Safety: Daily Oral Administration of CBD for 28 days in Healthy Dogs was Well Tolerated

Randomized, placebo-controlled, 28-day safety and pharmacokinetics evaluation of repeated oral cannabidiol administration in healthy dogs

M. Vaughn, L. J. Paulionis, J. E. Kulpa

2020

KEY TAKEAWAYS:

• Repeated CBD administration was well tolerated by dogs and no clinically relevant changes were observed related to the administration of any dose of CBD
• Veterinary examinations revealed no clinically important abnormal findings
• No observable differences between groups were detected in motor activity, ophthalmologic examinations, systolic arterial blood pressure (SAP), ECG and complete blood count (CBC) analysis 
• All adverse effects were mild and self-limiting, required no intervention, and occurred across all treatment groups, including the placebo group
• There was a greater frequency in side effects in the 12mg/kg group with hypersalivation being the most common one
• The most notable change was the increase in serum ALP (liver enzyme) activity; these increases began to decrease after 2 weeks of treatment and not all dogs developed this change, suggesting that such increase may not be a hallmark of CBD administration but an adaptive response. The dogs that had higher ALP activity didn´t show any sign of hepatocellular degeneration indicating it is an adaptive rather than adverse response to drug exposure

OBJECTIVES & HYPOTHESIS → The study set out to determine the safety profile of different doses of CBD administered to dogs once daily for 28 days and to ascertain the effect of repeated administration on the pharmacokinetic profile of CBD.

METHODS → A randomized, blinded, placebo-controlled trial was conducted enrolling 20 healthy Beagles (age, 1 year 9 months; body weight, 8 to 15 kg).  Dogs were first assigned to 5 sex-balanced treatment groups (n = 4) and the groups were then randomly assigned to a different treatment condition (CBD oil at 1, 2, 4, or 12 mg CBD/kg or placebo oil). Animal health observations were conducted twice daily by technicians blinded to treatment identity. Dogs were also fitted with accelerometers to determine changes in motor activity. The following outcomes were assessed: animal health observations, veterinary examination results, food consumption, 24-hour activity, body weight, intraocular pressure, tear production, SAP and ECG parameters. These were measured through daily health observations, veterinary examinations, CBC, and serum biochemical analysis. Moreover, dogs were observed for any signs that would not be expected in clinically normal dogs.

RESULTS → Findings indicated that once-daily oral administration of CBD in an MCT oil carrier at 1, 2, 4, or 12 mg/kg for 28 days was well tolerated by healthy Beagles. Veterinary examinations revealed no clinically important abnormal findings and no clinically relevant changes were noted in CBC, serum biochemical, intraocular pressure, tear production, SAP, ECG, or urinalysis data. Ophthalmologic examinations and SAP revealed no abnormal values during the 4-week treatment period that were considered clinically relevant. No clinically relevant findings were noted in ECG results for any dog throughout the study. There were also no observable differences between groups in motor activity. No significant or clinically relevant changes in the 13 measured CBC variables occurred with CBD versus placebo administration. All adverse effects were mild and self-limiting, required no intervention, and occurred across all treatment groups, including the placebo group, albeit the frequency of these AEs was greatest in the 12mg/kg group. The most common gastrointestinal AE in that group was hypersalivation. 

Graphic 1: Total number of various types of gastrointestinal AEs observed during the 4-week treatment period

Moreover, the most notable change occurred in serum ALP activity. 1 of 4 dogs in each of the 2 and 4mg/kg groups and 2 of 4 dogs in the 12mg/kg group had values that exceeded the ALP maximum limit. These increases in serum ALP activity generally began to decrease following 2 weeks of treatment in all 3 of these groups, suggesting an adaptive response. Dogs with high serum ALP activity did not develop any associated clinical signs, and no concomitant increases were noted in other hepatic markers. The finding that no dogs in the 1mg/kg group and not all dogs in the 2, 4, and 12mg/kg groups of the present study had an increase in serum ALP activity suggested that such increases may not be a hallmark of CBD administration and may be an adaptive response in only some dogs. Additionally, a 2012 Expert Workshop summary report prepared by the European Society of Toxicologic Pathology noted that increases in systemic ALP activity in the absence of hepatocellular degeneration in dogs could be interpreted as an adaptive rather than adverse response to drug exposure. Compared with values in the placebo group, mean body weight reductions were significantly greater in the 1, 2, and 4mg/kg groups, whereas differences in weight changes between the placebo and 12mg/kg groups were not significant.

Graphic 2: Mean serum ALP activity at various points; the horizontal dashed line represents the upper reference limit for serum ALP activity. * indicates a significant change in serum ALP activity between week 0 and 4 between the 12mg/kg group and the placebo group.

Repeated, daily oral administration of CBD led to dose-dependent increases in total systemic exposure to CBD and 24-hour trough plasma concentrations in healthy dogs. Following chronic administration, total systemic exposure to CBD increased by approximately 2 to 3 fold from values reached after the first dose in all CBD dose groups. Moreover, as a result of chronic administration, values for AUC0–last increased in a dose-dependent manner, with systemic CBD exposure being 3.3, 6.3, and 10.0 fold higher with CBD administered at 2, 4, or 12 mg/kg versus 1 mg/kg, respectively. For all doses, the t1/2λ of CBD also increased following repeated administration, suggesting less rapid CBD excretion with plasma accumulation. Following chronic administration, dose-normalized values for Cmax were similar for CBD across all CBD doses, suggesting the existence of linear kinetics for all doses including the highest dose (12 mg/mg), and plasma CBD concentrations increased proportionally to the administered dose.