Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy

Abstract

OBJECTIVE To assess the effect of oral cannabidiol (CBD) administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with idiopathic epilepsy. DESIGN Randomized blinded controlled clinical trial. ANIMALS 26 client-owned dogs with intractable idiopathic epilepsy. PROCEDURES Dogs were randomly assigned to a CBD (n = 12) or placebo (14) group. The CBD group received CBD-infused oil (2.5 mg/kg [1.1 mg/lb], PO) twice daily for 12 weeks in addition to existing antiepileptic treatments, and the placebo group received noninfused oil under the same conditions. Seizure activity, adverse effects, and plasma CBD concentrations were compared between groups. RESULTS 2 dogs in the CBD group developed ataxia and were withdrawn from the study. After other exclusions, 9 dogs in the CBD group and 7 in the placebo group were included in the analysis. Dogs in the CBD group had a significant (median change, 33%) reduction in seizure frequency, compared with the placebo group. However, the proportion of dogs considered responders to treatment (≥ 50% decrease in seizure activity) was similar between groups. Plasma CBD concentrations were correlated with reduction in seizure frequency. Dogs in the CBD group had a significant increase in serum alkaline phosphatase activity. No adverse behavioral effects were reported by owners. CONCLUSIONS AND CLINICAL RELEVANCE Although a significant reduction in seizure frequency was achieved for dogs in the CBD group, the proportion of responders was similar between groups. Given the correlation between plasma CBD concentration and seizure frequency, additional research is warranted to determine whether a higher dosage of CBD would be effective in reducing seizure activity by ≥ 50%.

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

“…Previous studies have reported increases in liver enzymes, specifically ALP, in dogs receiving CBD orally at doses ranging from 2 mg/kg (twice daily) to 10 mg/kg (twice daily) for 4, 6, or 12 weeks (17,20,21) with increases observed as early as 2 weeks following treatment initiation (20). In our study, one dog in the CBD oil group and one dog in the CBD/THC oil group experienced 2.9-or 3.6-fold increases in ALP from baseline to 24 h following the tenth dose (CBD oil) or fifth dose (CBD/THC oil).…”

“…In mice, oral doses ranging from 3 to 100 mg/kg showed no significant effects on catalepsy (29). In dogs, CBD has shown to be welltolerated at doses ranging from 2 to 2.5 mg/kg twice daily for 4 or 12 weeks (17,21) to 5 or 10 mg/kg twice daily for 6 weeks (20). Indeed, in their critical review report on CBD, the World Health Organization (WHO) concluded that "CBD is generally well-tolerated with a good safety profile (.…”

“…Plasma levels of CBD, THC, and their metabolites were highly variable between dogs in the same treatment group receiving either the ninth dose of CBD oil or THC oil. Others have also observed high variability in cannabinoid (CBD, THC) blood concentrations across dogs in single dose pharmacokinetic studies (16,19) and repeated administration studies (21), which may be explained by differences in absorption rates or cannabinoid metabolism across subjects. Following the ninth dose of the CBD oil (∼53 mg/kg), maximum plasma CBD levels achieved across the four dogs in the CBD oil group (62.3-896.0 ng/mL, at 4, 6, or 24 h post-dose) were comparable to the range in plasma CBD levels achieved across nine dogs (∼130-940 ng/mL) following repeated daily CBD dosing (2.5 mg/kg twice daily) for 12 weeks (21).…”

“…Others have also observed high variability in cannabinoid (CBD, THC) blood concentrations across dogs in single dose pharmacokinetic studies (16,19) and repeated administration studies (21), which may be explained by differences in absorption rates or cannabinoid metabolism across subjects. Following the ninth dose of the CBD oil (∼53 mg/kg), maximum plasma CBD levels achieved across the four dogs in the CBD oil group (62.3-896.0 ng/mL, at 4, 6, or 24 h post-dose) were comparable to the range in plasma CBD levels achieved across nine dogs (∼130-940 ng/mL) following repeated daily CBD dosing (2.5 mg/kg twice daily) for 12 weeks (21). With respect to plasma levels reached following the ninth dose of the THC oil (∼37 mg/kg), at 24 h post-dose, mean plasma THC (18.2 ng/mL) and 11-OH-THC (4.5 ng/mL) across three dogs approximated mean plasma levels reached by eight dogs receiving a cannabis extract (2.7 mg/kg THC + 2.5 mg/kg CBD) for 56 weeks: 22.0 ng/mL (THC) and 6.7 ng/mL (11-OH-THC) (11).…”

“…Dogs have been used in the course of developing the drug safety profile of Cesamet TM (nabilone, a synthetic THC; oral) and Sativex R (a combination of plant-based CBD and THC; buccal spray), both approved drugs in the U.S. and/or Canada for chemotherapy-induced nausea and vomiting (Cesamet TM ), or spasticity or pain in multiple sclerosis or advanced cancer (Sativex R ) (14,15). Published studies in dogs also exist on the pharmacokinetics of CBD (oral; 2-12 mg/kg) or THC (oral; 1.5 mg/kg) (16)(17)(18)(19) and on the safety and/or efficacy of orally administered CBD (17,20,21) or cannabis extracts (11) for 4-56 weeks.…”