There has been growing interest in standardized trials to determine efficacy and side effects using standardized dosing . Marijuana is also increasingly recognized as a promising therapeutic target in various digestive disorders including inflammatory bowel disease, irritable bowel syndrome, secretion and motility related disorders. Cross-sectional studies  have reported a correlation between daily marijuana use and increase in liver fibrosis and steatosis among hepatitis C patients. However, several subsequent cohort studies did not confirm the association between marijuana use and accelerated progression to fibrosis or cirrhosis in HCV or HIV/HCV coinfected patients. Whether marijuana use should be a contraindication for liver transplant is unclear. In a recent survey of transplant physicians, 47% identified marijuana use as a “controversial characteristic”. In fact, there is little consensus within the LT community whether marijuana users should be eligible for transplant listing at all . Despite this debate, there are few reports on overall survival among chronic liver disease patients who use marijuana. Consequently, marijuana use among LT candidates remains a controversial topic . Yet, in July 2015, California adopted Assembly Bill 258, the Medical Cannabis Organ Transplant Act, which prohibits transplant institutions from denying transplantation to medical marijuana users based on their use of marijuana alone. In fact, 6 other states have adopted similar measures protecting medical cannabis users: Arizona, Delaware, Illinois, Minnesota, New Hampshire and Washington. In addition, 6 states passed legislation or ballot measures to legalize medical marijuana in 2016 alone, bringing the total number of states with legalization of marijuana to twenty-eight in addition to the District of Columbia. Given the increasing trend towards legalization and protection of medical marijuana,indoor grow lights shelves understanding the impact of marijuana use on LT outcomes is not only practical but also essential. In the only prior study assessing LT-related outcomes among marijuana users, Ranney et al found no survival difference among LT candidates whether they consumed marijuana or not.

However, in this study, more than a third of eligible patients on the LT wait list were excluded due to missing tobacco, toxicology or psychiatric history. This large proportion of patients with missing toxicology data is likely to include many substance users who might be reluctant to undergo drug screening for fear of delisting or had poor follow up. Despite exclusion of these potentially high-risk patients, marijuana users were significantly less likely to receive LT . Given the proportion of missing data, it is plausible that this study may not have adequately captured adverse outcomes like death or delisting among marijuana users on the LT wait list. In light of the limited data on LT wait list outcomes, in the present study, we aimed to assess several outcomes among historical marijuana users who were evaluated for LT at our institution, including death or delisting on the LT waiting list and probability of receiving LT. In addition, we also sought to evaluate the prevalence of and factors associated with marijuana use among all patients undergoing LT evaluation at our center to guide future studies among this population. All adults presenting for a LT evaluation at University of California, San Francisco over a 2-year period, from January 1, 2012 through December 31, 2013, were included in this retrospective cohort study. The study was reviewed and approved by the UCSF institutional review board. During the study period, the UCSF LT program had a policy of not listing patients with active marijuana use. Prior to listing, patients were required to abstain from marijuana use and, therefore, all marijuana use among listed patients is likely to be historical. Marijuana use was defined as ‘recent’ if subjects self-reported ongoing marijuana use at the time of first LT evaluation and/or had positive drug toxicology on screening laboratory evaluation. These patients were generally asked to abstain from marijuana use before being listed for LT. ‘Prior’ use refers to self-reported historical use of marijuana. Similarly, tobacco, alcohol and illicit substance use was defined by combination of self-report and urine toxicology and further categorized as ‘prior’ and ‘recent’. Patient demographic and clinical data were collected by individual health record review and/or programmed capture from electronic medical record databases .

Substance use, including marijuana, information was obtained from review of detailed psychosocial assessment conducted by trained social workers at the time of first LT evaluation. Statistical analyses were performed using STATA versions 12 and 14 software . Marijuana use was defined as combination of self-report on psychosocial assessment or positive urine toxicology during initial LT evaluation and work up. Urine drug screening was performed at the discretion of the LT team based on perceived risk of drug use on the LT wait list. Our study includes the initial urine drug screen with further data captured at the end of the study period via final LT status . Marijuana use was further categorized as ‘prior’ or ‘recent’ at the time of first LT evaluation, as described previously. Factors associated with marijuana use were analyzed using a multi-variable log-link Poisson regression with robust standard errors to estimate adjusted incidence rate ratios . Using this method, the calculated IRR approximates the prevalence ratio. All risk factors with p-values of less than 0.05 were retained in the multi-variable model. Among those listed for LT, we calculated the cumulative incidence of death or delisting within strata of marijuana use. Similarly, we also calculated the cumulative incidence of receiving LT within strata of marijuana use. Observation time was measured from date of first LT evaluation to the first of dropout, wait list death, or transplant. Cumulative incidence estimates accounted for competing events and patients remaining on the waiting list were censored at the last known date on the list. Using Fine and Gray competing risk regression 19 we estimated the hazard ratios and 95% CI for risk of the 2 outcomes of interest, wait list death or delisting and receiving transplant on the wait list. Factors with a univariate p<0.2 and the primary explanatory variable, marijuana use, were included in the multi-variable modeling process. The final multi-variable models were selected by backward elimination with p>0.05 for removal while retaining marijuana use. Of all 884 LT candidates, 585 were listed for LT. Among them, 205 died or were delisted while 287 received LT. Among never users of marijuana, 69% were listed for LT. While, 65% and 51% of prior and recent users of marijuana were listed for LT, respectively. Listing and wait list outcomes for all participants are outlined in Figure 2. Among those listed for LT, there was no statistically significant difference in the cumulative incidence of death or delisting on the LT waiting list within strata of marijuana use .

Similarly, there was no statistically significant difference in the cumulative incidence of receiving LT within strata of marijuana use . Reasons for delisting from the LT wait list are presented in Table 4. The most common reasons for delisting included ‘too sick for transplant’ and ‘death’ . There were isolated cases of ‘substance abuse relapse’ with no significant differences between recent, prior and never users of marijuana . Our study presents a comprehensive assessment of marijuana use among LT candidates. We found no statistically significant association between the risk of wait list removal or death and historical marijuana use. On the other hand, notably,vertical indoor growing system a history of recent illicit drug use was associated with higher risk of death or delisting. This finding could be related to a number of possibilities including recidivism to drug abuse which would prompt delisting from LT wait list, or perhaps higher rate of medical illness from complications of drug use resulting in death or delisting. Illicit drug use may also reflect worse social circumstances and lack of support leading to delisting. On the other hand, a similar association with marijuana use was not found. This observation supports major differences in the impact of a history of marijuana use vs. illicit drug use among LT candidates. Similarly, in unadjusted and adjusted competing risk regression, we were unable to detect a statistically significant association between receiving LT and history of marijuana use. Factors associated with higher chance of receiving LT included MELD score ≥20 and HCC – both of which are consistent with and reflect current LT allocation practices . Marijuana use was highly prevalent among LT candidates at our institution. Almost half of all evaluated patients had a history of marijuana use and a considerable proportion were recent users at the time of evaluation. Among users, 13% had a self-reported history of weekly use while 16% had been daily users. Substance use, beyond marijuana, was a common feature among LT candidates – we found high prevalence of historical tobacco use , alcohol use , illicit drug use and prescription opiate/BDZ use . More than half of all alcohol users had a history of heavy use/abuse, and a significant proportion of candidates were recent users of illicit substances. We also found that almost a quarter of evaluated patients had recent opiate/BDZ prescriptions. Though detailed and systematic data about substance abuse among all LT candidates are limited, our findings are similar to prior reports, including those assessing patients with alcoholic liver disease .

We also identify several factors associated with marijuana use, including younger age and white race. Marijuana use was closely associated with other substance use – persons with alcoholic and HCV cirrhosis were more likely to have been marijuana users compared to those with HBV cirrhosis. Tobacco use, both prior and recent, was also associated with higher prevalence of marijuana use. Similarly, prior and recent illicit drug users had higher prevalence of marijuana use. Notably, never users of alcohol had much lower prevalence of marijuana use – this likely reflects a small proportion of LT candidates who have been abstinent or had very limited exposure to any substance use. There have been prior conflicting reports regarding an association between marijuana use and lower BMI. In univariate analysis, marijuana users were less likely to be obese compared to overweight , though this association was not significant after multi-variable adjustment . This is the first study to present detailed data on prevalence and multi-variable adjusted factors associated with marijuana use among LT candidates. Our findings are consistent with limited prior reports of marijuana use patterns among LT candidates. Recent national drug use surveys 27 have found that 6.5% of adults older than 25 had active marijuana use. These nationally representative estimates are in close agreement with our finding of 7% recent marijuana use among LT candidates. It is also important to note that marijuana use was not just limited to those with a history of substance abuse but was rather distributed across the spectrum of substance use, as demonstrated in Figure 1. Yet, in our study, despite noting a high prevalence of marijuana use and its associations with other substance use, we were unable to detect worse outcomes with historical marijuana use itself; whereas, illicit substance use did confer higher risk of death or delisting on the wait list. In a recent study, Greenan et al 28 also found that isolated recreational marijuana was not associated with poorer outcomes among kidney transplant patients. Though most patients underwent urine drug screening in addition to psychosocial evaluation to identify marijuana use in our cohort, we assessed for differences in sensitivity of marijuana use assessment between urine drug screening and psychosocial screening. Most marijuana users had positive urine toxicology – among ‘recent’ marijuana users 80% had positive urine toxicology while an additional 20% were identified based on self-report alone. Therefore, sensitivity of drug screening alone was 80% while that of self-report alone was 62% . We also assessed for differences in outcomes between those who tested negative for marijuana and those who were not tested with urine drug screening. A similar proportion of subjects with and without urine drug screen were positive for marijuana use – 48% and 46% , respectively, with no statistical difference detected . When comparing subjects without marijuana use by presence or absence of the urine test, risk of death/delisting and LT failed to differ statistically. Regardless of screening method, a similar proportion of patients were positive for marijuana use and wait list outcomes were similar.