This is the first study describing the pharmacokinetics of CBD in cattle after oral administration. Since the legalization of marijuana, companion animal and horse owners have been using cannabis to treat a multitude of medical conditions (9). The increased interest in used cannabis for its therapeutic effects has driven research into the safety and efficacy of the drug for all animal species.

Initial studies described CBD in companion animals, specifically dogs. Bartner et al. (2) investigated the pharmacokinetics of CBD in healthy dogs given three formulations of the drug: oral microencapsulate oil bead, oral CBD-infused oil, and CBD-infused transdermal cream. The PK parameters were determined after a single dose administration, as well as long term administration over 6 weeks. This study's results showed that the oral CBD-infused oil formulation had higher systemic exposure than the transdermal cream or microencapsulated oil bead and had a half-life of 3.2 h with a 75-mg dose (~10 mg/kg body weight per day) and 2.1 h with a 150-mg dose (~20 mg/kg body weight per day) (2). At these doses, it appeared that the clearance systems were not saturated, suggesting that evaluating our data using first-order kinetics was appropriate. Another PK study on dogs administered CBD within an enriched oil, reporting a half-life of 4.2 h (1). These studies were the basis for our study design.

More recently, Kleinhenz et al. (7) reported the PK parameters of industrial hemp administered orally in 10-week-old cattle. Specifically, they characterized the PK of cannabidiolic acid (CBDA), the precursor to CBD. The geometric mean maximum concentration of CBDA was 72.7 ng/mL and was found at 11.82 h. The geometric mean half-life was reported at 14.1 h, which was substantially longer than that reported for CBD in dogs (1, 7). Additionally, Kleinhenz et al. only found 2 of 8 calves with detectable CBD in their plasma, likely due to a much lower dose of CBD administered based on calf body weight compared to our work reported here. In that study, calves received an average dose of 0.57 mg/kg (range −0.52–0.63) CBD compared to 5 mg/kg in the current study (7).

The half-life reported here of 23.02 h is increased compared to CBDA following oral administration of industrial hemp in cattle, supporting that a longer persistence of cannaboids in cattle compared to dogs, regardless of the source. In the current study, plasma concentration of CBD remained prominent to the 48 h sampling time, with little decrease in plasma following development of the peak concentration (Figure 1). As a result, the extrapolated portion of the AUC_0−∞ was slightly more than the 20% that is generally considered as acceptable. This represents one of the weaknesses of the current study. Time points for this study were chosen from canine and equine studies. However, given the extended compound presence found for cattle in this study, an extended study of plasma level would be beneficial to get a more accurate assessment of total drug exposure and to gain further insight into the determination of CBD clearance and a potential withdrawal time following CBD administration to food producing species.

The results from this study were suggestive of a low bioavailability high variability of CBD after oral administration in cattle, which was expected based on the study results of other CBD studies. Canine PK studies have demonstrated highly variable bioavailability of 0–19% (1). Other dog and human PK studies of oral cannabis extracts have also found variable and low bioavailability, reporting that only 5–10% of the drug reaches its target site (9). A review of CBD pharmacology, reports oral absorption of the drug seems to be less bioavailable and more variable when compared to drug absorption via inhalation (10). Some of the variability may be explained by the preparation of the CBD in oil as standardized procedures product preparation may not be utilized. While oil extraction is known to more efficacious and less variable than water extraction, the lack of standard preparation could lead to CBD compound differences between company products (11). Within the production companies formulation of CBD compounds can also vary. According to one of the co-authors (JB), the formulation of the CBD compound can be altered which may improve bioavailability, which could serve as the investigatory basis of future work. Variability of CBD may also be affected by the stability of the product. Pacifici et al. (12) found 15–20% of cannabinoids in oil are lost in the first 14 days of storage at 4° C in darkness, but remains stable following the initial decrease for up to a year. Another study in to the stability of CBD, investigated CBD degradation at different temperatures and exposure to air oxygen. The study revealed stability for a period of 180 days for product in oil stored at 25 and 40°C in a closed vial not exposed to air oxygen. Significant degradation, up to 20%, was seen in products with an open vial exposed to air oxygen as early as 90 days (13). Storage conditions may lead to degradation of the CBD within the product, which may lead to some of the variability seen and needs to be taken into consideration when using CBD products.

Calf 6,523 had the lowest C_max and AUC and showed a significant deviation in apparent clearance and apparent volume of distribution from the other calves. The individual deviation observed could be attributed to the low bioavailability of CBD administered orally or to a failure of the calf to consume the CBD. We do not believe that the latter is the cause as we closely observed drug administration. Further conclusions cannot be drawn from this observation as there are no plasma bioavailability studies completed in cattle. Future work to determine oral bioavailability of CBD in cattle is required to make definitive conclusions. Additionally, the forestomachs of calves of this age are not active therefore absorption of orally administered drugs may be similar to that of monogastric animals. Given this, investigation into CBD absorption in ruminating cattle is warranted. Drug absorption differences between pre-ruminating and rumination cattle may change the pharmacokinetics of CBD.

The results of this study have implications for CBD as a therapeutic agent in cattle. In past studies it has been found that even with low bioavailability, CBD had been reported to have good clinical responses. A study completed in dogs found CBD given at 2 mg/kg produced a median maximum plasma concentration of 0.102 ug/mL (range −0.61–0.132 ug/mL) and had positive therapeutic implications. In that work, CBD reduced pain scores and increased activity in osteoarthritic dogs compared to dogs that received the placebo (9). Although CBD is not approved in cattle, obtaining similar maximum plasma concentrations in cattle could lead to its use for pain relief, appetite stimulation, and inflammatory modulation. Determination of PK parameters, can guide administration procedures and study design for future investigations into the therapeutic efficacy of CBD in cattle.

This study provides preliminary results describing the fate of the CBD upon oral uptake in cattle. From here, further work can be completed to describe the bioavailability and drug depletion from tissues of CBD. Additionally, investigation into the effectiveness of CBD as a therapeutic agent is required for cattle and other livestock species.