Currently marijuana has been legalized for medicinal and/or recreational use in 23 US states, as well as the District of Columbia, and its use in HIV/HCV-coinfected patients is common. Given that it is becoming more widely available and more regularly consumed, it is critical to assess its clinical effects, including any negative impact of THC use on liver fibrosis progression. We found no evidence that THC use increases the risk of progression of liver fibrosis in women with HIV/HCV coinfection on univariable or multi-variable analyses. We examined the impact of THC use in a few key subgroups including women with fibrosis at WIHS entry , daily THC users, and women with regular THC use throughout WIHS follow-up, and found no evidence of an association with accelerated liver fibrosis . The development of liver fibrosis can take years, and prolonged THC use may be required to change rates of liver fibrosis. Similar to other published studies, we found that presence of baseline fibrosis, entry CD4 count and HCV RNA level, and ongoing alcohol consumption were predictive of significant fibrosis in WIHS follow-up, whereas African American race was found to be protective.CB1 is up-regulated in chronic liver disease including HCV infection. CB2 is also up-regulated in chronic liver disease and prevents fibrosis progression, possibly through inhibition of hepatic myofibroblasts, or by increasing hepatocyte survival, down regulation of interleukin 17, and modulation of Kupffer cells. Thus,cannabis grow setup the balance between CB1 vs CB2 activation may modulate fibrosis progression in patients with liver disease. If over expression of both receptors is balanced, there is no change in liver fibrosis.
Previous cross-sectional analyses suggested that marijuana use was associated with accelerated fibrosis progression. In one study of HCV-monoinfected patients, daily THC use was associated with higher fibrosis progression rate than was occasional use or nonuse, and remained significant on multi-variable analysis. In another study, daily THC use was correlated with advanced fibrosis on liver biopsy in HCV-monoinfected and HIV/HCV coinfected participants. Although THC users appeared to have more advanced medical disease, daily THC use was predictive of significant fibrosis on multi-variable analysis. To our knowledge, there is only one other large longitudinal study that explores the relationship between THC use and fibrosis progression in HIV/HCV-coinfected individuals. In this study, participants were predominantly male and had minimal fibrosis at entry and at follow-up . This study also failed to demonstrate an increased risk of fibrosis progression with THC use. Importantly, median follow-up was only 2.7 years, perhaps insufficient time to demonstrate fibrosis progression in subjects with minimal fibrosis. In our cohort, the median follow-up time was 11 years, with 25% having >13 years of follow-up. Despite long followup, we still were unable to demonstrate a relationship between THC use and fibrosis progression. This is the first study describing liver fibrosis outcomes by THC use in HIV/HCV-coinfected women and one of the few longitudinal studies of the influence of THC on fibrosis progression. Strengths of this study include the long follow-up and prospective collection of relevant data. However, there are limitations. THC and alcohol use may have been under reported, which may impact results. Liver biopsy was not performed in this observational study, and therefore we determined fibrosis stage using noninvasive tests .
Although these measures may be less accurate than liver biopsy, FIB-4 was specifically developed for use in HIV/HCV-coinfected patients and accurately predicts liver fibrosis in this group, with areas under the receiver operating characteristic curve of 0.73–0.79 for predicting significant liver fibrosis. Although FIB-4 increases over time as age is incorporated into the calculation, it is an accepted noninvasive measure of liver fibrosis. Moreover, we repeated our calculations using APRI, which does not include age in its calculation, and similar results were obtained. Additionally, both APRI and FIB-4 have been validated in WIHS and shown to be independently associated with all-cause mortality in HCV/HIV-coinfected women. Overall THC use in this cohort was low, with 67% of women abstaining from THC or using less than weekly for the entire duration of follow-up. The relatively small number of heavy THC users in this cohort may have impacted our ability to detect an association between daily THC use and fibrosis progression. Nonetheless, the long duration of follow-up and size of the study allowed us to conclude that occasional THC use is unlikely to impact fibrosis progression. Current and ever THC use was recorded at entry without an estimate of duration or frequency of use prior to WIHS entry. Therefore, we are unable to assess the impact of THC use prior to WIHS or lifetime cumulative use on clinical outcomes. The majority of women in this cohort are African American, with well-described lower rates of fibrosis progression; therefore, our findings may not be generalizable to males or white individuals. This study was a cohort study recruited from the community, not a treatment study. Our data found that HIV status did predict liver fibrosis, shown by both CD4 and HIV RNA in univariate analyses. While baseline CD4 count remained significant in multi-variable analysis, HIV RNA load was not predictive of fibrosis progression in multi-variable analysis. This longitudinal cohort began in an era with more limited treatment options for HIV and HCV.
Few women received interferon-based antiviral therapy, with low rates of sustained virologic response. Most women were not receiving ART at study entry; therefore, entry FIB-4 may be influenced by HIV-associated thrombocytopenia or elevations in liver enzymes, leading to overestimates of baseline fibrosis, which may underestimate fibrosis progression. We safeguarded for this by censoring extreme laboratory values that were unlikely to be related to HCV fibrosis. It is also possible that viral factors played a more important role in the development and progression of fibrosis in this group of participants. Nonetheless, we did not identify a cohort effect when cohort and cohort were compared .Ibudilast is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor. It is theorized that IBUD promotes neurotrophin expression via inhibition of negative regulation and reduces neuroinflammation via inhibition of pro-inflammatory signaling . Increases in neurotrophins may restore mesolimbic dopamine function and reduction in pro-inflammatory signaling may decrease drug-seeking behavior . A randomized, placebo-control, human laboratory trial advanced IBUD development for alcohol use disorder and found that IBUD reduced tonic levels of alcohol craving— and for individuals reporting higher levels of depressive symptoms—reduced the stimulant and rewarding effects of alcohol . IBUD has similarly been studied for its safety and initial efficacy among individuals with methamphetamine use disorder and opioid use disorder . In sum, IBUD may be a promising pharmacotherapy for AUD and other substance use disorders. Critically, pharmacotherapies for addiction can alter other appetitive responses, particularly food craving. In detail, pharmacotherapies for addiction have had broad effects on eating frequency and amounts . However, studies with more precise measurement have revealed that these medications change cravings particularly for foods that are high in fat, sugar, or both fat and sugar ; these food types strongly engage the reward system . Thus, studying IBUD effects on food craving— particularly high-fat/high-sugar food craving—would further medication development. Moreover, IBUD may uniquely impact high-fat/high-sugar food craving because pro-inflammatory signaling may influence eating behavior. Chronic, elevated peripheral levels of pro-inflammatory cytokines are associated with depression, and both decreased and increased motivation to eat . Some individuals with depression engage in more comfort eating ,outdoor cannabis grow which is defined as eating high-fat/high sugar food to reduce negative emotions like stress . Modulating pro-inflammatory signaling may consequently decrease or increase motivation to eat, especially in the context of comfort eating. Thus, testing IBUD effects on high-fat/high sugar food craving may provide insight into the nuances between pro-inflammatory signaling and eating behavior. The present study had two objectives: to test the effects of IBUD versus placebo on tonic levels of high-fat/high-sugar food craving and to test the effects of IBUD versus PLAC on high-fat/high-sugar food craving following alcohol infusion and stress.
Certainly, a sizeable number of research studies indicate that small alcohol doses stimulate eating, particularly eating of high-fat/high-sugar food . This effect is not consistent and seems to nullify with increases in alcohol dose . Moreover, a large body of research demonstrates that psychological stress increases eating of high-fat/high sugar food; although for a subgroup , stress decreases eating . In light of this literature, the present study tests the main effects of alcohol administration and stress-induction on high-fat/high-sugar food craving. Given that other pharmacotherapies for addiction have reduced eating and high-fat/high-sugar food craving in samples with substance use disorder , we hypothesized that IBUD compared to PLAC would reduce tonic levels of high-fat/high-sugar food craving as well as reduce high-fat/high-sugar food craving following alcohol infusion and stress. Lastly, prior work demonstrated that IBUD interacted with depressive symptomatology to attenuate alcohol’s effect . Depressive symptomology may be especially relevant to examining the effects of IBUD on high-fat/high-sugar craving following psychological stress due to associations among chronic inflammation, depression, and comfort eating. Therefore, exploratory analyses tested the moderating role of depressive symptomatology in any effect of IBUD compared to PLAC on high-fat/high-sugar food craving following psychological stress. Additional exploratory analyses testing the moderating role of participant characteristics including biological sex, age, and Body Mass Index in any effect are provided in Supplemental Digital Content. The objectives of the present study were tested using secondary data from the first randomized, placebo-control, human laboratory trial developing IBUD for AUD. See Ray et al. for a full description of the methods for the trial, which was registered in clinicaltrials.gov . IBUD is still investigational for treatment of addictions. The University of California, Los Angeles Institutional Review Board approved all research activities. In order to test the present study aims, measures of food craving were amended into the study in July 2014. A total of 24 non-treatment seeking participants with current DSM-5 AUD completed the trial, of which 19 completed measures of food craving. Table 1 presents demographics, which were similar to those present in the whole sample. All participants provided informed consent and the visit procedure followed all the guidelines for experimental investigation with human participants required by the Universty of California, Los Angeles and California. Participants were deemed eligible for the study after a screening and physical exam by the study physician. The screening included a urine toxicology test negative for all drugs . The toxicology panel comprised cocaine, marijuana, opiate , amphetamine, methamphetamine, PCP, benzodiazepine, barbiturate, methadone, and oxycodone . The Beck Depression InventoryII and the Reward-Based Eating Drive Scale was administered during the screening. Each participant completed two separate 7-day intensive outpatient protocols, during which medication adherence was observed in the AM by a nurse and in the PM by a riboflavin tracer. At each AM visit, the nurse confirmed participant sobriety with a daily BrAC and toxicology test negative for all drugs . IBUD administration was as follows: 20 mg bid during days 1–2 and 50 mg bid during days 3–6. After reaching a stable target dose of the study medication , participants completed a stress reactivity paradigm and an intravenous alcohol administration , which started at 1PM and was followed by an overnight visit and discharge . The protocol required a minimum 7- day washout period . Based on prior research, we anticipated psychological stress would increase high-fat/high-sugar food craving; we sought to test IBUD effects on this potential stress-induced high-fat/high-sugar food craving. Participants were exposed to 5-minute taperecorded scripts recounting current and unresolved stressful events in the participants’ lives following standardized procedures . This procedure significantly increased negative mood and decreased positive mood in the study sample . High-fat/high-sugar food craving was measured at baseline and post-stress via the item: “How strong is your urge to eat high-fat/high-sugar food right now?” High-fat/high-sugar food craving was additionally measured post-stress via the item: “What was the highest urge to eat high-fat/high-sugar food that you felt during the time that the imagery was presented?” All responses were recorded on a 10-point Likert Scale wherein higher scores indicate greater urge.The objectives of the present study were to test if the neuroimmune modulator IBUD altered tonic high-fat/high-sugar food craving as well as high-fat/high-sugar food craving following alcohol administration and psychological stress induction in a sample with AUD.