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. 2020 Feb 11;7:51.
doi: 10.3389/fvets.2020.00051. eCollection 2020.

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

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Free PMC article

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

Dana Vaughn et al. Front Vet Sci. .
Free PMC article

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.

Keywords: CBD—cannabidiol; THC—tetrahydrocannabinol; adverse events; canine; cannabinoids; safety.

Figures

Figure 1
Figure 1
Total number and severity (mild, moderate, severe) of AEs experienced across five escalating doses of SF oil placebo (n = 4) and CBD/THC oil (n = 3 or 4) and 10 escalating doses of MCT oil placebo (n = 4), CBD oil (n = 4), and THC oil (n = 3 or 4). There were no moderate or severe AEs experienced with CBD oil and SF oil.
Figure 2
Figure 2
Total number of mild AEs per anatomic category. Mild AEs accounted for the majority (94.9%) of AEs. (A) Mild AEs across 10 doses of MCT oil placebo (n = 4), CBD oil (n = 4), or THC oil (n = 3 or 4). (B) Mild AEs across five doses of SF oil placebo (n = 4) or CBD/THC oil (n = 3 or 4). Gastrointestinal = nausea, vomiting, diarrhea, or other (hematemesis or blood or mucus in stool); Constitutional = lethargy, hyperesthesia, hypothermia, or other (weight loss, hypertonia, eyebrows raised and no blinking, abnormal posture, vocalization); Neurological = tremor (including hiccups) or ataxia; Ocular = mydriasis or other (epiphora, conjunctivitis, blepharospasm); Dermatological = pruritus or other (skin ulceration, purpura, alopecia, erythema, granuloma); Respiratory = nasal discharge or bradypnoea; Cardiovascular = bradycardia; Otic = external ear inflammation; Genitourinary = urinary incontinence or hematuria.
Figure 3
Figure 3
Average number (SEM) of AEs per dog per administered dose of oil. (A) Ten doses of MCT oil placebo (n = 4), CBD oil (n = 4), or THC oil (n = 3 or 4) were administered. (B) Ten doses of SF oil placebo (n = 4) and five doses of CBD/THC oil (n = 3 or 4) were administered.
Figure 4
Figure 4
Rectal temperature (mean ± SEM) after the 4th dose of the cannabinoid oils or the 6th dose of the placebo oils, measured on the same calendar day. (A) MCT oil (n = 4) vs. CBD oil (n = 4; 137.3 mg CBD) vs. THC oil (n = 4; 109.6 mg THC). (B) SF oil (n = 4) vs. CBD/THC oil (n = 4; 105.6/72.5 mg CBD/THC). Rectal temperature was measured pre-dose (time 0) and 1, 2, 3, 4, 6, and 9 h post-dose. The dotted line corresponds to a rectal temperature of 36.0°C, below which the dogs were considered to have hypothermia.
Figure 5
Figure 5
Plasma levels (mean ± SEM) of CBD, THC, and their metabolites (7-COOH-CBD, 11-OH-THC) pre-dose, and at 1, 2, 4, 6, and 24 h following the 9th dose of (A) CBD oil (549.0 mg CBD; n = 4) or (B) THC oil (448.2 mg THC; n = 3). Following exposure to the CBD oil, levels of 11-OH-THC were not detected or were below the lower level of quantitation in the majority of dogs. Following exposure to the THC oil, there were no detectable levels of CBD or its metabolite (7-COOH-CBD).

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