Cannabinoids for Symptom Management in Patients with Kidney Failure

Abstract

People with kidney failure can experience a range of symptoms that lead to suffering and poor quality of life. Available therapies are limited, and evidence for new treatment options is sparse, often resulting in incomplete relief of symptoms. There is growing interest in the potential for cannabinoids, including cannabidiol and tetrahydrocannabinol, to treat symptoms across a wide range of chronic diseases. As legal prohibitions are withdrawn or minimized in many jurisdictions, patients are increasingly able to access these agents. Cannabinoid receptors, CB1 and CB2, are widely expressed in the body, including within the nervous and immune systems, and exogenous cannabinoids can have anxiolytic, antiemetic, analgesic, and anti-inflammatory effects. Considering their known physiologic actions and successful studies in other patient populations, cannabinoids may be viewed as potential therapies for a variety of common symptoms affecting those with kidney failure, including pruritus, nausea, insomnia, chronic neuropathic pain, anorexia, and restless legs syndrome. In this review, we summarize the pharmacology and pharmacokinetics of cannabinoids, along with what is known about the use of cannabinoids for symptom relief in those with kidney disease, and the evidence available concerning their role in management of common symptoms. Presently, although these agents show varying efficacy with a reasonable safety profile in other patient populations, evidence-based prescribing of cannabinoids for people with symptomatic kidney failure is not possible. Given the symptom burden experienced by individuals with kidney failure, there is an urgent need to understand the tolerability and safety of these agents in this population, which must ultimately be followed by robust, randomized controlled trials to determine if they are effective for symptom relief.

Introduction

The hemp plant, Cannabis sativa, is the original source of the class of compounds known as cannabinoids. Although best known for its psychoactive properties, described by authors as diverse as Herodotus (1), Alexandre Dumas (2), and Cypress Hill (3), it has also been used therapeutically in various cultures for >2800 years (4). Now, with decriminalization or legalization spreading to many jurisdictions worldwide, there is growing access to cannabis and/or cannabinoids for recreational and medicinal use. Cannabis or cannabinoid-containing products are now potentially available to many patients in the Americas and Europe (although with important differences in permitted indications and formulations), and to some patients in Africa, Asia, and Oceania (Figure 1). Although current regulatory approved indications remain limited (Table 1), randomized studies suggest cannabinoids may improve chemotherapy-induced nausea and vomiting, reduce pain, and relieve spasticity (5). There is much interest in exploring the role of cannabinoids for a wider range of conditions and populations.

Figure 1.

Legal status of cannabis use and of cannabinoids worldwide (as of November 2021). Jurisdictions distinguished as (1) recreational cannabis use legal (green), (2) some legal access to cannabinoids (blue), and (3) no legal access (tan). Note that within category (2) there is wide variation in regulations, permitted indications, and ease of access. This category includes countries with well-established medicinal cannabis programs, but also countries where access to cannabinoids may be highly restricted and discretionary. Moreover, the status is unclear in many countries. For example, the Supreme Court of Mexico declared recreational use to be legal in June 2021, however, state and federal legislation has not yet changed to reflect this.

Table 1.

Cannabinoid products with approved indications

Drug	Name	Indication	Date of First Approval
Nabilone	Cesamet	Refractory nausea and vomiting associated with cancer chemotherapy	1985
Dronabinol	Marinol, Syndros,	Anorexia associated with weight loss in patients with AIDS; refractory nausea and vomiting associated with cancer chemotherapy	1985
Cannabis extract (includes both THC and CBD)	Sativexa	Refractory spasticity due to multiple sclerosis	2010
CBD	Epidiolex	Seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex	2018

These products have been approved for the indications listed in the United States and/or Canada, and by the European Medicines Agency. THC, tetrahydrocannabinol; CBD, cannabidiol.

^aNot approved by the Food and Drug Adminstration.

Kidney failure (a sustained reduction in eGFR <15 ml/min per 1.73 m²), whether treated with dialysis or conservatively, is associated with a poor quality of life and a significant and refractory symptom burden (6,7). Common symptoms include fatigue, chronic pain, pruritus, restless legs syndrome, nausea, anorexia, insomnia, and depression (7,8). These symptoms may emerge in individuals with less severe CKD, or where kidney failure has been treated with kidney transplantation, yet they are most common (and best described) in those with kidney failure. Unfortunately, such symptoms are often persistent despite current treatments, including initiating and optimizing dialysis (9). In addition to further development of clinical services, training, and resourcing dedicated to provide patients with holistic support, improved treatments for symptoms in patients with kidney failure are key priorities among both patients and clinicians (10). Recent reviews of treatments for pruritus (11), restless legs syndrome (12), sleep disorders (13), and depression (14,15) have consistently shown a range of small and heterogeneous randomized trials using a large array of interventions and a diverse set of comparators. Often these therapies are used off-label, have limited efficacy, or have substantial side effects (16,17).

A recent survey of 129 patients who are symptomatic and receiving dialysis at a Canadian dialysis unit found that only five had tried cannabis for symptom relief, including four who reported it to be efficacious for restless legs or pruritus, and 71% were interested in participating in a trial of cannabis products (18). Similarly, a survey of Canadian nephrologists revealed them to be broadly supportive of a trial of cannabinoids for refractory symptoms and of enrolling patients in clinical trials (19). This emphasizes the need for properly designed studies to determine the efficacy and safety of these agents in people with kidney failure. In this study, we review the pharmacology of cannabinoids and the evidence for their use in this patient population.

Overview of Cannabinoid Pharmacology

Cannabinoids are ligands of the two cannabinoid receptors (cannabinoid receptor 1 and 2; CB1 and CB2) and can be categorized as phytocannabinoids (derived from Cannabis sativa), endocannabinoids (endogenous ligands of CBs; e.g., anandamide), or synthetic cannabinoids (e.g., dronabinol and nabilone) (20,21). CB1 is expressed in both the central nervous system and peripherally, including the gastrointestinal tract, kidney, and skin. CB2 is predominantly expressed on cells of the immune system, including lymphocytes and other leukocytes. Tetrahydrocannabinol (THC) is the most well-known phytocannabinoid and is a partial agonist of CB1 and CB2. It has psychoactive and muscle-relaxing actions and may also have analgesic and antiemetic effects (Table 2) (22). The other primary phytocannabinoid, cannabidiol (CBD), acts as an inverse agonist at CB2 and is a noncompetitive antagonist of CB1. CBD is anticonvulsant, anti-inflammatory, and anxiolytic, but in contrast to THC, it is not psychoactive and has less analgesic, antiemetic, and abuse potential (20,23). Owing to the ability of CBD to inhibit the psychoactive effects of THC, a combination of THC and CBD may be used therapeutically. There is, however, no consensus as to whether THC or CBD dominant formulations, or some ratio of the two, should be preferred. The wide distribution of CB1 and CB2, and the complexity of cannabinoid pharmacology, makes rational selection of dosing ratios challenging.

Table 2.

Actions of tetrahydrocannabinol and cannabidiol

Tetrahydrocannabinol	Cannabidiol
Partial agonist at CB1 and CB2	Noncompetitive antagonist at CB1, inverse agonist at CB2
Analgesic	Anticonvulsant
Muscle relaxation	Anti-inflammatory
Antiemetic	Anxiolytic
Appetite stimulation	Analgesia
Psychoactive	Neuroprotective
	May inhibit psychoactive effects of THC

Adapted from Davison & Davison, 2011 (22). CB, cannabinoid receptor.

Absorption, Metabolism, and Excretion.

The most common methods of administration of cannabinoids are inhalation (smoking or vaporization) and oral ingestion. In comparison with inhalation, oral ingestion of THC and/or CBD is slower, producing effects within 30–90 minutes, with peak concentrations at 2 hours, but the effects can last 4–12 hours (20). Due to first-pass metabolism, oral bioavailability is low (approximately 6% for THC and 9%–13% for CBD [24]); however, because both compounds are highly lipophilic, absorption is significantly improved when administered with fatty food (25). The metabolism of THC and CBD is primarily via the liver and intestine, with a minor contribution from other organs, including the heart, brain, and lungs (26). THC and CBD are both metabolized by the cytochrome P450 enzyme system, in particular, CYP3A4. THC is also metabolized by CYP2C9, whereas CBD is an inhibitor of 2C9, 2D6, 2B6, and 2C19 (20). CBD may also inhibit glucuronidation via uridine glucuronosyltransferases UGT1A9 and 2B7 (27). A variety of drug interactions have been reported or can be predicted with medications such as amitriptyline, warfarin, and calcineurin inhibitors (Table 3) (27). Both THC and CBD are primarily eliminated through the fecal route. Less than 35% of THC is eliminated via the urine, with low kidney excretion attributed to tubular reabsorption due to its lipophilic nature (12). A systematic review of CBD pharmacokinetics found substantial variation in t_1/2, for example 1.4–10.9 hours for an oral mucosal spray, to 2–5 days after chronic oral administration (28). No studies included patients with kidney disease, and data on metabolites were sparse.

Table 3.

Important potential or reported drug interactions with tetrahydrocannabinol and cannabidiol

Drugs Affected by Tetrahydrocannabinol and Cannabidiol				Drugs Affecting Tetrahydrocannabinol and Cannabidiol Exposure
THC interacts with warfarin via an unknown mechanism	CBD inhibits CYP 2D6, 2B6, and 2C19, and UGT 1A9 and 2B7			Both THC and CBD are metabolized by CYP 3A4. CBD is also metabolized by 2C19
THC increases levels of:	CBD increases levels of:		CBD reduces levels of:	Increased levels of THC/CBD	Reduced levels of THC/CBD
Mechanism unclear Warfarin	2D6 substrates Amitriptyline Nortriptyline Desipramine Flecainide Haloperidol Risperidone 2C19 substrates Citalopram Diazepam Escitalopram Tacrolimus Voriconazole Warfarin Omeprazole	2B6 substrates Methadone UGT1A9 and UGT2B7 substrates Mycophenolate Dabigatran Mechanism unclear Everolimus Sirolimus	Dependent on 2D6 for activation Codeine Tamoxifen Tramadol Partly dependent on 2C19 for activation Clopidogrel	Strong 3A4 inhibitors Clarithromycin Itraconazole Ketoconazole Posaconazole Ritonavir Voriconazole Moderate 3A4 inhibitors Amiodarone Cyclosporine Diltiazem Erythromycin Fluconazole Grapefruit juice Imatinib Verapamil	Strong 3A4 inducers Carbamazepine Phenytoin Rifampin (rifampicin)a Moderate 3A4 inducers Bosentan Dabrafenib Dexamethasone Rifabutin St. John's wort 2C19 inducersb Apalutamide

References (106,27,107): Listed enzymes are cytochrome P450 (CYP) unless otherwise indicated. THC, tetrahydrocannabinol; CBD, cannabidiol; UGT, uridine 5′-diphospho-glucuronosyltransferase.

^aAlso an inducer of 2C19.

^bCBD only.

Cannabinoid Pharmacokinetics in CKD.

Tayo et al. studied the pharmacokinetics of a single 200-mg dose of CBD in 32 participants with varying levels of kidney function, including eight individuals with a creatinine clearance <30 ml/min per 1.73 m² (mean 21.7±6.0 ml/min per 1.73 m²). No individuals receiving dialysis were included (29). They found no differences in peak concentration or total exposure for CBD between participants with any level of kidney function. Urine CBD levels were too low to be estimated, supporting the assertion that kidney function is not required for its clearance. Few adverse events were reported, and none occurred in participants with moderate or severe impairment of kidney function. Neither the pharmacokinetics of inhaled cannabinoids, nor THC in any formulation, have been studied in people with impaired kidney function or those on dialysis. Because both THC and CBD have a very large volume of distribution (>10 L/kg) and are highly protein bound (26), these compounds are unlikely to be effectively removed by hemodialysis or peritoneal dialysis. The available data suggest that dose adjustment of cannabinoids due to kidney impairment is unnecessary, but given the reduction in albumin-binding capacity in uremia (30) and the complex physiology of this state, caution is warranted.

Cannabinoids and Symptoms Associated with Kidney Failure

The diverse physiologic effects of cannabinoids support the hypothesis that they may be effective for at least some of the symptoms associated with kidney failure (Figure 2). In the next section, we examine the available evidence concerning the potential efficacy of cannabinoids for a number of key symptoms in this population. At present, the majority of this evidence is limited to extrapolation from experiences in other patient populations and/or biologic plausibility (Table 4).

Figure 2.

Potential mechanisms of action of cannabinoids in symptoms associated with kidney failure. Arrows indicate a putative role for cannabinoids in treating specific symptoms.

Table 4.

Summary of evidence for cannabinoid effect on symptoms associated with kidney failure

Symptom	Potential Mechanism	Evidence in Non-CKD Population	Study Details	Evidence in CKD Population
Restless legs syndrome	CB1 found throughout the central nervous system Cannabinoids modulate dopaminergic and GABAergic signaling (37,39,40)	Patients with RLS: Symptom relief with smoked marijuana or sublingual CBD (41,42)	Two case series (same center), total n=18	Nil
Pruritus	Inhibition of TRPV1 (46) Reduced production of inflammatory cytokines (44)	Nil	Nonrandomized study, n=21	Hemodialysis patients: uncontrolled prospective study (n=21) found that an endocannabinoid-containing emollient was effective (51)
Insomnia	THC has sedating properties, possibly mitigated by CBD (54)	Patients with insomnia associated with fibromyalgia: Nabilone superior to amitriptyline (108)	Randomized, double-blinded, crossover trial, n=31	Nil
Anorexia	Activation of central CB1, resulting in appetite stimulation and shift of white and brown adipocytes to anabolic state (58–60)	(a) Patients with HIV-associated cachexia and anorexia nervosa: Modest efficacy with smoked cannabis and dronabinol (61–64) (b) Patients with cancer-related anorexia: Mixed results (65,66)	(a) Four RCTs, total n=204 (b) Two RCTs, total n=290	Nil
Pain	Actions on diverse range of neuronal ion-channels and receptors, including α-3 glycine receptors, 5HT1a receptors, and TRPV1 (68,74,75)	Patients with chronic non-cancer pain and neuropathic pain: Modest efficacy (69,78)	Two meta-analyses: 104 studies (47 RCTs, 57 observational), n=9958; 16 double-blind RCTs, n=1750	Nil
Nausea	Modulation of CB2 in the enteric nervous system, resulting in a reduction of enterotoxin-mediated gut motility (85) Potential action via central CB1	Patients with CINV: Nabilone, dronabinol and THC:CBD modestly effective (83,84)	Meta-analysis: 23 RCTs, n=1359; one further RCT, n=81	Nil

CB, cannabinoid receptor; GABA, gamma-aminobutyric acid; RLS, restless legs syndrome; CBD, cannabidiol; TRPV1, transient receptor potential cation channel subfamily V member 1; RCT, randomized controlled trial; 5HT1a, 5-hydroxytryptamine 1a; CINV, chemotherapy-induced nausea and vomiting; THC, tetrahydrocannabinol.

Restless Legs Syndrome.

Restless legs syndrome is a sensorimotor disorder defined by the unpleasant urge to move the legs. It typically occurs at rest, particularly at night, is partially or totally relieved by movement, and results in disturbed sleep and impaired quality of life (31). The etiology of restless legs syndrome is unclear, with current theories implicating disordered brain iron homeostasis and altered dopaminergic signaling (12,32). First-line pharmacological therapies are gabapentinoids, followed by dopamine agonists (33), yet many patients obtain little or incomplete relief of symptoms (34). Long-term therapy with dopamine agonists leads to the development of tolerance, and adverse effects for ≤20% of patients (32,35). Gabapentinoids may be more effective than dopamine agonists (12), but owing to kidney clearance, they must be used cautiously in patients with abnormal kidney function and treatment is frequently limited by side effects such as drowsiness (16). In patients who are refractory, clonazepam may be used (although without randomized evidence to support its efficacy [36]), which suggests cannabinoids, which modulate gamma-aminobutyric acid transmission, including via enhancing gamma-aminobutyric acid A receptor activity, might also be effective (37,38). There are also complex effects of cannabinoids on dopamine signaling, with CB1 receptors expressed abundantly within central dopaminergic pathways (39). Acute THC administration increases dopamine synthesis and dopaminergic cell activity, yet chronic cannabis users may have reduced dopamine synthesis capacity (39,40). At present, the evidence in restless legs syndrome is limited to a case series of 18 patients with refractory symptoms (without kidney disease) who demonstrated complete relief of symptoms with smoked marijuana or sublingual CBD (41,42).

Pruritus.

Uremic pruritus affects <55% of people receiving dialysis, and multiple pathways (both central and peripheral) have been implicated in its pathogenesis (43). Gabapentinoids are first-line pharmacotherapy (11). The endocannabinoid system has an important role in skin health and affects multiple cell types within the dermis, including keratinocytes, immune cells, and sensory nerves (44,45). In addition to action at CB1 and CB2, cannabinoids act at transient receptor potential (TRP) ion channels, including as inhibitors of the transient receptor potential vanilloid type 1 (TRPV1) (46), which play an important role in the pathogenesis of uremic pruritus (47). Topical capsaicin, an agonist of TRPV1, is effective for the treatment of uremic pruritus owing to subsequent downregulation of TRPV1 activity, but is frequently poorly tolerated given the initial discomfort in its application (11,48). Cannabinoids also have a diverse array of anti-inflammatory actions, mediated via the expression of CB2 receptors on immune cells (49). Activation of CB2 reduces production of inflammatory cytokines including TNF-α, IL-6, and IFN-γ (44), all of which are found in greater concentration in the skin of patients with uremic pruritus (50). A nonrandomized study of 21 people with uremic pruritus found that application of a cream containing an endogenous cannabinoid (acetylethanolamide) and a related noncannabinoid (palmitoylethanolamide) resulted in complete relief of symptoms in 38% of participants (51). No studies using THC or CBD for chronic pruritus of any cause have been published.

Insomnia.

People with kidney failure suffer poor sleep for a variety of reasons, including uncontrolled symptoms, metabolic derangements, and disturbed circadian rhythm (52). Treatment is typically multimodal, without sufficient evidence to guide clinicians (13). The role of the endocannabinoid system in sleep and circadian rhythm is complex and incompletely understood (53). THC has sedating properties, which may be mitigated by coadministration of CBD (54). The effect of CBD on sleep may be dose dependent, with low doses being stimulating and high doses sedating (53). Although habitual cannabis consumers often report that it aids in falling asleep, the effect of specific formulations of THC or CBD on sleep is not known, owing to a lack of clinical studies (55). A number of studies are underway in the non-CKD population (54,55).

Anorexia.

Anorexia and malnutrition are common in people with kidney failure and are strongly associated with mortality (56). Altered taste sensation and direct effects of uremic toxins are thought to contribute to poor appetite (57). Appetite stimulation is a common effect of recreational cannabis use and is mediated via activation of central CB1 (58,59). Cannabinoids also modulate metabolism, with activation of CB1 shifting both white and brown adipocytes to an anabolic state (60). Smoked cannabis and the synthetic cannabinoid, dronabinol, have shown modest efficacy in small studies in patients with HIV-associated cachexia (61–63) and anorexia nervosa (64). Yet, randomized, placebo-controlled studies in patients with cancer and cachexia/anorexia have found mixed results (65,66).

Chronic Pain.

Pain affects >50% of patients with CKD and has diverse etiologies (67). Treatment is often limited due to side effects, narrow therapeutic indices, and drug interactions. There has been much interest in the analgesic potential of cannabinoids. They have actions on a diverse range of neuronal ion-channels and receptors (68). Meta-analysis of randomized studies shows modest effects of cannabinoids on a range of noncancer pain syndromes and more frequent adverse effects compared with placebo (69). It is important to place these findings in the context of widespread acceptance of opioids, which are also only moderately effective and associated with important adverse events (17,70).

Neuropathy and neuropathic pain are common in patients with kidney failure and are often refractory to treatment (71). Beneficial effects of cannabinoids for neuropathic pain may be independent of CB1 and CB2, with possible alternate mediators of effect including alpha-3 glycine receptors, 5HT1a receptors, and TRPV1 (68). TRPV1 plays a key role in the transduction of neuropathic pain (72), and dysregulation of TRPV1 may be involved in the pathogenesis of uremic neuropathy (73). CBD has been shown to affect TRPV1-signaling at the level of the spinal cord (74) and centrally (75). In contrast to CBD, THC is not known to act at TRPV1, but may moderate TRPV2, TRPV3, and TRPV4 (76). A number of meta-analyses have examined the effect of cannabinoids on neuropathic pain, finding low to moderate quality evidence that cannabinoids result in modest improvement in chronic neuropathic pain, with an important degree of heterogeneity (77–79). The most recent of these meta-analyses (including 16 randomized, double-blind studies of cannabis products, and 1750 participants with a variety of causes of neuropathic pain, with no study reporting specifically on individuals with any degree of CKD) found that cannabinoids may modestly increase the proportion of people achieving ≥50% pain relief compared with placebo (21% versus 17%; risk difference 0.05, 95% confidence interval, 0.00 to 0.09); however, the quality of this evidence was rated as low (78). Another recent study suggests that topical CBD may be beneficial for peripheral neuropathic pain (80). Although cannabinoids show promise for some types of pain, further study is required to determine optimal dosing, THC:CBD ratios, and those patients likely to respond.

Nausea.

Nausea affects approximately one third of people with kidney failure (7). Standard pharmacotherapies are poorly tolerated (33) and lack evidence for efficacy in kidney failure. The cause of nausea is incompletely understood and is likely to be multifactorial (81,82). Synthetic cannabinoids (nabilone and dronabinol) are effective for chemotherapy-induced nausea and vomiting (83). A recent randomized controlled trial reported that a 1:1 THC:CBD oral formulation was efficacious for this syndrome, with more patients experiencing complete relief of symptoms with the combination of THC:CBD and standard antiemetics compared with standard antiemetics alone (25% versus 14%; relative risk 1.77, 95% confidence interval, 1.12 to 2.79) (84). Cannabinoid-related adverse events (including sedation, dizziness, and disorientation) were common, occurring in 31% of participants, but 83% of participants preferred THC:CBD to placebo. The antiemetic mechanism of cannabinoids is not clear, but may involve CB2, which is expressed in the enteric nervous system and activation of which reduces endotoxin-mediated gut motility, and potentially central action via CB1 (85).

Adverse Effects of Cannabinoids

Given the high comorbidity burden of the kidney failure population, tolerability is an important concern. Adverse effects associated with cannabinoids include dizziness, “feeling high,” hallucinations, panic attacks, slowed cognition or confusion, tachycardia, orthostatic hypotension, hypertension, and mood changes (20,65,86). Significant concern over the potential for adverse events with cannabinoids has been expressed, especially with regard to the possible neuropsychiatric effects on younger cannabis users (20). Meta-analysis of randomized studies in adults aged ≥50 years (for any indication, mostly with placebo as control) suggests adverse events are more common with both THC-only and THC:CBD preparations, but not for CBD-only preparations (87). The potential for THC-containing medications to cause disordered thinking or perception, and dizziness, in older adults has also been highlighted (88). Tolerance may develop to the effects of THC, including adverse effects, with studies in healthy volunteers showing that both psychotropic and physiologic side effects abate after a few days of consistent use (21). Fortunately, serious adverse events appear to be rare (89). Those reported with CBD, such as sedation, elevated liver enzymes, and pneumonia, appear to be largely restricted to childhood epilepsy studies that utilize high doses and where concurrent use of clobazam or valproate may have contributed to serious adverse events (90). Finally, monitoring of liver enzymes is important given multiple reports of elevations in patients treated with CBD (91,92). As yet, there are no data available to estimate the tolerability and safety of cannabinoids in those with kidney failure.

The Endocannabinoid System and CKD

Separately to their potential role in symptom management, emerging evidence supports further study into the effect of the cannabinoid system on the progression of CKD. Endocannabinoids and CB are expressed in adult and fetal kidney tissue (93,94). Predominantly via CB1, the kidney endocannabinoid system is thought to play a role in the regulation of kidney hemodynamics, sodium handling, and protein excretion (93). Human and animal studies have found upregulation of CB1 in kidney fibrosis, including in human kidney transplant recipients and patients with diabetic kidney disease (93,95,96). Animal studies (using CB1 receptor knockout or CB1 antagonists) suggest that inhibition of the CB1 pathway attenuates kidney fibrosis and albuminuria (93,96,97). Animal models also show upregulation of CB2 in injured kidneys; however, data conflict as to the role of these receptors in the development of injury and fibrosis. Activation of CB2 has been shown to be protective against ischemia-reperfusion and cisplatin-induced kidney injury (98,99). In addition, potentiation of CB2 expression has demonstrated antifibrotic action (100) and CB2 agonists have shown the ability to reduce albuminuria and fibrosis (96,101,102). Yet Zhou et al. report that activation of CB2-mediated signaling pathways directly promotes fibrosis, which was ameliorated by administration of an inverse agonist of CB2 (103,104), and a recent study found CBD worsened early diabetic kidney injury in a mouse model (105). In this context, there is interest in modulation of the endocannabinoid system as a means of modifying the course of diverse forms of CKD. Nevertheless, this research is at an early stage and the relevance of these observations to patients with established kidney failure (a state of advanced and irreversible kidney fibrosis), in whom preservation of residual kidney function must be balanced against relief of symptoms, is difficult to assess.

Although the growing body of evidence concerning the physiology of cannabinoids demonstrates diverse and complex actions, clinical studies have thus far shown, at best, modest efficacy for symptom relief. Yet, there are reasons to believe cannabinoids could prove useful for a range of common symptoms suffered by those with kidney failure. It is important to recognize that this hope is presently on the basis of biologic plausibility and on studies in other patient populations, which are of varied quality, offer mixed findings, and show clear evidence for potential harm. To date, no trials have assessed the efficacy or safety of cannabinoids in the management of symptoms in patients with kidney failure. This leaves patients and clinicians without guidance at a time when cannabinoids are becoming increasingly available. At most, one can conclude it is not unreasonable to consider a carefully monitored trial of cannabinoid therapy for refractory symptoms of kidney failure. However, this ought only to be after exhausting standard therapies for these conditions, and with the patient being thoroughly informed of the lack of evidence to support the use of these agents in people with kidney failure. In addition, although cannabinoid formulations appear generally well tolerated, adverse effects are not uncommon. A strict “start low, go slow” approach to cannabinoid dosing is imperative, particularly given the lack of understanding of the pharmacokinetics of these agents over extended dosing periods. Finally, both prescribers and patients need to be fully cognizant of the legal status of cannabinoids in their jurisdiction. For instance, limitations on driving and operating machinery may be in place, especially for products containing THC, which can leave patients at risk of criminal prosecution.

Future Directions

Although the use of cannabinoids in people with kidney failure cannot presently be recommended outside of a clinical trial, their potential effects in this population (and their increasing availability) make properly conducted studies essential. Preliminary studies are required to establish an understanding of safe dosing, tolerability, and pharmacokinetics. After this, placebo-controlled randomized trials using validated and responsive patient-reported outcome measures may be conducted to examine the effect of cannabinoids on various well-established symptoms of kidney failure. Further studies examining their use compared with, or as add-on to, current standard of care will ultimately be required to determine if these fascinating agents deserve a role in clinical practice.

Disclosures

D. Collister reports having consultancy agreements with Akebia. All remaining authors have nothing to disclose.

Funding

None.