Cannabis has been used for millennia for its psychoactive effects, but was illegal and restricted to the cultural margins for much of the recent human history.¹ Beginning around the turn of the 21st century, legislative and regulatory changes have gradually increased the availability of cannabis, or products derived from cannabis, to the point where recreational and/or medicinal cannabis products are available in most countries in the Western Hemisphere and Europe, and this is expanding globally. The pharmacology of phytocannabinoids, molecules derived from the cannabis plant, is fascinating (if at times confusing). Tetrahydrocannabinol (THC) is a partial agonist at cannabinoid receptors CB1 and CB2, and is largely responsible for the psychoactive actions of cannabis; whereas the other widely known phytocannabinoid, cannabidiol (CBD), is a negative allosteric modulator (i.e., a noncompetitive inhibitor) of CB1 with little effect on CB2, but with direct effects at a range of other sites with potential physiological relevance, including transient receptor potential vanilloid 1 and 5-hydroxytryptamine 1A.² Beyond this, cannabis products can contain a myriad of other phytocannabinoids (e.g., cannabinol, cannabigerol, cannabichromene, cannabivarin, and cannabicyclol, to name a handful) and terpenes with diverse and poorly described pharmacology.³

Synthetic compounds that mimic THC (e.g., dronabinol) were approved for use as an appetite stimulant for AIDS-associated anorexia in the 1980s; however, interest and acceptance of medicinal cannabinoids accelerated after the publication of randomized controlled trials demonstrating that a mixture of THC and CBD (Sativex) improved spasticity in multiple sclerosis and that CBD (Epidiolex) reduced seizure frequency in specific treatment-resistant epilepsy syndromes.¹ Cannabinoids have also been shown to be an effective addition to standard therapies for cancer-related nausea and vomiting (although there are now better contemporary treatments) and possibly chronic pain.¹ However, cannabinoids are associated with many different adverse events, including neurologic symptoms such as dizziness, vertigo, nausea or vomiting, fatigue, and altered level of consciousness and are known to have many drug-drug interactions.⁴

It is plausible that cannabinoids may be useful for people with chronic kidney disease (CKD), especially those with advanced CKD or kidney failure, who suffer a high symptom burden of multifactorial etiology. Common symptoms in people with kidney failure include pain, anorexia, and nausea or vomiting, for which cannabinoids have already demonstrated some efficacy in different populations. In addition, CBD could, via action at the transient receptor potential vanilloid 1, be a potential treatment for CKD-associated pruritus.¹ Cannabinoids are metabolized by the liver and a single dose study by Tayo et al. in people with varying levels of CKD (including estimated glomerular filtration rate [eGFR] < 30 ml/min per 1.73 m², but no participants with kidney failure requiring dialysis) found no important differences in the pharmacokinetics of CBD or its metabolites.⁵ Phytocannabinoids are generally highly protein-bound and have a large volume of distribution, making them unlikely to be meaningfully cleared by dialysis.¹ Early studies support further exploration of the potential for cannabinoids in people with symptoms associated with kidney failure. A pilot randomized double-blind placebo controlled cross-over trial that allocated people with pain receiving hemodialysis to an oil containing THC and CBD found that 12 of 15 participants tolerated the active agent for the 8-week treatment period with no significant effects on symptoms.⁶ Two recent randomized controlled trials have examined cannabinoids as treatment for CKD-associated pruritus, with a 60-participant study finding that a cannabis-containing cream significantly improved symptoms compared with placebo (albeit with only a modest −1.1 point difference in itch scores), and a 14-participant randomized crossover study of oral nabilone finding no impact on CKD-associated pruritus, sleep, or quality of life; although there was no difference in adverse events compared with placebo.^7,8

The present study by Sønderskov et al. provides valuable data regarding the pharmacokinetics and safety of THC or CBD in the setting of CKD.⁹ This single center open-label single-dose study from Denmark exposed adults to Sativex (2 sprays providing 4 mg THC and 5 mg CBD) and included a spectrum of eGFR ranging from healthy controls to < 15 ml/min per 1.73 m² and dialysis-dependent (the latter to be reported separately).The challenges of COVID-19 limited their recruitment to 49 participants (20 controls with eGFR > 60 ml/min per 1.73 m², 20 with eGFR between 16 and 30 ml/min per 1.73 m², and 9 with eGFR ≤ 15 ml/min per 1.73 m²). Cannabinoids and their metabolites were quantified using UHPLC-MS over 24-hour blood sampling and 24-hour urine collections. They found exposure to THC, CBD, and cannabinoid metabolites (as measured by maximum concentration and area under the curve) was significantly higher among both CKD groups as compared with controls. The area under the curve for THC, CBD, and cannabinoid metabolites correlated significantly with eGFR (although the correlation with the area under the curve of THC was not significant after adjustment for age, body mass index, and sex). As is common with cannabinoids, intersubject variability was high: the range of area under the curve and maximum concentration for both THC and CBD in both CKD groups also overlapped substantially with controls, which were not fully comparable across demographics and body composition. Adverse effects were mild, without any clear pattern toward more frequent adverse effects in those with CKD compared to healthy controls. The authors appropriately acknowledge limitations of the study to include a single low dose of Sativex, which may not be readily available clinically with only 24 hours follow-up, a focus on total but not free concentrations, and limited representation of stage 5 CKD.

As the first pharmacokinetic data for cannabinoids in people with kidney failure (eGFR < 15 ml/min per 1.73 m²), these data provide a foundation for further studies. The higher exposure to CBD in those with advanced CKD is different from that found by Tayo et al. (who found no differences),⁵ which could be due to a larger sample size in the present study, differences in estimating GFR, and selection of control groups relative to factors that may affect cannabinoid pharmacokinetics other than kidney clearance (e.g., age, sex, and body composition). The 2 studies may also not be comparable given the large difference in CBD dose (5 vs. 200 mg CBD) and it is worth noting that the maximum concentration of CBD in the earlier study was 2 orders of magnitude higher than in the present study (without any serious adverse effects). Additional pharmacokinetic data of other routes, formulations, and doses of THC or CBD are needed across the spectrum of CKD and kidney failure.

So where do we go now? This study simultaneously suggests that cannabinoid levels may be higher in people with advanced CKD, and reaffirms that inter individual differences in cannabinoid pharmacokinetics are imprecise. Extrapolating from this, when prescribing cannabinoids for people with advanced CKD, it makes sense to start with low doses and uptitrate slowly with caution. Nevertheless, this leaves many important questions unanswered. What is the safety and tolerability of various formulations of cannabinoids with extended dosing? Are adverse effects more common, particularly in the elderly and patients with comorbidities, including CKD? The biggest question is whether THC, CBD, or their combination, is efficacious for any of the symptoms commonly associated with CKD and kidney failure. Currently, there is no data to support the routine use of these drugs for any indication in people with advanced CKD. Given the burden of symptoms suffered by many people with CKD, especially those with kidney failure, and the potential of cannabinoids to relieve some of these symptoms, it is important that the above questions are answered by high quality blinded randomized controlled trials that focus on validated, reliable, and responsive patient-reported outcome measures.