Long-Term Frequent Cannabis Use and Related Serum Cannabinoid Levels Are Not Associated with Kidney Dysfunction

Abstract

Introduction:

Human studies about the impact of cannabis use on both healthy kidneys as well as kidney function in patients with kidney disease are lacking. To shed more light on this understudied topic, we reevaluated a previous clinical study. The sample of this study was exclusively suited for investigating effects of recreational long-term cannabis use on humans under real-life conditions.

Methods:

This special sample had sought and was undergoing inpatient detox-treatment. It was characterized by a lone and considerable cannabis-dependence without any other relevant active comorbidity (except of a concurrent nicotine-dependence). In the present post hoc analysis, we are focused on this sample's routine laboratory tests at admission, including the glomerular filtration rate (GFR), which is the key routine parameter for kidney function assessment. Next, we investigated the association between participants' GFR and their cannabis-related data, including serum cannabinoid levels (Δ-9-tetrahydrocannabinol and main metabolites 11-Hydroxy-Δ-9-tetrahydrocannabinol and 11-Nor-9-carboxy-Δ-9-tetrahydrocannabinol).

Results:

In the whole sample (N=42; 9 females; mean 28.7 years old), we found five persons (12%; 95% confidence interval [2.1–21.7%]) with a mild kidney dysfunction (GFR; 86–75 mL/min). These persons (two females), however, had reported a stronger nicotine misuse. Furthermore, we found no significant association between the study-populations' GFR and reported cannabis burden (median daily use 2.5 g for 36 months, moderate general symptom-load). Most remarkably, the GFR was also not significantly correlated with the serum cannabinoid-levels.

Conclusion:

Chronic recreational cannabis-use (including its related discomfort) did not affect the kidney function of our almost selectively “cannabis-burdened” population in a relevant manner.

Introduction

Cannabis comprises more than 400 compounds, including more than 100 phytocannabinoids.^1,2 Cannabinoids refer to all ligands of the cannabinoid receptors, that is, the G-protein coupled cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2)-receptors, and include phytocannabinoids, synthetic cannabinoid analogs, and endogenous ligands (endocannabinoids), such as some ethanolamides, anandamide, and 2-arachidonoylglycerol.^1,3 In Western countries, the use of cannabis preparations for recreational and medical purposes is prevalent and increasing, also with regard to medical cannabis.^1,4,5 Therefore, knowing the consequences of cannabis use on body and brain is essential. The psychotropic features of cannabis, including their potential to produce addictive behavior have guided intense scientific, medical, and public health research. Meanwhile, we know a lot about the risks and benefits of cannabis use for mammalian and human behavior as well as for several brain functions.^1–4 While we have some information about the impact of cannabis on the heart, lung, gastrointestinal tract (GI-tract), and endocrine functions,^1–4 surprisingly no clinical data have been published concerning the influence of cannabis on human renal function.^1,6,7 However, experimental data suggest that cannabis and cannabinoids could exert both, harmful and beneficial effects on kidney.^1,6,7 Animal models of kidney diseases have revealed that an imbalance of cannabinoid receptor signaling with dominant CB1-receptor activation over CB2-receptor activation can give rise to oxidative stress, inflammation, cell dysfunction, apoptosis, and fibrosis.^1,6,7

The main psychotropic phytocannabinoid represents Δ-9-tetrahydrocannabinol (THC), which is metabolized primarily to the psychotropic and hydrophilic 11-Hydroxy-Δ-9-tetrahydrocannabinol (THC-OH) and the nonpsychotropic and lipophilic 11-Nor-9-carboxy-Δ-9-tetrahydrocannabinol (THC-COOH).^1,8 Both compounds are mainly excreted into urine, especially if glucuronidated. The excretion of THC, mainly as acidic metabolites, occurs predominantly via feces (70–85%) over days to weeks resulting from relevant enterohepatic recirculation and high protein binding. Merely 15–30% of THC is excreted through the urine, and its high lipophilicity accounts for considerable tubular reabsorption and low renal excretion of the unchanged molecule.^1,8

To shed more light on the influence of chronic cannabis use on kidney function, we performed a post hoc analysis of routine laboratory data of 42 inpatient treatment-seeking cannabis dependents without any other concomitant substance abuse or dependence (except nicotine).^9,10 We included an evaluation of their serum THC, THC-OH, and THC-COOH-levels and its relationships to the kidney function.^9,10

Methods

The data were collected from 2006 to 2011, including patients who were voluntarily admitted to inpatient detoxification treatment to quit their problematic cannabis use.^9,10 The treatment was carried out in a specialized detoxification unit of the psychiatric ward of the University of Duisburg-Essen, Germany.

The present post hoc analysis of data from our previous observational study^9.10 includes patients who (1) were (apart from nicotine) solely dependent on cannabis according to International Statistical Classification of Diseases and Related Health Problems, Revision 10 (ICD-10),¹¹ (2) reported to have used cannabis recreationally daily or nearly daily over the last 6 months, (3) reported to have inhaled cannabis within 24 h before admission, (4) showed no active comorbidity requiring acute treatment, (5) showed no positive drug screen tests except for cannabis, (6) did not report to have used alcohol regularly during the last 6 months, and (7) had %carbohydrate-deficient transferrin (%CDT) ≤1.7.¹² All patients were informed about the background and procedures, and gave written consent, which was approved by the local Ethics Committee of the Medical Faculty of the University of Duisburg/Essen, No 14-57-16-BO).^9,10

For this post hoc analysis, participants were excluded if we had no data about their glomerular filtration rate (GFR) upon admission. The GFR represents the rate at which the primary urine is formed.¹³ For routine reporting, the serum creatinine-based estimated glomerular filtration rate (eGFR) was used and for our purposes, calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.^13,14 The eGFR is the most appropriate routine laboratory result for assessing the kidney function^13,14 and therefore, was used as primary outcome of our post hoc analysis. In healthy young adults, the eGFR is around 120 mm/min and decreases physiologically with age. Table 1 shows the stages of kidney dysfunction as estimated by eGFR.^13,14

Table 1.

Kidney Function of Adults as Estimated by Glomerular Filtration Rate

Description	GFR (mL/min)	Percent of kidney function, %
Normal to highly functioning kidney	>90	>90
Mild decrease in kidney function	60–89	60–89
Mild-to-moderate decrease in kidney function	30–59	30–59
Severe decrease in kidney function	15–29	15–29
Kidney failure	<15	<15

Adopted from Bergström and Helander¹² and Levey et al.¹³

GFR, glomerular filtration rate.

All patients had undergone a physical examination upon admission, including the determination of their body mass index (BMI), drug urine screening, electrocardiogram, and routine laboratory investigation, often including C-reactive protein (CRP).^9,10

For quantitative high-performance liquid chromatography (HPLC) (CDT) and gas chromatography-mass spectrometry (GC-MS)-analyses (THC, THC-OH, and THC-COOH), blood had been centrifuged, and the separated plasma was frozen at −20°C to be sent out to a commercial clinical chemistry laboratory.^9,10 The routine laboratory, including the eGFR, had been analyzed by the certificated hospital laboratory. At times of the measurements, the accepted laboratory reference value indicative for heavy drinking (>210 g ethanol/week/man or >140 g/ethanol/week/woman) was %CDT >1.7 (sensitivity 51.1%, specificity 92.8%).¹² The median %CDT of the study population had been 1.1 (minimum: 0.4, maximum: 1.7).⁹

The general symptom load (discomfort) was determined by the Clinical Global Impression-Severity-Score (CGI-Severity).¹⁵ For an estimation of depression and anxiety levels, we had used Hamilton Depression Rating Score (HAMD) and the Hamilton Anxiety Rating Scale (HAMA).¹⁰ The severity of the cannabis dependence was calculated by the number of fulfilled ICD-10-dependence criteria.¹¹ The severity of the cannabis withdrawal syndrome was determined by the Marihuana Withdrawal Checklist,¹⁶ as measured upon admission (MWC) and 24–36 h (MWC-2) later. All clinical records included a detailed addiction history.^9,10

In this post hoc analysis, we correlated the eGFR-levels with cannabis-related data, comprising serum levels of THC, THC-OH, and THC-COOH, and cannabis history data (amount and duration of the prior daily cannabis use, duration and severity of the cannabis dependence, and severity of the cannabis withdrawal syndrome). Moreover, we considered possible confounders such as age, gender, CRP, BMI, general symptom burden, depression, and anxiety.

Besides descriptive statistics, we performed Welch-corrected t tests for independent groups and Pearson correlations. A correlation coefficient r=0.1 was considered a small association within the sample, r=0.3 a medium, and r=0.5 a large association.¹⁷ We applied the Bonferroni–Holm method to adjust for multiple testing, to preserve a studywise 5% level of significance.¹⁸ The used software was IBM SPSS Statistics version 25.

Results

Sample characterization

The sample of this post hoc analysis consisted of 42 adult patients (9 females, 21.4%) who were predominantly Europeans (97.6%), with a median age of 27 years (Table 2). Patients reported near-daily cannabis use (median 2.5 g/day) over the last 6 months at least (median 36 months), and were all currently dependent on cannabis (median 4 ICD-10 dependence criteria,¹¹ as well as on tobacco (median 20 cigarettes/day; Table 2). All patients reported having inhaled cannabis within the last 8 h before admission. The majority of these patients (N=30) had smoked marihuana, seven persons both marihuana and hashish, and five persons hashish. Sample characteristics and laboratory results are shown in Table 2, which refers also to eGFR, creatinine, CRP, cannabis history data, serum cannabinoid levels as well as psychometric tests (CWS, CGI, HAMA, and HAMD). The burden of disease (discomfort) of the sample was moderate (median CGI-Severity 4 points); the patients' depression and anxiety level was low at baseline (median HAMD and HAMA: 8 and 7.5 points¹⁰ (Table 2).

Table 2.

Sample Characteristics Upon Admission

	N	Mean	Median	SD	Minimum	Maximum
Age	42	28.7	27	7.9	18	52
BMI (kg/m2)	38	22	22	3	17	35
CRP (mg/dL)	26	4.9	1.9	8	0.20	35
ALT (IU/L)	42	23	19.5	11.8	8	158
Renal laboratory
eGFR (mL/min)	42	104.4	105.7	13.5	78.8	126.8
Creatinine (mg/dL)	42	0.93	0.94	0.14	0.71	1.25
Cannabis dependence/history and nicotine
Number of dependence criteria (ICD-10)	42	4.14	4	0.35	4	5
Duration of ICD-10-cannabis dependence (years)	42	10	7	6.7	3	32
Daily cannabis use (g/day)	42	2.5	2.5	1.2	0.5	6
Duration of prior daily cannabis use (months)	42	55	36	62	6	360
Number of daily cigarettes	42	22.4	20	6.5	5	40
Serum cannabinoid levels
THC (ng/mL)	36	13.4	7.2	23.2	0.1	139.7
THC-OH (ng/mL)	37	4.1	1.6	7.9	0.1	50
THC-COOH (ng/mL)	37	151.1	112.9	149.7	6.9	741.4
Psychometry (points)
MWC	41	6.4	6	2.7	2	13
MWC-2	41	8.7	10	3.4	2	16
CGI-Severity	41	4	4	0.6	2	5
HAMD	38	8.9	8	6.5	1	30
HAMA	38	9.5	7.5	6.8	2	30

ALT, alanine aminotransferase; BMI, body mass index; CGI-Severity, Clinical Global Impression-Severity-Score; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Score; ICD-10, International Statistical Classification of Diseases and Related Health Problems, Revision 10; MWC, Marihuana Withdrawal Checklist upon admission; MWC-2, Marihuana Withdrawal Checklist at day 2 postadmission; SD, standard deviation; THC, Δ-9-tetrahydrocannabinol; THC-COOH, 11-Nor-9-carboxy-Δ-9-tetrahydrocannabinol; THC-OH, 11-Hydroxy-Δ-9-tetrahydrocannabinol.

Characterization of the patients with kidney dysfunction

Five (12%; 95% confidence interval [2.1–21.7%]) of the 42 patients had a decrease in kidney function, all mild (eGFR 89–60 mL/min, Table 1) as shown in Figure 1. Their individual eGFR-levels were between 86 and 75 mL/min, and these patients were between 19 and 45 years old (mean [standard deviation {SD}] 26 [11]; BMI 21 (1.5) kg/m², two females). On average (SD), they have smoked daily 30 (7.6) cigarettes and 2.6 (0.4) g cannabis over a period of 41 (32) months; and they had been for 9 (9.2) years dependent on this drug. Mean (SD) cannabinoid levels were THC 5.4 (1.7) ng/mL, THC-OH 1.4 (0.4) ng/mL, and THC-COOH 48.7 (38.2) ng/mL. As true for the psychometric test results, all these aforementioned characteristics of the five persons with mild kidney dysfunction did not differ significantly from their equivalents of the whole sample. The amounts of smoked cigarettes were reported to be lower in the whole sample (p=0.04). One patient had antiretroviral treatment for (asymptomatic) HIV (45-year-old male) and a 19-year-old female with a borderline personality disorder showed laboratory values reflecting an asymptomatic steatosis hepatis (alanine aminotransferase level 158 IU/L, BMI 23 kg/m², CRP 1 [mg/dL]). The other three patients of this sample had no comorbidity.

FIG. 1.

eGFR-profile (mL/min) of the sample (frequency, N=42) upon admission. eGFR, estimated glomerular filtration rate.

Correlation of eGFR with patients' characteristics

We corroborated the physiologically normal strong correlation between eGFR and serum creatinine (r=−0.7).^13,14 All other associations between eGFR and patient characteristics, including cannabis history data and serum cannabinoid levels, were not statistically significant (Table 3).

Table 3.

Pearson Correlations between Estimated Glomerular Filtration Rate and Other Variables

	eGFR
	R	p	N
Creatinine	−0.70	<0.0001*	42
THC	0.18	0.30	36
THC-OH	0.30	0.07	37
THC-COOH	0.28	0.09	37
MWC	−0.05	0.73	41
MWC-2	0.21	0.18	41
HAMD	−0.11	0.52	38
HAMA	−0.16	0.34	38
CGI-S	−0.16	0.34	38
Age	−0.15	0.34	42
BMI	0.06	0.69	42
CRP (mg/dL)	0.03	0.90	26
Cigarettes per day	0.01	0.95	42
ICD-10 criteria	0.04	0.82	42
Daily cannabis use (g)	0.24	0.13	42
Duration cannabis use (months)	−0.15	0.34	42
Duration cannabis dependence (years)	−0.20	0.20	42

^* Statistically significant at the Bonferroni–Holm adjusted α=0.05 level.¹⁸

Discussion

To our knowledge, the present study is the first to document kidney function in chronic cannabis users, and its association with characteristics related to cannabis use. We used a special convenience sample of 42 adult patients with pure cannabis (and nicotine) dependence. We found that this highly selective sample was only marginally affected by kidney dysfunction, since five persons (12%) showed a mild decrease in eGFR. These five persons smoked more cigarettes, on average, than the remaining patients; of whom, two cases showed comorbidity, which might have been responsible for the mild decrease in renal function. Neither cannabis history data nor serum cannabinoid levels were significantly associated with eGFR. The same applied to the severity of the cannabis dependence as well as the general symptom load, including depression and anxiety. Therefore, we did not find evidence that chronic recreational cannabis use, as well as the associated discomfort had a relevant negative impact on the kidney function. However, our results are not in line with the results of some animal experiments to this topic⁷ and did not include checking for microalbuminuria, which is required to gain better estimates of the chronification of a kidney dysfunction.^13,14

This study allows no conclusion about the influence of cannabis on kidney function when used orally or together with nephrotoxic drugs or pharmaceuticals. Special features of this study are the determination of the cannabinoid serum levels, and the opportunity to investigate a selective convenience sample of relatively pure active and chronic cannabis dependents, that is, they showed no other substance abuse and dependence apart from nicotine.^9,10 This allows more specific conclusions about the impact of cannabis on renal function as it would be possible via a more naturalistic convenience cohort. While naturalistic cohorts are normally easier to obtain and much larger than our sample, we needed 5 years to find 42 patients who had no relevant comorbidity and who sought inpatient detoxification treatment for cannabis use only—although the detox ward was located in a Metropolitan area and performed over 500 detoxification treatments per year.^9,10 A further strength of this study was the use of the CKD-EPI formula for our purposes, which is as accurate as the conventional Modification of Diet in Renal Disease Study equation for eGFR-levels <60 mL/min per 1.73 m² and substantially more accurate for values >60 mL/min per 1.73 m².¹⁹

While knowledge about cannabinoid levels in the adult patients' feces is generally lacking, the vast majority of clinical studies on the effect of cannabis on human health and diseases focused on cannabinoid levels in urine and blood (serum/plasma).^1,8,20,21 To detect unknown drugs in a patient, urine is the preferred matrix because of higher drug/metabolite concentrations and longer detection times, no invasive collection procedure, and larger available volumes compared to blood.^8,20,21 In our original study^9.10 we measured cannabinoid levels in the patients' blood serum, which for our previous purposes has the important advantage over urine to be more sensitive to detect relapses and is not susceptible to manipulations by the patients.^8,9,21,22

Nephroprotection by chronic cannabis use

Regular use of uncontaminated cannabis is not excluded to have indeed beneficial effects. For example, by reducing unfavorable consequences of an increased CB1-receptor activity and signaling, such as driving neolipogenesis and progression of renal disorders as demonstrated in several animal models.^1,23–26 From a metabolic point of view, it is interesting that chronic cannabis users are rather lean than obese^27,28 and have less lipogenesis, supposedly due to CB1 receptor desensitization/downregulation, alterations of the endocannabinoid tone, and/or epigenetics changes.^1,23–27 This may be also the case in the kidney, as chronic cannabis use may at least promote renal CB1-receptor desensitization as well as CB1-receptor expression^1,23–26 and by doing so, it “protects” the kidney.^25,26 However, the hypothesis that chronic cannabis use may be beneficial to renal health and diseases awaits first controlled clinical studies, then also considering determination of circulating levels of the main endocannabinoids^24–26 and checking whether these levels are correlated with kidney function.

Limitations

We provided no control group and therefore cannot determine if the 12% of patients (5/42) with mild kidney dysfunction was due to the high cannabis use or just normal for this set of patient population. Furthermore, our information about the inhaled cannabis were based upon self-reports without any opportunity to analyze the real composition and content of the used cannabis preparations as well as its possible contaminations. To fully assess the effect of cannabis ingestion on kidney function, more parameters would be desired (e.g., albuminuria, blood urea nitrogen, creatinine clearance rate from a 24-h urine sample), which, unfortunately, had not been included in our original data collection^9,10 and should be considered in future clinical investigations of the effect of recreational or medical cannabis use on human renal health and disease outcomes. Our findings are further limited by the small sample size which might have failed to include people who would have been constitutionally more vulnerable to a putative cannabis-mediated nephrotoxicity. In this context, it should be mentioned that our sample of selective and long-term adult cannabis users was relatively healthy, especially in terms of thyroid,²⁹ cardiovascular,²⁸ and liver functions.³⁰

Conclusion and Outlook

Altogether, the present study did not reveal a relevant harmful impact of chronic cannabis inhalation on the kidney function of physically healthy adults (apart from nicotine dependence). This view may change in consideration of the intake of synthetic cannabinoids³¹ or nouvelle consumption techniques, for example, dabbing THC-concentrates.³² Most synthetic cannabinoids are stimulating CB1-receptors as potent full-agonists, unlike THC, which is a partial agonist at this receptor type in most cells,³³ including kidney cells and the nephron.²⁶ In this context, there are actually a few patients suffering kidney failure due to acute tubular necrosis or acute interstitial nephritis, which has been attributed to a recreational synthetic cannabinoid use.^31,34 Similar cases are not described for recreational or medical cannabis as far as we know. Whether regular use of uncontaminated (e.g., medical) cannabis could be even beneficial to renal health and diseases would be a worthy subject of controlled clinical studies.

Abbreviations Used

%CDT

%carbohydrate-deficient transferrin

ALT

alanine aminotransferase

BMI

body mass index

CGI-Severity

Clinical Global Impression-Severity

CKD-EPI

Chronic Kidney Disease Epidemiology Collaboration

CRP

C-reactive protein

eGFR

estimated glomerular filtration rate

GFR

glomerular filtration rate

HAMA

Hamilton Anxiety Rating Scale

HAMD

Hamilton Depression Rating Score

MWC

Marihuana Withdrawal Checklist upon admission

SD

standard deviation

THC

Δ-9-tetrahydrocannabinol

THC-COOH

11-Nor-9-carboxy-Δ-9-tetrahydrocannabinol

THC-OH

11-Hydroxy-Δ-9-tetrahydrocannabinol

Authors' Contributions

Guarantor of integrity of the entire study: U.B. Study concepts: U.B., T.B., and M.S. Study design: U.B. Definition of intellectual content: all authors. Literature research: U.B. and T.B. Data acquisition: U.B. and T.B. Data analysis: U.B., T.B., and N.S. Statistical analysis: M.S. Article preparation: U.B., T.B., and M.S. Article editing: N.S. and M.S. All authors read and approved the final article.

Author Disclosure Statement

The authors declare that there is no conflict of interest.

Funding Information

No funding was received for this article.

Cite this article as: Bonnet U, Borda T, Scherbaum N, Specka M (2022) Long-term frequent cannabis use and related serum cannabinoid levels are not associated with kidney dysfunction, Cannabis and Cannabinoid Research 7:5, 670–676, DOI: 10.1089/can.2021.0086.