Article

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

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Abstract

Background: 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.

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... In the clinic, cannabis is mainly used for alleviating certain types of chronic pain, including pain from nerve damage, cancer, inflammation, and spasticity. Increasing evidence has shown that cannabis intake is associated with a lower risk of NAFLD (Adejumo et al., 2017;Kim et al., 2017;Farooqui et al., 2019). However, the causal relationship between cannabis consumption and the NAFLD risk in humans remains unclear. ...
... Adejumo et al. (2017) demonstrated that cannabis use was associated with a lower prevalence of NAFLD. A meta-analysis also showed cannabis use reduced the prevalence of NAFLD (Farooqui et al., 2019). However, the majority of these studies are cross-sectional and retrospective observational analyses, without an examination for causality. ...
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... This is especially intriguing because while marijuana use is associated with alcohol use, lower socioeconomic status, and increased calorie intake (including more soda); there is also reduced risk of obesity, diabetes, and MetS [65]. Additionally, in a metanalysis of biopsy studies, cannabis does not appear to worsen fibrosis in patients who already have NAFLD or chronic liver disease due to other etiologies [66], although there are few studies in this area. Potential mechanisms include an anti-inflammatory effect of cannabanoids [65] and modulation of lipid metabolism via hepatic endocannabinoids [67]. ...
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Classically, Non-Alcoholic Fatty Liver Disease (NAFLD) has been thought to be driven by excessive weight gain and obesity. The overall greater awareness of this disorder has led to its recognition in patients with normal body mass index (BMI). Ongoing research has helped to better understand potential causes of Lean NAFLD, the risks for more advanced disease, and potential therapies. Here we review the recent literature on prevalence, risk factors, severity of disease, and potential therapeutic interventions.
... There are conflicting data from studies of animal models as to whether cannabis contributes to or protects against fibrosis 102,108 . In population-level studies, cannabis has been shown to possibly be protective against fibrosis progression, likely through antiinflammatory pathways, via CB2, or other pathways 109 . Further research is needed in this topic. ...
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Medical and recreational cannabis use has increased dramatically over the last decade, resulting from mainstream cultural acceptance and legalization in several countries worldwide. Cannabis and its derivatives affect many gastrointestinal processes, via the endocannabinoid system (ECS). The ECS influences gastrointestinal homeostasis through anti-inflammatory, anti-nociceptive, and anti-secretory effects. Some gastrointestinal disorders might therefore be treated with cannabinoids. Despite numerous studies in cell lines and animals, few human studies have evaluated the therapeutic effects of cannabinoids. Cannabis’ schedule 1 drug status has limited its availability in research; cannabis has been only recently legalized, in some states, for medicinal and/or recreational use. Cannabinoids can alleviate chemotherapy-induced nausea and emesis and chronic pain. Studies have demonstrated the important roles of the ECS in metabolism, obesity, and non-alcoholic fatty liver disease and the anti-inflammatory effects of cannabis have been investigated in patients with inflammatory bowel diseases. Despite its potential benefits, undesired or even detrimental effects of cannabis can limit its use. Side effects such as cannabinoid hyperemesis syndrome affect some users. We review the ECS and the effects of cannabis and its derivatives on gastrointestinal and hepatic function in health and disease.
... Coffee is widely known to have hepatoprotective properties [22] and, in the HEPAVIH population, consumption of three or more cups/day was a major protective factor of overall mortality [15]. Cannabis use was previously associated with reduced risk of insulin resistance [23] and liver steatosis [24] in HIV/ HCV co-infected patients, and also in the general population [25], but no significant effect on liver fibrosis has been highlighted [26,27]. We hypothesized that the benefits of cannabis can also be observed for HCV-related mortality. ...
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Chapter
Cannabis education is an important step toward mitigating risks and promoting patient safety. It is important for healthcare providers to understand the considerations, precautions, relative contraindications, and contraindications associated with cannabinoid use. This allows for healthcare providers to accurately assess the benefits and risks of medical cannabis use for each patient individually. General contraindications for cannabis use include those who have severe and unstable cardiac and pulmonary conditions, psychosis, those who are pregnant/breastfeeding, and adolescents. As with any psychoactive medication, strategies to mitigate cannabis adverse events include “starting low and going slow,” shorter trial period, more frequent monitoring and reassessment for efficacy, adverse events, and drug interactions. The majority of adverse events are THC dose-dependent. As such, CBD-dominant products may be a useful alternative or addition to THC to mitigate risks.
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Background: Marijuana smoking is prevalent among hepatitis C virus-infected patients. The literature assessing the influence of marijuana on liver disease progression and hepatitis C virus antiviral treatment outcomes is conflicting. Methods: The authors evaluated hepatitis C virus RNA-positive patients followed at The Ottawa Hospital Viral Hepatitis Clinic (Ottawa, Ontario) from 2000 to 2009. Using The Ottawa Hospital Viral Hepatitis Clinic database and charts, information regarding demographics, HIV coinfection, alcohol use, liver biopsy results, treatment outcomes and self-reported marijuana use was extracted. Biopsy characteristics and hepatitis C virus antiviral treatment outcomes were assessed for association with categorized marijuana use by adjusted logistic regression; covariates were specified according to clinical relevance a priori. Results: Information regarding marijuana use was available for 550 patients, 159 (28.9%) of whom were using marijuana at the time of first assessment. Biopsy fibrosis stage and marijuana use data were available for 377 of these 550 (F0-2 = 72.3%). Overall, marijuana use did not predict fibrosis stage, inflammation grade or steatosis. Sustained virological response and marijuana use data were available for 359 of the 550 cohort participants; a total of 211 (58.8%) achieved a sustained virological response. Marijuana use was not associated with premature interruption of therapy for side effects, the likelihood of completing a full course of therapy or sustained virological response. Conclusion: Marijuana use did not influence biopsy histology or alter key hard outcomes of hepatitis C virus antiviral therapy.
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The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity, and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type-1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist, rimonabant, in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo(-/-)) mice and their wild-type littermate controls (Adipo(+/+)). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo(+/+) and Adipo(-/-) mice, while it reversed the HFD-induced hepatic steatosis, fibrosis and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin.
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Background. Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons. Methods. Data were analyzed for 690 HCV polymerase chain reaction positive (PCR-positive) individuals without significant fibrosis or end-stage liver disease (ESLD) at baseline. Time-updated Cox Proportional Hazards models were used to assess the association between the average number of joints smoked/week and progression to significant liver fibrosis (APRI≥1.5), cirrhosis (APRI≥2) or ESLD. Results. At baseline, 53% had smoked marijuana in the past 6 months, consuming a median of 7 joints/week (IQR, 1–21); 40% smoked daily. There was no evidence that marijuana smoking accelerates progression to significant liver fibrosis (APRI≥1.5) or cirrhosis (APRI≥2; hazard ratio [HR]: 1.02 [0.93–1.12] and 0.99 [0.88–1.12], respectively). Each 10 additional joints/week smoked slightly increased the risk of progression to a clinical diagnosis of cirrhosis and ESLD combined (HR, 1.13 [1.01–1.28]). However, when exposure was lagged to 6–12 months before the diagnosis, marijuana was no longer associated with clinical disease progression (HR, 1.10 [0.95–1.26]). Conclusions. In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection. A slight increase in the hazard of cirrhosis and ESLD with higher intensity of marijuana smoking was attenuated after lagging marijuana exposure, suggesting that reverse causation due to self-medication could explain previous results.
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Because of the pressure for timely, informed decisions in public health and clinical practice and the explosion of information in the scientific literature, research results must be synthesized. Meta-analyses are increasingly used to address this problem, and they often evaluate observational studies. A workshop was held in Atlanta, Ga, in April 1997, to examine the reporting of meta-analyses of observational studies and to make recommendations to aid authors, reviewers, editors, and readers. Twenty-seven participants were selected by a steering committee, based on expertise in clinical practice, trials, statistics, epidemiology, social sciences, and biomedical editing. Deliberations of the workshop were open to other interested scientists. Funding for this activity was provided by the Centers for Disease Control and Prevention. We conducted a systematic review of the published literature on the conduct and reporting of meta-analyses in observational studies using MEDLINE, Educational Research Information Center (ERIC), PsycLIT, and the Current Index to Statistics. We also examined reference lists of the 32 studies retrieved and contacted experts in the field. Participants were assigned to small-group discussions on the subjects of bias, searching and abstracting, heterogeneity, study categorization, and statistical methods. From the material presented at the workshop, the authors developed a checklist summarizing recommendations for reporting meta-analyses of observational studies. The checklist and supporting evidence were circulated to all conference attendees and additional experts. All suggestions for revisions were addressed. The proposed checklist contains specifications for reporting of meta-analyses of observational studies in epidemiology, including background, search strategy, methods, results, discussion, and conclusion. Use of the checklist should improve the usefulness of meta-analyses for authors, reviewers, editors, readers, and decision makers. An evaluation plan is suggested and research areas are explored.
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Over the last decade, the endocannabinoid system has emerged as a pivotal mediator of acute and chronic liver injury, with the description of the role of CB1 and CB2 receptors and their endogenous lipidic ligands in various aspects of liver pathophysiology. A large number of studies have demonstrated that CB1 receptor antagonists represent an important therapeutic target, owing to beneficial effects on lipid metabolism and in light of its antifibrogenic properties. Unfortunately, the brain-penetrant CB1 antagonist rimonabant, initially approved for the management of overweight and related cardiometabolic risks, was withdrawn because of an alarming rate of mood adverse effects. However, the efficacy of peripherally-restricted CB1 antagonists with limited brain penetrance has now been validated in preclinical models of NAFLD, and beneficial effects on fibrosis and its complications are anticipated. CB2 receptor is currently considered as a promising anti-inflammatory and antifibrogenic target, although clinical development of CB2 agonists is still awaited. In this review, we highlight the latest advances on the impact of the endocannabinoid system on the key steps of chronic liver disease progression and discuss the therapeutic potential of molecules targeting cannabinoid receptors.
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To determine the association between diabetes mellitus (DM) and marijuana use. Cross-sectional study. Data from the National Health and Nutrition Examination Survey (NHANES III, 1988-1994) conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. The study included participants of the NHANES III, a nationally representative sample of the US population. The total analytic sample was 10 896 adults. The study included four groups (n=10 896): non-marijuana users (61.0%), past marijuana users (30.7%), light (one to four times/month) (5.0%) and heavy (more than five times/month) current marijuana users (3.3%). DM was defined based on self-report or abnormal glycaemic parameters. We analysed data related to demographics, body mass index, smoking status, alcohol use, total serum cholesterol, high-density lipoprotein, triglyceride, serum 25-hydroxy vitamin D, plasma haemoglobin A1c, fasting plasma glucose level and the serum levels of C reactive protein and four additional inflammatory markers as related to marijuana use. OR for DM associated with marijuana use adjusted for potential confounding variables (ie, odds of DM in marijuana users compared with non-marijuana users). Marijuana users had a lower age-adjusted prevalence of DM compared to non-marijuana users (OR 0.42, 95% CI 0.33 to 0.55; p<0.0001). The prevalence of elevated C reactive protein (>0.5 mg/dl) was significantly higher (p<0.0001) among non-marijuana users (18.9%) than among past (12.7%) or current light (15.8%) or heavy (9.2%) users. In a robust multivariate model controlling for socio-demographic factors, laboratory values and comorbidity, the lower odds of DM among marijuana users was significant (adjusted OR 0.36, 95% CI 0.24 to 0.55; p<0.0001). Marijuana use was independently associated with a lower prevalence of DM. Further studies are needed to show a direct effect of marijuana on DM.
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Non-alcoholic fatty liver disease (NAFLD) is a frequent accompaniment of obesity and insulin resistance. With the prevalence approaching 85% in obese populations, new therapeutic approaches to manage NAFLD are warranted. A systematic search of the literature was conducted for studies pertaining to the effect of omega-3 polyunsaturated fatty acid (PUFA) supplementation on NAFLD in humans. Primary outcome measures were liver fat and liver function tests: alanine aminotransferase (ALT) and aspartate aminotransferase [1]. Data were pooled and meta-analyses conducted using a random effects model. Nine eligible studies, involving 355 individuals given either omega-3 PUFA or control treatment were included. Beneficial changes in liver fat favoured PUFA treatment (effect size=-0.97, 95% CI: -0.58 to -1.35, p<0.001). A benefit of PUFA vs. control was also observed for AST (effect size=-0.97, 95% CI: -0.13 to -1.82, p=0.02). There was a trend towards favouring PUFA treatment on ALT but this was not significant (effect size=-0.56, 95% CI: -1.16 to 0.03, p=0.06). Sub-analyses of only randomised control trials (RCTs) showed a significant benefit for PUFA vs. control on liver fat (effect size=-0.96, 95% CI: -0.43 to -1.48, p<0.001), but not for ALT (p=0.74) or AST (p=0.28). There was significant heterogeneity between studies. The pooled data suggest that omega-3 PUFA supplementation may decrease liver fat, however, the optimal dose is currently not known. Well designed RCTs which quantify the magnitude of effect of omega-3 PUFA supplementation on liver fat are needed.
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The role of cannabis and endocannabinoids in appetite regulation has been extensively studied, but the association of cannabis use with weight in the general population is not known. The authors used data from 2 representative epidemiologic studies of US adults aged 18 years or older, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; 2001–2002) and the National Comorbidity Survey–Replication (NCS-R; 2001–2003), to estimate the prevalence of obesity as a function of cannabis use. The adjusted prevalences of obesity in the NESARC and the NCS-R were 22.0% and 25.3%, respectively, among participants reporting no use of cannabis in the past 12 months and 14.3% and 17.2%, respectively, among participants reporting the use of cannabis at least 3 days per week. These differences were not accounted for by tobacco smoking status. Additionally, after adjustment for sex and age, the use of cannabis was associated with body mass index differences in both samples. The authors conclude that the prevalence of obesity is lower in cannabis users than in nonusers.
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The major cellular event in the development and progression of liver fibrosis is the activation of hepatic stellate cells (HSCs). Activated HSCs proliferate and produce excess collagen, leading to accumulation of scar matrix and fibrotic liver. As such, the induction of activated HSC death has been proposed as a means to achieve resolution of liver fibrosis. Here we demonstrate that cannabidiol (CBD), a major non-psychoactive component of the plant Cannabis sativa, induces apoptosis in activated HSCs through a cannabinoid receptor-independent mechanism. CBD elicits an endoplasmic reticulum (ER) stress response, characterized by changes in ER morphology and the initiation of RNA-dependent protein kinase-like ER kinase-, activating transcription factor-6-, and inositol-requiring ER-to-nucleus signal kinase-1 (IRE1)-mediated signaling cascades. Furthermore, CBD induces downstream activation of the pro-apoptotic IRE1/ASK1/c-Jun N-terminal kinase pathway, leading to HSC death. Importantly, we show that this mechanism of CBD-induced ER stress-mediated apoptosis is specific to activated HSCs, as it occurs in activated human and rat HSC lines, and in primary in vivo-activated mouse HSCs, but not in quiescent HSCs or primary hepatocytes from rat. Finally, we provide evidence that the elevated basal level of ER stress in activated HSCs has a role in their susceptibility to the pro-apoptotic effect of CBD. We propose that CBD, by selectively inducing death of activated HSCs, represents a potential therapeutic agent for the treatment of liver fibrosis.
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Alcohol abuse is a major cause of liver fibrosis and cirrhosis in developed countries. Alcoholic liver disease (ALD) is distinctively characterized by a pronounced inflammatory response due to elevated gut-derived endotoxin plasma levels, an augmented generation of oxidative stress with pericentral hepatic hypoxia and the formation of noxious ethanol metabolites (e.g. acetaldehyde or lipid oxidation products). These factors, based on a complex network of cytokine actions, together result in increased hepatocellular damage and activation of hepatic stellate cells, the key cell type of liver fibrogenesis. Recent studies suggest that the endocannabinoid system is a signaling system that also plays an important role in the pathogenesis of ALD. A study comparing chronic alcohol administration in cannabinoid receptor (CB) 1 or CB2 knockout versus wild-type mice revealed that CB1 signaling aggravated hepatic steatosis and fibrogenesis whereas CB2 protected the liver from ALD. These data suggested a protective role of CB2 (in contrast to CB1) in ALD. Similar results were found in global or hepatocyte-specific CB1 knockout mice that were resistant to ethanol-induced steatosis. Moreover, ethanol feeding upregulated the endocannabinoid 2-arachidonoyl glycerol and its biosynthetic enzyme diacylglycerol lipase-β selectively in hepatic stellate cells and subsequently increased expression of CB1 receptors in hepatocytes of wild-type mice leading to CB1-dependent hepatic steatosis by activation of lipogenic pathways. This ethanol-induced upregulation of CB1 receptors was partly dependent on the ethanol metabolite acetaldehyde. Thus, the hepatic endocannabinoid system offers emerging options for therapeutic exploitation not only for liver disease in general, but also for ALD.
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Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.
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Dietary (n-3) long-chain PUFA [(n-3) LCPUFA] ameliorate several metabolic risk factors for cardiovascular diseases, although the mechanisms of these beneficial effects are not fully understood. In this study, we compared the effects of dietary (n-3) LCPUFA, in the form of either fish oil (FO) or krill oil (KO) balanced for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content, with a control (C) diet containing no EPA and DHA and similar contents of oleic, linoleic, and alpha-linolenic acids, on ectopic fat and inflammation in Zucker rats, a model of obesity and related metabolic dysfunction. Diets were fed for 4 wk. Given the emerging evidence for an association between elevated endocannabinoid concentrations and metabolic syndrome, we also measured tissue endocannabinoid concentrations. In (n-3) LCPUFA-supplemented rats, liver triglycerides and the peritoneal macrophage response to an inflammatory stimulus were significantly lower than in rats fed the control diet, and heart triglycerides were lower, but only in KO-fed rats. These effects were associated with a lower concentration of the endocannabinoids, anandamide and 2-arachidonoylglycerol, in the visceral adipose tissue and of anandamide in the liver and heart, which, in turn, was associated with lower levels of arachidonic acid in membrane phospholipids, but not with higher activity of endocannabinoid-degrading enzymes. Our data suggest that the beneficial effects of a diet enriched with (n-3) LCPUFA are the result of changes in membrane fatty acid composition. The reduction of substrates for inflammatory molecules and endocannabinoids may account for the dampened inflammatory response and the physiological reequilibration of body fat deposition in obese rats.
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To assess and compare the quality of nonstructured and structured abstracts of original research articles in three medical journals. Blind, criterion-based observational study. Random sample of 300 abstracts (25 abstracts per journal each year) of articles published in the British Medical Journal (BMJ), the Canadian Medical Association Journal and the Journal of the American Medical Association (JAMA) in 1988 and 1989 (nonstructured abstracts) and in 1991 and 1992 (structured abstracts). The quality of abstracts was measured against 33 objective criteria, which were divided into eight categories (purpose, research design, setting, subjects, intervention, measurement of variables, results and conclusions). The quality score was determined by dividing the number of criteria present by the number applicable; the score varied from 0 to 1. The overall mean quality scores for nonstructured and structured abstracts were 0.57 and 0.74 respectively (p < 0.001). The frequency in meeting the specific criteria was generally higher for the structured abstracts than for the nonstructured ones. The mean quality score was higher for nonstructured abstracts in JAMA than for those in BMJ (0.60 v. 0.54, p < 0.05). The scores for structured abstracts did not differ significantly between the three journals. The findings support recommendations that promote the use of structured abstracts. Further studies should be performed to assess the effect of time on the quality of abstracts and the extent to which abstracts reflect the content of the articles.
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This study examined dietary intakes and nutritional status of marijuana users and non-current marijuana users in US adults aged 20 to 59 years. We used data from the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Information on self-reported drug use, including marijuana, was obtained as part of the NHANES III physical examination component. Nutritional status was assessed using height and weight, and blood biochemistries. Dietary intake was assessed using a 24-hour recall and a food-frequency questionnaire. Among adults 20-59 years of age, 45% reported ever having used marijuana in their lifetime. A total of 8.7% reported using marijuana in the past month. Current marijuana users had higher intakes of energy and nutrients than non-current marijuana users; however, body mass index (BMI) was slightly lower. We found higher cigarette-smoking rates and higher consumption of sodas and alcohol, specifically beer, among marijuana users than among non-current marijuana users. Marijuana users also consumed more sodium, fewer fruits, and more pork, cheese, and salty snacks. Nutritional status, using indicators of serum nutrients, serum albumin, haematocrit and haemoglobin, was similar between marijuana users and non-current marijuana users. Serum carotenoid levels were lower among marijuana users, independent of cigarette smoking. Dietary intake was different among marijuana users than among non-current marijuana users. Although overall nutritional status was similar, serum carotenoid levels were lower in marijuana users. The long-term health effects of these differences in marijuana users deserve careful consideration in future research.
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To explore the association between chronic cannabis abuse and a cyclical vomiting illness that presented in a series of cases in South Australia. Nineteen patients were identified with chronic cannabis abuse and a cyclical vomiting illness. For legal and ethical reasons, all patients were counselled to cease all cannabis abuse. Follow up was provided with serial urine drug screen analysis and regular clinical consultation to chart the clinical course. Of the 19 patients, five refused consent and were lost to follow up and five were excluded on the basis of confounders. The remaining nine cases are presented here and compared with a published case of psychogenic vomiting. In all cases, including the published case, chronic cannabis abuse predated the onset of the cyclical vomiting illness. Cessation of cannabis abuse led to cessation of the cyclical vomiting illness in seven cases. Three cases, including the published case, did not abstain and continued to have recurrent episodes of vomiting. Three cases rechallenged themselves after a period of abstinence and suffered a return to illness. Two of these cases abstained again, and became and remain well. The third case did not and remains ill. A novel finding was that nine of the 10 patients, including the previously published case, displayed an abnormal washing behaviour during episodes of active illness. We conclude that chronic cannabis abuse was the cause of the cyclical vomiting illness in all cases, including the previously described case of psychogenic vomiting.
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Endogenous cannabinoids acting at CB(1) receptors stimulate appetite, and CB(1) antagonists show promise in the treatment of obesity. CB(1) (-/-) mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB(1) in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB(1) agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB(1). High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB(1) density, and basal rates of fatty acid synthesis, and the latter is reduced by CB(1) blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB(1) ligands. We conclude that anandamide acting at hepatic CB(1) contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.
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Hepatic fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide. We recently showed that activation of hepatic cannabinoid CB2 receptors limits progression of experimental liver fibrosis. We also found that during the course of chronic hepatitis C, daily cannabis use is an independent predictor of fibrosis progression. Overall, these results suggest that endocannabinoids may drive both CB2-mediated antifibrogenic effects and CB2-independent profibrogenic effects. Here we investigated whether activation of cannabinoid CB1 receptors (encoded by Cnr1) promotes progression of fibrosis. CB1 receptors were highly induced in human cirrhotic samples and in liver fibrogenic cells. Treatment with the CB1 receptor antagonist SR141716A decreased the wound-healing response to acute liver injury and inhibited progression of fibrosis in three models of chronic liver injury. We saw similar changes in Cnr1-/- mice as compared to wild-type mice. Genetic or pharmacological inactivation of CB1 receptors decreased fibrogenesis by lowering hepatic transforming growth factor (TGF)-beta1 and reducing accumulation of fibrogenic cells in the liver after apoptosis and growth inhibition of hepatic myofibroblasts. In conclusion, our study shows that CB1 receptor antagonists hold promise for the treatment of liver fibrosis.
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Highlighting the association between schizophrenia and Cannabis sativa and the endogenous cannabinoid receptor system, respectively, two opposite aspects are of major relevance. On the one hand, cannabis is the most widely used illegal drug. There is substantial evidence that cannabis has to be classified as an independent risk factor for psychosis that may lead to a worse outcome of the disease. This risk seems to be increased in genetically predisposed people and may depend on the amount of cannabis used. On the other hand, during the last few years, an endogenous cannabinoid receptor system (including two known cannabinoid [CB(1) and CB(2)] receptors and five endogenous ligands) has been discovered. There are several lines of evidence suggesting that, at least in a subgroup of patients, alterations in the endocannabinoid system may contribute to the pathogenesis of schizophrenia (e.g., increased density of CB(1) receptor binding and increased levels of cerebrospinal fluid endocannabinoid anandamide). Accordingly, beside the 'dopamine hypothesis' of schizophrenia, a 'cannabinoid hypothesis' has been suggested. Interestingly, there is a complex interaction between the dopaminergic and the endocannabinoid receptor system. Thus, agents that interact with the cannabinoid receptor system, such as the nonpsychoactive cannabidiol, might be beneficial in the treatment of psychosis.
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Liver steatosis is common in Human Immunodeficiency Virus (HIV) - Hepatitis C Virus (HCV) co-infected patients. Some recent studies have found that cannabis use is negatively associated with insulin resistance in the general population and in HIV-HCV co-infected patients. Given the causal link between insulin resistance and steatosis, we hypothesized that cannabis use has a positive impact on steatosis. Therefore, we aimed to study whether cannabis use in this population was associated with a reduced risk of steatosis, measured by ultrasound examination. The ANRS CO13-HEPAVIH cohort is a French nationwide multicenter of HIV-HCV co-infected patients. Medical and socio-behavioral data from clinical follow-up visits and annual self-administered questionnaires were prospectively collected. A cross-sectional analysis was conducted using data from the first visit where both ultrasound examination data for steatosis (positive or negative diagnosis) and data on cannabis use were available. A logistic regression model was used to evaluate the association between cannabis use and steatosis. Among study sample patients (n=838), 40.1% had steatosis. Fourteen percent reported daily cannabis use, 11.7% regular use, and 74.7% no use or occasional use (“never or sometimes”). Daily cannabis use was independently associated with a reduced prevalence of steatosis (adjusted odds ratio [95%]=0.64 [0.42;0.99]; p=0.046), after adjusting for body mass index, hazardous alcohol consumption and current or lifetime use of lamivudine/zidovudine. Daily cannabis use may be a protective factor against steatosis in HIV-HCV co-infected patients. These findings confirm the need for a clinical evaluation of cannabis-based pharmacotherapies in this population. Eudract.ema.europa.eu number, DGS050367.
Article
Background: Marijuana (THC) use has been associated with liver fibrosis progression in retrospective analyses of chronic hepatitis C (HCV) patients. We studied long-term effects of THC on fibrosis progression in women co-infected with HIV/HCV enrolled in Women's Interagency HIV Study (WIHS). Methods: Liver fibrosis was categorized according to FIB-4 scores as none, moderate, or significant. THC and alcohol use were quantified as average exposure per week. Associations between THC use and progression to significant fibrosis were assessed using Cox proportional hazards regression. Results: Among 575 HIV/HCV co-infected women followed for 11 (6-17) years [median (IQR)], 324 (56%) reported no THC use; 141 (25%) reported less than weekly use; 70 (12%) weekly use; and 40 (7%) daily use at WIHS entry. In univariable analysis, entry FIB-4 [HR 2.26 (1.88-2.73) p<0.001], log HCV RNA [HR 1.19 (1.02-1.38) p=0.02], tobacco use [HR 1.37 (1.02-1.85) p=0.04], CD4+ count [risk per 100 count increase HR 0.90 (0.86-0.95) p<0.001] and log HIV RNA [HR 1.18 (1.05-1.32) p=0.005] were associated with progression to significant fibrosis, as was cumulative alcohol use in follow-up [HR 1.03 (1.02-1.04) p<0.001]. In multivariable analysis, entry FIB-4, entry CD4+ count and cumulative alcohol use remained significant. Cumulative THC use was not associated with fibrosis progression [HR 1.01(95% CI 0.92-1.10) p=0.83]. Conclusions: In this large cohort of HIV/HCV co-infected women, THC was not associated with progression to significant liver fibrosis. Alcohol use was independently associated with liver fibrosis, and may better predict fibrosis progression in HIV/HCV co-infected women.
Article
Objectives. —To estimate the rate of full publication of the results of randomized clinical trials initially presented as abstracts at national ophthalmology meetings in 1988 and 1989; and to combine data from this study with data from similar studies to determine the rate at which abstracts are subsequently published in full and the association between selected study characteristics and full publication. Data Sources. —Ophthalmology abstracts were identified by review of 1988 and 1989 meeting abstracts for the Association for Research in Vision and Ophthalmology and the American Academy of Ophthalmology. Similar studies were identified either from reports contained in our files or through a MEDLINE search, which combined the textword "abstract" with "or" statements to the Medical Subject Headings ABSTRACTING & INDEXING, CLINICAL TRIALS, PEER REVIEW, PERIODICALS, MEDICAL SOCIETIES, PUBLISHING, MEDLINE, INFORMATION SERVICES, and REGISTRIES. Study Selection. —Ophthalmolgy abstracts were selected from the meeting proceedings if they reported results from a randomized controlled trial. For the summary study, similar studies were eligible for inclusion if they described followup and subsequent full publication for a cohort of abstracts describing the results of any type of research study. All studies had to have followed up abstracts for at least 24 months to be included. Data Extraction. —Authors of ophthalmology abstracts were contacted by letter to ascertain whether there was subsequent full publication. Other information, including characteristics of the study design possibly related to publication, was taken from the abstract. For the summary study, rates of full publication were taken directly from reported results, as were associations between study factors (ie, "significant' results and sample size) and full publication. Data Synthesis. —Sixty-six percent (61/93) of ophthalmology abstracts were published in full. Combined results from 11 studies showed that 51% (1198/2391) of all abstracts were subsequently published in full. Full publication was weakly associated with "significant" results and sample size above the median. Conclusions. —Approximately one half of all studies initially presented in abstract form are subsequently published as full-length reports. Most are published in full within 2 years of appearance as abstracts. Full publication may be associated with "significant" results and sample size.(JAMA. 1994;272:158-162)
Article
This technical report updates the 2004 American Academy of Pediatrics technical report on the legalization of marijuana. Current epidemiology of marijuana use is presented, as are definitions and biology of marijuana compounds, side effects of marijuana use, and effects of use on adolescent brain development. Issues concerning medical marijuana specifically are also addressed. Concerning legalization of marijuana, 4 different approaches in the United States are discussed: legalization of marijuana solely for medical purposes, decriminalization of recreational use of marijuana, legalization of recreational use of marijuana, and criminal prosecution of recreational (and medical) use of marijuana. These approaches are compared, and the latest available data are presented to aid in forming public policy. The effects on youth of criminal penalties for marijuana use and possession are also addressed, as are the effects or potential effects of the other 3 policy approaches on adolescent marijuana use. Recommendations are included in the accompanying policy statement. Copyright © 2015 by the American Academy of Pediatrics.
Article
Endogenous cannabinoids (EC) are ubiquitous lipid signalling molecules providing different central and peripheral effects that are mediated mostly by the specific receptors CB1 and CB2. The EC system is highly upregulated during chronic liver disease and consistent experimental and clinical findings indicate that it plays a role in the pathogenesis of liver fibrosis and fatty liver disease associated with obesity, alcohol abuse and hepatitis C. Furthermore, a considerable number of studies have shown that EC and their receptors contribute to the pathogenesis of the cardio-circulatory disturbances occurring in advanced cirrhosis, such as portal hypertension, hyperdynamic circulatory syndrome and cirrhotic cardiomyopathy. More recently, the EC system has been implicated in the development of ascites, hepatic encephalopathy and the inflammatory response related to bacterial infection. Rimonabant, a selective CB1 antagonist, was the first drug acting on the EC system approved for the treatment of obesity. Unfortunately, it has been withdrawn from the market because of its neuropsychiatric side effects. Compounds able to target selectively the peripheral CB1 receptors are under evaluation. In addition, molecules stimulating CB2 receptor or modulating the activity of enzymes implicated in EC metabolism are promising areas of pharmacological research. Liver cirrhosis and the related complications represent an important target for the clinical application of these compounds.
Article
Background: There are limited data regarding the relationship between cannabinoids and metabolic processes. Epidemiologic studies have found lower prevalence rates of obesity and diabetes mellitus in marijuana users compared with people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes. To date, no study has investigated the relationship between marijuana use and fasting insulin, glucose, and insulin resistance. Methods: We included 4657 adult men and women from the National Health and Nutrition Examination Survey from 2005 to 2010. Marijuana use was assessed by self-report in a private room. Fasting insulin and glucose were measured via blood samples after a 9-hour fast, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance. Associations were estimated using multiple linear regression, accounting for survey design and adjusting for potential confounders. Results: Of the participants in our study sample, 579 were current marijuana users and 1975 were past users. In multivariable adjusted models, current marijuana use was associated with 16% lower fasting insulin levels (95% confidence interval [CI], -26, -6) and 17% lower HOMA-IR (95% CI, -27, -6). We found significant associations between marijuana use and smaller waist circumferences. Among current users, we found no significant dose-response. Conclusions: We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR, and smaller waist circumference.
Article
Chronic liver diseases represent a major health problem due to cirrhosis and its complications. During the last decade, endocannabinoids and their receptors have emerged as major regulators of several pathophysiological aspects associated with chronic liver disease progression. Hence, hepatic cannabinoid receptor 2 (CB(2)) receptors display beneficial effects on alcoholic fatty liver, hepatic inflammation, liver injury, regeneration and fibrosis. Cannabinoid receptor 1 (CB(1)) receptors have been implicated in the pathogenesis of several lesions such as alcoholic and metabolic steatosis, liver fibrogenesis, or circulatory failure associated with cirrhosis. Although the development of CB(1) antagonists has recently been suspended due to the high incidence of central side effects, preliminary preclinical data obtained with peripherally restricted CB(1) antagonists give real hopes in the development of active CB(1) molecules devoid of central adverse effects. CB(2) -selective molecules may also offer novel perspectives for the treatment of liver diseases, and their clinical development is clearly awaited. Whether combined treatment with a peripherally restricted CB(1) antagonist and a CB(2) agonist might result in an increased therapeutic potential will warrant further investigation.
Article
Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors.
Article
Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and it is present in both brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases and contributes to the underlying pathologies. In patients with cirrhosis of various etiologies, the activation of vascular and cardiac CB(1) receptors by macrophage-derived and platelet-derived endocannabinoids contributes to the vasodilated state and cardiomyopathy, which can be reversed by CB(1) blockade. In mouse models of liver fibrosis, the activation of CB(1) receptors on hepatic stellate cells is fibrogenic, and CB(1) blockade slows the progression of fibrosis. Fatty liver induced by a high-fat diet or chronic alcohol feeding depends on the activation of peripheral receptors, including hepatic CB(1) receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB(1) blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB(1) antagonists.
Article
Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain.
Article
This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.
Article
Obesity is one of the risk factors for liver fibrosis, in which plasma adiponectin, an adipocytokine, levels are decreased. Hepatic stellate cells play central roles in liver fibrosis. When they are activated, they undergo transformation to myofibroblast-like cells. Adiponectin suppresses the proliferation and migration of vascular smooth muscle cells, whose characteristics are similar to those of hepatic stellate cells. Adiponectin could have biological significances in liver fibrosis. The role of adiponectin on liver fibrosis induced by the administration of carbon tetrachloride twice a week for 12 weeks was tested by using adiponectin-knockout mice and an adenovirus-mediated adiponectin-expression system. We also investigated the effect of adiponectin in activated hepatic stellate cells. When mice were administered carbon tetrachloride (300 microL/kg body weight) twice a week for 12 weeks, knockout mice showed extensive liver fibrosis with an enhanced expression of transforming growth factor-beta 1 and connective tissue growth factor compared with wild-type mice (P < 0.05). Injection of adenovirus producing adiponectin (AdADN) before carbon tetrachloride (1000 microL/kg body weight) treatment prevented liver fibrosis in wild-type mice (P < 0.001). Injection of AdADN at 6 weeks attenuated liver fibrosis even though carbon tetrachloride was given for an additional 6 weeks (total of 12 weeks). In cultured hepatic stellate cells, adiponectin suppressed platelet-derived growth factor-induced proliferation and migration and attenuated the effect of transforming growth factor-beta 1 on the gene expression of transforming growth factor-beta 1 and connective tissue growth factor and on nuclear translocation of Smad2. The findings indicate that adiponectin attenuates liver fibrosis and could be a novel approach in its prevention.
Article
Hepatic myofibroblasts are central for the development of liver fibrosis associated with chronic liver diseases, and blocking their accumulation may prevent fibrogenesis. Cannabinoids are the active components of marijuana and act via 2 G-protein-coupled receptors, CB1 and CB2. Here, we investigated whether liver fibrogenic cells are a target of cannabinoids. CB2 receptors were characterized in biopsy specimens of normal human liver and active cirrhosis by immunohistochemistry, and in cultures of hepatic stellate cells and hepatic myofibroblasts by reverse-transcription polymerase chain reaction (RT-PCR), immunocytochemistry, and GTPgammaS assays. Functional studies were performed in cultured hepatic myofibroblasts and activated hepatic stellate cells. Carbon tetrachloride-induced liver fibrosis was studied in mice invalidated for CB2 receptors. In liver biopsy specimens from patients with active cirrhosis of various etiologies, CB2 receptors were expressed in nonparenchymal cells located within and at the edge of fibrous septa in smooth muscle alpha-actin-positive cells. In contrast, CB2 receptors were not detected in normal human liver. CB2 receptors were also detected in cultured hepatic myofibroblasts and in activated hepatic stellate cells. Their activation triggered potent antifibrogenic effects, namely, growth inhibition and apoptosis. Growth inhibition involved cyclooxygenase-2, and apoptosis resulted from oxidative stress. Finally, mice invalidated for CB2 receptors developed enhanced liver fibrosis following chronic carbon tetrachloride treatment as compared with wild-type mice. These data constitute the first demonstration that CB2 receptors are highly up-regulated in the cirrhotic liver, predominantly in hepatic fibrogenic cells. Moreover, this study also highlights the antifibrogenic role of CB2 receptors during chronic liver injury.
Article
Cannabinoids present in Cannabis sativa (marijuana) exert biological effects via cannabinoid receptors CB1 and CB2. We recently demonstrated that CB1 and CB2 receptors regulate progression of experimental liver fibrosis. We therefore investigated the impact of cannabis smoking on fibrosis progression rate in patients with chronic hepatitis C (CHC). Two hundred seventy consecutive untreated patients with CHC of known duration undergoing liver biopsy were studied. Demographic, epidemiological, metabolic, and virological data were recorded, and detailed histories of cannabis, alcohol, and tobacco use over the span of hepatitis C virus infection were obtained. Fibrosis stage, steatosis, and activity grades were scored according to Metavir system. Patients were categorized as noncannabis users (52.2%), occasional users (14.8%), or daily users (33.0%), and the relationship between cannabis use and fibrosis progression rate (FPR) or fibrosis stage was assessed. On multivariate analysis, six factors were independently related to a FPR greater than 0.074 (median value of the cohort): daily cannabis use (OR = 3.4 [1.5-7.4]), Metavir activity grade A2 or higher (OR = 5.4 [2.9-10.3]), age at contamination of more than 40 years (OR = 10.5 [3.0-37.1]), genotype 3 (OR = 3.4 [1.5-7.7]), excessive alcohol intake (OR = 2.2 [1.1-4.5]), and steatosis (OR = 2.0 [1.0-4.1]). Daily cannabis use was also an independent predictor of a rapid FPR (>0.15) (OR = 3.6 [1.5-7.5]). Finally, severe fibrosis (> or =F3) was also predicted by daily cannabis use (OR = 2.5 [1.1-5.6]; P = .034), independently of Metavir activity grade, excessive alcohol intake, age at liver biopsy, steatosis, and tobacco smoking. In conclusion, daily cannabis smoking is significantly associated with fibrosis progression during CHC. Patients with ongoing CHC should be advised to refrain from regular cannabis use.
Article
Since the discovery of the cannabinoid receptors and their endogenous ligands, significant advances have been made in studying the physiological function of the endocannabinoid system. The presence of cannabinoid receptors on cells of the immune system and anecdotal and historical evidence suggesting that cannabis use has potent immuno-modulatory effects, has led to research directed at understanding the function and role of these receptors within the context of immunological cellular function. Studies from chronic cannabis smokers have provided much of the evidence for immunomodulatory effects of cannabis in humans, and animal and in vitro studies of immune cells such as T cells and macrophages have also provided important evidence. Cannabinoids can modulate both the function and secretion of cytokines from immune cells. Therefore, cannabinoids may be considered for treatment of inflammatory disease. This review article will highlight recent research on cannabinoids and how they interact with the immune system and also their potential use as therapeutic agents for a number of inflammatory disorders.
Article
Studies initially reported as conference abstracts that have positive results are subsequently published as full-length journal articles more often than studies with negative results. Less than half of all studies, and about 60% of randomized or controlled clinical trials, initially presented as summaries or abstracts at professional meetings are subsequently published as peer-reviewed journal articles. An important factor appearing to influence whether a study described in an abstract is published in full is the presence of 'positive' results in the abstract. Thus, the efforts of persons trying to collect all of the evidence in a field may be stymied, first by the failure of investigators to take abstract study results to full publication, and second, by the tendency to take to full publication only those studies reporting 'significant' results. The consequence of this is that systematic reviews will tend to over-estimate treatment effects.
Article
Complications of HCV infection are primarily related to the development of advanced fibrosis and whether cannabis use is a risk factor for more severe fibrosis is controversial. Baseline data from a prospective cohort study of 204 persons with chronic HCV infection were used for analysis. The outcome was fibrosis score on biopsy, and the primary predictor evaluated was daily cannabis use. The median age of the cohort was 46.8 years, 69.1% were male, 49.0% were white, and the presumed route of infection was injection drug use in 70.1%. The median lifetime duration and average daily use of alcohol were 29.1 years and 1.94 drink equivalents per day, respectively. Cannabis use frequency (within prior 12 months) was daily in 13.7%, occasional in 45.1%, and never in 41.2%. Fibrosis stage, assessed by the Ishak method, was F0, F1-2, and F3-6 in 27.5%, 55.4%, and 17.2% of subjects, respectively. Daily compared with non-daily cannabis use was significantly associated with moderate to severe fibrosis (F3-6 vs F1-2) in univariate (odds ratio [OR], 3.21; 95% confidence interval [CI], 1.20-8.56, P = .020) and multivariate analyses (OR, 6.78; 95% CI, 1.89-24.31, P = .003). Other independent predictors of F3-6 were >or=11 portal tracts (compared with <5, OR, 6.92; 95% CI, 1.34-35.7, P = .021) and lifetime duration of moderate to heavy alcohol use (OR per decade, 1.72; 95% CI, 1.02-2.90, P = .044). Daily cannabis use is strongly associated with moderate to severe fibrosis, and HCV-infected individuals should be counseled to reduce or abstain from cannabis use.
Article
Steatosis is highly prevalent in patients with chronic hepatitis C (CHC) and has been reported to increase fibrosis and reduce the rate of viral eradication. Two recent studies indicate that endocannabinoids promote experimental steatosis via activation of hepatic CB1 receptors. We therefore investigated the impact of cannabis smoking on steatosis severity during CHC. A total of 315 consecutive patients with untreated CHC undergoing liver biopsy were included. Detailed histories of recent cannabis, alcohol, and tobacco use were recorded. Steatosis, activity, and fibrosis stage were assessed by 2 pathologists according to METAVIR. Marked steatosis was defined as >/=30%. Patients were categorized as cannabis nonusers (63.5%), occasional cannabis smokers (12.4%), or daily cannabis smokers (24.1%). Multivariate analysis identified 6 predictors of marked steatosis: daily cannabis use (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.01-4.5]), activity grade >/=A2 (OR, 2.1; 95% CI, 1.0-4.3), genotype 3 (OR, 5.4; 95% CI, 2.6-11.3), hyperglycemia or diabetes (OR, 5.1; 95% CI, 1.8-15.0), body mass index >27 kg/m(2) (OR, 2.1; 95% CI, 1.0-4.3), and serum HCV RNA load (OR, 1.7; 95% CI, 1.0-2.9). Upon adjustment of HCV genotype (3 vs non-3) or alcohol intake (<30 g/day vs >/=30 g/day), marked steatosis was more frequent in daily cannabis users compared with occasional users and nonusers (P = .03 and P = .008, respectively). Our results identify daily cannabis smoking as a novel independent predictor of steatosis severity during CHC and strongly argue for a steatogenic role of the cannabinoid system. Cannabis use should be discouraged in patients with CHC.
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Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity
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