Clinical Trials - Safety in Cats and Dogs - 2019

Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats - 2019

Kelly A. Deabold, Wayne S. Schwark, Lisa Wolf, and Joseph J. Wakshlag

The purpose of this study was to determine the pharmacokinetics and preliminary safety of an oral canine whole-plant CBD-infused soft chew and oral feline CBD-infused fish oil. It was hypothesized that there would be no significant changes in complete blood count (CBC) or serum biochemistry values and that the only adverse effects observed would be associated with oral administration of the product, particularly in cats.

Eight fasted, healthy, purpose-bred research Beagle dogs with a mean age of 3.2 years ranging from 11 months to 5 years of age, weighing an average of 9.7 kg (7.4 to 12.0 kg), were included in the study. The dogs were offered ElleVet Mobility Chews (ElleVet Sciences; Portland, ME, USA) at a dose of 2 mg/kg twice daily for 84 days. Small chews contained 10 mg of CBD as a 50% mix of CBD (5 mg per chew) and CBDA (CBDA—5 mg per chew). Large soft chews containing approximately 15 mg of CBD (equal mix of CBD/CBDA) were also used in the study.

Prior to the start of and every 4 weeks over the course of the study, 5 mm of blood was collected via jugular venipuncture in sterile syringes. Samples were split into two tubes, a red top coagulation tube and an ethylenediaminetetraacetic acid tube. Red top tubes were spun in a refrigerated centrifuge for 15 min at 1512× g after being allowed to clot for 10 min. Blood samples were packaged and sent priority-overnight for analysis to ANTECH Diagnostics (Fountain Valley, CA, USA). A white blood cell count, red blood cell count, hemoglobin, hematocrit (HCT), Mean corpuscle volume, mean corpuscle hemoglobin concentration, mean corpuscle hemoglobin, and platelet count along with a complete differential was performed. A serum chemistry screen was performed consisting of, albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, calcium, chloride, cholesterol, creatinine, creatine kinase, gamma glutamyl transferase, glucose, globulin, magnesium, phosphorus, potassium, sodium, total bilirubin, total protein, triglycerides, and urea nitrogen.

Eight fasted, healthy, purpose-bred domestic shorthair research cats with a mean age of 4.5 years ranging from 2–6.3 years of age, weighing an average of 4.2 kg (3.3 to 5.2 kg) were included in the study. The cats were dosed with CBD-infused fish oil (50/50% mix of CBD and CBDA; ElleVet Sciences; Portland, ME, USA) at 2 mg/kg. The total dose per 24 h period was 4 mg/kg, for 84 days. The initial pharmacokinetic dosing was done with capsules to ensure consumption and all cats were fasted from the previous day and were not fed until 6 h after initial dosing.

Prior to the start of and every 4 weeks throughout the course of the study, 5 mL of blood was collected via jugular venipuncture in sterile syringes. Samples were split into two tubes, processed as described above, and sent priority-overnight for CBC and serum chemistries to ANTECH Diagnostics (Fountain Valley, CA, USA). The same parameters as described previously were measured.

On the first day of dosing, 3 mL of blood was collected for a pharmacokinetic (PK) analysis from only 6 of the 8 dogs and cats in the study at each time point.

Dogs were observed for signs of adverse events twice a day for the 12-week study. Out of 1344 total observation periods, 53 adverse events were reported. Loose stool was the most common adverse event noted among the eight dogs and occurred 44 times (3.3% of the time).

Cats were observed for signs of adverse events twice a day for the 12-week study for a total of 1344 observation periods. The main adverse effects noted included licking and head shaking, which were observed 476 (35.4%) and 339 (25.2%) times, respectively. Other adverse events noted were pacing (n = 150, 11.1%), and chomping/chewing (n = 88, 6.5%).

In this uncontrolled preliminary study dosing of 2 mg/kg twice daily mixture of CBD and CBDA showed no abnormalities in weekly physical examinations, nor any evidence of organ dysfunction as assessed by blood parameters. The canine CBD-infused chews showed no ALP elevations, with no ALP values falling outside the reference range (5–131 U/L) for any dog in the study.

The absorption of CBD in the fish oil base is less than in dogs using plant oil bases, hence larger doses may be necessary for pharmacological effects. This information is important for feline practitioners that are considering the use of CBD products in cats for anxiety, arthritis, house soiling, seizure activity, or neoplasia.

The absorption of CBD in the fish oil base is less than in dogs using plant oil bases, hence larger doses may be necessary for pharmacological effects. This information is important for feline practitioners that are considering the use of CBD products in cats for anxiety, arthritis, seizure activity, or neoplasia.

In conclusion, hemp-based CBD appears to be relatively safe in healthy populations of dogs and cats, and dogs appear to absorb CBD better than cats. The lack of serum chemistry alterations in both species is comforting as it relates to preliminary toxicity findings; however, use of CBD-rich hemp products requires monitoring of liver enzyme values.

Citations: https: //www.ncbi.nlm.nih.gov/pmc/articles/ PMC6826847

Animals (Basel). 2019 Oct; 9(10): 832.

Clinical Trials - Preliminary Investigation of the Safety of CBD in Escalating Dosing in Dogs

Dana Vaughn, Justyna Kulpa, and Lina Paulionis

Objective: To determine the safety and tolerability of escalating doses of three cannabis oil formulations, containing predominantly CBD, THC, or CBD and THC vs. placebo in dogs.

Design: Randomized, placebo-controlled, blinded, parallel study.

Animals: Twenty healthy Beagle dogs (10 males, 10 females).

Methods: Dogs were randomly assigned to one of five treatment groups (n = 4 dogs per group balanced by sex): CBD-predominant oil, THC-predominant oil, CBD/THC-predominant oil, sunflower oil placebo, medium-chain triglyceride oil placebo. Up to 10 escalating doses of the oils were planned for administration via oral gavage, with at least 3 days separating doses. Clinical observations, physical examinations, complete blood counts, clinical chemistry, and plasma cannabinoids were used to assess safety, tolerability, and the occurrence of adverse events. Adverse events were rated as mild, moderate and severe.

Results: Of the three cannabinoid oil formulations tested, dose escalation of the CBD-predominant oil formulation was the most tolerated by dogs up to a maximum dose of 640.5 mg CBD (~62 mg CBD/kg) and only mild AEs were experienced. Dose escalation of the CBD-predominant oil formulation was shown to be as safe as placebo and safer than dose escalation of oils containing THC (CBD/THC oil or THC oil). AEs were reported in all dogs across the five groups and the majority (94.9%) were mild. Moderate AEs (4.4% of all AEs) and severe/medically significant AEs (0.8% of all AEs) manifested as constitutional (lethargy, hypothermia) or neurological (ataxia) symptoms and mainly occurred across the two groups receiving oils containing THC (CBD/THC oil or THC oil).

Conclusions and clinical significance: Overall, dogs tolerated dose escalation of the CBD oil well, experiencing only mild AEs. The favorable safety profile of 10 escalating doses of a CBD oil containing 18.3–640.5 mg CBD per dose (~2–62 mg/kg) provides comparative evidence that, at our investigated doses, a CBD-predominant oil formulation was safer and more tolerated in dogs than oil formulations containing higher concentrations of THC. Of the three cannabinoid oil formulations tested, dose escalation of the CBD-predominant oil formulation was the most tolerated by dogs up to a maximum dose of 640.5 mg CBD (~62 mg CBD/kg) and only mild AEs were experienced.

Citations: https: //www.ncbi.nlm.nih.gov/pmc/articles/ PMC7029731/

Front Vet Sci. 2020; 7: 51

A Report of Adverse Effects Associated with the Administration of Cannabidiol in Healthy Dogs

Journal of the American Holistic Veterinary Medical Association (JAHVMA). Article first appeared in Volume 52, Fall Issue, 2018.

1) The purpose of this study was to determine the tolerability of cannabidiol (CBD) by healthy dogs. The scientists hypothesized that CBD would be tolerated in a healthy population of dogs. A group of 30 healthy Beagle dogs were randomly assigned to receive CBD in the form of microencapsulated oil beads (capsule), CBD-infused oil, or CBD-infused transdermal cream at a dose of 10 mg/kg/day or 20 mg/ kg/day for 6 weeks. Complete blood counts, chemistry panels, urinalysis, and bile acids were performed at 0, 2, 4, and 6 weeks.

2) Clinically significant results were recorded as binary data indicating the presence or absence of the clinical outcome. Contingency tables were constructed for each of the analyses; and the Fisher's exact test was used to evaluate the significance of association between the formulations at each time point, and between the time points within each formulation for both doses of CBD. A P value of 0.05 was used to determine statistical significance.

3) Throughout the 6-week study period, gastrointestinal upset was the most frequently recorded adverse clinical sign. All of the dogs in the study developed diarrhea, and 6/30 (20%) dogs had single episodes of vomiting. The dogs that vomited were in the groups that received CBD orally in the form of capsules.

4) Erythematous pinnae was the second most common adverse clinical sign reported at week 2 and 4. A mild erythematous reaction of the pinnae occurred in 11 dogs (36%), 9 of whom belonged to the group that received the transdermal cream.

5) Limitations of this study include the lack of a control group and the short duration of the study period. Each dog served as its own control but an actual control group would have helped to confirm if adverse effects were secondary to CBD versus other causes, such as being housed in an unfamiliar setting or eating unfamiliar food especially with regard to the diarrhea.

Reference

https://www.ahvma.org/wp-content/uploads/AHVMA-2018-V52-CannabisAdverseEffects.pdf