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 T max of 1.9–2.3 h) and initially depleted rapidly (mean CBD T 1/2β of 2.3–2.6 h). A prolonged elimination phase (mean CBD T 1/2λ 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.

Low birth weight (LBW) offspring have a higher prevalence of long‐term cognitive impairments, possibly the result of altered blood flow control in the brain. Using a pig model, we tested the hypothesis that LBW progeny exhibit abnormal cerebral hemodynamics and vasomotor control during early developmental stages of growth. At birth, littermate pigs were identified as normal (NBW=1.7±0.1 kg) or low birth weight (LBW=1.2±0.2 kg). Measurements were obtained at 28 d (weaning) and 56 d of age (n=8/group, 4M/4F per group) : i) 28‐d old NBW (28‐NBW; body mass=10.0±0.4 kg); ii) 28‐d old LBW (28‐LBW; body mass=8.0±0.4 kg); iii) 56‐d old NBW (56‐NBW; body mass=23.0±1.0 kg); and iv) 56‐d old LBW (56‐LBW; body mass=17.0±0.8 kg). Cerebral blood flow velocity was measured using Transcranial Doppler ultrasound. Thereafter, pigs were euthanatized, their brains were harvested, weighed and their pial arteries were dissected for pressure myography experiments. Briefly, pial artery vasomotor control was studied in response to a Ca2+‐activated potassium (BK) channel α‐subunit agonist NS1619 (elicits vasodilation; 1e‐10‐1e‐4 M) and sympathetic co‐transmitter neuropeptide Y (NPY; potent vasoconstrictor; 1e‐10‐1e‐4 M). Brain mass and body mass were significantly lower in LBW vs. NBW pigs (p<0.01). Mean cerebral blood flow velocities were similar between LBW and NBW pigs (p≥0.20). Peak systolic velocities were greater (main effect of BW, p<0.01) and reductions in end diastolic velocities approached significance in LBW vs. NBW pigs (main effect of BW, p=0.08). Accordingly, the resistive index was greater in LBW vs. NBW pigs (main effect of BW, p<0.01). The maximum vasodilator response to NS1619 was not significantly different between LBW and NBW pigs (p=0.12). However, the overall magnitude of dilation (area under the curve) was lower in LBW vs. NBW pigs (main effect of BW, p<0.05). The maximum vasoconstrictor response to NPY was greater in LBW vs. NBW groups (main effect of BW, p<0.05). Similarly, the overall magnitude of constriction was greater in LBW vs. NBW pigs (main effect of BW, p<0.01). With respect to cerebral hemodynamics and vasomotor control, no main effects of age were observed (p≥0.50). Results from this study show that LBW pigs display alterations in cerebral hemodynamics as well as cerebral vasomotor control that persist for at least 56 days. Impaired BK channel function and enhanced vasoreactivity to sympathetic co‐transmitter NPY may underlie altered cerebrovascular hemodynamics in LBW pigs. Support or Funding Information SHRF Establishment grant (#4522) and NSERC