A Review of Cannabis in Chronic Kidney Disease Symptom Management This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License The side effects of CBD oil and the symptoms of chronic kidney disease show some similarities. But does CBD affect the kidneys? What does the research say?
A Review of Cannabis in Chronic Kidney Disease Symptom Management
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Purpose of Review:
Physical and psychological symptom burden in patients with advanced chronic kidney disease (CKD) is significantly debilitating; yet, it is often inadequately treated. Legalization of cannabis in Canada may attract increasing interest from patients for its medical use in refractory symptom management, but its indications and long-term adverse health impacts are poorly established, creating a challenge for clinicians to support its use. In this review, we summarize key clinical studies and the level of evidence for nonsynthetic cannabinoids in the treatment of common symptoms encountered in advanced stages of CKD, including chronic pain, nausea and vomiting, anorexia, pruritus, and insomnia.
Sources of Information:
Medline and Embase
A search was conducted in MEDLINE and EMBASE (inception to March 1, 2018) on cannabis and CKD symptoms of interest, complemented with a manual review of bibliographies. Studies that examined synthetic cannabinoids that are manufactured to mimic the effects of ∆9-tetrahydrocannabinol such as dronabinol, levonantradol, nabilone, and ajulemic acid were excluded. We focused on studies with higher level of evidence where available, and quality of studies was graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence (1a to 5).
Based on studies conducted in patients without renal impairment, those treated with nonsynthetic cannabinoids were 43% to 300% more likely to report a ≥30% reduction in chronic neuropathic pain compared with placebo. However, there is currently insufficient evidence to recommend nonsynthetic cannabinoids for other medical indications, although preliminary investigation into topical endocannabinoids for uremia-induced pruritus in end-stage renal disease is promising. Finally, any benefits of cannabis may be offset by potential harms in the form of cognitive impairment, increased risk of mortality post-myocardial infarction, orthostatic hypotension, respiratory irritation, and malignancies (with smoked cannabis).
Nonsynthetic cannabinoid preparations were highly variable between studies, sample sizes were small, and study durations were short. Due to an absence of studies conducted in CKD, recommendations were primarily extrapolated from the general population.
Until further studies are conducted, the role of nonsynthetic cannabinoids for symptom management in patients with CKD should be limited to the treatment of chronic neuropathic pain. Clinicians need to be cognizant that nonsynthetic cannabinoid preparations, particularly smoked cannabis, can pose significant health risks and these must be cautiously weighed against the limited substantiated therapeutic benefits of cannabis in patients with CKD.
Keywords: medical marijuana, cannabis, chronic kidney disease, chronic pain, neuropathic pain, nausea, vomiting, anorexia, pruritus, and insomnia
Les symptômes physiques et psychologiques ressentis par les patients souffrant d’insuffisance rénale chronique (IRC) sont particulièrement débilitants, et souvent traités inadéquatement. La légalisation du cannabis au Canada pourrait susciter un intérêt croissant chez ces patients avec l’emploi médical de cette substance pour le traitement de ces symptômes. Cependant, les indications thérapeutiques du cannabis et ses effets nocifs sur la santé à long terme sont mal connus, rendant difficile son soutien par les cliniciens. L’article présente l’état des preuves et une synthèse des principales études cliniques portant sur l’usage des cannabinoïdes non synthétiques dans le traitement des symptômes fréquemment observés aux stades avancés de l’IRC, soit la douleur chronique, les nausées, les vomissements, l’anorexie, le prurit et l’insomnie.
Medline et Embase
On a procédé à une recherche dans MEDLINE et EMBASE (de leur création jusqu’au 1 er mars 2018) sur le cannabis et les symptômes d’intérêt en contexte d’IRC, puis à un examen manuel des biographies. Ont été exclues les études portant sur le dronabinol, le levonantradol, le nabilone et l’acide ajulémique, des cannabinoïdes synthétiques fabriqués pour reproduire les effets du ∆9-tétrahydrocannabinol. Nous nous sommes intéressés aux études pour lesquelles le niveau de preuve était le plus élevé, et leur qualité a été établie avec le tableau de l’Oxford Centre for Evidence-based Medicine Levels of Evidence (niveaux 1a à 5).
Des études menées chez des patients non atteints d’insuffisance rénale montraient que les sujets recevant des cannabinoïdes non synthétiques étaient 43 à 300 % plus susceptibles de rapporter une réduction d’au moins 30 % de la douleur neuropathique chronique comparativement aux sujets recevant un placebo. Mais pour l’heure, les preuves permettant de recommander les cannabinoïdes non synthétiques à d’autres fins médicales sont insuffisantes; quoique des résultats préliminaires soient prometteurs avec les endocannabinoïdes topiques dans le traitement du prurit provoqué par l’urémie en contexte d’IRC. Cependant, tout bienfait du cannabis pourrait se voir neutralisé par de potentiels effets nocifs tels que troubles cognitifs, risque accru de mortalité après un infarctus du myocarde, hypotension orthostatique, irritation des voies respiratoires ou tumeurs malignes (dues à l’inhalation).
Les préparations de cannabinoïdes non synthétiques employées dans les études retenues étaient très variables, les échantillons étaient faibles et les études de courte durée. En absence d’études menées en contexte d’IRC, les résultats présentés sont principalement extrapolés d’une population générale.
Jusqu’à ce que d’autres études soient menées, l’utilisation des cannabinoïdes non synthétiques chez les patients atteints d’IRC devrait se limiter au soulagement des douleurs neuropathiques chroniques. Les cliniciens doivent comprendre que les cannabinoïdes non synthétiques, particulièrement lorsqu’ils sont inhalés, comportent des risques significatifs pour la santé et que ceux-ci doivent être examinés avec prudence en regard des bienfaits thérapeutiques limités du cannabis chez les patients atteints d’IRC.
What was known before
Synthetic cannabinoids such as dronabinol and nabilone have been approved for a wide range of indications such as HIV/AIDS-induced anorexia, chemotherapy-induced nausea and vomiting, and neuropathic pain. Although nonsynthetic cannabinoids have been used for a plethora of therapeutic claims, the evidence to support these indications has not been well reviewed, particularly with respect to chronic kidney disease.
What this adds
This review summarizes the evidence for the use of nonsynthetic cannabinoids in common symptoms encountered in chronic kidney disease and potential risks in relevance to renal impairment.
Patients with chronic kidney disease (CKD) have limited life expectancy: the estimated residual life span is approximately 8 to 4.5 years after dialysis initiation for those aged 40 to 64 years, respectively. 1 Consequently, optimizing quality of life (QOL) is of high priority. Unfortunately, patients are often afflicted with numerous symptoms, with one cross-sectional study reporting an average of 13 symptoms experienced by patients with stage 4 CKD and above. 2 Symptom burden and QOL of end-stage renal disease (ESRD) have also been compared with that of terminal malignancy 3 and commonly experienced symptoms such as pain, nausea, anxiety, and insomnia remain significantly undertreated, with only 20% to 60% of patients with CKD receiving treatment. 4,5 Conventional pharmacological agents exist, but adverse effects, intolerances, refractory conditions, and heavy pill burden can limit their use. In stage 5 CKD, poorly controlled uremic symptoms are managed with the initiation of dialysis. Nonetheless, compared with late dialysis initiation, early dialysis initiation in progressive CKD has been associated with higher dialysis costs without improving survival or overall QOL. 6 -8
Following legalization in Canada, softening of social attitudes and reduced stigmatism toward cannabis use is expected to garner increased interest in medical cannabis, especially for chronic refractory symptoms and palliative conditions such as those observed in patients with CKD. With expanded cannabis access through licensed retailers and self-grown plants, self-medicating of cannabis will also become inevitable among some patients with suboptimal symptom control. To minimize the risk of adverse drug effects and potential for substance abuse, it is paramount that clinicians are able to provide evidence-based guidance and education to patients to make well-informed decisions. However, our understanding of the effects of cannabis on patients with CKD and its role in symptom management remains limited. In this article, we aim to review the benefits and risks of cannabis use in this population and, where available, establish evidence-based indications of cannabis for CKD-related symptom management.
Properties of Cannabinoids
Cannabis is derived from the dried flowering tops and leaves of the hemp plant Cannabis Sativa and its subspecies, Cannabis sativa, Cannabis indica, and Cannabis ruderalis, which are comprised of more than 400 compounds with at least 66 phytocannabinoids identified. 9 Cannabinoids refer to all ligands of the cannabinoid receptors, CB1 and CB2, and encompass phytocannabinoids, synthetic cannabinoid analogues, and endogenous ligands, such as anandamide and 2-arachidonoylglycerol. 10 CB1 receptors are present in peripheral organs such as the gastrointestinal tract, where CB1 activation influences gut motility, promotes energy storage, and impairs glucose and lipid metabolism. 11,12 High densities of CB1 receptors in the forebrain and cerebellum contribute to cannabinoid effects on cognitive impairment and depressed motor function; contrastingly, minimal presence in the lower brainstem explains the lack of lethal respiratory and cardiovascular depressive effects with high doses such as those observed in opioid overdoses. 13 CB2 receptors, on the contrary, are predominantly distributed on leukocytes, macrophages, lymphocytes, spleen, and thymus, resulting in immunosuppressive and anti-inflammatory responses via inhibition of neutrophil migration, suppression of pro-inflammatory factor proliferation, and reduction of signaling to T cells. 14 -18 The varying affinity of cannabinoids to each of these receptors accounts for differences in a range of physiological effects.
Despite the numerous phytocannabinoids found in marijuana, studies have primarily focused on the most abundant and major active components, cannabidiol (CBD), a nonpsychoactive phytocannabinoid that activates the body’s endocannabinoid system (ECS) during pain, nausea, or inflammation, and ∆9-tetrahydrocannabinol (THC), the principal psychoactive ingredient in marijuana. 19 Effects of THC include muscle relaxation, analgesia, antiemesis, and sedation, but psychosis, anxiety, and psychoactive effects limit its potential therapeutic benefits. 20,21 While THC is a partial agonist of both CB1 and CB2 receptors, CBD is an antagonist with low affinity for both receptors that indirectly inhibits the reuptake and hydrolysis of the endogenous ligand anandamide. 22 Because CBD inhibits the metabolism of THC into its psychoactive metabolite 11-hydroxyTHC, it mitigates THC-induced paranoia and anxiety and potentiates the nonpsychoactive effects of THC through its indirect mechanism. 17 CBD has less analgesic and antiemetic effects than THC; however, its anxiolytic, antipsychotic, anticonvulsant, and neuroprotective properties have raised great interest in its potential therapeutic role. 23 -26
The administration routes of marijuana are diverse, with inhalation via smoking or vaporization and oral ingestion being the most common methods. Studies have shown comparable THC plasma concentration changes and onset of psychotropic effects between inhalation by smoking and intravenous injection. 27 Following inhalation, maximum plasma concentrations of THC occur within 3 to 10 minutes while psychotropic effects present within seconds to minutes, peaking at 15 to 30 minutes and lasting for up to 3 hours. 6 In contrast, oral absorption is slower and more erratic; psychotropic effects occur at 30 to 90 minutes with peak concentrations at 2 hours and lasting for 4 to 12 hours depending on product potency. 6
With respect to metabolism, cannabinoids are mainly dependent on the liver and, to a lesser extent, on the heart and lungs. 28 -30 Specifically, hepatic cytochrome 450 (CYP450) isoenzymes 2C9 and 3A4 are involved in the metabolism of THC, while CBD is metabolized by 3A4, but inhibits 2C9, 2D6, and 2C19. 31 -33 Data on drug interactions between marijuana use and other medications are scarce, but similar to the effects of polycyclic aromatic hydrocarbons in cigarette smoking, inhalation of marijuana results in CYP1A1 and CYP1A2 induction. 34 As a result, marijuana can not only increase the clearance of drugs that are CYP1A2 substrates, such as chlorpromazine, clozapine, olanzapine, and theophylline, but the combined use of tobacco and marijuana can also have additive clearance on these drugs. 30,35,36 Moreover, the effect on drug clearance is dependent on the frequency of marijuana use: increased clearance of theophylline was only observed with the use of ≥2 marijuana joints per week, but not with occasional use or N-desmethylclobazam. 40 The product monograph of Sativex ® also warns of increased effects of amitriptyline and fentanyl due to CYP2C19 and CYP3A4 interactions. 41 As a result, during both initiation and discontinuation of marijuana use, consideration should be given to possible altered drug response from such interactions.
Physiological Effects of Δ9-THC and CBD. 9,10
• Aggravation of psychotic states
• Memory disturbance
• Deterioration or amelioration of motor coordination
• Orthostatic hypotension
• Increase in oxygen demand
• Appetite stimulation
• Delayed gastric emptying
Note. THC = tetrahydrocannabinol; CBD = cannabidiol.
Finally, excretion of THC, mostly as acidic metabolites, occurs predominantly via feces (65%-80%) over days to weeks as a result of significant enterohepatic recirculation and high protein binding. 6 Only 20% to 35% of THC is excreted through the urine; its high lipophilicity leads to high tubular reabsorption and low renal excretion of the unchanged drug. 6,42 The pharmacokinetics of other cannabinoids resemble THC in that there is a large volume of distribution and high protein binding; as a result, they are unlikely to be effectively removed by conventional hemodialysis or peritoneal dialysis. 43 As THC and CBD elimination is primarily achieved through the fecal route with minimal renal excretion, renal dose adjustment is unnecessary for the 2 most abundant cannabinoids in cannabis. Furthermore, in spite of the paucity of pharmacokinetic data of other cannabinoids and their metabolites, the clinical significance of potential accumulation in renal impairment is low given their relative trace amounts in nonsynthetic cannabis. It is unclear whether other compounds, chemical contaminants, or adulterants, particularly in recreational cannabis, may pose nephrotoxic risks. Until clinical trials of cannabis are conducted in severe renal impairment, close monitoring is still highly warranted in CKD.
Cannabinoid Effects on the Kidney
While both CB1 and CB2 receptors are expressed in the kidneys, the effects of the endocannabinoid system (ECS) in the kidneys are not well understood. Endocannabinoids, such as anandamide, have been shown to influence renal hemodynamics and tubular sodium reabsorption via CB1 receptor activation. 44 Several animal models of kidney diseases have also demonstrated that an imbalance of cannabinoid receptor signaling with dominant CB1 receptor activation over CB2 receptor activation can lead to deleterious effects such as oxidative stress, inflammation, cell dysfunction, apoptosis, and fibrosis. 45 More importantly, restoration of the imbalance in the ECS via CB1 blockade and CB2 agonism may be renoprotective and counter the effects of metabolic syndrome. In obese insulin-resistant rats, CB1 receptor blockade prevented proteinuria, renal function decline, and reduced both glomerular and tubule interstitial fibrosis in conjunction with improving body weight, fasting glucose, and lipids. 46 Without influencing body weight, CB1 receptor deletion, specifically in the renal proximal tubules, has also been shown to reduce renal lipotoxicity and nephropathy in obese rats, suggesting direct endocannabinoid effects in the kidneys. 47 Similarly, in nondiabetic animal models, excessive CB1 receptor activity resulted in podocyte damage, nephron loss, and proteinuria, and correction of systemic and peripheral imbalance of CB1 and CB2 receptor activation reduced albuminuria and podocin loss in diabetic animals for secondary prevention. 48,49 The association between endocannabinoid imbalance and diabetic nephropathy has yet to be replicated in human studies; nonetheless, these preliminary findings suggest that CB1 receptor blockade and CB2 receptor agonism may be possible therapeutic targets for the management of diabetic nephropathy. The impact of recreational marijuana on these processes in the kidney, however, is less clear given that concentrations of cannabinoids vary with each strain and the affinity of each cannabinoid can fall along a wide spectrum between agonism and antagonism to each receptor.
A search was conducted in MEDLINE and EMBASE (inception to March 1, 2018) on cannabis and CKD symptoms of interest, complemented with a manual review of bibliographies. We examined the role of medical marijuana in the treatment of the following common CKD symptoms: chronic pain, nausea, anorexia, pruritus, and insomnia. Due to the paucity of studies conducted with cannabinoids in CKD, we reviewed and extrapolated findings from populations with normal renal function in absence of data in renal impairment. Studies that examined synthetic cannabinoids that are manufactured to mimic the effects of ∆9-THC such as dronabinol, levonantradol, nabilone, and ajulemic acid were excluded. We focused on studies with higher level of evidence where available, and quality of studies was graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence (1a to 5).
Approximately two thirds of predialysis patients with CKD stages 3 to 5 are afflicted with chronic pain, and among them, 48% report their pain as severe. 50 Although opioids are frequently prescribed in patients with CKD, concerns for increased risk of adverse drug effects, physical dependency, and addiction have been raised. Moreover, neuropathic pain in patients with diabetic CKD is often less responsive to opioids than visceral and somatic pain, and treatment options with anticonvulsant and antidepressant agents can be limited. In marijuana-legalized states in the United States, observational studies have not only shown a significant decline in annual opioid doses prescribed per physician through Medicare, but also a 24.8% reduction in annual opioid overdose mortality rate. 51,52 Amid a surge in opioid-related deaths in Canada and the United States, patients afflicted with chronic pain are anticipated to increasingly pursue cannabinoids as a means of curbing opioid use and opioid-related morbidity and mortality.
Due to a lack of studies conducted in patients with CKD, we identified 3 systematic reviews that examined nonsynthetic cannabinoids in patients without renal impairment for a variety of pain conditions. In a large meta-analysis (n = 1370) of nonsynthetic cannabinoids by Whiting et al, 53 7 trials on nabiximols as Sativex ® oromucosal spray (natural extract of 27 mg THC and 25 mg CBD per mL, maximum dose of 8 sprays/3 h or 48 sprays/24 h) and 1 trial on smoked cannabis (3.56% THC inhaled thrice a day for 5 days) were pooled together and included diabetic neuropathy, central neuropathic pain from multiple sclerosis, HIV-associated sensory neuropathy, fibromyalgia, rheumatoid arthritis, and cancer pain. Although a greater proportion of patients in the cannabinoid group achieved a minimum of 30% pain reduction compared with placebo, which is considered moderately clinically meaningful, 54 statistical significance was not achieved (odds ratio [OR] = 1.4 [95% confidence interval (CI) = 0.99-2.00], I 2 = 47.6%). The greatest benefit was driven by the single randomized controlled trial (RCT) with smoked cannabis (OR = 3.43 [95% CI = 1.03-11.48]), 55 which was similar to the effect size seen in a pooled analysis of inhaled cannabinoids by Andreae et al that did achieve statistical significance. Nabiximols demonstrated greater pain reduction on several pain scales, but findings were not consistent across trials and there was no difference in average quality-of-life scores according to the EQ-5D health status index (weighted mean difference= −0.01 [95% CI = −0.05 to 0.02]; 3 trials). Moderate heterogeneity was introduced to the meta-analysis due to the wide assortment of pain conditions that were pooled together. Other limitations of individual studies included short duration of follow-up, ineffective participant blinding secondary to the psychoactive effects of THC, incomplete outcome reporting, and unclear blinding of outcome observer, leading to possible high risk of detection and performance bias. Whiting et al concluded that based on GRADE methodology, there was overall moderate quality evidence to support the use of cannabinoids in the treatment of chronic pain, which indicates that further research is likely to have an impact on the confidence of estimated effects and potentially change the estimate.
Andreae et al 56 conducted a Bayesian meta-analysis of 5 RCTs using individual patient data (n = 178) that investigated the effect of inhaled cannabis (vaporizer, pre-rolled cigarettes, and gelatin capsules smoked through pipe) compared with placebo on neuropathic pain. Two of these RCTs were included in a review by Whiting et al. Doses of cannabis ranged from THC 1% to 9.4% inhaled 3 to 4 times a day via cigarette and pipe and 1.29% to 3.53% for 8 to 12 puffs per day via vaporizer. Inhaled cannabis achieved more than 30% clinical reduction in chronic neuropathic pain on the visual analog scale (VAS) for 1 in every 6 patients (number needed to treat [NNT] = 5.6 [95% Bayesian credible interval (CRI) = 3.35-13.7]) with an OR of 3.2 (95% CRI = 1.59-7.24; Bayes factor of 332 corresponding to a posterior probability of effect of 99.7%) in a dose-dependent manner. The use of individual patient data enhanced the power of the study, as evidenced by the high posterior probability of effect, and permitted exploration of heterogeneity at the patient level, which was highly homogeneous (Bayesian I 2 analogue = 0%). Studies were mostly of good quality in the different domains of the Cochrane Risk of Bias tool with the exception of blinding of participants and outcome observers due to the psychotropic effects of the intervention. Other shortcomings of the studies included brief treatment duration (3 to 5 days) of individual studies and a lack of power to adequately assess publication bias through funnel plot due to the synthesis of less than 10 studies.
Finally, a systematic review commissioned by the Veterans Health Administration by Nugent et al 57 included all RCTs from the previous 2 reviews with 3 additional RCTs and 3 observational studies of nonsynthetic cannabinoids (inhaled, oils, extracts) in neuropathic pain, multiple sclerosis, cancer pain, and other mixed pain conditions. Although studies did not identify any difference between placebo and cannabis on continuous pain scales for neuropathic pain, a greater proportion of patients receiving cannabis achieved clinically significant pain relief (defined as ≥30% reduction, 2-point reduction on numerical rating scale [NRS], or 20-mm reduction on VAS) up to several months later. Moreover, a study-level meta-analysis of 9 RCTs found that patients receiving cannabis were more likely to report a minimum of 30% clinical improvement in neuropathic pain (OR = 1.43 [95% CI = 1.16-1.88], I 2 = 38.6%, P = .111). However, most of the RCTs were limited to 2 to 3 weeks in duration and studies with low risk of bias had few patients enrolled. Findings were also inconsistent and there was high variability in dosing and delivery mechanism. As such, Nugent et al concluded that there was low-strength evidence to support the use of cannabis for neuropathic pain based on the consistency, coherence, and applicability of the body of evidence, in addition to the internal validity of individual studies. For multiple sclerosis, cancer pain, and mixed pains, the strength of evidence was insufficient to support a conclusion.
The majority of evidence in pain was derived from patients with neuropathic pain associated with peripheral neuropathy, post-herpetic neuralgia, nerve or spinal cord injury, complex regional pain syndrome, HIV, and diabetes. Despite the exclusion of patients with renal impairment from studies, treatment of neuropathic pain is highly relevant in patients with CKD due to its common occurrence as a diabetic complication in this population. Based on systematic reviews of low to moderate heterogeneity, there is sufficient evidence that, compared with placebo, nonsynthetic cannabinoids can achieve a moderate reduction of chronic neuropathic pain, defined as a minimum of 30% pain reduction 57 (level of evidence 1a). As estimated in the meta-analysis by Andreae et al, the NNT is 5.6 with nonsynthetic cannabinoids. 56 In contrast, a more recent Cochrane systematic review that was published beyond our search date reported the NNT to achieve ≥30% and 50% pain reduction to be 11 (risk difference [RD] = 0.09 [95% CI = 0.03-0.15], P = .004, I 2 = 34%) and 20 (61% vs 29%; RD = 0.38 [95% CI = 0.18-0.58]), respectively. 60 While the study pooled data from both synthetic and nonsynthetic cannabinoids and would have been excluded from our review, the results were primarily driven by nabiximols in the form of the oromucosal spray. These benefits were outweighed, however, by an increase in adverse effects of the nervous system (number needed to harm [NNH] of 3) and associated with higher treatment withdrawal due to adverse events (NNT = 25). With respect to the lower NNT observed in a review by Andreae et al, the authors of the Cochrane review attributed the difference to the inclusion of unpublished studies with negative reviews and the exclusion of studies of short duration (less than 12-week duration) and vague definitions of neuropathic pain in their analysis. When compared with other pharmacological treatments, the NNT to achieve at least moderate pain benefit as defined by Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) for gabapentin in diabetic neuropathy is 6.6 (95% CI = 4.9-9.9) at doses ≥900 mg daily in patients without renal impairment, suggesting nonsynthetic cannabinoids have lower to comparable efficacy at best. 61 Currently, there is inconclusive evidence to comment on the effects of cannabis on other specific types of pain such as cancer pain and multiple sclerosis.
Nausea and Vomiting
Incidences of nausea and vomiting in patients receiving hemodialysis are estimated to be as high as 18.2% to 28.3% and 9.8% to 11.7%, respectively. 58,59 In CKD stages 4 and 5, changes in salivary composition likely related to uremia, such as higher salivary sodium levels and greater sodium to potassium ratio, have been linked to nausea. 62 Although acidosis and uremia-induced nausea and vomiting typically resolve with initiation of dialysis, disequilibrium syndrome, aggressive fluid removal, dialyzer reactions, and intravenous iron administration during dialysis can also precipitate these symptoms. Moreover, other comorbidities such as diabetic gastroparesis and adverse effects of medications can further obscure the underlying cause. The multifactorial nature of nausea and vomiting in patients with renal impairment renders it a complex condition to explore. Although there are a few case reports, a small crossover study, and expert opinion to support the use of metoclopramide, ondansetron, and haloperidol for uremia-induced nausea and vomiting, 63 -65 the effects of cannabis in uremia-induced nausea and vomiting have not been examined.
Evidence to support cannabinoid use in the treatment of nausea and vomiting has primarily been in the setting of severe or refractory chemotherapy-induced nausea and vomiting (CINV) with synthetic cannabinoids, which exclude the CKD population. Nabilone and dronabinol, for instance, have comparable efficacy with prochlorperazine and metoclopramide for treatment of nausea and vomiting in moderate to highly emetogenic chemotherapy regimens, but with higher incidences of patient withdrawal due to adverse effects such as dizziness and sedation 66 (level of evidence 1a).
Evidence to support the use of nonsynthetic cannabinoids for CINV is less established: nonsynthetic cannabinoids in CINV were studied in only 3 small RCTs (n < 20) in the form of Sativex ® oromucosal spray and inhaled marijuana 67 -69 (level of evidence 2b). Compared with placebo, Sativex ® oromucosal spray achieved greater complete antiemetic response in 16 patients refractory to standard antiemetic prophylaxis (corticosteroids, 5-HT3 receptor antagonists, metoclopramide) while receiving moderate emetogenic chemotherapy regimens (OR = 3.22, 95% CI = 0.01-0.75). 70 Two older, small RCTs combined preparations of nonsynthetic oral THC followed by inhaled THC if vomiting persisted and found that THC was effective as an antiemetic for low emetogenic chemotherapy regimens, but not for chemotherapy of high emetogenic potential 68,69 (level of evidence 2b). In the study with high emetogenic chemotherapy, THC plasma concentrations achieved were low and the authors attributed this to inadequate inhalation of THC by inexperienced patients. Studies also demonstrated that inhaled cannabis achieved better therapeutic plasma concentrations of THC than the oral route and a linear relationship existed between increasing THC plasma concentration and antiemetic effect. Incidences of nausea and vomiting were 44%, 21%, and 6% with concentrations of 10 ng/mL, respectively. Similar to previous studies, the rate of adverse drug reaction (ADR) was high: 80% of patients experienced sedation in the study with low emetogenic chemotherapy. Evidence to support the use of nonsynthetic cannabinoids in CINV is significantly limited by small study sizes and low doses of THC used (1.95%).
Aside from CINV, a small study (n = 13) found a modest effect of smoked marijuana (2.11% THC) in reducing ipecac-induced emesis, which is caused by activation of emetic sensory receptors at the proximal small intestines and central stimulation of the medullary chemotherapy trigger zone. 70,71 However, the study also found that ondansetron was a more effective antiemetic as it completely eliminated emetic effects of ipecac, which, again, suggests that cannabinoids may not offer an advantage over conventional antiemetics. Further studies are still necessary to determine whether cannabinoids are effective for causes of nausea and vomiting beyond CINV and to advise on the optimal THC and CBD ratio to mitigate cannabinoid adverse effects.
As a manifestation of uremic syndrome, anorexia progressively leads to malnutrition, cachexia, and poor QOL toward later stages of CKD. The cause of uremic anorexia is multifaceted and arises from a combination of increased anorexigenic compounds and cytokines such as TNF-alpha, pro-inflammatory substances, and disturbances in amino acid concentrations in the central nervous system, which triggers the synthesis of serotonin, an appetite suppressant. 72 THC induces appetite by activating CB1 receptors centrally in the hypothalamic region responsible for homeostatic regulation of feeding and peripherally to signal the nutritional state of the gut and lipogenesis. 73,74
The use of cannabinoids for anorexia has only been studied in the context of AIDS and HIV wasting syndrome, cancer, and anorexia nervosa, but has not been explored in uremic anorexia.
In adults with cancer-related anorexia-cachexia syndrome, a double-blinded RCT (n = 243) demonstrated no differences in appetite or QOL between a natural cannabis extract of 2.5 mg THC and 1 mg CBD, 2.5 mg THC, and placebo administered orally twice a day for 6 weeks 75 (level of evidence 1b). Due to insufficient differences between study arms, patient recruitment was terminated early on the recommendation of an independent data review committee.
In HIV-associated wasting syndrome, 2 small within-subjects studies (total n = 40) demonstrated a significant dose-dependent effect on increasing caloric intake and body weight with smoked marijuana (up to 3.9% THC) and oral dronabinol (up to 40 mg daily) through increased frequency of daily food intake and proportion of daily calories from fat intake (level of evidence 2b). 76,77 Significant weight gain for nonsynthetic cannabinoids in HIV- and AIDS-associated wasting syndrome was also observed as a secondary outcome in a 3-week RCT (n = 67) that compared smoked marijuana (3.95% THC, up to 3 cigarettes per day) (3.0 kg, P = .021), dronabinol 2.5 mg orally 3 times daily (3.2 kg, P = .004), and oral placebo (1.1 kg). 78 While synthetic cannabinoids such as dronabinol have been Food and Drug Administration (FDA) approved for this indication, the primary study behind the approval was a 6-week RCT (n = 139) with a mean weight gain of only 0.1 kg in the dronabinol group compared with a weight loss of 0.4 kg in the placebo group over 6 weeks (95% CI = 0.72-6.06) (level of evidence 2b). 79 The high risk for attrition bias from protocol violations in the placebo group (presence of cannabinoids in urine in placebo group) and the brevity of the study duration warrant cautious interpretation of the benefits shown in the study.
Studies evaluating nonsynthetic cannabinoids in anorexia nervosa were not identified, but a small double-blinded crossover RCT found benefit with a synthetic cannabinoid. Dronabinol 2.5 mg PO bid for 4 weeks resulted in significant weight gain of 1 kg compared with placebo. 80
Although increased appetite is a known effect, there is currently inadequate evidence to support or disprove the use of nonsynthetic cannabinoids as appetite stimulants in uremia-induced anorexia and cachexia in patients with CKD due to a lack of studies in this population. There is some literature to support the short-term use of cannabis and oral cannabinoids in improving appetite and weight gain in patients with HIV- and AIDS-associated wasting syndrome, but the pathophysiology of this condition is significantly different from uremic anorexia. As well, these benefits have not been replicated in other types of anorexia including cancer-associated anorexia and anorexia nervosa.
Systemic inflammation, imbalance in opioid receptor expression, poorly controlled mineral bone disease, and mast cell release of histamine and other pruritogens have all been implicated in uremic pruritus, but treatment remains nonspecific and limited. Moreover, uremic pruritus impacts 40% of patients with ESRD to a moderate to severe degree. 81 Cannabinoids have been identified as neuronal modulators of pruritus and a single observational study appears promising for uremic pruritus. In the absence of antihistamine effects, peripheral transdermal administration of cannabinoid receptor agonists can attenuate histamine-induced itch by decreasing nerve fiber activation and subsequent neuropeptide and inflammatory mediator release. 82,83 In a small study of patients receiving hemodialysis experiencing uremic pruritus (n = 21), endocannabinoids containing N-acetylethanolamine and N-palmitoylethanolamine with structured physiological lipids (Derma Membrane Structure) in the form of a topical cream (Physiogel AI cream ® ) applied twice daily for 3 weeks effectively reduced both pruritus and xerosis. 84 Pruritus and xerosis were completely eliminated in 38.1% and 81% of patients, respectively (level of evidence 2b). Due to the brevity of the study duration, minute sample size, and absence of adjustment for potential confounders of this observation study, there is currently insufficient evidence to recommend the use of nonsynthetic cannabinoids for uremic pruritus. Nonetheless, the advantage of topical endocannabinoids to minimize systemic adverse drug effects compared with oral and inhaled routes and their potential role in managing uremic pruritus certainly warrant further investigation.
The incidence of sleep disorders is greater in patients with ESRD compared with the general population, with insomnia, restless leg syndrome, sleep-disordered breathing, and excessive daytime sleepiness being the most frequently reported. 85 Research in cannabinoid for treatment of insomnia began in the 1970s, but has excluded patients with renal impairment.
Literature on cannabinoids for insomnia has predominantly been in the context of concomitant neuropathic pain, rather than in primary insomnia. Whiting et al identified 17 RCTs in a systematic review with placebo comparators that assessed nonsynthetic cannabinoids for neuropathic pain and spasticity in patients with multiple sclerosis and included insomnia as a secondary outcome. 56 There were 2 pooled analyses of very low GRADE rating, mostly of nabiximols, which demonstrated a higher average improvement in sleep quality (weighted mean difference of −0.58 on NRS of 0 to 10 [95% CI = −0.87 to −0.29]; 8 trials) and sleep disturbance (weighted mean difference of −0.26 on NRS [95% CI = −0.52 to 0.00]; 3 trials) compared with placebo. However, the minor difference of −0.58 observed over a 10-point scale is unlikely to be clinically significant. Moreover, as a secondary outcome, these findings are not only hypothesis generating, but also confounded by concomitant improvement in neuropathic pain and multiple sclerosis-related spasticity. As cannabinoids are effective in the treatment of neuropathic pain, studies in primary insomnia are needed to definitively establish cannabinoid effects on sleep without the interference of confounders.
Current evidence is insufficient to provide guidance on the use of cannabinoids for primary insomnia or in association with chronic pain, but provokes further studies. Preliminary studies in healthy volunteers and animal models have also suggested that a ratio of high-dose CBD and low-dose THC may be therapeutically favorable for sleep, 86 but this remains to be validated through adequately powered clinical trials in the general population and in CKD patients with insomnia.
Adverse Effects of Marijuana
The adverse effect of marijuana can be described in 3 general themes: behavioral, respiratory, and effects in other body systems. With respect to adverse effects in patients with ESRD, cognitive impairment is of concern for home dialysis patients and those driving to a dialysis center. Also concerning is the association of an increased mortality post-myocardial infarction (MI), and respiratory complications, as described below.
A recent paper described the effects on cognition, motivation, and psychosis noting that adolescents may be particularly vulnerable to longer term neuropsychological impairment. 88 Young adults with long-term cannabis use may underachieve in education and have impaired motivation. 89 More troubling is the finding that cannabis may trigger a long-term psychiatric illness in those with a genetic vulnerability. 90 Given the evidence, it is now accepted that use be limited to the adult population older than the age of 25 years. In the short term, THC can induce dose-dependent positive and negative symptoms such as panic attacks, paranoid thoughts, and hallucinations. 91 In addition, cannabis use impairment increases the risk of being involved in a motor vehicle accident—a recent systematic review determined that THC in body fluids was associated with a 20% to 30% higher odds, described as a low to moderate risk. 92 Vehicle accident studies do have a number of confounders but overall the evidence is considered substantial. 93 Finally, cannabis dependence is estimated to occur in approximately 1 in 10 users who smoke cannabis. 94
With regard to the respiratory system, cannabis can be an irritant, leading to chronic bronchitis. 95 When combined with tobacco use, dyspnea, hoarseness, chronic obstructive pulmonary disease (COPD), or pharyngitis have been noted. 96,97 When smoked, cannabis has been associated with tumors of the upper respiratory tract, gastrointestinal tract, lungs, bladder, and nasopharyngeal area. It is not associated with head and neck tumors (level of evidence 2b). 98 All-cause mortality is affected by motor vehicle accidents and tumors attributed to cannabis but the data are from systematic reviews of case reports (level of evidence 3a). 99 Evidence of other effects on the respiratory system, skin, mucosa and on the immune system are rated at a level 4.
In the cardiovascular system, there is a dose-dependent relationship between cannabis consumption and mortality after a MI with a hazard ratio of 4.2 for weekly consumption (level of evidence 1b). 100 Metabolically, chronic cannabis users have a higher proportion of abdominal fat and demonstrated higher adipocyte resistance to insulin and lower oral glucose tolerance (level of evidence 2b). 99 Given the burden of cardiovascular disease and diabetes in the renal failure population, these effects may be magnified although this has not been determined. The THC in cannabis has been associated with dose-dependent transient rises in heart rate and a modest rise in supine blood pressure, 101,102 but a clear association with hypertension has not been established. Episodes of orthostatic hypotension and syncopal episodes have also been reported with smoked cannabis particularly with high doses (level of evidence 2b-), 103 which may preclude its use in CKD patients with symptomatic orthostatic hypotension secondary to diabetic autonomic neuropathy. However, following 1 to 2 days of repeated exposure, tolerance develops and chronic cannabis use has been associated with reduced heart rate and resolution of orthostatic hypotension. 103
Unapproved for human consumption, synthetic cannabinoids in the form of designer drugs such as “K2” and “Spice” are analogs of THC, but with greater potency and binding affinity to CB1 receptors. Although the term synthetic cannabinoids is frequently used to refer to these designer drugs, they are unregulated drugs of abuse and are distinctively different from pharmaceutical synthetic cannabinoids such as dronabinol and nabilone. These designer drugs are frequently dissolved in a solvent, sprayed onto dried plant material, and either smoked or vaped and have been linked to acute kidney injury. In a case series of 9 men, one required dialysis with all surviving. 105 A similar cluster has been also reported with 5 of 16 previously young healthy patients requiring hemodialysis, and in most cases, renal biopsies have demonstrated acute tubular necrosis. 104 It is unclear whether reports of AKI associated with smoked synthetic cannabinoids is due to a prior unrecognized toxicity, the effects of contaminants or known nephrotoxin, or a specific synthetic cannabinoid compound in the market. It should be emphasized that cannabis itself has not been shown to be associated with a loss of kidney function. In a large observational study of US veterans (n = 6788) with advanced CKD and progression to dialysis, those who tested positive for cannabis use within the year of dialysis initiation did not experience a more rapid loss in kidney function compared with those who did not use cannabis. 106
Adverse Effects and Precautions With Cannabis Use.
|Adverse effects||Precautions with cannabis use|
|Central nervous system||Impaired cognition, drowsiness, dizziness, euphoria 9,10||• Driving under the influence of cannabis increases the risk of motor vehicle accidents. All patients should be advised not to drive for a minimum of 3 to 4 h after smoking, 6 h after oral consumption, and 8 h if euphoria occurs. 87 Patients who drive to hemodialysis centers may need to consider an alternative mode of transportation if the above administrative precautions cannot be adhered to.
• Avoid in late-stage predialysis CKD patients who may be at risk for uremic encephalopathy.
• Avoid in patients with heavy alcohol consumption or receiving high-dose opioids, benzodiazepines, or sedatives due to potential for additive effects on cognitive impairment.
|Cannabis use disorder 94||• Avoid in patients with active substance abuse.|
|Anxiety and panic attacks 91||• Avoid in patients with mood or anxiety disorder.|
|Psychosis, hallucinations 9,10||• Avoid in patients with a history or strong family history of psychosis.• Avoid in patients aged 25 years or younger due to increase risk of long-term neuropsychological impairment and psychiatric illness in those with genetic vulnerabilities. 88 -90|
|Cardiovascular||Increased mortality post-myocardial infarction
100 Orthostatic hypotension 103
|• Avoid smoked cannabis in patients with cardiovascular disease.
• Consider initiating at a low dose with gradual titration. Tolerance may develop with repeated administration in 1 to 2 days. 103
|Respiratory||Chronic bronchitis, COPD, lung cancer 95 -97||• Avoid smoked cannabis in patients with respiratory disease.|
|Gastrointestinal||Cannabinoid hyperemesis syndrome 115||• Associated with chronic cannabinoid use and has been associated with prerenal acute kidney injury. 108 -114|
Note. CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease.
Finally, it is worth noting that for heavy cannabis users, cannabis withdrawal syndrome has been noted to occur during conventional hemodialysis. Nervousness, irritability, restlessness, twitch, nausea, stomach pain, increased appetite, and muscle pain occurred in one case report at hour 3 of dialysis as THC may be more dialyzed than previously thought. 107 In addition, there are at least 7 case reports of cannabinoid hyperemesis syndrome–associated prerenal acute kidney injury and dehydration from intractable vomiting and, in a few cases, concomitant compulsive hot showering. 108 -114 Cannabinoid hyperemesis syndrome is associated with chronic cannabinoid use and is characterized by recurrent nausea, vomiting, abdominal pain, and frequent hot bathing, a learned behavior that temporarily alleviates the syndrome. Clinicians should be aware that cannabinoid hyperemesis syndrome may initially be viewed as uremic symptoms so a routine inquiry into cannabis use is prudent. 115
The focus of this article has been on nonsynthetic cannabis as opposed to synthetic cannabinoids such as dronabinol and nabilone, as the effects of isolated cannabinoids can be different from that produced by the whole plant. However, there are significant methodological challenges of studying nonsynthetic cannabis: standardization of drug delivery and exposure is poor due to the diversity of cannabis strains and their administration routes. Aside from nabiximols, which is available as a fixed dose of THC:CBD as an oromucosal spray, there is high variability in cannabis preparations in literature, which is further complicated by a lack of reporting of cannabis strains used. For studies that examine whole plant cannabis, dosage is frequently reported only based on proportion of THC, which limits guidance to the different effects of cannabis strains and hybridized breeds available. Variation in smoking techniques, such as depth and frequency of inhalation, can also lead to inconsistent drug delivery to study participants. Moreover, it is unclear whether administration methods such as vaporization, which spares the production of toxic combustion compounds by heating cannabinoids at a lower temperature, produce comparable efficacy and bioavailability of cannabinoids as smoking. Implementation of an effective placebo is also a significant barrier to conducting quality cannabis trials. Despite of double blinding of RCTs, psychotropic effects of THC are difficult to mask, particularly among experienced cannabis users; hence, risk for detection and performance bias is often high. The significant increase in THC potency from 3% to 12% since 1980s to 2012 in confiscated marijuana suggests that relevance of earlier studies with low potency cannabis may be limited, particularly with respect to long-term adverse effects. 116
Summary of Evidence of Nonsynthetic Cannabinoids for Symptom Management in CKD.
|Indication||Level of evidence a||Conclusion|
|Chronic pain||1a||• Based on extrapolated evidence from patients without renal impairment, nonsynthetic cannabinoids have a moderate effect on the reduction of chronic neuropathic pain, which is a minimum of 30% pain reduction. 53,56,57,60|
|Nausea and vomiting||—||• There is a lack of evidence to support or disprove the use of nonsynthetic cannabinoids for uremia-induced nausea and vomiting, as cannabinoids have not been studied for this indication.|
|2b||• Based on limited evidence extrapolated from patients without renal impairment, nonsynthetic cannabinoids may possibly be effective in the treatment of chemotherapy-induced nausea and vomiting secondary to low-to-moderate emetogenic chemotherapy regimens. 67 -69|
|1a||• Based on extrapolated evidence from patients without renal impairment and receiving moderate to highly emetogenic chemotherapy regimens, synthetic cannabinoids, nabilone, and dronabinol b have comparable efficacy with prochlorperazine and metoclopramide for the treatment of chemotherapy-induced nausea and vomiting, but with higher incidences of adverse effects. 66|
|Anorexia||—||• There is a lack of evidence to support or disprove the use of nonsynthetic cannabinoids as appetite stimulants in uremia-induced anorexia and cachexia due to an absence of studies for this indication.|
|2b||• In extrapolated data from patients without renal impairment with HIV-associated wasting syndrome, there is limited evidence that nonsynthetic cannabinoids are effective in increasing caloric intake and body weight in the short term. 76 -78|
|1b||• In extrapolated data from patients without renal impairment, nonsynthetic cannabinoids are ineffective for increasing appetite or improving quality of life in cancer-related anorexia-cachexia syndrome. 75|
|—||• There is a lack of evidence to support or disprove the use of nonsynthetic cannabinoids as appetite stimulants in patients with anorexia nervosa, as they have not been studied for this indication.|
|Uremic pruritus||2b||• Topical endocannabinoids may possibly be effective for uremic pruritus in patients receiving hemodialysis based on limited evidence from a small observational study. 84|
|Insomnia||—||• There is currently a lack of evidence to support or disprove the use of nonsynthetic cannabinoids for insomnia, as studies have not been conducted in patients with primary insomnia.|
Note. CKD = chronic kidney disease.
It is crucial that clinicians justify the degree of therapeutic benefit of nonsynthetic cannabinoids for CKD symptom management against its harms, particularly with inhaled cannabis, which has a similar carcinogenic chemical profile as tobacco smoke. 117 -119 If treatment with cannabis were pursued, it would be prudent to engage a clinical pharmacist to assess for potential drug interactions involving cytochrome P450 isoenzymes and to consider implications on the risk for adverse effects in patients with hepatic impairment. With current studied doses, the neuropathic analgesia and antiemetic effects in CINV of cannabinoids have demonstrated only modest improvement and may be less efficacious or, at best, comparable with conventional pharmacological treatments. Nonetheless, with the risk for dependency, cognitive impairment, and mortality post-MI, the adverse effect profile can potentially be more harmful than conventional treatments in patients with CKD. Considering this, cannabinoids should be reserved for patients with intolerances or refractory conditions where conventional therapies have failed and benefits may outweigh the risks. As well, their role may be most impactful in patients with ESRD, where life span is often limited particularly with advanced age, and transition to palliative care is most frequent.
Due to limited treatment options, symptom management in patients with CKD can be challenging, and therefore therapeutic alternatives are in high demand. In recent years, medical marijuana has emerged as an attractive therapeutic option, but continues to be used for a variety of unsubstantiated indications with minimal guidance on known risks, particularly with respect to the altered physiological state of patients with CKD. At this time, the supportive evidence for using nonsynthetic cannabinoids for symptom management is limited to the treatment of chronic neuropathic pain, with promising potential when used topically for the treatment of uremic pruritus. Clinicians need to be cognizant that nonsynthetic cannabinoids, particularly smoked cannabis, pose significant health risks which must be cautiously weighed against the limited substantiated therapeutic benefits of cannabis.
Oxford Centre for Evidence-based Medicine Levels of Evidence (March 2009). 120
|Systematic reviews (with homogeneity) of randomized controlled trials
Systematic reviews of randomized controlled trials displaying worrisome heterogeneity
|Individual randomized controlled trials (with narrow confidence interval)
Individual randomized controlled trials (with a wide confidence interval)
|1c||All or none randomized controlled trials|
|Systematic reviews (with homogeneity) of cohort studies
Systematic reviews of cohort studies displaying worrisome heterogeneity
|Individual cohort study or low-quality randomized controlled trials (eg, Individual cohort study or low-quality randomized controlled trials (eg,|
|2c||“Outcomes” research; ecological studies|
|Systematic review (with homogeneity) of case-control studies
Systematic review of case-control studies with worrisome heterogeneity
|3b||Individual case-control study|
|4||Case-series (and poor quality cohort and case-control studies)|
|5||Expert opinion without explicit critical appraisal or based on physiology bench research or “first principles”|
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
1. Collins A, Foley R, Herzog C, et al. Excerpts from the us renal data system 2009 annual data report . Am J Kidney Dis . 2010; 55 ( 1 ):A6-A7. [PMC free article] [PubMed] [Google Scholar]
2. Almutary H, Bonner A, Douglas C. Which patients with chronic kidney disease have the greatest burden? a comparative study of advanced CKD stage and dialysis modality . J Ren Care . 2016; 42 ( 2 ):73-82. [PubMed] [Google Scholar]
3. Saini T, Murtagh F, Dupont P, et al. Comparative pilot study of symptoms and quality of life in cancer patients and patients with end stage renal disease . Palliat Med . 2006; 20 ( 6 ):631-636. [PubMed] [Google Scholar]
4. Claxton R, Blackhall L, Weisbord S., et al. Undertreatment of symptoms in patients on maintenance hemodialysis . J Pain Symptom Manage . 2010; 39 ( 2 ):211-218. [PubMed] [Google Scholar]
5. Wang R, Tang C, Chen X, et al. Poor sleep and reduced quality of life were associated with symptom distress in patients receiving maintenance hemodialysis . Health Qual Life Outcomes . 2016; 14 ( 1 ):125. [PMC free article] [PubMed] [Google Scholar]
6. 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 :609-619. [PubMed] [Google Scholar]
7. Harris A, Cooper BA, Bulfone L, et al. Cost-effectiveness of initiating dialysis early: a randomized controlled trial . Am J Kidney Dis . 2011; 57 ( 5 ):707-715. [PubMed] [Google Scholar]
8. Caskey F, Wordsworth S, Ben T, et al. Early referral and planned initiation of dialysis: what impact on quality of life? Nephrol Dial Transplant . 2003; 18 ( 7 ):1330-1338. [PubMed] [Google Scholar]
9. Grotenhermen F, Russo E. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential . 1st ed Binghamton, NY: The Haworth Press, Inc; 2002. [Google Scholar]
10. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids . Clin Pharmacokinet . 2003; 42 ( 4 ):327-360. [PubMed] [Google Scholar]
11. Duncan M, Mouihate A, Mackie K, et al. Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats . Am J Physiol Gastrointest Liver Physiol . 2008; 295 ( 1 ):G78-G87. [PMC free article] [PubMed] [Google Scholar]
12. Gruden G, Barutta F, Kunos G, et al. Role of the endocannabinoid system in diabetes and diabetic complications . Br J Pharmacol . 2016; 173 :1116-1127. [PMC free article] [PubMed] [Google Scholar]
13. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain . Proc Natl Acad Sci U S A . 1990; 87 ( 5 ):1932-1936. [PMC free article] [PubMed] [Google Scholar]
14. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy . Pharmacol Rev . 2006; 58 :389-462. [PMC free article] [PubMed] [Google Scholar]
15. Patel KD, Davison JS, Pittman QJ, et al. Cannabinoid CB2 receptors in health and disease . Curr Med Chem . 2010; 17 :1393-1410. [PubMed] [Google Scholar]
16. Giacoppo S, Gugliandolo A, Trubiani O, et al. Cannabinoid CB2 receptors are involved in the protection of RAW264.7 macrophages against the oxidative stress: an in vitro study . Eur J Histochem . 2017; 61 ( 1 ):2749. [PMC free article] [PubMed] [Google Scholar]
17. Basu S, Ray A, Dittel BN. Cannabinoid receptor 2 is critical for the homing and retention of marginal zone b lineage cells and for efficient t-independent immune responses . J Immunol . 2011; 187 ( 11 ):5720-5732. [PMC free article] [PubMed] [Google Scholar]
18. Nilsson O, Fowler C, Jacobsson S. The cannabinoid agonist WIN 55,212-2 inhibits TNF-α-induced neutrophil transmigration across ECV304 cells . Eur J Pharmacol . 2006; 547 ( 1-3 ):165-173. [PubMed] [Google Scholar]
19. Pertwee R, Howlett A, Abood M, et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2 . Pharmacol Rev . 2010; 62 ( 4 ):588-631. [PMC free article] [PubMed] [Google Scholar]
20. Bostwick J. Blurred boundaries: the therapeutics and politics of medical marijuana . Mayo Clin Proc . 2012; 87 ( 2 ):172-186. [PMC free article] [PubMed] [Google Scholar]
21. Howard P, Twycross R, Shuster J, et al. Cannabinoids . J Pain Symptom Manage . 2013; 46 ( 1 ):142-149. [PubMed] [Google Scholar]
22. Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide . Br J Pharm . 2001; 134 :845-852. [PMC free article] [PubMed] [Google Scholar]
23. Devinsky O, Cross J, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome . N Engl J Med . 2017; 376 ( 21 ):2011-2020. [PubMed] [Google Scholar]
24. Campos A, Fogaça M, Sonego A, et al. Cannabidiol, neuroprotection and neuropsychiatric disorders . Pharmacol Res . 2016; 112 :119-127. [PubMed] [Google Scholar]
25. Bergamaschi M, Queiroz R, Chagas M, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients . Neuropsychopharmacology . 2011; 36 ( 6 ):1219-1226. [PMC free article] [PubMed] [Google Scholar]
26. Leweke F, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia . Transl Psychiatry . 2012; 2 ( 3 ):e94. [PMC free article] [PubMed] [Google Scholar]
27. Ohlsson A, Lindgren J, Wahlen A, et al. Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking . Clin Pharmacol Ther . 1980; 28 ( 3 ):409-416. [PubMed] [Google Scholar]
28. Harvey DJ, Paton WDM. Examination of the metabolites of Δ1-tetrahydrocannabinol in mouse, liver, heart and lung by combined gas chromatography and mass spectrometry . In: Nahas GG, ed. Marihuana: Chemistry, Biochemistry and Cellular Effects . New York, NY: Springer-Verlag; 1976:93-107. [Google Scholar]
29. Nakazawa K, Costa E. Metabolism of delta 9-tetrahydrocannabinol by lung and liver homogenates of rats treated with methylcholanthrene . Nature . 1971; 234 ( 5323 ):48-49. [PubMed] [Google Scholar]
30. Widman M, Nordqvist M, Dollery CT, et al. Metabolism of delta1-tetrahydrocannabinol by the isolated perfused dog lung. Comparison with in vitro liver metabolism . J Pharm Pharmacol . 1975; 27 ( 11 ):842-848. [PubMed] [Google Scholar]
31. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review . Drug Metab Rev . 2014; 46 :86-95. [PubMed] [Google Scholar]
32. Ujváry I, Hanuš L. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy . Cannabis Cannabinoid Res . 2016; 1 :90-101. [PMC free article] [PubMed] [Google Scholar]
33. Grotenhermen F, Müller-Vahl K. Cannabis und cannabinoide in der medizin: fakten und ausblick . Suchttherapie . 2016; 17 :71-76. [Google Scholar]
34. Anderson G, Chan L. Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products . Clin Pharmacokinet . 2016; 55 ( 11 ):1353-1368. [PubMed] [Google Scholar]
35. Jusko W, Schentag J, Clark J, et al. Enhanced biotransformation of theophylline in marihuana and tobacco smokers . Clin Pharmacol Ther . 1978; 24 ( 4 ):406-410. [PubMed] [Google Scholar]
36. Jusko WJ, Gardner MJ, Mangione A, et al. Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol . J Pharm Sci . 1979; 68 ( 11 ):1358-1366. [PubMed] [Google Scholar]
37. Gardner M, Tornatore K, Jusko W, et al. Effects of tobacco smoking and oral contraceptive use on theophylline disposition . Br J Clin Pharmacol . 1983; 16 ( 3 ):271-280. [PMC free article] [PubMed] [Google Scholar]
38. Stott C, White L, Wright S, et al. A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers . Springerplus . 2013; 2 ( 1 ):236. [PMC free article] [PubMed] [Google Scholar]
39. 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 ( 3 ):294-300. [PubMed] [Google Scholar]
40. Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy . Epilepsia . 2015; 56 ( 8 ):1246-1251. [PubMed] [Google Scholar]
41. GW Pharmaceuticals. Sativex (Product Monograph) . Cambridge, UK: GW Pharmaceuticals Ltd; 2010. [Google Scholar]
42. Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol in man . J Pharmacol Exp Ther . 1980; 215 ( 1 ):35-44. [PubMed] [Google Scholar]
43. Chambers E, Germain M, Brown E. Supportive Care for the Renal Patient . Oxford, UK: Oxford University Press; 2010. [Google Scholar]
44. Ritter JK, Li G, Xia M, et al. Anandamide and its metabolites: what are their roles in the kidney . Front Biosci . 2016; 8 ( 2 ):264-277. [PMC free article] [PubMed] [Google Scholar]
45. Barutta F, Bruno G, Mastrocola R, et al. The role of cannabinoid signaling in acute and chronic kidney diseases . Kidney Int . 2018; 94 ( 2 ):252-258. [PubMed] [Google Scholar]
46. Janiak P, Poirier B, Bidouard JP, et al. Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese zucker rats . Kidney Int . 2007; 72 :1345-1357. [PubMed] [Google Scholar]
47. Udi S, Hinden L, Earley B, et al. Proximal tubular cannabinoid-1 receptor regulates obesity-induced CKD . J Am Soc Nephrol . 2017; 28 :3518-3532. [PMC free article] [PubMed] [Google Scholar]
48. Hsu YC, Lei CC, Shih YH, Ho C, et al. Induction of proteinuria by cannabinoid receptors 1 signaling activation in CB1 transgenic mice . Am J Med Sci . 2015; 349 : 162-168. [PubMed] [Google Scholar]
49. Jourdan T, Park JK, Varga ZV, et al. Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy . Diabetes Obes Metab . 2018; 20 :698-708. [PubMed] [Google Scholar]
50. Wu J, Ginsberg J, Zhan M, et al. Chronic pain and analgesic use in CKD: implications for patient safety . Clin J Am Soc Nephrol . 2015; 10 ( 3 ):435-442. [PMC free article] [PubMed] [Google Scholar]
51. Bachhuber M, Saloner B, Cunningham C, et al. Medical cannabis laws and opioid analgesic overdose mortality in the united states, 1999-2010 . JAMA Intern Med . 2014; 174 ( 10 ):1668. [PMC free article] [PubMed] [Google Scholar]
52. Bradford A, Bradford W. Medical marijuana laws reduce prescription medication use in medicare part D . Health Aff (Millwood) . 2016; 35 ( 7 ):1230-1236. [PubMed] [Google Scholar]
53. Whiting P, Wolff R, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis . JAMA . 2015; 313 ( 24 ):2456-2473. [PubMed] [Google Scholar]
54. Dworkin R, Turk D, McDermott M, et al. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations . Pain . 2009; 146 ( 3 ):238-244. [PubMed] [Google Scholar]
55. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial . Neurology . 2007; 68 :515-521. [PubMed] [Google Scholar]
56. Andreae M, Carter G, Shaparin N, et al. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data . J Pain . 2015; 16 ( 12 ):1221-1232. [PMC free article] [PubMed] [Google Scholar]
57. Nugent SM, Morasco BJ, O’Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harms . Ann Intern Med . 2017; 167 ( 5 ):319-331. [PubMed] [Google Scholar]
58. Chong VH, Tan J. Prevalence of gastrointestinal and psychosomatic symptoms among Asian patients undergoing regular hemodialysis . Nephrology (Carlton) . 2013; 18 :97-103. [PubMed] [Google Scholar]
59. Asgari M, Asghari F, Ghods A, et al. Incidence and severity of nausea and vomiting in a group of maintenance hemodialysis patients . J Renal Inj Prev . 2016; 6 ( 1 ):49-55. [PMC free article] [PubMed] [Google Scholar]
60. Mücke M, Phillips T, Radbruch L, et al. Cannabis-based medicines for chronic neuropathic pain in adults . Cochrane Database Syst Rev . 2018; 3 :CD012182. [PMC free article] [PubMed] [Google Scholar]
61. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults . Cochrane Database Syst Rev . 2012; 4 :CD007938. [PMC free article] [PubMed] [Google Scholar]
62. Manley K. Saliva composition and upper gastrointestinal symptoms in chronic kidney disease . J Ren Care . 2014; 40 ( 3 ):172-179. [PubMed] [Google Scholar]
63. Andrews PA, Quan V, Ogg CS. Ondansetron for symptomatic relief in terminal uraemia . Nephrol Dial Transplant . 1995; 10 ( 1 ):140. [PubMed] [Google Scholar]
64. Ljutić D, Perković D, Rumboldt Z, et al. Comparison of ondansetron with metoclopramide in the symptomatic relief of uremia-induced nausea and vomiting . Kidney Blood Press Res . 2002; 25 ( 1 ):61-64. [PubMed] [Google Scholar]
65. Douglas C, Murtagh FE, Chambers EJ, et al. Symptom management for the adult patient dying with advanced chronic kidney disease: a review of the literature and development of evidence-based guidelines by a United Kingdom Expert Consensus Group . Palliat Med . 2009; 23 ( 2 ):103-110. [PubMed] [Google Scholar]
66. Smith LA, Azariah F, Lavender VTC, et al. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy . Cochrane Databaes Syst Rev . 2015; 11 :CD009464. [PMC free article] [PubMed] [Google Scholar]
67. Duran M, Pérez E, Abanades S, et al. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting . Br J Clin Pharmacol . 2010; 70 ( 5 ):656-663. [PMC free article] [PubMed] [Google Scholar]
68. Chang AE, Shiling DJ, Stillman RC, et al. Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate; a prospective, randomized evaluation . Ann Intern Med . 1979; 91 :819-824. [PubMed] [Google Scholar]
69. Chang AE, Shiling DJ, Stillman RC. A prospective evaluation of delta-9-tetrahydroncannabinol as an antiemetic in patients receiving adriamycin and cytoxan chemotherapy . Cancer . 1981; 47 ( 7 ):1746-1751. [PubMed] [Google Scholar]
70. Soderpalm AH, Schuster A, de Wit H. Antiemetic efficacy of smoked marijuana: subjective and behavioral effects on nausea induced by syrup of ipecac . Pharmacol Biochem Behav . 2001; 69 ( 3-4 ):343-350. [PubMed] [Google Scholar]
71. Nelson L, Lewin N, Howland M, et al. Goldfrank’s Toxicologic Emergencies . 9th ed. New York, NY: The McGraw-Hill Companies; 2011. [Google Scholar]
72. Aguilera A, Selgas R, Diez JJ, et al. Anorexia in end-stage renal disease: pathophysiology and treatment . Expert Opin Pharmacother . 2001; 2 ( 11 ):1825-1838. [PubMed] [Google Scholar]
73. Kirkham TC, Williams CM, Fezza F, et al. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol . Br J Pharmacol . 2002; 136 :550-557. [PMC free article] [PubMed] [Google Scholar]
74. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis . J Clin Invest . 2003; 112 :423-431. [PMC free article] [PubMed] [Google Scholar]
75. Strasser F, Luftner D, Possinger K, et al. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the cannabis-in-cachexia-study group . J Clin Oncol . 2006; 24 ( 21 ):3394-3400. [PubMed] [Google Scholar]
76. Haney M, Rabkin J, Gunderson E, et al. Dronabinol and marijuana in HIV+ marijuana smokers: acute effects on caloric intake and mood . Psychopharmacology . 2005; 181 ( 1 ):170-178. [PubMed] [Google Scholar]
77. Haney M, Gunderson E, Rabkin J, et al. Dronabinol and marijuana in HIV+ marijuana smokers. Caloric intake, mood, and sleep . J Acquir Immune Defic Syndr . 2007; 45 ( 5 ):545-554. [PubMed] [Google Scholar]
78. Abrams D, Hilton J, Leiser R, et al. Short-term effects of cannabinoids in patients with hiv-1 infection: a randomized, placebo-controlled clinical trial . Ann Intern Med . 2003; 139 ( 4 ):258-266. [PubMed] [Google Scholar]
79. Beal J, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with aids . J Pain Sym Manage . 1995; 10 ( 2 ):89-97. [PubMed] [Google Scholar]
80. Andries A, Frystyk J, Flyvbjerg A, et al. Dronabinol in severe, enduring anorexia nervosa: a randomized controlled trial . Int J Eat Disord . 2014; 47 ( 1 ):18-23. [PubMed] [Google Scholar]
81. Combs S, Teixeira J, Germain M. Pruritus in kidney disease . Semin Nephrol . 2015; 35 ( 4 ):383-391. [PMC free article] [PubMed] [Google Scholar]
82. Dvorak M, Watkinson A, McGlone F, et al. Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin . Inflamm Res . 2003; 52 ( 6 ):238-245. [PubMed] [Google Scholar]
83. Schlosburg J, O’Neal S, Conrad D, et al. CB1 receptors mediate rimonabant-induced pruritic responses in mice: investigation of locus of action . Psychopharmacology . 2011; 216 ( 3 ):323-331. [PMC free article] [PubMed] [Google Scholar]
84. Szepietowski JC, Szepietowski T, Reich A. Efficacy and tolerance of cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: a preliminary study . Acta Dermatovenerol Croat . 2005; 13 ( 2 ):97-103. [PubMed] [Google Scholar]
85. Ezzat H, Mohab A. Prevalence of sleep disorders among ESRD patients . Ren Fail . 2015; 37 ( 6 ):1013-1019. [PubMed] [Google Scholar]
86. Babson K, Sottile J, Morabito D. Cannabis, cannabinoids, and sleep: a review of the literature . Curr Psychiatry Rep . 2017; 19 ( 4 ):23. [PubMed] [Google Scholar]
87. Kahan M, Srivastava A, Spithoff S, et al. Prescribing smoked cannabis for chronic noncancer pain: preliminary recommendations . Can Fam Physician . 2014; 60 ( 12 ):1083-1090. [PMC free article] [PubMed] [Google Scholar]
88. Volkow N, Swanson J, Evins A, et al. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review . JAMA Psychiatry . 2016; 73 ( 3 ):292-297. [PubMed] [Google Scholar]
89. Silins E, Horwood L, Patton G, et al. Young adult sequelae of adolescent cannabis use: an integrative analysis . Lancet Psychiatry . 2014; 1 ( 4 ):286-293. [PubMed] [Google Scholar]
90. Caspi A, Moffitt T, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-o-methyltransferase gene: longitudinal evidence of a gene x environment interaction . Biol Psychiatry . 2005; 57 ( 10 ):1117-1127. [PubMed] [Google Scholar]
91. Freeman D, Dunn G, Murray R, et al. How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol to identify key cognitive mechanisms leading to paranoia . Schizophr Bull . 2014; 41 ( 2 ):391-399. [PMC free article] [PubMed] [Google Scholar]
92. Rogeberg O, Elvik R. The effects of cannabis intoxication on motor vehicle collision revisited and revised . Addiction . 2016; 111 ( 8 ):1348-1359. [PubMed] [Google Scholar]
93. Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda, Board on Population Health and Public Health Practice, Health and Medicine Division, National Academies of Science, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research . Washington, DC: The National Academies Press; 2017. [Google Scholar]
94. World Health Organization. The health and social effects of nonmedical cannabis use . http://www.who.int/substance_abuse/publications/cannabis_report/en/index5.html. Accessed February 28, 2018.
95. Tetrault J, Crothers K, Moore BA, et al. Effects of marijuana smoking on pulmonary function and respiratory complications . Arch Intern Med . 2007; 167 ( 3 ):221-228. [PMC free article] [PubMed] [Google Scholar]
96. Lee M, Hancox R. Effects of smoking cannabis on lung function . Expert Rev Respir Med . 2011; 5 ( 4 ):537-547. [PubMed] [Google Scholar]
97. Owen K, Sutter M, Albertson T. Marijuana: respiratory tract effects . Clin Rev Allergy Immunol . 2013; 46 ( 1 ):65-81. [PubMed] [Google Scholar]
98. Hoch E, Bonnetn U, Thomasius R, et al. Risks associated with the non-medicinal use of cannabis . Dtsch Arztebl Int . 2015; 112 ( 16 ):271-278. [PMC free article] [PubMed] [Google Scholar]
99. Muniyappa R, Sable S, Ouwerkerk R, et al. Metabolic effects of chronic cannabis smoking . Diabetes Care . 2013; 36 ( 8 ):2415-2422. [PMC free article] [PubMed] [Google Scholar]
100. Mittleman M, Lewis R, Maclure M, Sherwood JB, et al. Triggering myocardial infarction by marijuana . Circulation . 2001; 103 ( 23 ):2805-2809. [PubMed] [Google Scholar]
101. Franz CA, Frishman WH. Marijuana use and cardiovascular disease . Cardiol Rev . 2016; 24 :158-162. [PubMed] [Google Scholar]
102. 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. [PMC free article] [PubMed] [Google Scholar]
103. Jones RT. Cardiovascular system effects of marijuana . J Clin Pharmacol . 2002; 42 :58S-63S. [PubMed] [Google Scholar]
104. Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012 . Morb Mortal Wkly Rep . 2013; 62 ( 6 ):93-98. [PMC free article] [PubMed] [Google Scholar]
105. Buser G, Gerona R, Horowitz B, et al. Acute kidney injury associated with smoking synthetic cannabinoid . Clin Toxicol . 2014; 52 ( 7 ):664-673. [PubMed] [Google Scholar]
106. Potukuchi P, Streja E, Kalantar-Zadeh K, et al. Cannabis use and its association with eGFR decline in advanced CKD patient transitioning to ESRD [abstract FR-PO234] . ASN Kidney Week; October 26 2018; San Diego, CA. [Google Scholar]
107. Laprevote V, Gambier N, Cridlig J, et al. Early withdrawal effects in a heavy cannabis smoker during hemodialysis . Biol Psychiatry . 2015; 77 ( 5 ):e25-e26. [PubMed] [Google Scholar]
108. Habboushe J, Sedor J. Cannabinoid hyperemesis acute renal failure: a common sequela of cannabinoid hyperemesis syndrome . Am J Emerg Med . 2014; 32 ( 6 ):690e1-6902. [PubMed] [Google Scholar]
109. Bramstedt J, Dissmann R. Cannabinoid hyperemesis syndrome inducing acute prerenal failure and electrolyte disturbance . Dtsch Med Wochenschr . 2011; 136 ( 34-35 ):1720-1722. [PubMed] [Google Scholar]
110. Chang CC, Hsu YJ, Chu P, et al. Repetitive vomiting and acute renal failure as the presenting features of cannabinoid hyperemesis syndrome . J Med Sci . 2013; 33 ( 3 ):163-165. [Google Scholar]
111. Abodunde OA, Nakda J, Nweke N. Cannabinoid hyperemesis syndrome presenting with recurrent acute renal failure . J Med Cases . 2013; 4 ( 3 ):173-175. [Google Scholar]
112. Baron M, Haymann J, Wolfromm A. The smoker and the nephrologist . Kidney Int . 2011; 79 :1385-1386. [PubMed] [Google Scholar]
113. Price SL, Fisher C, Kumar R, et al. Cannabinoid hyperemesis syndrome as the underlying cause of intractable nausea and vomiting . J Am Osteopath Assoc . 2011; 111 ( 3 ):166-169. [PubMed] [Google Scholar]
114. Srihari P, Liu M, Punzell S, Shebak SS, et al. Cannabinoid hyperemesis syndrome associated with compulsive showering and acute kidney injury . Prim Care Companion CNS Disord . 2016; 18 ( 1 ). doi: 10.4088/PCC.15l01847 [PMC free article] [PubMed] [Google Scholar]
115. Qipo A, DeLorme J, Anis K, et al. Cannabinoid hyperemesis syndrome versus uremia in a patient with end stage renal disease . Am J Kidney Dis . 2014; 63 ( 5 ):B92. [Google Scholar]
116. Volkow N, Baler R, Compton W, et al. Adverse health effects of marijuana use . N Engl J Med . 2014; 370 ( 23 ):2219-2227. [PMC free article] [PubMed] [Google Scholar]
117. Hoffmann D, Brunneman DK, Gori GB, et al. On the carcinogenicity of marijuana smoke . Recent Adv Phytochem . 1975; 9 :63-81. [Google Scholar]
118. Moir D, Rickert WS, Levasseur G, et al. A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions . Chem Res Toxicol . 2008; 21 :494-502. [PubMed] [Google Scholar]
119. Novotný M, Merli F, Wiesler D, et al. Fractionation and capillary gas chromatographic—mass spectrometric characterization of the neutral components in marijuana and tobacco smoke condensates . J Chromatogr A . 1982; 238 :141-150. [Google Scholar]
120. Centre for Evidence-based Medicine. Oxford centre for evidence-based medicine-levels of evidence (March 2009). https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed February 5, 2019.
Articles from Canadian Journal of Kidney Health and Disease are provided here courtesy of SAGE Publications
CBD oil side effects on kidneys
The side effects of Cannabidiol (CBD) oil reported so far include dry mouth, fatigue, change in appetite, and nausea. But, does CBD oil cause side effects on kidneys? Let us review in this post.
To precisely understand the gravity of the situation, let us begin with some background facts about kidney disease.
- 10% of people worldwide are affected by Chronic Kidney Disease (CKD). And the number of deaths is increasing each year due to a lack of access to affordable treatment.
- CKD was ranked 18th in the 2010 Global Burden of Disease study.
- CKD is progressively getting identified as a global health problem.
- The WHO reports that kidney diseases increase the risks of five other complications that include diabetes, hypertension, cardiovascular diseases, HIV, and malaria.
These alarming facts indicate the pressing need for spreading primary awareness and information about chronic kidney disease among susceptible populations that could help prevent delays in diagnosis and treatment.
What is chronic kidney disease? (CKD)
Let us quickly recall the vital functions performed by the kidneys.
- Kidneys are responsible for producing varieties of hormones that include vitamin D, erythropoietin (EPO), calcitriol, and renin.
- Regulate the flow of body fluids, water, minerals, electrolytes, chemicals, etc.
- Removal and excretion of excess fluids, toxins, and waste products.
When the kidneys are no longer able to carry out these functions, they create lasting damage over time eventually causing chronic kidney disease. (CKD)
If this damage is irreversible, they stop functioning and result in Kidney failure, also called end-stage renal disease (ESRD). At this stage, dialysis or kidney transplant are the only options to support affected patients to stay alive.
Equally important to note that CKD leads to other associated health conditions that affect the blood vessels, heart, nerves, and bones.
Common causes of kidney disease
Diabetes and high blood pressure are the leading causes of kidney failure cases.
Some of the other causes that lead to kidney failure are:
- Glomerulonephritis(GN): Glomeruli are tiny clusters of looping blood vessels that filter the blood sent to the kidneys. Damage or inflammation in the glomeruli leads to a leak of proteins and red blood cells through the urine. The excretion process of the kidneys also gets obstructed in such a condition. Hence, waste begins to build up in the blood leading to kidney failure. Infection, toxic drugs, diabetic nephropathy, or lupus are possible causes that lead to such a condition.
- IgA Nephropathy another form of glomerular disease.
- Systemic sclerosis is a condition that arises due to the overproduction of proteins and collagen in various tissues.
- Genetic reasons that cause polycystic kidney disease.
- Severe urinary tract infection.
- Prostate enlargement.
- Goodpasture Syndrome is a rare autoimmune disease that affects the lungs and kidneys. is another cause that leads to kidney disease. In this condition, the protein content becomes very high in the urine but very low in the blood, accompanied by other complications like high cholesterol, swelling in feet, hands, etc. Although not a disease in itself, it may occur along with other conditions.
- Infection, liver damage or elevated liver enzymes, low blood pressure, blockage in the bladder, injury, or prolonged sickness, and hospitalization could cause a sudden renal failure leading to Acute Kidney Injury (AKI)
- Other generic causes include old age, family history, heart disease, ethnicity, etc.
Side effects of CBD oil and Symptoms of kidney diseases – An analogy
General symptoms of kidney diseases.
- External Itching, Renal Itching or Rash, Uremic pruritus ( chronic itching accompanied by pain)
- Nausea and vomiting
- Loss of appetite
- Disturbed sleep
- Short breath
- Frequent urge to urinate
- Sexual dysfunction is common in CKD and ESRD
Now let us look at some of the side effects of Cannabidiol(CBD)
- A 2011 study 1 points out that some studies report that CBD can induce side effects like blocking the liver to metabolize drugs, decreased fertilization capacity, decreased hepatic drug metabolism, decreased activities of drug transporting mechanism, and decreased cell viability.
- References from a 2019 study 2 report excessive sleepiness, sedation and lethargy, fatigue, decreased appetite, diarrhea, vomiting, and abdominal pain.
We see similarities between the side effects of CBD and the symptoms of kidney disease. That does prompt us to inquire further. Let us discuss.
Some takeaways from the same 2019 study 3 are:
- Since the Intraperitoneal ( IP) and Intravenous (IV) routes provided higher bioavailability, they increased the adverse effects and toxicity of CBD. However, the occurrence of such situations is likely in patients receiving treatment for epilepsies and psychiatric disorders.
- Further research is needed to investigate the after-effects of chronic administration of CBD on hormones, enzymes, interactions with other drugs, drug transporters, and toxicity that affects the DNA.
- Excessive sleepiness and sedative effects of CBD are dose-dependent. In most cases, they occur when administered along with other anti-epileptic drugs, central nervous system (CNS) depressants, and alcohol.
- Broad dosage range and self-medication also influence the adverse side effects of CBD. The study also points to the variability in CBD products available in the form of tablets, capsules, sprays, e-liquids, and oils as a risk that adds to its adverse effects.
A recent study 4 indicates that currently available research related to cannabis is biased towards recreational cannabis.
In the same lines, synthetic cannabinoids (developed for research purposes) are now turning out to be dangerous recreational drugs. Moreover, synthetic cannabinoids do not get detected on standard blood and urine tests. Hence could mislead nephrologists treating patients with AKI.
Cannabinoid Hyperemesis Syndrome (CHS) is occasionally associated with prerenal AKI.
Other takeaways from this study:
- CBD may increase tacrolimus levels. But a small case study showed that a low dose of CBD administered for chronic pain in kidney transplant patients did not change tacrolimus levels.
( Tacrolimus test or TAC, is conducted to assess the amount of the drug in the blood to make sure if it has reached a therapeutic level and is below the toxic level. )
Reference from the 2017 study 5 : TAC is an immunosuppressant and used in patients with heart, liver, kidney, or pancreas transplantation.
Adding to this inference, another study 6 reports the importance of TAC in immunosuppressive therapy in kidney transplantation. At the same time also points out the increased risk of post-transplant diabetes.
- THC and CBD may interact with the metabolism of prescription medications.
- At a dose of 200mg of oral CBD, maximum plasma concentration showed no change.
- High doses of CBD could increase liver enzymes.
- There is no evidence so far to suggest that CBD has any adverse effect on kidney function.
- If CKD patients used cannabis, they should use the lowest dose and avoid the smoking route to evade pulmonary complications.
Potential effects of CBD on kidneys: what does the research say?
- The 2017 study 7 points out the presence of CB1 and CB2 receptors are found in kidneys and could be activated by cannabis ingredients. But considering the type of kidney disease and state of injury, experimental studies show that its effects on kidneys could be detrimental and beneficial.
- Contrary to the above, a 2019 study 8 reports that although CB1 and CB2 are expressed in the kidneys, the effects of the endocannabinoid system (ECS) in the kidneys are not yet well understood.
- But the study indicates that preliminary investigations on synthetic cannabinoids used as topicals in uremic pruritus in ESRD are promising.
- When it comes to symptoms of kidney diseases, neuropathic pain is highly relevant in patients with CKD. But, the study concludes that the role of cannabis in symptom management for CKD is limited. It is worth recalling here, the post CBD for back pain highlights the role of topical application of CBD, and its potential to block nociceptive and neuropathic pain.
- However, 4 the 2020 study reports that patients with progressive CKD may be more inclined to use medical cannabis for symptom management. It also adds that the National Academies concluded the existence of valuable evidence for the use of cannabis and cannabinoids to treat chronic pain.
Kidney disease and COVID 19
While the world is still fighting the novel coronavirus, research on it is in swift progress. The magnitude of the epidemic has jolted the medical research fraternity across the globe.
In this scenario, a new report reveals that people hospitalized for COVID-19 treatment are at a higher risk of developing Acute Kidney Injury(AKI). Kidney tubular injury, increased blood clotting, kidney infections are some of the after-effects of COVID-19, adds the report. Moreover, patients who have recovered from COVID-19 related AKI continue to show lowered kidney functions.
Therefore, the study recommends such patients get regular consultations from kidney specialists.
What are the simple lab tests to detect kidney functions?
Kidney diseases are common, painful but they can be treated with early diagnosis. Simple urine and blood tests can help us check our kidney functions.