15% of US adults are estimated to have kidney disease, & with the potential benefits of CBD, it's essential to look at the benefits & risks. Cannabinoids and the kidney: effects in health and disease Address for reprint requests and other correspondence: C. P. Kovesdy, Univ. of Tennessee Health Science Center, Memphis, TN 956 Court
CBD Oil Side Effects on Kidneys: What Studies Found
Chronic kidney disease (CKD) and kidney injury are two significant threats to renal function. Depending on the cause, kidney health issues can – at best – affect your quality of life and – at worst – be fatal.
Conventional treatments have existed for quite a while, and some are very effective. Unfortunately, the potential adverse effects can make those options unbearable. Naturally, some people with chronic kidney disease or kidney injury (among others) decide to look outside mainstream options.
Cannabinoid medicine exploded in recent years, with millions claiming cannabidiol (CBD) helped relieve their symptoms where prescription medication doesn’t cut it.
So how can CBD oil help with chronic kidney disease – or any renal disorder? It’s a complicated topic that, despite some research, leaves more questions than answers.
What is CBD Oil?
If you’re familiar with CBD, you likely know about CBD oil. Content and potency vary depending on the oil and brand. But at its core, CBD oil is a type of natural extract from all forms of cannabis Sativa L. – the plant species often (incorrectly) separated into “marijuana” and “hemp.”
Manufacturers extract the CBD and other compounds using methods like hydrocarbon (butane), alcohol, or CO2. Once separated, the CBD is infused into a carrier oil, like MCT, grapeseed, hemp, or coconut.
You then ingest a pre-measured amount based on your CBD dosage needs. But although many claim CBD works for symptom management, there are also CBD oil side effects to consider. We’ll get to that shortly.
How CBD is Absorbed Into the Body
CBD is absorbed into the body using a vast internal network known as the endocannabinoid system (ECS). The ECS consists of specific pathways known as the CB1 and CB2 receptors located in the central nervous and peripheral systems.
Cannabinoids like THC bind to both the CB1 and CB2, which is why recreational or medical cannabis users experience mental and physical effects.
Other cannabinoids interact with just one receptor, but CBD is one of many exceptions. Instead, cannabidiol impacts other receptors and pathways, ultimately altering the shapes of the CB1 and CB2 receptors.
This reaction affects how external (phytocannabinoids) and internal (endocannabinoids) affect the brain and body. These “adjustments” are often beneficial, as are CBD’s interactions with the serotonin, vanilloid, and other vital receptors.
But before it can do all of that, CBD needs to get into your bloodstream. There are several ways to do this. All consumption methods have advantages and disadvantages, which alter the strength, duration, and effects of CBD.
Those being treated for chronic kidney disease or (other kidney diseases) should also consider potential drug interactions.
Inhalation offers a more authentic experience for vape and joint smokers. When consumed through the lungs, CBD hits the bloodstream almost instantly. As a result, you notice effects within minutes. However, the effects wear off faster than any other method – usually within two to four hours.
Many vendors don’t offer inhalable products, often due to health concerns. We’re all aware of the vape illness epidemic that dominated the news in 2019 (and continues to this day). We also don’t know the long-term damage of inhaling burnt cannabis plant matter – although it seems safer than tobacco.
Ingestion offers a broad range of options for taking CBD. Cannabidiol extracts can be infused into hundreds of foods and drinks, from desserts smoothies – even beer and wine! A few examples are:
With ingestion, the majority of CBD is broken down in the liver. Consequently, eating or drinking CBD is the slowest-acting option. But it makes up for this by lasting up to eight hours – longer than any other method.
Topicals are another diverse group of CBD products. But unlike smoking and eating, topicals don’t enter your bloodstream. Applied directly to the skin, these products provide a more focused, instant effect.
Is CBD Oil Excreted Through the Kidneys?
We know how CBD enters the body, but how does it leave? Considering urine tests are a common way to detect drug use, you’d think the kidneys eliminate a lot of THC and CBD. But a 2019 review in the Canadian Journal of Kidney and Health Disease shows that nothing could be further from the truth.
The authors explain THC and CBD mostly exit through the feces. As a result, they feel CBD’s minor effects on kidneys don’t require a CBD dosage adjustment. However, they’re unsure if we eliminate minor cannabinoids in the same fashion.
What are the Side Effects of CBD Oil?
Studies universally found that CBD is well-tolerated with no possibility for abuse or addiction. Side effects of CBD oil are mild, especially compared to prescription medication. Still, it might not be for you. Keep an eye out for some common side effects:
- Dry mouth
- Appetite changes
High doses of CBD – especially when introduced immediately without titrating – are more likely to trigger those effects. If these problems persist or worsen, stop using CBD.
Since hemp oil contains little to no tetrahydrocannabinol (THC), CBD extracts shouldn’t make you high. However, if you feel intoxicated, it’s possible the manufacturer mislabeled their product.
Common Causes of Kidney Disease
According to the National Institute of Diabetes and Digestive and Kidney Diseases, chronic kidney disease (CKD) is usually caused by diabetes or high blood pressure.
However, there are many other reasons, including (but not limited to):
- Drug interactions
- Physical injury
Symptoms of Kidney Disease
The symptoms of kidney disease can be difficult to pinpoint since various common infections or toxins often cause them. However, if you have high blood pressure or diabetes, pay extra close attention to the following signs:
- Nausea and vomiting
- Back pain
- Increased or decreased urination
- Sleep issues
- Muscle cramps
- Dry or itchy skin
- Swelling of the feet or ankles
- Chest pain
- Shortness of breath
- Hypertension (high blood pressure)
Regardless of the cause, chronic kidney disease is a serious threat to kidney function. If you’re concerned about your renal health, talk to a doctor as soon as possible.
Does CBD Oil Hurt Your Kidneys?
CBD oil may hurt the kidneys, but it also might help renal function. Preliminary research is either promising, inconclusive, or negative.
We’ll look at all the results next.
What Studies Say About CBD Oil Side Effects on Kidneys
The relationship between chronic kidney disease (or any other kidney health issue) and CBD oil isn’t well understood. Some research looks positive.
For example, a 2009 Study in the Journal of Pharmacology and Experimental Therapeutics discovered that CBD might help alleviate inflammation, oxidative stress, and cell destruction, reducing nephrotoxicity.
“Nephrotoxicity” refers to kidney damage from drugs or toxins. This condition makes it difficult to eliminate urine or waste, leading to a potentially deadly outcome.
The authors of the said review found that the activation of the CB1 receptors regulates renal vascular blood flow. Meanwhile, the renal CB2 receptors reduce the effects of inflammation, oxidative stress, and renal fibrosis. These findings support and explain the 2009 study’s observations.
Subsequent 2017 research in the American Journal of Physiology also concluded that cannabinoids have potentially beneficial effects on kidneys. However, they caution that we don’t know about the effects of CBD on acute kidney injury (AKI) or chronic kidney disease.
The following study shows how accurate this warning may have been.
Among the promising or inconclusive findings are some upsetting discoveries. One 2018 study in the American Society of Nephrology Found that cannabis consumers with impaired kidney function showed a faster decline than non-cannabis users.
One important detail, however, is that these subjects used THC and CBD products. This makes it difficult to determine if CBD or THC is responsible (if at all).
However, the mix of positive and negative findings might be attributed to CBD rather than CBD products. According to
2o2o review from Current Opinion in Nephrology and Hypertension says, “There is no evidence to suggest that CBD has any adverse effect on kidney function. In fact, CBD prevented cisplatin-induced nephrotoxicity in a mouse model by reducing oxidative stress. However, some products may contain toxic contaminants such as heavy metals, pesticides, and solvents.”
So are CBD’s effects on kidneys good or bad? For now, we don’t know. But even if cannabidiol is effective, quality CBD may be hard to find. Without a green light from the Food and Drug Administration, there’s no way to guarantee CBD oil is free of the aforementioned contaminants.
Potential Benefits of CBD Oil in Kidney Diseases
The effects of CBD oil on kidney disease are mostly promising but still warrant caution. But there’s some good news. Even if CBD has no direct therapeutic effects on those organs, chronic kidney disease patients can (and do) use cannabis for symptom control.
The 2020 study above mentions CBD’s potential for pain management. Researchers believe CBD may help mitigate chronic pain related to kidney disease.
They also theorize that maybe CBD’s analgesic benefits could reduce the need for opioids – but that’s an enormous “maybe.”
Dosage and Precautions for CBD Oil and Kidneys
We know very little about the effects of CBD oil on kidneys and next to nothing about the proper CBD dosage. Unfortunately, dosing cannabinoids isn’t an exact science, despite decades of research. Synthetic cannabinoids, like Sativex and Marinol, being are a couple of exceptions.
However, those prescription drugs are designed to treat specific symptoms rather than the broad range of potential benefits assigned to CBD.
It also doesn’t help that we can’t (yet) conclusively prove that CBD oil side effects on kidneys outweigh the possible beneficial effects of CBD.
But if you feel it helps with symptoms like nausea or chronic pain, you can at least benefit from those effects.
In this case, follow the “start low and go slow” rule. Begin with the smallest dose possible (usually 2.5 to 5 mg) and increase every few days as needed.
That being said, don’t try adding CBD to your daily health routine without consulting a doctor – especially if you have kidney disease.
Summary: CBD Oil Side Effects on Kidneys
There’s some promising CBD research that could be a game-changer for those with kidney injury, chronic kidney disease, or other renal function problems.
But while exciting, we need to remember Despite some worthwhile findings, none of the potential benefits have been evaluated by the Food and Drug Administration. CBD oil isn’t intended to prevent, diagnose, or treat any illness.
However, we should see these discoveries as springboards to inspire further research.
“Causes of Chronic Kidney Disease | NIDDK.” National Institute of Diabetes and Digestive and Kidney Diseases, Oct. 2016, www.niddk.nih.gov/health-information/kidney-disease/chronic-kidney-disease-ckd/causes. Accessed 25 Nov. 2021.
CDC. “Outbreak of Severe Pulmonary Disease Linked with E-Cigarette Product Use.” Centers for Disease Control and Prevention, 6 Sept. 2019, www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html. Accessed 25 Nov. 2021.
Ho, Claudia, et al. “A Review of Cannabis in Chronic Kidney Disease Symptom Management.” Canadian Journal of Kidney Health and Disease, vol. 6, Jan. 2019, p. 205435811982839, www.ncbi.nlm.nih.gov/pmc/articles/PMC6388458/, 10.1177/2054358119828391. Accessed 26 Nov. 2021.
Nesbitt, Hal. “American Society of Nephrology | Kidney Week – Abstract Details.” Www.asn-Online.org, www.asn-online.org/education/kidneyweek/2018/program-abstract.aspx?controlId=3017229. Accessed 26 Nov. 2021.
Pan, Hao, et al. “Cannabidiol Attenuates Cisplatin-Induced Nephrotoxicity by Decreasing Oxidative/Nitrosative Stress, Inflammation, and Cell Death.” Journal of Pharmacology and Experimental Therapeutics, vol. 328, no. 3, 12 Dec. 2008, pp. 708–714, 10.1124/jpet.108.147181. Accessed 26 Nov. 2021.
Park, Frank, et al. “Cannabinoids and the Kidney: Effects in Health and Disease.” American Journal of Physiology-Renal Physiology, vol. 313, no. 5, Nov. 2017, pp. F1124–F1132, www.ncbi.nlm.nih.gov/pmc/articles/PMC5792153/, 10.1152/ajprenal.00290.2017. Accessed 26 Nov. 2021.
Rein, Joshua L. “The Nephrologistʼs Guide to Cannabis and Cannabinoids.” Current Opinion in Nephrology and Hypertension, vol. 29, no. 2, Mar. 2020, pp. 248–257, 10.1097/mnh.0000000000000590. Accessed 26 Nov. 2021.
Cannabinoids and the kidney: effects in health and disease
Address for reprint requests and other correspondence: C. P. Kovesdy, Univ. of Tennessee Health Science Center, Memphis, TN 956 Court Ave., Memphis TN 38163 (e-mail: [email protected]).
Consumption of cannabis and various related products (cannabinoids) for both medicinal and recreational use is gaining popularity. Furthermore, regulatory changes are fostering a cultural shift toward increasing liberalization of cannabis use, thereby increasing the likelihood of even larger numbers of individuals being exposed in the future. The two different types of receptors (CB1 and CB2) that are activated by the pharmacologically active ingredients of cannabis are found in numerous tissues, including the kidneys. Experimental studies suggest that stimulation of these receptors using pharmacologic agents or their naturally occurring ligands could have both deleterious and beneficial effects on the kidneys, depending on receptor distribution, type of renal insult, or the timing of the activation during acute or chronic states of kidney injury. To date, the mechanisms by which the CB1 or CB2 receptors are involved in the pathology of these renal conditions remain to be fully described. Furthermore, a better understanding of the impact of exocannabinoids and endocannabinoids on the renal system may lead to the development of new drugs to treat kidney disease and its complications. Given the increasing public health relevance of cannabis exposure, it is clear that more research is necessary to clarify the various physiological and pathophysiological effects of cannabis and related analogs on the kidney. This will help limit the deleterious effects of these substances while promoting their potential beneficial impact on renal function in various types of kidney diseases.
cannabis , also known as marijuana, is an umbrella term used for preparations obtained from plants that fall under the genus Cannabis in the plant family cannabaceae (60). Cannabis and products derived from it have been widely used for recreational and/or medicinal purposes dating back to 4000 B.C. in ancient Asia (7a). The first cannabinoid, cannabinol, was isolated in 1896 and was further synthesized in 1940. Another major cannabinoid, delta-9-tetrahydrocannabinol (THC), was isolated in 1964 in Israel by Raphael Mechoulam, and this subsequently led to the discovery of the cannabinoid receptors (CB) and the endocannabinoid system (23). Currently, two synthetic cannabinoids, dronabinol (schedule III) and nabilone (schedule II), are approved by the FDA for clinical use in patients (5).
Marijuana is presently categorized as a schedule I illegal substance (defined as being a drug with no probable medical use and high abuse potential) (5). Cannabis was used in the United States for centuries as a drug for the treatment of different ailments. However, in 1937, the Marijuana Tax Act was passed, and federal prohibition started, which then led to criminalization of its use, culminating in the 1970s and 1980s with a war on drugs and the placement of marijuana in the most restricted drug category. In the 1990s, California was the first state to approve medical use of marijuana for select diagnoses. Subsequently, legalization of marijuana became a political issue, and in 2012, Colorado and Washington were the first U.S. states to legalize recreational use of marijuana. In 2013, Uruguay became the first country to legalize marijuana nationwide (7a). By 2016, 28 states legalized medical marijuana, and eight states and Washington, D.C. legalized the recreational use of this substance in the United States. The journey of marijuana from prohibition to criminalization and subsequently to decriminalization/legalization has led to an increase in the rate of use of this substance.
Use of cannabis for recreational purposes is popular; it is estimated that 182.5 million people worldwide in the age group 15–64 used cannabis at least once in 2014 (56). On the basis of United Nations Office of Drugs and Crime data, the prevalence of cannabis use was 16.2% in the United States in 2014 ( Fig. 1 ). On the basis of National Survey on Drug Use and Health data, the percentage of people that used cannabis at least once in the prior year increased from 11% in 2002 to 13% in 2014, with the most accentuated increase seen in the age groups 18–25 and 26 or above (7% and 44% respectively; Fig. 2 ).
Prevalence of cannabis use worldwide in 2014. Modified from United Nations Office on Drugs and Crime, United Nations Office on Drugs and Crime. http://www.unodc.org/wdr2016/field/1.2.2._Prevalence_cannabis.pdf, accessed on March 27, 2017.
Percentage marijuana use during the past 12 mo among people aged ≥12 yr, overall and by age group. Modified from National Survey on Drug Use and Health Data. https://www.cdc.gov/mmwr/volumes/65/ss/ss6511a1.htm, accessed on March 27, 2017.
Although cannabis is mostly consumed for its effects on the central nervous system, by activating the CB receptors (CB1 or CB2) within the endocannabinoid (EC) system, its use may have both beneficial and harmful side effects on many other organ systems. In addition, although the activation of these receptors plays a vital role in numerous physiological processes, including memory, mood, pain sensation, sleep patterns, energy metabolism, and immune function, the effect of cannabinoids can also be mediated via CB receptor-independent pathways, details of which are beyond the scope of this article. Hence, there are a large number of disease conditions, which can be targets of cannabis research, including anxiety, cachexia, obesity, metabolic syndrome, atherosclerosis, depression, emesis and nausea, epilepsy, hypertension, multiple sclerosis (especially for spasms), and rheumatoid arthritis. Furthermore, cannabis users may encounter cardiovascular, pulmonary, dental, and other adverse effects related to activation of the EC system (5, 11, 46, 57, 59). Therefore, a thorough understanding of the risks and benefits of cannabis use is essential for future development of its use in the clinical setting.
The kidneys are among the organ systems where CB1 and CB2 receptors are expressed (34), and experimental studies suggest that cannabis can have both beneficial and harmful effects on kidney function (see above). However, there is a paucity of human studies examining not only the impact of cannabis use on healthy kidneys, but also on kidney function in patients with preexisting kidney disease. As a result of the spreading legalization of marijuana, it is expected that the number of patients exposed to cannabis will continue to increase, and this makes understanding the health effects associated with cannabis use, including the impact on renal function and kidney disease, of paramount importance. Furthermore, the potential cannabinoid-related renal physiological effects raise the possibility of targeting this system for the development of novel therapies in the treatment of different forms of kidney disease.
Cannabinoids and Their Cognate Receptors in the Kidney
In addition to exocannabinoids, a number of endogenous ligands, known as endocannabinoids, have also been readily detected in the circulating blood (54). The best characterized endocannabinoids are N-arachidonoyl ethanolamide, also known as anandamide (AEA), and 2-arachidonoylglycerol (2-AG) (7), which have also been detected in substantial concentrations in renal tissue. This is further supported by the presence of cellular machinery necessary to synthesize and catabolize endocannabinoids in the kidney (25, 50). These arachidonoyl-containing lipid-derived mediators can be produced on demand by the metabolism of cell membrane glycerophospholipids and, typically, are thought to act locally in an autocrine or paracrine manner by interacting with two distinct receptor types, cannabinoid type 1 (CB1) and 2 (CB2) receptors (41). Moreover, 2-AG and AEA can be rapidly degraded by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase, respectively, thereby producing arachidonic acid.
At present, the biological response elicited by exocannabinoids and endocannabinoids in the kidney remains to be fully understood under normal and pathological conditions, in part, because of the complex regulation of endocannabinoid production and catabolism (13, 14, 25, 50). In addition, the unique distribution and temporal expression profile of the CB1 and CB2 receptors within various cell types in the kidney can produce diverse signaling outputs. The two known CB receptors, type 1 and type 2 (41), are categorized as G protein-coupled receptors due to their seven-transmembrane serpentine configuration through the plasma membrane. Many of the signaling outputs controlled by the CB1 and CB2 receptors are sensitive to pertussis toxin, which demonstrates the functional dependency of these receptors on the activation of heterotrimeric G proteins consisting of Gαi subunits (13). The CB1 receptor association with the Gαi subunit can inhibit adenylyl cyclase activity, reduce activity of MAPK, directly control the activation status of ion channels, and stimulate nitric oxide synthase (14, 27). Similarly, CB2 receptors interact with the Gαi subunit to exert an inhibitory effect on adenylyl cyclase activity, but there has been no data to demonstrate any regulatory effect on ion channels (14, 27).
Even though there is a common G protein subunit that facilitates the actions of the CB1 and CB2 receptors, their signaling output can be distinct and, in some cases, lead to opposite biological effects. The diversity of the CB1 and CB2 response on cell signaling pathways remains to be fully described, but likely depends on several factors. First, other Gα subunits, including Gαq/11, have been shown to associate with CB1 to promote a variety of effects, including increased intracellular calcium (28). Second, the relative abundance and distribution of the CB1 and CB2 receptors can differentially change during normal and diseased states. Third, the Gα subunits associated with the CB1 and CB2 may not be localized to the same cell types. As an example, the Gαo subunits, which are primary G protein subunits, interact with CB1 and CB2 in the brain, but are absent in the kidney (47). Fourth, the generation of the diverse signaling outputs observed may be related to other accessory proteins that can interact with the CB receptors, such as G protein-coupled receptor kinase and β-arrestin (13). Lastly, the localization of the CB1 and CB2 receptors in specific cell types, i.e., vascular, tubular, or interstitial, in the kidney could play a crucial role in the distinct signaling output produced by activation of each receptor.
Table 1 provides a summary of the studies describing CB1 or CB2 expression changes and localization in the kidneys from mice, rats, and humans. In human kidneys, CB1 receptor protein has been detected in proximal convoluted tubules, distal tubules, and intercalated cells of the collecting duct (27). In rodents, CB1 receptor protein was also detected in isolated thick ascending limbs of loop of Henle (53), podocytes in the glomerulus (3, 22), and resistance (i.e., afferent and efferent) arterioles (26). In cultured mesangial and endothelial cells, the expression of CB1 and CB2 mRNA has also been detected. Furthermore, CB2 receptor expression has been reported in cultured proximal tubule (17, 18) or glomerular mesangial cells (6) and sporadically in glomerular podocytes (3, 27). In addition, there are pharmacological studies that have shown that endocannabinoids in the renal vasculature can promote vasodilation via a non-CB1 receptor mechanism, and this may be one possible mechanism responsible for promoting the vascular effects of CB ligands in the kidney (61).
Summary of CB1 and CB2 receptor localization in mammalian kidneys
|Animal Model||Kidney Region/Cell Type||Expression||Technique Used to Measure Changes|
|Sprague-Dawley rat (18)||Whole kidney||+||RT-PCR, WB|
|Sprague-Dawley rat + STZ (19)||Whole kidney||+ (↑)||WB|
|Wistar rat + STZ (33)||Whole kidney||+ (↑)||RT-PCR, WB|
|Sprague-Dawley rat + HFD (21)||Whole kidney||+ (↑)||WB|
|ZDF rats (22)||renal cortex (PCT, Glm)||+ (↑)||RT-PCR, IHC|
|Wistar rats (53)||isolated TAL||+||WB|
|Sprague-Dawley rat (26)||afferent/efferent arteriole||+||RT-PCR|
|CB1 transgenic mice (15)||Whole kidney||+ (↑)||RT-PCR, WB|
|db/db mice (43)||Glm||+ (↑)||IF|
|C57BL/6 mice (control) (29)||kidney cortex||−||IHC|
|C57BL/6 mice (UUO) (29)||Kidney cortex (interstitial, tubules, Glm)||+||IHC|
|C57BL/6 mice + cisplatin (39)||whole kidney||+ (↔)||RT-PCR, WB|
|Human kidneys (27)||PCT, DT, IC CD||+||IHC|
|Sprague-Dawley (18)||Whole kidney||+||RT-PCR, WB|
|Sprague-Dawley + STZ (17)||Whole kidney||+ (↑)||WB|
|Sprague-Dawley + HFD (20)||Whole kidney||+ (↓)||WB|
|Wistar rat (53)||isolated TAL||−||WB|
|C57BL/6 + STZ (3)||Glomerulus||+ (↔)||IF|
|Human Type 2 Diabetic (3)||Glomerulus||+ (↓)||IF|
|Human kidneys (27)||kidney cortex||−||IHC|
STZ, streptozotocin; HFD, high fat diet; ZDF, Zucker diabetic fatty; UUO, unilateral ureteral obstruction; PCT, proximal convoluted tubule; Glm, glomerulus; DT, distal tubule; IC CD, intercalated cells of the collecting duct; BV, blood vessels; TAL, thick ascending limb of Henle; +/−, presence or absence of transcript or protein expression. The change in expression, if any, is shown as an increase (↑), decrease (↓), or no change (↔). The molecular techniques used to identify the expression of the cannabinoid 1 (CB1)/CB2 receptors were RT-PCR, Western blot analysis (WB), immunohistochemistry (IHC), and immunofluorescence (IF).
Given the role of these ligands in the activation of the CB receptors under physiological conditions, dysregulation in the synthesis and metabolism of various components of the EC system in disease states has the potential to have pathophysiological consequences.
Physiology and Signaling Pathways of the Cannabinoid System in the Kidneys From Animal Model Studies
Under normal conditions, the endocannabinoid system plays a critical role in renal homeostasis, as related to the control of renal hemodynamics and tubular sodium reabsorption, in large part through the activation of the CB1 receptor (6, 15, 26, 30, 49, 53).
Renal vasculature and blood flow regulation.
The systemic cardiovascular effects mediated by the endocannabinoid system have been extensively studied and reviewed elsewhere (35, 45, 48). To date, however, there remains limited information as to the specific effects of endocannabinoids on renal hemodynamics, including control of blood flow parameters and its direct impact on blood pressure. Intravenous administration of AEA was found to decrease glomerular filtration rate and increase renal blood flow in rats (26). In vitro juxtamedullary preparations demonstrated that AEA could vasodilate either the afferent (6) or efferent arterioles (6, 26) to regulate glomerular filtration rate by activating nitric oxide-dependent pathways through the CB1 receptor. Another study showed that infusion of AEA into the renal medullary interstitium led to a rapid diuretic effect through a CB1-dependent mechanism (30). Similar increases on renal blood flow and its associated rise in urine flow may also involve a metabolic breakdown product of AEA, which could act through a non-CB1 receptor mechanism (49). No change in systemic blood pressure was measured, even with alterations in renal medullary blood flow (49).
Renal tubular epithelial cells.
To determine whether a tubular component was involved in the CB1-dependent increase in urine flow, isolated thick ascending limbs of Henle’s loop (TAL) were tested for sodium transport and oxygen consumption ( Fig. 3C ). Sodium transport through Na + /H + exchanger and sodium-potassium-chloride cotransporter, and oxygen consumption in TAL was inhibited by the activation of CB1 receptors, an effect mediated via the nitric oxide synthase axis (53). These studies demonstrate that the increased urine and sodium output may be a combination of both vascular and tubular control exerted by the EC system via the CB1 receptor, but further genetic and pharmacological studies are needed to determine whether renal control mechanisms activated by the CB receptors are capable of manipulating blood pressure regulation.
Cannabinoid receptor signaling in renal glomerular and tubular epithelial cells. Cannabinoid 1 (CB1) receptor activation activates distinct pathways in the podocytes/mesangial cells of the glomerulus (A), proximal tubule (B), and thick ascending limb of Henle (C). ROS, reactive oxygen species; NOX, NADPH oxidase; CARM1, coactivator-associated arginine methyltransferase 1; AMPK, 5′ AMP-activated protein kinase; ERK, extracellular signal-regulated kinase; PPARγ, peroxisome proliferator-activated receptor gamma; IL-1β, interleukin-1β; SOCS3, suppressor of cytokine signaling 3; ICAM-1, intercellular adhesion molecule 1; TNF-α, tumor necrosis factor-α; NO, nitric oxide; NOS, nitric oxide synthase; iNOS, inducible nitric oxide synthase; TGF-β, transforming growth factor-β; CCR2, C-C motif chemokine receptor 2; PARP, poly ADP ribose polymerase; BK, bradykinin receptor; AT-1, angiotensin type 1 receptor; PKC, protein kinase C; PKA, protein kinase A; PA, palmitic acid; PLA2, phospholipase A2; BV, blood vessels; TRPV1, transient receptor potential vanilloid 1; DAG, diacylglycerol; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate.
The physiological function of CB1 and CB2 receptors in the glomerulus under normal conditions remains to be fully elucidated; however, genetic or biological perturbations that lead to changes in CB receptor levels or activity have provided valuable insights regarding the role of CB1 and CB2 in the glomerulus ( Fig. 3A ). For instance, in the CB1 transgenic mice, overexpression of the CB1 receptor throughout the kidney, including the podocytes and mesangial cells of the glomerulus, was associated with increased urinary protein excretion (15). Proteinuria was also detected in normal rats following treatment with a selective CB1 agonist, WIN55212-2 (15). Increased stimulation or production of the CB1 receptor was found to elevate VEGF synthesis with a concomitant decrease in nephrin (15), which is known to play a central role in controlling podocyte function through its interaction with podocin. These results would suggest that even normal animals that exhibit dysregulation of the CB1 receptor or its activity can develop pathological glomerular defects.
Animal models of renal disease and injury.
Various forms of acute and chronic kidney disease have demonstrated changes in CB receptor expression or activity (1, 3, 22, 43). Biopsied kidney samples from patients with either IgA or diabetic nephropathy have shown elevated expression of CB1 mRNA (29). Concomitant with the increased levels of CB1 receptor, there is evidence that glomerular CB2 receptor levels are decreased in experimental mice and humans with diabetic nephropathy (3, 20). These findings have led to the speculation that modulating CB receptor function and activity may be a viable therapeutic intervention for renal injury and disease.
Chronic kidney disease.
Toward this end, antagonism of the CB1 receptor or activation of the CB2 receptors using selective pharmacological agents have shown to be associated with improvement of the renal structure and function in experimental and genetic models of chronic kidney disease (CKD) (1, 16, 21, 22, 43).
In a mouse model of chemically induced diabetic nephropathy, proteinuria was markedly reduced through the preservation of glomerular podocytes following administration of a selective CB1 receptor antagonist (AM251) (1). Similar findings were observed using genetic rodent models of diabetic nephropathy (22, 43). In db/db mice, chronic blockade of the CB1 receptor resulted in a reduction in microalbuminuria and decreased expansion of mesangial cells in the glomerulus (43). In Zucker diabetic obese rats, CB1 inverse agonist, JD5037, improved renal function and reduced albuminuria after long-term chronic administration (22). On the other hand, activation of the CB2 receptor has been shown to play a protective role in the diabetic nephropathy (3, 20). Functionally, CB2 receptor stimulation using AM1241 has been shown to ameliorate albuminuria, restore podocyte protein expression, and decrease expression of profibrotic markers (collagen type IV and TGF-β) in diet-induced obese rats (20). Similar findings were observed in a study using streptozotocin-treated mice (3).
In other rodent models of CKD, similar protection of the glomerulus was observed in kidneys from rats with diet-induced obesity by blocking the CB1 receptor (21). In addition to the improvement in glomerular function, blockade of the CB1 receptor has been shown to reduce the progression of renal fibrosis in the unilateral ureteral obstruction mouse model (29). The mechanism by which the CB1 receptor antagonism reduces protein excretion may involve VEGF production, which is known to be linked to nephrin expression. In addition, CB1 antagonism may also improve renal function through reduced glomerular and proximal tubular apoptosis (1, 16, 31), although further in vivo studies are needed to confirm these initial in vitro observations.
Acute kidney injury.
In acute kidney injury (AKI), there were initially conflicting results as to the role of each respective CB receptor and their ligands following exposure to ischemia/reperfusion injury or nephrotoxic agents. Feizi et al. (8) showed a dose-dependent effect by both selective CB1 and CB2 receptor agonists to beneficially reduce tubular damage in the kidney following renal ischemia/reperfusion injury. Conversely, administration of cannabidiol, which functions as an antagonist by weakly binding to both CB1 and CB2 receptors, resulted in partial prevention of renal tubular injury following bilateral renal ischemia/reperfusion (9). More recently, CB2 receptor agonists have been shown to reduce markers of renal injury following bilateral renal ischemia-reperfusion (44).
Similar findings were observed in another series of studies using cisplatin-induced renal injury (12, 38–40). Blockade of the CB1 receptor (39) or activation of the CB2 receptor (38, 40) was shown to be protective against tubular damage by attenuating renal oxidative stress and inflammation. Similar protection of the kidney from the deleterious effects of cisplatin was observed using a natural product, β-caryophyllene, which can act as a CB2 agonist (12).
The mechanism by which CB1 and CB2 receptors regulate tubular epithelial cell survival and/or recovery following sublethal damage remains to be fully determined. On a molecular level, renal CB1 mRNA (39) and protein (39, 55) or CB2 protein (55) were not significantly altered using multiple rodent models of AKI. However, biopsied kidney samples from humans with acute interstitial nephritis showed increased CB1 receptor mRNA (29). These molecular differences may be related to the type of AKI and the species from which the kidneys were obtained. Furthermore, although there may be overlap in the distribution of the CB receptors between specific cell types, the physiological outcome of CB receptor activation is likely dependent upon a number of other factors, such as the expression level of CB1 and CB2 receptors relative to each other, the G proteins associated with them, and the type of accessory proteins that are in close proximity of the receptors, which can amplify or dampen the signaling output.
In animal models of AKI, CB1 receptor activation is associated with increased production of reactive oxygen species, which can either activate NF-κβ-dependent transcription of downstream proinflammatory target genes, or alternatively activate p38 MAPK and JNK. In the end, both of these pathways activate programmed cell death by apoptosis ( Fig. 3B ) (39). This was demonstrated in a series of in vitro studies, which found that phospholipase-A2 metabolism of palmitic acid could promote apoptosis by stimulating CB1 receptors (31). Conversely, the role of the CB2 receptor in proximal tubules remains largely unknown, but there is evidence that activation of the CB2 receptor reverses the proapoptotic signaling mediated by the CB1 receptor (38, 40). In addition, activation of the CB2 receptor had an anti-inflammatory effect causing decreased infiltration of immune cells, specifically leukocytes, into the kidney and attenuating inflammatory cytokine release (40). To date, however, the heterotrimeric G protein and accessory protein signaling complexes associated with CB1 and CB2 receptors in the kidney remain to be fully described. The latter point may be significant given the difficulties in predicting the overall outcome of EC system activation based on what is known about the CB receptors at the current time. For instance, a recent study using a bilateral ischemia-reperfusion model of AKI found that renal ischemia-reperfusion injury was associated with a significant increase in kidney 2-AG content. While enhancement of renal 2-AG concentrations using an MAGL inhibitor resulted in improvement of markers of renal function, mRNA expression of genes indicative of renal inflammation (such as cytokines) was unchanged. In fact, there was a nonsignificant trend toward increased expression of these genes (36). Therefore, the totality of EC system activation is dependent on many factors and may be more complex than what is predicted on the basis of CB receptor function alone.
Future studies will need to further define the role of the CB receptors in the context of the endocannabinoid system in health and kidney disease. In addition, mechanistic in vivo studies are needed to decipher how the CB receptors are expressed and activated under different conditions similar to the findings in vitro ( Table 2 ), and which signaling cascades are responsible for the effect observed in each specific pathophysiological scenario. Furthermore, CB receptor-independent mechanisms will also need to be delineated to better understand which effects are due to CB receptor activation. These studies will be vital to future development of therapies targeting aberrant renal CB receptor activity and EC axis in kidney disease. Moreover, a thorough understanding of the different components of the EC system, especially the CB receptors, will be key to future research on the impact of cannabis use on renal physiology and disease.
In vitro changes in CB1 and CB2 receptor expression
|Cell Culture Condition||Cell Type||Receptor||Expression||Technique used to Measure Changes|
|Normal (18)||HK-2||CB1, CB2||+||RT-PCR, WB|
|Normal (52)||LLC-PK1||CB1, CB2||+||RT-PCR, IF|
|Normal (6)||Rat mesangial cells||CB1, CB2||+||RT-PCR|
|EC from renal BV||CB1||+||RT-PCR|
|↑ Glucose (17)||HK-2||CB2||+ (↔)||RT-PCR|
|↑ Glucose + albumin (17)||HK-2||CB2||+ (↓)||RT-PCR|
|↑ Glucose (19)||HK-2||CB1||+ (↔)||RT-PCR, WB|
|↑ Albumin (19)||HK-2||CB1||+ (↑)||WB|
|↑ Glucose + albumin (19)||HK-2||CB1||+ (↑)||RT-PCR, WB|
|↑ Glucose (32)||Rat mesangial cells||CB1||+ (↑)||RT-PCR, WB|
HK-2, immortalized proximal tubule epithelial cell line from normal adult human kidney; LLC-PK1, porcine kidney proximal tubule cell line; EC, endothelial cells; BV, blood vessels. +/−, presence or absence of transcript or protein expression. The change in expression, if any, is shown as an increase (↑), decrease (↓), or no change (↔). The molecular techniques used to identify the expression of the CB1/CB2 receptors were RT-PCR, WB, and IF.
The widespread and increasing recreational and medicinal use of cannabis and its synthetic derivatives has resulted in the exposure of a large number of individuals to these agents. On the basis of mounting evidence detailing the physiological and pathophysiological effects exerted by renal CB1 and CB2 receptor and EC system activation (see previous sections), it is likely that in individuals using these substances, there may be discernible effects on the development and prognosis of both AKI and CKD. Unfortunately, there continues to be a scarcity of epidemiological observations from large-population cohorts regarding such potential effects of cannabis use.
Several reports described the development of AKI in patients exposed to synthetic cannabinoids. A case report of a healthy 22-yr-old male, who smoked an unidentified synthetic cannabinoid (“fake weed”), described the development of AKI, with the kidney biopsy showing acute tubular necrosis (24). Another case report of four previously healthy men consuming the synthetic cannabinoid Spice (also known as K2) described the development of oliguric AKI, with kidney biopsies (performed in three of the individuals) showing changes consistent with tubular necrosis (4). Newspaper reports of clusters of AKI associated with the consumption of synthetic cannabinoids (Spice, or K2) suggest that similar events may be occurring more often than being reported in the medical literature (37, 51). A collaborative investigation by several U.S. State Health Departments uncovered 16 additional cases of AKI associated with synthetic cannabinoid use (42). Most of the available biopsy reports showed acute tubular necrosis, but there were also three reports of acute interstitial nephritis. Because of the illicit nature of the products in these case reports, it is not always possible to identify the components responsible for the kidney injury [nine different street products were identified in the cases where this was available (42)], and the role of noncannabinoid contaminants or adulterant agents in the observed pathology cannot be excluded. It is also unclear whether similar adverse effects could occur with medicinal or recreational cannabis use (as opposed to synthetic cannabinoids). A systematic review of 31 studies (23 randomized controlled trials and 8 observational studies) involving medical cannabis use for an average of 2 wk, described mostly nonserious adverse effects, no cases of acute kidney injury, and only one reported case of hematuria (59).
Information about the effects of cannabis and cannabinoid use on the development and progression of CKD is also very limited. In a single center cohort of 647 patients interviewed about illicit drug use, those who consumed any kind of illicit substance had a significantly higher risk of mild kidney function decline over a 7-yr follow-up period, but the association of marijuana use with kidney function decline was not statistically significant (although the risk was nominally elevated) (58). In a small prospective trial, medical marijuana use for pain control over 1 yr did not result in significant changes in serum creatinine. Lastly, in an observational cohort of 1,225 kidney transplant recipients, recreational marijuana use was not associated with increased risk of death or worse renal allograft function at one year after transplant (10). None of these studies reported albuminuria, and the limited size of the cohorts and the relatively short duration of follow-up make it difficult to determine with certainty the long-term effects of cannabis or synthetic cannabinoids on kidney function.
Future Directions and Research Recommendations
It is plausible to hypothesize that the stimulation of CB1 and/or CB2 receptors and activation of the EC system in the kidneys may have a significant impact on renal function, which could include both deleterious and beneficial effects. Thus, it is important to further elucidate the physiological roles of these receptors and their ligands in experimental models of the kidney disease and renal physiology, as well as the circumstances under which their stimulation or blockage could result in renal damage or in beneficial effects. Studies of large cohorts will be paramount to clarify the effects of cannabis and cannabinoid exposure on renal outcomes, including AKI, incident CKD, and worsening or improvement in the progression of established CKD. In addition, cohort studies are especially important to examine deleterious renal (and other) consequences of cannabis exposure, since it would be unethical to conduct randomized controlled trials to study these effects. Finally, randomized controlled trials will ultimately be needed to test the safety and efficacy of potential drugs developed to improve kidney function or alleviate kidney damage based on their effects on CB receptors and EC system in the kidneys.
The use of cannabis (and related) products for both recreational and medicinal use is prevalent, and it is likely to further increase in the near future. Therefore, understanding the consequences of cannabis use on the kidneys and the body as a whole is of significant relevance from a scientific, medical, and public health standpoint. While experimental data suggest that cannabis and cannabinoids could have important effects on kidney function, there is not sufficient evidence from clinical research studies to determine the dangers faced by users of these products in respect to the development of AKI or CKD. Furthermore, it is possible that under certain circumstances, the application of some cannabis-related products could even be beneficial, hence providing a novel potential area of drug discovery to address different forms of kidney disease. Future research is necessary to provide much-needed clarity in this important and dynamically evolving area.
H. Moradi is supported by a career development award from the Office of Research and Development of the Department of Veterans Affairs 1 IK CX 001043-01A2. F. Park is supported by National Institutes of Health R01 DK-90123.
No conflicts of interest, financial or otherwise, are declared by the authors.