Preliminary Investigation of the Safety of Escalating Cannabinoid Doses in Healthy Dogs

Abstract

Objective: To determine the safety and tolerability of escalating doses of three cannabis oil formulations, containing predominantly CBD, THC, or CBD and THC (1.5:1) 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 (1.5:1), 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 (AEs). AEs were rated as mild, moderate, or severe/medically significant.Results: 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). The placebo oils were delivered up to 10 escalating volumes, the CBD oil up to the tenth dose (640.5 mg; ∼62 mg/kg), the THC oil up to the tenth dose (597.6 mg; ∼49 mg/kg), and the CBD/THC oil up to the fifth dose (140.8/96.6 mg CBD/THC; ∼12 mg/kg CBD + 8 mg/kg THC). 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.

Pharmacokinetic and Safety Evaluation of Various Oral Doses of a Novel 1:20 THC:CBD Cannabis Herbal Extract in Dogs

“…The changes in chemistry parameter values were not considered clinically relevant and were likely attributable to changes in feeding or hydration status of the dogs at the time of blood sampling. Lack of changes in hematology or clinical chemistry parameters has been noted in other studies after chronic CHE administration in dogs ( 13 , 17 ). Because of the small sample size and limited duration of CHE administration in this study, uncommon adverse events or biochemical abnormalities may not have been observed.…”

“…The PK of CBD and/or THC after administration of various CHE formulations and dose regimens have recently been published in dogs ( 1 , 12 , 13 , 15 – 17 ). The range of CBD and THC doses previously reported guided the dose range selected for this trial (2–10 mg CBD and 0.1–0.5 mg THC per kg bw), with the exception of those studies using much higher THC doses ( 16 , 17 ).…”

“…However, the specific pharmacological activities of individual cannabinoid metabolites have not been quantified in dogs. One prominent CBD metabolite produced in both humans and dogs is 7-carboxy-cannabidiol (7-COOH-CBD), but was not included in the analytical method because of its purportedly limited pharmacological activity ( 17 , 23 , 26 ). However, should this metabolite be demonstrated to have pharmacological activity in dogs, its inclusion in cannabinoid assays would be warranted in future trials.…”

“…The current study was specifically designed to evaluate subtle neurological changes, with examinations performed by clinicians highly experienced in neurologic assessments, which might explain the absence of reporting of neurological signs in published studies. A safety-specific CHE study in dogs ( 17 ) demonstrated no adverse events utilizing CBD-only doses up to ~62 mg/kg, but increasing and medically significant neurologic adverse events with escalating doses of THC (up to 49 mg/kg) or CBD+THC (up to 12 + 8 mg/kg, respectively). Based on the extremely high THC doses used in that study (up to 98× the maximum THC dose used in this study), even more frequent and severe adverse effects would be expected.…”

“…However, potentially low oral bioavailability of the various CHE formulations used in these studies could account for the relative lack of adverse events noted. For example, the studies noted a mean THC C max of only 69.8 ng/mL after administering a THC dose of ~37 mg/kg to three dogs ( 17 ) and a median THC C max of up to 24.3 ng/mL after administration of 1.5 mg THC/kg bw ( 16 ). These values are substantially lower than the mean THC C max (138.3 ng/mL) in the highest-dose group (only 0.5 mg THC/kg bw) in the current study.…”