cbd liver inflammation

Cbd liver inflammation

The endocannabinoid system (ECS) is found in all mammals and consists of receptors (CB1 and CB2) endogenous cannabinoids, and enzymes that facilitate their production or break them down.

Inflammation is one of the main causes of hepatic encephalopathy. A study conducted on mice models of hepatic encephalopathy reported positive effects. The research team observed that applying CBD to mice could restore the neurological functions and cognitive performance in the mice. CBD also reduced the levels of ammonia in the blood, helping restore liver function and normalize the number of liver enzymes (7).

CBD Oil for Viral Hepatitis

As mentioned earlier in the article, CBD has an excellent safety profile. People turn to CBD because it’s a low-risk alternative to conventional treatment options for liver disease. That being said, it has a few relatively mild effects when consumed in high doses, including:

We also encourage you to consult a doctor knowledgeable about CBD and cannabis in general. A qualified physician should help you avoid potential interactions with other medications and determine the right dosage range.

CBD Oil for Alcohol-Induced Liver Injury

The studies performed on how CBD affects liver function have brought conflicting results.

Cbd liver inflammation

Even though astrogliosis was found a week before cognitive function was observed, and it is not definite whether it was long-lasting, this mechanism seems, in our eyes, to account for the cognitive dysfunction, rather than the increase in 5-HT level ( Figure 5 ). The latter mechanism does not seem to be related to the cognitive dysfunction, even though this increase in 5-HT was reversed by CBD ( Figure 5 ), as 5-HT depletion, not increase, has been shown to cause memory deficits in the eight arm maze (Mazer et al., 1997). On the other hand, there is much evidence that ammonia induces astrocyte swelling which via a number of mechanisms leads to impaired astrocyte/neuronal communication and synaptic plasticity, thereby resulting in a disturbance of oscillatory networks. The latter accounts for the symptoms of HE (for review see Häussinger and Görg, 2010), among them presumably the cognitive dysfunction.

Serum for alanine transaminase (ALT), aspartate transaminase (AST), bilirubin and ammonia measurements was obtained on day 3 in glass tubes, centrifuged, and analysed on the day of sampling using a Kone Progress Selective Chemistry Analyzer (Kone Instruments, Espoo, Finland). All serum samples were processed in the same laboratory using the same methods and the same reference values.

Figure 4 shows images of slices from brains of animals from the control group (A), control + CBD group (B), TAA group (C) and TAA + CBD group (D), immunostained for the detection of astrogliosis. Astrogliosis was observed in visual fields studied in TAA animals, as evident both by the increase in the number of GFAP-positive cells·mm −2 ( Figure 4E ; anova : F3,298= 26.8, P < 0.001; Bonferroni: P < 0.001) and by the increased % of GFAP-positive surface ( Figure 4F ; anova : F3,298= 19.21, P < 0.001; Bonferroni: P < 0.001). Both parameters were unaffected in CBD-treated controls ( Figure 4E and F ). However, the number of GFAP-positive cells·mm −2 in TAA + 5 mg·kg −1 CBD-treated animals was reduced compared to TAA-treated animals ( Figure 4E ; Bonferroni: P= 0.002). In contrast, CBD had no effect on the % of GFAP-positive surface in TAA animals ( Figure 4F ). Overall, it seems that TAA administration increased the number of activated astrocytes and CBD significantly reduced this effect. However, astrocytes in both CBD- and vehicle-treated TAA animals did not differ as regards their cellular size or extension of processes.

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TAA administration induces acute liver failure which leads to CNS changes related to those seen in HE (Zimmermann et al., 1989; Magen et al., 2008; Avraham et al., 2006; 2008a; 2009;). The hepatotoxicity of TAA is due to the generation of free radicals and oxidative stress (Zimmermann et al., 1989). However, it is not clear whether TAA affects the brain directly or the liver (Albrecht et al., 1996). In previous studies both a CB1 antagonist and a CB2 or TRPV1 agonist have been shown to ameliorate the brain and liver damage that occurs in liver disease and HE (Avraham et al., 2006; 2008a,b; 2009; Mallat and Lotersztajn, 2008). Also CBD, an agonist of the 5-HT1A receptor, was found to ameliorate brain damage in a chronic model of HE induced by bile duct ligation. Hence, we investigated the potential of CBD as a treatment for HE induced by FHF. Our results indicated that it has a neuroprotective role in HE induced by FHF; CBD was found to restore liver function, normalize 5-HT levels and improve the brain pathology in accordance with normalization of brain function. We also showed that CBD affects both central functions: neurological score, motor and cognitive functions, brain 5-HT levels as well as astrogliosis and peripheral functions: reduced liver enzymes, ammonia and bilirubin. Therefore, we conclude that it acts both centrally and peripherally. In addition, it has been shown that CBD can cross the blood – brain barrier and act centrally (for review see Pertwee, 2009). Therefore, its effect may result from a combination of its actions in the liver and the brain. However, to elucidate its mechanism of action future experiments are needed to determine the effects of central administration of CBD.

5-HT levels

An increased level of 5-HT in the brain of rats after TAA administration was reported by Yurdaydin et al. (1990). In addition, there is indirect evidence that this increase is related to decreased motor activity, as the nonselective 5-HT receptor antagonist methysergide increased motor activity in TAA-injected rats, while the selective 5-HT2 receptor antagonist seganserin did not (Yurdaydin et al., 1996). Likewise, we found that the level of 5-HT was increased following TAA administration and this was restored after CBD treatment ( Figure 5 ). In parallel, motor activity was decreased following TAA injection and increased after CBD treatment, indicating a link between the increase in 5-HT and decrease in motor activity. Hence, it seems that CBD reversed the increased 5-HT level in the brains of TAA mice and thus reversed the decrease in their motor activity. A possible mechanism can be activation of 5-HT1A receptors by CBD (Russo et al., 2005; receptor nomencalture follows Alexander et al., 2008), as these receptors have been reported to inhibit 5-HT synthesis (Invernizzi et al., 1991). We have shown that the effects of CBD in a chronic model of HE, bile duct ligation, are mediated via the 5-HT1A receptors (Magen et al., 2010), and in an earlier study with the same model we demonstrated that the effects of CBD can be also mediated via A2A adenosine receptors (Magen et al., 2009). Thus, the effects of CBD can be mediated by 5-HT1A or/and A2A adenosine receptors. We think that in the current study the effects of CBD were mediated by the 5-HT1A receptor since activation of the receptor by CBD caused depletion of 5-HT ( Figure 5 ). In our previous studies we showed that cognition is multifactorial and not dependent only on 5-HT levels, and therefore there is no direct correlation between cognition and 5-HT levels.

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Cognitive function studies were performed 8 days after the induction of hepatic failure. The animals were placed in an eight-arm maze, which is a scaled-down version of that developed for rats (Olton and Samuelson, 1976; Pick and Yanai, 1983). Mice were deprived of water 2 h prior to the test and a reward of 50 µL of water was presented at the end of each arm, in order to motivate them to perform the task. Animals were divided between treatment groups so that all groups had similar baselines neurological scores after TAA induction. The mice were tested (no. of entries) until they made entries into all eight arms or until they completed 24 entries, whichever came first. Hence, the lower the score the better the cognitive function. Food and water were given at the completion of the test. Maze performance was calculated on each day for five consecutive days. Results are presented as area under the curve (AUC) utilizing the formula: (day 2 + day 3 + day 4 + day 5) − 4*(day 1) (Pick and Yanai, 1983).

The reversal of astrogliosis was probably related to reduced hepatic toxin formation. Indeed, there is much evidence that ammonia induces astrocyte swelling, which via a number of mechanisms leads to impaired astrocyte/neuronal communication and synaptic plasticity, thereby resulting in a disturbance of oscillatory networks. The latter accounts for the symptoms of HE (for review see Häussinger and Görg, 2010), among them presumably the cognitive dysfunction. Neurological and motor functions were improved 2 and 3 days, respectively, after induction of hepatic failure at the same time as a partial reversal of the astrogliosis and reduced levels of ammonia, bilirubin and liver enzymes were noticed. It seems that the behavioural effects of CBD are dramatic and occur within 3 days.

Brain histopathology and immunohistochemistry

Astrogliosis has also been shown to be involved in learning and memory deficits in a mouse model of Alzheimer’s disease. In this study, astrogliosis was reduced by caloric restriction, which also reversed the cognitive deficits and increased the expression of neurogenesis in related genes (Wu et al., 2008). Further studies, such as expression analysis of such genes using DNA microarray and evaluation of neurogenesis using BrdU staining, needs to be performed in order to explore the mechanisms through which TAA-induced astrogliosis impairs cognition, and through which CBD acts to improve it.

Kerfoot et al. (2006) showed the infiltration of peripheral monocytes into the brain of bile duct-ligated mice 10 days after the ligation and suggested that this infiltration may cause the activation of inflammatory cells in the brain. Therefore, it is conceivable that such a mechanism was responsible for the astrogliosis observed in our study, since we found evidence of liver inflammation (data not shown). As evident from the histopathology results, CBD did not appear to affect the development of TAA-induced necrotic lesions in the liver of mice. However, the levels of liver transaminases in the serum of CBD-treated mice were significantly reduced compared to their untreated counterparts, indicating that this substance contributed to a partial restoration of liver function. Recent evidence elucidating the complicated mechanisms involved in the release of hepatocyte cytosolic enzymes such as ALT and AST in the blood may explain the discrepancy between histopathology and serum biochemistry data observed in the present study. Indeed, it is now generally accepted that the release of cytosolic enzymes during both the reversible and irreversible phases of hepatocyte injury and therefore their appearance in blood does not necessarily indicate cell death and also that enzyme release during reversible cell damage occurs with an apparent lack of histological evidence of necrosis (Solter, 2005). Following this reasoning, it could be hypothesized that although CBD did not reduce the levels of histologically detectable necrosis, it may have ameliorated the minute reversible hepatocyte damage that causes the so-called ‘leakage’ of cytoplasmic ALT and AST in blood. The interaction between hyperammonaemia and inflammation as a precipitating factor for HE has been discussed in two recent reviews (Shawcross and Jalan, 2005; Wright and Jalan, 2007). Further work is required to reveal the exact mechanism/s of the manner by which liver damage is related to dysfunction/damage in the brain, and studies using antagonists of the A2A adenosine receptors, which are potential targets of CBD that may mediate its anti-inflammatory effect (Carrier et al., 2006), need to be carried out in order to elucidate the receptors involved in this effect.

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Cbd liver inflammation

The Farm Bill removed all hemp-derived products, including CBD, from the Controlled Substances Act, which criminalizes the possession of drugs. In essence, this means that CBD is legal if it comes from hemp, but not if it comes from cannabis (marijuana) – even though it is the exact same molecule. Currently, many people obtain CBD online without a medical marijuana license, which is legal in most states.

CBD, or cannabidiol, is the second most prevalent active ingredient in cannabis (marijuana). While CBD is an essential component of medical marijuana, it is derived directly from the hemp plant, a cousin of marijuana, or manufactured in a laboratory. One of hundreds of components in marijuana, CBD does not cause a “high” by itself. According to a report from the World Health Organization, “In humans, CBD exhibits no effects indicative of any abuse or dependence potential…. To date, there is no evidence of public health related problems associated with the use of pure CBD.”

Is cannabidiol legal?

Outside of the US, the prescription drug Sativex, which uses CBD as an active ingredient, is approved for muscle spasticity associated with multiple sclerosis and for cancer pain. Within the US, Epidiolex is approved for certain types of epilepsy and tuberous sclerosis.

How is cannabidiol different from marijuana, cannabis and hemp?

CBD has been touted for a wide variety of health issues, but the strongest scientific evidence is for its effectiveness in treating some of the cruelest childhood epilepsy syndromes, such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), which typically don’t respond to antiseizure medications. In numerous studies, CBD was able to reduce the number of seizures, and, in some cases, stop them altogether. Epidiolex, which contains CBD, is the first cannabis-derived medicine approved by the FDA for these conditions.