KLEIN1

Marijuana in Solid Organ Transplant: Dis-Joint-ed Standards for Listing Eligibility

Kelsey Klein, PharmD PGY2 Solid Organ Transplant Pharmacy Resident

University Health System Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center University of Texas Health San Antonio

February 1st, 2019

Learning Objectives: 1. Describe the physiological effects of marijuana.2. Summarize current implications of marijuana use on transplant centers’ listing policies for

transplantation candidates.3. Identify considerations regarding marijuana use specific to a solid organ transplant

population.4. Review safety literature regarding marijuana use in solid organ transplant recipients.

KLEIN2

Marijuana in Solid Organ Transplant:

Dis-Joint-ed Standards for Listing Eligibility

Learning Objectives: At the completion of this activity, the participant will be able to:

1. Describe the physiological effects of marijuana. 2. Summarize current implications of marijuana use on transplant centers’ listing policies for

transplantation candidates. 3. Identify considerations regarding marijuana use specific to a solid organ transplant

population. 4. Review safety literature regarding marijuana use in solid organ transplant recipients.

Assessment Questions:

1. Which phytocannabinoid mediates the majority of psychotropic and addictive properties of

marijuana?

a. Tetrahydrocannabinol (THC) b. Cannabidiol (CBD) c. Cannabinol (CBN) d. Cannabigerol (CBG)

2. True or False: International organ-specific transplant guidelines for listing criteria provide

specific recommendations regarding marijuana use in transplant candidates.

a. True b. False

3. Which infection has been associated most with inhaled marijuana use in immunosuppressed

patients?

a. Pneumonia b. Cytomegalovirus c. Aspergillus d. Histoplasmosis

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez2@uhs-sa.com *** Speaker Disclosure: Kelsey Klein has indicated she has no relevant financial relationships to disclose relative to the content of her presentation.

KLEIN3

Marijuana (MJ) Background

I. Marijuana1-4 a. Most widely used illicit drug worldwide b. Used by mankind for > 6,000 years c. Complex plant with > 400 chemical entities

Two main species:

CBD, cannabidiol THC, tetrahydrocannabinol

d. Potency of natural MJ plant has increased over past 10 years from 4% THC to 12% through

novel and improved cultivation techniques II. Mechanisms of Action1,5,6

a. MJ contains ~60 phytocannabinoids i. Primary phytocannabinoids in MJ products: THC and CBD

1. THC: mediates most psychotropic and addictive properties 2. CBD: mediate most non-psychotropic properties

b. Cannabinoid receptor system7 i. Helps regulate function of other body systems, integral part of central homeostatic

modulatory system ii. Cannabinoid 1 receptors (CB1Rs) mainly found in brain

iii. Cannabinoid 2 receptors (CB2Rs) mainly expressed on leukocytes

Table 1. THC and CBD Effects

THC CBD

Anticonvulsant + ++

Neuroprotective + ++

Anxiolytic ± ++

Antipsychotic --- ++

Muscle relaxant ++ +

Psychotropic ++ ---

Short-term memory problems + ---

Distortion of perception of time ++ ---

Anti-inflammatory + +

Immunomodulatory + + THC, tetrahydrocannabinol CB2, cannabinoid 2 receptor CBD, cannabidiol CNS, central nervous system CB1, cannabinoid 1 receptor

Cannabis indica

CBD > THC

Cannabis sativa

THC > CBD

Figure 1. Cannabis Species

KLEIN4

III. Formulations Available8-9 a. THC preparations

i. Cannabis leaves/flowers and wax for inhalation, edibles a. Synthetic cannabinoid agonists: sprayed on inert plant material b. Hemp: contains minimal (<1%) amounts of THC

i. Used for producing textiles, paper, clothing, etc. b. CBD preparations: oil concentrates, capsules, edibles, sprays, topical products, vape pens,

buccal tinctures, and patches

Table 2. Medical CBD Products (↑CBD, ↓THC)9

Generic (Brand)

Approval Indication Preparations Notes

Dronabinol (Marinol®, Syndros®)

FDA-approved

Chemotherapy-induced nausea, vomiting

Anorexia in pts with AIDS

Capsules, oral solution

Synthetic THC compound

Nabilone (Cesamet®)

Refractory, chemotherapy-induced nausea and vomiting

Capsules Semisynthetic THC analog, ~10x more

potent vs. dronabinol

Cannabidiol (Epidolex®)

Seizures associated with LGS or DS

Oral solution Highly concentrated,

strawberry flavor

Nabiximol (Sativex®)

Approved in Canada for all

indications

Approved in UK, Spain,

New Zealand for MS

symptoms

Opioid-resistant, treatment-refractory cancer-associated

pain

MS-associated neuropathic pain and spasticity refractory

to other therapies

Oromucosal spray

Racemic mixture of THC and CBD

AIDS, Acquired Immunodeficiency Syndrome MS, multiple sclerosis LGS, Lennox-Gastaut Syndrome THC, tetrahydrocannabinol DS, Dravet Syndrome CBD, cannabidiol IV. Pharmacokinetics

a. Most common routes: inhalation, oral, and oral mucosa

Table 3. MJ Pharmacokinetics7,10-14

PK Parameter Inhalation Oral

Oral mucosa

Onset of action Rapid (seconds-30 min) 30 min-2 hrs 15-40 min

Absorption/ Bioavailability

2-56% Variable, BA 4-20% Lower plasma levels vs. similar

dose inhaled

Duration 2-3 hrs 5-8 hrs 45 min-2 hrs

Half-life 20 hrs 20-30 hrs Biphasic

(initial 1-2 hrs, then 24-36 hrs)

Metabolism Brain, liver, lung Primarily liver Liver

Elimination Feces (65%), urine (20%) Feces (60%), urine (22%) Feces (65%), urine (35%) PK, pharmacokinetics BA, bioavailability

KLEIN5

V. Possible Beneficial Effects of MJ5 a. Chronic pain, neuropathic pain15-18

i. Dronabinol: robust reductions in pain sensitivity ii. Anti-inflammatory effects by inducing apoptosis and inhibiting cytokine production

b. Gastrointestinal disease19-21 i. May treat nausea, promotion of appetite

1. Varied evidence with chemotherapy as anti-emetic 2. More evidence in AIDs-associated anorexia and wasting syndrome

c. Epilepsy22-23 i. Subjective efficacy for refractory treatment reported

ii. Animal models also show potential efficacy iii. Difficult to conduct research, thus limited data on safety and efficacy

d. Multiple sclerosis24-26 i. Non-blind, non-placebo study: no benefit seen for MS-related spastic pain in pts

taking nabiximol ii. Double-blind placebo-controlled RCT: nabiximol had statistically significant

improvement in spasticity in MS pts VI. Possible Adverse Effects of MJ

a. Cognitive outcomes, brain development27-31 i. Acute use: verbal learning, memory, psychomotor function, and executive

functioning affected ii. Chronic MJ use: motivation, memory, and judgment abilities affected

iii. Normal and healthy neuronal development may be affected3 b. Psychiatric disorders32-34

i. Psychosis risk factors: heavy MJ use, high-potency products, exposure at young age ii. Depression and anxiety effects unclear, potentially increases symptoms

c. Infections and pulmonary disease35-57 i. Associated with two separate outbreaks of tuberculosis

ii. May cause bronchitis, worsening of asthma or cystic fibrosis symptoms, or COPD-like illness

iii. Additional infections seen in case reports discussed under SOT and MJ section d. Cardiovascular disease38

i. Acute intoxication associated with vascular conditions that increase risk of myocardial infarction, stroke, and transient ischemic attack

e. Renal disease39 i. Case reports: acute tubular necrosis with inhaled synthetic cannabinoids in

otherwise young healthy male ii. Case reports of renal dysfunction in SOTRs discussed under SOT and MJ section

f. Gastrointestinal disease40-42 i. Chronic use associated with cannabinoid hyperemesis syndrome (CHS)

1. CHS: cyclic vomiting and compulsive hot showers associated with chronic, high-dose MJ use

ii. Possible worsening fibrosis in pts with Hepatitis C

KLEIN6

MJ Legality in the United States

g. Addiction43-45 i. MJ use disorder occurs in 9% of users

1. 17% begin in adolescence, and 25-50% are daily users ii. Withdrawal symptoms: anxiety, craving, decreased appetite, depressed mood,

insomnia, irritability, restlessness, strange dreams 1. May start after one day of abstinence, peak on days 2-5, and last up to 14

days

I. Legality in 20189 Enacted medical MJ laws

Medical CBD with state-qualifying conditions

Legalized MJ for personal use

States that have decriminalized MJ

KLEIN7

MJ made Schedule I

↑ MJ use and MJ Use Disorder

10 state legislatures & DC: recreational MJ sale & possession legal

FDA declined downgrading MJ schedule

Solid Organ Transplantation and MJ

II. MJ History45-49

a. Schedule I substance: no accepted medical uses, high abuse potential, lack of acceptable safety profile

b. Opioids and stimulants are Schedule II (accepted medical uses, high abuse potential) c. Use of MJ has increased (Appendix A)

i. MJ use in solid organ transplantation (SOT) now more relevant d. Use of MJ use disorder has increased (Appendix A) as defined by DSM-IV (Appendix B) e. Schedule I classification limits MJ access for potential researchers to single supply grown at

a federal facility f. MJ use one of the most controversial characteristics in listing of candidates, in addition to

incarceration and psychiatric diagnoses

I. Waiting List Survival50 a. Total pts on organ-specific waiting lists in Appendix C, D

1970

2018

Figure 2. MJ Timeline

Figure 3. Survival Rates on Kidney Waiting List

P<0.001

KLEIN8

Fungal Infections

•Concerns reported: 76%

•Observed fungal infections: 43%

Nonadherence

•Concerns reported: 72%

•Observed problems: 43%

TDM Difficulties

•Concerns reported: 32%

•Observed problems: 15%

No Concerns

•4% of respondents

Screening

•All pts: 55%

•Organ-specific: 20%

Listing Acceptance

•Medical: 50%

•Medical & personal: 10%

Listing Rejection

•All pts: 26%

II. General Transplant Listing Process a. Comorbidities b. Presence of malignancies c. Presence of infections d. Alcohol and/or drug abuse e. Current medications

f. Barriers to adherence g. Social support h. Desire to have a transplant i. Financial clearance

III. Transplant Listing Guidance

Table 4. International Guidance Regarding MJ Use

Kidney Disease: Improving Global Outcomes, KDIGO51

Kidney (2018): “…patients with ongoing substance abuse disorder (as defined by DSM) despite appropriate treatment, that adversely impacts decision-making or increases the level of post-transplant risk that is higher than acceptable to the transplant program not be accepted for transplantation.”

International Society for Heart and Lung Transplantation, ISHLT52-53

Heart (2016): MJ: “…is at best an issue for which no clear direction exists,” “…each center will need to develop its own specific criteria for adjudicating candidacy for marijuana users.”

Lung (2014): Substance abuse or dependence (including marijuana) is listed as absolute contraindication

American Association for the Study of Liver Diseases, AASLD54

Liver (2013): “While some programs exclude patients with active marijuana use from liver transplantation, this remains controversial, despite well-founded fears of its adverse effect on the course of liver disease.”

United Network for Organ Sharing, UNOS (2017)55

“The decision on whether to list the patient or not is really up to the transplant program. We don’t have any real policy that says a patient like this must be accepted or must be denied.”

IV. MJ Use and Listing Eligibility Among Transplant Centers

a. Survey of American Society of Transplantation (AST), 225 members (2018)45

Figure 4. AST Survey Results

TDM, therapeutic drug monitoring

KLEIN9

Clinical Question: Should MJ Use Be a Contraindication to Transplantation Listing?

b. Survey of 49 liver transplant programs (2018)56 i. 14% list active MJ users

ii. 28% list patients who abstain at time of transplant c. Informal survey of transplant programs (2016)57

i. Policies ranged from denying listing, requiring abstinence period, and assessing on case-by-case basis

d. Survey of heart transplant programs, including 360 providers (2016)46 i. Will list: medical use 65%, recreational use 28%, with abstinence period 68%

e. Survey of 16 programs, including Canada, U.S., Norway, and Australia (2007)45 i. Policies ranged from abstinence for 3-6 months required, abstinence not required,

and no identifiable policy or consensus f. Single liver transplant center in Ontario58

i. MJ use permitted depending on social support and medication compliance g. Center-specific policies to deny transplant are often based on case reports26,52,57-58 h. States that have passed legislation banning denial of transplant listing based on medical MJ

use: California, Washington, Illinois, Arizona, Maine, Delaware, and New Hampshire46

I. SOT and MJ Considerations

a. Literature: sparse data, retrospective or observational with small sample sizes

b. Potential SOT-related MJ benefits i. Rejection13,59-62

1. Immunomodulatory, anti-inflammatory effects seen 2. Reduction in T-cell proliferation and activation reported

ii. Ischemia reperfusion injuries (IRI)63-64 1. IRI: deficient O2 supply and ensuing blood flow restoration causing tissue

damage, and is leading cause of delayed graft function post-transplant 2. Protection from IRI seen in animal studies

iii. Pain management65 1. Case report: liver transplant recipient and chronic opioid user

a. Weaned to opioid dose lower than pre-transplant with medical MJ c. Adherence, high-risk behaviors29,43-44,47,66-73

i. Acute use: impairs attention, coordination, learning, memory, and sense of time ii. Chronic use: impairs attention, executive functions, learning, memory, and verbal

abilities iii. Substance use disorder is independent risk factor for medication nonadherence and

associated graft failure 1. Potential for deficiencies in ability to drive to appointments, take

medications on time, and understand instructions iv. Potential for addictive behaviors, addiction pattern occurs in 9% of users v. Potentially abusing other substances

1. NESARC survey (Appendix A): MJ use increased risk for other substance use

KLEIN10

Literature Review

d. Drug interactions45,58,74-76 i. Role of cannabinoid as metabolism substrate, inducer and inhibitor overall unclear

1. > 500 phytocannabinoids in MJ with different enzymatic activities

Table 5. MJ Drug Interactions75

THC CBD

CYP3A4, 2C9, 2C19, 1A2 substrate CYP3A4, 2D6, 2C19, P-gp inhibitor

CYP1A2 inducer

ii. Azoles commonly used in transplant, may raise THC levels

iii. In vitro studies, case reports: CBD decreases metabolism of calcineurin inhibitors iv. Inconsistencies seen in product purity when analyzed should be considered

e. Infections77-83 i. Case reports: association with Aspergillus and other fungal infections in transplant

recipients ii. Pencillium spp. and Mucorales have been isolated from MJ leaves

iii. Case report: lipoid pneumonia described in renal transplant recipient smoking oil iv. Genomic analysis study found Cryptococcus laurentii, Mucor circinelloides,

Aspergillus fumigatus in 20 MJ samples from dispensaries f. Cardiovascular disease84

i. Case report: heart transplant recipient using MJ developed ventricular tachycardia g. Renal disease39,85-86

i. 21 known cases of synthetic cannabinoid use causing acute kidney injury ii. Case report: renal transplant pt developed membranous glomerulonephritis

iii. Case report: renal transplant pt experienced 4 episodes of severe hyponatremia associated with sepsis over 4-year period

h. Gastrointestinal disease40-41 i. Possibility of CHS + adverse GI effects of immunosuppressive medications

i. Insurance transplant coverage i. Some transplant centers have reported denial of coverage based on MJ use

I. Ranney, et al. (2008)73

Table 6. Marijuana Use in Potential Liver Transplant Candidates

Hypothesis Pts with chronic liver disease who were MJ users will have inferior survival compared to MJ non-users

Methods

Design Retrospective review from 1999 to 2007 at University of Michigan

UNOS Region 10: strict policies for MJ use and listing

Patient Population

Inclusion

Adult pts with chronic liver disease evaluated for liver transplant during study period

Exclusion

Insufficient toxicology data

Intervention MJ users o Positive cannabinoid toxicology screen between LT evaluation period and either date of

transplant or most recent follow-up

Non-users incuded never users and past users

KLEIN11

Outcomes Primary: time-dependent, adjusted pt survival from time of liver transplant evaluation

Statistics Chi square analysis, Kaplan-Meier, multivariable Cox proportional hazards model, 2-tailed students

t-test

Results

Baseline Characteristics

Baseline Characteristics (N=1489)

Characteristic, % MJ non-users (N=155) MJ users (N=1334) P-value

Age at liver evaluation, mean±SD 52.1±9.4 48.3±9.2 0.001

Male 63 78.1 0.001

Non-black 82.5 81.3 0.696

Positive hepatitis C status 40.6 63.9 0.001

MELD at eval, mean±SD 12.4±6.9 10.7±5.1 0.004

Positive transplant status 21.8 14.8 0.048

(+) Psychiatric hospitalization 2.6 3.2 0.600

(+) Smoker 35.6 57.1 0.001

(+) Ethanol 2.2 3.9 0.164

(+) Narcotics 19.9 31.0 0.002

(+) Benzodiazepines 10 21.9 0.001

(+) Other substances 2.6 7.7 0.002

Endpoints Transplantation Status

27% (43/155) MJ users listed for transplant vs. 44% (593/1334) non-users o Of those listed, 14.8% MJ users transplanted vs. 21.8% non-users (p=0.048)

10 pts tested positive after signing substance abuse policy and were removed from listing Survival Rates

Unadjusted survival rates from time of evaluation: similar between two groups Univariate and Multivariate Analyses

MJ users did not have significantly higher hazard of mortality (HR 1.09, 95% CI 0.78-1.54)

Covariates independently associated with hazard of mortality o Age at evaluation (HR 1.03, 95% CI 1.02-1.04) o MELD at evaluation (HR 1.01, 95% CI 1.09-1.12) o Positive hepatitis C (HR 1.75, 95% CI 1.41-2.17) o Transplantation (HR 0.75, 95% CI 0.65-0.86)

Author’s Conclusion

Survival of MJ users with chronic liver disease who present for transplant evaluation is not significantly different from MJ non-users

Reviewer’s Critique

Strengths

Objective criteria used to define MJ user

Attempted to evaluate poorly studied area in liver transplantation (pre-liver)

Multivariate analysis to attempt to limit confounders

Limitations Retrospective, single-center study design

Large study population overall, smaller sample size for MJ user group

Non-users included past-users (number not specified), also possible unidentified MJ users incuded

Possible some in MJ user group did not use MJ until after transplant

Unable to assess frequency, duration or modality of MJ use

Information for reason pts not transplanted after listing not provided

Unclear whether MJ use recreational or medicinal

May not be generalizable to other organ groups outside of liver

Conclusion MJ users less likely to get transplanted, and transplantation was protective factor against mortality

MJ users more likely to use tobacco, narcotics, benzos, amphetamines, cocaine, or barbiturates

UNOS Region 10 has more stringent criteria for MJ use compared to cigarette use

KLEIN12

II. Greenan, et al. (2016)87

Table 7. Recreational Marijuana Use is Not Associated with Worse Outcomes After Renal Transplantation

Objective Compare pt characteristics and renal graft outcomes between MJ users and non-users in large, urban, contemporary post-transplant population

Methods

Design Retrospective review from 2008 to 2013 at University of Maryland Medical Center

Patient Population

Inclusion

Adult pts who received living or deceased donor renal transplantation during time period

Exclusion

Multi-organ transplant

Delayed graft function requiring dialysis within the first 48 hours of transplant

Intervention MJ users o Positive urine toxicology screen and/or self-reported current use at pre-transplant evaluation

Non-users o Never users, past users, pts with missing data

Outcomes Primary

Death at 1-yr

Graft failure at 1-yr (MDRD GFR <20 mL/min/1.73 m2)

Secondary

Graft function at 1-yr (mean SCr & MDRD GFR in pts with GFR > 20)

Statistics Unpaired t-test, two-tailed Fisher’s exact test, logistic regression

Results

Baseline Characteristics

No reported medical MJ use

31.7% of transplants were living donors, percentage not specified between groups

30% of MJ users stated they had “never” used MJ

Baseline Characteristics (N=1225)

Characteristic, % MJ non-users (N=1169) MJ users (N=56) P-value

Mean age (y), meanSD 53.1±13.7 45.8±12.6 <0.0001

Male 56.9 71.4 0.065

Race White African American Other

47.3 45.6 7.1

38.1 58.7 3.2

0.69

Married or partnered 68.7 40.7 <0.0001

Without high school diploma or GED 9.1 17.3 0.084

Without college degree 11.5 32.3 0.003

EPTS score, mean±SD 48±31.4 36±27.0 0.0043

Other positive toxicology Narcotics Cocaine Other

3.5 0.9 0.4

2.2 2.3 0

0.7555

Alcohol use Current or prior

43.4

65.5

0.003

Tobacco use Current or prior > 10 cigs/day

41.3 31.6

78.6 60.7

<0.0001 <0.0001

High/moderate risk, per social work evaluation 24.6 61.9 0.0001

Treated substance addiction 5.6 17.4 0.002 EPTS, estimated post-transplant survival

KLEIN13

Endpoints Primary and Secondary Outcomes

Outcome, % MJ non-users (N=1169) MJ users (N=56) P-value

Patient survival 97.7 100 0.62

Graft failurea 17.4 19.7 0.62

Mean creatinine of functioning grafts at 1 y

(95% CI)

1.42 mg/dL (1.42-1.49)

1.52 mg/dL (1.39-1.69)

0.38

Mean GFR of functioning grafts at 1 y (95% CI)

49.5 mL/min2 (48.3-50.7)

50.7 mL/min2 (45.6-

56.5) 0.65

aDefined as GFR<20 mL/min/1.73 m2 at 1 year. Percentages calculated only among those with 1-year follow-up data. When those lost to follow-up were included in functioning grafts, 1-year graft failure rates are <10% in both groups.

Combined Outcome of Death or Graft Failure

Odds Ratio P-value

Unadjusted analysis 1.07, 95% CI 0.45-2.57 0.87

Analysis adjusted for EPTS & living donor status 0.79, 95% CI 0.28-2.28 0.67 EPTS, estimated post-transplant survival

Tobacco use, alcohol use, education, marital status not associated with 1-yr outcomes

Poor outcomes more common with deceased donors (9.4% vs. 1.3%, p<0.0001)

Author’s Conclusion

Recreational MJ use should not necessarily be considered absolute contraindication to renal transplantation

Reviewer’s Critique

Strengths

First study to look at the effect of MJ use on pts after renal transplantation

Attempted to use objective data to identify MJ use (urine drug screen)

Multiple providers asked pt about MJ use, with encouraging/supportive communication

Cross-checked multiple electronic records to minimize missing data

Ran multivariate analysis to attempt to limit confounders

Limitations Retrospective, single-center study design

Large sample size overall, but relatively small number of pts in MJ user group

Not able to completely evaluate frequency or modality of MJ use

Majority of pts in MJ group used less than daily

Possible that MJ users were not using post-transplant or vice-versa

May have labeled pts as ‘non-MJ users’ if past user, or anuric/oliguric at time of drug test

Not able to analyze longer term outcomes

Possible type II error, power calculation not met, significant difference not identified

Not generalizable to organ groups outside of kidney, or to medical MJ use

Poor outcomes more common with deceased donors, article did not specify amount in each group

Rejection rates not reported

Conclusion MJ users more likely to use tobacco, smoke >10 cigarettes/day, be considered moderate or high-risk by social worker assessment, and have history of treated substance addiction

1-yr survival and renal allograft outcomes similar in pts who use MJ recreationally vs. non-users o May consider avoiding making MJ use alone a contraindication for listing transplant o When considering listing pts, comprehensive pts review should occur

KLEIN14

III. Opportunistic Infections a. 20 MJ samples genomically analyzed found ~4,000 fungal taxonomic classifications83

i. Many containing opportunistic infections such as Cryptococcus, Mucor, Aspergillus

IV. Aspergillus spp. a. Most frequently found fungus in the environment, spores ubiquitous b. IA risk factors: BMT and SOT recipients, pts with hematologic malignancies and chronic

granulomatous diseases, and pts with AIDS, diabetes, and severe burns78 c. Mortality rate of SOT recipients with invasive aspergillus (IA): up to 90%78

Table 8. Case Reports

Case Report 1: BMT Recipient77

Background 34 yo M POD75 BMT for chronic myelogenous leukemia

MJ inhalation daily for several weeks prior to admission

Admitted with respiratory symptoms

Hospital Course MJ culture: (+) Aspergillus fumigatus – morphology, growth characteristics identical to organism grown from open lung biopsy specimen

IA treatment: amphotericin B

Expired on POD110

Autopsy Findings Disseminated aspergillosis: lung, endocardium, brain

Case Report 2: Renal Transplant Recipient78

Background 48 yo F POD28 renal transplant, resumed MJ inhalation day of transplant discharge

Admitted with respiratory symptoms

Hospital Course Readmitted POD28 with pulmonary symptoms

Bronchoalveolar washings gram stain: septated hyphae

Biopsy specimens: bronchial wall invasion

IA treatment: decrease in IS, itraconazole, amphotericin B

Post-Admission Course

Itraconazole and amphotericin B outpatient

MJ culture grew (+) mixed Aspergillus spp.

1-year after event: no further complications POD, post-operative day IA, invasive aspergillus BMT, bone marrow transplant IS, immunosuppression

I. Summary a. Prevalence of MJ use in transplant population increasing b. Potential effects of MJ range from pain relief to renal disease c. Mortality of SOT candidates higher on waiting list vs. transplant d. No consensus among transplant centers for effect of MJ use on transplant listing policies e. SOT considerations: adherence, high-risk behaviors, drug interactions, etc. f. No mortality difference seen in renal transplant recipients who use MJ vs. non-users g. Infection risks with MJ inhalation h. Data evaluating MJ in SOT pts lacking, but practitioners must create stances

Conclusions & Recommendations

KLEIN15

Personal vs. medicinal use

Other substance use

Frequency, route Other illegal

actions Stable job

Support system

Medication, appointment compliance

II. Recommendations a. Factors to consider

b. MJ use alone should not be contraindication to listing pt for transplant (exception: lung) i. Important not to let stigma drive these decisions

ii. Pt should be evaluated comprehensively 1. Consider how MJ use is affecting the pt’s individual behavior 2. Evaluate whether MJ use is masking other problems

c. All candidates should be tested for MJ during evaluation d. If MJ use meets criteria for substance abuse disorder, or pt has demonstrated they will

not take responsibility for their complex medication regimen post-transplant: i. Recommend requiring abstinence period of 6 months, substance abuse

program, and contract prior to listing e. Consider Aspergillus risk for pts inhaling MJ f. Social worker and psychologist should evaluate pt for these considerations g. Pharmacists play important role and should evaluate pt from medication standpoint h. These discussions should be made cohesively and collaboratively within

multidisciplinary team

III. Future Directions a. Clinical elucidation of adherence concerns in transplant recipients b. Effect of frequency, duration, modality of MJ use on transplant outcomes c. Possible benefits: Rejection, IRI, and pain management d. Safety outcomes of MJ use in non-renal organ transplant recipients e. Larger studies in post-transplant population

https://indiehoy.com/series/walter-white

Figure 5. Patient-Specific Considerations

KLEIN16

References 1. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol.

2012;2(6):241-254. 2. Li H. (1973) An archaeological and historical account of cannabis in China. Economic Botany. 1973;28:437-448. 3. ElSohly M. Potency monitoring program quarterly report no. 123—Reporting Period: 09: 16/2013-12/15/2013. Oxford, MS:

University of Mississippi and National Institute for Drug Abuse. 2014. 4. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in cannabis potency over the last 2 decades (1995–

2014): analysis of current data in the United States. Biol Psychiatry. 2016;79(7):613-619. 5. Strouse TB. Cannabinoids in Medical Practice. Cannabis Cannabinoid Res. 2016;1(1):38-43. 6. Sharma P, Murthy P, Bharath MM. Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry.

2012;7(4):149-156. 7. Aggarwal SK. Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results. Clin J

Pain. 2013;29(2):162-171. 8. Rai HS, Winder GS. Marijuana Use and Organ Transplantation: A Review and Implications for Clinical Practice. Curr Psychiatry

Rep. 2017;19(11):91. 9. Working to Reform Marijuana Laws. In: The National Organization for the Reform of Marijuana Laws.

https://norml.org/states. Accessed 5 November 2018. 10. Zuurman L, Ippel AE, Moin E, et al. Biomarkers for the effects of cannabis and THC in healthy volunteers. Br J Clin Pharmacol.

2009;67(1):5-21. 11. Sharma P, Murthy P, Bharath MM. Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry.

2012;7(4):149-156. 12. Agurell S, Halldin M, Lindgren JE, et al. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other

cannabinoids with emphasis on man. Pharmacol Rev. 1986;38(1):21-43. 13. Sativa® [package insert]. Mississuaga, Ontario: Bayer Inc; 2015. 14. Leussink VI, Husseini L, Warnke C, et al. Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating

spasticity. Ther Adv Neurol Disord. 2012;5(5):255-266. 15. Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and

hyperalgesia in healthy volunteers. J Am Soc Anesthesiologists. 2007;107(5):785-796.

16. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in

neuropathic pain. J Pain. 2008;9(6):506-521.

17. Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and smoked marijuana in daily marijuana smokers. Neuropsychopharmacology. 2013;38(10):1984-1992.

18. Nagarkatti P, Pandey R, Rieder SA, et al. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333-1349.

19. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr. 2008;30(3):271-280.

20. D’Souza G, Matson P, Grady CD, et al. Medicinal and recreational marijuana use among HIV- infected women in the

Women’s Interagency HIV cohort (WIHS), 1994-2010. J Acquir Immune Defic Syndr. 2012;61(5):618.

21. Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev. 2013(4):1-45.

22. Porter BE, Jacobson C. Report of a parent survey of cannabidiol- enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29(3):574-577.

23. Hill T, Cascio MG, Romano B, Duncan M, et al. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol. 2013;170(3):679-692.

24. Centonze D, Mori F, Koch G, et al. Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurol Sci. 2009;30(6):531.

25. Collin C, Davies P, Mutiboko I, et al. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol. 2007;14(3):290-296.

26. Allen LA, Ambardekar AV. Hashing It Out Over Cannabis: Moving Toward a Standard Guideline on Substance Use for Cardiac Transplantation Eligibility That Includes Marijuana. Circ Heart Fail. 2016;9(7):1-3.

27. Levenson JL. The American psychiatric publishing textbook of psychosomatic medicine: psychiatric care of the medically ill. Arlington. American Psychiatric Pub. 2011.

28. Broyd SJ, van Hell HH, Beale C, et al. Acute and chronic effects of cannabinoids on human cognition—a systematic review. Biol Psychiatry. 2016;79(7):557-67.

29. Volkow ND, Swanson JM, Evins AE, et al. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry. 2016;73(3):292.

30. Stanslowsky N, Jahn K, Venneri A, et al. Functional effects of cannabinoids during dopaminergic specification of human neural precursors derived from induced pluripotent stem cells. Addict Biol. 2016;22(5):1329-42.

31. Gaffuri A-L, Ladarre D, Lenkei Z. Type-1 cannabinoid receptor signaling in neuronal development. Pharmacology. 2012;90(1–2):19-39.

KLEIN17

32. Di Forti M, Sallis H, Allegri F, et al. Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. Schizophr Bull. 2014;40(6):1509-17.

33. Blanco C, Hasin DS, Wall MM, et al. Cannabis use and risk of psychiatric disorders: prospective evidence from a US national longitudinal study. JAMA Psychiatry. 2016;73(4):388-95.

34. Patton GC, Coffey C, Carlin JB, et al. Cannabis use and mental health in young people: cohort study. BMJ. 2002;325(7374):1195-8.

35. Munckhof W, Konstantinos A, Wamsley M, et al. A cluster of tuberculosis associated with use of a marijuana water pipe. Int J Tuberc Lung Dis. 2003;7(9):860-5.

36. Oeltmann JE, Oren E, Haddad MB, et al. Tuberculosis outbreak in marijuana users, Seattle, Washington, 2004. Emerg Infect Dis. 2006;12(7):1156.

37. Tetrault JM, Crothers K, Moore BA, et al. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. 2007;167(3):221-8.

38. Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know. AmJ Cardiol. 2014;113(1):187-90.

39. Kazory A, Aiyer R. Synthetic marijuana and acute kidney injury: an unforeseen association. Clin Kidney J. 2013;6(3):330-3. 40. Allen JH, de Moore GM, Heddle R, et al. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis

abuse. Gut. 2004;53(11):1566–70. 41. Simonetto DA, Oxentenko AS, Herman ML, et al. Cannabinoid Hyperemesis: A Case Series of 98 Patients. Mayo Clin Proc.

2012;87(2):114-9. 42. Hézode C, Roudot‐Thoraval F, Nguyen S, et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic

hepatitis C. Hepatology. 2005;42(1):63-71. 43. Fergusson DM, Boden JM. Cannabis use and later life outcomes. Addiction. 2008;103(6):969-76. 44. Lopez-Quintero C, de los Cobos JP, Hasin DS, et al. Probability and predictors of transition from first use to dependence on

nicotine, alcohol, cannabis, and cocaine: results of the national epidemiologic survey on alcohol and related conditions (NESARC). Drug Alcohol Depend. 2011;115(1):120-30.

45. Levi ME, Montague BT, Thurstone C, et al. Marijuana Use in Transplantation: A Call for Clarity. Clin Transplant. 2018;e13456. 46. Neyer J, Uberoi A, Hamilton M, et al. Marijuana and listing for heart transplant: a survey of transplant providers. Circulation

Heart Failure. 2016;9(7):1-8. 47. Hasin DS, Saha TD, Kerridge BT, et al. Prevalence of marijuana use disorders in the United States between 2001–2002 and

2012–2013. JAMA Psychiatry. 2015;72(12):1235-42. 48. Grucza RA, Agrawal A, Krauss MJ, et al. Recent trends in the prevalence of marijuana use and associated disorders in the

United States. JAMA Psychiatry. 2016;73(3): 300-1. 49. Secunda K, Gordon EJ, Sohn MW, et al. National Survey of Provider Opinions on Controversial Characteristics of Liver

Transplant Candidates. Liver Transplantation. 2013; 19:395-403. 50. Rana A, Gruessner A, Agopian VG, et al. Survival benefit of solid-organ transplant in the United States. JAMA Surg.

2015;150(3):252-9. 51. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. KDIGO.

2018, in press. 52. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for

heart transplantation: A 10-year update. J Heart Lung Transplant. 2016;35(1):1-23. 53. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014--an update

from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015;34(1):1-15.

54. 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. Hepatology. 2014;59(3):1144-65.

55. CNN Wire. A ‘catch-22’ of medical marijuana and organ transplants 2017. https://wtkr.com/2017/04/01/a-catch-22-of-medical-marijuana-and-organ-transplants/. Accessed November 15th, 2018.

56. Zhu J, Chen PY, Frankel M, et al. Contemporary Policies Regarding Alcohol and Marijuana Use Among Liver Transplant Programs in the United States. Transplantation. 2018 Mar;102(3):433-439.

57. Pondrom S. Transplantation and Marijuana Use. Am J Transplant. 2016 Jan;16(1):1-2. 58. Arya A, Hernandez-Alejandro R, Marotta P, Uhanova J, Chandok N. Recipient ineligibility after liver transplantation

assessment: a single centre experience. Can J Surg. 2013;56(3):E39-E43. 59. Gabbay E, Avraham Y, Ilan Y, et al. Endocannabinoids and liver disease—review. Liver Int. 2005;25:921–926. 60. Kirkham T. Endocannabinoids and the neurochemistry of gluttony. J Neuroendocrinol. 2008 (in press). 61. Nagaarkatti M, Rieder S, Hegde V, et al. Do cannabinoids have a therapeutic role in transplantation? Trends Pharmacol Sci.

2010;31(8):345-350. 62. Sido JM, Nagarkatti PS, Nagarkatti M. Δ9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays

skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells. J Leukoc Biol. 2015;98:435-447.

63. Hochhauser E, Lahat E, Sultan M, et al. Ultra low dose delta 9-tetrahydrocannabinol protects mouse liver from ischemia reperfusion injury. Cell Physiol Biochem. 2015;36(5):1971–81.

KLEIN18

64. Mukhopadhyay P, Rajesh M, Horváth B, et al. Cannabidiol protects against hepatic ischemia/ reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic Biol Med. 2011;50(10):1368–81.

65. Meng H, Hanlon JG, Katznelson R, et al. The prescription of medical cannabis by a transitional pain service to wean a patient with complex pain from opioid use following liver transplantation: a case report. Can J Anesth/Journal canadien d'anesthésie. 2016;63(3):307–10.

66. Yamaori S, Koeda K, Kushihara M, et al. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet. 2012; 27:294-300.

67. Bonn-Miller M, Loflin M, Thomas BF, et al. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. 2017;Nv 7; 318(17):1708-1709.

68. Parker R, Armstrong MJ, Corbett C, et al. Alcohol and substance abuse in solid-organ transplant recipients. Transplantation. 2013; 96:1015-1024.

69. Lentine KL, Lam NN, Xiao H, et al. Associations of pre-transplant prescription narcotic use with clinical complications after kidney transplantation. Am J Nephrol. 2015; 41:165-176.

70. Lentine KL, Yuan H, Tuttle-Newhall JE, et al. Quantifying prognostic impact of prescription opioid use before kidney transplantation through linked registry and pharmaceutical claims data. Transplantation. 2015; 99: 187-196.

71. Garg J, Karim M, Tang H, et al. Social adaptability index predicts kidney transplant outcome: a single-center retrospective analysis. Nephrol Dial Transplant. 2012; 27:1239-1245.

72. Blanco C, Hasin DS, Wall MM, et al. Cannabis use and risk of psychiatric disorders: prospective evidence from a US national longitudinal study. JAMA Psychiatry. 2016;73(4):388-95.

73. Ranney DN, Acker WB, Al-holou SN, et al. Marijuana use in potential liver transplant candidates. Am J Transplant. 2009;9(2):280-5.

74. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86-95.

75. Anderson GD, Chan LN. Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products. Clin Pharmacokinet. 2016;55(11):1353-1368.

76. Hauser N, Sahai T, Richards R, et al. High on cannabis and calcineurin inhibitors: a word of warning in an era of legalized marijuana. Case Reports in Transplantation. 2016;2016:1-3.

77. Hamadeh R, Ardehali A, Locksley RM. Fatal aspergillosis associated with smoking contaminated marijuana, in a marrow transplant recipient. Chest. 1988;94(2):432–3.

78. Marks WH, Florence L, Lieberman J, et al. Successfully treated invasive pulmonary aspergillosis associated with smoking marijuana in a renal transplant recipient. Transplantation. 1996;61(12):1771-4.

79. Kagen SL, Kurup VP, Sohnie PG. Marijuana smoking and fungal sensitization. J Allergy and Clin Immunol. 1983;71(4): 389-393. 80. Kagen SL. Aspergillus: an inhalable contaminant of marijuana. NEJM. 1981 Feb 19;304(8): 483-4. 81. Verweij PE, Kerremans JJ, Voss A, et al. Fungal contamination of tobacco and marijuana. JAMA. 2000;284(22):2875. 82. Vethanayagam D, Pugsley S, Dunn EJ, et al. Exogenous lipid pneumonia related to smoking weed oil following cadaveric renal

transplantation. Can Respi J. 2000 Jul-Aug; 7(4):338-42.

83. Thompson GR, Tuscano JM, Dennis M, et al. A microbiome assessment of medical marijuana. Clin Microbiol Infect. 2017;23(4):269-270.

84. Lázaro IJS, Bonet LA, Sancho-Tello MJ, et al. Ventricular tachycardia due to marijuana use in a heart transplant patient. Revista Española de Cardiología (English Edition). 2009;62(4):459-61.

85. Bohatyrewicz M, Urasinska E, Rozanski J, et al. Membranous glomerulonephritis may be associated with heavy marijuana abuse. Transplantation Proceedings. Elsevier; 2007.

86. Catalano C, Seck S, Enia G. Severe hyponatraemia during sepsis and marijuana addiction. BMJ Case Rep. 2011;1-2. 87. Greenan G, Ahmad SB, Anders MG, et al. Recreational marijuana use is not associated with worse outcomes after renal

transplantation. Clin Transplant. 2016;30(10):1340-1346. 88. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Washington, DC:

American Psychiatric Association, 2000. 89. Optn.transplant.hrsa.gov. Organ Procurement and Transplantation Network. https://optn.transplant.hrsa.gov/data/.

Updated December 27th, 2018. Accessed December 29th, 2018.

KLEIN19

Table 9. Abbreviations

2-AG: 2-arachidonoylglycerol

AASLD: American Association for the Study of Liver Diseases

ABCD: amphotericin B colloidal dispersion

ADH: antidiuretic hormone

AEA: arachidonoylethanolamide

AIDS: acquired immunodeficiency syndrome

AmphoB: amphotericin B

AST: American Society of Transplantation

BA: bioavailability

BDNF: brain-derived neurotrophic factor

BMT: bone marrow transplant

CBD: cannabidiol

CBN: cannabinol

CB1R: cannabinoid 1 receptor

CB2R: cannabinoid 2 receptor

CHS: cannabinoid hyperemesis syndrome

CI: confidence interval

CNS: central nervous system

COPD: chronic obstructive pulmonary disease

CsA: cyclosporine

DEA: Drug Enforcement Agency

DGF: delayed graft function

DHPG: dihydroxyphenylglycine

DS: Dravet Syndrome

DSM: Diagnostic and Statistical Manual of Mental Disorders

EPTS: estimated post-transplant survival

ESRD: end-stage renal disease

FDA: Food and Drug Administration

fMRI: functional magnetic resonance imaging

GFR: glomerular filtration rate

GI: gastrointestinal

GVHD: graft-versus-host-disease

HCV: hepatitis C virus

KDIGO: Kidney Disease: Improving Global Outcomes

HPLC: high-performance liquid chromatography

Hr(s): hour(s)

IA: invasive aspergillus

IQ: intelligence quotient

ISHLT: International Society for Heart and Lung Transplantation

IV: intravenous

LGS: Lennox-Gastaut Syndrome

MDRD: modification of diet in renal disease

MELD: Model End-Stage Liver Disease

Min: minutes

MJ: marijuana

MOA: mechanism of action

MS: multiple sclerosis

NESARC: National Epidemiological Survey of Alcohol and Related Conditions

NSDUH: National Survey on Drug Use and Health

O2: oxygen

PCP: phencyclidine

P-gp: permeability glycoprotein

PO: by mouth

POD: post-operative day

Ppx: prophylaxis

Pt(s): patient(s)

QID: four times daily

RCT: randomized controlled trial

SCr: serum creatinine

SOT: solid organ transplant

SOTR: solid organ transplant recipient

T: temperature

THC: tetrahydrocannibinol

Txsp: transplant

UNOS: United Network for Organ Sharing

Wk: week

Yo: years old

KLEIN20

Appendices

Appendix A. U.S. Past-Year Prevalence Estimates of Marijuana Use and Marijuana Use Disorder

Registry Prevalence (95% CI)

MJ Use MJ Use Disorder

NESARC47

(N=40,000)

2002 2013

Relative change, %

10.5 (9.9 to 11.0) 12.5 (12.0 to 13.0)

19 (12 to 22)

1.6 (1.4 to 1.8) 1.5 (1.3 to 1.6)

-8 (-22 to 8)

NSDUH48

(N=450,000)

2001-2002 (wave 1) 2012-2013 (wave 3) Relative change, %

4.1 (3.8 to 4.4) 9.5 (9.0 to 10.0) 131 (117 to 146)

1.5 (1.3 to 1.7) 2.9 (2.6 to 3.2) 93 (73 to 113)

NESARC, National Epidemiological Survey of Alcohol and Related Conditions NSDUH, National Survey on Drug Use and Health Marijuana use disorder, > 3 of 6 DSM-IV dependence criteria

Appendix B. DSM-IV Dependence Criteria88

Tolerance Need for markedly increased amounts to achieve desired effect, or markedly diminished effect with continued use of same amount

Withdrawal Characteristic withdrawal syndrome for the substance or closely related substance is taken to relieve withdrawal symptoms

Substance often taken in larger amounts or over longer period than intended

Persistent desire or unsuccessful efforts to cut down or control use

A great deal of time is spent in activities necessary to obtain or use substance, or recover from its effects

Important social, occupational, or recreational activities are given up or reduced because of use

Substance use is continued despite knowledge of having a persistent physical or psychological problem likely to have been caused or exacerbated by the substance

Most recent DSM guidelines are DSM-V, however DSM-IV used to define substance use disorder in surveys listed in Appendix A.

Appendix C. Waiting List Totals89

Current Total Number of Patients on Waiting List 114,231

Number of Transplants Performed in 2018 33,431

Number of Donors in 2018 16,026

Appendix D. Number of Patients on Waiting List by Organ89

Kidney: 103,244 Liver: 13,876

Pancreas: 886 Kidney/Pancreas: 1,672

Heart: 3,883 Lung: 1,471

Heart/Lung: 49 Intestine: 248