Category Archives: Cirrhosis

Hepatoprotective Effect of Cannabidiol on the Progression of Experimental Hepatic Cirrhosis in Rats

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“Introduction: Liver cirrhosis is a condition characterized by the gradual replacement of normal liver tissue with scar tissue, ultimately leading to liver failure. This slow and progressive disease begins with a chronic inflammatory process induced by a noxious agent. In its advanced stages, the disease lacks effective therapies. Research has demonstrated the significant involvement of the endocannabinoid system in the pathogenesis of this disease. This study evaluated the hepatoprotective effect of cannabidiol (CBD) in the progression of experimental hepatic cirrhosis induced by thioacetamide (TAA) in rats. 

Methods: A randomized experimental design was employed using Holtzman rats. Hepatic cirrhosis was induced by intraperitoneal administration of TAA at a dose of 150 mg/kg for 6 weeks, with treatment initiated additionally. The groups were as follows: Group 1: TAA + vehicle; Group 2: TAA + CBD 2 mg/kg; Group 3: TAA + CBD 9 mg/kg; Group 4: TAA + CBD 18 mg/kg; Group 5: TAA + silymarin 50 mg/kg; and Group 6: Healthy control. Serum biochemical analysis (total bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, and albumin) and hepatic histopathological study were performed. The Knodell histological activity index (HAI) was determined, considering periportal necrosis, intralobular degeneration, portal inflammation, fibrosis, and focal necrosis. 

Results: All groups receiving TAA exhibited an elevation in AST levels; however, only those treated with CBD at doses of 2 mg/kg and 18 mg/kg did not experience significant changes compared to their baseline values (152.8 and 135.7 IU/L, respectively). Moreover, ALT levels in animals treated with CBD showed no significant variation compared to baseline. The HAI of hepatic tissue was notably lower in animals treated with CBD at doses of 9 and 18 mg/kg, scoring 3.0 and 3.25, respectively, in contrast to the TAA + vehicle group, which recorded a score of 7.00. Animals treated with CBD at 18 mg/kg showed a reduced degree of fibrosis and necrosis compared to those receiving TAA alone (p ≤ 0.05). 

Conclusion: Our findings demonstrate that cannabidiol exerts a hepatoprotective effect in the development of experimental hepatic cirrhosis induced in rats.”

https://pubmed.ncbi.nlm.nih.gov/38885158/

https://www.liebertpub.com/doi/10.1089/can.2023.0285


Cannabidiol alleviates carbon tetrachloride-induced liver fibrosis in mice by regulating NF-κB and PPAR-α pathways

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“Liver fibrosis has become a serious public health problem that can develop into liver cirrhosis and hepatocellular carcinoma and even lead to death.

Cannabidiol (CBD), which is an abundant nonpsychoactive component in the cannabis plant, exerts cytoprotective effects in many diseases and under pathological conditions.

In our previous studies, CBD significantly attenuated liver injury induced by chronic and binge alcohol in a mouse model and oxidative bursts in human neutrophils. However, the effects of CBD on liver fibrosis and the underlying mechanisms still need to be further explored. A mouse liver fibrosis model was induced by carbon tetrachloride (CCl4) for 10 weeks and used to explore the protective properties of CBD and related molecular mechanisms. After the injection protocol, serum samples and livers were used for molecular biology, biochemical and pathological analyses.

The results showed that CBD could effectively improve liver function and reduce liver damage and liver fibrosis progression in mice; the expression levels of transaminase and fibrotic markers were reduced, and histopathological characteristics were improved. Moreover, CBD inhibited the levels of inflammatory cytokines and reduced the protein expression levels of p-NF-κB, NF-κB, p-IκBα, p-p38 MAPK, and COX-2 but increased the expression level of PPAR-α. We found that CBD-mediated protection involves inhibiting NF-κB and activating PPAR-α.

In conclusion, these results suggest that the hepatoprotective effects of CBD may be due to suppressing the inflammatory response in CCl4-induced mice and that the NF-κB and PPAR-α signaling pathways might be involved in this process.”

https://pubmed.ncbi.nlm.nih.gov/38711461/

“In summary, we have shown that intraperitoneal injection of CBD exerts potent anti-inflammatory and antifibrotic activities in vivo. Moreover, we found that the first time CBD efficacy in reducing CCl4-induced hepatic fibrosis by multiple mechanisms. These mechanisms may involve inhibition of NF-κB, activation of the PPAR-α pathway, and inhibition of oxidative stress. Based on these findings, CBD has the potential to be further developed as a treatment for hepatic fibrosis, especially as a combination therapy with the currently available therapies.”

https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2024.10141/full

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

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ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

 

“Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830475/

Cannabis Use May Reduce Healthcare Utilization and Improve Hospital Outcomes in Patients with Cirrhosis

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Cover image Annals of Hepatology“Introduction and objectives: Previous studies reveal conflicting data on the effect of cannabis use in patients with cirrhosis. This research evaluates the impact of cannabis on hepatic decompensation, health care utilization, and mortality in patients with cirrhosis.

Results: Cannabis use was detected in 370 (2.1%) of 17,520 cirrhotics admitted in 2011 and in 1,162 (5.3%) of 21,917 cirrhotics in 2015 (p-value <0.001). On multivariable analysis, cirrhotics utilizing cannabis after its legalization experienced a decreased rate of admissions related to hepatorenal syndrome (Odds Ratio (OR): 0.51; 95% Confidence Interval (CI): 0.34-0.78) and ascites (OR: 0.73; 95% CI: 0.63-0.84). Cirrhotics with an etiology of disease other than alcohol and hepatitis C had a higher risk of admission for hepatic encephalopathy if they utilized cannabis [OR: 1.57; 95% CI: 1.16-2.13]. Decreased length of stay (-1.15 days; 95% CI: -1.62, -0.68), total charges (-$15,852; 95% CI: -$21,009, -$10,694), and inpatient mortality (OR: 0.68; 95% CI: 0.51-0.91) were also observed in cirrhotics utilizing cannabis after legalization compared to cirrhotics not utilizing cannabis or utilizing cannabis prior to legalization.

Conclusion: Cannabis use in patients with cirrhosis resulted in mixed outcomes regarding hospital admissions with hepatic decompensation. A trend towards decreased hospital utilization and mortality was noted in cannabis users after legalization. These observations need to be confirmed with a longitudinal randomized study.”

https://pubmed.ncbi.nlm.nih.gov/33157269/

“The effectiveness of medicinal cannabis has been noted for many digestive system diseases including cirrhosis. Medicinal cannabis is associated with improved patient and hospital outcomes in cirrhotics”

https://www.sciencedirect.com/science/article/pii/S1665268120302052?via%3Dihub

Reduced Incidence and Better Liver Disease Outcomes among Chronic HCV Infected Patients Who Consume Cannabis.

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“The effect of cannabis use on chronic liver disease (CLD) from Hepatitis C Virus (HCV) infection, the most common cause of CLD, has been controversial. Here, we investigated the impact of cannabis use on the prevalence of CLD among HCV infected individuals.

Our study revealed that cannabis users (CUs) had decreased prevalence of liver cirrhosis, unfavorable discharge disposition, and lower total health care cost versus, compared to noncannabis users (NCUs).

Among CUs, dependent cannabis use was associated with lower prevalence of liver cirrhosis, compared to nondependent use.

CONCLUSIONS:

Our findings suggest that cannabis use is associated with decreased incidence of liver cirrhosis, but no change in mortality nor LOS among HCV patients. These novel observations warrant further molecular mechanistic studies.”

https://www.ncbi.nlm.nih.gov/pubmed/30345261

The Role of Cannabinoids in the Setting of Cirrhosis.

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“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.”

https://www.ncbi.nlm.nih.gov/pubmed/29890719

http://www.mdpi.com/2305-6320/5/2/52

Implication of cannabinoids in neurological diseases.

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“1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally. 2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Delta(9)-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases. 3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB(1) receptor antagonists have therapeutic potential in Parkinson’s disease. 4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/16699878

“Medical marijuana: emerging applications for the management of neurologic disorders.” https://www.ncbi.nlm.nih.gov/pubmed/15458761

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

Long-term cannabinoid type 2 receptor agonist therapy decreases Bacterial Translocation In Rats with cirrhosis and ascites.

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“Intestinal hyper-permeability, impaired peritoneal macrophages (PMs) phagocytosis, and, bacterial translocation (BT) resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP), together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications.

Manipulation of cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokines release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats…

CONCLUSIONS:

Our study suggests that CB2R agonist have the potential to treat BT and various relevant abnormalities through the inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα releases in cirrhosis. Overall, chronic CB2R agonist treatment affects multiple approach mechanisms, and the direct effect on hyperdynamic circulation is only minor.”

http://www.ncbi.nlm.nih.gov/pubmed/24953022

Therapeutic potential of cannabinoid medicines.

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Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract