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Cbd oil for hepatic encephalopathy

The Role of Cannabinoids in the Setting of Cirrhosis

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Abstract

Although the mortality rates of cirrhosis are underestimated, its socioeconomic burden has demonstrated a significant global impact. Cirrhosis is defined by the disruption of normal liver architecture after years of chronic insult by different etiologies. Treatment modalities are recommended primarily in decompensated cirrhosis and specifically tailored to the different manifestations of hepatic decompensation. Antifibrogenic therapies are within an active area of investigation. The endocannabinoid system has been shown to play a role in liver disease, and cirrhosis specifically, with intriguing possible therapeutic benefits. The endocannabinoid system comprises cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) and their ligands, endocannabinoids and exocannabinoids. CB1 activation enhances fibrogenesis, whereas CB2 activation counteracts progression to fibrosis. Conversely, deletion of CB1 is associated with an improvement of hepatic fibrosis and steatosis, and deletion of CB2 results in increased collagen deposition, steatosis, and enhanced inflammation. CB1 antagonism has also demonstrated vascular effects in patients with cirrhosis, causing an increase in arterial pressure and vascular resistance as well as a decrease in mesenteric blood flow and portal pressure, thereby preventing ascites. In mice with hepatic encephalopathy, CB1 blockade and activation of CB2 demonstrated improved neurologic score and cognitive function. Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects. The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis.

Keywords: cirrhosis, treatment of cirrhosis, endocannabinoid system, endocannabinoids, exocannabinoids, THC, CB1, CB2, cannabinoids

1. Introduction

Cirrhosis results from chronic insults to the liver, causing persistent wound healing and fibrosis that result in the disruption of normal liver architecture [1]. The socioeconomic burden is vast [2] and mortality rates, although underestimated globally, are high [3,4]. Multiple etiologies can cause liver injury, all of which risk progression to cirrhosis [1]. The transition of liver parenchyma from initial injury to cirrhosis is scored by the MATEVIR scoring system based on histologic progression [5]. Treatment recommendations are focused on specific interventions for manifestations of decompensated cirrhosis such as ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, and variceal hemorrhage. However, antifibrogenic treatment modalities are still being studied. The endocannabinoid system and its pharmacomodulation have shown promising therapeutic benefits in cirrhosis. Because of the socioeconomic burden of cirrhosis, partially attributed to the lack of antifibrogenic therapies, and the concurrent increased use of recreational and therapeutic marijuana, the investigation of endocannabinoid system in cirrhosis may be beneficial based on its pro- and anti-fibrogenic properties.

2. Epidemiology

Approximately 3.9 million adults in the United States were diagnosed with liver disease in 2015 [6]. A study conducted the same year estimated the prevalence of cirrhosis as 0.27%, with a higher prevalence in non-Hispanic blacks and Mexican Americans, those living below the poverty level, and those with an education level less than high school [3]. Death rates for chronic liver disease and cirrhosis within the United States increased 31% between 2000 and 2015 in both men and women between ages 45 and 64 [3]. In 2004, the direct costs of chronic liver disease and cirrhosis in the United States (excluding patients with hepatitis C) were estimated at $2.5 billion, and indirect costs were estimated at $10.6 billion [2]. The societal impact of cirrhosis includes total costs and reduced employment, especially in those who have received liver transplants [2]. Although the global health burden of cirrhosis is undeniable, the global mortality data is vague due to a paucity of information in 58 out of 187 countries, primarily in Africa [4].

3. Definition, Etiologies and Clinical Presentation

Cirrhosis is defined as a condition that disrupts the normal architecture of the liver. It is caused by chronic insults which lead to persistent wound healing and hepatic parenchymal fibrosis resulting in progressive, diffuse, fibrosing architecture [1]. Common causes include alcohol, biliary obstruction, biliary cirrhosis, chronic hepatitis B or C, hemochromatosis, and NAFLD [1]. Less common causes include autoimmune hepatitis, drugs/toxins, genetic metabolic diseases, infection, vascular abnormalities, veno-occlusive disease, and idiopathic etiologies. In early and compensated disease, patients can present with anorexia, weight loss, fatigue, weakness, and osteoporosis [1]. In decompensated disease, patients may present with ascites, variceal bleeding from portal hypertension, hepatic encephalopathy, spontaneous bacterial peritonitis, jaundice, icterus, pruritus, or coagulopathy [1].

Physical exam findings may additionally reveal spider angiomata, spider telangiectasias, gynecomastia, fetor hepaticus, clubbing, hypertrophic osteoarthropathy, Cruveilhier–Baumgarten murmur, Dupuytren’s contracture, Kayser–Fleischer rings, nail changes, palmar erythema, splenomegaly, or testicular atrophy [1].

4. Pathogenesis

Liver fibrosis occurs as a result of exposure to chronic stimuli (i.e., aforementioned etiologies) that cause insult to its architecture [7]. Chronic stimuli cause progressive accumulation and decreased remodeling of the extracellular matrix which can result in fibrosis and progression to cirrhosis [7]. The extracellular matrix transitions from a normal low-density basement-membrane type matrix to an interstitial type, which influences hepatocytes, hepatic stellate cells (HSCs), and endothelial cells [8]. Activation of HSCs is a primary event in hepatic fibrosis [9]. HSCs, found in the space of Disse storing vitamin A and retinoids, are activated by inflammatory cytokines such as platelet-derived growth factor, transforming growth factor-beta (TGF-β), tumor necrosis factor-α, and interleukin-1 [9]. Their activation results in collagen and extracellular matrix deposition as well as their transformation into myofibroblasts [9]. Additionally, defenestration of liver sinusoidal endothelial cells and their subsequent capillarization contribute to hepatocyte dysfunction [9]. Kupffer cells, which are activated by injurious stimuli, also mediate inflammation, further stimulating injury and fibrosis [9]. Apoptosis of the parenchymal cells of the liver (hepatocytes) promotes inflammation, fibrogenesis, and development of cirrhosis due to the release of reactive oxygen species and fibrogenic mediators, activation of HSCs, and stimulation of myofibroblasts [9]. Hypoxic hepatocytes secrete TGF-β, which exacerbates fibrogenesis [9]. Additionally, the extracellular matrix can amplify fibrosis [7] via changes in membrane receptors that oppose focal adhesion, activation of matrix matalloproteases to release fibrogenic and proliferative growth factors, and stiffening of the matrix [10].

Cytokines and microRNAs also play major roles in mediating cirrhosis [7,9]. Cytokines are predominantly produced by CD4 T-helper lymphocytes [7]. Platelet-derived growth factor activates HSCs and reduces extracellular matrix degradation, resulting in mitogenic and fibrogenic effects [9]. TGF-β is pro-fibrogenic as it inhibits degradation of extracellular matrix, and causes deposition of collagen [9]. It also induces apoptosis of hepatocytes by inhibiting DNA synthesis [9]. Tumor necrosis factor-α activates HSCs and increases synthesis of extracellular matrix [9]. Interleukins, some of which are anti-fibrogenic, can also be pro-fibrogenic [9]. Interleukin-1 activates HSCs and promotes their production of matrix metalloproteinases, which causes fibrosis [9]. Interleukins 17, 22, and 6 have also been named pro-inflammatory and pro-fibrogenic [9]. Micro RNAs control fibrosis progression and are expressed by HSCs [7]. Specific pathogenic mechanisms can also be associated with type of injury, such as alcohol-induced injury and viral hepatitis [7].

5. Diagnosis

The gold standard for the diagnosis of cirrhosis and the underlying etiology for liver injury is a liver biopsy [5]. Liver biopsy yields a sample of core liver tissue that is sent for pathologic analysis [5]. Degree of fibrosis is then scaled by different scoring systems including the Ishak, METAVIR, Scheuer, and Batts-Ludwig scoring systems [5]. The diagnostic accuracy of the biopsy, however, can be affected by the size of the sample, etiology of the liver disease, and inter-observer variability [5]. Complications of liver biopsy include mortality from hemoperitoneum, specifically in those with hepatocellular carcinoma or cirrhosis, hypotension, or post-procedural pain [5]. The American Association of the Study of Liver Diseases (AASLD) recommends that liver biopsy be obtained when the diagnosis is unclear or when a specific diagnosis may alter management and can be considered if fibrosis stage is necessary to guide treatment [11].

Therefore, due to the liver biopsy’s invasive nature, limitations, and potential for complications, non-invasive assessments are being increasingly utilized and recommended. These include radiologic techniques, elastography techniques, and indirect and direct serum biomarkers [5]. Radiologic techniques include ultrasound, computed tomography, and magnetic resonance imaging [5]. Elastography techniques include transient elastography (i.e., Fibroscan), acoustic radiation force imaging, supersonic shear wave imaging, and magnetic resonance elastography [5]. Indirect serum biomarkers include the Aspartate Aminotransferase-Platelet Ratio Index (APRI), fibrotest (also known as Fibrosure), FIB4 (which is calculated using age, aspartate aminotransaminase, platelet count, and alanine transaminase), Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis score, and fibroindex [5]. Direct markers include hyaluronic acid, amino terminal of serum procollagen III peptide (PIIINP), chondrex (YKL-40), and the ELF score [5].

6. Classification

Cirrhosis can be subcategorized into compensated and decompensated cirrhosis based on prognostic stage [12]. Patients can further be risk stratified by their Child-Turcotte-Pugh classification [12]. This scoring system is based upon serum bilirubin, serum albumin, prothrombin time, ascites, and grade of encephalopathy [13]. Compensated cirrhosis is generally asymptomatic but can be further categorized into those with mild portal hypertension versus those with clinically significant portal hypertension, in whom the hepatic venous pressure gradient is greater than 10 [12]. Those with clinically significant disease are at risk of complications including ascites, encephalopathy, varices, variceal hemorrhage, postsurgical decompensation and hepatocellular carcinoma [12]. Serum albumin, presence of gastroesophageal varices, and Model for End-Stage Liver Disease [MELD] are predictors of decompensation in these patients [12]. Decompensated cirrhosis refers to those who possess one of these complications in the setting of cirrhosis [12]. This classification is specifically relevant to treatment guidelines posed by the AASLD in terms of portal hypertensive bleeding [12]. The MELD score is also used in determining prognosis in cirrhosis patients as well as in the allocation of donor organs for liver transplantation [13].

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7. Natural History

The METAVIR score stages fibrosis based on histologic progression [5]. Stage F0 indicates no fibrosis; F1 indicates portal fibrosis without septa; F2 indicates presence of few septa; F3 indicates numerous septa without cirrhosis; and F4 indicates cirrhosis [5]. Cirrhosis can remain compensated for years and can transition to decompensated cirrhosis at a rate of 5–7% per year [13]. Median survival rate for compensated cirrhotic patients ranges between 9 and 12 years [13]. Decompensated cirrhotic patients have poor survival with a 1-year survival rate less than 50% in patients with ascites and variceal hemorrhage [13].

8. Treatment/Management

The treatment of cirrhosis largely involves specific management of complications of cirrhosis, treatment of etiologies to prevent development of cirrhosis, and liver transplantation based on etiology of cirrhosis [14]. For those with ascites, first-line treatment as recommended by the AASLD includes cessation of alcohol use if present, sodium restriction, diuretic therapy, discontinuation of non-steroidal anti-inflammatories, and evaluation for liver transplant [15]. Second-line therapy as recommended by the AASLD includes discontinuation of beta blockers, angiotensin converting enzymes, and angiotensin receptor blockers, consideration of midodrine, therapeutic paracenteses, evaluation for liver transplantation, and/or transjugular intrahepatic portosystemic shunt (TIPS) [15]. Third-line treatment as recommended by the AASLD includes a peritoneovenous shunt [15]. The European Association for the Study of Liver (EASL) recommends no intervention for mild ascites, restriction of sodium intake and diuretics for moderate ascites evident by symmetrical distention of the abdomen, and large volume paracentesis followed by sodium restriction and diuretics in those with large or gross ascites [16]. Therapies proposed by EASL for refractory ascites include repeated large volume paracenteses, TIPS under certain criteria, and peritovenous shunt [16].

For those patients with spontaneous bacterial peritonitis (SBP), treatment includes the use of antibiotics as recommended by EASL and AASLD with chemoprevention thereafter to prevent recurrence [15,16]. Recommendations regarding management of hyponatremia include fluid restriction and use of vaptans in certain scenarios [15,16]. If a patient develops hepatorenal syndrome, EASL suggests specific monitoring parameters and potentially, drug therapy and renal replacement therapy; ultimately, EASL recommends liver transplantation [16]. AASLD also recommends evaluation for liver transplantation for those with hepatorenal syndrome [15]. For those who develop hepatic encephalopathy, lactulose is the recommended first-line agent as suggested by AASLD and EASL [15]. Rifaximin is suggested to be added on to lactulose to prevent recurrence [15]. Guidelines also exist in the management of portal hypertensive bleeding secondary to cirrhosis based on very specific classifications and parameters [12].

In addition to management of complications of cirrhosis, other modalities of treatment associated with cirrhosis include treatment of the etiologies and diseases underlying cirrhosis [9]. Drug therapy in viral hepatitis, abstinence from alcohol, control of metabolic dysfunction, and chelation in the setting of copper and iron overload have been used as specific therapies for certain etiologies for liver disease [9]. Therapy targeting the pathogenesis of cirrhosis to treat the disease, itself, is still being studied. Anti-inflammatory and anti-oxidative drugs such as celcoxib, taurine, and vitamin E have shown antifibrotic effects [9]. Glucocorticoids, azathioprine, colchicine, and rapamycin have exhibited anti-inflammatory, anti-fibrotic, and immunomodulatory effects [9]. Drugs that have exhibited a hepatoprotective effect include silymarin, ursodeoxycholic acid, tauroursodeoxycholic acid, and verapamil [9]. Gene therapy, specifically miRNA-based therapy, has also been implicated as a therapeutic modality in cirrhosis [9]. Antifibrotic drug therapies, however, are still unavailable, although the endocannabinoid system is being studied as a target for pharmaco-modulation in the setting of cirrhosis.

9. The Cannabinoid System in Liver Disease

Cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) are two G-protein receptors identified within the endocannabinoid system that may play a role in liver disease [17]. CB1 and CB2 are activated by highly lipophilic ligands called endocannabinoids [17]. CB1 is predominantly found in the brain and is accountable for the psychotropic and behavioral effects manifested by cannabinoid use [17]. CB2 is expressed in the peripheral tissues functioning in the modulation of innate immunity and bone mass with some antitumor properties [17]. Within the liver, CB1 has been detected in endothelial cells and hepatocytes whereas CB2 has been detected in Kupffer cells and is prominently expressed in the cirrhotic liver [17,18]. Known endocannabinoids include anandamide (arachidonoyl ethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG), which activate CB1 and CB2 [17]. Exocannabinoids, major components of cannabis, include tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), and cannabidiol (CBD) [19,20]. THC acts on CB1, CB2, transient receptor potential cation channel subfamily C member 1, and G protein-coupled receptors GPR56 and GPR11 [19]. THCV is an analog of THC and function as a CB1/CB2 agonist in high doses and a CB1/CB2 neutral antagonist in lowdoses [21]. CBD functions as an indirect agonist on CB1 via increase of endocannabinoid tone or CB1 constitutional activity [21].

10. Cannabinoids in Cirrhosis

CB1 and CB2 agonism and antagonism have been studied in cirrhosis. Mallat et al. demonstrated that CB1 and CB2 are upregulated in cirrhotic liver samples [17]. CB1 activation enhances fibrogenesis whereas CB2 activation counteracts progression to fibrosis [17]. Conversely, in rodent models, deletion of CB1 demonstrated improvement of hepatic fibrosis and steatosis, and deletion of CB2 demonstrated increased collagen deposition, steatosis, and enhanced inflammation [19,22]. CB1 antagonism and/or CB1 deficiency not only reduces liver fibrosis, but has been shown to decrease TGF-β, increase apoptosis of activated myofibroblasts, and decrease activation of HSCs [23,24].

Studies prior to these findings showed that CB2 deficiency resulted in prolonged survival of liver fibrogenic cells, increasing fibrosis with increased deposition of fibrotic tissue [24,25]. In one study, CB2 antagonism in mice exposed to carbon tetrachloride exhibited enhanced fibrosis whereas stimulation of CB2 demonstrated prevention of fibrosis progression [24,26]. Mallat et al. also demonstrated that CB2 accelerates the regenerative response following acute liver injury, possibly related to paracrine effects of hepatic myofibroblasts [17]. Additionally, Julien et al. demonstrated that CB2 receptor activation exhibits antifibrogenic activity by triggering growth inhibition and apoptosis with a possible role in the counteracting liver fibrogenesis [25]. JWH-133, a CB2 selective agonist, was found to enhance the regenerative response to acute liver injury and accelerate liver regeneration [18]. Subsequent studies supported these findings with administration of JWH-133 resulting in improved liver fibrosis, decrease in inflammatory infiltrate, and decreased density of hepatic myofibroblasts secondary to apoptosis [27].

Mallat et al. demonstrated that CB1-deficient mice exhibited reduced fibrosis after exposure to carbon tetrachloride [26]. CB1 blockade or inactivation has been associated with reduced progression to fibrosis, reduced hepatic expression of TGF-β1, and decreased quantity of fibrogenic cells, thought to be secondary to antiproliferative and apoptotic properties of CB1 antagonism in hepatic cells [17]. In fact, in common bile-duct-ligated rodents with biliary cirrhosis, CB1 blockade in the hepatic microcirculation resulted in decreased collagen deposition in cirrhotic livers [28]. CB1 has also been implicated in liver regeneration, as CB1 blockade by rinomabant (SR141716A) or lack of CB1 receptors demonstrated reduced liver regeneration [29].

CB1 antagonism by rimonabant has also demonstrated effects on vasculature. It specifically causes increased arterial pressure with reversal of arterial hypotension, increased splanchnic vascular resistance, and reduced mesenteric blood flow and portal pressure in rodents with cirrhosis [19,24,30]. Rimonabant, therefore, demonstrated prevention of ascites [24,31,32].

Endocannabinoids, themselves, also have mechanistic roles in cirrhosis. AEA has exhibited antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death [30]. Like CB1 mechanisms, endocannabinoids may also cause hemodynamic alterations in cirrhosis by acting on CB1 on the splanchnic and hepatic vascular endothelium [33]. They may be involved in apoptosis of hepatocytes [33]. In rodents with cirrhosis, AEA was found to induce mesenteric vasodilation and hypotension via CB1 induction [18,19]. AEA was also found to contribute to cirrhotic cardiomyopathy as mediated by activation of CB1 receptors by lowering cardiac contractility [24]. AEA notably demonstrated induction of hepatocyte proliferation [19]. 2-AG was found to be a fibrogenic mediator independent of CB receptors, but in higher doses, it induced apoptosis of HSCs, which may have antifibrotic properties [18]. The aforementioned study by Julien et al. demonstrated that 2-AG showed growth inhibitory and cytotoxic effects independent of CB2 [25]. It also showed that the exocannabinoid, THC, causes apoptosis by oxidative stress [25]. In particular, THC suppresses proliferation of hepatic myofibroblasts and stellate cells and induces their apoptosis, which may reveal antifibrotic, hepatoprotective mechanisms [18].

The endocannabinoid system, in addition to mediating effects on cardiovascular complications of cirrhosis, may be a target for treatment in hepatic encephalopathy secondary to decompensated cirrhosis. CB1 blockage by rimonabant and activation of CB2 by HU-308 demonstrated improved neurologic score and cognitive function in mice with hepatic encephalopathy [19,24,30]. 2-AG was found to improve hepatic encephalopathy [19,30]. Cannabidiol, independent of CB1 and CB2, was found to improve cognitive and motor function, as well as neuroinflammation in patients with hepatic encephalopathy [19].

Specific findings regarding the role and impact of the endocannabinoid system have been studied for etiologies of chronic liver disease that can progress to cirrhosis. In those with hepatitis C, daily cannabis use was associated with more severe fibrosis and steatosis [34]. Dai et al. demonstrated that CB1 and CB2 were expressed in patients with chronic hepatitis B and the degree of fibrosis was increased with increased expression of both [35]. In alcoholic liver disease, animal studies demonstrated that blockade of CB2 results in more pronounced liver damage after ethanol intake, suggesting a protective mechanism for CB2 in the setting of chronic alcohol use [36]. In the same study, fibrogenesis was increased in CB1 blockade in the setting of chronic alcohol use [36]. In hepatic ischemic-reperfusion injury, the data regarding endocannabinoids are conflicting [22].

The roles of exocannabinoids are as aforementioned. As THC, functions on multiple receptors in addition to CB1 and CB2 [19], THCV was found as dose-dependent, functioning as a CB1 antagonist in low doses or a CB1 agonist in high doses [21,37]. In a study by Bolognini, et al., THCV was investigated for its anti-inflammatory properties particularly for its function as a CB1 antagonist in vivo and a CB2 agonist in vitro in humans and in vivo and vitro in mice [38]. CBD functions primarily on CB1 [21]. Therefore, based on the associations made with CB1 and CB2 agonism and antagonism in the literature, hypotheses can be developed as to the effect of THC, cannabidiol, THCV, and cannabis in cirrhosis although prospective studies are warranted.

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11. Conclusions

The socioeconomic burden and high mortality rates associated with cirrhosis emphasize the need for therapeutic interventions. Because most treatment recommendations for cirrhosis aim to address complications of decompensated cirrhosis, there is a need for further investigation of antifibrogenic therapies that can slow the progression of fibrosis and thereby prevent cirrhosis and its complications. The endocannabinoid system has demonstrated powerful antifibrogenic as well as profibrogenic properties, as summarized in Table 1 and Table 2 , that can be pharmacologically manipulated to potentially treat cirrhosis at the histologic level. Further research is warranted to develop pharmacotherapies that utilize this endogenous system as a means of treating a debilitating, costly disease. Additionally, further studies investigating exocannabinoid use in cirrhosis may be warranted as marijuana is the most widely used illicit drug in the United States to recommend for or against its use in this context [39].

Table 1

Functions of Cannabinoid Receptors of the Endocannabinoid System in Cirrhosis.

CBD and Liver Damage: How Does It Affect Liver Functions?

As the use of CBD is booming across the United States, people have become more aware of its health benefits as well as potential risks associated with the consumption of CBD products.

One recent study has sparked concerns among CBD users when it comes to liver function. While the study did show that extremely large amounts of CBD can damage the liver, the news coverage that warned about the potential risk of taking CBD failed to put the study into context.

It goes without saying that CBD — like any supplement or medication — does have side effects, including dose-dependent danger to liver health. However, while users using the peak-tested dosages should have their liver enzymes in check, the vast majority of people can safely use CBD without worrying about a negative impact on their liver function.

In this article, we’ll explain the context of the said study and provide evidence supporting the health benefits of regular doses of CBD for liver health.

Let’s resolve the doubts surrounding the topic of CBD and liver function.

Is CBD Oil Bad for Your Liver?

CBD has a remarkably good safety profile. Researchers have tested the efficacy and safety of CBD in humans using doses as high as 1,500 mg – 3000 mg CBD daily.

With 1,500 mg of CBD taken for a six-week period, no dangerous side effects were observed (1).

However, the recent 2019 study on mice showed that high doses of CBD can damage the liver — causing widespread sensation all over the media.

The study has also garnered attention among CBD skeptics who have been trying to undermine the therapeutic potential of CBD looking for at least one serious side effect.

Now, we’re not saying CBD doesn’t have any side effects — it does, like any other health supplement — but should you actually worry about your liver when you use normal doses?

Let’s shed some light on the infamous study on mice.

The Study on CBD and the Liver of Mice

According to researchers from the University of Arkansas, who investigated the effects of treatments of various doses of CBD on a group of 8-week-old mice, the study addressed the problem of a “lack of comprehensive toxicological studies devoted to CBD safety that are critical for further marketing of CBD and CBD-containing products.” (2)

The majority of mice tolerated the CBD, but those administered the highest doses — an equivalent to 200 mg of CBD in humans — showed clear symptoms of liver toxicity, as reported by the researchers.

In addition, repeated doses of a smaller amount of CBD (50 mg) also showed signs of liver damage and swelling.

Here’s what the authors wrote at the end of the paper:

“Although (a dose of) 200 mg is not applicable to most real-life scenarios, it does provide critical information regarding the potential consequences of CBD overdose as well as for doses needed for further subchronic and chronic toxicity studies.”

However, one of the caveats of this study was that it tested the maximum recommended daily dosage for humans. While all mammals share the same endocannabinoid system, mice and humans are different physiologically. The size of the liver is just one of the many variables that should be taken into consideration when evaluating the safety of CBD in human subjects.

Experts Say It’s About the Dosage

Although the results of the above study sound potentially discouraging, most experts say there’s no need to freak out over the impact of CBD on the liver. While experts stress the importance of knowing the risks of taking health supplements, the amount of CBD the mice were exposed to is much higher than what most humans take.

According to Dr. Diana Martins-Welch, attending physician in palliative medicine at Northwell Health in New Hyde Park, New York, there are certain quantities in which CBD may not be safe for humans; CBD also isn’t always more effective in high doses.

“Many people know that taking too much ibuprofen or Tylenol can have detrimental consequences. CBD is no different. Generally speaking, therapeutic CBD doses range from 0.5 mg/kg/day to 20 mg/kg per day. This study in mice used significantly higher doses of CBD (in relation to their weight) than what is usually taken for therapeutic benefit in humans.” Martins-Welch explained.

Martins-Welch also said that therapeutic-range CBD is generally safe, and while toxicity at extremely high doses is a concern, it is no different than with other supplements or medicines.

Therefore, what the study essentially showed was how people need to be careful if they take high doses of CBD daily.

Human studies that have examined the safety of different doses of CBD have found no negative effects at the recommended maximum daily dosage of 20 mg/kg. This dosage was taken from the trial of Epidiolex, a CBD-based pharmaceutical for treatment-resistant seizures. To put that in context, an individual weighing 150 pounds would need to take over 1,300 mg of CBD per day, which is way above what most people take (10–80 mg daily).

Effects of CBD On the Liver

Okay, so now you know that extremely high doses of CBD may cause liver toxicity when taken regularly. You also know that it’s impossible to trigger toxicity with normal doses of CBD oil.

Now it’s time to ask a different question: what positive effects does CBD have on the liver?

There are plenty, to be honest.

In the next section, we elaborate on the potential therapeutic uses of CBD oil for liver function.

CBD Oil for Fatty Liver

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.

The ECS is responsible for regulating many of our homeostatic control processes. In other words, this network controls the balance of various systems and organs in the body, including the liver.

When the liver gets damaged, inflamed, or dysfunctional, the body starts to release more endocannabinoids to solve the problem. A healthy liver is correlated with a modest activity of the endocannabinoid system. In fact, this particular organ has a relatively low concentration of the ECS components.

However, inflammation in the liver causes the endocannabinoid to be very active in this area. Unfortunately, an overactive endocannabinoid system plays a role in the development of fatty liver disease (3).

CBD is the modulator of CB1 and CB2 receptors. In simple English, it keeps them from going crazy by stopping the compounds that make these receptors go haywire in the liver.

CBD ensures the proper functioning of a system that balances us. So while it won’t cure fatty liver disease, it can prevent its development. And should the disease occur, it may be able to reduce the inflammation in the organ, protecting it against further damage.

CBD Oil for Liver Cancer

To this day, studies on cannabinoids and their effect on liver cancer show that cannabinoids can both prevent the dividing of tumor cells and kill cancer cells while protecting the healthy ones. Besides stopping cancer proliferation, there are several mechanisms CBD uses to help tackle liver cancer.

First, it provides anti-metastatic actions, preventing distant tumor masses from forming in the liver.

Second, it prevents the formation of blood vessels that facilitate tumor growth.

And last but not least, CBD triggers apoptosis, which is programmed cell death. Researchers have found this ability during animal and laboratory models; these properties apply to both CBD and THC (4).

Although no study has yet analyzed the effects of CBD on liver cancer in humans, current research supports the use of cannabinoids as a complementary therapy as well as a means of reducing the side-effects of chemotherapy and radiation.

CBD Oil for Viral Hepatitis

Viral hepatitis is one of the most common infectious diseases characterized by inflammation. It is also a great contributor to many deaths globally. Hepatitis can lead to the formation of liver cancer and cirrhosis.

CBD has been shown to have therapeutic effects on the models of viral hepatitis, especially Hepatitis C. According to a study published in the journal Pharmacognosy Research, CBD was shown to inhibit the replication of hepatitis C virus by almost 90% (5).

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The inhibitory effects on the virus were dose-dependent but showed little toxicity towards the cells. CBD was also found to induce death in the infected cells containing the hepatitis B virus, although it did not inhibit the virus itself.

Finally, the attenuation of the immune response through the interaction with the ECS in the immune cells may help in alleviating autoimmune hepatitis.

CBD Oil for Hepatic Ischemia

Ischemia is a very common injury that occurs as an aftermath of liver surgeries and liver transplantations. It involves major inflammation and is responsible for deaths in the case of transplants and rejections. Oxidative stress can worsen the condition.

CBD is known for its anti-inflammatory and antioxidative properties, so it could be useful in reducing the inflammatory response and protecting the liver against oxidative damage. In experimental models, CBD effectively reduced inflammation, oxidative stress, and promoted the death of malignant cells in the liver.

Other studies found that administration of CBD to the rats with ischemic liver injury resulted in a significant reduction of liver damage associated with the condition (6).

CBD Oil for Hepatic Encephalopathy

Hepatic encephalopathy is characterized by psychological changes resulting from the damage and failure of the liver. Some symptoms include altered personality, confusion, movement problems, etc. It can lead to a coma in severe cases.

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 Autoimmune Hepatitis

Autoimmune hepatitis results from a weakened immune system that attacks the liver. Again, inflammation is the key player in the development of this disease. One study has reported that the activation of TRPV1 vanilloid receptor — part of the ECS — lowers inflammation by activating myeloid-derived suppressor cells (MDSCs). These cells, in turn, block inflammation and the development of autoimmune hepatitis.

CBD happens to activate the TRPV1 receptors, not only reducing the pain but also inhibiting the proliferation of T cells that trigger inflammation (8). Therefore, it’s within reason to assume that CBD could be used for the prevention and treatment of liver inflammation and autoimmune hepatitis.

CBD Oil for Alcohol-Induced Liver Injury

Liver fibrosis is a common result of chronic liver damage caused by binge drinking. It can lead to cirrhosis and liver failure.

CBD has been shown to have anti-fibrosis properties by eliminating cells that secrete collagen and cause fibrosis. It can also reverse alterations in the liver associated with alcohol-induced injury (9).

Does CBD Oil Increase Liver Enzymes?

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

For example, one study found that 10% of the subjects had higher levels of liver enzymes and had to stop using CBD for this reason. Other studies suggest that CBD can improve liver function. Since CBD is metabolized by the liver — as shown by the studies done on Epidiolex — patients with liver diseases should limit over-the-counter (OTC) medications to avoid potential CBD-drug interactions and reduce the stress experienced by the liver.

Long story short, CBD is generally safe for your liver enzymes if you don’t exceed the dose of 20 mg CBD/kg/day.

CBD Dosage for Liver

If you’re looking to improve liver function with CBD oil, you’re probably wondering how much CBD is enough to provide relief from pain and inflammation and to keep this organ healthy.

Unfortunately, there are no official dosage recommendations when it comes to CBD and the liver. Most clinical trials that suggest specific dosages of CBD have been performed on anxiety, chronic disorder such as epilepsy, and multiple sclerosis models in humans. No clinical study has yet investigated the efficacy of different doses of CBD on the symptoms of liver disease.

The optimal amount of CBD for each individual depends on factors such as weight, metabolism, age, gender, the severity of symptoms, and previous history with CBD products.

The best approach you can take is to start low and gradually increase the dose until you experience the desired relief. We suggest that you start with 5–10 mg CBD and try it out for one week, monitoring the effects. If you deem the dose insufficient, add another 5 milligrams and continue for another week, reassessing the results.

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.

Side Effects of CBD

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:

  • Dry mouth
  • Changes in appetite
  • Dizziness
  • Sedation
  • Diarrhea

Some of these side effects may result from consuming a mislabeled product that has more than 0.3% THC, or one that has been sourced from poor-quality hemp or extracted with aggressive solvents. When you take high-quality CBD oil at regular doses, the above side effects are nearly non-existent.

However, there’s a risk of potential drug interactions, as CBD is metabolized by the same group of enzymes that process active ingredients in pharmaceuticals. As an inhibitor of those enzymes, CBD can lead to either subtherapeutic effects or substance toxicity when taken along with medications for liver function. That’s why we recommend consulting a doctor before adding CBD oil to your routine.

CBD Oil and Liver: Bottom Line

The liver is a fundamental detoxifying organ that performs many important functions to keep the body in the optimum state. It plays a role in digestion, detoxification, drug metabolism, and more.

There are many diseases affecting the liver as it is constantly exposed to environmental damage from pollutants, alcohol, drugs, medications, etc. It is also prone to autoimmune diseases.

CBD has been shown to have therapeutic effects in many major liver diseases, including viral hepatitis, fatty liver disease, ischemia-reperfusion injury, cirrhosis, fibrosis, and liver cancer.

High-quality full-spectrum CBD oil could be beneficial in a range of disorders that involve liver dysfunction and might help replace the long-term use of other medications.

Although extremely high doses of CBD taken daily have been associated with liver toxicity, so have other supplements and medications. Therefore, it’s best to keep your use of CBD within reason. Doses as high as 20 mg of CBD per kg don’t pose a threat to your liver’s health, as tested in the clinical trial of Epidiolex, a CBD-based anti-seizure medication.

Patients should seek medical consultation before incorporating CBD into their routine to discuss the dosage and establish the right time schedule to avoid potential interactions with other medications.

References:

  1. Iffland, Kerstin, and Franjo Grotenhermen. “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” Cannabis and cannabinoid research vol. 2,1 139-154. 1 Jun. 2017, doi:10.1089/can.2016.0034
  2. Ewing, Laura E et al. “Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model.” Molecules (Basel, Switzerland)vol. 24,9 1694. 30 Apr. 2019, doi:10.3390/molecules24091694
  3. Purohit, Vishnudutt et al. “Role of cannabinoids in the development of fatty liver (steatosis).” The AAPS journal vol. 12,2 (2010): 233-7. doi:10.1208/s12248-010-9178-0
  4. Vara, D et al. “Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy.” Cell death and differentiation vol. 18,7 (2011): 1099-111. doi:10.1038/cdd.2011.32
  5. Lowe, Henry I C et al. “Potential of Cannabidiol for the Treatment of Viral Hepatitis.” Pharmacognosy research vol. 9,1 (2017): 116-118. doi:10.4103/0974-8490.199780
  6. Fouad, Amr A, and Iyad Jresat. “Therapeutic potential of cannabidiol against ischemia/reperfusion liver injury in rats.” European journal of pharmacology vol. 670,1 (2011): 216-23. doi:10.1016/j.ejphar.2011.08.048
  7. Avraham, Y et al. “Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.” British journal of pharmacology vol. 162,7 (2011): 1650-8. doi:10.1111/j.1476-5381.2010.01179.x
  8. Muller, Chanté et al. “Cannabinoid Ligands Targeting TRP Channels.” Frontiers in molecular neuroscience vol. 11 487. 15 Jan. 2019, doi:10.3389/fnmol.2018.00487
  9. Zurier, Robert B, and Sumner H Burstein. “Cannabinoids, inflammation, and fibrosis.” FASEB journal : official publication of the Federation of American Societies for Experimental Biology vol. 30,11 (2016): 3682-3689. doi:10.1096/fj.201600646R
Livvy Ashton

Livvy is a registered nurse (RN) and board-certified nurse midwife (CNM) in the state of New Jersey. After giving birth to her newborn daughter, Livvy stepped down from her full-time position at the Children’s Hospital of New Jersey. This gave her the opportunity to spend more time writing articles on all topics related to pregnancy and prenatal care.

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CBD treatment for Hepatic Encephalopathy, Liver Cirrhosis, and Nonalcoholic steatohepatitis (NASH)

Treatment of liver disease (Cirrhosis/steatosis) and hepatic encephalopathy with cannabidiol or capsaicin and/or cannabinoids (THC/HU308) / endocannabinoids (2-AG): We have shown in mouse experimental models that cannabinoids/endocannabinoids and/or capsaicin or cannabidiol, improve both liver and brain functions. We suggest a treatment modality based on the following mechanism/s: blocking the CB1 receptor and stimulating the CB2 receptor by 2AG or HU308 or THC (for hepatic encephalopathy) and/or the TRPV1 receptors by capsaicin and/or the 5HTIA receptors by Cannabidiol . Thus, inducing therapeutic effect which is mediated through effects in the liver and brain.

It has been shown to improve both liver and brain function in a mouse models of hepatic encephalopathy (in both acute and chronic models).

The Business Opportunity

We are presently seeking to raise 0.5M.US$ to complete efficacy and safety studies in animal models and to Progress to preliminary human studies (safety and proof of concept) once pre-clinical safety has been determined .