Cannabidiol (CBD)-containing products are widely commercially available for companion animals, mirroring popularity in human use. Although data on the safety and efficacy of long-term oral supplementation are increasing in dogs, evidence remains lacking in cats. The purpose of these studies was to address gaps in the knowledge around the long-term suitability and tolerance of a tetrahydrocannabinol (THC)-free CBD distillate in clinically healthy cats. The studies were randomized, blinded, and placebo-controlled. The first study supplemented cats with either a placebo oil (n = 10) or with 4 mg/kg body weight (BW) CBD in placebo oil (n = 9) daily, with a meal, for 4 weeks. The concentration of CBD in plasma was measured over 4 h at d0 (first dose) and again at d14 (after 2 weeks of daily dosing). The second study supplemented cats daily with either placebo oil (n = 10) or 4 mg/kg BW CBD in placebo oil (n = 10) for a period of 26 weeks. A comprehensive suite of physiological health measures was performed throughout the study at baseline (week 0) and after 4, 10, 18, and 26 weeks of feeding, followed by a 4-week washout sample (week 30). Postprandial plasma CBD time course data, at both d0 and d14, showed a peak plasma CBD concentration at 2 h after the dose. This peak was 251 (95% CI: 108.7, 393.4) and 431 (95% CI, 288.7, 573.4) ng/mL CBD at d0 and d14, respectively, and the area under the curve concentration was higher by 91.5 (95% CI, 33.1, 149.9) ng-h/mL after 2 weeks of supplementation (p = 0.002). While in the first study the CBD group displayed increased alanine aminotransferase (ALT; 68.7 (95% CI, 43.23, 109.2) U/L) at week 4 compared to the placebo control group [1.44-fold increase (95% CI, 0.813, 2.54)], statistical equivalence (at 2-fold limits) was found for ALT across the duration of the second, long-term study. All other biochemistry and hematology data showed no clinically significant differences between supplement groups. Data presented here suggest that a THC-free, CBD distillate fed at a dose of 4 mg/kg BW was absorbed into plasma and well tolerated by healthy cats when supplemented over a period of 26 weeks.
1 Introduction
Cannabis sativa, also known as hemp, contains hundreds of phytocompounds including cannabidiol (CBD), tetrahydrocannabinol (THC), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and cannabivarin (CBDV) to name a few (1, 2). These compounds differ in their chemical properties and physiological impacts. CBD is the non-psychotropic, and main, component of C. sativa, receiving a wealth of interest over recent years due to its potential for anti-inflammatory, anti-oxidative, neuroprotective, and anti-anxiety effects (3). As such it has made for a promising candidate in many therapeutic areas such as pain management in osteoarthritis, epilepsy, Alzheimer’s disease, multiple sclerosis, and anxiety in humans (3), benefits which may translate to animals (4). CBD, therefore, shows efficacy for a wide variety of conditions which act via numerous pathways linked to the endocannabinoid system (5), and these have been collectively labeled the endocannabinoidome (6), indicating there are several potential modes of action. These include, but are not limited to, G-protein-coupled cannabinoid receptors type 1 and 2 (CB1 and CB2), transient receptor vanilloid type-1 (TRPV1) channel, G-protein-coupled receptor 55 (GPR55) or 119 (GPR119), and peroxisome proliferator-activated receptors (PPAR)α and γ (5). There are also promising effects of CBD in the treatment of neurodevelopmental disorders such as schizophrenia directly and indirectly via dopamine receptors (7). THC, a psychoactive component of C. sativa, is found in small quantities (lower than 0.3%) in hemp extracts (3). When present in combination with CBD during companion animal trials, THC is thought to lead to the observation of more severe dose-dependent adverse events (8).
To date, no regulatory body has deemed the current safety and efficacy literature surrounding CBD sufficient for pets (9). Despite this, the use of CBD products in pets has increased as they have gained traction in the human market (10). Recent publications have demonstrated that 4 mg CBD/kg BW per day administered over a 6-month period in dogs is well tolerated (11) and that a single 4 mg/kg BW dose reduces anxiety during a car journey or separation test (12). Another study evaluating the effect of long-term supplementation of a CBD-rich dose in beagles found that it was generally well tolerated (13). However, due to higher frequency of abnormal fecal scores and a higher alkaline phosphatase (ALP), the authors advised extra caution at a daily 10 mg/kg BW dose compared to 5 mg/kg BW (13). In contrast, very little information exists on the safety of CBD for cats, and there is no current literature on its efficacy in the treatment of disorders.
In one feline CBD tolerance study, eight cats were fed capsules containing 2 mg/kg CBD in fish oil (50:50 mix of CBD and CBDA) twice a day for 12 weeks (14). All biochemistry data were found to be within normal ranges with the exception of one cat which had elevated alanine aminotransferase (ALT) during the treatment, and no further information on health of the cat was provided. The authors heavily caveated that the lack of a control group limited the ability to know whether any of these effects were due to the CBD dose, the carrier oil, or other environmental factors (14). Pharmacokinetic data from the same manuscript established that CBD could be detected in serum for up to 8 h. In another recently published study, CBD pharmacokinetics showed a mean peak CBD value of 282 mg/mL at 2 h following a CBD dose of 1.37 mg/kg (15). These cats were dosed twice a day with a paste comprised of mainly CBD and CBDA (6.4 mg/g and 5.3 mg/g, respectively), with THC, THCA, CBG, and CBGA included at 25-fold lower amounts, and meals were fed 1 h after dosing (15). When comparing dog and cat, data suggest that CBD has a lower bioavailability in cats compared to dogs but with a similar half-life (16). Although food is known to increase bioavailability of CBD in humans (17), there have been no postprandial investigations of CBD distillate given in low doses concurrently with a meal in cats to understand whether this finding is translatable. The CBD-containing anti-seizure drug Epidiolex®, when given to fasted and fed cats in a cross-over design study at a dose of 5 mg/kg BW, identified a higher area under the curve and maximum concentration of CBD in the plasma of fed cats (18).
Here, we describe the findings of a 6-month tolerance study of a single daily 4 mg/kg dose of a THC-free, CBD distillate and an additional four-week postprandial plasma CBD time course study in healthy adult cats.
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