoid system. We analyzed a panel of serum endocannabinoids (eCBs) and eCB-like lipids, measuring their levels before and after immunotherapy in both groups. Levels of serum eCBs and eCB-like lipids, before immunotherapy, showed no significant differences between cannabis users to nonusers. Nevertheless, the levels of four eCB and eCB-like compounds were associated with patients’ overall survival time. Collectively, cannabis consumption has considerable immunomodulatory effects, and its use among cancer patients needs to be carefully considered due to its potential effects on the immune system, especially during treatment with immunotherapy.
... Cannabinoids and, particularly, various phytocannabinoids have been shown to affect the functional activities of immune cells [7,[30][31][32][33][34], while the inhibitory effect of cannabis on lymphocytes has been widely observed before [35]. For example, phytocannabinoids have the potential to modulate the activation and balance of human T-helper 1 (Th1)/T-helper 2 (Th2) cells, lymphocytes, and killer cells [36,37]. ...
... Cannabidiol has been reported to decrease the production of T-helper 2 cytokines such as IL-10, which is well known to play an important role in humoral immunity [125]. Furthermore, Malfait et al. showed that i.p. or s.c. ...
Article
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Cannabis sativa L. is a plant long used for its textile fibers, seed oil, and oleoresin with medicinal and psychoactive properties. It is the main source of phytocannabinoids, with over 100 compounds detected so far. In recent years, a lot of attention has been given to the main phytochemicals present in Cannabis sativa L., namely, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). Compared to THC, CBD has non-psychoactive effects, an advantage for clinical applications of anti-tumor benefits. The review is designed to provide an update regarding the multi-target effects of CBD in different types of cancer. The main focus is on the latest in vitro and in vivo studies that present data regarding the anti-proliferative, pro-apoptotic, cytotoxic, anti-invasive, anti-antiangiogenic, anti-inflammatory, and immunomodulatory properties of CBD together with their mechanisms of action. The latest clinical evidence of the anticancer effects of CBD is also outlined. Moreover, the main aspects of the pharmacological and toxicological profiles are given.
... Overall, these major signaling networks play important roles in CB2Rmediated effects on immune cell functions including migration, proliferation, differentiation, apoptosis, and cytokine production (28). Generally, effects of the EC system on immune cells appear directed toward an anti-inflammatory action, although the context-dependent action of cannabinoids may support different responses in different cell types and states (62,(173)(174)(175)(176). ...
Article
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Cannabis has been used for centuries for recreational and therapeutic purposes. Whereas, the recreative uses are based on the psychotropic effect of some of its compounds, its therapeutic effects range over a wide spectrum of actions, most of which target the brain or the immune system. Several studies have found cannabinoid receptors in the auditory system, both at peripheral and central levels, thus raising the interest in cannabinoid signaling in hearing, and especially in tinnitus, which is affected also by anxiety, memory, and attention circuits where cannabinoid effects are well described. Available studies on animal models of tinnitus suggest that cannabinoids are not likely to be helpful in tinnitus treatment and could even be harmful. However, the pharmacology of cannabinoids is very complex, and most studies focused on neural CB1R-based responses. Cannabinoid effects on the immune system (where CB2Rs predominate) are increasingly recognized as essential in understanding nervous system pathological responses, and data on immune cannabinoid targets have emerged in the auditory system as well. In addition, nonclassical cannabinoid targets (such as TRP channels) appear to play an important role in the auditory system as well. This review will focus on neuroimmunological mechanisms for cannabinoid effects and their possible use as protective and therapeutic agents in the ear and auditory system, especially in tinnitus.
... Keen and colleagues [49] have reported similar results, showing that cannabis users present low systemic levels of IL-6. It is known that TNF-α and IL-6 are important to induce an appropriate innate and adaptive immune response to viral, parasitic and bacterial infection, which in deficiency circumstances can impair the necessary immunity in pathological process [50]. Previous research had reported that the cannabis use may actually be harmful, as the immune system is unable to recruit the proper immune cells to fight off infections, such as HIV [51] and hepatitis C [52]. ...
Article
Illicit drug use can cause a variety of effects including alterations in the immune system. The aim of this study was to investigate the effects of illicit drugs on circulating lipopolysaccharide (LPS), systemic inflammation and oxidative stress markers in drug users. We evaluated the levels of soluble CD14 (sCD14), LPS, inflammatory (TNF-α and IL-6) and regulatory (IL-10) cytokines, as well as C-reactive protein (CRP), lipid peroxidation (TBARS) and total thiols in the peripheral blood of 81 men included in groups of cannabis (n = 21), cocaine (n = 12), cannabis-plus-cocaine users (n = 27), and non-drug users (n = 21). The use of cannabis plus cocaine leads to higher systemic levels of LPS, CRP, IL-6 and higher IL-6/IL-10 ratio, characterizing a proinflammatory profile. In contrast, a regulatory profile as viewed by lower systemic TNF-α and IL-6 levels and lower TNF-α/IL-10 ratio were observed in cannabis users compared to the control group. Moreover, cocaine users presented a lower content of non-enzymatic antioxidant thiol compared to control group, cannabis group and cannabis plus cocaine group. In conclusion, our results indicate that the use of cannabis contributes to an anti-inflammatory/or regulatory profile while the concomitant cannabis plus cocaine consumption coexists with increased circulating amounts of LPS and proinflammatory status.
... However, CBs seem able to cause both an anti-inflammatory and a suppressive effect against T lymphocytes: CBs can reduce cytokine release, and phytocannabinoids may play an immunomodulatory role both in terms of the cellular and of the humoral response, binding the CB2R [141,142]. In this context, CB2R inhibition with JTE907, a selective CB2R inverse agonist, when combined with a CB1R/CB2R gene silencing approach, demonstrated that CB2R, but not CB1R, is responsible for phytocannabinoid-mediated immune suppression [143]. ...
Article
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The endocannabinoid system (ECS) is a composite cell-signaling system that allows endogenous cannabinoid ligands to control cell functions through the interaction with cannabinoid receptors. Modifications of the ECS might contribute to the pathogenesis of different diseases, including cancers. However, the use of these compounds as antitumor agents remains debatable. Pre-clinical experimental studies have shown that cannabinoids (CBs) might be effective for the treatment of hematological malignancies, such as leukemia and lymphoma. Specifically, CBs may activate programmed cell death mechanisms, thus blocking cancer cell growth, and may modulate both autophagy and angiogenesis. Therefore, CBs may have significant anti-tumor effects in hematologic diseases and may synergistically act with chemotherapeutic agents, possibly also reducing chemoresistance. Moreover, targeting ECS might be considered as a novel approach for the management of graft versus host disease, thus reducing some symptoms such as anorexia, cachexia, fatigue, anxiety, depression, and neuropathic pain. The aim of the present review is to collect the state of the art of CBs effects on hematological tumors, thus focusing on the essential topics that might be useful before moving into the clinical practice.
... Overall, these major signaling networks play important roles in CB2Rmediated effects on immune cell functions including migration, proliferation, differentiation, apoptosis, and cytokine production (28). Generally, effects of the EC system on immune cells appear directed toward an anti-inflammatory action, although the context-dependent action of cannabinoids may support different responses in different cell types and states (62,(173)(174)(175)(176). ...
Chapter
inner ear immunology in vestibular migraine and meniere disease, difrential proinflammatory profile
... The oral consumption of cannabis was also found to increase the rate of survival of mice infected with malaria. A study also revealed that administering endocannabinoids in increased levels was helpful in treating mice infected with helminths in intestine and lungs, presenting their immune response at elevated doses combined with post infection immunity [85]. The clinical anti-infective role of cannabinoids can be ascribed to its anti-inflammatory property upon exposure to certain pathogens. ...
Article
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Over the last 25 years, the human endocannabinoid system (ECS) has come into the limelight as an imperative neuro-modulatory system. It is mainly comprised of endogenous cannabinoid (endocannabinoid), cannabinoid receptors and the associated enzymes accountable for its synthesis and deterioration. The ECS plays a proven role in the management of several neurological, cardio-vascular, immunological, and other relevant chronic conditions. Endocannabinoid or endogenous cannabinoid are endogenous lipid molecules which connect with cannabinoid receptors and impose a fashionable impact on the behavior and physiological processes of the individual. Arachidonoyl ethanolamide or Anandamide and 2-arachidonoyl glycerol or 2-AG were the endocannabinoid molecules that were first characterized and discovered. The presence of lipid membranes in the precursor molecules is the characteristic feature of endocannabinoids. The endocannabinoids are released upon rapid enzymatic reactions into the extracellular space via activation through G-protein coupled receptors, which is contradictory to other neurotransmitter that are synthesized beforehand, and stock up into the synaptic vesicles. The current review highlights the functioning, synthesis, and degradation of endocannabinoid, and explains its functioning in biological systems.
... Alternative medicines are thus needed for these treatments. 26 Given the wide use of cannabis in a number of medical conditions, its immunosuppressive effect on T cells should be considered in the treatment of these diseases. Moreover, marijuana is one of the most used illegal drugs for psychoactive recreation. ...
Article
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The combination of immune checkpoint blockade (ICB) with chemotherapy significantly improves clinical benefit of cancer treatment. Since chemotherapy is often associated with adverse events, concomitant treatment with drugs managing side effects of chemotherapy is frequently used in the combination therapy. However, whether these ancillary drugs could impede immunotherapy remains unknown. Here, we showed that Δ 9-tetrahydrocannabinol (THC), the key ingredient of drugs approved for the treatment of chemotherapy-caused nausea, reduced the therapeutic effect of PD-1 blockade. The endogenous cannabinoid anandamide (AEA) also impeded antitumor immunity, indicating an immunosuppressive role of the endogenous cannabinoid system (ECS). Consistently, high levels of AEA in the sera were associated with poor overall survival in cancer patients. We further found that cannabinoids impaired the function of tumor-specific T cells through CNR2. Using a knock-in mouse model expressing a FLAG-tagged Cnr2 gene, we discovered that CNR2 binds to JAK1 and inhibits the downstream STAT signaling in T cells. Taken together, our results unveiled a novel mechanism of the ECS-mediated suppression on T-cell immunity against cancer, and suggest that cannabis and cannabinoid drugs should be avoided during immunotherapy. Signal Transduction and Targeted Therapy (2022) 7:99 ; https://doi.
... Further research is needed to assess the longitudinal effects of drug use on inflammation among this population, particularly as it appears to differ based on HIV diagnosis. Past research has observed an association between cannabinoids and a reduction in levels of inflammation [38][39][40] . This earlier work, however, was conducted among primarily either laboratory animals or heterosexual and older populations. ...
Article
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The use of marijuana is highly prevalent among young men who have sex with men (YMSM). Past work has also shown that inflammation is elevated among YMSM, independent of HIV status. Here, we aim to examine the relationship between marijuana use and inflammation among this high-risk cohort, relative to use of other substances. Data were collected among YMSM aged 16–29 in Chicago. Multiplex cytokine and inflammatory biomarker assays were run on plasma from all persons living with HIV (PLWH) (n = 195) and a subset of HIV-negative participants (n = 489). Bivariate analyses and multivariable models assessed relationships between various substances and inflammatory biomarkers. Models were stratified by HIV status and adjusted for demographic characteristics. Most participants reported use of marijuana in the past 30 days (416, 60.8%). Mean blood C-reactive protein (CRP) levels were above the upper limit of normal (3.0 mg/L), indicative of increased risk for cardiovascular disease (mean CRP was 3.9 mg/L; SD = 8.5). In adjusted, stratified analyses, CRP was significantly lower among participants reporting frequent marijuana use (≥ 6 times per month), relative to those reporting never using marijuana, (β = − 0.38; 95% CI: − 0.73, − 0.03). However, this was entirely accounted for by an association among the HIV-negative participants and there was no significant association between marijuana use and blood CRP level among the PLWH. In summary, YMSM had markedly elevated marijuana use and blood CRP levels. Frequent marijuana use was associated with lower inflammation among only those not diagnosed with HIV. Further research is needed to explicate why there are differences between HIV-negative participants and PLWH and to leverage this information to characterize biological mechanisms by which marijuana decreases inflammation.
... The anti-inflammatory and immune modulatory properties of cannabinoids are well known [7,59,126,164,170] and have been reviewed in the context of HIV-1 infection [19,54,106,242, see also Tables 1-3]. Cannabis use has been reported to lower inflammatory responses in HIV-1 infection from immune cells [33,146,197] and the peripheral nervous system in PWH and animal models [34,160,239], with this section focusing on the effects of cannabinoids on neuroinflammatory processes and its consequence on neuronal health. ...
Article
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Human immunodeficiency virus type 1 (HIV-1) is known to provoke microglial immune responses which likely play a paramount role in the development of chronic neuroinflammatory conditions and neuronal damage related to HIV-1 associated neurocognitive disorders (HAND). In particular, HIV-1 Tat protein is a proinflammatory neurotoxin which predisposes neurons to synaptodendritic injury. Drugs targeting the degradative enzymes of endogenous cannabinoids have shown promise in reducing inflammation with minimal side effects in rodent models. Considering that markers of neuroinflammation can predict the extent of neuronal injury in HAND patients, we evaluated the neurotoxic effect of HIV-1 Tat-exposed microglia following blockade of fatty acid amid hydrolyze (FAAH), a catabolic enzyme responsible for degradation of endocannabinoids, e.g. anandamide (AEA). In the present study, cultured murine microglia were incubated with Tat and/or a FAAH inhibitor (PF3845). After 24 h, cells were imaged for morphological analysis and microglial conditioned media (MCM) was collected. Frontal cortex neuron cultures (DIV 7–11) were then exposed to MCM, and neurotoxicity was assessed via live cell calcium imaging and staining of actin positive dendritic structures. Results demonstrate a strong attenuation of microglial responses to Tat by PF3845 pretreatment, which is indicated by 1) microglial changes in morphology to a less proinflammatory phenotype using fractal analysis, 2) a decrease in release of neurotoxic cytokines/chemokines (MCP-1/CCL2) and matrix metalloproteinases (MMPs; MMP-9) using ELISA/multiplex assays, and 3) enhanced production of endocannabinoids (AEA) using LC/MS/MS. Additionally, PF3845's effects on Tat-induced microglial-mediated neurotoxicity, decreased dysregulation of neuronal intracellular calcium and prevented the loss of actin-positive staining and punctate structure in frontal cortex neuron cultures. Interestingly, these observed neuroprotective effects appeared to be independent of cannabinoid receptor activity (CB1R & CB2R). We found that a purported GPR18 antagonist, CID-85469571, blocked the neuroprotective effects of PF3845 in all experiments. Collectively, these experiments increase understanding of the role of FAAH inhibition and Tat in mediating microglial neurotoxicity in the HAND condition.
... Another approach to probing the role of CB2 receptors in immune responses is to use synthetic, CB2 selective agonists (Huffman et al., 1996;Hanuš et al., 1999;Huffman et al., 1999;Pacher and Mechoulam, 2011). With these approaches, the majority of studies on cannabinoids have shown them to be anti-inflammatory, immunosuppressive (Croxford and Yamamura, 2005;Klein, 2005;Eisenstein and Meissler, 2015) and to polarize immune responses towards a Th2 phenotype (Newton et al., 1994;Klein et al., 2000;Yuan et al., 2002;Yang et al., 2014). Immunosuppression by Δ 9 -THC has been associated with increases in the immunosuppressive and anti-inflammatory cytokines, TGF-β and IL-10 (Zhu et al., 2000), and it was shown that TGF-β induction occurs via the CB2 receptor (Gardner et al., 2002). ...
Article
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Previous work from our laboratory showed that a CB2 selective agonist, O-1966, blocked the proliferative response of C57BL/6 mouse spleen cells exposed to spleen cells of C3HeB/FeJ mice in vitro in the mixed lymphocyte reaction (MLR). The MLR is widely accepted as an in vitro correlate of in vivo grant rejection. Mechanisms of the immunosuppression induced by the cannabinoid were explored, and it was shown that O-1966 in this in vitro assay induced CD25 ⁺ Foxp3 ⁺ Treg cells and IL-10, as well as down-regulated mRNA for CD40 and the nuclear form of the transcription factors NF-κB and NFAT in T-cells. The current studies tested the efficacy of O-1966 in prolonging skin grafts in vivo . Full thickness flank skin patches (1-cm ² ) from C3HeB/FeJ mice were grafted by suturing onto the back of C57BL/6 mice. O-1966 or vehicle was injected intraperitoneally into treated or control groups of animals beginning 1 h pre-op, and then every other day until 14 days post-op. Graft survival was scored based on necrosis and rejection. Treatment with 5 mg/kg of O-1966 prolonged mean graft survival time from 9 to 11 days. Spleens harvested from O-1966 treated mice were significantly smaller than those of vehicle control animals based on weight. Flow cytometry analysis of CD4 ⁺ spleen cells showed that O-1966 treated animals had almost a 3-fold increase in CD25 ⁺ Foxp3 ⁺ Treg cells compared to controls. When dissociated spleen cells were placed in culture ex vivo and stimulated with C3HeB/FeJ cells in an MLR, the cells from the O-1966 treated mice were significantly suppressed in their proliferative response to the allogeneic cells. These results support CB2 selective agonists as a new class of compounds to prolong graft survival in transplant patients.
... The apparent contradictions between stimulatory and inhibitory effects of cannabinoids on phagocytic cells have been correlated to a well-known biphasic response which can be observed by using different ligand concentrations [38]. Indeed, many of the inhibitory effects of cannabinoids in vitro have been described in the micromolar concentration range, whereas stimulatory concentrations have been observed in the nanomolar range [39]. Under our experimental conditions, the suppressive effects of AEA on hemocyte phagocytosis were observed at 10 nM and 100 nM in a dose-dependent manner, whereas the lowest concentration (1 nM) appeared as ineffective. ...
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Anandamide (AEA) is one of the best characterized members of the endocannabinoid family and its involvement in many pathophysiological processes has been well documented in vertebrates and invertebrates. Here, we report the biochemical and functional characterization of key elements of the endocannabinoid system in hemocytes isolated from the Mediterranean mussel Mytilus galloprovincialis. We also show the effects of exogenous AEA, as well as of capsaicin, on the cell ability to migrate and to activate the respiratory burst, upon in vitro stimulation of phagocytosis. Interestingly, our findings show that both AEA and capsaicin suppress the hemocyte response and that the use of selective antagonists of CB2 and TRPV1 receptors revert their inhibitory effects. Overall, present data support previous evidence on the presence of endocannabinoid signaling in mollusks and advance our knowledge about the evolutionary origins of this endogenous system and its role in the innate response of mollusks.
... In the last years, the nonpsychoactive cannabinoid CBD, very common in certain strains of cannabis, has gained clinical relevance. Besides psychoactivity, cannabis have shown antinociceptive [45], anticonvulsant [46], immunosuppressive [47], antiemetic [48], appetite stimulation [49] and antimicrobial [50,51] properties. These effects result from either cannabinoid receptor activation or eCBs-metabolic enzyme competition. ...
Article
Although cannabis use is increasing in general population, their prevalence among young adults is remarkably high. In recent years, their medical use gained a renewed interest. However, it can underline the reputation of cannabis being a harmless drug. Between cannabinoids, uniquely found on the cannabis plant, Δ9-tetrahydrocannabinol (THC) is the well-studied compound. It is responsible for the psychoactive effects via central cannabinoid receptors. Nevertheless, cannabinoids interact with other chemical signalling systems such as the hypothalamic-pituitary-gonadal axis. THC indirectly decreases gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus. The consequences are diverse, and several key hormones are affected. THC disturbs important reproductive events like folliculogenesis, ovulation and sperm maturation and function. Although generally accepted that cannabinoid consumption impacts male and female fertility, prevailing evidence remains largely on pre-clinical studies. Here, we introduce cannabinoids and the endocannabinoid system, and we review the most prominent clinical evidence about cannabis consumption in reproductive potential and teratogenicity.
... D9-Tetrahydrocannabinol (THC), a primary psychoactive component of cannabis, can directly bind to cannabinoid receptors, which are distributed extensively in the brain [9]. THC also exhibits a wide range of immunosuppressive effects, which may decrease host defense to infections [10,11]. The connection and interaction between the gut microbiome and CNS function via the microbiota-gut-brain axis have been studied [12], but the oral cavity also hosts a large community of different bacteria that interact with each other and with the host. ...
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Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Methods In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder (n = 16) and in non-smoking controls (n = 27). The saliva microbiome was analyzed using microbial 16S rRNA sequencing. To investigate the function of cannabis use-associated oral microbiome, mice were orally inoculated with live Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice per week for six months, which mimicked human conditions. Findings We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. Among the distinct species bacteria in cannabis smokers, the enrichment of Actinomyces meyeri was inversely associated with the age of first cannabis smoking. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bacteria, decreased global activity, increased macrophage infiltration, and increased β-amyloid 42 protein production in the mouse brains. Interpretation This is the first study to reveal that long-term oral cannabis exposure is associated oral enrichment of Actinomyces meyeri and its contributions to CNS abnormalities.
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Crohn's disease (CD) is a type of chronic, inflammatory bowel disease (IBD) which affects any part of the gastrointestinal tract. This study aims to understand the mechanism which activate mucosal fibroblasts in the microenvironment of the colon in CD and colorectal carcinomas and to extract fibroblasts phenotypes via a novel framework based on non-negative factorization of matrix (NMF). The results identify a fibroblast phenotype characterized by intense pro-inflammatory activity ensured by the presence of genes belonging to the APOBEC1 family, such as APOBEC3F and APOBEC3G. These results demonstrated that there is a difference in fibroblast response in producing a pro-tumorigenic effect in CD. The different activation mechanisms could represent useful biomarkers in controlling CD development without generalizing its significance as IBD.
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Acute respiratory distress syndrome (ARDS) is a serious lung condition characterized by severe hypoxemia leading to limitations of oxygen needed for lung function. In this study, we investigated the effect of anandamide (AEA), an endogenous cannabinoid, on Staphylococcal enterotoxin B (SEB)-mediated ARDS in female mice. Single-cell RNA sequencing data showed that the lung epithelial cells from AEA-treated mice showed increased levels of antimicrobial peptides (AMPs) and tight junction proteins. MiSeq sequencing data on 16S RNA and LEfSe analysis demonstrated that SEB caused significant alterations in the microbiota, with increases in pathogenic bacteria in both the lungs and the gut, while treatment with AEA reversed this effect and induced beneficial bacteria. AEA treatment suppressed inflammation both in the lungs as well as gut-associated mesenteric lymph nodes (MLNs). AEA triggered several bacterial species that produced increased levels of short-chain fatty acids (SCFAs), including butyrate. Furthermore, administration of butyrate alone could attenuate SEB-mediated ARDS. Taken together, our data indicate that AEA treatment attenuates SEB-mediated ARDS by suppressing inflammation and preventing dysbiosis, both in the lungs and the gut, through the induction of AMPs, tight junction proteins, and SCFAs that stabilize the gut-lung microbial axis driving immune homeostasis.
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Fibromyalgia (FM) is characterized by widespread chronic pain, sleep disturbance, and fatigue, as well as comorbidities including mood disturbance and hypervigilance [1]. Given this complexity and variability in symptoms, FM remains a challenge to treat effectively. In the absence of a “gold standard” treatment, cannabis-based medicines have been proposed as an option. Cannabinoids have the potential to impact many symptoms, including pain, sleep disturbance, anxiety, and mood disorders. Clearly, an agent with an impact on many symptoms could offer an advantage.
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Multicenter, randomized, double-blind, placebo controlled, clinical trial. The objective of this paper is to evaluate the effectiveness of cannabinoids and an anti-inflammatory diet, alone and in combination, for the management of neuropathic pain (NP) after spinal cord injury (SCI). Two Canadian SCI rehabilitation centers. A sample of 144 individuals with SCI will receive either an anti-inflammatory diet, cannabinoids or a placebo for 6 weeks. Following this, a combined effect of these treatments will be evaluated for a further 6 weeks. The primary outcome measure will be the change in NP as assessed by the numeric rating scale (NRS). Secondary outcomes will include changes in inflammation, mood, sleep, spasticity, cost-effectiveness, and function. This study will assess the efficacy of an anti-inflammatory diet and cannabinoids (individually and in combination) for the treatment of NP following SCI. Results may reveal a cost-effective, side-effect free intervention strategy which could be utilized for the long-term management of NP following SCI.
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Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Results In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder and in non-smoking controls. We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. To investigate the function of cannabis use-associated microbiome, mice were orally exposured to Actinomyces. meyeri, Actinomyces. odontolyticus, or Neisseria. elongate through oral gavage twice per week for six months which mimics human conditions. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bactreria, decreased global activity and increased β-amyloid 42 protein production in the mouse brains. Conclusions This is the first study to reveal that cannabis-associated enrichment of Actinomyces meyeri may contribute to a hallmark of neuropathology.
Chapter
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Chapter
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Chapter
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Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease, which may be initiated by a virus infection. Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4+ T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry), but because of de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (that is, epitope spreading). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.
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Previous investigations from our laboratories have demonstrated that cannabinoids possess immunosuppressive properties. The present studies were designed to determine whether these agents decrease host resistance to infections with Listeria monocytogenes and herpes simplex virus type 2. Host resistance was measured by changes in the 50% lethal dose of the pathogen in cannabinoid-treated and control mice. The effect of cannabinoids on resistance to L. monocytogens was dose dependent. Delta-9-tetrhydrocannabinol at doses of 38, 75, and 150 mg/kg suppressed resistance to infection by 10-, 17-, and 657-fold, respectively. Marijuana extract was less active but significantly reduced resistance to L. moncytogenes at all tested doses. Resistance to systemic herpes simplex virus type 2 infection was decreased 96-fold by delta-9-tetrahydrocannabinol, although marijuana extract was inactive. The doses and regimen of treatment with cannabinoids that produced significant decreases in host resistance were similar to those which caused suppression of delayed-type hypersensitivity to sheep erythrocytes. The possible mechanisms and public health aspects of the decreased host resistance produced by marijuana extract and its cannabinoids are discussed.
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Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
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A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
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Two subtypes of G-protein–coupled cannabinoid receptors have been identified to date: the CB1 central receptor subtype, which is mainly expressed in the brain, and the CB2 peripheral receptor subtype, which appears particularly abundant in the immune system. We investigated the expression of CB2 receptors in leukocytes using anti-CB2 receptor immunopurified polyclonal antibodies. We showed that peripheral blood and tonsillar B cells were the leukocyte subsets expressing the highest amount of CB2 receptor proteins. Dual-color confocal microscopy performed on tonsillar tissues showed a marked expression of CB2 receptors in mantle zones of secondary follicles, whereas germinal centers (GC) were weakly stained, suggesting a modulation of this receptor during the differentiation stages from virgin B lymphocytes to memory B cells. Indeed, we showed a clear downregulation of CB2 receptor expression during B-cell differentiation both at transcript and protein levels. The lowest expression was observed in GC proliferating centroblasts. Furthermore, we investigated the effect of the cannabinoid agonist CP55,940 on the CD40-mediated proliferation of both virgin and GC B-cell subsets. We found that CP55,940 enhanced the proliferation of both subsets and that this enhancement was blocked by the CB2 receptor antagonist SR 144528 but not by the CB1 receptor antagonist SR 141716. Finally, we observed that CB2 receptors were dramatically upregulated in both B-cell subsets during the first 24 hours of CD40-mediated activation. These data strongly support an involvement of CB2 receptors during B-cell differentiation.
Chapter
Multiple sclerosis (MS) is a disease of central white matter with prominent demyelination and oligodendrocyte loss. Recent data on MS pathogenesis has implicated disruption of glutamate homeostasis as a disease mechanism, at the center of which, molecules of the glutamate clearance pathway are selectively downregulated on oligodendrocytes. Thus, oligodendrocytes are unable to process extracellular glutamate appropriately, rendering these cells targets for glutamate excitotoxicity. This concept has been supported by data from animal models of inflammatory demyelination and from oligodendroglial cell culture studies. Since oligodendrocyte damage by glutamate excitotoxicity has been described in a number of unrelated white matter conditions, glutamate excitotoxicity may be a common pathway in white matter injury.
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Reversible airway hyperreactivity underlies the pathophysiology of asthma, yet the precise mediators of the response remain unclear. Human studies have correlated aberrant activation of T helper (Th) 2-like effector systems in the airways with disease. A murine model of airway hyperreactivity in response to acetylcholine was established using mice immunized with ovalbumin and challenged with aerosolized antigen. No airway hyperractivity occurred in severe combined immunodeficient mice. Identically immunized BALB/c mice developed an influx of cells, with a predominance of eosinophils and CD4+ T cells, into the lungs and bronchoalveolar lavage fluid at the time that substantial changes in airway pressure and resistance were quantitated. Challenged animals developed marked increases in Th2 cytokine production, eosinophil influx, and serum immunoglobulin E levels. Neutralization of interleukin (IL) 4 using monoclonal antibodies administered during the period of systemic immunization abrogated airway hyperractivity but had little effect on the influx of eosinophils. Administration of anti-IL-4 only during the period of the aerosol challenge did not affect the subsequent response to acetylcholine. Finally, administration of anti-IL-5 antibodies at levels that suppressed eosinophils to < 1% of recruited cells had no effect on the subsequent airway responses. BALB/c mice had significantly greater airway responses than C57BL/6 mice, consistent with enhanced IL-4 responses to antigen in BALB/c mice. Taken together, these data implicate IL-4 generated during the period of lymphocyte priming with antigen in establishing the cascade of responses required to generate airway hyperractivity to inhaled antigen. No role for IL-5 or eosinophils could be demonstrated.
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2-Arachidonylglycerol (2-AG) inhibits the production in vitro of tumor necrosis factor-α (TNF-α) by mouse macrophages, as well as in mice. It has no effect on the production of nitric oxide (NO). The effect on TNF-α is enhanced when 2-AG is administered together with 2-linoleylglycerol (2-Lino-G) and 2-palmitylglycerol (2-PalmG), an ‘entourage effect’ previously noted in several behavioral and binding assays. 2-AG also suppresses the formation of radical oxygen intermediates.
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ANANDAMIDE (N-arachidonoyl-ethanolamine) was recently identified as a brain arachidonate derivative that binds to and activates cannabinoid receptors1–4, yet the mechanisms underlying formation, release and inactivation of this putative messenger molecule are still unclear. Here we report that anandamide is produced in and released from cultured brain neurons in a calcium ion-dependent manner when the neurons are stimulated with membrane-depolarizing agents. Anandamide formation occurs through phos-phodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine. A similar mechanism also governs the formation of a family of anandamide congeners, whose possible roles in neuronal signalling remain unknown. Our results and those of others5,6indicate therefore that multiple biochemical pathways may participate in anandamide formation in brain tissue. The life span of extracellular anandamide is limited by a rapid and selective process of cellular uptake, which is accompanied by hydrolytic degradation to ethanolamine and arachidonate. Our results thus strongly support the proposed role of anandamide as an endogenous neuronal messenger.
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The stimulus-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in intact mouse J774 macrophages and the inactivation of 2-AG by the same cells or by rat circulating macrophages was studied. By using gas chromatography-mass spectrometry, we found that ionomycin (5 µm) and lipopolysaccharide (LPS, 200 µg·mL−1) cause a 24-fold and 2.5-fold stimulation of 2-AG levels in J774 cells, respectively, thus providing unprecedented evidence that this cannabimimetic metabolite can be synthesized by macrophages. In J774 cells, LPS also induced a 7.8-fold increase of the levels of the other endocannabinoid, anandamide, and, in rat circulating macrophages, an almost twofold increase of 2-AG levels. Extracellular [3H]2-AG was cleared from the medium of intact J774 macrophages (t1/2 = 19–28 min) and esterified to phospholipids, diacylglycerols and triglycerides or hydrolyzed to [3H]arachidonic acid and glycerol. These catabolic processes were attenuated differentially by various enzyme inhibitors. Rat circulating macrophages were shown to contain enzymatic activities for the hydrolysis of 2-AG, including: (a) fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide breakdown and previously shown to catalyse also 2-AG hydrolysis, and (b) a 2-AG hydrolase activity different from FAAH and down-regulated by LPS. High levels of FAAH mRNA were found in circulating macrophages but not platelets, which, however, contain a 2-AG hydrolase. Both platelets and macrophages were shown to express the mRNA for the CB1 cannabinoid receptor. A macrophage 2-AG hydrolase with apparent Km = 110 µm and Vmax = 7.9 nmol·min−1·(mg protein)−1 was partially characterized in J774 cells and found to exhibit an optimal pH of 6–7 and little or no sensitivity to typical FAAH inhibitors. These findings demonstrate for the first time that macrophages participate in the homeostasis of the hypotensive and immunomodulatory endocannabinoid 2-AG through metabolic mechanisms that are subject to regulation.
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The endogenous fatty acid ethanolamide, palmitylethanolamide, alleviated, in a dose-dependent manner, pain behaviors elicited in mice by injections of formalin (5%, intraplantar), acetic acid (0.6%, 0.5 ml per animal, intraperitoneal, i.p.), kaolin (2.5 mg per animal, i.p.), and magnesium sulfate (120 mg per kg, i.p.). The antinociceptive effects of palmitylethanolamide were prevented by the cannabinoid CB2 receptor antagonist SR144528 [N-([1s]-endo-1.3.3-trimethylbicyclo[2.3.1]heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], not by the cannabinoid CB1 receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide·HCl]. By contrast, palmitylethanolamide had no effect on capsaicin-evoked pain behavior or thermal nociception. The endogenous cannabinoid, anandamide (arachidonylethanolamide), alleviated nociception in all tests (formalin, acetic acid, kaolin, magnesium sulfate, capsaicin and hot plate). These effects were prevented by the cannabinoid CB1 receptor antagonist SR141716A, not the cannabinoid CB2 receptor antagonist SR141716A. Additional fatty acid ethanolamides (oleylethanolamide, myristylethanolamide, palmitoleylethanolamide, palmitelaidylethanolamide) had little or no effect on formalin-evoked pain behavior, and were not investigated in other pain models. These results support the hypothesis that endogenous palmitylethanolamide participates in the intrinsic control of pain initiation. They also suggest that the putative receptor site activated by palmitylethanolamide may provide a novel target for peripherally acting analgesic drugs.
Article
Anandamide and allied fatty acylethanolamides (AEs) may act as signalling molecules in brain and peripheral tissues. In the present study, we describe an electron-impact gas chromatography/mass spectrometry (GC/MS) method based on isotope dilution, which may be used for the identification and quantification of anandamide and other AEs in biological matrices. The calibration curves for standard AEs were linear over the range 0–1000 pmol (r2=0.99) with a coefficient of variation of 4% at 2.5 pmol. Detection and quantification limits were in the high fmol to low pmol range for all AEs. Using this method we measured nanomolar concentrations of three endogenous AEs in deproteinated rat blood plasma (anandamide: 5.2 pmol/ml; palmitylethanolamide: 16.7 pmol/ml; oleylethanolamide: 8.1 pmol/ml). These results are consistent with a regulatory role of anandamide and other AEs in peripheral tissues.
Article
Cannabinoid receptors have been described in sea urchin sperm and shown to mediate inhibition of sperm acrosome reaction. Anandamide (arachidonoyl-ethanolamide), the mammalian physiological ligand at the cannabinoid CB1 receptor, has been subsequently found to effect this inhibition. Here we present data showing that ovaries from the sea urchin Paracentrotus lividus contain anandamide and two related acyl-ethanolamides, as well as enzymatic activities potentially responsible for their biosynthesis and degradation. Pilot experiments carried out with either ovaries or spermatozoa, extracted from both P. lividus and Arbacea lixula and radiolabelled with [14C]ethanolamine, showed that in sexually mature ovaries of both species significant levels of radioactivity were incorporated into a lipid component with the same chromatographic behaviour as anandamide. Lipid extracts from P. lividus ovaries were purified and analysed by gas chromatography/mass spectrometry which showed the presence of low but measurable amounts of anandamide, palmitoyl- and stearoyl-ethanolamides. The extracts were also found to contain lipid components with the same chromatographic behaviour as the N-acyl-phosphatidyl-ethanolamines, the phospholipid precursors of acyl-ethanolamides in mammalian tissues, and capable of releasing anandamide, palmitoyl- and stearoyl-ethanolamides upon digestion with S. chromofuscus phospholipase D. Accordingly, whole homogenates from P. lividus contained an enzymatic activity capable of converting synthetic [3H]N-arachidonoyl-phosphatidyl-ethanolamine into [3H]anandamide. Finally, mature ovaries of P. lividus were shown also to contain an amidohydrolase activity which catalyses the hydrolysis of anandamide and palmitoyl-ethanolamide to ethanolamine. This enzyme displayed subcellular distribution, pH/temperature dependency profiles and sensitivity to inhibitors similar but not identical to those of the previously described `anandamide amidohydrolase' from mammalian tissues. These data support the hypothesis, formulated in previous studies, that anandamide or related metabolites may be oocyte-derived cannabimimetic regulators of sea urchin fertility. © 1997 Elsevier Science B.V. All rights reserved.
Article
We have investigated the inhibition of lipopolysaccharide stimulated nitric oxide production in RAW264.7 macrophages by the cannabinoids and the putative cannabinoid CB2-like receptor ligand, palmitoylethanolamide. (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate ((+)-WIN55212) and, to a lesser extent (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexan-1-ol (CP55940), significantly inhibited lipopolysaccharide stimulated nitric oxide production. The level of inhibition was found to be dependent on the concentration of lipopolysaccharide used to induce nitric oxide production. Palmitoylethanolamide significantly inhibited nitric oxide production induced by lipopolysaccharide. The inhibition of nitric oxide production by (+)-WIN55212 but not palmitoylethanolamide was significantly attenuated in the presence of the cannabinoid CB2 receptor antagonist, N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528). (+)-WIN55212 produced a pertussis toxin-sensitive parallel rightward shift in the log concentration–response curve for lipopolysaccharide, causing a fivefold increase in the EC50 value for lipopolysaccharide with no change in the Emax value. (−)-WIN55212 had no effect on the log concentration–response curve for lipopolysaccharide. Palmitoylethanolamide did not produce a rightward shift in the lipopolysaccharide concentration–response curve. However, it did produce a pertussis toxin-insensitive reduction in the Emax value. The results suggest that the inhibition of lipopolysaccharide mediated nitric oxide release by (+)-WIN55212 in murine macrophages is mediated by cannabinoid CB2 receptors. In contrast, the inhibition by palmitoylethanolamide does not appear to be mediated by cannabinoid receptors.
Article
The effect of Δ8-THC on experimental autoimmune encephalomyelitis (EAE) was examined. Δ8-THC is an analogue of Δ9-THC, the psychoactive component of marihuana. It is more stable and less psychotropic than Δ9-THC and like the latter it binds to the brain cannabinoid receptor. Two strains of rats were incolulated for EAE, and Δ8-THC (40 mg/kg) was administered for up to 21 days. Δ8-THC significantly reduced the incidence and severity of neurological deficit in both rat strains. The beneficial influence of Δ8-THC only occured on oral administration and not with parenteral injection. Serum corticosterone levels were twofold elevated in rats with EAE chronically treate with Δ8-THC. These results suggest that suppression of EAE cannabinoids may be related to their effect on corticosterone secretion.