Cannabidiol (CBD)-rich hemp extract use is increasing in veterinary medicine with little examination of serum cannabinoids. Many products contain small amounts of Δ9-tetrahydrocannabinol (THC), and precursor carboxylic acid forms of CBD and THC known as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). Examination of the pharmacokinetics of CBD, CBDA, THC, and THCA on three oral forms of CBD-rich hemp extract that contained near equal amounts of CBD and CBDA, and minor amounts (<0.3% by weight) of THC and THCA in dogs was performed. In addition, we assess the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) to better understand the pharmacokinetic differences between three formulations regarding THC and CBD, and their metabolism. Six purpose-bred female beagles were utilized for study purposes, each having an initial 7-point, 24-h pharmacokinetic study performed using a dose of 2 mg/kg body weight of CBD/CBDA (~1 mg/kg CBD and ~1 mg/kg CBDA). Dogs were then dosed every 12 h for 2 weeks and had further serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectroscopy (LC-MS/MS). Regardless of the form provided (1, 2, or 3) the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar, with only Form 2 generating enough data above the lower limit of quantitation to assess pharmacokinetics of THC. CBDA and THCA concentrations were 2- to 3-fold higher than CBD and THC concentrations, respectively. The 1- and 2-week steady-state concentrations were not significantly different between the two oils or the soft chew forms. CBDA concentrations were statistically higher with Form 2 than the other forms, showing superior absorption/retention of CBDA. Furthermore, Form 1 showed less THCA retention than either the soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the quantitation limit of the assay for nearly all samples. Overall, these findings suggest CBDA and THCA are absorbed or eliminated differently than CBD or THC, respectively, and that a partial lecithin base provides superior absorption and/or retention of CBDA and THCA.

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Pharmacokinetics of Cannabidiol, Cannabidiolic Acid, Δ9-Tetrahydrocannabinol, Tetrahydrocannabinolic Acid and Related Metabolites in Canine Serum After Dosing With Three Oral Forms of Hemp Extract.

Objective: To determine the pharmacokinetics (PK) and safety of various oral doses of a Cannabis herbal extract (CHE) containing a 1:20 ratio of THC:CBD in 13 healthy Beagle-cross dogs. Methods: Single-dose PK was assessed after oral administration of CHE at low, medium, or high doses (2, 5, or 10 mg CBD and 0.1, 0.25, or 0.5 mg THC per kg bw, respectively; n=6 per group). Dogs were monitored for adverse events for up to 48 h post-dose. Evaluations of neurological signs, clinical laboratory abnormalities, and other adverse events were performed in two separate study phases; a multiple-dose phase with 12 dogs receiving 5 medium doses (5 mg CBD/kg bw) at 12 h intervals, and a single low-dose (2 mg CBD/kg bw), randomized, blinded, negative controlled study with 13 dogs. Results: Cannabinoids CBD, THC, CBC and metabolites 6-OH-CBD, 7-OH-CBD, 11-OH-THC, and THC-COOH were quantified in plasma. CBD and THC were rapidly absorbed (mean Tmax of 1.9 – 2.3 h) and initially depleted rapidly (mean CBD T1/2 β of 2.3 – 2.6 h). A prolonged elimination phase (mean CBD T1/2 λ of 13.3 – 24.4 h) was observed. CBD and THC concentrations increased in a dose-dependent (non-linear) manner, with disproportionally greater cannabinoid exposure relative to the dose increase. Neurological signs (hyperesthesia or proprioceptive deficits) were noted in 5 of 6 dogs in the high dose group, but only occasionally or rarely in the medium and low dose groups, respectively. Presence and severity of clinical signs correlated with plasma cannabinoid concentrations. Dogs appeared to develop a tolerance to cannabinoid effects after multiple CHE doses, with fewer neurological signs noted after the final (5th) versus first dose. No clinically meaningful changes in blood count or chemistry values occurred after multiple CHE doses. Clinical significance: Dogs tolerated the 1:20 THC:CBD formulation well at low and medium doses, but clinically meaningful neurological signs were observed at high doses. Due to nonproportional increases in plasma cannabinoid concentrations with increasing doses, as well as potential differences in CHE product composition and bioavailability, the possibility of adverse events and dose regimen consistency should be discussed with dog owners.

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

The development of multidrug-resistant bacteria has revealed the need for new antimicrobial compounds Cannabis sativa preparations have a long history of medical applications, including the treatment of infectious diseases This review collects the information about the activity of C sativa extracts and its main components (cannabinoids and terpenes) against pathogenic bacteria and fungus, to assess its potential using as antimicrobial agents

The antimicrobial effect behind Cannabis sativa.

OBJECTIVE To determine the safety and pharmacokinetics of various doses of plant-derived cannabidiol (CBD) versus placebo following repeated oral administration. ANIMALS 20 healthy adult Beagles. P...

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

Interest is increasing regarding use of Cannabidiol (CBD) in companion animals due to anecdotal evidence of beneficial behavioral and health effects. The purpose of this investigation was to evaluate the influence of CBD on behavioral responses to fear-inducing stimuli in dogs. Sixteen dogs (18.1 ± 0.2 kg) were utilized in a replicated 4 × 4 Latin square design experiment with treatments arranged in a 2 × 2 factorial, consisting of control, 25 mg CBD, trazodone (100 mg for 10-20 kg BW, 200 mg for 20.1-40 kg BW), and the combination of CBD and trazodone. A fireworks model of noise-induced fear was used to assess CBD effectiveness after 7 d of supplementation. Each test lasted a total of 6 min and consisted of a 3 min environmental habituation phase with no noise and a 3 min noise phase with a fireworks track. Plasma was collected 1 h before, immediately after, and 1 h following testing for cortisol analysis. Behaviors in each 3 min block were video recorded, and heart rate (HR) sensors were fitted for collection of HR and HR variability parameters. Research personnel administering treats and analyzing behavioral data were blinded as to the treatments administered. Data were tested for normality using the UNIVARIATE procedure in SAS, then differences examined using the MIXED procedure with fixed effects of treatment, period, time, and treatment x time interaction. Inactivity duration and HR increased during the first minute of the fireworks track compared with 1 min prior (P < 0.001 and P = 0.011, respectively), indicating the fireworks model successfully generated a fear response. Trazodone lowered plasma cortisol (P < 0.001), which was unaffected by CBD (P = 0.104) or the combination with CBD (P = 0.238). Neither CBD nor trazodone affected the duration of inactivity (P = 0.918 and 0.329, respectively). Trazodone increased time spent with tail relaxed (P = 0.001). CBD tended to increase HR (P = 0.093) and decreased the peak of low- and high-frequency bands (LF and HF, P = 0.011 and 0.022, respectively). These results do not support an anxiolytic effect of CBD in dogs given 1.4 mg CBD/kg BW/d.

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The Impact of Feeding Cannabidiol (CBD) Containing Treats on Canine Response to a Noise-Induced Fear Response Test.

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.

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

ObjectivesThe aim of this study was to determine the safety and tolerability of escalating doses of orally delivered cannabis oils predominant in cannabidiol (CBD), tetrahydrocannabinol (THC), or b...

Safety and tolerability of escalating cannabinoid doses in healthy cats.

The present technology relates to a method for treating anxiety or an anxiety-related disorder in an animal subject, the method comprising administering an effective amount of cannabidiol (CBD) to the animal subject.

Justyna E. Kulpa

Papers

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

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

Safety and tolerability of escalating cannabinoid doses in healthy cats.

Methods and compositions for treatment of anxiety in animals