- Email: [email protected]
Marijuana and Cannabinoids in ESRD and Earlier Stages of CKD
Perspective Marijuana and Cannabinoids in ESRD and Earlier Stages of CKD Joshua L. Rein, DO, and Christina M. Wyatt, MD Marijuana is the most commonly used recreational drug in the United States, and legal recreational and medicinal use has gained public acceptance during the last decade. Twenty-nine US states have established medical marijuana programs, 8 of which have also legalized recreational marijuana, and Canada is expected to legalize recreational marijuana in 2018. Advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) are chronic conditions with significant associated morbidity and mortality. Patients experience substantial symptom burden that is frequently undertreated due to adverse medication side effects. This article reviews the available evidence for the use of medical marijuana to manage chronic pain, nausea/vomiting, anorexia/cachexia, and pruritus, all of which are frequently reported by patients with advanced CKD or ESRD. Potential adverse health effects of medical and recreational marijuana use are also discussed. Regardless of personal, social, and political beliefs, marijuana use is becoming mainstream, and nephrologists should be aware of the potential impact on our patient population. Further research is warranted to investigate the renal endocannabinoid system, the impact of marijuana use on kidney disease outcomes, and the risks and benefits of medical marijuana use on symptoms of advanced CKD and ESRD. Am J Kidney Dis. -(-):---. ª 2017 by the National Kidney Foundation, Inc. INDEX WORDS: Marijuana; cannabis; synthetic cannabinoids; medical marijuana; end-stage renal disease (ESRD); chronic kidney disease (CKD); chronic pain; nausea; anorexia; cachexia; pruritus; transplantation; recreational drug use.
M
arijuana is the most commonly used recreational drug in the United States, and legal recreational and medicinal use of marijuana has increased during the last decade. As of June 2017, twenty-nine US states and the District of Columbia have medical marijuana programs. Eight states and the District of Columbia also allow for recreational use (Fig 1),1 although marijuana remains illegal under federal law. Legal marijuana sales in the United States are projected to grow to more than $20 billion by 2020. Canada also has a well-established medical marijuana program and is expected to legalize recreational use in 2018. With increasing use and availability of marijuana, it is important to understand the impact of marijuana use on the risk for chronic kidney disease (CKD) and the potential role of medical marijuana in the management of symptoms related to CKD and end-stage renal disease (ESRD). Marijuana is the dried flower bud from the Cannabis sativa and Cannabis indica plants and naturally contains numerous phytocannabinoids. The most abundant phytocannabinoids are D9tetrahydrocannabinol (THC) and cannabidiol, with differing activities and affinities for the G-protein– coupled cannabinoid receptors CB1 and CB2. Plant breeding has created genetically unique Cannabis strains with varying concentrations of different phytocannabinoids, enhancing certain desired effects. For example, because THC mediates the psychotropic effects of marijuana, strains with a higher THC concentration are selectively produced for recreational use. The endogenous cannabinoids, or endocannabinoids, anandamide and 2-arachidonoylglycerol are Am J Kidney Dis. 2017;-(-):---
eicosanoids derived from cell membrane phospholipids and are the natural ligands for the cannabinoid receptors. Further detail about cannabinoid receptors and the endocannabinoid system is available in recent reviews.2,3 Marijuana can be smoked, vaporized, or consumed as a capsule or in food. Inhalation provides an onset of action within minutes and allows for real-time dose titration. Peak effects are seen within 15 to 30 minutes, and half-life is 1 to 2 hours. After oral consumption, the onset of action may be delayed up to 1 to 2 hours, with peak effects at 2 to 3 hours and half-life of 3 to 6 hours. Urinary excretion accounts for 20% of metabolite elimination. Cannabinoid-based pharmaceuticals are also available or in development to treat a variety of conditions. Dronabinol (Marinol and Syndros), a synthetic form of THC, and nabilone (Cesamet) are US Food and Drug Administration (FDA)-approved to treat AIDS cachexia and chemotherapy-induced nausea/ vomiting. Nabiximols (Sativex) is approved outside the United States for the treatment of multiple From the Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Received February 28, 2017. Accepted in revised form June 19, 2017. Address correspondence to Joshua L. Rein, DO, Division of Nephrology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Pl, Box 1243, New York, NY 10029. E-mail: [email protected] 2017 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2017.06.020 1
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Figure 1. Map of the United States shows states with legalized use of medical or recreational marijuana, superimposed on the prevalence of end-stage renal disease (ESRD) by state. Reproduced with permission from Mount Sinai Health System.
sclerosis–related spasticity. In addition to pharmaceutical cannabinoids, more than 170 synthetic cannabinoids have been developed for use in laboratory research, some of which have been adopted as drugs of abuse. Potential Impact of Marijuana and Cannabinoid Use on the Kidney It is unknown whether and to what extent marijuana use might affect kidney disease. Both CB1 and CB2 are expressed throughout the body, including in podocytes, mesangial cells, and tubular epithelial cells.4 In animal models, overactivation of CB1 in podocytes promotes diabetic nephropathy,5 whereas blocking CB1 decreases albuminuria6 and renal fibrosis.7 Activation of CB2, which in general has opposing effects, has been shown to reduce albuminuria and podocyte loss,8 whereas knockout of CB2 worsens kidney function in a mouse model of diabetic nephropathy.9 Cannabinoids also have diuretic properties. THC activation of CB1 has been reported to increase urine output in rats,10 possibly by inhibiting the Na/K/2Cl cotransporter NKCC2 and a sodium/hydrogen exchanger in the thick ascending limb.11 Data for the relationship between marijuana use and kidney disease in humans are scarce. Cross-sectional studies using nationally representative data have demonstrated lower odds of metabolic syndrome12,13 2
and diabetes14 among marijuana users compared with nonusers; however, renal outcomes were not evaluated. In a prospective cohort of 647 men attending the hypertension clinic at a single Veterans Administration medical center, any self-reported history of recreational drug use was associated with a significant increase in risk for kidney function decline (serum creatinine increase . 0.5 mg/dL) over a median of 7 years. Although marijuana was the most commonly reported drug, marijuana use was not significantly associated with kidney function decline. The nonsignificant trend associated with marijuana use may reflect concomitant use of other drugs, including cocaine or psychedelics, which were independently associated with kidney function decline.15 Similarly, a small cross-sectional study found elevated b2microglobulin concentrations in 2 of 42 cannabinoid users, but not in control patients. Although this could suggest subtle proximal tubular injury with cannabinoid use, the authors did not control for comorbid conditions or concomitant drug or medication use.16 Electrolyte concentration abnormalities have been reported with the use of other recreational drugs, but do not appear to be an important complication of isolated marijuana use. Hypophosphatemia was observed in a case series of 6 men with cannabinoid hyperemesis syndrome, an uncommon complication of long-term marijuana overuse.17 Alkalemia-induced transcellular shift of phosphate from hyperventilation or vomiting was hypothesized as a possible mechanism. Am J Kidney Dis. 2017;-(-):---
Marijuana and Cannabinoids in Kidney Disease
Synthetic Cannabinoid Abuse Originally developed for laboratory research, synthetic cannabinoids have become popular, and dangerous, drugs of abuse.18 Synthetic cannabinoids are commonly referred to as “Spice” or “K2” and are sold in smoke shops, convenience stores, and on the internet. Several case series have linked synthetic cannabinoids to acute kidney injury,19-21 although the mechanism is unknown. Among 21 cases, presenting symptoms included nausea and vomiting in all and flank pain in 15 patients. Kidney biopsy was performed in 13 patients, revealing acute tubular necrosis in 10 and acute interstitial nephritis in 3 cases.22 Synthetic cannabinoids are not detected on standard blood and urine toxicology screens. Therefore, nephrologists should have a high index of suspicion when diagnosing unexplained acute kidney injury. Synthetic cannabinoids may be intrinsically nephrotoxic, but a noncannabinoid contaminant has been proposed as an alternative explanation.23,24 Because plant-based cannabinoids have not been associated with AKI, future investigations comparing marijuana and synthetic cannabinoid users may provide insight into potential mechanisms of kidney injury with synthetic cannabinoid use.
Medical Marijuana for Symptoms of Advanced CKD and ESRD Overview Patients with advanced CKD and ESRD experience substantial symptom burden that is frequently undertreated due to adverse medication side effects.25 Among dialysis patients, anorexia, pain, sleep disturbance, anxiety, nausea, and depression have been reported in one-quarter to one-half of respondents.26 Several of these symptoms are approved indications for medical marijuana; in addition, anxiety, depression, and insomnia are the most common psychiatric conditions self-treated with marijuana.27
Although a small number of states have approved medical marijuana for the treatment of symptoms in any terminal or debilitating condition, Washington is the only state to specifically classify ESRD as a qualifying condition. Common indications for medical marijuana include human immunodeficiency virus (HIV) infection/AIDS (28 states), cachexia (23 states), chronic pain (23 states), and nausea (20 states). The National Academies of Sciences, Engineering, and Medicine recently concluded that there is evidence that cannabis and pharmaceutical cannabinoids are effective for the treatment of chronic pain and chemotherapy-induced nausea and vomiting,28 whereas further studies are needed to establish benefit for other indications. Medical marijuana or prescription cannabinoids can improve quality of life29 and may be a reasonable alternative to manage symptoms in patients with CKD and ESRD. In addition, medical management of “uremic” symptoms in patients with advanced CKD may help delay initiation of dialysis therapy. Because data suggest no survival benefit associated with earlier initiation of dialysis therapy,30 this approach could allow patients to maintain independence off dialysis therapy and could also translate into cost savings for the health care system.31 The following sections summarize the available evidence for the use of medical marijuana to manage symptoms commonly experienced by patients with advanced CKD or ESRD (Table 1). To date, no rigorous studies have examined the role of medical marijuana or cannabinoids in this group of patients. Chronic Pain More than half of all patients with CKD and ESRD experience chronic pain.32 An estimated 60% to 100% of dialysis patients have uremic neuropathy, while others have neuropathy as a result of underlying conditions such as diabetes.33 Opioid analgesics have increased adverse effects in patients with CKD and
Table 1. Potential Benefits of Medical Marijuana Use for Symptoms of Advanced CKD and ESRD Rationale for Use
Chronic pain
Evidence for treating chronic pain28
Nausea
Substantial evidence for treating chemotherapy-induced nausea and vomiting28; FDA-approved to treat chemotherapy-induced nausea and vomiting Anecdotal evidence of appetite stimulation; FDA-approved to treat anorexia associated with AIDS Preclinical evidence suggests a role of CB1 in the central nervous system response to itch42; emollient containing endocannabinoids effectively treated uremic pruritus in a small trial43
Anorexia and cachexia Pruritus
Comments
Legalization of medical marijuana has been associated with decreases in opioid-related hospitalizations34 and overdose deaths35 Evidence limited to chemotherapy-induced nausea and vomiting Limited evidence base mostly focused on AIDS population Lack of effective treatments; could be studied as a secondary outcome in studies focused on other indications
Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal disease; FDA, US Food and Drug Administration. Am J Kidney Dis. 2017;-(-):---
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ESRD due to accumulation of renally cleared metabolites. Legalization of medical marijuana has been associated with decreases in opioid-related hospitalizations34 and overdose deaths,35 suggesting decreased use and dependence on these medications. Preclinical data also suggest a role for cannabinoids in treating opioid addiction.36 After reviewing the scientific literature since 1999, the National Academies concluded that there is evidence for the use of marijuana and cannabinoids to treat chronic pain.28 Nausea Nausea is commonly experienced by patients with CKD and ESRD. Causes may include uremia, dialysis disequilibrium, excessive or rapid ultrafiltration, medication side effects, or comorbid conditions such as diabetic gastroparesis. In a prospective singlecenter study, 39 of 139 (28%) patients with advanced CKD started dialysis therapy due to nausea and vomiting.37 The clinical efficacy of cannabinoids to treat nausea was first rigorously demonstrated in the 1970s in a randomized placebo-controlled trial of 20 patients using THC to treat chemotherapy-induced nausea and vomiting.38 The more recent literature, including clinical trials of the FDA-approved pharmaceutical cannabinoids, has remained focused on this condition. A meta-analysis of randomized controlled trials demonstrated that more patients achieve a complete nausea and vomiting response with cannabinoids compared with both active comparators and placebo.39 In their report, the National Academies found conclusive evidence that cannabis and cannabinoids are effective for the treatment of chemotherapy-induced nausea and vomiting.28 Currently, no literature exists on the use of marijuana or cannabinoids to treat nausea associated with CKD or ESRD. Anorexia and Cachexia Anorexia in patients with advanced CKD and ESRD can be caused by nausea, uremic toxins, acidemia, systemic inflammation, and comorbid conditions. In patients receiving peritoneal dialysis, glucose absorption and early satiety with dialysate infusion can also decrease appetite. Inadequate dietary intake of protein and calories leads to the protein-energy wasting state of CKD, which is associated with adverse outcomes.40 The ability of marijuana to stimulate appetite has been well recognized for centuries, and 2 pharmaceutical cannabinoids are approved to treat anorexia associated with weight loss in patients with AIDS. Currently, no data exist on the use of marijuana to treat anorexia and cachexia in CKD or ESRD. Conversely, the use of marijuana to treat other symptoms may lead to increased intake of sodium, potassium, phosphorus, and fluids, which 4
could be detrimental in patients with advanced CKD or ESRD. Pruritus Pruritus is a troubling symptom with limited effective therapies, reported in up to 40% of patients with ESRD.41 Preclinical data suggest a role for CB1 in the central nervous system response to itch.42 In a study of 21 hemodialysis patients with uremic pruritus, 81% responded to 3 weeks of treatment with an emollient containing 2 endocannabinoids.43 This study has not been replicated, but together with the preclinical data, these results provide a rationale for considering pruritus as a secondary outcome in future studies.
Medical Marijuana and Kidney Transplantation Marijuana use has potential implications for transplant candidacy because some transplantation centers decline patients with a positive blood or urine drug screen. Lipophilic cannabinoid metabolites can be detected in urine for days to weeks with occasional use; therefore, a positive result may not reflect longterm use. Seven US states, led by Washington state,44 have passed organ transplant listing protections for medical marijuana users. Data for marijuana use and kidney transplant outcomes are scarce. Recently, a single-center study concluded that recreational marijuana use does not affect mortality, transplant loss, or transplant function 1 year posttransplantation.45 Cannabidiol inhibits hepatic cyclosporine metabolism in vitro and in mice, but the impact on cyclosporine levels has not been studied in humans.46 Marijuana may also have immunomodulatory effects. In a mouse model of allogeneic skin grafts, THC reduced T-cell proliferation and activation and delayed transplant rejection.47 Recently, secondary analysis of a randomized trial of THC in patients with chronic pain demonstrated alterations in the mTOR pathway, although the clinical relevance is unknown.48 Case reports have described pulmonary complications of marijuana use in kidney transplant recipients.49,50 However, the risk associated with medical marijuana use is very low because quality control measures include screening for infectious and chemical contaminants. If future studies support the use of medical marijuana to reduce symptoms associated with advanced CKD or ESRD, it will be important to re-evaluate the need for ongoing treatment after transplantation. Although a functioning kidney transplant may resolve many of the symptoms experienced by patients with ESRD, some patients may continue to benefit from medical marijuana for neuropathy or pain. For others, transplantation programs could offer additional Am J Kidney Dis. 2017;-(-):---
Marijuana and Cannabinoids in Kidney Disease
support during the discontinuation of medical marijuana therapy. Potential Adverse Health Effects Although studies are warranted to evaluate medical marijuana for symptom management in advanced CKD and ESRD, it is necessary to weigh the potential risks (Table 2). Evidence regarding the adverse effects of marijuana use is largely based on recreational use and may not be generalizable to users of medical marijuana. Recreational marijuana is typically high in THC and low in CBD, whereas this ratio is reversed in many medical marijuana strains, which may mitigate the adverse effects of THC. However, medical marijuana users, particularly those with CKD or ESRD, are likely to be older and frailer and to have more comorbid conditions and comedications, potentially enhancing the adverse effects. Additionally, most studies have evaluated the adverse effects of smoked marijuana and the findings may not apply to oral preparations or prescription cannabinoids. Smoking is associated with increased mortality among dialysis patients.51 Although smoked marijuana is a source of oxidative stress to the respiratory tract,52 regular heavy use of marijuana is associated with lower risk for pulmonary complications compared to tobacco use.53,54 In contrast, rats exposed to marijuana secondhand smoke demonstrated impaired arterial endothelial function similar to the effect of tobacco smoke,55 and an analysis of nationally representative data suggested that longterm marijuana use is associated with a modest increase in systolic blood pressure.56 Although the mechanism is unknown, a cross-sectional study of
105 peritoneal dialysis patients found that serum concentrations of the endocannabinoid anandamide were significantly elevated in those with volume expansion compared with euvolemic patients, suggesting that endocannabinoids may have a role in the response to volume expansion.57 Acutely, marijuana use can cause orthostatic hypotension, which could limit ultrafiltration in patients on hemodialysis therapy and may increase the risk for falls, particularly when combined with the sedation and spatial-visual distortion often associated with acute marijuana use. Limited evidence from case reports and observational studies suggests a possible association between marijuana use and cardiovascular events,58,59 although causality has not been established. In an observational study of 3,882 patients interviewed within days of an acute myocardial infarction, a casecrossover analysis demonstrated 5-fold increased risk for myocardial infarction within the first hour of smoking marijuana. The risk was not significantly elevated beyond the first hour.60 Although the study was not designed to investigate mechanisms, the temporal relationship would be consistent with the rapid onset of action and acute hemodynamic effects of smoked marijuana. More recently, a prospective cohort study of HIV-positive men demonstrated a higher incidence of cardiovascular events among heavy marijuana users, after adjusting for markers of HIV disease severity, tobacco smoking, and traditional risk factors.61 However, other large prospective cohort studies do not support these findings. Neither cumulative lifetime nor recent use of marijuana was associated with incident cardiovascular events or cardiovascular mortality over 25 years of follow-up in the community-based CARDIA (Coronary Artery Risk Development in Young Adults) Study cohort.62
Table 2. Potential Adverse Effects of Marijuana Use Risks
Cardiovascular
Pulmonary
Cognitive
Orthostatic hypotension (acute effect); higher incidence of cardiovascular events suggested by some observational studies,58,59,61 with other studies showing no increased risk62; long-term use may be associated with modest increase in systolic blood pressure56; vascular endothelial dysfunction observed with secondhand smoke exposure in rats55 Acute and chronic bronchitis; inconsistent data regarding marijuana use and lung cancer
Impaired verbal learning, memory, and attention with acute and long-term use of marijuana66; acutely, may cause sedation and impaired spatial-visual distortion
Comments
Orthostatic hypotension may limit ultrafiltration and increase risk for falls; evidence limited to inhaled marijuana
Risks avoided with noninhaled routes of administration; lower rate of pulmonary complications compared to tobacco smoking53,54,63; recreational marijuana use is associated with tobacco use Medical marijuana use may be associated with improved cognitive function29; animal studies demonstrate improvement in cognitive performance and restored learning and memory performance in older mice67
Note: The majority of evidence is based on studies of recreational marijuana use by inhalation. Am J Kidney Dis. 2017;-(-):---
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Similarly, in a prospective birth cohort from New Zealand, long-term marijuana use for up to 20 years was associated with periodontal disease, but not with systemic inflammation, pulmonary function, or metabolic health.63 Ultimately, patients with cardiac or pulmonary disease should exercise caution with marijuana use, particularly by inhalation, until further data are available. Another important concern is the potential for marijuana use to exacerbate cognitive impairment, which has been reported in as many as 30% to 70% of dialysis patients. A recently published cohort study of patients on long-term hemodialysis therapy demonstrated significant declines in cognitive function, most notably executive function, over a median follow-up of 2.1 years. No significant decline in memory was observed64; however, a recent meta-analysis found both memory and executive function to be impaired in patients on long-term hemodialysis therapy.65 Whether marijuana use exacerbates these cognitive deficits in patients with ESRD is unknown. Although the impact of marijuana use on problem solving and reasoning has been inconsistent across studies in other patient populations, a recent systematic review of 105 studies concluded that immediate and long-term recreational use of marijuana can impair verbal learning, memory, and attention.66 In contrast, a recent prospective study of 24 new medical marijuana users demonstrated modest improvements in some tests of executive function. The authors speculated that the improvements reflect the treatment of previously uncontrolled symptoms, improved sleep, or improved cognition from decreased use of opioids.29 In animal models, long-term administration of low-dose THC resulted in a profound and long-lasting improvement in cognitive performance and restored learning and memory performance in older mice.67 The cognitive effects of marijuana use could adversely affect adherence to prescribed medications, diets, or dialysis treatments, although this has not been well studied. Because adequate treatment of symptoms or avoidance of opiates with medical marijuana use may counteract this effect, future studies should consider the net impact of medical marijuana use on adherence. Like any treatment decision, the potential benefits of medical marijuana or therapeutic cannabinoids must be weighed against the known and potential risks. Currently, limited evidence hinders shared decision making and provides a rationale for further research to investigate the balance of risk and benefit in patients with advanced CKD or ESRD. In particular, studies are needed to determine the impact of therapeutic use on cardiovascular outcomes and cognitive function, areas of high relevance to the CKD and ESRD population. Studies should first focus 6
on evidence-based indications for medical marijuana, such as chronic pain or chemotherapy-induced nausea and vomiting, for which participants are likely to obtain the most benefit. Careful assessment of adverse and beneficial off-target effects would inform future studies in this population. Conclusion Medical marijuana may be an effective alternative to treat symptoms commonly experienced by patients with advanced CKD and ESRD. Further research is required to determine the efficacy, safety, and acceptability of medical marijuana use in this population. With growing acceptance of both medical and recreational marijuana use, future research is also needed to investigate the renal endocannabinoid system and the impact of marijuana use on kidney disease outcomes.
ACKNOWLEDGEMENTS We thank the patients who influenced and the physicians who encouraged the development of this article and Jill K. Gregory, CMI, FAMI, Icahn School of Medicine at Mount Sinai, for preparing the illustration. Support: None. Financial Disclosure: The authors declare that they have no financial interests. Peer Review: Evaluated by 3 external reviewers, an Associate Editor, and Deputy Editor Berns.
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30. Cooper BA, Branley P, Bulfone L, et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med. 2010;363(7):609-619. 31. Harris A, Cooper BA, Li JJ, et al. Cost-effectiveness of initiating dialysis early: a randomized controlled trial. Am J Kidney Dis. 2011;57(5):707-715. 32. Koncicki HM, Unruh M, Schell JO. Pain management in CKD: a guide for nephrology providers. Am J Kidney Dis. 2017;69(3):451-460. 33. Krishnan AV, Kiernan MC. Uremic neuropathy: clinical features and new pathophysiological insights. Muscle Nerve. 2007;35(3):273-290. 34. Shi Y. Medical marijuana policies and hospitalizations related to marijuana and opioid pain reliever. Drug Alcohol Depend. 2017;173:144-150. 35. Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10): 1668-1673. 36. Hurd YL. Cannabidiol: swinging the marijuana pendulum from ‘weed’ to medication to treat the opioid epidemic. Trends Neurosci. 2017;40(3):124-127. 37. Ifudu O, Dawood M, Homel P, Friedman EA. Timing of initiation of uremia therapy and survival in patients with progressive renal disease. Am J Nephrol. 1998;18(3):193-198. 38. Sallan SE, Zinberg NE, Frei E 3rd. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med. 1975;293(16):795-797. 39. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456-2473. 40. Ikizler TA, Cano NJ, Franch H, et al. Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism. Kidney Int. 2013;84(6): 1096-1107. 41. Combs SA, Teixeira JP, Germain MJ. Pruritus in kidney disease. Semin Nephrol. 2015;35(4):383-391. 42. Schlosburg JE, O’Neal ST, Conrad DH, Lichtman AH. CB1 receptors mediate Rimonabant-induced pruritic responses in mice: investigation of locus of action. Psychopharmacology. 2011;216(3):323-331. 43. Szepietowski JC, Reich A, Szepietowski T. Emollients with endocannabinoids in the treatment of uremic pruritus: discussion of the therapeutic options. Ther Apher Dial. 2005;9(3): 277-279. 44. Suitability for Organ Transplant, Medical Cannabis, RCW 69.51A.110, 2011 c 181 x 408. http://app.leg.wa.gov/rcw/default. aspx?cite569.51A.110. Accessed April 20, 2017. 45. Greenan G, Ahmad SB, Anders MG, Leeser A, Bromberg JS, Niederhaus SV. Recreational marijuana use is not associated with worse outcomes after renal transplantation. Clin Transplant. 2016;30(10):1340-1346. 46. Jaeger W, Benet LZ, Bornheim LM. Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes. Xenobiotica. 1996;26(3):275-284. 47. Sido JM, Nagarkatti PS, Nagarkatti M. D⁹-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(3):435-447. 48. Utomo WK, de Vries M, Braat H, et al. Modulation of human peripheral blood mononuclear cell signaling by medicinal cannabinoids. Front Mol Neurosci. 2017;10:14.
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Rein and Wyatt 49. 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):1771-1774. 50. Vethanayagam D, Pugsley S, Dunn EJ, Russell D, Kay JM, Allen C. Exogenous lipid pneumonia related to smoking weed oil following cadaveric renal transplantation. Can Respir J. 2000;7(4): 338-342. 51. Liebman SE, Lamontagne SP, Huang LS, Messing S, Bushinsky DA. Smoking in dialysis patients: a systematic review and meta-analysis of mortality and cardiovascular morbidity. Am J Kidney Dis. 2011;58(2):257-265. 52. Sarafian TA, Magallanes JA, Shau H, Tashkin D, Roth MD. Oxidative stress produced by marijuana smoke. An adverse effect enhanced by cannabinoids. Am J Respir Cell Mol Biol. 1999;20(6):1286-1293. 53. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10(3):239-247. 54. Pletcher MJ, Vittinghoff E, Kalhan R, et al. Association between marijuana exposure and pulmonary function over 20 years. JAMA. 2012;307(2):173-181. 55. Wang X, Derakhshandeh R, Liu J, et al. One minute of marijuana secondhand smoke exposure substantially impairs vascular endothelial function. J Am Heart Assoc. 2016;5(8):e003858. 56. Alshaarawy O, Elbaz HA. Cannabis use and blood pressure levels: United States National Health and Nutrition Examination Survey, 2005-2012. J Hypertens. 2016;34(8):1507-1512. 57. Bai Q, Zhang J, Zhang AH, et al. Role of arachidonoylethanolamine in blood pressure regulation in volumeresistant patients on peritoneal dialysis. Int Urol Nephrol. 2012;44(6):1855-1860. 58. Jouanjus E, Lapeyre-Mestre M, Micallef J. French Association of the Regional Abuse and Dependence Monitoring Centres (CEIP-A) Working Group on Cannabis Complications.
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Cannabis use: signal of increasing risk of serious cardiovascular disorders. J Am Heart Assoc. 2014;3(2):e000638. 59. Rumalla K, Reddy AY, Mittal MK. Recreational marijuana use and acute ischemic stroke: a population-based analysis of hospitalized patients in the United States. J Neurol Sci. 2016;364: 191-196. 60. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana. Circulation. 2001;103(23):2805-2809. 61. Lorenz DR, Dutta A, Mukerji SS, Holman A, Uno H, Gabuzda D. Marijuana use impacts midlife cardiovascular events in HIV-infected men [published online ahead of print April 25, 2017]. Clin Infect Dis. http://dx.doi.org/10.1093/cid/cix391. 62. Reis JP, Auer R, Bancks MP, et al. Cumulative lifetime marijuana use and incident cardiovascular disease in middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Am J Public Health. 2017;107(4):601-606. 63. Meier MH, Caspi A, Cerdá M, et al. Associations between cannabis use and physical health problems in early midlife: a longitudinal comparison of persistent cannabis vs tobacco users. JAMA Psychiatry. 2016;73(7):731-740. 64. Drew DA, Weiner DE, Tighiouart H, et al. Cognitive decline and its risk factors in prevalent hemodialysis patients. Am J Kidney Dis. 2017;69(6):780-787. 65. O’Lone E, Connors M, Masson P, et al. Cognition in people with end-stage kidney disease treated with hemodialysis: a systematic review and meta-analysis. Am J Kidney Dis. 2016;67(6):925-935. 66. Broyd SJ, van Hell HH, Beale C, Yücel M, Solowij N. Acute and chronic effects of cannabinoids on human cognition-a systematic review. Biol Psychiatry. 2016;79(7):557-567. 67. Bilkei-Gorzo A, Albayram O, Draffehn A, et al. A chronic low dose of D9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med. 2017;23(6):782-787.
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M
arijuana is the most commonly used recreational drug in the United States, and legal recreational and medicinal use of marijuana has increased during the last decade. As of June 2017, twenty-nine US states and the District of Columbia have medical marijuana programs. Eight states and the District of Columbia also allow for recreational use (Fig 1),1 although marijuana remains illegal under federal law. Legal marijuana sales in the United States are projected to grow to more than $20 billion by 2020. Canada also has a well-established medical marijuana program and is expected to legalize recreational use in 2018. With increasing use and availability of marijuana, it is important to understand the impact of marijuana use on the risk for chronic kidney disease (CKD) and the potential role of medical marijuana in the management of symptoms related to CKD and end-stage renal disease (ESRD). Marijuana is the dried flower bud from the Cannabis sativa and Cannabis indica plants and naturally contains numerous phytocannabinoids. The most abundant phytocannabinoids are D9tetrahydrocannabinol (THC) and cannabidiol, with differing activities and affinities for the G-protein– coupled cannabinoid receptors CB1 and CB2. Plant breeding has created genetically unique Cannabis strains with varying concentrations of different phytocannabinoids, enhancing certain desired effects. For example, because THC mediates the psychotropic effects of marijuana, strains with a higher THC concentration are selectively produced for recreational use. The endogenous cannabinoids, or endocannabinoids, anandamide and 2-arachidonoylglycerol are Am J Kidney Dis. 2017;-(-):---
eicosanoids derived from cell membrane phospholipids and are the natural ligands for the cannabinoid receptors. Further detail about cannabinoid receptors and the endocannabinoid system is available in recent reviews.2,3 Marijuana can be smoked, vaporized, or consumed as a capsule or in food. Inhalation provides an onset of action within minutes and allows for real-time dose titration. Peak effects are seen within 15 to 30 minutes, and half-life is 1 to 2 hours. After oral consumption, the onset of action may be delayed up to 1 to 2 hours, with peak effects at 2 to 3 hours and half-life of 3 to 6 hours. Urinary excretion accounts for 20% of metabolite elimination. Cannabinoid-based pharmaceuticals are also available or in development to treat a variety of conditions. Dronabinol (Marinol and Syndros), a synthetic form of THC, and nabilone (Cesamet) are US Food and Drug Administration (FDA)-approved to treat AIDS cachexia and chemotherapy-induced nausea/ vomiting. Nabiximols (Sativex) is approved outside the United States for the treatment of multiple From the Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Received February 28, 2017. Accepted in revised form June 19, 2017. Address correspondence to Joshua L. Rein, DO, Division of Nephrology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Pl, Box 1243, New York, NY 10029. E-mail: [email protected] 2017 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2017.06.020 1
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Figure 1. Map of the United States shows states with legalized use of medical or recreational marijuana, superimposed on the prevalence of end-stage renal disease (ESRD) by state. Reproduced with permission from Mount Sinai Health System.
sclerosis–related spasticity. In addition to pharmaceutical cannabinoids, more than 170 synthetic cannabinoids have been developed for use in laboratory research, some of which have been adopted as drugs of abuse. Potential Impact of Marijuana and Cannabinoid Use on the Kidney It is unknown whether and to what extent marijuana use might affect kidney disease. Both CB1 and CB2 are expressed throughout the body, including in podocytes, mesangial cells, and tubular epithelial cells.4 In animal models, overactivation of CB1 in podocytes promotes diabetic nephropathy,5 whereas blocking CB1 decreases albuminuria6 and renal fibrosis.7 Activation of CB2, which in general has opposing effects, has been shown to reduce albuminuria and podocyte loss,8 whereas knockout of CB2 worsens kidney function in a mouse model of diabetic nephropathy.9 Cannabinoids also have diuretic properties. THC activation of CB1 has been reported to increase urine output in rats,10 possibly by inhibiting the Na/K/2Cl cotransporter NKCC2 and a sodium/hydrogen exchanger in the thick ascending limb.11 Data for the relationship between marijuana use and kidney disease in humans are scarce. Cross-sectional studies using nationally representative data have demonstrated lower odds of metabolic syndrome12,13 2
and diabetes14 among marijuana users compared with nonusers; however, renal outcomes were not evaluated. In a prospective cohort of 647 men attending the hypertension clinic at a single Veterans Administration medical center, any self-reported history of recreational drug use was associated with a significant increase in risk for kidney function decline (serum creatinine increase . 0.5 mg/dL) over a median of 7 years. Although marijuana was the most commonly reported drug, marijuana use was not significantly associated with kidney function decline. The nonsignificant trend associated with marijuana use may reflect concomitant use of other drugs, including cocaine or psychedelics, which were independently associated with kidney function decline.15 Similarly, a small cross-sectional study found elevated b2microglobulin concentrations in 2 of 42 cannabinoid users, but not in control patients. Although this could suggest subtle proximal tubular injury with cannabinoid use, the authors did not control for comorbid conditions or concomitant drug or medication use.16 Electrolyte concentration abnormalities have been reported with the use of other recreational drugs, but do not appear to be an important complication of isolated marijuana use. Hypophosphatemia was observed in a case series of 6 men with cannabinoid hyperemesis syndrome, an uncommon complication of long-term marijuana overuse.17 Alkalemia-induced transcellular shift of phosphate from hyperventilation or vomiting was hypothesized as a possible mechanism. Am J Kidney Dis. 2017;-(-):---
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Synthetic Cannabinoid Abuse Originally developed for laboratory research, synthetic cannabinoids have become popular, and dangerous, drugs of abuse.18 Synthetic cannabinoids are commonly referred to as “Spice” or “K2” and are sold in smoke shops, convenience stores, and on the internet. Several case series have linked synthetic cannabinoids to acute kidney injury,19-21 although the mechanism is unknown. Among 21 cases, presenting symptoms included nausea and vomiting in all and flank pain in 15 patients. Kidney biopsy was performed in 13 patients, revealing acute tubular necrosis in 10 and acute interstitial nephritis in 3 cases.22 Synthetic cannabinoids are not detected on standard blood and urine toxicology screens. Therefore, nephrologists should have a high index of suspicion when diagnosing unexplained acute kidney injury. Synthetic cannabinoids may be intrinsically nephrotoxic, but a noncannabinoid contaminant has been proposed as an alternative explanation.23,24 Because plant-based cannabinoids have not been associated with AKI, future investigations comparing marijuana and synthetic cannabinoid users may provide insight into potential mechanisms of kidney injury with synthetic cannabinoid use.
Medical Marijuana for Symptoms of Advanced CKD and ESRD Overview Patients with advanced CKD and ESRD experience substantial symptom burden that is frequently undertreated due to adverse medication side effects.25 Among dialysis patients, anorexia, pain, sleep disturbance, anxiety, nausea, and depression have been reported in one-quarter to one-half of respondents.26 Several of these symptoms are approved indications for medical marijuana; in addition, anxiety, depression, and insomnia are the most common psychiatric conditions self-treated with marijuana.27
Although a small number of states have approved medical marijuana for the treatment of symptoms in any terminal or debilitating condition, Washington is the only state to specifically classify ESRD as a qualifying condition. Common indications for medical marijuana include human immunodeficiency virus (HIV) infection/AIDS (28 states), cachexia (23 states), chronic pain (23 states), and nausea (20 states). The National Academies of Sciences, Engineering, and Medicine recently concluded that there is evidence that cannabis and pharmaceutical cannabinoids are effective for the treatment of chronic pain and chemotherapy-induced nausea and vomiting,28 whereas further studies are needed to establish benefit for other indications. Medical marijuana or prescription cannabinoids can improve quality of life29 and may be a reasonable alternative to manage symptoms in patients with CKD and ESRD. In addition, medical management of “uremic” symptoms in patients with advanced CKD may help delay initiation of dialysis therapy. Because data suggest no survival benefit associated with earlier initiation of dialysis therapy,30 this approach could allow patients to maintain independence off dialysis therapy and could also translate into cost savings for the health care system.31 The following sections summarize the available evidence for the use of medical marijuana to manage symptoms commonly experienced by patients with advanced CKD or ESRD (Table 1). To date, no rigorous studies have examined the role of medical marijuana or cannabinoids in this group of patients. Chronic Pain More than half of all patients with CKD and ESRD experience chronic pain.32 An estimated 60% to 100% of dialysis patients have uremic neuropathy, while others have neuropathy as a result of underlying conditions such as diabetes.33 Opioid analgesics have increased adverse effects in patients with CKD and
Table 1. Potential Benefits of Medical Marijuana Use for Symptoms of Advanced CKD and ESRD Rationale for Use
Chronic pain
Evidence for treating chronic pain28
Nausea
Substantial evidence for treating chemotherapy-induced nausea and vomiting28; FDA-approved to treat chemotherapy-induced nausea and vomiting Anecdotal evidence of appetite stimulation; FDA-approved to treat anorexia associated with AIDS Preclinical evidence suggests a role of CB1 in the central nervous system response to itch42; emollient containing endocannabinoids effectively treated uremic pruritus in a small trial43
Anorexia and cachexia Pruritus
Comments
Legalization of medical marijuana has been associated with decreases in opioid-related hospitalizations34 and overdose deaths35 Evidence limited to chemotherapy-induced nausea and vomiting Limited evidence base mostly focused on AIDS population Lack of effective treatments; could be studied as a secondary outcome in studies focused on other indications
Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal disease; FDA, US Food and Drug Administration. Am J Kidney Dis. 2017;-(-):---
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ESRD due to accumulation of renally cleared metabolites. Legalization of medical marijuana has been associated with decreases in opioid-related hospitalizations34 and overdose deaths,35 suggesting decreased use and dependence on these medications. Preclinical data also suggest a role for cannabinoids in treating opioid addiction.36 After reviewing the scientific literature since 1999, the National Academies concluded that there is evidence for the use of marijuana and cannabinoids to treat chronic pain.28 Nausea Nausea is commonly experienced by patients with CKD and ESRD. Causes may include uremia, dialysis disequilibrium, excessive or rapid ultrafiltration, medication side effects, or comorbid conditions such as diabetic gastroparesis. In a prospective singlecenter study, 39 of 139 (28%) patients with advanced CKD started dialysis therapy due to nausea and vomiting.37 The clinical efficacy of cannabinoids to treat nausea was first rigorously demonstrated in the 1970s in a randomized placebo-controlled trial of 20 patients using THC to treat chemotherapy-induced nausea and vomiting.38 The more recent literature, including clinical trials of the FDA-approved pharmaceutical cannabinoids, has remained focused on this condition. A meta-analysis of randomized controlled trials demonstrated that more patients achieve a complete nausea and vomiting response with cannabinoids compared with both active comparators and placebo.39 In their report, the National Academies found conclusive evidence that cannabis and cannabinoids are effective for the treatment of chemotherapy-induced nausea and vomiting.28 Currently, no literature exists on the use of marijuana or cannabinoids to treat nausea associated with CKD or ESRD. Anorexia and Cachexia Anorexia in patients with advanced CKD and ESRD can be caused by nausea, uremic toxins, acidemia, systemic inflammation, and comorbid conditions. In patients receiving peritoneal dialysis, glucose absorption and early satiety with dialysate infusion can also decrease appetite. Inadequate dietary intake of protein and calories leads to the protein-energy wasting state of CKD, which is associated with adverse outcomes.40 The ability of marijuana to stimulate appetite has been well recognized for centuries, and 2 pharmaceutical cannabinoids are approved to treat anorexia associated with weight loss in patients with AIDS. Currently, no data exist on the use of marijuana to treat anorexia and cachexia in CKD or ESRD. Conversely, the use of marijuana to treat other symptoms may lead to increased intake of sodium, potassium, phosphorus, and fluids, which 4
could be detrimental in patients with advanced CKD or ESRD. Pruritus Pruritus is a troubling symptom with limited effective therapies, reported in up to 40% of patients with ESRD.41 Preclinical data suggest a role for CB1 in the central nervous system response to itch.42 In a study of 21 hemodialysis patients with uremic pruritus, 81% responded to 3 weeks of treatment with an emollient containing 2 endocannabinoids.43 This study has not been replicated, but together with the preclinical data, these results provide a rationale for considering pruritus as a secondary outcome in future studies.
Medical Marijuana and Kidney Transplantation Marijuana use has potential implications for transplant candidacy because some transplantation centers decline patients with a positive blood or urine drug screen. Lipophilic cannabinoid metabolites can be detected in urine for days to weeks with occasional use; therefore, a positive result may not reflect longterm use. Seven US states, led by Washington state,44 have passed organ transplant listing protections for medical marijuana users. Data for marijuana use and kidney transplant outcomes are scarce. Recently, a single-center study concluded that recreational marijuana use does not affect mortality, transplant loss, or transplant function 1 year posttransplantation.45 Cannabidiol inhibits hepatic cyclosporine metabolism in vitro and in mice, but the impact on cyclosporine levels has not been studied in humans.46 Marijuana may also have immunomodulatory effects. In a mouse model of allogeneic skin grafts, THC reduced T-cell proliferation and activation and delayed transplant rejection.47 Recently, secondary analysis of a randomized trial of THC in patients with chronic pain demonstrated alterations in the mTOR pathway, although the clinical relevance is unknown.48 Case reports have described pulmonary complications of marijuana use in kidney transplant recipients.49,50 However, the risk associated with medical marijuana use is very low because quality control measures include screening for infectious and chemical contaminants. If future studies support the use of medical marijuana to reduce symptoms associated with advanced CKD or ESRD, it will be important to re-evaluate the need for ongoing treatment after transplantation. Although a functioning kidney transplant may resolve many of the symptoms experienced by patients with ESRD, some patients may continue to benefit from medical marijuana for neuropathy or pain. For others, transplantation programs could offer additional Am J Kidney Dis. 2017;-(-):---
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support during the discontinuation of medical marijuana therapy. Potential Adverse Health Effects Although studies are warranted to evaluate medical marijuana for symptom management in advanced CKD and ESRD, it is necessary to weigh the potential risks (Table 2). Evidence regarding the adverse effects of marijuana use is largely based on recreational use and may not be generalizable to users of medical marijuana. Recreational marijuana is typically high in THC and low in CBD, whereas this ratio is reversed in many medical marijuana strains, which may mitigate the adverse effects of THC. However, medical marijuana users, particularly those with CKD or ESRD, are likely to be older and frailer and to have more comorbid conditions and comedications, potentially enhancing the adverse effects. Additionally, most studies have evaluated the adverse effects of smoked marijuana and the findings may not apply to oral preparations or prescription cannabinoids. Smoking is associated with increased mortality among dialysis patients.51 Although smoked marijuana is a source of oxidative stress to the respiratory tract,52 regular heavy use of marijuana is associated with lower risk for pulmonary complications compared to tobacco use.53,54 In contrast, rats exposed to marijuana secondhand smoke demonstrated impaired arterial endothelial function similar to the effect of tobacco smoke,55 and an analysis of nationally representative data suggested that longterm marijuana use is associated with a modest increase in systolic blood pressure.56 Although the mechanism is unknown, a cross-sectional study of
105 peritoneal dialysis patients found that serum concentrations of the endocannabinoid anandamide were significantly elevated in those with volume expansion compared with euvolemic patients, suggesting that endocannabinoids may have a role in the response to volume expansion.57 Acutely, marijuana use can cause orthostatic hypotension, which could limit ultrafiltration in patients on hemodialysis therapy and may increase the risk for falls, particularly when combined with the sedation and spatial-visual distortion often associated with acute marijuana use. Limited evidence from case reports and observational studies suggests a possible association between marijuana use and cardiovascular events,58,59 although causality has not been established. In an observational study of 3,882 patients interviewed within days of an acute myocardial infarction, a casecrossover analysis demonstrated 5-fold increased risk for myocardial infarction within the first hour of smoking marijuana. The risk was not significantly elevated beyond the first hour.60 Although the study was not designed to investigate mechanisms, the temporal relationship would be consistent with the rapid onset of action and acute hemodynamic effects of smoked marijuana. More recently, a prospective cohort study of HIV-positive men demonstrated a higher incidence of cardiovascular events among heavy marijuana users, after adjusting for markers of HIV disease severity, tobacco smoking, and traditional risk factors.61 However, other large prospective cohort studies do not support these findings. Neither cumulative lifetime nor recent use of marijuana was associated with incident cardiovascular events or cardiovascular mortality over 25 years of follow-up in the community-based CARDIA (Coronary Artery Risk Development in Young Adults) Study cohort.62
Table 2. Potential Adverse Effects of Marijuana Use Risks
Cardiovascular
Pulmonary
Cognitive
Orthostatic hypotension (acute effect); higher incidence of cardiovascular events suggested by some observational studies,58,59,61 with other studies showing no increased risk62; long-term use may be associated with modest increase in systolic blood pressure56; vascular endothelial dysfunction observed with secondhand smoke exposure in rats55 Acute and chronic bronchitis; inconsistent data regarding marijuana use and lung cancer
Impaired verbal learning, memory, and attention with acute and long-term use of marijuana66; acutely, may cause sedation and impaired spatial-visual distortion
Comments
Orthostatic hypotension may limit ultrafiltration and increase risk for falls; evidence limited to inhaled marijuana
Risks avoided with noninhaled routes of administration; lower rate of pulmonary complications compared to tobacco smoking53,54,63; recreational marijuana use is associated with tobacco use Medical marijuana use may be associated with improved cognitive function29; animal studies demonstrate improvement in cognitive performance and restored learning and memory performance in older mice67
Note: The majority of evidence is based on studies of recreational marijuana use by inhalation. Am J Kidney Dis. 2017;-(-):---
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Similarly, in a prospective birth cohort from New Zealand, long-term marijuana use for up to 20 years was associated with periodontal disease, but not with systemic inflammation, pulmonary function, or metabolic health.63 Ultimately, patients with cardiac or pulmonary disease should exercise caution with marijuana use, particularly by inhalation, until further data are available. Another important concern is the potential for marijuana use to exacerbate cognitive impairment, which has been reported in as many as 30% to 70% of dialysis patients. A recently published cohort study of patients on long-term hemodialysis therapy demonstrated significant declines in cognitive function, most notably executive function, over a median follow-up of 2.1 years. No significant decline in memory was observed64; however, a recent meta-analysis found both memory and executive function to be impaired in patients on long-term hemodialysis therapy.65 Whether marijuana use exacerbates these cognitive deficits in patients with ESRD is unknown. Although the impact of marijuana use on problem solving and reasoning has been inconsistent across studies in other patient populations, a recent systematic review of 105 studies concluded that immediate and long-term recreational use of marijuana can impair verbal learning, memory, and attention.66 In contrast, a recent prospective study of 24 new medical marijuana users demonstrated modest improvements in some tests of executive function. The authors speculated that the improvements reflect the treatment of previously uncontrolled symptoms, improved sleep, or improved cognition from decreased use of opioids.29 In animal models, long-term administration of low-dose THC resulted in a profound and long-lasting improvement in cognitive performance and restored learning and memory performance in older mice.67 The cognitive effects of marijuana use could adversely affect adherence to prescribed medications, diets, or dialysis treatments, although this has not been well studied. Because adequate treatment of symptoms or avoidance of opiates with medical marijuana use may counteract this effect, future studies should consider the net impact of medical marijuana use on adherence. Like any treatment decision, the potential benefits of medical marijuana or therapeutic cannabinoids must be weighed against the known and potential risks. Currently, limited evidence hinders shared decision making and provides a rationale for further research to investigate the balance of risk and benefit in patients with advanced CKD or ESRD. In particular, studies are needed to determine the impact of therapeutic use on cardiovascular outcomes and cognitive function, areas of high relevance to the CKD and ESRD population. Studies should first focus 6
on evidence-based indications for medical marijuana, such as chronic pain or chemotherapy-induced nausea and vomiting, for which participants are likely to obtain the most benefit. Careful assessment of adverse and beneficial off-target effects would inform future studies in this population. Conclusion Medical marijuana may be an effective alternative to treat symptoms commonly experienced by patients with advanced CKD and ESRD. Further research is required to determine the efficacy, safety, and acceptability of medical marijuana use in this population. With growing acceptance of both medical and recreational marijuana use, future research is also needed to investigate the renal endocannabinoid system and the impact of marijuana use on kidney disease outcomes.
ACKNOWLEDGEMENTS We thank the patients who influenced and the physicians who encouraged the development of this article and Jill K. Gregory, CMI, FAMI, Icahn School of Medicine at Mount Sinai, for preparing the illustration. Support: None. Financial Disclosure: The authors declare that they have no financial interests. Peer Review: Evaluated by 3 external reviewers, an Associate Editor, and Deputy Editor Berns.
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