Abstract
Objective: To determine the pharmacokinetics (PK) and safety of various oral doses of a Cannabis herbal extract (CHE) containing a 1:20 ratio of Δ9-tetrahydrocannabinol (THC):cannabidiol (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 of body weight (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 five 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 T1/2β of 2.3–2.6 h). A prolonged elimination phase (mean CBD T1/2λ 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 five of six 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 (fifth) vs. 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. Because of non-proportional 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.
Highlights
Cannabis-derived herbal extracts (CHEs) are increasingly popular for both human and animal use, with recent legalization of such products in Canada and some European countries and American states
Substantial differences can exist between CHE formulations produced by licensed vs. unlicensed producers, with wide variations in cannabinoid composition and label accuracy [7, 8]
Despite widespread use in pet animals [9], no CHE products have been approved for veterinary use by North American regulatory authorities, and veterinarians cannot legally authorize use of CHE products in their patients
Summary
Cannabis-derived herbal extracts (CHEs) are increasingly popular for both human and animal use, with recent legalization of such products in Canada and some European countries and American states. Most available evidence of cannabinoid toxicity in veterinary species is associated with the accidental ingestion of recreational cannabinoids [10]; assessment of efficacy and toxicity of various CHE formulations is limited in veterinary patients. Such CHE products contain varying amounts of cannabinoids, cannabidiol (CBD) and 9-tetrahydrocannabinol (THC), as well as oil bases or excipients that influence cannabinoid absorption [11]. Before large-scale clinical efficacy trials of CHE products can be performed, in client-owned animals, preliminary assessments of cannabinoid PK, and safety should be performed in a controlled setting. The objective of this study was to generate such data in a colony of teaching dogs after administering various doses of a CBDenriched CHE product containing 1:20 THC:CBD
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