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.

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 RESULTS 2 dogs in the CBD group developed ataxia and were withdrawn from the study.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%.

[1]  Anup D. Patel,et al.  Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes , 2018, Epilepsy & Behavior.

[2]  Sangeeta Rao,et al.  Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. , 2018, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[3]  FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy , 2018, Case Medical Research.

[4]  Anup D. Patel,et al.  Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome , 2018, The New England journal of medicine.

[5]  Anup D. Patel,et al.  Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome , 2018, Neurology.

[6]  Eric Marsh,et al.  Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial , 2018, The Lancet.

[7]  J. Szaflarski,et al.  Interactions between cannabidiol and commonly used antiepileptic drugs , 2017, Epilepsia.

[8]  Rongrui Tang,et al.  Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. , 2017, The New England journal of medicine.

[9]  H. Volk,et al.  Investigating the potential of the anti-epileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy , 2017, BMC Veterinary Research.

[10]  Anup D. Patel,et al.  Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial , 2016, The Lancet Neurology.

[11]  Shery Jacob,et al.  A simple practice guide for dose conversion between animals and human , 2016, Journal of basic and clinical pharmacy.

[12]  L. Hanuš,et al.  Cannabinoids and Cytochrome P450 Interactions. , 2016, Current drug metabolism.

[13]  M. Podell,et al.  2015 ACVIM Small Animal Consensus Statement on Seizure Management in Dogs , 2016, Journal of veterinary internal medicine.

[14]  M. Podell,et al.  International veterinary epilepsy task force consensus proposal: diagnostic approach to epilepsy in dogs , 2015, BMC Veterinary Research.

[15]  E. Thiele,et al.  Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy , 2015, Epilepsia.

[16]  K. Knupp,et al.  Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy , 2015, Epilepsy & Behavior.

[17]  E. Maa,et al.  The case for medical marijuana in epilepsy , 2014, Epilepsia.

[18]  D. Rusakov,et al.  Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses , 2013, Proceedings of the National Academy of Sciences.

[19]  I. McGonnell,et al.  Questionnaire-based behaviour analysis of Cavalier King Charles spaniels with neuropathic pain due to Chiari-like malformation and syringomyelia. , 2012, Veterinary journal.

[20]  F. Guimarães,et al.  Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors. , 2012, Journal of psychiatric research.

[21]  S. Platt,et al.  Canine idiopathic epilepsy: prevalence, risk factors and outcome associated with cluster seizures and status epilepticus. , 2012, The Journal of small animal practice.

[22]  Benjamin J. Whalley,et al.  Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures , 2011, Seizure.

[23]  T. Bisogno,et al.  Effects of cannabinoids and cannabinoid‐enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes , 2011, British journal of pharmacology.

[24]  H. Volk,et al.  Behavioral changes in dogs associated with the development of idiopathic epilepsy , 2011, Epilepsy & Behavior.

[25]  Benjamin J. Whalley,et al.  Cannabidiol Displays Antiepileptiform and Antiseizure Properties In Vitro and In Vivo , 2010, Journal of Pharmacology and Experimental Therapeutics.

[26]  Holger A Volk,et al.  The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. , 2008, Veterinary journal.

[27]  O. Devinsky,et al.  Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature. , 2007, Reviews in neurological diseases.

[28]  C. Hillard,et al.  Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[29]  B. Hart,et al.  Evaluation of a behavioral assessment questionnaire for use in the characterization of behavioral problems of dogs relinquished to animal shelters. , 2005, Journal of the American Veterinary Medical Association.

[30]  H. Miura.  Zonisamide monotherapy with once-daily dosing in children with cryptogenic localization-related epilepsies: clinical effects and pharmacokinetic studies , 2004, Seizure.

[31]  D. Jackson,et al.  Anticonvulsant effects of cannabinoids in mice: Drug interactions within cannabinoids and cannabinoid interactions with phenytoin , 1974, Psychopharmacologia.

[32]  J. Serpell,et al.  Development and validation of a questionnaire for measuring behavior and temperament traits in pet dogs. , 2003, Journal of the American Veterinary Medical Association.

[33]  J. Serpell,et al.  Development and validation of a novel method for evaluating behavior and temperament in guide dogs. , 2001, Applied animal behaviour science.

[34]  L. Trepanier,et al.  Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996). , 1998, Journal of the American Veterinary Medical Association.

[35]  G. G. Sanwal,et al.  Influence of chronic oral intake of cannabis extract on oxidative and hydrolytic metabolism of xenobiotics in rat. , 1991, Biochemical pharmacology.

[36]  J. Ellison,et al.  Complex partial seizure symptoms affected by marijuana abuse. , 1990, The Journal of clinical psychiatry.

[37]  M. Correia,et al.  Effect of cannabidiol on cytochrome P-450 isozymes. , 1989, Biochemical pharmacology.

[38]  W. Löscher,et al.  Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. , 1985, Journal of veterinary pharmacology and therapeutics.

[39]  H. A. Jensen,et al.  Therapeutic serum concentrations of primidone and its metabolites, phenobarbital and phenylethylmalonamide in epileptic dogs. , 1983, Journal of the American Veterinary Medical Association.

[40]  R. Mechoulam,et al.  Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. , 1982, European journal of pharmacology.

[41]  E. Carlini,et al.  Chronic administration of cannabidiol to healthy volunteers and epileptic patients. , 1980, Pharmacology.

[42]  P. Consroe,et al.  Cannabidiol--antiepileptic drug comparisons and interactions in experimentally induced seizures in rats. , 1977, The Journal of pharmacology and experimental therapeutics.