The Effects of Cannabinoids on the Kidney

Abstract

Cannabinoids are a class of drugs derived from the Cannabis plant that are widely used for the treatment of various medical conditions and recreational use. Common examples include Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), spice, and 2-arachidonoylglycerol (2-AG). With more than 100 cannabinoids identified, their influence on the nervous system, role in pain management, and effects due to illicit use have been extensively studied. However, their effects on peripheral organs, such as the kidneys, require further examination. With dramatic rises in use, production, and legalization, it is essential to understand the impact and mechanistic properties of these drugs as they pertain to renal and cardiovascular physiology. The goal of this review is to summarize prior literature on the expression of cannabinoid receptors and how cannabinoids influence renal function. This review first discusses the interaction of the endocannabinoid system and renal physiology and pathophysiology. Following, we briefly discuss the role of the endocannabinoid system in various kidney diseases and the potential therapeutic applications of drugs targeting the cannabinoid system. Lastly, recent studies have identified several detrimental effects of cannabinoids, not only on the kidney but also in contributing to adverse cardiovascular outcomes. Thus, the negative impact of cannabinoids on renal function and the development of various cardiovascular diseases is also discussed.

Introduction

Cannabinoids are frequently used across the globe for purposes ranging from recreational use to therapeutic use, including appetite stimulation, glaucoma treatment, nausea and vomiting treatment, and anti-epileptic therapy.^1-3 Cannabinoids are compounds/molecules derived from various genera of Cannabis plants. There are three classes of cannabinoids: phytocannabinoids, synthetic cannabinoids, and endocannabinoids.⁴ Phytocannabinoids are formulations organically synthesized by the Cannabis plant, of which over 100 exist.⁵ The two most commonly used phytocannabinoids are cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC).^5,6 Regarding use, CBD lacks psychoactive effects and is FDA approved to treat seizures, inflammation, pain, and anxiety.^7,8 THC is commonly used recreationally for its psychoactive effects, such as euphoria and altered cognition, which classifies it as a controlled substance. However, it is also FDA-approved for the treatment of nausea, vomiting, and cachexia.^6,7,9 Synthetic cannabinoids are manufactured in a laboratory setting, chemically resembling natural cannabinoids. XLR-11 and HU-210 are examples of synthetic cannabinoids.¹⁰ Synthetic cannabinoids are a global health problem due to their potential to cause morbidity and mortality.^10,11 Endocannabinoids are compounds produced endogenously, bind to cannabinoid receptors, and are involved in many physiological functions including reproduction, mood regulation, metabolic function, nephronal ion transport and renal hemodynamics.¹² Examples of endocannabinoids include 2-arachidonoylglycerol (2-AG) and Anandamide (ANA).¹³ Table 1 summarizes those discussed in this review and their effects on the kidney.

Table 1.

Common cannabinoids and their known effects on the kidney^{21,22,24,69,72,77,83,86}.

Cannabinoid	Type	Receptor Mechanism of Action	Renal Effect
XLR11	Synthetic	Full CB1R and CB2R Agonist	Altered mitochondrial integrity (proximal tubule cells) Increased apoptosis (proximal tubule cells)
JWH-122	Synthetic	CB1R and CB2R Agonist	Increased ATP production (proximal tubule cells) Increased apoptosis (proximal tubule cells) Altered mitochondrial membrane dynamics (proximal tubule cells)
Spice/K2	Synthetic Blend	CB1R and CB2R Agonist	Acute tubular injury Elevates BUN Elevates creatinine Oliguric AKI
THC	Phytocannabinoid	CB1R and CB2R Agonist	No definitive adverse renal outcomes
CBD	Phytocannabinoid	Low affinity for CB1R/CB2R	No definitive adverse renal outcomes-conflicting evidence Improves serum creatinine Decreased renal inflammation Decreased renal oxidative stress Improved blood urea nitrogen Improves hyperglycemia Worsens nephropathy associated with diabetes
ANA	Endocannabinoid	CB1R/ lower affinity for CB2R	During hypertension: increased activation of the TGFβ1/Smad 3 pro-fibrotic signaling pathway and increased renal fibrosis, glomerular damage, and substantial increases in blood pressure

The classification of cannabinoids, particularly THC, as a Schedule I controlled substance under federal law remains a regulatory hurdle for scientists and researchers. As of now, THC is classified as a Schedule I substance, meaning it is considered to have a high potential for abuse and no accepted medical use in treatment in the US, which imposes strict regulations on its study and use in scientific research. However, at the present time, the United States Department of Justice is actively generating a proposition to redesignate marijuana from a Schedule I drug to a less restrictive Schedule III substance. Concurrently, to reinforce regulatory standards surrounding hemp-derived (hemp plants with <0.3 %THC) cannabinoid products, amendments to the Farm Bill, the legislation responsible for directing food and agricultural protocols, are in motion. Propositions include reform to the prior notion of hemp products being legal if containing less than 0.3% THC, to make hemp products containing any amount of THC illegal.¹⁴ From a scientific research standpoint, this raises an interesting challenge. Hemp-derived products, which require urgent investigation due to increased public use, will be less accessible, while marijuana will be easier to obtain for research purposes.

The endocannabinoid system (ECS) also includes metabolic enzymes associated with the breakdown and synthesis of cannabinoids and the cannabinoid receptors.¹⁵ The two cannabinoid receptors are cannabinoid receptor 1 and cannabinoid receptor 2 (CB₁R and CB₂R, respectively).¹⁶ CB₁R and CB₂R are typical G protein-coupled receptors (GPCRs); they are widespread throughout the body and triggering G_i protein pathways in the numerous cells.¹⁵ It is important to acknowledge the complexity of the ECS, as it integrates with multiple biological signaling pathways throughout the body. This system modulates a variety of physiological processes by influencing the activity of ion channels, the metabolism of ceramides, mitochondrial dynamics, and more.^15,17-19

Due to evolving cannabinoid research, further work is needed on the mechanistic properties of the drugs, potential adverse effects on the body, and possible beneficial use as legalization rates are increasing. Specifically, organs such as the kidney can be therapeutically or adversely affected by cannabinoid use. For example, in a therapeutic approach, synthetic cannabinoid JWH-133 activated the renal CB₂R receptor and reduced inflammation and apoptosis, thus decreasing glomerular and tubular damage in a kidney ischemia-reperfusion (IR) rat model.²⁰ Conversely, and of critical importance, clinical presentations encompassing synthetic cannabinoid use reported symptoms, including acute tubular necrosis (ATN) and increased serum creatinine.^11,21,22 Several similar research reports prompted a statement from the Center for Disease Prevention and Control (CDC), which links acute kidney injury (AKI) to synthetic cannabinoid use.^22,23

The conflicting evidence surrounding cannabinoid use and its precise effects on the kidney requires further investigation to generate clarity for public health knowledge. This review provides a brief insight into current mechanistic knowledge of cannabinoid renal physiology, illustrates the therapeutic potential of manipulating the ECS to treat various renal pathologies, and delineates the adverse effects of cannabinoids in the kidney.

Cannabinoid Physiology and the Kidney

The relationship between the endocannabinoid and renal system is a topic of ongoing research; however, its complete understanding requires further elucidation. Some data demonstrate that activation/inhibition of the ECS can affect various kidney functions, including efferent and afferent artery dilation, regulation of glomerular filtration rate (GFR), blood pressure regulation, reduction of renal endothelial dysfunction, urinary protein excretion, glucose reabsorption, changes in mitochondrial dynamics, redox balance and tubular sodium transport.^24-28 We will briefly discuss the physiological functions of the ECS receptors with respect to renal mechanics, as their involvement is pivotal in understanding the therapeutic or adverse effects of the ECS in the kidney.

Principle Receptor Mechanism

CB₁R and CB₂R are class A, seven helical transmembrane-spanning GPCRs varying in their tissue location.^25,29 Both receptors are linked to G_i/G₀ intracellular proteins and activate mitogen-activated protein kinase (MAPK) and decrease adenylate cyclase (AC) activity levels.³⁰ The increased activity in MAPK affects cell function and is linked to changes in gene expression, cell proliferation regulation, and cell fate determination.³⁰ The attenuation of cyclic adenosine monophosphate (cAMP) due to decreased AC activity affects numerous cellular functions, including decreased protein kinase A (PKA) activity, altered metabolic activity, altered gene expression, and cell proliferation and survival.³¹ An illustration of the principle ECS receptor mechanism is displayed in Figure 1. It should be noted that both receptors are involved in the regulation of intracellular Ca²⁺ mobilization through the inhibition of voltage-gated channels^32,33 and activation of K⁺ conductance, specifically by their coupling with inward rectifying K⁺ (K_ir) channels³⁴. Moreover, cannabinoids can directly regulate mitochondrial function by activating their receptors on mitochondrial membranes^35,36. This and the other reports describing the role of CBR in nitric oxide synthase (NOS) activation and nitic oxide signal transduction^37,38 make ECS an essential player in redox cell signaling regulation. Recently, ECS activation is also linked to a variety of metabolic-related pathways, including lipid and glucose homeostasis, endoplasmic reticulum stress-dependent synthesis of specific ceramides³⁹, and leptin bioactivity⁴⁰. Finally, our previous reports suggest that the activation of ECS may promote the release of extracellular ATP and d-serine, correspondingly impacting purinergic signaling and cell-to-cell signaling⁴¹.

Figure 1. Endocannabinoid System (ECS) Receptor Mechanism of Action.

CB₁R and CB₂R are seven-transmembrane G protein-coupled receptors (GPCRs) primarily coupled with G_i/G₀ intracellular proteins, triggering several key cellular mechanisms, including ceramide metabolism, mitogen-activated protein kinase (MAPK) signaling, and reduced adenylate cyclase (AC) activity. The activation of these cannabinoid receptors (CBRs) affects various cellular functions by regulating gene expression, cell proliferation, and cell fate determination. Both receptors also control intracellular Ca²⁺ mobilization by inhibiting voltage-gated channels and enhancing K⁺ conductance through inward rectifying K⁺ (K_ir) channels. Moreover, CBRs can directly interact with other GPCRs, such as Ang II receptors, modulating corresponding signaling cascades and cellular functions.

CB₁R and Renal Physiology

Analysis of kidney sections revealed the expression of CB₁R in the glomerulus, tubules, and arterioles. CB₁R, expressed by the Cnr1 gene, was reported in most kidney cells, including podocytes, mesangial cells, and proximal and distal tubular epithelial cells.^28,42-44 Studies have been conducted examining the function of CB₁R in the kidney. In one study utilizing renal proximal tubule cells (RPTC) both in vivo and in vitro, CB₁R agonism generated mitochondrial fragmentation, indicating a role of CB₁R in tubule cell bioenergetics.¹⁷ In another study investigating the involvement of the ECS in renal hemodynamics, administration of ANA in Sprague Dawley (SD) rats evoked increased CB₁R expression in both efferent and afferent arterioles.⁴⁵ Further, the administration of ANA increased both afferent and efferent dilation via the CB₁R, evoking an association between CB₁R and renal blood flow. Interestingly, a meta-analysis concluded CB₁R antagonism as a possible therapeutic strategy in approaching kidney disease as the study concluded reductions in albuminuria, blood urea nitrogen, and serum creatinine.⁴⁶

CB₂R and Renal Physiology

The CB₂R has been studied significantly less than its counterpart, CB₁R, in the kidney and requires further investigation to understand its expression and mechanistic properties. Studies have confirmed its presence in tubule cells and the glomerulus, where their role was proposed in mechanisms contributing to renal perfusion and the development of albuminuria during pathological conditions.^47,48 CB₂R has been the subject of increasing research interest, particularly regarding its role in inflammation and fibrosis, including in the kidneys. In a study employing a unilateral ureteral obstruction (UUO) model, researchers observed increased expression of CB₂R upon injury concomitant with a β-catenin-mediated increase in renal fibrosis.⁴⁹ Given the minimal knowledge surrounding the precise function and expression of CB₂R as it pertains to renal physiology, further research is imperative because, based on meta-analyses, CB₂R activation could serve as a novel therapeutic avenue in various kidney pathologies.⁴⁶

Therapeutic Applications of Cannabinoids in the Kidney

Targeting the ECS in the Treatment of Chronic Kidney Disease

There is evidence surrounding the therapeutic potential of the ECS in the settings of chronic kidney disease (CKD).^50,51 Thus, it has been demonstrated that CB₁R serves as an important mediator in the development of renal fibrosis, boasting increased expression in kidney myofibroblasts, thus increasing transforming growth factor beta (TGF-β) and collagen production.^52,53 A recent study revealed that obesity alters the ECS in human kidneys, linking higher ANA levels and reduced CB₁R expression to kidney damage and CKD.¹⁸ In a UUO mouse model of renal fibrosis, the authors demonstrated, using gene expression hybridization technology, that the Cnr1 gene is one of the top ten most upregulated genes in renal fibrosis.⁵³ Further, it was reported that pharmacological obstruction of CB₁R and genetic knockout of Cnr1 resulted in significant declines in fibrosis generation in mice when subjected to UUO.⁵³ Another study utilizing a novel RPTC CB₁R knockout mouse line subjected to a high-fat diet to induce CKD revealed decreased renal fibrosis quantified by decreased profibrotic mRNA indicators and decreased collagen production.²⁸ These studies indicate attenuating CB₁R mechanics could serve as a novel therapeutic target in the treatment of CKD.

Approaches targeting CB₁R have been made in treating CKD; however, an optimal therapeutic approach requires further investigation. A novel approach to attenuating CKD progression incorporating CB₁R antagonism could be a combined therapy strategy. For example, in an obese model of CKD, mice were treated with hybrid CB₁R/iNOS antagonist MRI-1867.⁵⁴ Results showed marked decreases in renal injury, reactive oxygen species (ROS) production, and fibrosis.⁵⁴ The theoretical protocol could incorporate ARB/ACEi to attenuate Renin-Angiotensin-Aldosterone System (RAAS) activation and induce renal anti-mitogenic effects. This, combined with CB₁R antagonism to mitigate renal fibrosis, nuclear factor erythroid 2 (Nrf2) activation to mitigate renal ROS, and the incorporation of bempedoic acid or statin to attenuate lipotoxicity could serve as a comprehensive cardiorenal therapeutic approach in mitigating the progression of CKD. An overview of the theoretical therapeutic approach is depicted in Figure 2. It should be noted that the use of CB₁R antagonists has had some difficulty in translating to clinical practice. First-generation CB₁R antagonist rimonabant did produce the desired obesity-corrective effects; however, it was withdrawn from the market in 2008 due to its lack of peripheral restriction and production of adverse neurological effects, including increased suicidal ideation rates and anxiety.⁵⁵ Currently, numerous studies involving next-generation CB₁R antagonists and hybrid therapy CB₁R/iNOS antagonists are reaching the pre-clinical level.⁵⁵ To be effective at the clinical level, the ideal CB₁R antagonist therapeutic would boast minimal off-target effects combined with a high degree of CNS safety and tolerability.⁵⁵

Figure 2. Incorporation of the endocannabinoid system (ECS) in a comprehensive theoretical strategy in the treatment of chronic kidney disease (CKD).

CKD emerges from a multitude of signaling pathways. Prolonged activation of the renin-angiotensin aldosterone system (RAAS), lipotoxicity, and oxidative stress contribute to increased myofibroblast activity, increased inflammation, nephron loss and increased deposition of the extracellular matrix. Genetically decreasing CB₁R expression or CB₁R antagonist administration, combined with statin/bempedoic acid, angiotensin-converting enzyme inhibition (ACEi)/Angiotensin receptor blocker (ARB) and nuclear factor erythroid 2-related factor agonism (Nrf2) could serve as an encompassing therapeutic approach in the treatment of CKD. Treatments are denoted by green checkpoints in above signaling pathway.

Targeting the ECS in the Treatment of Diabetic Nephropathy

Diabetic Nephropathy (DN) is a renal complication associated with both type 1 and type 2 diabetes mellitus (DM) and serves as the primary causal factor for end-stage renal disease (ESRD).⁵⁶ The development of DN is complex, comprised of increased adverse factors and signaling pathways resulting from hyperglycemia.^56-58 The physiological renal consequences of DN include decreased GFR and increased albuminuria.⁵⁸ Regarding mechanisms and signaling pathways, the hyperglycemia associated with DM is known to induce oxidative stress, inflammation, fibrosis, metabolic alterations, and hemodynamic irregularities.^57,58 CB₁R and CB₂R undergo changes during the development of DN, where CB₁R expression is upregulated, and CB₂R expression is reduced.⁵⁹

CB₁R upregulation in DN is linked to each of the signaling pathways mentioned above, and many antagonism or blockade therapeutic attempts have been investigated to treat DN.⁶⁰ For example, in one study, authors elucidated a novel mechanism where hyperglycemia activates CB₁R in the proximal tubule in mice, thus increasing the mammalian target of rapamycin complex 1 (mTORC1), augmenting glucose transporter 2 (GLUT2) activity and contributing to the development of diabetes in the kidney.⁶¹ In a diabetic mouse model study, mice were treated daily with peripherally restricted CB₁R inverse agonist INV-202 for 28 days.⁶² Results demonstrated improved GFR, a reduction in renal fibrosis confirmed via histological and mRNA pro-fibrotic gene analysis, declines in oxidative stress gene expression markers, conservation of podocyte injury, and declined glomerular injury.⁶² In a study using a Zucker diabetic fatty type 2 DN model, rats were administered CB₁R inverse agonist JD5037 for 90 days.⁶³ Results of this trial revealed improved GFR, plasma creatinine, polyuria, and albumin excretion nearly to baselines.⁶³ Further, treatment with JD5037 normalized cytokines tumor necrosis factor (TNF), interleukin 18 (IL-18), and interleukin 6 (IL-6), as well as prevented renal cortical oxidative stress and attenuated overactive RAAS.⁶³ This study supports the potential of attenuating the activity of CB₁R in the treatment of DN. In a parallel study performed by the same group, the researchers employed a CB₁R podocyte knockout murine model treated with streptozotocin to generate DN.¹⁹ Results of this study unveiled that after 3 months of streptozotocin treatment, the knockout mice exhibited attenuated podocyte loss and albuminuria; however, the hyperglycemia remained similar to controls.¹⁹ Additionally, the knockout mice displayed improved cortical circulation, reduced tubular dysfunction, and attenuated fibrosis compared to controls.¹⁹ In a similar approach targeting upregulated CB₁R via genetic editing, an increased glucose rat mesangial cell culture line was transfected with microRNA29A (miRNA29A).⁶⁴ miRNA29A is a small non-coding molecule that can post-transcriptionally alter gene expression.⁶⁴ Also, transgenic mice overexpressing miRNA29A were generated and treated with streptozotocin to induce diabetic glomerulopathy.⁶⁴ Results demonstrated successful suppression of CB₁R in mesangial cells upon miRNA29A transfection.⁶⁴ In the miRNA29A overexpression diabetic mouse model, the group observed a significant reduction in renal hypertrophy and significant reductions in renal fibrotic injury.⁶⁴ qRT-PCR revealed declines in pro-inflammatory/fibrotic markers TNF-α, type 4 collagen, IL-6, and transcription factor jun (c-Jun).⁶⁴ Histomorphometric analysis of the glomerular mesangium aligned with the RT-PCR findings, exhibiting pronounced declines in type 4 collagen deposition.⁶⁴ It is important to note here there are challenges involved in translating gene therapeutics to the clinic, most of which require extensive further research. An ideal gene therapy protocol would involve an optimal balance of correct dosing, delivery, safety, tolerability, and efficacy.⁶⁵ In a trail navigating away from CB₁R antagonism and investigating CB₂R agonism in addressing DN, the investigators utilized streptozotocin to induce DN and treated the mice with CB₂R agonist AM1241 for 3.5 months.⁶⁶ Noted outcomes of the trial included improved albuminuria, improved monocyte intrusion at the glomerulus, and augmented podocyte protein upregulation.⁶⁶ This study complements the potential therapeutic application of CB₂R agonism in the treatment of DN.

Also, in a parallel medical condition, a study displayed a role of the ECS in diabetes insipidus, particularly suggesting that WIN55,212-2 (WIN) administration, a nonselective cannabinoid receptor agonist, induced central diabetes insipidus in mice research model.⁴⁴ The studies show clear colocalization of CB₁R expression with AQP-2 negative cells in the kidney, the mechanism of WIN-induced diuresis, and the corresponding influence of CB₁R activation on AVP secretion. These studies conclude that manipulation of ECS could open novel avenues to regulate renal function, and the consumption of cannabis products could be associated with dehydration. It is important to note that although the results of the mentioned therapeutic approaches exhibit positive outcomes, the precise mechanisms of the therapeutic effects require further elucidation. Figure 3 depicts an overview of the potential role of the ECS in DN.

Figure 3. Targeting the endocannabinoid system (ECS) in the setting of diabetic nephropathy (DN).

Adverse Effects of Cannabinoid Use in the Kidney and other Cardiovascular Diseases

Given the increased popularity and legalization rates of cannabinoids, new products such as cannabinoid vape products, cannabinoid edibles and cannabinoid derivatives are being developed at an impetuous rate. Accompanying this rapid production rate is lagging knowledge regarding their safety. Slow progress in the research in the understanding of ECS regulation and mechanisms is critical and requires significant changes in policies to ease the legalization process for the scientific community. Similar to other medical compounds on the market, we should first implement rigorous research and gradually approve new cannabinoids, which is unfortunately not the case. Recent studies show that cannabis has adverse cardiovascular and pulmonary effects and is linked with malignancy.^67,68 Here, we discuss the adverse effects of synthetic, endogenous, and phytocannabinoids on the kidney and other cardiovascular diseases.

Adverse Effects of Synthetic Cannabinoids on the Kidney

Spice or K2 are blends of synthetic cannabinoid formulated to emulate the effects of marijuana which contain modified psychoactive elements such as JWH-073 to help maintain their legality.⁶⁹ Case reports have established a relationship between spice use and AKI.²¹ A case of a 23-year-old male chronic spice user presenting with nausea/vomiting, decreased heart rate, increased blood urea nitrogen (BUN), and increased serum creatinine displayed declining renal function after attempted intravenous (IV) therapy.²¹ Upon declining renal function, the patient developed oliguric AKI with mild acute tubular injury revealed by renal biopsy. The patient’s renal function improved and he did not require dialysis.²¹ There are many case studies reporting similar outcomes of renal damage due to spice use. A significant gap exists in understanding the precise mechanisms and signaling pathways encompassing the effects of spice on the kidney.

XLR-11 is a synthetic cannabinoid introduced to the market in 2012 and can be found in smoking blends used across the globe.⁷⁰ XLR-11 is a full agonist of both the CB₁R and CB₂R and is linked to the induction of AKI.²³ In a multistate comprehensive case report, five out of seven cases of AKI included the presence of XLR-11 metabolites confirmed by liquid chromatography time of flight mass spectrometry.²³ All cases reported chief complaints of abdominal pain accompanied by nausea and vomiting.²³ In a study utilizing a human proximal tubule cell line, studies concluded XLR-11 altered mitochondrial activity confirmed by tetramethyl rhodamine ethyl ester (TMRE) analysis.⁷¹ Observations included a 1.4-fold increase in dysregulation in mitochondrial membrane potential upon exposure.⁷¹ Another profound finding was the notion that apoptotic cell death occurs in human RPTC due to XLR-11 use. Cells treated with XLR-11 for 6 hours resulted in a significant increase in caspase 3 activity, displaying a 1.9-fold increase when compared to controls.⁷¹ These findings establish a correlation between synthetic cannabinoid XLR-11 use and the pathogenesis of AKI.

JWH-122 is a synthetic cannabinoid commonly added to spice exhibiting affinity for both CB₁R and CB₂R.⁷² Studies have shown that JWH-122 administration has similar renal effects to XLR-11, dysregulating mitochondrial function and augmenting apoptosis in the kidney.²⁴ In similar experiments using human RPTC, the investigators observed mitochondrial membrane hyperpolarization upon JWH-122 administration.²⁴ Further, proximal tubular cellular ATP levels increased 1.8 fold upon JWH-122 administration indicating a pathological disruption in cellular bioenergetics.²⁴ Lastly, upon exposure to JWH-122, caspase 3 activity doubled, indicative of increased apoptosis.²⁴ These conclusions are in line with the other reports suggesting that synthetic cannabinoids may promote severe acute and chronic toxicity directly or indirectly leading to fatal cases^72-74.

Adverse Effects of Phytocannabinoids and Endogenous Cannabinoids on the Kidney

Of illicit drugs used in the United States, marijuana is the most extensively used, with use rates increasing in adults and adolescents each year.⁷⁵ There are very few studies investigating the effects of marijuana on the kidney. This presents a major research gap in the field, and the precise effects, and signaling mechanisms involved in marijuana use and the effects on the kidney require further attention.

There are studies that present evidence that there are no associated adverse renal effects upon marijuana use in young adults, and the adverse renal effects are limited to individuals using synthetic cannabinoids. In a longitudinal cohort study, diverging from the coronary artery risk development in young adults study, starting at year 10, young adults with preserved GFR were examined.⁷⁶ The group investigated the relationship between GFR and marijuana use over a 15-year time span.⁷⁶ Results showed 83% (3131) of the cohort used marijuana, and over the course of 10 subsequent years, 504 displayed GFR decline. Over 15 years, albuminuria was significant in 426 individuals.⁷⁶ Although these renal physiological observations were present, the authors reported them as insignificant and declared no relationship between decreased GFR, albuminuria and longitudinal marijuana use in the young adult group.⁷⁶ Based on these conflicting notions, it is not known if marijuana has adverse effects on the kidney and, if so, to what magnitude.⁷⁷ Further investigations should be carried out to elucidate the precise mechanisms involved in marijuana use and its associated renal consequences.

CBD is a multi-target phytocannabinoid present in the cannabis plant lacking the psychoactive profile found in THC.⁷⁸ CBD functions as an antioxidant and a negative allosteric modulator of CB₁R, which may contribute to its anti-fibrotic properties. CBD has gained popularity in recent years due to its therapeutic effects, including anti-inflammation, pain relief, and anxiety reduction.⁷⁸ CBD is commonly consumed orally or applied topically.⁷⁹ There is no definitive evidence present coupling CBD use to unfavorable renal outcomes.⁸⁰ Conversely, many studies have demonstrated the therapeutic potential of CBD in the kidney. In one study utilizing doxorubicin-induced kidney damage in SD rats, researchers concluded CBD administration decreased oxidative stress, lowered serum creatinine, and decreased inflammatory mediators IL-6 and MDA.⁸¹ Another study employing a streptozotocin treated mouse model to induce DN, administration of +CBD hydroxypentylester (HPE) reduced creatinine levels, BUN levels, hyperglycemia, apoptosis, and pro-inflammatory markers.⁸² One study reported detrimental effects of CBD use in nephropathy.⁸³ This study observed conflicting evidence compared to the studies above. In this investigation, mice treated with streptozotocin to DN were pretreated with CBD for 8 days prior to DN.⁸³ Results demonstrated no improvement in hyperglycemia, improved glomerular hypertrophy, and overall exacerbated renal damage when compared to healthy and control groups.⁸³ The researchers note to practice caution when type 1 diabetic patients use CBD as use could augment the degree of nephropathy.⁸³ While CBD does not appear to impact kidney function in healthy individuals, it is crucial to closely monitor renal function in those with CKD. CKD often leads to complications affecting multiple organs, including the liver, resulting in altered drug metabolism, increased risk of liver fibrosis, and a higher prevalence of non-alcoholic fatty liver disease. Additionally, high doses of CBD can be hepatotoxic^84,85. Since CBD is extremely popular and sold practically without regulation, a more thorough assessment of its potential positive effects and harmful effects is necessary, especially in patients with CKD. Importantly, further investigations are needed to expand the knowledge surrounding CBD use and renal function.

Regarding endogenous cannabinoids, our group aimed to investigate the effects of ANA on renal injury and blood pressure. Our study utilized Dahl salt-sensitive rats fed a high salt or normal salt diet accompanied by acute or chronic low or high doses ANA administration.⁸⁶ Our data suggests upon intravenous bolus administration of either high- or low-dose ANA under normal dietary conditions, no effect on blood pressure was observed.⁸⁶ However, during the development of hypertension, chronic exposure to high dose ANA in rats fed a high-salt diet resulted in significant augmentation of renal fibrosis, glomerular damage, and substantial increases in blood pressure.⁸⁶ These findings prompted further mechanistic investigation, and our group unveiled increased activation of the TGFβ1/Smad 3 pro-fibrotic signaling pathway.⁸⁶ This work demonstrates a potential correlation between the ECS and the regulation of blood pressure and renal injury.⁸⁶

Adverse Effects of Cannabinoids on Other Cardiovascular Diseases

There is evidence supporting the interrelationship between cannabinoid use and adverse cardiovascular outcomes, including vascular dysfunction, stroke, arrhythmias, ischemia, atherosclerosis, hypotension, vasospasm, and thrombosis.^87,88 These adverse cardiovascular outcomes can have direct effects on renal function. For example, in the heart, a study investigating the effects of JWH-073, a compound found in spice, reported weakened maximal contraction and increased relaxation rates when administered to cardiomyocytes in vitro.⁸⁹ Furthermore, in a case report, the authors reported three instances of myocardial infarction in adolescent individuals upon recreational spice use.⁹⁰ Pertaining to the vasculature, synthetic cannabinoid HU-210, a compound also found in spice mixes, has been shown to have proatherogenic effects.⁹¹ In this study, researchers utilized EVC304 cells treated with ANA or HU-210 activated MAPK, a signaling pathway component that drives atherosclerosis generation.⁹¹ Conversely, HU-210 has also been demonstrated to exhibit cardioprotective effects.⁹² In one study, isolated rat hearts underwent ischemia-reperfusion injury and were then perfused with HU-210.⁹² Results revealed marked decreases in creatine phosphokinase, a known marker of tissue damage.⁹² Lastly, chronic THC use is linked to a rare disease known as cannabis arteritis, where the vasculature becomes inflamed and individuals present with digital necrosis, stenosis of distal arteries and atherosclerosis.⁹³ The precise mechanism of cannabis arteritis is unknown, but the disease exemplifies the potential adverse cardiovascular consequences of cannabinoid use, which, in turn, can affect the kidney. Further research is needed on the effects of cannabinoids on the cardiovascular system as the two systems, the cardiovascular and renal, are linked. Insight into the adverse cardiovascular complications associated with cannabinoid use could generate a comprehensive understanding of the cross-talk of the cardio and renal systems thus, leading to strategies aimed at preserving cardiorenal function in cannabinoid users.

Conclusions

The topics mentioned in this review address the relationship between cannabinoids and the kidney and emphasize the complexity of their relationship. The presented work discusses the endocannabinoid system's therapeutic potential for treating renal pathologies. However, we further emphasize the conflicting, lacking available data surrounding the adverse effects of cannabinoids on the kidney, mainly concluding detrimental renal and cardiovascular outcomes associated with cannabinoid use. It is crucial to advance knowledge in this field due to the growing medical and illicit use of cannabinoids, with the aim of improving human health and longevity. Overall, the ECS presents a potential therapeutic avenue for treating renal pathologies. However, there are significant detrimental effects of cannabinoids on renal function, all of which require further investigation.

Non-Standard Acronyms and Abbreviations

2-AG

2-arachidonoylglycerol

AC

Adenylate Cyclase

AKI

Acute Kidney Injury

ANA

Anandamide

ARBs

Angiotensin Receptor Blockers

ATN

Acute Tubular Necrosis

BUN

Blood Urea Nitrogen

cAMP

Cyclic Adenosine Monophosphate

CBD

Cannabidiol

CB₁R

Cannabinoid Receptor 1

CB₂R

Cannabinoid Receptor 2

CDC

Center for Disease Prevention and Control

c-Jun

Transcription Factor Jun

DM

Diabetes Mellitus

DN

Diabetic Nephropathy

ECS

Endocannabinoid System

ESRD

End Stage Renal Disease

GFR

Glomerular Filtration Rate

GPCR

G Protein-Coupled Receptor

HPE

Hydroxypentylester

IL-6

Interleukin 6

IL-18

Interleukin 18

iNOS

Inducible Nitric Oxide Synthase

IR

Ischemia Reperfusion

IV

Intravenous

MAPK

Mitogen Activated Protein Kinase

MiRNA29A

MicroRNA 29A

mTORC1

Mammalian Target of Rapamycin Complex 1

NrF2

Nuclear Factor Erythroid Related Factor 2

PKD

Polycystic Kidney Disease

PKA

Protein Kinase A

qRT-PCR

Quantitative Reverse Transcription-Polymerase Chain Reaction

RAAS

Renin-Angiotensin-Aldosterone System

ROS

Reactive Oxygen Species

RPTC

Renal Proximal Tubule Cells

SD

Sprague Dawley

TGF-β

Transforming Growth Factor Beta

THC

Δ⁹-tetrahydrocannabinol

TMRE

Tetramethyl Rhodamine Ethyl Ester

TNF-α

Tumor Necrosis Factor α

UUO

Unilateral Ureteral Obstruction

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.