Cannabis Research Publishing

 source: Cell death & disease

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. Cell Death and Disease (2011) 2, e170; doi:10.1038/cddis.2011.52; published online 9 June 2011
Subject Category: Experimental Medicine...read full publication (pdf)

source: Molecular Pharmacology

Dr. Iris Lavon, Pharmos LTD, Kiryat Weizmann, Bld #13b, Rehovot 76326, Israel. E-mail: lavoni@netvision.net.il

Abstract

The therapeutic potential of cannabinoids has been described previously for several inflammatory diseases, but the molecular mechanisms underlying the anti-inflammatory properties of cannabinoids are not well understood. In this study, we investigated the mechanism of action of a novel synthetic cannabinoid, [(+)(6aS,10aS)-6,6-Dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-9-(1H-imidazol-2-ylsulfanylmethyl]-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran (PRS-211,092) that has no psychotropic effects but exhibits immunomodulatory properties.

Treatment with PRS-211,092 significantly decreased Concanavalin A-induced liver injury in mice that was accompanied by: 1) promotion of early gene expression of interleukin (IL)-6 and IL-10 that play a protective role in this model; 2) induction of early gene expression of the suppressors of cytokine signaling (SOCS-1 and 3), followed by 3) inhibition of several pro-inflammatory mediators, including IL-2, monocyte chemoattractant protein-1 (MCP-1), IL-1β, interferon-γ, and tumor necrosis factor α.

Based on these results, we propose a mechanism by which PRS-211,092 stimulates the expression of IL-6, IL-10 and the SOCS proteins that, in turn, negatively regulates the expression of pro-inflammatory cytokines. Negative regulation by PRS-211,092 was further demonstrated in cultured T cells, where it inhibited IL-2 production and nuclear factor of activated T cells activity. These findings suggest that this cannabinoid derivative is an immunomodulator that could be developed as a potential drug for hepatitis as well as for other short- or long-term inflammatory diseases.... Read full publication

This work was previously presented in part at the following conferences: Reichenbach V, Ros J, Fernández-Varo G, Muñoz-Luque J, Morales-Ruiz M, Makriyannis A, and Jiménez W (2008) Chronic stimulation of cannabinoid CB2 receptor represses fibrosis progression in CCl₄-treated rats.

59th Annual Meeting of the American Association for the Study of Liver Diseases; 2008 Oct 31–Nov 4; San Francisco, CA. American Association for the Study of Liver Diseases, Alexandria, VA. Reichenbach V, Ros J, Fernández-Varo G, Casals G, Melgar-Lesmes P, Pauta M, Morales-Ruiz M, and Jiménez W (2010) Activation of the hepatic apelin system is of major relevance in early stages of liver fibrosis. International Liver Conference 2010; 2010 Apr 14–18; Vienna, Austria. European Association for the Study of the Liver, Geneva, Switzerland.

Footnotes

• This work was supported by the Dirección General de Investigación Científica y Técnica [Grants SAF09-08839, SAF07-63069] (to W.J. and M.M.-R., respectively); Agència de Gestió d'Ajuts Universitaris i de Recerca [Grant SGR 2009/1496]; Dirección General de Investigación Científica y Tecnológica [Grant BES-2004-5186] (to P.M.-L.); and Instituto de Salud Carlos III [“Contrato Post Formación Sanitaria Especializada” FIS CM07/00043] (to G.C.). Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas was founded by the Instituto de Salud Carlos III (Spain).

• Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  http://dx.doi.org/10.1124/jpet.111.188078.

Eur J Gastroenterol Hepatol Oct 2006 18:1057-1063
Diana L. Sylvestrea,b, Barry J. Clementsb and Yvonne Malibub
Department of Medicine, University of California, San Francisco, California, USA
and bOrganization to Achieve Solutions in Substance-Abuse (OASIS), Oakland, California, USA
 
Note from Jules Levin: this study was first presented at a conference 2 years ago or longer.
 
"...The results of this observational study suggest that the use of cannabis during HCV treatment can improve adherence by increasing the duration of time that patients remain on therapy; this translates to reduced rates of post-treatment virological relapse and improved SVR....."
 
As shown in Fig. 3, cannabis users were no more likely than non-users to take at least 80% of the prescribed interferon, 91 versus 76% (P=0.2), nor were they more likely to take at least 80% of the prescribed ribavirin, 91 versus 84% (P>0.5). However, cannabis users were significantly more likely than non-users to remain on HCV treatment for at least 80% of the projected treatment course, 95 versus 67% (P=0.01). The average duration of HCV treatment in cannabis users was 38 weeks compared with 33 weeks for the non-users.
 

ABSTRACT
Objectives: Despite the widespread use of polypharmacy, the management of hepatitis C virus (HCV) treatment-related side-effects is often incomplete, and many patients turn to cannabis for symptom relief. Unfortunately, there are few data about cannabis use on treatment outcomes, leaving clinicians without the data needed to inform recommendations.
 
Methods: To define the impact of cannabis use during HCV treatment, we conducted a prospective observational study of standard interferon and ribavirin treatment in 71 recovering substance users, of whom 22 (31%) used cannabis and 49 (69%) did not.
 
Results:
Seventeen of the 71 study patients (24%) discontinued therapy early, one cannabis user (5%) and 16 non-users (33%) (P = 0.01).
 
Overall, 37 patients (52%) were end-of-treatment responders, 14 (64%) cannabis users and 23 (47%) non-users (P =0.21).
 
A total of 21 out of 71 (30%) had a sustained virological response: 12 of the 22 cannabis users (54%) and nine of the 49 non-users (18%) (P =0.009), corresponding to a post-treatment virological relapse rate of 14% in the cannabis users and 61% in the non-users (P = 0.009).
 
Overall, 48 (68%) were adherent, 29 (59%) non-users and 19 (86%) cannabis users (P =0.03).
 
Although cannabis users were no more likely than non-users to take at least 80% of the prescribed interferon or ribavirin, they were significantly more likely to remain on HCV treatment for at least 80% of the projected treatment duration, 95 versus 67% (P =0.01).
 
Conclusions: Our results suggest that modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them maintain adherence to the challenging medication regimen.
 
Introduction
Although hepatitis C virus (HCV) treatment outcomes have improved dramatically over the past decade, the intolerability of interferon/ribavirin combination therapy remains a barrier to treatment success.

The majority of patients develop significant treatment-related side effects, with almost 80% experiencing an initial 'flulike syndrome that includes fevers, chills, and muscle and joint aches. Although the acute effects of treatment tend to modulate over time, many will experience debilitating fatigue (70-72%), headaches (66-67%), nausea (35-46%), anorexia (19-27%), depression (21-44%), and insomnia (30-39%) among others.
 
Many patients require the use of adjunctive pharmacological agents for side-effect management [5,8]. These include a spectrum of medications including antiemetics, anti-inflammatory agents, antihistamines, sleeping pills, antidepressants, anxiolytics, stimulants, and antipsychotics. Unfortunately, symptom relief is often incomplete despite the widespread use of polypharmacy, and patients so affected may compensate by reducing their interferon or ribavirin doses or by discontinuing treatment altogether.

Maximizing HCV treatment outcomes thus requires a thorough familiarity with an array of successful side-effect management strategies.
 
Faced with intolerable treatment-related side-effects that respond inadequately to conventional medications, some patients turn to Cannabis sativa (marijuana) for symptom relief. Cannabis sativa contains over 400 chemical entities, but delta-9-tetrahydrocannabinol (THC) is the major psychoactive component.

Although the majority of studies of cannabis are observational in nature, there is anecdotal evidence that it may have benefits in modulating some of the common side-effects associated with HCV treatment, including nausea, anorexia, weight loss, musculoskeletal pain, insomnia, anxiety, and mood instability. However, the benefits of cannabis during HCV treatment remain unconfirmed and concerns about its safety remain.

Cannabinoid receptors appear to be upregulated in hepatic myofibroblasts of human cirrhotic liver samples, and smoking daily cannabis has been reported to accelerate the progression of hepatic fibrosis in patients with chronic HCV.

Cannabinoid receptors are also present on immune cells, and cannabis use may suppress a variety of immune functions, including antibody production, cell proliferation, natural killer cell activity, and macrophage function, and also alter the production of such cytokines as interferon gamma and tumor necrosis factor.

In addition, there is a potential drug-drug interaction between ribavirin and marijuana, as both are metabolized by the cytochrome P450 system.

Obviously, the overall benefit of cannabis in terms of side-effect management may be outweighed by worsening histology and impairments in virological outcomes; therefore, its use as a potential therapeutic agent must be more clearly defined in the setting of HCV treatment.
 
Although widespread restrictions limit the ease with which these questions can be formally studied, the pervasive use of cannabis during HCV treatment provides a means for an observational study of its potential risks and benefits. I

n the context of a prospective study of HCV treatment in recovering heroin users maintained on methadone we have conducted such a study, by measuring the impact of intercurrent cannabis use on treatment adherence, retention rates, and virological outcomes.
 
Discussion
The results of this observational study suggest that the use of cannabis during HCV treatment can improve adherence by increasing the duration of time that patients remain on therapy; this translates to reduced rates of post-treatment virological relapse and improved SVR.

Although other potential mechanisms may contribute to its enhancement of treatment outcomes, such as altered immunological function and improved nutritional status, it appears that the moderate use of cannabis

Although its availability in the United States has been restricted since 1937 and its benefit unconfirmed, cannabis is frequently obtained illicitly for self-medication. It has been used recreationally for millennia, and is the third most commonly used drug after tobacco and alcohol. In the United States, 6.2% of individuals aged 12 years or older have used cannabis in the past month, with 4.8 million individuals using it on 20 or more days.
 
THC can produce alterations in mood, perception,cognition, and memory, and studies have shown that THC has anticonvulsive, analgesic, anti-anxiety, and anti-emetic properties.

Clinical trials have demonstrated that cannabinoids reduce nausea and improve appetite in humans, and cannabis has shown benefit in modulating the nausea of cancer chemotherapy, multiple sclerosis-related spasticity, and the wasting syndrome of HIV.

Progress has been made in understanding the pharmacology of cannabinoids in humans. Of the two known cannabinoid receptors, CB1 is responsible for the neurological and behavioral effects of marijuana. CB1 was the first cannabinoid receptor identified, and is the most abundant G-protein-coupled receptor in the central nervous system.

It is also expressed on peripheral neurons and is found abundantly in the basal ganglia, cerebellum, and hippocampus, accounting for its effects on motor coordination and short-term memory.

It is also expressed at high concentrations on primary afferent nociceptors of the dorsal spinal cord, which are responsible for the ability of cannabinoids to inhibit pain.
 
Although CB1 cannabinoid receptors mediate the central nervous system effects of cannabinoids , an additional subset of cannabinoid receptors, the CB2 receptors, is present on immune cells. The presence of these receptors on B lymphocytes and natural killer cells suggests that cannabinoids may impact upon the immune response.

Some studies have shown that THC can be immunosuppressive and can impair cell-mediated immunity, humoral immunity, and cellular defences against a variety of infectious agents in experimental animals. There is an increased recurrence of herpes simplex viral lesions in marijuana smokers and an altered responsiveness of human papilloma virus to IFN-a 2a treatment.

Although uncontrolled studies suggested an association between marijuana use and the progression of HIV disease, a recent prospective study demonstrated no evidence of detrimental effects of cannabinoids on immune parameters in patients with HIV.

The majority of studies on the effects of cannabis have been conducted in cell culture or on animal models with supraphysiological doses of the compound, and their clinical relevance is unclear.
 
Although their potential contribution to liver disease is not understood, both the CB1 and CB2 receptors have also been reported to be expressed on hepatic myofibroblasts in cirrhotic livers.

Activation of these receptors can lead to cellular apoptosis, and a recent study demonstrated that the use of cannabis on a daily basis may enhance the progression of hepatitis fibrosis in patients with HCV. By implicating these receptors as mediators of the fibrotic process, these results raise concerns about the safety of cannabis use in patients with HCV.
 
In spite of this, our results suggest that moderate cannabis use during HCV treatment may offer significant benefit to certain patients.

Although the lack of a direct dose response suggests that its principal contribution is related to a non-specific improvement in the tolerability of the challenging medication regimen, we cannot rule out additional biological effects.

We did not measure relevant immune parameters in our patients, nor did we assess potential differences in nutritional status. P450-mediated drug-drug interactions between cannabinoids and ribavirin may have led to additional benefit, but these were not assessed.

However, the lack of dose response in our study argues against specific receptor or metabolismrelated effects, and suggests instead that cannabis exerted its benefit by non-specific improvements in symptom management. Interestingly, because the bene fits of heavy cannabis use were less apparent, we cannot rule out the possibility that detrimental biological or immunological mechanisms may be relevant at higher levels of consumption. Obviously, further study is needed.
 
Our study has a number of additional limitations that warrant caution in its interpretation. First, we confined our study to methadone-maintained patients, a population with relatively high rates of medical and psychiatric co-morbidity.

Second, the use of additional illicit substances was not uncommon, and although not differing between the two cohorts, the impact of these substances or even of methadone on study outcomes cannot be excluded.

Third, the use of marijuana was quantified by self-report and may have introduced bias as a result of underreporting or even overreporting.

Fourth, illicitly obtained marijuana, even that obtained through 'cannabis clubs', may be highly variable in its content of bioactive compound, leaving in question a true quantitation of the amount of cannabis that may or not be beneficial.

And finally, significant limitations are introduced by our observational study design; however, with legal proscriptions against cannabis use limiting its study, the design and conduct of randomized, prospective research studies is virtually impossible at this time.
 
Despite its shortcomings, this study begins to answer some of the key questions that arise about the use of cannabis during HCV treatment.

Our results suggest that the modest use of cannabis does not appear to impact negatively upon HCV treatment outcomes and need not elicit undue alarm.

The widespread use of illicit cannabis during HCV therapy highlights the inadequacies of our current side-effect management strategies; our study suggests that cannabis use may offer benefit for some patients undergoing HCV treatment by helping them maintain adherence to the frequently debilitating medication regimen.

However, the mechanisms through which cannabis exerts its benefit are unclear, and controlled studies may further elucidate the mechanisms through which cannabis may impact upon clinical outcomes during HCV treatment.
 
Results
Baseline characteristics
Seventy-one patients were enrolled; 22 (31%) smoked cannabis while undergoing HCV treatment and 49 (69%) did not. The demographic characteristics of the study patients are shown in Table

1. The median age was 50 years, and 43 (61%) were male, 53 (75%) Caucasian, 10 (14%) African-American, and eight (11%) Latino; there were no differences in the demographic characteristics between the cannabis users and non-users.

The median estimated duration of HCV exposure was 30±9 years. Forty patients (56%) had genotype 1, 29 (41%) had genotypes 2 or 3, one patient had genotype 8a, and one patient's genotype was untypable. There was no difference in the frequencies of genotypes between the cannabis users and non-users; 30 of the non-users (61%) and 10 of the cannabis users (48%) had genotype 1 (P=0.31). Thirty patients underwent liver biopsy.

Among these, the mean METAVIR inflammation grade was 2.4 (1.5-3.5) and the mean fibrosis stage was 2.6 (0-4). There was no significant difference in liver fibrosis between the two groups; the mean fibrosis stage was 2.5±0.4 for the cannabis users and 2.7±0.2 for the nonusers (P=0.36). The 20 patients (28%) who had platelet counts of less than 100 000 cells/ml were also equally divided between the groups, comprising 29% (n=14) of the non-users and 27% (n=6) of the group that used cannabis.
 
Forty-two patients (59%) reported a previous psychiatric diagnosis; the majority had depression (n=33) or depression/anxiety (n=6). Cannabis users were no more likely to report a psychiatric diagnosis than non-users (P>0.5), and there were no differences in the rates of antidepressant use between users and non-users during HCV treatment (P>0.5).

Similarly, a total of 25 (35%) used other illicit substances during HCV treatment, including heroin, cocaine, and methamphetamine, but this did not differ between the two groups (37% in the cannabis non-users and 32% in the users; P>0.5), nor were there differences in rates of alcohol consumption (24% in the non-users and 14% in the users; P=0.36).
 
Treatment outcomes
The majority of patients, 93% (n=66), reported at least one treatment-related side-effect, most commonly 'flulike symptoms, nausea, or headache, but there was no difference in reported symptoms between the cannabis users and non-users (P>0.5).

The association of cannabis use with HCV treatment outcomes is shown in Fig. 1. Seventeen of the 71 study patients (24%) discontinued therapy before completing the full course. Of these, 16 did not use cannabis and one was a cannabis user. The discontinuation rate of the 49 cannabis nonusers was 33%; it was 5% in the cannabis users (P=0.01). Of the 16 non-users who terminated treatment early, eight discontinued as a result of intolerable side-effects and four discontinued because of depression.

Three of the 16 were terminated at the discretion of the medical provider: one because of excessive alcohol intake, one because of worsening liver disease, and one because of intractable anemia. The remaining patient in this cohort relocated and was unable to obtain medications. The single cannabis user who discontinued treatment developed worsening liver disease and was unable to continue.
 
Overall, 37 of the 71 patients (52%) were end-of-treatment responders and 21 (30%) had an SVR. The association of cannabis use with response rates is shown in Fig. 1. Fourteen of the cannabis users (64%) and 23 of the non-users (47%) were end-of-treatment responders (P=0.21).

Twelve of the 22 cannabis users (54%) and nine of the 49 non-users (18%) had an SVR, corresponding to a post-treatment relapse rate of 14% (n=2) with the cannabis users and 61% (n=14) with the non-users. Multivariate logistic regression analysis taking sex, race, genotype, and the use of other illicit substances into account, revealed that this finding was statistically significant (P=0.009).
 
The association of the estimated quantity of cannabis used with virological outcomes is shown in Fig. 2. Ten of the 16 occasional cannabis users (62%) had an end-oftreatment virological response compared with four of the six regular users (67%, P>0.5). SVR were also not statistically different between the occasional and regular users of cannabis, seen in two of six of the regular users (33%) and 10 of the 16 (62%) occasional users (P=0.35).
 
Adherence
The association of cannabis use with the components of treatment adherence is shown in Fig. 3. Overall, 48 of the 71 study patients (68%) took at least 80% of the prescribed interferon and ribavirin for at least 80% of the projected duration of treatment, and were therefore considered adherent. Of those, 29 did not use cannabis and 19 were cannabis users.

The corresponding adherence rates were 59% in the non-cannabis group and 86% in the cannabis group (P=0.03); there was no difference in adherence between occasional users (87%) and regular users (83%) (P>0.5).
 
As shown in Fig. 3, cannabis users were no more likely than non-users to take at least 80% of the prescribed interferon, 91 versus 76% (P=0.2), nor were they more likely to take at least 80% of the prescribed ribavirin, 91 versus 84% (P>0.5). However, cannabis users were significantly more likely than non-users to remain on HCV treatment for at least 80% of the projected treatment course, 95 versus 67% (P=0.01). The average duration of HCV treatment in cannabis users was 38 weeks compared with 33 weeks for the non-users.
 
Methods
Study setting and eligibility Recruitment and treatment took place at OASIS (Organization to Achieve Solutions in Substance-Abuse), a community-based non-profit clinic providing medical and psychiatric treatment to substance users in Oakland, CA.

Although the clinic does not provide methadone treatment, comprehensive primary medical and psychiatric care services are provided on-site. All experimental procedures were followed in accordance with the Helsinki Declaration of 1975, as revised in 1983, and were approved by the Ethical Review Committee (Kansas City, Missouri, USA).
 
Men and women aged 18 years and older were considered eligible if they had been maintained on methadone for a period of 3 months or more and had a positive HCV polymerase chain reaction (PCR). Patients with non-HCV-related liver disease or decompensated liver disease were excluded. Those with untreated depression were excluded until stabilized on antidepressant treatment. Drug use was assessed by self-report as well as by random monthly urine toxicology testing, as per standard protocol at the methadone clinics.
 
Medications
HCV treatment consisted of IFN-a 2b, 3 x 106 units administered subcutaneously three times a week and ribavirin capsules, 1000 mg taken orally daily in two divided doses for patients weighing less than 165 lb, or 1200 mg daily for those weighing 165 lb or more.

Patients were initially treated for 48 weeks regardless of genotype; however, subsequent data supporting the efficacy of 24 weeks of treatment for genotypes 2 and 3 led to a protocol amendment that shortened the treatment course for patients with these genotypes. Medications were selfadministered unless patients specifically requested otherwise.
 
Cannabis use
The use of cannabis during study was neither endorsed nor prohibited by study staff, and all patients obtained their cannabis outside the construct of the study protocol. However, because marijuana use was legalized for medical use in the state of California, it was often obtained with outside medical approval through local 'cannabis clubs'. Cannabis use was quantified by self-report, with 'regular' use defined as the use of cannabis every day or every other day for a minimum duration of 4 weeks; 'occasional' reflected the use of less than daily quantities.
 
Procedures
After providing informed consent, participants completed a questionnaire that elicited baseline demographic, psychosocial, psychiatric, and substance use characteristics. The duration of HCV infection was estimated as one less than the number of years since injection drug use was initiated. Liver biopsy was suggested but not required, and was scored on the METAVIR scale of 0-4, with 0, none; 1, minimal-mild; 2, mild-moderate; 3, moderate-severe; and 4, cirrhosis.
 
Patients were monitored for treatment-related neutropenia, thrombocytopenia, and hemolytic anemia using standard published algorithms, and medication doses were adjusted accordingly .

Drug and alcohol consumption were assessed by monthly self-report questionnaires, and monthly random urine drug test results were obtained from the subject's methadone treatment program.

An HCV-RNA PCR was performed at baseline, at 6 months, at the end of treatment, and 6 months after the completion of therapy. Substance use during HCV therapy was actively discouraged, but did not result in treatment discontinuation unless the patient became unreliable in attending appointments or the clinician felt it represented a safety risk.

HCV treatment was discontinued if requested by the patient, or for severe cytopenias, uncontrolled or worsening psychiatric conditions, or decompensating liver disease. The protocol was evaluated and approved by the Ethical Review Committee, Kansas City, Missouri, USA.
 
Outcome measures
The primary study endpoint was sustained virological response (SVR), as determined by undetectable levels of HCV RNA on analysis 6 months after the completion of therapy using the Bayer HCV-RNA branched DNA 3.0 assay, with a lower limit of detection of 550 IU/ml.

Patients were classified as sustained virological responders at this time point if they had no detectable virus, or as non-responders if the PCR was positive. End-oftreatment response was defined as undetectable levels of HCV RNA at the completion of therapy. All analyses were performed on an intent-to-treat basis.
 
Adherence
Adherence to interferon was assessed by the timing of returned empty interferon vials and by a monthly questionnaire that detailed the number of missed doses of medication. Adherence to ribavirin therapy was assessed by pill counting and by query during a monthly questionnaire. Using adherence criteria developed by others, patients were considered adherent to the HCV treatment regimen if they took 80% or more of the prescribed interferon and 80% or more of the prescribed ribavirin for at least 80% of the projected treatment course [9].
 
Statistical analysis
All data were compiled in and analysed using SPSS version 11.5.0 for Windows (SPSS Inc., Chicago, Illinois, USA). Associations between outcome measures and cannabis use were determined using the Student's t or Wilcoxon signed rank test for categorical variables.

Bivariate analysis of categorical data was performed using the chi-square and Fisher's exact tests. P values less than 0.05 in two-tailed comparisons were considered statistically significant. Logistic regression was used to assess for statistical independence among variables that showed a univariate association with a P value of 0.20 or less.

Jay R. Cavanaugh, PhD


Hepatitis C (HCV) is a blood borne pathogen that presently infects some four to eight million Americans making it the leading blood borne virus in America.

HCV is the primary cause of liver cancer and cirrhosis and kills over 10,000 Americans each year. Hepatitis C is the leading factor in patients who require liver transplant. Some 80% of those who contract HCV will go on to develop chronic infection and 20% of these will develop cirrhosis, liver cancer, or liver failure. A slim 20% of those infected will eliminate the virus from their body on their own.

Patients can contract Hepatitis C from using shared needles, accidental needle stick injuries, blood transfusions (prior to 1990), and to a minor degree from unprotected sex. HCV can be transmitted from an infected tattoo needle, dental instruments, or tools used in commercial nail care. Anything that assists the transfer of HCV infected blood from one person to another can be a vector. The blood of a patient with HCV can be highly contagious and precautions should be taken to not come in contact with it.

Hepatitis C usually produces no early symptoms. The disease can go unrecognized for decades. This is why HCV is termed a "silent killer". During the decades of quiescence the virus can continue to slowly destroy liver cells without the patient having any idea this is happening. The following groups are considered "high risk" and should be tested for the virus:

• IV drug users who have shared needles
• Sexual partners of HCV patients
• Family members of HCV patients
• Individuals receiving a blood transfusion prior to 1990
• Patients who undergo dialysis
• Individuals with tattoos or who have their nails frequently done
• Individuals who have suffered a needle stick incident
• Patients who have been diagnosed with any liver disease

Symptoms:

While patients are generally unaware of HCV infection for many years, some 80% may eventually develop symptoms which can include:
Fatigue and malaise
Loss of appetite
Weight loss
Jaundice
Joint pain and headache
Fluid retention in the abdomen (ascites)
Nausea and vomiting
Itching

Diagnosis:

Diagnosis begins with a simple history and blood test. The history looks at risk factors and symptoms. The blood test is generally to measure both liver enzymes (produced when the liver is damaged) and to detect antibodies to the Hepatitis C virus and/or to quantify the amount of virus present in the blood stream. The amount of virus is called the "titer" and is determined using the polymerase chain reaction (PCR) with HCV "primers".

Additional blood tests can determine the specific strain of virus present (some strains are more pathogenic than others). A physical examination will be conducted that includes probing the liver for enlargement and looking for other possible factors such as swelling in the legs and feet and jaundice.

Prior to the initiation of treatment, it is common practice to conduct additional tests to more closely ascertain the status of the liver and the need for treatment. A liver scan using radioactive isotopes and X-ray can highlight liver structures and blood flow.

A CAT scan may be conducted to look for tumors or blockage. The definitive diagnostic procedure is a liver biopsy where small samples of the liver are extracted through an office surgical procedure and examined for pathology. A liver biopsy taken from different quadrants of the liver can reveal hepatocarcinoma (liver cancer), fatty deposits, and cirrhosis (scarring).

Why is the liver important?

The liver is the largest internal organ. It is within the liver that medications and toxins are neutralized, metabolized, and eliminated (with the help of the kidneys). The liver is the site of sugar storage (glycogen) and plays a vital role in maintaining normal blood sugar along with the pancreas. The body’s fluid balance and blood clotting are largely controlled by the liver as is the processing of proteins.

Bile produced in the liver aides in the digestion of food. Most noticeable is the role of the liver in energy production which is why fatigue is so common in liver disease.

Treatment for Hepatitis C:

Current therapy focuses on the subcutaneous administration of a combination of Interferon alpha (an immunomodulator) and the anti-viral drug Ribavirin. Depending upon the type of Interferon used, dosing can be one to three times a week for six to 18 months.

Approximately 50% of those treated respond although it is not yet known how long the response might last. Combination drug therapy is usually not attempted when there is no sign of liver damage as determined by histopathology following biopsy.

Drug therapy is also contraindicated when patients have long standing problems with depression or heart disease. The major side effects of the therapy include flu like symptoms, joint pain, nausea, anemia and depression.

The decision to undergo combination therapy is a very serious one and should be done only under the supervision of a qualified and experienced physician. HCV patients with liver impairment must avoid hepatotoxins, particularly alcohol and acetaminophen (Tylenol).

Alcohol is a key toxin that damages the liver. Normal healthy adults are advised to drink no more than two drinks a day for men and one for women. With liver disease that recommendation drops to zero. Yet, many in the general population and the HCV population are heavy drinkers. Cannabis can be an effective harm reduction agent for those with alcohol problems along with therapy and self help.

Long term Complications of Hepatitis C:

Cirrhosis - As liver cells are destroyed by virally induced inflammation, they can be replaced by scar tissue (hence the name) which does not function to conduct normal liver functions. Cirrhosis is chronic and progressive.

Cirrhosis occurs in approximately 20% of all HCV cases and may lead to cancer. The course of cirrhosis is variable but usually includes fluid build up in the abdomen (ascites), portal hypertension, and esophageal varices (swollen blood vessels).

Treatment is limited to alleviating symptoms. Fluid may be periodically drained and medicines provided to reduce hypertension and fluid imbalances. Cirrhosis can cause uncontrolled bleeding, coma, and death.

Hepatocellular carcinoma (liver cancer) - Constant cell death and division caused by HCV can lead to tumors in 1-5% of all patients. Liver cancer is curable only in its earliest stages if it is contained within the liver in an area approachable by surgery. In other cases various treatments can be used including cryotherapy (freezing) and ethanol ablation.

Chemotherapy, at present, is not usually effective with liver tumor. Liver cancer is generally terminal with treatment limited to symptomatic relief and improving the quality and length of life.

Liver failure and transplantation - As HCV destroys liver tissue; liver function can be increasingly compromised leading to failure. As the liver fails toxins can circulate that harm other organs and effect perception and behavior.

Medications are not metabolized normally and have an increased risk of side effects and adverse reaction. Essential clotting factors may not be produced leading to uncontrolled internal bleeding. Complete failure results in coma and death.

Patients with cirrhosis, cancer, and/or liver failure can sometimes be helped by a liver transplant. Hard to come by, transplants are usually restricted to those cases where they may materially help.

Patients who continue to abuse alcohol or drugs are often excluded from transplant waiting lists as are those whose cancer has spread beyond the liver. Others excluded are surgical risks (usually those with cardiac disease) and those with compromised immune systems. Patients survive transplantation in nearly 80% of trials although continued use of immunosuppressants is needed.

Can medical cannabis help?

The short answer is yes. The primary role of cannabis is to stimulate appetite, reduce nausea and vomiting, and treat joint pain. This role is applicable to HCV patients undergoing chemotherapy, those with cancer or cirrhosis, and those with joint pain and headache. Cannabis is far less toxic than other medications that might be prescribed for these conditions and where liver impairment is concerned, it is vital to avoid toxicity.

Cannabis may help alleviate the depression often produced by chronic illness and by combination drug therapy. Additionally, cannabis based food products may provide needed extra nutrition without taxing the liver. Using cannabis in place of alcohol is an established harm reduction technique particularly important when liver disease is present.

Perhaps more important but still unknown is the possibility that some of the chemical components of cannabis (the Cannabinoids) may actually reduce liver inflammation and slow the progression of both cirrhosis and Hepatocellular carcinoma.

The cannabinoids have been shown to be powerful anti-inflammatories and anti-oxidants. They have also been shown to have anti-neoplastic activity, at least in gliomas (a form of brain cancer). Cannabinoids both slow programmed cell death (apoptosis) in normal cells while accelerating apoptosis in cancer cells.

Since cannabis is nontoxic it might as well be tried, particularly in patients who have chronic progressive disease that is likely to result in death. It is important to point out that whole cannabis (whether smoked, vaporized, elixir, or in food products) is preferable to Marinol. The prescription drug Marinol contains only one cannabinoid (THC) and lacks the other healing properties of the whole herb and its extracts.

Dosing is up to the physician and patient. Usually patients "self-titrate" or use only what they feel they need for symptomatic relief. This may be a mistake as the protective effects of cannabis are best achieved with a steady state minimal blood level of Cannabinoids. It is recommended that a base line level of Cannabinoids be maintained with regular doses of oral cannabis products and the smoked or vaporized form of cannabis used for acute symptomatic relief.

Josh Richman, The Oakland Tribune, 14th September 2006

• The American Society for Pharmacology and Experimental Therapeutics

By Liz Highleyman

Interferon-based therapy for chronic hepatitis C virus (HCV) infection is often limited by side effects including flu-like symptoms, fatigue, insomnia, loss of appetite, nausea, muscle and joint pain, and depression, which can lead to poor adherence, dose reduction, or treatment discontinuation.

Medicinal cannabis may relieve such side effects and help patients stay on treatment, according to a study published in the October 2006 European Journal of Gastroenterology and Hepatology.

Several studies - as well as ample anecdotal evidence - have demonstrated that medical marijuana can reduce nausea, increase appetite, and improve wasting in people with HIV.

Diana Sylvestre, MD, of the University of California at San Francisco and colleagues conducted a study to define the impact of cannabis use during HCV treatment.

The prospective observational study included 71 patients at OASIS (Organization to Achieve Solutions in Substance Abuse), a community-based clinic providing medical and psychiatric treatment to substance users in Oakland, California.

Patient Demographics

Eligible participants were recovering substance users with HCV who had been on methadone maintenance therapy for at least 3 months.

Patients with non-HCV-related liver disease or decompensated cirrhosis were excluded.

Among the 30 patients with liver biopsy results, the mean Metavir inflammation grade was 2.4 and the mean fibrosis stage was 2.6. Subjects with untreated depression were first stabilized on antidepressants.

Use of cannabis during the study was "neither endorsed nor prohibited." About one-third of participants used marijuana during hepatitis C treatment. "Regular" marijuana use was defined as every day or every other day for at least 4 weeks.

Drug and alcohol use were assessed by self-report and random monthly urine testing.

22 patients (31%) reported cannabis use during ant-HCV treatment, while 49 (69%) did not.

Baseline characteristics were generally similar between marijuana users and non-users.

The median age was about 50 years in both groups.

Compared with non-users, cannabis users were somewhat more likely to be male (68% vs 57%) and Caucasian (86% vs 69%), but less likely to have genotype 1 HCV (48% vs 61%).

About 60% of participants reported a previous psychiatric diagnosis (usually depression); cannabis users and non-users had similar rates of psychiatric diagnosis and antidepressant use.

32% of cannabis users and 37% of non-users reported use of other illicit substances during HCV treatment (including heroin, cocaine, and methamphetamine), while 14% and 24%, respectively, reported alcohol consumption; these differences were not statistically significant.

Participants were treated with conventional interferon alfa-2b (3 million units 3 times weekly) plus 1000-1200 mg daily ribavirin. Patients were initially treated for 48 weeks regardless of genotype, but the protocol was later amended to allow 24-week therapy for those with genotypes 2 or 3.

Adherence to therapy was assessed by self-report, ribavirin pill counts, and returned empty interferon vials. Participants were considered adherent if they took 80% or more of prescribed interferon and ribavirin for at least 80% of the projected treatment course.

Results

In an intent-to-treat analysis, 37 patients (52%) achieved an end-of-treatment response (undetectable HCV RNA at the end of 24 or 48 weeks of therapy):

- 14 cannabis users (64%);
- 23 non-users (47%) (P = 0.21).

Overall, 21 out of 71 participants (30%) achieved sustained virological response (SVR), or continued undetectable HCV RNA 6 months after the end of therapy:

- 12 of 22 cannabis users (54%);
- 9 of 49 non-users (18%) (P = 0.009).

Post-treatment virological relapse rates were 14% for cannabis users and 61% for non-users (P = 0.009).

End-of-treatment response rates were similar among occasional cannabis users (10 of 16; 62%) and regular users (4 of 6; 67%).

10 of 16 occasional users (62%) went on to achieve SVR, compared with 2 of 6 regular users (33%), but the difference was not statistically significant.

Most patients (93%) reported at least one treatment-related side-effect, with similar rates among cannabis users and non-users.

Overall, 17 of 71 patients (24%) discontinued therapy early:

- 1 cannabis user (5%);
- 16 cannabis non-users (33%) (P = 0.01).

Overall, 48 patients were adherent (68%):

- 19 cannabis users (86%);
- 29 non-users (59%) (P = 0.03).

There was no significant difference in adherence between occasional and regular cannabis users (87% vs 83%)

91% of cannabis users took at least 80% of prescribed interferon, compared with 76% of non-users. For ribavirin, the corresponding rates were 91% and 84%; these differences were not statistically significant.

However, cannabis users were significantly more likely than non-users to remain on therapy for at least 80% of the projected treatment duration (95% vs 67%; P = 0.01).

The average duration of HCV treatment was 38 weeks for cannabis users, compared with 33 weeks for non-users.

Conclusion

In conclusion, the authors wrote, "Our results suggest that modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them maintain adherence to the challenging medication regimen."

Discussion

In their discussion, the authors wrote that their results "suggest that the use of cannabis during HCV treatment can improve adherence by increasing the duration of time that patients remain on therapy; this translates to reduced rates of post-treatment virological relapse and improved SVR."

"Although other potential mechanisms may contribute to its enhancement of treatment outcomes, such as altered immunological function and improved nutritional status," they added, "it appears that the moderate use of cannabis during HCV treatment does not lead to deleterious consequences."

In this study, it appears that the treatment response benefit was primarily due to improved ability to stay on adequate doses of interferon and/or ribavirin. Sylvestre told HIV and Hepatitis.com that the researchers could not judge whether there was a direct antiviral effect. "It was probably more of a side-effect management effect than an antiviral effect, but we can't rule out the latter," she said.

There remain concerns about the safety of marijuana use by individuals with chronic hepatitis C. Cannabinoid receptors are present on immune cells, and use of the drug may suppress immune function. In addition, there is some evidence that frequent marijuana use may contribute to liver fibrosis. As reported in the July 2005 issue of Hepatology, French researchers found that HCV positive individuals who smoked cannabis daily were more likely to have severe fibrosis and were at higher risk for rapid fibrosis progression than those who used marijuana only occasionally or not at all. However, the participants in that study were not receiving treatment for hepatitis C.

Notably, in the current study, there was no direct dose-response relationship between the amount of cannabis consumed and the likelihood of sustained virological response. In fact, the patients who used the largest amounts of cannabis did not show as much benefit from hepatitis C therapy. The researchers did not perform pre- and post-treatment histological assessments using paired liver biopsies, and did not measure immune parameters.

"The lack of dose response in our study argues against specific receptor or metabolism-related effects, and suggests instead that cannabis exerted its benefit by non-specific improvements in symptom management," the authors stated. "Interestingly, because the benefits of heavy cannabis use were less apparent, we cannot rule out the possibility that detrimental biological or immunological mechanisms may be relevant at higher levels of consumption. Obviously, further study is needed."

Unfortunately, because cannabis is strictly controlled in the U.S. and the federal government considers the drug illegal even in states with medical marijuana laws, it is difficult to conduct randomized, controlled trials.

Editorial

In an accompanying editorial, a group of hepatitis C experts from Canada and Germany noted that people who use illicit drugs are the main risk group for new hepatitis C infections, and "will form the largest HCV treatment population for years to come."

While past treatment guidelines advised against hepatitis C treatment for active substance users and those with a recent history of active use, this categorical recommendation is no longer in effect in the U.S. and Europe, since recent studies have shown that such patients can achieve good treatment outcomes as long as they are able to maintain adequate adherence. Treatment remains a challenge for this population, however, in part because substance users have a higher prevalence of depression and other psychiatric conditions, which are associated with an increased likelihood of neuropsychological side effects during interferon therapy.

Sylvestre's study, the editorial authors wrote, "suggests that cannabis use may benefit treatment retention and outcomes in illicit drug users undergoing HCV treatment" and that "there is substantial evidence that cannabis use may help address key challenges faced by drug users in HCV treatment." Several recent studies have demonstrated the benefits of combining anti-HCV therapy with methadone maintenance, in effect offering "one-stop shopping."

The authors suggested that the therapeutic effects of cannabis "may be of principal importance and benefit for the distinct needs of illicit drug users" on methadone maintenance, because methadone itself is associated with some of the same side effects as interferon (bone aches, loss of energy, depression).

"Overall, cannabis use may thus even offer dual benefits, in facilitating adherence to both methadone maintenance therapy and HCV treatment in the HCV-infected drug user, and thus contribute to public health benefits related to both these interventions," they noted.

"While further research is required on the biological and clinical aspects of the benefits of cannabis use for HCV treatment, and the effectiveness of cannabis use for HCV treatment needs to be explored in larger study populations," they concluded, "we advocate that in the interim existing barriers to cannabis use are removed for drug users undergoing HCV treatment until the conclusive empirical basis for evidence-based guidance is available."

In particular, they suggested that medical marijuana laws and programs that specify its use for patients with specific conditions such as AIDS and cancer should also include people with hepatitis C.

9/15/06

References

D L Sylvestre, B J Clements, Y Malibu. Cannabis use improves retention and virological outcomes in patients treated for hepatitis C. European Journal of Gastroenterology and Hepatology 18(10): 1057-1063. October 2006.

B Fischer, J Reimer, M Firestone, and others. Treatment for hepatitis C virus and cannabis use in illicit drug user patients: implications and questions. European Journal of Gastroenterology and Hepatology 18(10): 1039-1042. October 2006.

C Hezode, F Roudot-Thoraval, S Nguyen, and others. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 42(1): 63-71. July 2005.


Source

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