The nephrologist’s guide to cannabis and cannabinoids
Joshua L. Rein
Purpose of review
Cannabis (marijuana, weed, pot, ganja, Mary Jane) is the most commonly used federally illicit drug in the United States. The present review provides an overview of cannabis and cannabinoids with relevance to the practice of nephrology so that clinicians can best take care of patients.
Cannabis may have medicinal benefits for treating symptoms of advanced chronic kidney disease (CKD) and end-stage renal disease including as a pain adjuvant potentially reducing the need for opioids. Cannabis does not seem to affect kidney function in healthy individuals. However, renal function should be closely monitored in those with CKD, the lowest effective dose should be used, and smoking should be avoided. Cannabis use may delay transplant candidate listing or contribute to ineligibility. Cannabidiol (CBD) has recently exploded in popularity. Although generally well tolerated, safe without significant side effects, and effective for a variety of neurological and psychiatric conditions, consumers have easy access to a wide range of unregulated CBD products, some with inaccurate labeling and false health claims.
Importantly, CBD may raise tacrolimus levels.
Patients and healthcare professionals have little guidance or evidence regarding the impact of cannabis use on people with kidney disease. This knowledge gap will remain as long as federal regulations remain prohibitively restrictive towards prospective research.
Keywords : cannabidiol, kidney, marijuana, nephrology, renal
- Cannabis may have medicinal uses for treating symptoms of advanced CKD and ESRD.
- In the context of the opioid epidemic, cannabis could have a therapeutic role in pain management while decreasing opioid prescriptions among patients with CKD and ESRD.
- Cannabis use may have transplant listing implications and may delay candidate listing or contribute to ineligibility, but evaluation criteria vary by center.
- Research regarding kidney outcomes is limited to a few retrospective cohort studies that nephrologists should be familiar with to best address patient concerns.
- With growing acceptance of both medical and recreational cannabis use, future research is warranted to investigate the renal endocannabinoid system and the impact of cannabis use on kidney disease outcomes.
Cannabis (marijuana, weed, pot, ganja, Mary Jane; Fig. 1) is the most commonly used federally illicit drug in the United States. As of December 2019, 33 states and the District of Columbia have medical
cannabis programs. Eleven states and the District of Columbia have legalized recreational use. Several countries worldwide have legalized recreational use whereas many others have medical cannabis
and decriminalization laws. The prevalence of cannabis use more than doubled between 2001 and 2013 in the United States  particularly among people over the age of 50 and even more so among those over 65 years [2&,3,4&,5&]. These age groups are enriched with chronic illness including chronic kidney disease (CKD) that is associated with excess morbidity and mortality .
Cannabis is the dried flower bud of the Cannabis sativa and Cannabis indica plants, and naturally
contains numerous phytocannabinoids. D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most abundant and well described phytocannabinoids, with differing activities and affinities for the ubiquitously expressed Gi/o-protein-coupled cannabinoid receptors CB1 and CB2. THC is the primary psychoactive component of cannabis and is a partial agonist to CB1 and CB2 receptors. In contrast, CBD is nonintoxicating and has little affinity for these receptors but acts as a negative allosteric modulator of CB1 with pharmacological effects on other receptor systems including GPR55, TRPV1, 5-HT1A, adenosine A2A, and nonreceptor mechanisms . Plant breeding has created numerous genetically unique Cannabis chemovars, enhancing certain desired effects. For example, chemovars with a higher concentration of THC are selectively produced for recreational use, because THC activation of CB1 mediates the psychotropic effects of cannabis, whereas medical cannabis generally has higher CBD levels than recreational chemovars, often even exceeding the THC content. In fact, symptom relief may be obtained with THC doses lower than what is needed to induce psychotropic effects. Endogenous cannabinoids are eicosanoids derived from cell membrane phospholipids. The two primary endocannabinoids are anandamide/ N-arachidonoylethanolamine and 2-arachidonoylglycerol, which are the natural ligands for the cannabinoid receptors. The endocannabinoid system is present in many tissues including the kidney where it has been shown to influence renal blood flow [8,9], glomerular filtration rate , fibrosis [11–13], proteinuria [14–21], and tubular function [22–27]. The endocannabinoid system has been comprehensively reviewed elsewhere [28,29&,30] including specific interactions with the kidney [31,32,33&,34&,35–38]. Whole cannabis contains numerous cannabinoid compounds with different affinities, making the predicted cumulative effect on cannabis receptors, and potential renal effects difficult to predict.
Physicians remain poorly educated with respect to cannabis and the endocannabinoid system [39,40&]. The federal stigma against cannabis in the United States, leading up to the Marihuana Tax Act of 1937 and the Controlled Substances Act of 1970, have strongly limited research and prevented teaching about the drug in medical education. State legalized consumption of cannabis is in conflict with federal law where it remains a Schedule I controlled substance without accepted medical use and a high potential for abuse. Despite this, the World Health Organization classifies CBD as having no potential for abuse  and several oral cannabinoid-based pharmaceuticals are U.S. Food and Drug Administration (FDA) approved, having demonstrated efficacy in treating certain medical conditions.
Cannabis derived CBD (Epidiolex) is an FDA approved medication for pediatric epilepsy whereas synthetic THC is FDA approved as dronabinol (Marinol, Syndros), and a synthetic THC analogue as nabilone (Cesamet). The cannabis extract nabiximols (Sativex, THC/CBD 1:1) is approved for medical use outside of the United States.