Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome.

toxins-logo “In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB1R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB1R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB1R once again.”

https://www.ncbi.nlm.nih.gov/pubmed/31096702

https://www.mdpi.com/2072-6651/11/5/275

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Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-κB and NLRP3 inflammasome pathway.

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“Cannabidiol (CBD), an abundant nonpsychoactive constituent of marijuana, has been reported previously to protect against hepatic steatosis.

In this study, we studied further the functions and mechanisms of CBD on liver inflammation induced by HFC diet.

Mice feeding an HFC diet for 8 weeks were applied to test the protective effect of CBD on livers. RAW264.7 cells were incubated with LPS + ATP ± CBD to study the mechanisms of the effect of CBD against inflammasome activation.

We found that CBD alleviated liver inflammation induced by HFC diet.

CBD significantly inhibited the nuclear factor-κappa B (NF-κB) p65 nuclear translocation and the activation of nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome both in vivo and in vitro studies, which lead to the reduction of the expression of inflammation-related factors in our studies.

In addition, Inhibitor of activation of NF-κB partly suppressed the NLRP3 inflammasome activation, while adding CBD further inhibited NF-κB activation and correspondingly suppressed the NLRP3 inflammasome activation in macrophages.

In conclusion, the suppression of the activation of NLRP3 inflammasome through deactivation of NF-κB in macrophages by CBD might be one mechanism of its anti-inflammatory function in the liver.”

https://www.ncbi.nlm.nih.gov/pubmed/31032942

https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.28728

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AM-1241 CB2 Receptor Agonist Attenuates Inflammation, Apoptosis and Stimulate Progenitor Cells in Bile Duct Ligated Rats.

 “The cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator of liver disease.

Cannabinoid CB2 receptor activation has been reported to attenuate liver fibrosis in CCl4 exposed mice and also plays a potential role in liver regeneration in a mouse model of I/R and protection against alcohol-induced liver injury.

AIM:

In this study, we investigated the impact of CB2 receptors on the antifibrotic and regenerative process associated with cholestatic liver injury.

RESULTS:

Following bile duct ligation (BDL) for 3 weeks, there was increased aminotransferase levels, marked inflammatory infiltration and hepatocyte apoptosis with induced oxidative stress, as reflected by increased lipid peroxidation. Conversely, following treatment with the CB2 agonist, AM-1241, BDL rats displayed a reduction in liver injury and attenuation of fibrosis as reflected by expression of hydroxyproline and α-smooth muscle actin. AM1241 treatment also significantly attenuated lipid peroxidation end-products, p53-dependent apoptosis and also attenuated inflammatory process by stimulating IL-10 production. Moreover, AM1241 treated rats were associated with significant expression of hepatic progenitor/oval cell markers.

CONCLUSION:

In conclusion, this study points out that CB2 receptors reduce liver injury and promote liver regeneration via distinct mechanisms including IL-10 dependent inhibition of inflammation, reduction of p53-reliant apoptosis and through stimulation of oval/progenitor cells. These results suggest that CB2 agonists display potent hepatoregenrative properties, in addition to their antifibrogenic effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30976335

https://www.id-press.eu/mjms/article/view/oamjms.2019.194

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Protective effects of specific cannabinoid receptor 2 agonist GW405833 on concanavalin A-induced acute liver injury in mice.

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“Cannabinoid receptor 2 (CB2R) is highly expressed in immune cells and plays an important role in regulating immune responses. In the current study, we investigated the effects of GW405833 (GW), a specific CB2R agonist, on acute liver injury induced by concanavalin A (Con A).

In animal experiments, acute liver injury was induced in mice by injection of Con A (20 mg/kg, i.v.). The mice were treated with GW (20 mg/kg, i.p., 30 min after Con A injection) or GW plus the selective CB2R antagonist AM630 (2 mg/kg, i.p., 15 min after Con A injection).

We found that Con A caused severe acute liver injury evidenced by significantly increased serum aminotransferase levels, massive hepatocyte apoptosis, and necrosis, as well as lymphocyte infiltration in liver tissues. Treatment with GW significantly ameliorated Con A-induced pathological injury in liver tissue, decreased serum aminotransferase levels, and decreased hepatocyte apoptosis.

Our results suggest that GW protects against Con A-induced acute liver injury in mice by inhibiting Jurkat T-cell proliferation through the CB2Rs.”

https://www.ncbi.nlm.nih.gov/pubmed/30918343

https://www.nature.com/articles/s41401-019-0213-0

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Marijuana Consumption in Liver Transplant Recipients.

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“Marijuana is legalized for either medical or recreational use in over half of the United States and in Canada, but many transplant centers will not list patients who are using marijuana. However, the effect of marijuana on transplant outcomes remains unclear. Thus, we performed a retrospective analysis of all adult (≥18 years old) liver transplant patients treated at our center between 2007 and 2017. After adjustment, current tobacco users were over three times as likely to die within 5 years, compared to never users, but no difference was seen between current/former and never marijuana users. No significant differences in inpatient respiratory complications, reintubation, or >24 hours intubation was seen. Overall, pre-transplant marijuana use, past or current, does not appear to impact liver transplant outcomes; however, tobacco smoking remains detrimental.”

https://www.ncbi.nlm.nih.gov/pubmed/30693668

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/lt.25417

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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

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Marijuana is not associated with progression of hepatic fibrosis in liver disease: a systematic review and meta-analysis.

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“An estimated 22 million adults use marijuana in the USA. The role of marijuana in the progression of hepatic fibrosis remains unclear.

AIMS:

We carried out a systematic review and meta-analysis to evaluate the impact of marijuana on prevalence and progression of hepatic fibrosis in chronic liver disease.

PATIENTS AND METHODS:

We searched several databases from inception through 10 November 2017 to identify studies evaluating the role of marijuana in chronic liver disease. Our main outcome of interest was prevalence/progression of hepatic fibrosis. Adjusted odds ratios (ORs) and hazards ratios (HRs) were pooled and analyzed using random-effects model.

RESULTS:

Nine studies with 5 976 026 patients were included in this meta-analysis. Prevalence of hepatic fibrosis was evaluated in nonalcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV), and hepatitis C and HIV coinfection by two, four, and one studies. Progression of hepatic fibrosis was evaluated by two studies. Pooled OR for prevalence of fibrosis was 0.91 (0.72-1.15), I=75%. On subgroup analysis, pooled OR among NAFLD patients was 0.80 (0.75-0.86), I=0% and pooled OR among HCV patients was 1.96 (0.78-4.92), I=77%. Among studies evaluating HR, pooled HR for progression of fibrosis in HCV-HIV co-infected patients was 1.03 (0.96-1.11), I=0%.

CONCLUSION:

Marijuana use did not increase the prevalence or progression of hepatic fibrosis in HCV and HCV-HIV-coinfected patients. On the contrary, we noted a reduction in the prevalence of NAFLD in marijuana users. Future studies are needed to further understand the therapeutic impact of cannabidiol-based formulations in the management of NAFLD.”

https://www.ncbi.nlm.nih.gov/pubmed/30234644

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Cannabis in liver disorders: a friend or a foe?

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“The recent legalization of recreational marijuana use in some parts of the world, the discovery of new indications for the clinical application of cannabis, and the acceptance of the use of cannabis in practice has been paralleled by extensive research on the active components of cannabis and the endocannabinoid system within the human body.

In this review, we evaluate the available evidence on cannabis and its constituents and the application of this evidence in clinical practice, focusing particularly on the liver and liver diseases.

Constituents of cannabis, such as cannabidiol and Δ-tetrahydrocannabinol, have shown anti-inflammatory, antioxidant, and hepatoprotective effects both in in vitro and clinical studies, and appear to have potential in the symptom management and treatment of various liver diseases that were previously considered difficult to manage conservatively.

In addition, the manipulation of the inherent endocannabinoid response system has found favor in many clinical fields and has generated considerable research and clinical interest. Moreover, evidence with regard to the adverse effects of marijuana use in liver diseases is weak, which has led to raise a question on the prior rules, with regard to a denial of liver transplantation to marijuana users.

All in all, the recent trends in research, clinical experiences, as well as the legislature, has opened up new avenues towards the widespread clinical application of cannabis and its derivatives as well as modifiers of the components of the endocannabinoid system. More research is required to fully exploit these new evidences.”

https://www.ncbi.nlm.nih.gov/pubmed/30169449

https://insights.ovid.com/crossref?an=00042737-900000000-97980

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Cannabinoids and reduced risk of hepatic steatosis in HIV-HCV co-infection: paving the way for future clinical research

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“Whether or not cannabis itself or cannabinoids contained in it may help to reduce hepatic steatosis in HIV-HCV coinfected patients remains an open question. The existing body of knowledge on the interactions between cannabis and the liver suggest a protective effect of cannabinoids on insulin resistance, diabetes, and NAFLD in the general population. Clinical research with randomized study designs is needed to evaluate the efficacy and safety of cannabis-based pharmacotherapies in HIV-HCV coinfected patients. Targeting the endocannabinoid system seems essential to differently manage several pathological conditions such as intestinal inflammation, obesity, diabetes and fatty liver disease. However, to date, few drugs have been tested in clinical trials. CB1-antagonists and CB2 agonists appear to be viable therapeutic options that need to be explored for the management of liver diseases. As HCV cure rates are coming close to 100% in the era of direct-acting antivirals, it is especially important to be able to identify modifiable risk factors of complications and death in HIV-HCV coinfected patients, as well as possible levers for intervention. Given the persistence of metabolic risk factors after HCV eradication, cannabis-based therapies need to be evaluated both as preventive and therapeutic tools in patients living with or at risk of liver steatosis, possibly in combination with existing conventional approaches.”

https://www.tandfonline.com/doi/full/10.1080/14787210.2018.1473764

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Long-Term Heavy Recreational Cannabis Use and Serum Delta-9-Tetrahydrocannabinol Levels are not Associated with an Impaired Liver Function in Cannabis Dependents.

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“To shed more light on the influence of chronic cannabis use on liver function, we performed a post-hoc analysis of routine lab data of 42 inpatient treatment-seeking (9 female, median: 27 years old) pure cannabis dependents. Serum liver function tests (LFT: transaminases, bilirubin), C-reactive protein (CRP), carbohydrate-deficient transferrin (CDT), and body mass index (BMI) were considered. The LFT were correlated with CDT, BMI, and cannabis-related clinical data (CR); i.e., the serum levels of delta-9-tetrahydrocannabinol (THC) and its major metabolites 11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), plus the cannabis-history data. The LFT was normal in 32 (76.2%) patients. There was no significant association of LFT with BMI, CRP, CDT, and CR. No significant differences were found between the group with elevated LFT (N = 10) and the group without elevated LFT (N = 32) regarding BMI, CRP, CDT, and CR, except for THC-OH, which was even lower in the elevated-LFT group. These results argue against a relevant harmful impact of chronic cannabis inhalation on the liver function of relatively healthy humans (apart from nicotine dependence). Specifically, the liver function tests were not significantly influenced by THC and THC-COOH levels, both objective markers for the amount and duration of prior cannabis use.”

https://www.ncbi.nlm.nih.gov/pubmed/30052163

https://www.tandfonline.com/doi/abs/10.1080/02791072.2018.1482031?journalCode=ujpd20

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