Article

Experimental cannabidiol treatment reduces early pancreatic inflammation in type 1 diabetes

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Abstract

Background: Destruction of the insulin-producing beta cells in type 1 diabetes (T1D) is induced by invasion of immune cells causing pancreatic inflammation. Cannabidiol (CBD), a phytocannabinoid, derived from the plant, Cannabis sativa, was shown to lower the incidence of diabetes in non-obese diabetic (NOD) mice, an animal model of spontaneous T1D development. Objective: The goal of this study was to investigate the impact of experimental CBD treatment on early pancreatic inflammation in T1D by intravital microscopy (IVM) in NOD mice. Methods: Seven-week-old female NOD mice were prophylactically administered daily 5 mg/kg CBD or control vehicle i.p. five times weekly for ten weeks. Animals underwent IVM following confirmation of T1D diagnosis by blood glucose testing. Leukocyte activation and functional capillary density (FCD) were quantified via IVM. Results: CBD-treated NOD mice developed T1D later and showed significantly reduced leukocyte activation and increased FCD in the pancreatic microcirculation. Conclusions: Experimental CBD treatment reduced markers of inflammation in the microcirculation of the pancreas studied by intravital microscopy.

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... We observed that CBD-treated animals developed T1D later than control-treated subjects (Figure 6.2). CBD administration was also able to significantly reduce leukocyte rolling and adhesion, and improve functional capillary density (FCD) in pancreatic microvasculature, when compared to vehicle-treated control animals ( Figure 6.1A-C; Lehmann et al., 2016). Histological analysis of pancreatic tissues from control-vehicle ( Figure 6.3A) and CBD-treated (Figure 6.3B) female NOD mice as well as untreated female CD-1 control mice (Figure 6.3C) showed that CBD administration appears to maintain pancreatic beta cell and acinar cell functionality and density. ...
... .1, A-C) and delayed T1D onset in a mouse model of spontaneous T1D (female NOD mice;Figure 6.2;Lehmann et al., 2016). ...
Chapter
Sepsis represents a severe dysregulation of the immune system with organ dysfunction in response to infection. Despite a variable disease course, an initial hyper-inflammatory response is frequently followed by a state of immunosuppression. There are no sepsis therapies targeted to the immune dysregulation available to date, however, the role of the endocannabinoid system in immunomodulation suggests promise. Specifically, activation of the cannabinoid type 2 receptor (CB2R) has been shown to have anti-inflammatory action. This might suggest that activation of CB2R could improve sepsis outcomes by dampening the initial hyper-inflammatory immune state. Knockout of CB2R decreased survival in animal models of sepsis confirming the complexity in the interaction between CB2R and progression of sepsis. Other avenues of endocannabinoid system (ECS) modulation in sepsis may include blockade of cannabinoid type 1 receptor (CB1R), with anti-inflammatory and blood pressure stabilizing effects, as well as antagonism of the endocannabinoid-activated G-protein coupled receptor 55 (GPR55), which has anti-inflammatory actions.
... Regarding to diabetes, studies show that CBD may have beneficial effects in relation to the diabetic state per se, reducing the incidence of type 1 diabetes in mice and the early pancreatic inflammation in this type of diabetes [26][27][28]. Using the streptozotocin-induced diabetes animal model, our group recently showed that acute treatment with CBD (at doses of 3 mg/kg; i.p.) exerted a significant reduction of mechanical allodynia, suggesting that CBD may be effective in the treatment of painful diabetic neuropathy (submitted data). ...
... This absence of effect may be due to the short time of treatment with the CBD. In that sense, it has been noticed that a more prolonged treatment with CBD has a protective effect on pancreatic cells, reducing the markers of inflammation in the microcirculation of pancreas from non-obese DBT mice [27] and the insulitis [26]. In addition, as already shown in previous studies, DBT animals present a reduction in locomotor activity (Tables 1 and 2 [7,61,62];) that was not altered by acute or sub-chronic treatment with CBD. ...
Article
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Depression associated with diabetes has been described as a highly debilitating comorbidity. Due to its complex and multifactorial mechanisms, the treatment of depression associated with diabetes represents a clinical challenge. Cannabidiol (CBD), the non-psychotomimetic compound derived from Cannabis sativa, has been pointed out as a promising compound for the treatment of several psychiatric disorders. Here, we evaluated the potential antidepressant-like effect of acute or sub-chronic treatment with CBD in diabetic rats using the modified forced swimming test (mFST). Also, to better understand the functionality of the endocannabinoid system in diabetic animals we also evaluated the effect of URB597, a fatty acid amide hydrolase inhibitor. Four weeks after the treatment with streptozotocin (60 mg/kg; i.p.; diabetic group-DBT) or citrate buffer (i.p.; normoglycemic group-NGL), DBT animals received an acute intraperitoneal injection of CBD (0, 0.3, 3, 10, 30 or 60 mg/Kg), 1 hour before the mFST, or URB597 (0, 0.1, 0.3 or 1 mg/Kg) 2 hours before the mFST. In another set of experiments, animals were sub-chronically treated with CBD (0, 0.3, 3, 30 or 60 mg/Kg i.p.), 24, 5 and 1 hour before the mFST or URB597 (0, 0.1, 0.3 or 1 mg/Kg i.p.) 24, 5 and 2 hours before the mFST. The NGL group was acutely treated with CBD (0, 30 mg/kg i.p.) or URB597 (0, 0.3 mg/kg; i.p.). Acute treatment with either CBD or URB induced an antidepressant-like effect in NGL rats, but not in DBT rats. However, sub-chronic treatment with CBD (only at a dose of 30 mg/kg), but not with URB597, induced a mild antidepressant-like effect in DBT animals. Neither body weight nor blood glucose levels were altered by treatments. Considering the importance of the endocannabinoid system to the mechanism of action of many antidepressant drugs, the mild antidepressant-like effect of the sub-chronic treatment with CBD, but not with URB597 does not invalidate the importance of deepening the studies involving the endocannabinoid system particularly in DBT animals.
... In this sense, the most abundant non-psychotomimetic compound found in the Cannabis sativa plant, the cannabidiol (CBD) has gained great prominence. This recognition is due to its potential therapeutic in several disorders such as anxiety, epilepsy, schizophrenia, chronic pain, depression and also diabetes (Booz 2011;Campos et al. 2012;Chaves et al. 2020;Crippa et al. 2011;de Gregorio et al. 2019;de Mello Schier et al. 2014;de Morais et al. 2016;Devinsky et al. 2014;Freitas et al. 2017;Gaetani et al. 2009;Gobbi et al. 2005;Hill et al. 2009;Horváth et al. 2012;Izzo et al. 2009;Lehmann et al. 2016;Lutz et al. 2015;Patel et al. 2017;Réus et al. 2011;Zhou et al. 2017;Zuardi et al. 2017). Studies show that CBD was able to reduce the incidence of DM1 in mice and early pancreatic inflammation in this type of diabetes, and may also delay the damage caused by diabetes in pancreatic-β cells (Di Marzo et al. 2011;Lehmann et al. 2016;Weiss et al. 2006). ...
... This recognition is due to its potential therapeutic in several disorders such as anxiety, epilepsy, schizophrenia, chronic pain, depression and also diabetes (Booz 2011;Campos et al. 2012;Chaves et al. 2020;Crippa et al. 2011;de Gregorio et al. 2019;de Mello Schier et al. 2014;de Morais et al. 2016;Devinsky et al. 2014;Freitas et al. 2017;Gaetani et al. 2009;Gobbi et al. 2005;Hill et al. 2009;Horváth et al. 2012;Izzo et al. 2009;Lehmann et al. 2016;Lutz et al. 2015;Patel et al. 2017;Réus et al. 2011;Zhou et al. 2017;Zuardi et al. 2017). Studies show that CBD was able to reduce the incidence of DM1 in mice and early pancreatic inflammation in this type of diabetes, and may also delay the damage caused by diabetes in pancreatic-β cells (Di Marzo et al. 2011;Lehmann et al. 2016;Weiss et al. 2006). The few studies conducted have shown that the treatment with CBD in diabetic animals was able to block the increased oxidative stress by reducing lipid peroxidation, increasing serotonergic neurotransmission, decreasing levels of tumor necrosis factor-α, vascular endothelial growth factor and intercellular adhesion molecule-1 and acting by reducing pro-inflammatory cytokines (Chaves et al. 2020;de Morais et al. 2018;El-Remessy et al. 2006). ...
Article
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Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists − 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.
... showed that CBD improved mitochondrial function and biogenesis in a myocardial injury model, which could also contribute to its beneficial properties observed in diabetes and other diabetic complications. Lehmann et al. [77] using the intravital microscopy showed that CBD treatment reduced early pancreatic inflammation in non-obese diabetic mice, an animal model of type-1 diabetes, i.e., the treatment reduced leukocyte activation and increased functional capillary density in the pancreatic microcirculation. Interestingly, in a randomized, doubleblind, placebo-controlled study, the CBD treatment in subjects with noninsulin-treated type 2 diabetes decreased resistin and increased glucose-dependent insulinotropic peptide, consequently decreasing insulin resistance and favoring the production of plasma insulin, respectively [79]. ...
... 33,58,77]. Hao et al.[78] ...
Article
The prevalence rates of depression and anxiety are at least two times higher in diabetic patients, increasing morbidity and mortality. Cannabidiol (CBD) has been identified as a therapeutic agent viable to treat diverse psychiatric disorders. Thus, this study aimed to investigate the effect of CBD treatment (once a day for 14 days starting two weeks after diabetes induction; at doses of 0, 3, 10 or 30 mg/kg, i.p.) on depression- and anxiety-like behaviors associated with experimental diabetes induced by streptozotocin (60 mg/kg; i.p.) in rats. Levels of plasma insulin, blood glucose, and weight gain were evaluated in all experimental groups, including a positive control group treated with imipramine. The rats were tested in the modified forced swimming test (mFST) and elevated plus maze (EPM) test. Besides, the levels of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in two emotion-related brain regions, the prefrontal cortex (PFC) and hippocampus (HIP) were evaluated using high-pressure liquid chromatography. Our results showed that CBD treatment (only at the higher dose of 30 mg/kg) reduced the exaggerated depressive- and anxiogenic-like behaviors of diabetic (DBT) rats, which may be associated with altered 5-HT, NA and/or DA levels observed in the PFC and HIP. Treatment with CBD (higher dose) also induced a significant increase in weight gain and the insulin levels (and consequently reduced glycemia) in DBT rats. The long-term CBD effects gave rise to novel therapeutic strategies to limit the physiological and neurobehavioral deficits in DBT rats. This approach provided evidence that CBD can be useful for treating psychiatry comorbidities in diabetic patients.
... Further research is required to establish if this effect can be maintained and/or enhanced by more prolonged CBD treatment. The current study supports the growing evidence that CBD may be beneficial against a number of problems associated with diabetes including inflammation (Weiss et al., 2006(Weiss et al., , 2008Lehmann et al., 2016), endothelial dysfunction (Rajesh et al., 2007), cardiomyopathy (Rajesh et al., 2010), retinal function (El-Remessy et al., 2006, and neuropathic pain (Toth et al., 2010). ...
Article
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Background and purpose: We have shown that in vitro treatment with cannabidiol (CBD, 2 h) enhances endothelial function in arteries from Zucker diabetic fatty (ZDF) rats, partly due to a cyclooxygenase (COX)-mediated mechanism. The aim of the present study was to determine whether treatment with CBD in vivo would also enhance endothelial function. Experimental approach: Male ZDF rats, or ZDF Lean rats, were treated for 7 days (daily i.p. injection) with either 10mg/kg CBD or vehicle (n = 6 per group). Sections of mesenteric resistance arteries, femoral arteries and thoracic aortae were mounted on a wire myograph, and cumulative concentration-response curves to endothelium-dependent (acetylcholine, ACh, 1 nM–100 μM) or endothelium-independent (sodium nitroprusside, SNP, 1 nM–100 μM) agents were constructed. Multiplex analysis was used to measure serum metabolic and cardiovascular biomarkers. Key results: Vasorelaxation to ACh was significantly enhanced in mesenteric arteries from CBD-treated ZDF rats, but not ZDF Lean rats. The enhanced vasorelaxation in ZDF mesenteric arteries was no longer observed after COX inhibition using indomethacin or nitric oxide (NO) inhibition using L-NAME. Increased levels of serum c-peptide, insulin and intracellular adhesion molecule-1 observed in the ZDF compared to ZDF Lean rats were no longer significant after 7 days CBD treatment. Conclusion and implications: Short-term in vivo treatment with CBD improves ex vivo endothelium-dependent vasorelaxation in mesenteric arteries from ZDF rats due to COX- or NO-mediated mechanisms, and leads to improvements in serum biomarkers.
... En effet, selon qu'ils soient administrés/actifs avant ou après le déclenchement de la PA, ils peuvent avoir un effet protecteur ou aggravant. Les mécanismes restent flous et impliquent soit l'innervation sensorielle, soit la pression artérielle viscérale voire les phénomènes inflammatoires médiés par les leucocytes voire la microcirculation pancréatique [18]. En parallèle de ces études pré-cliniques, il a bien été démontré à partir d'une étude clinique à large échelle (étude nationale américaine à partir de 37 712 PA post-CPRE, avec une prévalence Encadr e 2 Le profil de la pancréatite aiguë due au cannabis Patient de moins de 35 ans Prédominance masculine Aucun antécédent pancréatique personnel ou familial Consommation quotidienne de 2 à 3 grammes par jour depuis 3 à 10 ans Pas de consommation d'alcool Pancréatites aiguës bénignes Pancréatites récurrentes dans la moitié des cas Lésions de pancréatite chronique dans 10 % des cas Bilan étiologique exhaustif négatif en dehors du cannabis Le sevrage ou à défaut la diminution de 50 % de la consommation stoppe les récidives de pancréatite aiguë de 0,4 % de consommateurs de cannabis), que chez les consommateurs chronique de cannabis, le risque de PA post-CPRE était significativement augmenté sans augmentation de la morbimortalité [19]. ...
Article
Points essentiels La pancréatite aiguë secondaire à la consommation de cannabis seul pourrait représenter 2 à 3 % des étiologies. Le profil type est un homme jeune, avec une consommation journalière, ancienne et importante. Les pancréatites sont récurrentes dans la moitié des cas et à majorité bénignes. Le sevrage ou la diminution de 50 % de la dose journalière de cannabis stoppent les poussées de pancréatite. Il s’agit d’une nouvelle étiologie mais les mécanismes induisant la pancréatite aiguë sont encore méconnus.
... It is noteworthy that there is a growing interest in potential therapeutic effects of another cannabis constituent, cannabidiol (CBD), which is included in Sativex, a drug containing approximately equal parts of THC and CBD. Preclinical studies testing combinations of THC and CBD, as well as clinical studies using Sativex to demonstrate antiinflammatory (Lodzki et al, 2003;Malfait et al, 2000;Xiong et al, 2012) and antinociceptive effects (King et al, 2017;Langford et al, 2013;Lehmann et al, 2017;Serpell et al, 2014;Ward et al, 2014) are reported in the literature. However, as CBD does not bind cannabinoid receptors, this review will not discuss this phytocannabinoid at length. ...
Article
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A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (ie, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models. Emerging clinical studies show that ‘medicinal’ cannabis or cannabinoid-based medications relieve pain in human diseases, such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here, we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.
... Initially, it was considered to be devoid of biological activity, until a study by Nobel Laureate Julius Axelrod and his group discovered that both cannabidiol and THC were neuroprotective anti oxidants with a potency exceeding that of many known reference antioxidants 137 . Subsequently, a large number of preclinical studies demonstrated potent anti-inflammatory effects of cannabidiol in neuroinflammation, neurodegenetion, colitis, liver and kidney injury, primary diabetes [138][139][140] , and diabetic complications 134,141,142 . On the basis of in vitro assays, numerous mechanisms have been proposed to account for the anti-inflammatory and tissue-protective effects of cannabidiol, but these mechanisms have not been validated in vivo 134 . ...
Article
Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ9-tetrahydrocannabinol (THC), is an agonist of both CB1R and CB2R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.
... In line with these data, cooccurrence of Q63R polymorphism and immune-mediated disorders in chronic hepatitis C virus (HCV) infection was also observed (70), whereas the healthy CB2 variant was associated with more severe inflammation and hepatocellular necrosis, most probably because the intact CB2 could more efficiently inhibit antiviral T cell functions (71). Thus, the concepts to positively modulate eCB tone, to activate CB2 receptor and to administer certain pCBs has already been suggested in, e.g., RA, T1DM, autoimmune myocarditis, ulcerative colitis, Crohn's disease, etc. as well (63,(72)(73)(74)(75)(76)(77)(78)(79)(80)(81), but so far, the "cannabinoid-wise" best explored autoimmune disease is unambiguously the multiple sclerosis (MS). ...
Article
Full-text available
It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (−)-trans-Δ9-tetrahydrocannabinol (THC), (−)-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able to produce endogenous analogs of these substances [“endocannabinoids” (eCB), e.g., arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol (2-AG), etc.]. These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoid receptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS), a recently emerging regulator of several physiological processes. The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc. Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis) or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption. Thus, the objective of the current article is (i) to summarize the most recent findings of the field; (ii) to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii) to identify open questions and key challenges; and (iv) to suggest promising future directions for cannabinoid-based drug development.
... The results of several preclinical and clinical studies point to the pharmacological effects of CBD in psychiatric disorders and in the control of some pathophysiological effects, such as pain, anxiety, dysphoria, emesis, insomnia and inflammation (Lehmann et al., 2016;Parker, Rock, Sticht, Wills, & Limebeer, 2015;Welty, Luebke, & Gidal, 2014). Based on this evidence describing the pharmacological properties of CBD, public and political pressure for the legalization of the medical use of marijuana has been increasing recently in several countries. ...
Article
Children and adults with frequent and severe episodes of epilepsy that do not respond to standard treatments (such as carbamazepine, phenytoin and valproate) have long been prescribed cannabidiol (CBD) as an anticonvulsant drug. However, the safety of its chronic use in relation to reproduction has not been fully examined. This study aimed to assess the effects of chronic CBD exposure on the male reproductive system. CBD was orally administered to 21‐day‐old male Swiss mice at doses of 15 and 30 mg kg⁻¹ daily (CBD 15 and 30 groups, respectively), with a control group receiving sunflower oil, for 34 consecutive days. After a 35 day recovery period, the following parameters were evaluated: weight of reproductive organs, testosterone concentration, spermatogenesis, histomorphometry, daily sperm production and its morphology. The CBD 30 group had a 76% decrease in total circulating testosterone, but it remained within the physiological normal range (240–1100 ng dl⁻¹). CBD treatment induced a significant increase in the frequency of stages I–IV and V–VI of spermatogenesis, and a decrease in the frequency of stages VII–VIII and XII. A significant decrease in the number of Sertoli cells was observed only in the CBD 30 group. In both CBD groups the number of spermatozoa in the epididymis tail was reduced by 38%, sperm had head abnormalities, and cytoplasmic droplets were observed in the medial region of flagellum. These results indicated that chronic CBD exposure was associated with changes in the male reproductive system, suggesting its reproductive toxicity.
... The results of several preclinical and clinical studies point to the pharmacological effects of CBD in psychiatric disorders and in the control of some pathophysiological effects, such as pain, anxiety, dysphoria, emesis, insomnia and inflammation (Lehmann et al., 2016;Parker, Rock, Sticht, Wills, & Limebeer, 2015;Welty, Luebke, & Gidal, 2014). Based on this evidence describing the pharmacological properties of CBD, public and political pressure for the legalization of the medical use of marijuana has been increasing recently in several countries. ...
... The results of several preclinical and clinical studies point to the pharmacological effects of CBD in psychiatric disorders and in the control of some pathophysiological effects, such as pain, anxiety, dysphoria, emesis, insomnia and inflammation (Lehmann et al., 2016;Parker, Rock, Sticht, Wills, & Limebeer, 2015;Welty, Luebke, & Gidal, 2014). Based on this evidence describing the pharmacological properties of CBD, public and political pressure for the legalization of the medical use of marijuana has been increasing recently in several countries. ...
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Subsequent to the publication of the paper by Carvalho et al. (), it was noticed that the data on Table are the same with Table 2. The correct Table is given below: Sperm count and DSP on testis of 90-day-old Swiss mice orally treated for 34 days with 15 and 30 mg kg⁻¹ body weight of CBD 15 and CBD 30 groups, respectively, and control group (Table presented.) CBD, cannabidiol; DSP, daily sperm production. Values are mean ± standard deviation (P < 0.05). No significant differences using ANOVA.
... There is current interest in the medical use of cannabinoids (Fraguas-Sanchez and Torres-Suarez, 2018;Olah et al., 2017), including for immunosuppression in autoimmune disease (Katchan et al., 2016). In particular there have been suggestions for the use of cannabinoids in rheumatic disease (Katz-Talmor et al., 2018) and type 1 diabetes (Lehmann et al., 2016). In multiple sclerosis, cannabinoids are approved for the treatment of spasticity, but do not affect disease activity (Zajicek et al., 2005). ...
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Neurotransmitters and neurochemicals can act on lymphocytes by binding to receptors expressed by lymphocytes. This review describes lymphocyte expression of receptors for a selection of neurotransmitters and neurochemicals, the anatomical locations where lymphocytes can interact with neurotransmitters, and the effects of the neurotransmitters on lymphocyte function. Implications for health and disease are also discussed.
... Whereas D9-THC induced glucose tolerance in mice when chronically administered, CB1R blockade inhibited hyperglycemia and controlled obesity in mice [77]; this was also observed in cannabis users [78]. Finally, previous reports have shown that CBD administration ameliorates T1DM symptoms in nonobese diabetic (NOD) mice [79]. ...
Article
Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).
... These mice can spontaneously develop T1DM, with symptoms similar to those of T1DM in humans [28]. An intensifying inflammatory response is accompanied by progressive pancreatic necrosis, which greatly promotes the pathological progression of NOD mice to T1DM [29]. We used NOD mice as an experimental model to investigate the inhibitory effects of aplysin on pancreatic necrosis in this study. ...
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Aplysin is a brominated sesquiterpene with an isoprene skeleton and has biological activities. The purpose of this study is to investigate the inhibitory effect of aplysin on spontaneous pancreatic necrosis in nonobese diabetic (NOD) mice and its potential mechanisms. Results showed that NOD mice at 12 weeks of age showed obvious spontaneous pancreatic necrosis, damaged tight junctions of intestinal epithelia, and widened gaps in tight and adherens junctions. Aplysin intervention was able to alleviate spontaneous pancreatic necrosis in NOD mice, accompanied with decreased serum endotoxin levels and downregulated expressions of Toll-like receptor 4 and its related molecules MyD88, TRAF-6, NF-κB p65, TRIF, TRAM, and IRF-3, as well as protein levels of interleukin-1β and interferon-β in pancreatic tissues. In addition, we observed obvious improvements of intestinal mucosal barrier function and changes of gut microbiota in the relative abundance at the phylum level and the genus level in aplysin-treated mice compared with control mice. Together, these data suggested that aplysin could retard spontaneous pancreatic necrosis and inflammatory responses in NOD mice through the stabilization of intestinal barriers and regulation of gut microbial composition.
... CBD has suppressive effects on the immune system, including inflammatory response reduction, cellular and humoral immunity suppression, and induction of apoptosis in some lymphocytes; these effects are beneficial for treating inflammatory diseases [113,114]. Type 1 diabetes is an example of an inflammatory-based disease that can benefit from CBD preemptive treatment; non-obese diabetic mice receiving CBD had delayed development of diabetes, and had significantly lower activation of leukocytes than mice receiving control vehicle [115]. Zhou, Wang, Ji, Lou, and Fan [116] demonstrated anti-neuroinflammatory properties of hemp seed using an experimental mouse model. ...
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Industrial hemp (Cannabis sativa L., Cannabaceae) is an ancient cultivated plant originating from Central Asia and historically has been a multi-use crop valued for its fiber, food, and medicinal uses. Various oriental and Asian cultures kept records of its production and numerous uses. Due to the similarities between industrial hemp (fiber and grain) and the narcotic/medical type of Cannabis, the production of industrial hemp was prohibited in most countries, wiping out centuries of learning and genetic resources. In the past two decades, most countries have legalized industrial hemp production, prompting a significant amount of research on the health benefits of hemp and hemp products. Current research is yet to verify the various health claims of the numerous commercially available hemp products. Hence, this review aims to compile recent advances in the science of industrial hemp, with respect to its use as value-added functional food ingredients/nutraceuticals and health benefits, while also highlighting gaps in our current knowledge and avenues of future research on this high-value multi-use plant for the global food chain.
... J Cannabis Res (2021) 3:20 diabetes-prone mice (Weiss et al. 2008(Weiss et al. , 2006. In addition, limited studies reported CBD's ameliorative effects against diabetic complications including endothelial dysfunction (Stanley et al. 2013) and early pancreatic inflammation (Lehmann et al. 2016) in rodent diabetes models, as well as diabetic cardiomyopathy in primary human cardiomyocytes (Rajesh et al. 2010). However, to date, CBD's anti-diabetic mechanisms, such as the identification of its biochemical targets including enzymes, are not reported. ...
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Objective Cannabidiol (CBD) has been reported to have anti-diabetic effects in pre-clinical and clinical studies but its inhibitory effects on α -glucosidase, a carbohydrate hydrolyzing enzyme, remain unknown. Herein, we evaluated CBD’s inhibitory effects on α -glucosidase using in vitro assays and computational studies. Methods CBD’s inhibitory effect on α -glucosidase activity was evaluated in a yeast enzymatic assay and by molecular docking. The stability of CBD in simulated gastric and intestinal fluids was evaluated by high-performance liquid chromatography analyses. Results CBD, at 10, 19, 38, 76, 152, 304, 608, and 1216 μM, inhibited α -glucosidase activity with inhibition of 17.1, 20.4, 48.1, 56.6, 59.1, 63.7, 74.1, and 95.4%, respectively. Acarbose, the positive control, showed a comparable inhibitory activity (with 85.1% inhibition at 608 μM). CBD’s inhibitory effect on α -glucosidase was supported by molecular docking showing binding energy (-6.39 kcal/mol) and interactions between CBD and the α -glucosidase protein. CBD was stable in simulated gastric and intestinal fluids for two hours (maintained ≥ 90.0%). Conclusions CBD showed moderate inhibitory effect against yeast α -glucosidase activity and was stable in gastric and intestinal fluids. However, further studies on CBD’s anti- α -glucosidase effects using cellular and in vivo models are warranted to support its potential application for the management of type II diabetes mellitus.
... This hyperglycemic disorder may significantly benefit from preventive CBD therapy. Furthermore, non-obese hyperglycemic mammals administered with CBD exhibited a delayed onset of diabetes mellitus and substantially reduced leukocyte activation (Lehmann et al. 2016). ...
... For example, CBD has been reported to improve motor activity, 2 affect depression, 3 exhibit antitumorigenic activity in vitro and in vivo, 4 anti-inflammatory effects through reduction of pro-inflammatory cytokine synthesis, 5 ameliorate lipid and glycemic parameters in Type 2 Diabetes, 6 and to reduce markers of inflammation in pancreas microcirculation in a Type 1 Diabetes mice model. 7 An interesting study in humans showed that a single high dose of CBD decreased neuronal activity in limbic and paralimbic areas of the brain leading the investigators to conclude that CBD has anxiolytic effects. 8 These results were in accordance with a study 9 reporting that a similar high dose of CBD was optimally effective in inducing anxiolytic effects in a simulated public speaking test. ...
Article
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Cannabidiol (CBD) is the second most abundant component of the Cannabis plant and is known to have effects distinct from Δ9 -tetrahydrocannabinol (THC). Many studies that examined the behavioral effects of CBD concluded that it lacks the psychotomimetic effects attributed to THC. However, CBD was shown to have a broad spectrum of effects on several conditions such as anxiety, inflammation, neuropathic pain, and epilepsy. It is currently thought that CBD engages different targets and hence CBD's effects are thought to be due to multiple molecular mechanisms of action. A well-accepted set of targets include GPCRs and ion channels, with the serotonin 5-HT1A receptor and the transient receptor potential cation channel TRPV1 channel being the two main targets. CBD has also been thought to target G protein-coupled receptors (GPCRs) such as cannabinoid and opioid receptors. Other studies have suggested a role for additional GPCRs and ion channels as targets of CBD. Currently, the clinical efficacy of CBD is not completely understood. Evidence derived from randomized clinical trials, in vitro and in vivo models and real-world observations support the use of CBD as a drug treatment option for anxiety, neuropathy, and many other conditions. Hence an understanding of the current status of the field as it relates to the targets for CBD is of great interest so, in this review, we include findings from recent studies that highlight these main targets.
... This hyperglycemic disorder may significantly benefit from preventive CBD therapy. Furthermore, non-obese hyperglycemic mammals administered with CBD exhibited a delayed onset of diabetes mellitus and substantially reduced leukocyte activation (Lehmann et al. 2016). ...
Chapter
Bhanga (Cannabis) has been reported with numerous therapeutic, traditional, commercial, and sacred uses in India and across the globe. Its uses are deeply rooted in the cultural, social, and economic lives of the people. The inclusion of Cannabis under ‘Scheduled E1’ drugs in India restricts its use. However, being a crop of economic and medicinal importance, the pharmaceutical and various other sectors are showing much interest in the plant. The present review article delineates traditional, culinary, cosmetic, ritual, social, spiritual, recreational, economic, and therapeutic uses of Cannabis. The review illustrates various uses of Cannabis across the globe; noted from articles, publications, and books providing description of various parts, viz. leaves and seeds (Bhanga), flowering and fruiting tops (Ganja), resin (Charas), extract, tincture, and whole plant, stalks (Fibers). The review may be helpful to researchers, clinicians, and pharmaceutical companies to carry out further research for developing cost-effective healthcare options.
... Alcohol, cocaine, marijuana, and methamphetamine use have been linked to diabetic ketoacidosis (DKA), possibly due to insulin omission while using these substances versus a direct impact on insulin secretion and glucose metabolism (5)(6)(7)(8)(9). Additionally, very heavy alcohol consumption and smoking are well known risk factors for chronic pancreatitis, with alcohol, cocaine, and opioid use linked to presentations of acute pancreatitis and altered insulin secretion profiles (10)(11)(12)(13)(14). Studies have conflicted when evaluating the role of cannabis in pancreatic inflammation, beta cell function, and acute pancreatitis (15)(16)(17)(18)(19)(20)(21). Overall, it is not known whether substance use affects islet histopathology, including insulitis and insulin positivity; and the extent which substance use affects exocrine pancreatic histopathology in nPOD donors. ...
Article
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Access to human pancreas samples from organ donors has greatly advanced our understanding of type 1 diabetes pathogenesis; however, previous studies have shown that donors have a high rate of substance use, and its impact on pancreatic histopathology in this disease is not well described. One-hundred-thirty-one type 1 diabetes and 111 control organ donor pancreata from persons 12-89 years of age (mean 29.8 ± 15.5 years) within the Network for Pancreatic Organ donors with Diabetes (nPOD) were examined for insulin positivity, insulitis, amyloid staining, acute and chronic pancreatitis, and chronic exocrine changes (acinar atrophy, fibrosis, fatty infiltration, or periductal fibrosis); findings were compared by history of substance use. A secondary analysis compared exocrine pancreatic histopathologic findings in type 1 diabetes versus control organ donors regardless of substance use history. We observed a high but congruent rate of substance use in type 1 diabetes and control organ donors (66.4% and 64% respectively). Among donors with type 1 diabetes (but not controls), islet amyloid (OR 9.96 [1.22, 81.29]) and acute pancreatitis (OR 3.2 [1.06, 9.63]) were more common in alcohol users while chronic exocrine changes (OR 8.86 [1.13, 69.31]) were more common in cocaine users. Substance use impacted the pancreata of donors with type 1 diabetes more than controls. Overall, despite similar rates of substance use, acute pancreatitis (15.3% versus 4.5%, p=0.0061), chronic pancreatitis (29.8% versus 9.9%, p=0.0001), and chronic exocrine changes (73.3% versus 36.9%, p<0.0001) were more common in type 1 diabetes donors than controls. Alcohol and/or cocaine use in type 1 diabetes organ donors increases exocrine pancreas pathology and islet amyloid deposition but does not affect insulitis or insulin positivity. Exocrine pathology in type 1 diabetes donors is common, and further study of the pathophysiology of these changes is needed.
... There are other promising applications for CBD-like smoking cessation [15], drug withdrawal treatment [16], treating seizures and epilepsy [17], anxiety treatment [18], reducing some of the effects of Alzheimer's [19], and antipsychotic effects on patients with schizophrenia [20]. Future applications include combating type I diabetes [21] and cancer treatment [22,23]. Anecdotal evidence suggests that this is a promising and versatile treatment, although more research is needed. ...
Article
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Cannabis is currently the most consumed illicit substance in the world, and gradual legalization in the USA makes it important to understand the health consequences of the use of this substance. With growing body of evidence that some cannabis ingredients may be beneficial in various aspects of hemostasis, additional research is clearly needed in various clinical areas. In addition to understanding the efficacy, research efforts should also include studies that address any harmful effects of the compounds or administration methods that may result in adverse effects. This review is focused on the cardiometabolic effects of cannabis use. Cardiometabolic diseases are among the leading causes of death in the USA and around the world. The purpose of this review was to provide an overview of the known medicinal benefits of selected cannabis cannabinoids and the known side effects or contraindications. More importantly, we have proposed new questions and signposts in cannabis research to uncover additional medicinal benefits and identify the health hazards with focus on cardiovascular disease.
... CBD has been shown to reduce the inflammation in cultured human sebocytes and human skin organ culture through coupling to A2A adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of NF-κB signaling (Oláh et al., 2014). Moreover, the intervention of CBD delayed the onset of type 1 diabetes in non-obese diabetic mice and alleviated pancreas inflammation (Lehmann et al., 2016). It has also been shown that the administration of CBD targeted NF-κB and NLRP3 inflammasome pathways in macrophages, which could be a novel treatment for NASH (Mridha et al., 2017). ...
Article
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Alcohol abuse and high-fat diet–induced liver diseases have been the most prevalent chronic liver diseases and the leading reasons for liver transplantation around the world. Cannabidiol (CBD) is a botanical component extracted from marijuana plants without psychoactive impact. In our previous reports, we found that CBD can prevent fatty liver induced by Lieber–DeCarli ethanol diet or non-alcoholic fatty liver disease (NAFLD) induced by high-fat high-cholesterol diet. The current work is a further study on whether CBD can alleviate liver injuries induced by ethanol plus high-fat high-cholesterol diet (EHFD), which is a model simulating heavy alcohol drinkers in a Western diet. A mice liver injury model induced by EHFD for 8 weeks was applied to explore the protective properties of CBD and the underlying mechanisms. We found that CBD prevented liver steatosis and oxidative stress induced by EHFD. CBD treatment inhibited macrophage recruitment and suppressed activation of NFκB–NLRP3–pyroptosis pathway in mice livers. The hepatoprotective property of CBD in the current model might be a result of inhibition of inflammation via alleviating activation of the hepatic NFκB–NLRP3 inflammasome–pyroptosis pathway by CBD.
... 75,76 Moreover, Lehmann et al. used CBD as a prophylactic anti-inflammatory in NOD mice and observed a reduced activation of immune cells within the pancreatic microcirculation in the early stages of the disease that delayed the development of insulitis. 77 On the other hand, different studies have shown that 6-9-THC also has an antioxidant effect. In fact, in the streptozotocin-induced diabetic mouse model, 6-9-THC reduced not only the expression of proinflammatory cytokines (IL-1 and IL-6) but also diminished the levels of malondialdehyde (the final product of polyunsaturated fatty acids peroxidation) and increased the levels of nitric oxide (NO). ...
Article
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Introduction: Cannabinoids such as ▵-9-THC and CBD can downregulate the immune response by modulating the endocannabinoid system. This modulation is relevant for the treatment of prevalent autoimmune diseases (ADs), such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), diabetes mellitus type 1 (DMT1), and rheumatoid arthritis (RA). These conditions require new therapeutic options with fewer side effects for the control of the autoimmune response. Objective: to conduct a literature review of preclinical scientific evidence that supports further clinical investigations for the use of cannabinoids (natural or synthetic) as potential immunomodulators of the immune response in ADs. Methodology: A systematic search was carried out in different databases using different MeSH terms, such as Cannabis sativa L., cannabinoids, immunomodulation, and ADs. Initially, 677 journal articles were found. After filtering by publication date (from 2000 to 2020 for SLE, DMT1, and RA; and 2010 to 2020 for MS) and removing the duplicate items, 200 articles were selected and analyzed by title and summary associated with the use of cannabinoids as immunomodulatory treatment for those diseases. Results: Evidence of the immunomodulatory effect of cannabinoids in the diseases previously mentioned, but SLE that did not meet the search criteria, was summarized from 24 journal articles. CBD was found to be one of the main modulators of the immune response. This molecule decreased the number of Th1 and Th17 proinflammatory cells and the production of the proinflammatory cytokines, interleukin (IL)-1, IL-12, IL-17, interferon (IFN)-γ, and tumor necrosis factor alpha, in mouse models of MS and DMT1. Additionally, new synthetic cannabinoid-like molecules, with agonist or antagonist activity on CB1, CB2, TRPV1, PPAR-α, and PPAR-γ receptors, have shown anti-inflammatory properties in MS, DMT1, and RA. Conclusion: Data from experimental animal models of AD showed that natural and synthetic cannabinoids downregulate inflammatory responses mediated by immune cells responsible for AD chronicity and progression. Although synthetic cannabinoid-like molecules were evaluated in just two clinical trials, they corroborated the potential use of cannabinoids to treat some ADs. Notwithstanding, new cannabinoid-based approaches are required to provide alternative treatments to patients affected by the large group of ADs.
... Type 1 diabetes is often associated with neuropathic pain development. In a rodent diabetes type 1 model, CBD delayed disease development and exerted a beneficial effect on pancreatic microcirculation in tested animals (reduction in leukocyte activation and increased functional capillary density) and attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrosative stress, inflammation and cell death, while enhancing the ability of arteries to relax via enhanced production of vasodilator cyclooxygenase-1/2-derived products [50,76,77]. Intranasal and i.p. administration of CBD also attenuated neuropathic pain and inhibited elevation of microglial density and phosphorylated p38 mitogen-activated protein kinases [78]. ...
Article
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Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD’s mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD’s action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD’s action and future perspectives for research.
Chapter
Cannabis and its extracts have been used for its medicinal and recreational properties since antiquity, yet the dependence liability of this drug has only recently gained general acceptance. The systematic study of the biological systems underlying the effects of these drugs has contributed to a tremendous wealth of knowledge in understanding not only the molecular basis of the pharmacological effects of cannabis but also led to the identification of the endogenous cannabinoid system. In this chapter, we introduce this system, including the key cannabinoid receptors, endocannabinoids that bind and activate these receptors, and the biosynthetic and catabolic enzymes that regulate the endogenous ligands. We emphasize pharmacological strategies to target key components of the endogenous cannabinoid system that hold promise for treating cannabis use disorder.
Article
Introduction: The endocannabinoid system (ECS) is an endogenous regulatory system involved in a wide range of physiologic and disease processes. Study of ECS regulation provides novel drug targets for disease treatment. Intravital microscopy (IVM), a microscopy-based imaging method that allows the observation of cells and cell-cell interactions within various tissues and organs in vivo, has been utilized to study tissues and cells in their physiologic microenvironment. This article reviews the current state of the IVM techniques used in ECS-related inflammation research. Methodological Aspects of IVM: IVM with focus on conventional fluorescent microscope has been introduced in investigation of microcirculatory function and the behavior of individual circulating cells in an in vivo environment. Experimental setting, tissue protection under physiologic condition, and microscopical observation are described. Application of IVM in Experimental Inflammatory Disorders: Using IVM to investigate the effects of immune modulation by cannabinoids is extensively reviewed. The inflammatory disorders include sepsis, arthritis, diabetes, interstitial cystitis, and inflammatory conditions in the central nervous system and eyes. Conclusion: IVM is a critical tool in cannabinoid and immunology research. It has been applied to investigate the role of the ECS in physiologic and disease processes. This review demonstrates that the IVM technique provides a unique means in understanding ECS regulation on immune responses in diseases under their physical conditions, which could not be achieved by other methods.
Article
Objectives: Cannabis legalization has increased its use. The incidence of acute pancreatitis (AP) and severe acute pancreatitis (SAP) has also increased. In this study, data on pancreatitis were obtained from 2 states before and after cannabis legalization and compared with 2 states without legalized cannabis. Methods: Data were extracted from State Inpatient Databases from the states of Colorado and Washington before recreational cannabis legalization (2011) and after legalization (2015). Arizona and Florida were used as the nonlegalized cannabis states. Multivariable logistic regression models were fit for AP and SAP to determine a trend difference between legalized and nonlegalized cannabis states. Results: Cannabis use, AP, and SAP increased in all states. The increase in AP and SAP was not significantly different between the states that legalized cannabis use and those that did not. Legalized cannabis states had lower charges for AP and SAP and shorter length of hospitalizations. Conclusions: The trend of AP and SAP increased during the study period, but this was not correlated to cannabis use. Cannabis users had lower hospitalization costs and hospital stay. The effects of other confounders such as cannabis dose and delivery methods, alcohol, tobacco, and others need to be studied further as use increases.
Article
Cannabidiol (CBD) is one of the most abundant phytocannabinoids present in the plant Cannabis sativa (marijuana). There have been several studies of CBD in the last few decades, mainly focused on its neuroprotective properties, particularly after the identification of the endocannabinoid system and its participation in the central nervous system. On the other hand, the peripheral effects of CBD, particularly on reproductive physiology, were also evidenced. A narrative review was conducted using the PubMed database to identify studies that analyzed the pharmacological effects of CBD on the male reproductive system of vertebrates and invertebrates. Thirty-two citations (in vivo and in vitro) were identified. Among the vertebrates, the studies were carried out with men, monkeys, rats and mice. Studies with invertebrates are centered exclusively on the sea urchin. The CBD treatment periods include mostly acute and subacute evaluations. Exposure to CBD is associated with a reduction in mammalian testis size, the number of germ and Sertoli cells in spermatogenesis, fertilization rates, and plasma concentrations of hypothalamic, pituitary and gonadal hormones. Moreover, chronic doses of CBD have impaired sexual behavior in mice. From the studies identified in this review, it is possible to conclude that CBD has negative effects on the reproductive system of males. However, knowledge is still limited, and additional research is required to elucidate fully the mechanisms of action, as well as the reversibility of CBD effects on the reproductive system.
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Introduction: Cannabidiol (CBD) as Epidiolex® (GW Pharmaceuticals) was recently approved by the U.S. Food and Drug Administration (FDA) to treat rare forms of epilepsy in patients 2 years of age and older. Together with the increased societal acceptance of recreational cannabis and CBD oil for putative medical use in many states, the exposure to CBD is increasing, even though all of its biological effects are not understood. Once such example is the ability of CBD to be anti-inflammatory and immune suppressive, so the purpose of this review is to summarize effects and mechanisms of CBD in the immune system. It includes a consideration of reports identifying receptors through which CBD acts, since the "CBD receptor," if a single one exists, has not been definitively identified for the myriad immune system effects. The review then provides a summary of in vivo and in vitro effects in the immune system, in autoimmune models, with a focus on experimental autoimmune encephalomyelitis, and ends with identification of knowledge gaps. Conclusion: Overall, the data overwhelmingly support the notion that CBD is immune suppressive and that the mechanisms involve direct suppression of activation of various immune cell types, induction of apoptosis, and promotion of regulatory cells, which, in turn, control other immune cell targets.
Article
Cannabidiol (CBD), a compound obtained from Cannabis sativa, has wide range of therapeutic properties, including mitigation of diabetes and neurodegeneration. Cerebral ischemia and consequent learning disabilities are aggravated in elderly diabetic subjects. However, there are no studies showing the effect of CBD treatment in elderly diabetes patients suffering cerebral ischemia. The present work tested the hypothesis that CBD treatment improves metabolic dysfunctions in middle-aged diabetic rats submitted to chronic cerebral hypoperfusion. In this work, 350-day-old male Wistar streptozotocin-induced diabetic rats were used. To induce cerebral ischemia was used a chronic cerebral hypoperfusion (CCH), surgically, via the four-vessel occlusion/internal carotid artery (4-VO/ICA). Four diabetic groups were established: Non-CCH Treated Diabetic (DNT), CCH Treated Diabetic (DCT), Non-CCH Vehicle Diabetic (DNV), and CCH Vehicle Diabetic (DCV). Vehicle groups were not treated with CBD. The animals were treated during 30 days with 10 mg CBD/Kg bw/day. After treatment, the animals were euthanized, and blood levels of glucose, insulin, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides, fructosamine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were evaluated. DCT group presented reduction of hyperglycemia and an increase of insulinemia. Also was observed lower fructosamine, LDL, HDL, triglycerides and total cholesterol levels. AST and ALT concentration were reduced in CBD treated groups. CBD may be used as therapeutic tool to protect metabolism against injuries from diabetes aggravated by cerebral ischemia.
Article
Objectives: Tardive dyskinesia (TD) unlike acute dystonia may be irreversible. This study investigated the effects of oral cannabidiol (CBD) on haloperidol induced vacuous chewing movement (VCM) model of TD. Methods: There were six experimental groups with different combinations of oral cannabidiol with 5mg/kg of haloperidol given orally. Behavioural assays and FBS were measured. Vacuous chewing movements were assessed after the last dose of medication. Blood for oxidative stress assay was collected on the 8th day after the administration of the last dose of medication. Results: This study found that CBD co-administration with haloperidol attenuated the vacuous chewing movements and increased motor tone produced by haloperidol. CBD alone at 5 mg/kg appears to have anxiolytic properties but may not be as effective as haloperidol which exhibited a greater anxiolytic effect at 5 mg/kg. Treatment with CBD alone at 5mg/kg also appeared to enhance brain DPPH scavenging activity. Conclusions: We confirmed that CBD can ameliorate motor impairments produced by haloperidol. Our data suggest that CBD can be combined with haloperidol to prevent the emergent of extrapyramidal side effects and long-term movement disorders, such as acute dystonic disorder and tardive dyskinesia.
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Time-lapse fluorescence microscopy is one of the main tools used to image subcellular structures in living cells. Yet for decades it has been applied primarily to in vitro model systems. Thanks to the most recent advancements in intravital microscopy, this approach has finally been extended to live rodents. This represents a major breakthrough that will provide unprecedented new opportunities to study mammalian cell biology in vivo and has already provided new insight in the fields of neurobiology, immunology, and cancer biology.
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The phytocannabinoid cannabidiol (CBD) exhibits antioxidant and antiinflammatory properties. The present study was designed to explore its effects in a mouse model of sepsis-related encephalitis by intravenous administration of lipopolysaccharide (LPS). Vascular responses of pial vessels were analyzed by intravital microscopy and inflammatory parameters measured by qRT-PCR. CBD prevented LPS-induced arteriolar and venular vasodilation as well as leukocyte margination. In addition, CBD abolished LPS-induced increases in tumor necrosis factor-alpha and cyclooxygenase-2 expression as measured by quantitative real time PCR. The expression of the inducible-nitric oxide synthase was also reduced by CBD. Finally, preservation of Blood Brain Barrier integrity was also associated to the treatment with CBD. These data highlight the antiinflammatory and vascular-stabilizing effects of CBD in endotoxic shock and suggest a possible beneficial effect of this natural cannabinoid.
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Microcirculatory perfusion is disturbed in sepsis. Recent research has shown that maintaining systemic blood pressure is associated with inadequate perfusion of the microcirculation in sepsis. Microcirculatory perfusion is regulated by an intricate interplay of many neuroendocrine and paracrine pathways, which makes blood flow though this microvascular network a heterogeneous process. Owing to an increased microcirculatory resistance, a maldistribution of blood flow occurs with a decreased systemic vascular resistance due to shunting phenomena. Therapy in shock is aimed at the optimization of cardiac function, arterial hemoglobin saturation and tissue perfusion. This will mean the correction of hypovolemia and the restoration of an evenly distributed microcirculatory flow and adequate oxygen transport. A practical clinical score for the definition of shock is proposed and a novel technique for bedside visualization of the capillary network is discussed, including its possible implications for the treatment of septic shock patients with vasodilators to open the microcirculation.
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Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.
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The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.
Chapter
Type 1 diabetes (T1D) results from a chronic and selective destruction of insulin-secreting β-cells within the islets of Langerhans of the pancreas by autoreactive CD4+ and CD8+ T lymphocytes. The use of animal models of T1D was instrumental for deciphering the steps of the autoimmune process leading to T1D. The non-obese diabetic (NOD) mouse and the bio-breeding (BB) rat spontaneously develop the disease similar to the human pathology in terms of the immune responses triggering autoimmune diabetes and of the genetic and environmental factors influencing disease susceptibility. The generation of genetically modified models allowed refining our understanding of the etiology and the pathogenesis of the disease. In the present review, we provide an overview of the experimental models generated and used to gain knowledge on the molecular and cellular mechanisms underlying the breakdown of self-tolerance in T1D and the progression of the autoimmune response. Immunotherapeutic interventions designed in these animal models and translated into the clinical arena in T1D patients will also be discussed.
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Adequate monitoring of patients on intensive care units is of highest priority to provide optimal treatment and to detect patients at risk. Within recent years the microcirculation became more and more attention due to its central importance for the outcome of patients. Microcirculatory disorders may include capillary flow disturbances as well as changes in the density of perfused vessels. In the clinical setting, the most often used parameter to detect alterations in the microcirculation is serum lactate. Since this parameter is characterized by major limitations, other strategies including non-invasive methods to quantify microvascular perfusion have been developed. A successful surveillance of the microcirculation in the individual patient may guide diagnostic and treatment strategies in order to optimize organ perfusion and oxygenation, subsequently leading to an individualized therapy. Intravital microscopy has been used to stratify patients at risk and to predict patients' outcome. The aim of this review is to evaluate clinical correlates of microcirculatory disorders as well as giving an overview of newer diagnostic devices that may directly or indirectly evaluate the microcirculation and are available for use in critically ill patients.
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Studies over the past 35 years in the nonobese diabetic (NOD) mouse have shown that a number of agents can prevent or even reverse type 1 diabetes mellitus (T1DM); however, these successes have not been replicated in human clinical trials. Although some of these interventions have delayed disease onset or progression in subsets of participants, none have resulted in a complete cure. Even in the most robust responders, the treatments do not permanently preserve insulin secretion or stimulate the proliferation of β cells, as has been observed in mice. The shortfalls of translating NOD mouse studies into the clinic questions the value of using this model in preclinical studies. In this Perspectives, we suggest how immunological and genetic differences between NOD mice and humans might contribute to the differential outcomes and suggest ways in which the mouse model might be modified or applied as a tool to develop treatments and improve understanding of clinical trial outcomes.
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Although, diabetes is reaching pandemic proportions, the exact aetiology of either type 1 (T1D) or type 2 diabetes (T2D) remains to be determined. Mounting evidence, however, suggests that islet inflammation is a likely common denominator during early development of either type of the disease. In this review, we highlight some of the inflammatory mechanisms that appear to be shared between T1D and T2D, and we explore the utility of intravital imaging in the study of islet inflammation. Intravital imaging has emerged as an indispensable tool in biomedical research and a variety of in vivo imaging approaches have been developed to study pancreatic islet physiology and pathophysiology in the native environment in health and disease. However, given the scattered distribution of the islets of Langerhans within the ‘sea’ of the exocrine pancreas located deep within the body and the fact that the islets only constitute 1–2% of the total volume of pancreatic tissue, studying the pancreatic islet in situ has been challenging. Here, we focus on a new experimental approach that enables studying local islet inflammation with single‐cell resolution in the relevant context of the in vivo environment non‐invasively and longitudinally and, thereby improving our understanding of diabetes pathogenesis.
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Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly with regard to disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Technological improvements in insulin pumps and continuous glucose monitors help patients with type 1 diabetes manage the challenge of lifelong insulin administration. Agents that show promise for averting debilitating disease-associated complications have also been identified. However, despite broad organisational, intellectual, and fiscal investments, no means for preventing or curing type 1 diabetes exists, and, globally, the quality of diabetes management remains uneven. This Seminar discusses current progress in epidemiology, pathology, diagnosis, and treatment of type 1 diabetes, and prospects for an improved future for individuals with this disease.
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Until recently, the idea of observing life deep within the tissues of a living mouse, at a resolution sufficient to pick out cellular behaviors and molecular signals underlying them, remained a much-coveted dream. Now, a new era of intravital fluorescence microscopy has dawned. In this Primer, we review the technologies that made this revolution possible and demonstrate how intravital imaging is beginning to provide quantitative and dynamic insights into cell biology, immunology, tumor biology, and neurobiology.
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Challenges in EUS-guided FNA (EUS-FNA) include sampling error, nondiagnostic cytology, and limited on-site cytological evaluation. A prototype needle-based confocal laser endomicroscopy (nCLE) probe is a submillimeter probe that provides real-time imaging at the microscopic level through the FNA needle. To evaluate the feasibility of nCLE during EUS-FNA of pancreatic lesions. Feasibility study. Multicenter, tertiary care. Eighteen patients presenting for EUS-FNA. Patients were injected with 2.5 mL of 10% fluorescein. The lesion was interrogated with the nCLE probe positioned at the tip of a 19-gauge FNA needle. Device integrity, technical ease, safety, and image acquisition. Cases included 16 cysts and 2 masses. There were no device malfunctions. Technical challenges were encountered in 6 of 18 attempts to image and reflected challenges with a postloading technique, the longer ferule tip, and a transduodenal approach. Technical feasibility to perform imaging with nCLE during a pancreatic EUS-FNA procedure was achieved in 17 of 18 cases. Ten cases had good to very good image quality. Two serious adverse events occurred; both were pancreatitis requiring hospitalization. Limited sample size, small number of patients with confirmed pathological diagnosis, lack of coregistered pathology and images. nCLE in the pancreas is technically feasible via a 19-gauge needle under endosonographic guidance. Future studies will address identification of structures, diagnostic accuracy, and complication profiles. The rate of pancreatitis needs to be further clarified and mitigated.
Article
We have shown that the major active agent of Cannabis sativa, Delta(9)-tetrahydrocannabinol, activates peroxisome proliferator-activated receptor gamma [PPARgamma, O'Sullivan, S.E., Tarling, E.J., Bennett, A.J., Kendall, D.A., Randall, M.D., 2005c. Novel time-dependent vascular actions of delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem. Biophys. Res. Commun. 337, 824-831]. The aim of the present study was to investigate whether another pharmacologically active phytocannabinoid, cannabidiol, similarly activates PPARgamma. Functional vascular studies were carried out in rat aortae in vitro by myography. PPARgamma activation was investigated using reporter gene assays, a PPARgamma competition-binding assay and an adipogenesis assay. Cannabidiol caused time-dependent (over 2 h) vasorelaxation of pre-constricted aortae, sensitive to PPARgamma antagonism (GW9662, 1 microM) and super oxide dismutase inhibition. The vascular effects of cannabidiol were not affected by endothelial denudation, nitric oxide synthase inhibition, pertussis toxin, cannabinoid CB1 or cannabinoid CB2 receptor antagonism, or capsaicin pre-treatment. When aortae were contracted with U46619 in a Ca2+-free buffer, vasorelaxation to cannabidiol was substantially reduced. Furthermore, cannabidiol (1-30 microM) inhibited the contractile response to the re-introduction of Ca2+. In a reporter gene assay, cannabidiol increased the transcriptional activity of PPARgamma. Cannabidiol was also found to bind to PPARgamma and stimulate the differentiation of 3T3-L1 fibroblasts into adipocytes, a PPARgamma-mediated response. These results show that cannabidiol binds to and activates PPARgamma, which partially underlies the time-dependent vascular effects of cannabidiol. However, cannabidiol-induced vasorelaxation in the rat isolated aorta appears to be largely due to calcium channel inhibition.
Article
A single dose of cyclophosphamide (250 mg/kg) is known to synchronize and accelerate development of diabetes in non-obese diabetic mice. We have reported previously that cyclophosphamide treatment of 10-week-old female non-obese diabetic mice induces a shift from T-helper type 2 to T-helper type 1 activity in islet lesions. We now show that this shift in regulatory T-cell function is preceded by the expression of interleukin-12 in the islets as well as in the spleen. In the spleen macrophages were identified as the interleukin-12 expressing cell type. At the same time there was little induction of tumour necrosis factor alpha gene expression by macrophages. Since interleukin-12 is well known to drive T-helper cell type 1 responses we assume that interleukin-12 released by macrophages mediates the accelerating effect of cyclophosphamide on islet inflammation in non-obese diabetic mice. mRNA expression of the p40 chain of interleukin-12 in response to cyclophosphamide was not seen in macrophages of Balb/c mice and thus represents an immune abnormality of non-obese diabetic mice favouring T-helper type 1 reactions.
Article
Cannabidiol, the major non-psychoactive component of marijuana, has various pharmacological actions of clinical interest. It is reportedly effective as an anti-inflammatory and anti-arthritic in murine collagen-induced arthritis. The present study examined the anti-inflammatory and anti-hyperalgesic effects of cannabidiol, administered orally (5–40 mg/kg) once a day for 3 days after the onset of acute inflammation induced by intraplantar injection of 0.1 ml carrageenan (1% w/v in saline) in the rat. At the end of the treatment prostaglandin E2 (PGE2) was assayed in the plasma, and cyclooxygenase (COX) activity, production of nitric oxide (NO; nitrite/nitrate content), and of other oxygen-derived free radicals (malondialdehyde) in inflamed paw tissues. All these markers were significantly increased following carrageenan. Thermal hyperalgesia, induced by carrageenan and assessed by the plantar test, lasted 7 h. Cannabidiol had a time- and dose-dependent anti-hyperalgesic effect after a single injection. Edema following carrageenan peaked at 3 h and lasted 72 h; a single dose of cannabidiol reduced edema in a dose-dependent fashion and subsequent daily doses caused further time- and dose-related reductions. There were decreases in PGE2 plasma levels, tissue COX activity, production of oxygen-derived free radicals, and NO after three doses of cannabidiol. The effect on NO seemed to depend on a lower expression of the endothelial isoform of NO synthase. In conclusion, oral cannabidiol has a beneficial action on two symptoms of established inflammation: edema and hyperalgesia.
Article
We have previously reported that cannabidiol (CBD) lowers the incidence of diabetes in young non-obese diabetes-prone (NOD) female mice. In the present study we show that administration of CBD to 11-14 week old female NOD mice, which are either in a latent diabetes stage or with initial symptoms of diabetes, ameliorates the manifestations of the disease. Diabetes was diagnosed in only 32% of the mice in the CBD-treated group, compared to 86% and 100% in the emulsifier-treated and untreated groups, respectively. In addition, the level of the proinflammatory cytokine IL-12 produced by splenocytes was significantly reduced, whereas the level of the anti-inflammatory IL-10 was significantly elevated following CBD-treatment. Histological examination of the pancreata of CBD-treated mice revealed more intact islets than in the controls. Our data strengthen our previous assumption that CBD, known to be safe in man, can possibly be used as a therapeutic agent for treatment of type 1 diabetes.
  • R Mechoulam
  • M Peters
  • E Murillo-Rodriguez
  • L O Hanuš
R. Mechoulam, M. Peters, E. Murillo-Rodriguez and L.O. Hanuš, Cannabidiol -Recent advances. Vol. 4, Chemistry and Biodiversity. 2007; pp. 1678-1692.
  • M J Pittet
  • R Weissleder
M.J. Pittet and R. Weissleder, Intravital imaging, Cell 147(5) (2011), 983-991.