Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal Diverticulitis is defined as inflammation in the diverticulum (intestine), often resulting in hernia-like pockets or bulges in the intestine’s walls The use of hemp CBD oil for diverticulitis has been doing some rounds in the medical field today. We will try to understand the benefits of using cannabidiol as a daily supplement to reduce the effects of the ailment.
Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability
Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro.
Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL −1 ). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB1, CB2, TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids.
Δ 9 -Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB1 receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB1 antagonism. No role for the CB2 receptor was identified in these studies. Co-application of THC, cannabidiol or a CB1 antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation.
CONCLUSIONS AND IMPLICATIONS
These findings suggest that locally produced endocannabinoids, acting via CB1 receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation.
This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7
Keywords: intestinal permeability, inflammation, Caco-2 cells, cytokines, transepithelial electrical resistance (TEER), endocannabinoid, cannabinoid CB1 receptor, Δ 9 -tetrahydrocannabinol and cannabidiol
The pathogenesis of many intestinal disorders involves interactions between alterations in intestinal permeability and luminal exogenous agents, such as bacteria, toxins and foreign antigens, as well as secretory products of the mucosa itself, such as cytokines and growth factors (Madara and Pappenheimer, 1987; Hecht et al., 1992; Ma et al., 2004; Poritz et al., 2004). It is widely believed that the intestinal barrier becomes dysfunctional in certain disease states, potentially exposing the organism to lethal risk by permitting toxic material to enter the portal venous and lymphatic systems, and thus threaten the organism as a whole (Morehouse et al., 1986; Unno and Fink, 1998; Ammori et al., 1999). Inflammatory bowel disease (IBD) is accompanied by impaired epithelial barrier function in the small and large intestine (Gassler et al., 2001; Bruewer et al., 2006; Amasheh et al., 2009). This has two consequences; firstly contributing to diarrhoea by a leak flux mechanism, and secondly, perpetuating inflammation through increased luminal antigen and macromolecular uptake.
For many centuries, the plant Cannabis sativa has been used to treat various disorders of the gastrointestinal tract, such as vomiting, anorexia, abdominal pain, gastroenteritis, diarrhoea, intestinal inflammation and diabetic gastroparesis (Coutts and Izzo, 2004; Duncan et al., 2005; Sanger, 2007; Izzo and Camilleri, 2008). The presence of a functional endocannabinoid system has been identified in the gut. CB1 receptors are expressed in the gastrointestinal tract of many species, including rats, guinea-pigs and humans (Croci et al., 1998; Kulkarni-Narla and Brown, 2000; Coutts et al., 2002; Casu et al., 2003). Immunohistochemical studies indicate that the enteric nervous system is the main site of CB1 receptor expression and could be the main site of action for cannabinoids in the gastrointestinal tract (Coutts et al., 2002). In human colonic tissue, CB1 receptors are expressed in the epithelium, smooth muscle and the submucosal myenteric plexus (Wright et al., 2005). The CB2 receptor has been detected in rat peritoneal mast cells (Facci et al., 1995) and enteric neurons (Duncan et al., 2008). In human colonic tissue, CB2 is expressed in plasma cells and the lamina propria (Wright et al., 2005), and in the epithelium of colonic tissue characteristic of IBD (Wright et al., 2005; Izzo, 2007).
Recent studies have confirmed that the endocannabinoid system becomes activated during inflammatory conditions, both in animal models and in tissue samples from patients suffering from inflammatory disorders. In an experimental model of colitis, D’Argenio et al. found that the levels of the endogenously produced cannabinoids, anandamide (AEA), but not 2-arachidonylglycerol (2-AG), were significantly increased (D’Argenio et al., 2006). AEA levels are also increased in colon biopsies from patients with ulcerative colitis (D’Argenio et al., 2006), small bowel samples from patients with diverticular disease (Guagnini et al., 2006) and from individuals in the atrophic phase of coeliac disease (D’Argenio et al., 2007). During croton oil induced inflammation in murine small bowel, the expression of CB1 receptors and fatty acid amide hydrolase (FAAH), a membrane protein that metabolises AEA, are enhanced, and CB1 activation inhibits motility (Izzo et al., 2001). Colonic CB1 receptor expression has also been shown to be up-regulated in a murine colitis model, and genetic or pharmacological blockage of CB1 receptors worsens epithelial damage (Massa et al., 2004). However, pharmacological inhibition of the CB1 receptor has also been shown to inhibit ulcer formation and plasma TNF levels in an indomethacin-induced model of small intestinal inflammation (Croci et al., 2003). CB2 receptor expression is also increased in human intestinal epithelium in IBD (Wright et al., 2005; 2008). The role of CB2 receptors in inflammation is supported by the inhibition of TNFα-induced IL-8 release by CB2 receptor antagonists in human colonic epithelial cells (Ihenetu et al., 2003). CB2 receptor agonists have also been shown to offset LPS-induced inflammation in rats through COX-derived products (Mathison et al., 2004).
The ability to modulate intestinal permeability during the inflammatory process may be important in devising future therapeutic strategies to restore a ‘leaky’ tight junction paracellular barrier. Given the beneficial effects of cannabinoids in inflammatory conditions in the gut, and our recent findings that cannabinoids are capable of modulating intestinal permeability altered with EDTA (Alhamoruni et al., 2010), the aim of the present study was to determine whether cannabinoids modulate increased permeability associated with inflammation. To do this, carcinoma colon cell line (Caco-2) monolayers were used as an in vitro intestinal epithelial model system, and inflammatory conditions were mimicked by the co-application of the pro-inflammatory mediators IFNγ and TNFα. We found that endocannabinoids further worsen the increased permeability associated with cytokine application to Caco-2 cells, while phytocannabinoids or CB1 receptor antagonism speeded the recovery of permeability in inflammatory conditions. Inhibition of endocannabinoid degradation worsened the effects of inflammation on intestinal permeability, and inhibition of endocannabinoid synthesis ameliorated the increased permeability associated with inflammation. Our data suggest that locally produced endocannabinoids, acting via the CB1 receptor, play a role in mediating changes in permeability associated with inflammation.
The nomenclature for drugs and for their molecular targets conforms to BJP’s Guide to Receptors and Channels (Alexander et al., 2011).
Caco-2 cells (ECACC, Wiltshire, UK, passages 56–72) were cultured in Minimum Essential Medium Eagle supplemented with 10% fetal bovine serum, 1% L-glutamine and 1% penicillin/streptomycin. Cells were kept at 37°C in 5% CO2 and 95% humidity. Cells were grown in 12-well plates and seeded at 50 000 cells per insert on 12 mm diameter, 0.4 µm pore polycarbonate membrane inserts. Cells were grown for a minimum of 14 days and used for experimentation between days 14 and 21, when each insert had a transepithelial electrical resistance (TEER) value greater than 1000 Ω cm 2 .
The TEER measurement was used to evaluate the paracellular permeability of cell monolayers (Madara et al., 1988). The TEER of the monolayer was determined using an EVOM™ voltohmmeter (World Precision Instruments, Sarasota, FL, USA) according to the methods of Wells and colleagues (Wells et al., 1998).
Initial TEER readings were made before the addition of 10 ng·mL −1 IFNγ (basolateral compartment). After 8 h, TEER was measured again, and 10 ng·mL −1 TNFα was added for another 16 h. TEER was measured again after a total of 24 h incubation with the cytokines, which caused an average fall in TEER of 20–25%, representing increased epithelial permeability.
Intestinal permeability to fluorescein isothiocyanate (FITC)-dextran molecular mass 4 kDa (FD4), a tracer for the paracellular pathway, was evaluated by measuring the flux of FD4 across cell monolayers. Cannabinoids [cannabidiol (CBD, 1 µM), AM251 (100 nM) and methandamide, mAEA 100 Nm] were applied apically either concomitant with the cytokines (0 h) or following the inflammatory protocol (24 h), for a further 6 h. Cell layers (30 h) were then washed with HBSS/20 mM HEPES (pH 7.4) and left for 30 min at 37°C to equilibrate. FD4 (3 mg·mL −1 ) was applied apically and 100 µL aliquots were collected from the basolateral side of each insert after 30 min and 1 h. FD4 levels in the medium were measured using a fluorescence microplate reader at an excitation wavelength of 490 nm and emission wavelength of 520 nm (VICTOR, Perkin Elmer, USA). FD4 flux was calculated as the average fluorescence value of two samples taken from the same well, and expressed as a percentage of the FD4 permeability of vehicle control monolayers in the same experiment.
Cell viability (MTS) and membane integrity (lactate dehydrogenase release) assays
To show that the effect of cytokine application was not due to cellular damage and changes in transcellular permeability, we performed MTS (Promega, Madison, WI, USA) and lactate dehydrogenase (LDH) assays (Bio Vision, CA, USA), according to the manufacturer’s instructions, on Caco-2 treated with 10 ng·mL −1 IFNγ and 10 ng·mL −1 TNFα for up to 72 h.
Effects of cannabinoids on Caco-2 cell monolayer integrity (apical application)
Fresh medium, with or without cannabinoids [Δ 9 -tetrahydrocannabinol (THC), CBD, AEA or 2-AG (all 10 µM)], was applied apically to plates where inflammation had been established (i.e. after 24 h). Vehicle (0.1% ethanol) was applied to control wells. TEER values were measured every 1 h for the next 8 h, and then again 48 and 72 h after cannabinoid administration. Our initial experiments showed that a single dose of THC or CBD (10 µM) ameliorated the fall in TEER caused by cytokines, while a single dose of AEA or 2-AG (10 µM) worsened this (see Figure 1 ). Therefore, we proceeded to perform concentration–response curves to THC, CBD, AEA and 2-AG by adding increasing concentrations of each drug to inserts. TEER values were monitored at all time points as described above.
The effects of phytocannabinoids (THC and CBD, 10 µM, A) and endocannabinoids (AEA and 2-AG, 10 µM, C) applied apically on the fall in TEER values caused by the inflammatory cytokines (IFNγ and TNFα, 10 ng·mL −1 ). Integrated response over time (area under curve) to THC and CBD (C) and AEA and 2-AG (D) on the fall in TEER values caused by the inflammatory cytokines. Data are given as means with error bars representing SEM. (n= 3, *P < 0.05, **P < 0.01, ***P < 0.001, anova ).
In some experiments, 10 µM of either THC or CBD was applied at the apical compartment at 0 h (i.e. at the same time as the cytokines) or 48 h after cytokine application. TEER values were measured as above.
Target sites of action of cannabinoids
The following antagonists were co-applied with cannabinoids (24 h after inflammation was established); AM251 (CB1 receptor antagonist), AM630 (CB2 receptor antagonist), capsazepine (TRPV1 antagonist), GW9662 (PPARγ antagonist), GW6471 (PPARα antagonist) and O-1918 (proposed cannabinoid receptor antagonist). All antagonists were used at 1 µM except AM251, which was used at 100 nM (see Alhamoruni et al., 2010) and appropriate vehicles were applied to control inserts. TEER values were measured as above.
In some experiments, 100 nM of either AM251 or AM630 was applied at the apical compartment at 0 h (i.e. at the same time as the cytokines) or 24 h after cytokine application (when increased permeability was induced). TEER values for each group were monitored over time.
Effects of cannabinoids on Caco-2 cell monolayer permeability (basolateral application)
Fresh medium, with or without cannabinoids (THC, CBD, AEA or 2-AG, all 10 µM), was applied basolaterally to plates where inflammation had been established.
Effects of enzyme inhibitors on increased permeability induced by cytokines
To establish the role of the FAAH enzyme on the AEA effect on intestinal permeability, AEA (10 µM) was applied to the apical side of inserts in the absence or presence of an FAAH inhibitor 24 h after inflammation was established (URB597, 1 µM). Similarly, 2-AG (10 µM) was applied to the apical side of inserts either alone or together with a monoacylglycerol lipase (MGL) inhibitor (JZL 184, 1 µM). In both experiments, the vehicle [ethanol and dimethyl sulfoxide (DMSO)] was applied to control wells. TEER values were measured hourly for the next 8 h, and then again at 48, and 72 h after cannabinoid administration.
In some experiments, 1 µM of URB597 or JZL 184, alone or together with CB1 antagonist AM251 (100 nM), were applied at the apical compartment at the same time as the cytokines.
Orlistat (1 µM), a 2-AG synthesis inhibitor, alone or together with CB1 antagonist (AM251, 100 nM) was applied at the apical compartment at the same time as cytokine application.
Chemicals and reagents
All chemicals were purchased from Sigma-Aldrich (Poole, UK) unless otherwise stated. IFNγ and TNFα were purchased from Invitrogen (Paisley, UK), and further dilutions in BSA stored at −80°C for IFNγ and −20°C for TNFα. All cannabinoids and antagonists were purchased from Tocris Bioscience (Bristol, UK) except THC and capsazepine, which were obtained from Sigma UK. CBD, THC, capsazepine, AEA and 2-AG were dissolved in ethanol to a stock concentration of 10 mM with further dilutions made in distilled water. GW9662, AM251 and AM630 were dissolved in DMSO to 10 mM, with further dilutions made in distilled water. URB597, JZL 184 and Orlistat were dissolved in DMSO to 10 mM, with further dilutions made in fresh media.
In each protocol, values are expressed as mean ± SEM. Area under the curve (AUC) values were calculated using GraphPad Prism 5 software using the trapezoidal method. Data were compared, as appropriate, by Student’s t-test or by anova with statistical significance between manipulations and controls determined by Dunnett’s post hoc test.
Cytokines increased permeability without affecting cell viability or membrane integrity
Combined application of IFNγ and TNFα (10 ng·mL −1 ) in Caco-2 cells caused a reversible decrease in TEER (i.e. increased permeability) over the 72 h measurement period. Application of IFNγ and TNFα to Caco-2 cells did not affect the Caco-2 cell mitochondrial activity at any point over the 72 h experimental period compared with the vehicle group, as indicated by the MTS assay (OD at 72 h; vehicle 0.54 ± 0.03, cytokine application, 0.52 ± 0.01, n= 4). The total LDH release from Caco-2 cells treated with cytokines was also not significantly different to vehicle at any point over the 72 h experimental period (OD at 72 h; vehicle 0.22 ± 0.01, cytokine application, 0.11 ± 0.01, n= 4).
Apical application of phytocannabinoids recovers cytokine-induced increased permeability
Twenty-four hours after exposure to IFNγ and TNFα, apical application of either THC or CBD (10 µM) accelerated the recovery of TEER values (see Figure 1A ), and the total response over time (AUC) was significantly different to vehicle controls for both THC and CBD (P < 0.01, Figure 1B ). Further experiments showed that the ability of THC and CBD to speed the recovery of TEER values after 24 h cytokine application was concentration-dependent (see Figure 2 and Table 1 ). When a sigmoidal concentration–response curve was plotted with the AUC data presented in Table 1 , the logEC50 of THC and CBD were −6.03 and −5.68, respectively.
Concentration–response curves to THC (A), CBD (B), AEA (C) and 2-AG (D) applied apically on the fall in TEER caused by cytokine application. Data are given as means with error bars representing SEM. (n= 3, *P < 0.05, **P < 0.01, ***P < 0.001, anova ).
Area under the curve values (%·min −1 ) for the concentration–responses to cannabinoids on TEER
|Vehicle||1062 ± 96||1327 ± 210||1330 ± 162||1018 ± 72|
|100 nM||1097 ± 113||1192 ± 92||1258 ± 41||1059 ± 45|
|300 nM||868 ± 67||1134 ± 81||1353 ± 73||985 ± 57|
|1 µM||726 ± 168||843 ± 40 *||1663 ± 132||1224 ± 81|
|3 µM||519 ± 130 **||665 ± 177 **||1671 ± 76||1265 ± 86|
|10 µM||315 ± 20 ***||336 ± 14 ***||1763 ± 84 *||1622 ± 103 **|
|30 µM||226 ± 12 ***||263 ± 49 ***||2519 ± 65 ***||2694 ± 129 ***|
Data are given as means with error bars representing SEM. Significant difference between vehicle and drug responses,
Apical application of endocannabinoids further increases permeability after cytokine application
Twenty-four hours after exposure to IFNγ and TNFα, apical application of endocannabinoids (10 µM of either AEA or 2-AG) caused a further and sustained drop in TEER in addition to the effects of cytokines (P < 0.05, Figure 1C and D ). Further experiments showed that this effect was concentration-dependent (see Figure 2 and Table 1 ). When a sigmoidal concentration–response curve was plotted with the AUC data presented in Table 1 , the logEC50 of AEA and 2-AG were −3.95 and −3.78, respectively.
The effects of both phytocannabinoids and endocannabinoids are CB1 mediated
The effects of THC and CBD were only significantly inhibited by the cannabinoid CB1 receptor antagonist, AM251. Similarly, the effects of the endocannabinoids AEA and 2-AG were also only sensitive to AM251 ( Figure 3 and Table 2 ).
The effects of various receptor antagonists on the effects of THC (10 µM, A), CBD (10 µM, B), AEA (10 µM, C) and 2-AG (10 µM, D) applied apically on the fall in TEER caused by cytokine application. Data are given as means with error bars representing SEM. (n= 3, *P < 0.05, **P < 0.01, ***P < 0.001, anova ).
Area under the curve values (%·min −1 ) for the effects of cannabinoids on TEER in the presence of various receptor antagonists
|Vehicle||1442 ± 334||1386 ± 247||1232 ± 47||1100 ± 34|
|Cannabinoid (10 µM)||531 ± 85 **||555.5 ± 62 ***||1886 ± 62 **||1561 ± 71 **|
|& AM251||1152 ± 157||1351 ± 30||1112 ± 17||1137 ± 121|
|& AM630||513 ± 50 **||519 ± 4 ***||1787 ± 77 **||1627 ± 61 **|
|& GW9662||477 ± 69 ***||531 ± 4 ***||1834 ± 121 **||1591 ± 28 **|
|& GW6471||519 ± 50 **||586 ± 5 **||1772 ± 163 **||1591 ± 57 **|
|& Capsazepine||499 ± 25 **||579 ± 55 ***||1784 ± 156 **||1528 ± 60 **|
|& O-1918||491 ± 39 **||547 ± 28 ***||1749 ± 71 *||1538 ± 134 **|
Data are presented as means with error bars representing SEM. Significant difference between vehicle and drug responses,
Basolateral application of cannabinoids and permeability after cytokine application
When applied to the basolateral membrane after cytokine application, neither THC, CBD, AEA or 2-AG had any significant effect on TEER (data not shown).
Phytocannabinoids prevented increased permeability associated with cytokine application
When inserts were treated with cytokines (basolateral) and THC or CBD (apical) at the same time (0 h), THC and CBD (10 µM) completely inhibited the fall in TEER caused by the cytokines (see Figure 4A ). However, when THC or CBD were applied 48 h after cytokine application, they had no effect on the response to these cytokines ( Figure 4B ).
The effect of phytocannabinoids (THC and CBD, 10 µM) applied apically at time 0 h (A), or after 48 h (B) on the fall in TEER caused by cytokine application. Data are given as means with error bars representing SEM. (n= 3, *P < 0.01, ***P < 0.001, anova ).
CB1 antagonism reduces the increased permeability associated with cytokines
To determine whether the effect of cytokines can be prevented by cannabinoid receptor antagonism, AM251 or AM630 (both 100 nM, apical application) were added at the same time as cytokine application (0 h) or after cytokine-induced increases in TEER were induced (24 h). When applied at time 0, AM251 significantly reduced the fall in TEER caused by cytokines. However, when AM251 was applied after 24 h, there was no effect of this compound ( Figure 5A ). AM630 did not affect TEER values when co-applied with cytokines, or when applied after inflammation was induced ( Figure 5B ), indicating no role for CB2 receptor activation.
The effects of the CB1 receptor antagonist, AM251 (100 nM, A) on TEER applied apically at the same time as (0 h), or 24 h after cytokine application. The effects of the CB2 receptor antagonist, AM630 (100 nM, B) on TEER applied at the same time as (0 h), or 24 h after cytokine application. Data are given as means with error bars representing SEM. (n= 3, *P < 0.05, **P < 0.01, anova ).
FAAH and MGL inhibition worsened endocannabinoids effects on increased permeability after cytokine application
URB597 alone caused no significant change in the recovery of TEER compared with the vehicle (see Figure 6A and B ). As previously shown, AEA alone caused a significant drop in TEER in addition to the effects of cytokines compared with vehicle. However, application of URB597 together with AEA caused a significantly greater drop in TEER than AEA alone (Bonferroni’s multiple comparison test, Figure 6A and B ). JZL 184 alone also caused no significant change in the recovery of TEER compared with vehicle. 2-AG alone caused a significant decrease in TEER as compared with vehicle group, and application of JZL 184 with 2-AG caused a significantly greater drop in TEER than 2-AG alone ( Figure 6C and D ).
The effect of the FAAH inhibitor URB597 (1 µM, A) and MGL inhibitor JZL 184 (1 µM, C) applied apically alone, or in combination with AEA or 2-AG on the fall in TEER values caused by inflammatory cytokines. (B, D) Integrated response over time (area under curve). Data are given as means with error bars representing SEM. (n= 3, *P < 0.05, **P < 0.01, ***P < 0.001, compared with vehicle group; ## P < 0.01, ### P < 0.001, compared with endocannabinoid alone, anova ).
To test the hypothesis that locally produced AEA and 2-AG partly mediates the increase in permeability caused by cytokines, and whether these effects, if any, are mediated by CB1 receptors, URB597 or JZL 184 (1 µM each) were applied apically at the same time as cytokine application either alone or with AM251 (100 nM). When applied at the same time as cytokines, URB597 alone caused a further drop in TEER (i.e. increased permeability) than cytokine application alone, and this effect was inhibited by AM251 ( Figure 7A and B ). Similarly, JZL 184 application led to a decrease in TEER, and this effect was also inhibited by AM251 ( Figure 7C and D ).
The effect of endocannabinoid enzyme inhibitors (URB597, 1 µM, A; JZL 184, 1 µM, C; Orlistat, 1 µM, E) applied apically at the same time as cytokines, either alone or together with the CB1 antagonist AM251 (100 nM) on the fall in TEER values caused by inflammatory cytokines. (B, D and F) Integrated response over time (area under curve). Data are given as means with error bars representing SEM. (n= 3, *P < 0.05, **P < 0.01, ***P < 0.001, compared with vehicle group; ## P < 0.01, ### P < 0.001, compared with inhibitors alone, anova ).
To further investigate the possible role of locally produced 2-AG on the TEER reduction caused by cytokines, Orlistat (1 µM), a 2-AG synthesis inhibitor was applied either alone or together with AM251 (100 nM). It was observed that Orlistat inhibited the drop in TEER caused by cytokines as compared with vehicle group ( Figure 7E and F ). This was not further affected by AM251.
FD4 flux was increased by cytokines and modulated by cannabinoids
To support our TEER data, we performed key experiments to measure the functional outcome of junctional change, that is, paracellular permeability, by using FITC-conjugated dextran (FD4) as a tracer. Cytokine application [interferon gamma and TNF alpha (IT)] induced an increase of 22 ± 4% in permeability to FD4 when compared with basal flux ( Figure 8A ). CBD both reversed (IT + CBD) and prevented (CBD + IT) this increase, as previously observed in the TEER experiments. As before, the CB1 antagonist AM251 (100 nM) blocked the CBD effect on cytokine-induced FD4 flux.
The effect of cannabinoids on cytokine-induced FD4 flux. (A) CBD (1 µM) or mAEA (100 nM) was applied apically at time zero together with the cytokines (IFNγ and TNFα, 100 ng·mL −1 ) or after 24 h of cytokine application (basal application). AM251 (100 nM) was applied apically with CBD or mAEA after 24 h cytokine application. (B) AM251 or AM630 (both at 100 nM) were applied apically either with cytokines at time zero or after 24 h of cytokine application. Data are given as means with error bars representing SEM. (n= 3, ***P < 0.001, as compared with vehicle group; ## P < 0.01, ### P < 0.001, as compared with cytokine-treated group, anova ).
In addition, reflecting the AEA effect on cytokine-induced TEER changes, mAEA (100 nM) further enhanced the increased permeability to FD4 to 35.2 ± 3.1% (an enhancement of approximately 12%), which was also blocked by AM251.
AM251 (100 nM) was able to both partially inhibit and prevent the cytokine-induced increase in FD4 flux, whereas the CB2 receptor antagonist/inverse agonist, AM630, had no effect (see Figure 8B ), again in support of the previous TEER data.
Cannabinoids have been used to treat various disorders of the gastrointestinal tract, such as vomiting, anorexia, abdominal pain, gastroenteritis, diarrhoea, intestinal inflammation and diabetic gastroparesis (Coutts and Izzo, 2004,Duncan et al., 2005; Sanger, 2007; Izzo and Camilleri, 2008). Many of these digestive disorders are associated with acute or chronic inflammatory processes, and with alterations in intestinal permeability. Our data show that cannabinoids have the ability to both positively and negatively modulate permeability through the CB1 receptor. Specifically, endocannabinoids seem to be involved in the increase in permeability associated with the development of inflammation, while phytocannabinoids can inhibit or restore increased permeability after cytokine application.
In our model, basolateral application of 10 ng·mL −1 IFNγ and TNFα led to increased permeability in confluent Caco-2 monolayers, as reflected by a fall in TEER of around 20%. In our study, the effect of cytokines was reversible, as TEER values normalized after washing. Furthermore, LDH levels in media after Caco-2 monolayers were treated with IFNγ and TNFα for 3 days were comparable to those within a non-treated control group. Cell proliferation was also not negatively affected by cytokine application in our study. This indicates that the effect of cytokine application on TEER was not due to cellular damage and changes in transcellular permeability.
Our first main finding was that during inflammatory conditions, the phytocannabinoids THC and CBD both enhanced TEER recovery over time in a concentration-dependent fashion. Cannabinoids have previously been shown to reverse increases in permeability in other models. For example, in a co-culture of endothelial cells and astrocytes, CP55940 and ACEA, both synthetic CB1 receptor agonists, inhibited HIV-1-induced or substance P-induced decreases in epithelial permeability (Lu et al., 2008). Rajesh et al. (2007) also found that CBD attenuates the effects of high glucose-associated increased cellular permeability in human coronary endothelial cells. Furthermore, CBD treatment has been shown to significantly reduce vascular hyperpermeability in the diabetic retina (El-Remessy et al., 2006), improve type I diabetes-induced cardiac dysfunction and inflammation (Rajesh et al., 2010a) and attenuates TNFα signalling, inflammation and kidney dysfunction in a nephropathy model (Pan et al., 2009).
We found that the effects of THC and CBD in reversing the increase in permeability were sensitive to antagonism of the CB1 receptor, but not the CB2 receptor. We also examined a number of other potential sites of action at which cannabinoids are known to act, such as TRPV1 (see Di Marzo and De Petrocellis, 2010) and the PPAR nuclear receptors (see O’Sullivan, 2007), but did not find any contribution from these target sites. Our TEER data were supported by FD4 flux data, demonstrating that CBD reversed increase flux associated with cytokines, and that this was inhibited by a CB1 receptor antagonist. The effect of THC and CBD on permeability is in agreement with our previous study showing phytocannabinoid-mediated changes in intestinal epithelial permeability and tight junction protein expression were brought about through activation of the CB1 receptor (Alhamoruni et al., 2010). It should be noted that received wisdom is that CBD is a poor/ineffective agonist at CB1 receptors (Pertwee, 2008). However, Capasso et al. (2008) and de Filippis et al. (2008) have similarly both shown that the effects of CBD in inhibiting hypermotility in mice were sensitive to CB1 antagonism, which might suggest that CBD agonizes CB1 in the gut. However, another explanation for the effects of CBD in the present study could be that CBD is antagonizing CB1-mediated increases in permeability mediated by locally produced endocannabinoids.
Our data suggest that there may be a therapeutic role for THC or CBD in reversing abnormally increased permeability associated with intestinal inflammation. A prophylactic role was also suggested by our finding that applying THC or CBD at the same time as cytokines completely abolished their deleterious effects on permeability. Similarly, CBD could prevent the increased flux of FD4 if applied at the same time as cytokines. However, if applied 48 h after inflammation was established, the positive effects of phytocannabinoids were no longer observed, suggesting there is a therapeutic window for the use of these compounds in reversing increased permeability. However, this may be different in vivo, as the inflammatory insult may not be reversible as was the case in our current experiments.
Our second main finding was that the endocannabinoids AEA and 2-AG further increased Caco-2 permeability in addition to the effects of the cytokines, and that this effect was concentration-dependent and mediated by the CB1 receptor. This is in agreement with our previous work showing that endocannabinoid application to Caco-2 cells was associated with increased permeability (Alhamoruni et al., 2010). In another cell model, Wang and colleagues have also demonstrated that mAEA (a non-hydrolysable analogue of AEA) increased paracellular permeability in alveolar cells (Wang et al., 2003). We similarly showed in the present study that mAEA further increases the flux of FD4 in addition to the effects of cytokines, and that this effect is mediated by the CB1 receptor.
Several studies have demonstrated increased AEA levels in biopsies from untreated ulcerative colitis patients (D’Argenio et al., 2006), coeliac disease (D’Argenio et al., 2007) and diverticular disease (Guagnini et al., 2006). 2-AG also has been found to be elevated in samples from patients with active coeliac disease, with direct correlations observed between endocannabinoids levels and the most active disease manifestations (D’Argenio et al., 2007). It is therefore possible that overproduction of endocannabinoids plays a role in increased gut permeability in these conditions. We performed a series of experiments examining the potential role of the endocannabinoid system in changes in permeability associated with inflammation. In the first experiment, we showed that a CB1 receptor antagonist (but not a CB2 receptor antagonist) was able to limit the fall in TEER associated with cytokines, and that a CB1 receptor antagonist (but not a CB2 receptor antagonist) limited the increased FD4 flux associated with inflammatory conditions. This suggests that CB1 activation at least partially underlies increased permeability, and we have previously shown that both AEA and 2-AG change the expression of certain tight junction proteins via CB1 activation (Alhamoruni et al., 2010). In an experimental model of diabetic nephropathy in mice, CB1 receptors were found to be overexpressed within the glomeruli, and i.p. injection of AM251 for 14 weeks was found to ameliorate albuminuria by a restoration of the glomeruli junction complex (Barutta et al., 2010). Furthermore, in the small intestine, CB1 receptor antagonism has been shown to inhibit ulcer formation and plasma TNF levels in an indomethacin-induced model of small intestinal inflammation (Croci et al., 2003). CB1 activation is increasingly being shown to be pro-inflammatory in several conditions, including nephropathy (see Mukhopadhyay et al., 2010) and in endothelial and cardiac dysfunction (Rajesh et al., 2010b), supporting our suggestion that endocannabinoid-mediated activation of the CB1 receptor may play a role in mediating the effects of inflammation in our Caco-2 cell model.
In further experiments, we showed that inhibition of the enzymes that degrade either AEA or 2-AG in combination with AEA and 2-AG application caused a very large and irreversible increase in permeability (within our time frame), in addition to the effects of cytokines. More importantly, we also found that application of these enzyme inhibitors alone at the same time as cytokine application worsened the effect cytokines on cell permeability, and this could be antagonized by a CB1 receptor antagonist. This suggests that endocannabinoids may be produced by intestinal epithelial cells during inflammation, and that their activation of the CB1 receptor contributes to tight junction disruption and thus increased permeability. Interesting, the FAAH and MGL inhibitors only worsened the fall in permeability when they were applied at the same time as cytokines ( Figure 7 ), and not when applied after inflammation had been established ( Figure 8 ). This suggests that it is in the development of inflammation that endocannabinoid production may play a role in modulating permeability. It is of note that enhanced tissue inflammation has been observed in FAAH knockout mice in models of inflammation and tissue damage in the liver and cardiac tissue (Siegmund et al., 2006; Mukhopadhyay et al., 2011), again supporting our theory that under pathological conditions, endocannabinoid activation of CB1-dependent mechanisms may contribute to injury in inflammation.
Finally, we found that inhibiting 2-AG synthesis significantly reduced the increased permeability associated with cytokines, demonstrating a role for the local production of 2-AG during inflammation. Unfortunately, no commercially available inhibitor of AEA synthesis exists, so we were unable to test whether a similar reduction might be observed. However, taken together, our data strongly suggest that local release of endocannabinoids, acting via the CB1 receptor, and potentially via changes in tight junction proteins (Alhamoruni et al., 2010) underlie the changes in intestinal epithelial permeability associated with inflammation.
Finally, we did not find that basolateral application of either phytocannabinoids or endocannabinoids influenced the changes in permeability after cytokine application. These findings may reflect differential expression of target sites of action for cannabinoids across epithelial cells in inflammatory conditions, and indicate that it is the apical (luminal) membrane that it is more important in the regulation of permeability in these circumstances. In the light of our findings regarding the potential role for endocannabinoid release during inflammation causing changes in permeability, it also suggests that it is endocannabinoid production at the luminal membrane that may play a role.
In conclusion, our study demonstrates for the first time that cannabinoids are capable of modulating intestinal permeability in an in vitro model of inflammation. In particular, endocannabinoids caused further increases in Caco-2 cell permeability, whereas phytocannabinoids restored increased permeability induced by cytokines. The effects of cytokines on increased permeability were inhibited by a CB1 receptor antagonist and a 2-AG synthesis inhibitor, and were enhanced by inhibitors of the degradation of AEA or 2-AG, suggesting that local production of endocannabinoids activating CB1 may play a role in the modulation of gut permeability during inflammation. Our study also suggests that cannabis-based medicines may possess therapeutic benefit in inflammatory intestinal disorders associated with abnormal intestinal permeability.
We would like to thank the technical support of Mrs Averil Warren and Mr Andrew Lee.
Can CBD Help Diverticulitis Symptoms? A Guide to CBD & Diverticulitis
How Might Diverticulosis Symptoms be Prevented? Diverticulitis is defined as inflammation in the diverticulum (intestine), often resulting in hernia-like pockets or bulges in the intestine’s walls. This can cause serious health complications, depending on the level of severity one experiences, making diverticulitis a chronic and challenging disorder to live with. As all of us get older, our immune system becomes weaker, and a healthy lifestyle is harder to maintain. Surprising as it may sound, CBD may have great potential to supplement symptoms of diverticulitis. A myriad of research shows that along with potential analgesic properties, CBD may possibly help those suffering from symptoms of bowel inflammation, loss of appetite, and nausea. Scientists have already discovered that our body has the endocannabinoid system (ECS), which maintains our overall well-being. This system may be the key to targeting such severe disorders as diverticulitis.
Diverticulosis vs. Diverticulitis
Diverticulosis, or diverticular disease, is a pathological process in the colon in which multiple diverticula (saccular protrusions) form in the wall of the intestine. Diverticula can range in size, from being as small as a pea to much larger. Diverticula are formed due to increased gas, waste, or liquid pressure on weakened areas of the intestinal wall. Besides, diverticula can form during straining during bowel movements, such as constipation. Most often, diverticula form in the lower part of the colon (known as the sigmoid colon).
Alphagreen 10% cbd oil – only £30
Comes with 30 day money back guarantee
Diverticulosis usually does not cause any symptoms, and is usually only diagnosed after one is scanned for a different medical reason. Some people may experience abdominal discomfort or cramps; however, this disease has a tendency to progress fast. It is essential to see the differences between diverticulosis, diverticulitis, and diverticular disease:
- Diverticulosis occurs when you experience no symptoms, but still have diverticula in your intestinal walls.
- Diverticulitis (which we will be focusing on today) occurs when diverticula are infected or inflamed, causing severe health symptoms.
- Diverticular disease is something of a middle ground, where one has symptoms caused by diverticula in the intestines, however they are not inflamed or infected.
Diverticulitis is an inflammatory process that occurs against the background of an infection in one or more diverticula. Typically, diverticulitis develops when stool accumulates in the same area as diverticula,where bacteria multiplies and causes infection.
Diverticulosis in general is fairly common, affecting 10% of people over 40 and 50% of those over 60. Doctors believe that the risk of diverticulosis rises with age, and may reach almost 100% in people over 80, making it more common amongst the elderly.
Possible reasons and Risk factors
The possible causes of diverticulitis are poorly understood, and may vary from person to person. It has long been thought that diverticulitis develops when a small hole ( known as micro or macro perforation) occurs in the diverticulum, leading to the release of intestinal bacteria that cause inflammation. However, new evidence may suggest that in some patients, acute diverticulitis is more inflammatory than infection-based. Many attribute their diverticulitis symptoms to other factors, like:
. For the intestines to work correctly, a person needs to consume a sufficient amount of dietary fiber, as this helps your body produce softer stools that are easier to pass. On the contrary, harder stools put more pressure on the colon as it moves the stool down, leading to weak spots in the muscle wall that allow diverticula to develop.
- Complications set against a background of intestinal infections. The risk of a problem arising in the face of weakened immunity (caused by infection) is incredibly high.
- Decreased muscle tone and deterioration of peristalsis – as a rule, this happens alongside many age-related changes, then colon diverticulitis manifests itself.
- Dysbiosis, which also entails a general decrease in immunity.
- Worms or other similar intestinal parasites. The mucous membrane of gut cells is damaged by the parasites- and because of this, diverticulitis of the sigmoid colon begins.
- Genetics is also thought to be a significant factor.
Many of the factors causing intestinal diverticulitis can be avoided if you lead a healthy lifestyle and regularly monitor your condition. For example, people who sit a lot, barely move, and have weak muscles are at high risk for diverticulitis. In contrast, developed abdominal muscles help the intestines to function properly.
Anyone who does not keep themselves well-hydrated is also at risk – without enough moisture, the intestine contents become too dense, damaging its walls. Those who do not follow basic hygiene rules and poorly monitor their health in general are also in danger.
While diverticulosis doesn’t generally come with symptoms you’ll notice in daily life, diverticulitis is caused by an infection or inflammation within your intestine. As such, you may notice these symptoms of diverticulitis:
- Pain in the lower abdomen. It may feel like a biting pinprick, and bother only a specific place. It can hurt for several days before fading and then starting anew. The sensation usually increases with sharp muscle contractions, such as during laughter, coughing, or physical activity.
- Increased painful sensations after a bowel movement, which may include feeling pressure.
- Stool disorders – intestinal diverticulitis may manifest itself as constipation and/or diarrhea.
- The presence of blood in the feces- usually, the bleeding is not very abundant, and is observed in only a tenth of patients.
- A fever and chills. When it comes to diverticulitis, symptoms of this nature are rare, but they are also possible.
- Lack of appetite – not wanting to eat, or not wanting to eat as much as usual.
- Nausea, vomiting, and general weakness of the body – these signs of diverticulitis may seem very similar to food poisoning symptoms.
Methods of diverticulitis treatment depend on the severity of the patient’s condition. Sometimes, antibiotics and pain medications are prescribed, but in some cases diverticulitis patients may need surgery in addition to dietary changes. To potentially help symptoms of diverticulitis, many turn towards CBD supplements as a natural, no-side effects dietary additive.
How Might Diverticulosis Symptoms be Prevented?
The most important thing when it comes to preventing diverticulosis (or even reducing its possible complications) is doing your best to ensure regular bowel movements- in other words, get rid of any constant constipation. As part of the proper maintenance of regular bowel movements, it is recommended that you:
- Do exercise that engages the abdominal muscles.
- Eat an adequate amount of dietary fiber- roughly 30 grams per day, according to the NHS. Foods rich in fiber include whole-grain bread, cereals, and crackers, berries, fruits, vegetables (broccoli, cabbage, spinach, carrots, asparagus, zucchini, beans), brown rice, bran, peas, and beans. Foods high in fiber help prevent constipation and may even provide other health benefits. It lowers blood pressure, blood cholesterol levels, and may reduce the risk of developing certain intestinal disorders.
- Drink a sufficient amount of liquid (at least eight glasses a day).
- Achieve adequate hours of sleep and rest.
The Endocannabinoid System and Gut Inflammation
You may wonder what CBD has to do with our inner body processes like digestion and inflammation, and the answer is simple. Our body has a unique Endocannabinoid system that produces endocannabinoids (cannabinoids made by the body and not the cannabis plant), known as anandamide and 2-arachidonoyl glycerol (2-AG). Generally, this system is a crucial part of our body which controls many inner processes like homeostasis, appetite control, pain perception, sleep cycle, mood, and even immune response.
The importance of the Endocannabinoid system can not be overstated as it plays a vital role in many of our most vital systems. As was mentioned above, our endocannabinoids interact with specific cannabinoid receptors- CB1 and CB2. As both of these receptors are present all over the body (CB2 in immune cells and CB1 mainly in the brain, CNS, and in the nerves connecting your gut to your brain), they can be valuable in both pain and inflammation management, making CBD a potential supplement for diverticulitis. Interestingly, CB1 receptor activation may reduce gastrointestinal (GI) inflammation in various animal models.
So, what roles might the ECS play in the work of the gastrointestinal tract? It turns out, quite a few:
- Regulation of stomach acid
- Visceral sensation (ability to perceive body organs)
- Satiety and the feeling of being full
- GI tract motility (ability to move food automatically)
- Pain perception
- Inflammation processes, such immune responses to bacteria invasion, worms, erosions, or chronic diseases
This 10% CBD Oil from Alphagreen is designed to be placed beneath the tongue for maximum absorption and maximum soothing results.
SPICE UP YOUR SEX LIFE – Foria’s Awaken Arousal Oil supports female sexual wellness by enhancing pleasure, easing discomfort and increasing sensitivity.
Brace yourself for a fantastic experience with this 40% CBD Oil from Naturecan. This product will allow you to enjoy your daily CBD dose in a fast and convenient way.
GREAT FLAVOUR, REAL EFFECTS: Zen Bear’s gummies offer a delicious way to consume CBD with no gimmicks. Pop a couple a day and see the effects in no time!
Arima’s High Strength Pure CBD Oil is a high-quality formula made by blending Cannabis Sativa L extract with organic olive oil to create a fantastic cannabidiol experience.
Spirited Euphoria by Edi is the world’s first non-alcoholic distilled spirit crafted from natural hemp and 280mg of THC-free CBD isolate.
CBD Brothers Blue Edition Oil Sativa is a high-quality CBD product containing full-spectrum CBD diluted in organic hemp seed oil.
Raw CBD Oil 30mg CBD/ml (medium) represents a full-spectrum formula with 300mg of CBD+CBDa per bottle.
Foria’s Intimacy Sex Oil is a lube that makes sex better, providing you and your partner with the all-natural moisture to soothe, arouse, and exhilarate your sex life.
10% CBD Oil from Purity Hemp Company is a mid-strength broad-spectrum CBD oil that can be used to restabilise your health and wellbeing.
This CBD Oil – 750mg by Green Roads is a health supplement that is a fantastic way to support your daily wellness routine.
The Potential of CBD for Diverticulitis Symptoms
Cannabidiol (CBD) is a non-psychoactive chemical compound, one of over one hundred cannabinoids found in hemp and cannabis plants. CBD is a major phytocannabinoid and can be as high as 40% in plant extracts. However, many people when it comes to CBD products due to the “high” effect produced by recreational cannabis. Such a psychoactive effect is not caused by CBD, but by another phytocannabinoid known as tetrahydrocannabinol, or THC. Instead, CBD may supplement certain unwanted symptoms of diverticulitis. There are three main ways CBD for diverticulitis may supplement symptoms of the condition.
Unfortunately, there are few studies on the direct correlation between CBD’s possible effects on diverticulitis. However, CBD has already shown a potential capacity for reducing symptoms of pain. Studies by Ethan B Russo et al. from 2008 present a great review on various cannabis-derived drugs, which may include CBD as an active ingredient. The FDA approved an Investigational New Drug application to conduct advanced clinical trials for cancer symptom-related pain in January 2006. In general, it seems CBD’s potential pain-relieving properties have been well-tolerated in trials with few noticeable side effects.
Several studies by Massa and Monory 2006 published in the British Journal of Pharmacology demonstrated a vital role the ECS may play in intestinal pain when it comes to irritable bowel syndrome (IBS) through its perceived control on various pain-related systems.
In 2011, animal studies by Linda A Parker showed that CBD may have an antiemetic effect (meaning it may prevent symptoms like from feeling nauseous). CBD may interact with CB1 receptors and 5-HT3 (serotonin receptors) in the dorsal vagal complex (DVC) (located in the muscles beneath the diaphragm), which mediates vomiting symptoms. In this study, based on animal models, anandamide and the endogenous cannabinoids like CBD were thought to have possible effects on the 5-HT3 receptors in the DVC, providing a mechanism through which symptoms of nausea may be controlled.
Digestive Inflammation Reduction
Findings from a 2012 laboratory study by A Alhamoruni suggest that certain endocannabinoids, acting via CB1 receptors, may play a role in mediating changes in inflammation, as well as implying that certain phytocannabinoids may have therapeutic potential for symptoms associated with inflammation.
Another study by Francesca Borrelli et al.,2009, published in the Journal of Molecular Medicine, showed in mice tests that oral CBD administration could reduce IL-1beta and IL-10 levels, which are the primary immune response agents to inflammation in the body. In certain cells, CBD purportedly reduced signs of inflammation. Another experiment on mouse models by Ester Pagano implied that CBD may have potential when it comes to mucosal inflammation and hypermotility in intestinal inflammation.
Forms of CBD
Hundreds of CBD companies offer various ways to consume CBD oil and other products. Some of them may be more effective in addressing diverticulitis, but ultimately, the best way to consume CBD depends on what feels best for you. Let’s see what the different ways of taking CBD are:
CBD Oils and Tinctures
Using tinctures is probably the most prevalent way of intaking CBD. Who hasn’t heard of a classic CBD oil? This type of CBD is administered sublingually (placed under the tongue), stays there for up to a minute, and is then swallowed. Since some of the CBD may be absorbed by the sublingual gland, the compound may find its way to the bloodstream fairly immediately. Usually, any potential effects are perceived after around 20 minutes, and may last up to 6 hours.
CBD Edibles and Capsules
You can also ingest CBD orally, in the form of CBD infused gummies, snacks, sweets, drinks, capsules, and other edibles. This is probably the most straightforward and familiar method for most people, but it takes longer for the potential effects to occur. This is due to the fact that the CBD must pass through the digestive system, where some of the compound may be degraded before it can be properly absorbed by the body.
Vaping CBD is another favourite option. You can put CBD in a portable vaporizer, which heats the compound to a temperature required for vaporization. When you inhale the vapor, CBD may enter the bloodstream fairly instantaneously. As a result, using a CBD vape may be the best way to take CBD for people who want instant possible results. However, the potential effect isn’t as long-lasting when compared to the above forms of CBD.
How to Choose the Best CBD Product
Another critical factor to consider is the actual concentration of CBD in the product. Besides various shapes and tastes of CBD, it is essential to understand that there are also several types of CBD on the market:
CBD Isolate is CBD in its purest form. The extraction process removes or filters out all plant compounds except cannabidiol, removing terpenes, flavonoids, plant parts, chlorophyll, organic matter, and other cannabinoids. CBD isolate can be used to make CBD oils, cosmetics, vape liquids, and even be added to food. Of course, it’s THC-free, which is a major benefit for many people. CBD isolate is commonly used by people who want to reduce symptoms of anxiety and inflammatory processes with a natural antioxidant.
Full-spectrum CBD. This extract is passed, purified, and decarbonized to remove foreign impurities from the compound, but maintains all the original plant cannabinoids (including trace amounts of THC). That gives a synergistic ‘entourage’ effect of potentially enhancing therapeutic actions and effects on the human body. Depending on the raw material, it can have a different cannabinoid profile- but will certainly include cannabinoids like CBGA, CBDA, CBV, CBG, CBC, CBN, CBD and THC in different percentages. Many of these cannabinoids may be beneficial to the body and potentially provide various therapeutic effects. Of course, the THC level is fairly negligible (no more than 0.2%), and you are not likely to receive any psychoactive effects from the compound. However, some drug tests can show the presence of THC in the body even in trace amounts, which can be undesirable. In this case, it is worth looking at other extracts with lower or zero levels of THC.
Broad-spectrum CBD may be an excellent in-between, having almost all of the original plant cannabinoids present in the final product- without the THC.
Important things to remember
If you are a CBD newbie, there are few basic rules you should know before purchasing the product:
- Always shop from reputable CBD brands– One of the easiest ways of ensuring you purchase good quality CBD products is by purchasing your CBD products from reputable suppliers. Responsible brands guarantee you are buying CBD products that adhere to the necessary regulations. They only make their CBD products from the accepted industrial hemp plants, and are happy to provide you with a full certificate of analysis and ingredient list, or evidence of even seed-to-sale tracking.
- Third-party lab tested – Every CBD product you purchase should be third-party lab tested and have a Certificate of Approval (COA) that confirms the quality of the CBD, the ingredients, their concentrations, and the precise concentration of CBD in the product. By purchasing third-party lab-tested CBD products, you’re assured of the quality of ingredients and CBD concentration.
Possible Side Effects of CBD
It is essential to be aware of the potential side effects of CBD before starting to use it. While rare and often minor, it’s important to be informed regarding any supplements you take.
Therefore, it is vital to take CBD vigilantly and consciously. Start with a low dose, and build up gradually. If you notice any unwanted side effects, reduce the amount. Among the most common side effects are:
- Mouth dryness- While the chances are low, CBD may cause thirst, dry mouth, or “cotton mouth”.
- Lowered blood pressure- If a higher CBD oil dose is taken, a slight drop in blood pressure may be one of the potential side effects. However, this condition is not thought to be permanent or fatal, usually lasting only a few minutes. Nevertheless, if you are currently taking blood pressure medications or blood thinners, we recommend you consult your doctor before trying CBD for the first time.
- Dizziness- This is often caused by a drop in blood pressure when high doses of CBD are taken. However, this potential effect is also temporary, and can usually be reversed with a cup of tea or coffee, or simply giving yourself a few minutes to sit or lie down.
- Drowsiness- A lot of people add CBD to their drinks and coffee in the morning as CBD is purported to be a possible wakefulness-inducing agent. However, at higher doses, CBD may affect people in different ways and cause drowsiness. In such cases, avoid driving or operating heavy equipment – reduce the dose of CBD you are taking.
Altogether, it may be said that, although CBD-related research has achieved remarkable progress in the last decade, there is still a lot of work to do. CBD is thought to show great promise in supplementing symptoms of diverticulitis, from pain and anxiety to gut inflammation and nausea. However, remember that CBD is not an approved treatment for diverticulitis, and you should always consult your doctor before trying CBD alongside mainstream medications.
Verified by a health professional
Anastasiia Myronenko is a Medical Physicist actively practicing in one of the leading cancer centers in Kyiv, Ukraine. She received her master’s degree in Medical Physics at Karazin Kharkiv National University and completed Biological Physics internship at GSI Helmholtz Centre for Heavy Ion Research, Germany. Anastasiia Myronenko specializes in radiation therapy and is a fellow of Ukrainian Association of Medical Physicists.
Hemp CBD Oil For Diverticulitis
Hemp CBD oil for diverticulitis has been a topic for debate amongst many medical professionals. While naturally occurring CBD, derived directly from the stalk of the hemp plant, has a lot of effects and is different from its cousin Marijuana plant, there are speculations regarding its usage. We will try to walk you through the points that may help you understand its effects better.
- One of the positive effects of hemp CBD oil is that it is gaining popularity because of its anti-inflammatory effects.
- This is a huge breakthrough for all ailments and diseases that result due to inflammation, including diverticulitis.
- It is said that diverticulitis can cause inflammation in the colon that can be helped with the use of hemp CBD oil for diverticulitis.
- Hemp CBD oil can help ease the pain arising with this ailment and mediate the signals allowing you to get a little relief.
- Consuming hemp CBD daily fibers and oils may help with diverticulitis by releasing the right amount of cannabidiol into the source of the problem when you digest it.
Along with the right medication it is said that hemp CBD oil will help to remove the issues arising by diverticulitis, thus helping in quicker recovery. However, we do advise you to check with your doctor before taking a final call.
For more information regarding our supplements, connect with us via www.cleanremedies.com today!
Our USDA Certified Organic Hemp must benefit your well being and meet our high standards of efficacy. We never test on animals. We are a Woman-Owned, Family-Operated business taking pride in helping people feel their best.
This product has not been approved by or evaluated by the Food and Drug Administration and is not intended to diagnose, treat, cure or prevent any disease.