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Marijuana use and post-transplant complications and non-compliance in liver transplant patients

Published:October 03, 2022DOI:https://doi.org/10.1016/j.amjms.2022.09.022

      Abstract

      Background

      Liver transplant (LT) is a lifesaving treatment for patients with end stage liver disease. Historically, institutions across the United States have deemed active marijuana use as an exclusion criterion for listing. This study aims to investigate LT outcomes in patients with history of marijuana use prior to LT.

      Methods

      We performed a retrospective review of 111 patients who tested positive for marijuana on urine drug screen during initial LT evaluation between February 2016 and January 2021. 100 non-marijuana users who underwent LT were cross matched for control. Patient demographics, substance use history, and transplant decisions were recorded. Post-LT variables were also collected up to 1 year post surgery including postoperative infections, issues with non-compliance, and continued substance use. Chi-square analysis was used to assess the association between pre-transplant marijuana use and post-transplant complications. Logistics regression was implemented to measure associations amongst the entire cohort.

      Results

      From 111 marijuana users, 32 (29%) received a transplant. There was no statistical difference in post-LT outcomes between marijuana and non-marijuana users, including incidence of cardiac, respiratory, renal, psychiatric, or neurological complications, as well as readmission rates post-surgery. There were no statistically significant associations between marijuana use with post-transplant bacterial or fungal infections, medication non-compliance, or continued substance use (all p>0.05). Marijuana use was associated with pre-LT tobacco use (p = 0.020).

      Conclusions

      Our data indicates that marijuana is not associated with increased risk of postoperative noncompliance, other organ complications, infections, or death. As a single factor, marijuana may not need to be a contraindication for LT.

      Keywords

      Introduction

      Liver transplant (LT) is a life-saving treatment for patients with liver disease. Nearly 5000 transplants are performed every year in the United States (U.S.).

      U.C.S.F. Health. “Living donor liver transplant: the facts.” Ucsfhealth.org, UCSF Health, 22 Sept. 2021. https://www.ucsfhealth.org/education/living-donor-liver-transplant-the-facts.

      Prior to receiving LT, candidates go through an extensive evaluation to identify any underlying comorbidities and psychosocial factors, including substance use, that may need to be addressed to make the intraoperative and postoperative course more successful.
      • Martin P.
      • DiMartini A.
      • Feng S.
      • et al.
      Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
      Marijuana continues to be the most common drug of use in the U.S. and has remained a controversial topic when it comes to solid organ transplant.
      Data and Statistics
      Centers for disease control and prevention.
      ,
      • Rai H.S.
      • Winder G.S.
      Marijuana use and organ transplantation: a review and implications for clinical practice.
      In medical practice, patients with marijuana use are considered to be at risk for post-transplant complications including noncompliance with immunosuppression, relapse or use of other illicit drugs, infections, particularly fungal infections, and behavioral and neuropsychiatric disorders.
      • Likhitsup A.
      • Saeed N.
      • Winder G.S.
      • et al.
      Marijuana use among adult liver transplant candidates and recipients.
      ,
      • Serrano Rodriguez P.
      • Strassle P.D.
      • Barritt 4th, A.S.
      • et al.
      Marijuana consumption in liver transplant recipients.
      A few studies have shown some benefits of marijuana use, particularly in cirrhotic patients, including improved hospitalization stay, mortality and symptom burden.
      • Adejumo A.C.
      • Adegbala O.M.
      • Adejumo K.L.
      • et al.
      Reduced incidence and better liver disease outcomes among chronic HCV infected patients who consume cannabis.
      ,
      • Sobotka L.A.
      • Mumtaz K.
      • Hinton A.
      • et al.
      Cannabis use may reduce healthcare utilization and improve hospital outcomes in patients with cirrhosis.
      However, given the scarcity of allografts and the abundance of patients needing a new liver, careful selection of candidates becomes a necessity.
      • Kwon Y.K.
      • Etesami K.
      • Genyk Y.
      Should living donor liver transplant selection be subject to the same restrictions as deceased donor transplant?.
      Thus, it is no surprise that many institutions in the US require patients to be abstinent from substances such as alcohol, tobacco, and illicit drugs, including marijuana, to qualify for a LT.
      Only a few studies to date have looked at marijuana and post-LT complications and noncompliance.
      • Serrano Rodriguez P.
      • Strassle P.D.
      • Barritt 4th, A.S.
      • et al.
      Marijuana consumption in liver transplant recipients.
      ,
      • Guorgui J.
      • Ito T.
      • Markovic D.
      • et al.
      The impact of marijuana use on liver transplant recipients: a 900 patient single center experience.
      With increasing legalization of marijuana across the U.S., it has become important to understand its implications when it comes to LT.

      Karmen Hanson, Alise Garcia. “State medical cannabis laws.” State Medical Cannabis Laws. https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx.

      We aimed to investigate pre-transplant marijuana use and its correlation with post-transplant outcomes including risk of infections, particularly fungemia, organ dysfunction, and other complications including rehospitalizations and death. We also aimed to assess non-compliance post-LT in patients with history of marijuana use.

      Methods

      Study design and patient population

      We performed a retrospective review of patients over the age of 18 that were initially evaluated for LT between January 2016 and January 2021 at the University of Alabama at Birmingham in Birmingham, Alabama. Informed consent was obtained from all participants, and the study was carried out in accordance with the Code of Ethics as described in the Declaration of Helsinki. The study group consisted of a total of 111 patients that tested positive for marijuana on urine drug screen during initial evaluation for LT. The study group was then matched by sex, gender, and race to 100 patients that underwent LT and had tested negative for marijuana during initial LT evaluation. Per the institution's policy at the time, patients were required to be abstinent from marijuana for at least 6 months and have 2 consecutive negative urine drug screens to qualify for a liver transplant.

      Data collection

      Data were collected through retrospective review of the electronic medical record where patient information was de-identified and stored in a secure excel file. For data collection on our study and control groups, in addition to patient demographics and baseline variables, we collected information on other substances used, aside from marijuana, near the time of LT evaluation: alcohol, tobacco or other illicit drug use. Clinical factors including etiology of cirrhosis, MELD-Na score, and manifestations of decompensation were collected. We also gathered data on reasons for LT denial as mentioned in the most up to date LT decision meetings. Post-transplant complications were recorded, which included continued substance use, infections, specifically fungal infections, other major cardiac, respiratory, neurologic, oncologic, or renal complications, and death. Non-compliance was also recorded on each patient and defined by resumption or use of alcohol, tobacco or illicit substances post LT, failure to follow up for multiple appointments, and nonadherence to medications or various treatments. In terms of substance use other than marijuana, we grouped patients into current, recent (quit within the last 6 months prior to LT evaluation), and former (last use over 6 months prior to evaluation) alcohol, tobacco, or other drug use.

      Statistical analysis

      Data analysis consisted of descriptive statistics as a mean ± standard deviation (SD) for continuous variables and frequency percentage for categorical variables. The data was further stratified to analyze pre- and post-transplant outcomes in those patients who underwent LT, and this cohort included both marijuana and non-marijuana users. Chi squared analysis was used to compare categorical variables between the 2 groups and student 2 sample t-test was implemented to compare continuous variables between groups. We also separately analyzed marijuana users who underwent LT evaluation but did not receive transplantation during the time of this study. Logistic regression analysis was also used to calculate adjusted odds ratios (OD) for measures of associations for certain variables amongst the entire cohort. All statistics were performed using the Stata Statistical Software (StataCorp LLC, College Station, TX, USA) and IBM SPSS Statistics for Macintosh.
      StataCorp
      Stata Statistical Software: Release 17.
      ,

      IBM SPSS Statistics for Macintosh, Version 28.0. Armonk, NY: IBM Corp.

      Results

      Study population

      From the 111 patients in our study group with active marijuana use at time of initial LT evaluation, 32 patients (29%) eventually received a LT. All 100 patients in our control group received a LT and were non-users at time of initial evaluation. Regarding substance use, 72% of all marijuana users had a history of tobacco use compared to 58% of non-marijuana users having a history of tobacco use (p = 0.032). In addition, a significantly higher number of patients with current marijuana use at time of evaluation also had reported current or recent tobacco use compared to the non-marijuana users’ group (42% vs 27%, p = 0.020). History of alcohol use was not significantly associated with marijuana use (p = 0.161).

      Marijuana use and post LT outcomes

      The average age of the entire LT cohort was 54.91 ± 11.94 with 99 (75%) males. Cirrhosis etiology mainly included 29 (22%) nonalcoholic steatohepatitis (NASH), 44 (33%) alcohol (EtOH), 23 (17%) viral-mediated cirrhosis, 6 (5%) auto-immune, 10 (8%) biliary and 20 (15%) others. In terms of cirrhotic decompensations prior to LT, 92 (70%) presented with ascites or volume overload, 79 (60%) had a history of varices, 30 (23%) had an episode of variceal bleeding, 82 (62%) had a diagnosis of hepatic encephalopathy (HE), and 27 (20%) had a diagnosis of hepatocellular carcinoma (HCC).
      Comparing marijuana users and non-users from the LT cohort, marijuana users were on average 10 years younger than non-users (p = 0.00). Both groups had 25% females, and the average MELD at time of transplant was 23.31 ± 9.7 for marijuana users and 23.82 ± 8.9 for non-users. We also found no difference in pre-transplant comorbidities including cardiac, renal, psychiatric, or neurologic disease. Alcohol (69% vs 65%) and tobacco use (63% vs 58%) between the marijuana users and non-users was not significant (all p>0.05) (Table 1). Exactly one patient from the marijuana group and two patients from the non-marijuana group were using other illicit drugs aside from marijuana at the time of evaluation. Looking at post-transplant outcomes up to one year after surgery, there was no statistically significant difference in either groups in incidence of post-LT congestive heart failure, malignancy including liver associated cancers, seizure or other neurological disorders, coronary artery disease, arrhythmias, chronic kidney disease, respiratory or psychiatric disorders (all p >0.05). In addition, rates of postoperative infection requiring treatment were similar between the two groups as were readmission rates, including readmissions secondary to hepatic complications, up to one-year post-LT (all p>0.05) (Table 2).
      Table 1Variables shown as percentages comparing demographics and comorbidities prior to LT in marijuana and non-marijuana users.
      VariablesMarijuana Users (n = 32)Non-Marijuana Users (n = 100)P value
      Age, Mean ± SD47.5 ± 2.4957.28 ± 10.15<0.01
      Female, n (%)8 (25%)25 (25%)1.000
      MELD-Na, Mean ± SD23.31 ± 1.7023.82 ± 0.880.783
      Tobacco Use, n (%)20 (63%)58 (58%)0.652
      Alcohol Use, n (%)22 (69%)65 (65%)0.697
      Comorbidities, n (%)
       Congestive Heart Failure0 (0%)4 (4%)0.251
       History of Malignancy8 (25%)17 (17%)0.315
       Seizure Disorder0 (0%)1 (1%)0.750
       Arrythmia1 (3%)8 (8%)0.341
       CAD1 (3%)10 (10%)0.235
       CKD3 (9%)17 (17%)0.295
       Psychiatric9 (28%)18 (18%)0.216
       Neuro5 (16%)5 (5%)0.048
      Table 2Variables shown as percentages comparing post-LT outcomes in marijuana users and non-marijuana users prior to LT.
      Variables (n%)Marijuana Users (n = 32)Non-Marijuana Users (n = 100)P value
      1 year Mortality3 (9%)8 (8%)0.806
      Overall Mortality8 (25%)17 (17%)0.315
      Urgent/Emergent Transplant4 (13%)8 (8%)
      Infection17 (53%)44 (44%)0.368
       Post-op PNA6 (19%)13 (13%)0.420
       UTI2 (6%)10 (10%)0.521
       Cerebellar Abscess1 (3%)1 (1%)0.392
       Bacterial Peritonitis4 (13%)6 (6%)0.226
       Cellulitis1 (3%)2 (2%)0.710
       Bacteremia6 (19%)11 (11%)0.255
       CMV Viremia1 (3%)11 (11%)0.177
       C. Diff2 (6%)7 (7%)0.884
       Post-Op Fungemia3 (9%)3 (3%)0.132
      Readmission Rate18 (56%)50 (50%)0.538
      Liver Complications Requiring Admission10 (56%)24 (48%)0.582
      MI0 (0%)4 (4%)0.251
      Arrythmia1 (3%)6 (6%)0.528
      Cardiac Arrest0 (0%)4 (4%)0.251
      AKI9 (28%)28 (28%)0.989
      Thrombosis4 (13%)5 (5%)0.143
      Respiratory Complications4 (13%)5 (5%)0.143
      Noncompliance7 (22%)10 (10%)0.081
      Importantly, there was no significant difference in overall mortality between marijuana users and non-users (9% vs 8%, p = 0.806). Marijuana users were more likely to be noncompliant post-transplant compared to non-users, however this finding was not significant (22% vs 10%, p = 0.081) (Fig. 2).

      Post-LT non-compliance analysis

      Univariate logistic regression was performed for correlation between baseline variables and post-LT non-compliance. No significant correlations were found for tobacco, alcohol, drug use, or prior psychiatric history with post-LT non-compliance (all p>0.05) (Table 3).
      Table 3Calculated odds ratio of post-LT noncompliance with pre-LT tobacco, alcohol and marijuana use, and psychiatric history.
      Univariate Analysis
      NoncomplianceOR [95% CI]P value
      Tobacco use1.21 [0.53–2.74]0.652
      Alcohol use4.47 [0.98–20.54]0.054
      Marijuana Use2.52 [0.87–7.30]0.088
      Psychiatric History1.23 [0.37–4.13]0.737

      Non-LT marijuana users

      A total of 79 patients with active marijuana use at the time of initial evaluation did not receive LT. This cohort consisted of 57 males, and the average MELD score was 14.95 ± 6.9. Etiology of cirrhosis included 5 (6%) NASH, 5 (6%) NASH/EtOH, 31 (39%) EtOH, 25 (32%) HCV/HBV or both, 4 (5%) autoimmune, 5 (6%) biliary, and 3 (4%) others. Twenty-seven (34%) of the patients had a confirmed diagnosis of HCC. Cirrhotic decompensations in this cohort included 41 (52%) ascites, 30 (38%) varices with 5 (6%) patients having a history of variceal bleed, and 39 (49%) HE. Reasons for denial for LT during liver transplant committee meetings included the following: 41 (52%) for continued marijuana use, 20 (25%) for tobacco use, 7 (9%) for financial or insurance reasons, 9 (11%) for non-compliance including failure to attend appointments or follow pre-liver transplant protocols and rules, and others (Fig. 1). Only 11 (14%) patients were denied solely for marijuana use, whereas the majority had additional reasons for denial including ongoing marijuana use. Denial for LT due to active marijuana use was significantly correlated with denial secondary to active alcohol use (p = 0.008) and tobacco use (p<0.001).
      Fig. 1
      Fig. 1Reasons for denial during liver transplant committee meetings in patients with marijuana use that did not undergo liver transplant.

      Discussion

      Marijuana has been a common barrier when it comes to solid organ transplantation for many years. It has been known to be associated with psychiatric disorders, organ complications in transplant patients and social issues.
      • Rey J.M.
      • Tennant C.C.
      Cannabis and mental health.
      ,
      • Melaragno J.I.
      • Bowman L.J.
      • Park J.M.
      • et al.
      The clinical conundrum of cannabis: current practices and recommendations for transplant clinicians: an opinion of the immunology/transplantation PRN of the American College of Clinical Pharmacy.
      In 2018, a survey conducted of LT centers in the U.S. showed that 33 out of 46 programs would not accept recreational marijuana use, and 18 programs would not accept medical or recreational marijuana use.
      • Zhu J.
      • Chen P.Y.
      • Frankel M.
      • et al.
      Contemporary policies regarding alcohol and marijuana use among liver transplant programs in the United States.
      A study done in 2009 showed that 14.8% of marijuana users received a LT, whereas 21.8% of non-users were able to be transplanted. However, the survival rates from the time of transplant evaluation to post-transplant were similar between the two groups.
      • Ranney D.N.
      • Acker W.B.
      • SN Al-Holou
      • et al.
      Marijuana use in potential liver transplant candidates.
      Moreover, recent studies have shown that there is no statistical difference between marijuana users and non-users when it comes to death or delisting (as a result of the patient being too sick) when patients are on the list for LT.
      • Kotwani P.
      • Saxena V.
      • Dodge J.L.
      • et al.
      History of marijuana use does not affect outcomes on the liver transplant waitlist.
      We conducted a study to identify whether marijuana use had other psychosocial factors or comorbidities associated pre-LT, and various post-transplant outcomes within one year of surgery. Our study consisted of 111 patients who were current marijuana users as documented by a positive urine drug screen during initial LT evaluation, with 29% eventually receiving a LT. The control arm consisted of 100 individuals who were non-marijuana users, of which 100% received a LT. We found that marijuana use prior to LT was not associated with post-transplant infections or readmissions up to one year post-surgery (Table 2).
      Marijuana has been traditionally linked to several complications including arrhythmias and coronary artery disease (CAD) with concerns that its use increases myocardial demand.
      • Rezkalla S.
      • Stankowski R.
      • Kloner R.A.
      Cardiovascular effects of marijuana.
      ,
      • Umapathi K.K.
      • Thavamani A.
      • Dhanpalreddy H.
      • et al.
      Prevalence of cardiac arrhythmias in cannabis use disorder related hospitalizations in teenagers from 2003 to 2016 in the United States.
      The connection between marijuana and potential for renal dysfunction is yet to be fully studied, but deleterious effects have been noted in vitro.
      • Ho C.
      • Martinusen D.
      • Lo C.
      A review of cannabis in chronic kidney disease symptom management.
      Studies have shown inconclusive results as to whether regular marijuana use contributes to beneficial and/or detrimental psychiatric and neurologic effects.
      • Fife T.D.
      • Moa wad H.
      • Moschonas C.
      • et al.
      Clinical perspectives on medical marijuana (cannabis) for neurologic disorders.
      ,
      • Jenkins B.W.
      • Khokhar J.Y.
      Cannabis use and mental illness: understanding circuit dysfunction through preclinical models.
      In our study, we found no statistical difference in both groups regarding past medical history or post-liver transplant outcomes including cardiac, renal, psychiatric, neurological, or other complications (Tables 1 and 2).
      Our study did show a significant association between current marijuana use with co-morbid tobacco use, most importantly within the last 6 months at the time of initial evaluation. This finding is similar to several studies that have raised concern for associated tobacco use with marijuana use prior to LT.
      • Yan K.
      • Forman L.
      Cannabinoid use among liver transplant recipients.
      We also found that patients with marijuana use were denied listing for LT more so for concurrent alcohol or tobacco use, rather than just marijuana use alone (Fig. 1).
      There have been concerns raised for nonadherence in patients undergoing organ transplant who have a history of substance use, including marijuana use, however not a lot of studies have assessed noncompliance in LT patients.
      • Likhitsup A.
      • Saeed N.
      • Winder G.S.
      • et al.
      Marijuana use among adult liver transplant candidates and recipients.
      ,
      • Lieber S.R.
      • Volk M.L.
      Non-adherence and graft failure in adult liver transplant recipients.
      ,
      • Wu E.M.
      • Menesis K.G.
      • Kang S.
      • et al.
      Clinical impact of marijuana usage in liver transplant recipients.
      Moreover, with the immunosuppressive state of having a transplanted organ, there have been questions raised as to whether marijuana would contribute to increased infections, particularly fungal infections, however the data is lacking as well in the LT world.,
      • Hamadeh R.
      • Ardehali A.
      • Locksley R.M.
      • et al.
      Fatal aspergillosis associated with smoking contaminated marijuana, in a marrow transplant recipient.
      ,
      • Marks W.H.
      • Florence L.
      • Lieberman J.
      • et al.
      Successfully treated invasive pulmonary aspergillosis associated with smoking marijuana in a renal transplant recipient.
      ,
      • Gabardi S.
      • Kubiak D.W.
      • Chandraker A.K.
      • et al.
      Invasive fungal infections and antifungal therapies in solid organ transplant recipients.
      Our study found that pre-LT marijuana use was not associated with a significant increase in non-adherence or fungal infections up to one year post surgery. However, as shown in Fig. 2, most of the non-compliance reasons were tied to resumption of tobacco and alcohol (4 vs 3 and 4 vs 2 patients in the non-marijuana and marijuana groups respectively). Interestingly, exactly 1 patient belonging to the non-marijuana group was noted to use marijuana post LT, whereas no patients from the marijuana group were identified to be using after LT. The findings highlight that marijuana use is often not the sole reason for denial for LT candidacy, and other factors need to be taken into consideration when determining eligibility, including concurrent substance use.
      Fig. 2
      Fig. 2Reasons for noncompliance in marijuana and non-marijuana users post-liver transplant (LT). Number of patients represented on x axis and reasons represented on the y axis.
      We acknowledge the presence of some limitations in our study. Our study had a small sample size, necessitating further large multi-center studies in the future. Data was collected solely through retrospective chart review, and information provided in the charts may be incomplete. Hospitalization data and post-transplant complications were recorded only if the patient presented to our institution. Since post-LT substance or marijuana use as well as general compliance were documented from the chart based on the patient's self-report, the findings may have underestimated usage. In addition, our data is limited to post-transplant outcomes up to one year, and further studies need to be performed to assess long term outcomes of marijuana use and LT.

      Conclusions

      In conclusion, pre-LT marijuana use was not associated with increased post-LT infections, noncompliance, readmissions, respiratory or renal failure, cardiac or oncologic complications, or death up to one year post surgery. Further studies are needed amongst multiple centers to identify issues with post-LT medical complications and noncompliance with pre-LT marijuana use, as well as how concurrent alcohol, tobacco and marijuana use may interplay with these complications.

      Conflicts of Interest

      The authors have no conflicts of interest or financial arrangements to declare.

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