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The use of CBD in conjunction with conventional antiepileptic drugs in dogs with idiopathic epilepsy | VETgirl Veterinary Continuing Education Podcasts

In this VETgirl online veterinary continuing education podcast, we review the use of cannabidiol (CBD) in conjunction with conventional antiepileptic drugs (AEDs) in dogs with idiopathic epilepsy. Not only are seizures a common problem in our canine patients, but idiopathic epilepsy can be an incredibly frustrating and challenging disease to treat. A recent consensus statement on seizure management was released by the American College of Veterinary Internal Medicine, which provides valuable guidance to clinicians when navigating the various AEDs on the market (Podell). If you are like VETgirl here, you may have started receiving questions from owners about the use of CBD for various ailments, including seizures. This is particularly relevant given that the FDA has approved a CBD therapy for humans with drug-resistant epilepsy (USDHHS). Unlike tetrahydrocannibinol (THC), CBD is non-psychotropic and appears fairly safe in dogs. The biggest issue for veterinarians regarding CBD, however, is the lack of studies investigating its safety and efficacy in dogs.

So, McGrath and al based out of Colorado State University (of course) wanted to evaluate the effect of oral CBD in addition to conventional therapies on seizure frequency in dogs with idiopathic epilepsy in a study entitled 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. This was a randomized, blinded, controlled clinical trial. To be included, dogs had to have two or more seizures per month for at least 16 weeks while being treated with at least one AED, and they could not have any anomalies on CBC or biochemical analysis that could explain the seizures. Additionally, they had to have an unremarkable MRI and CSF analysis, negative infectious disease panels, and phenobarbital or bromide levels within a therapeutic range. If the dogs were receiving zonisamide or levetiracetam, the doses must have been in a labeled dose range. Exclusion criteria included any comorbidities associated with a poor prognosis.

Dogs were randomly assigned to a CBD group or a placebo group using a computer-based random number generator. The patient’s AED type and dose at the start of the study was maintained throughout the study. The CBD formulation provided was a CBD-infused oil, given orally at 2.5 mg/kg twice daily for 12 weeks. Again remember that the AEDs were continued unchanged, meaning the only change to the dogs’ medication regimen was the addition of CBD or a placebo. The dogs in the placebo group received the same oil preparation without CBD, and the CBD oil was analyzed to verify component concentrations, including both CBD and THC. A CBC, biochemical profile, and serum phenobarbital or bromide levels were measured at the beginning and end of the 12-week study period, as were neurologic and general physical examinations. A plasma CBD level was measured every 4 weeks. Furthermore, owners kept daily seizure journals, and a response to treatment was defined as a 50% or greater reduction in average monthly seizure frequency from the study start date to study completion. Lastly, a validated behavioral questionnaire consisting of 100 behavioral questions was completed at the start and end dates of the study, which offered monitoring of drug side effects and behavior changes.

Overall, 26 dogs were enrolled in the study, with 12 in the CBD group and 14 in the placebo group. Of these, 17 dogs completed the study, but the other dogs had to withdraw. Reasons for withdrawal included AED adjustment, owner’s inability to comply with appointment schedules, general proprioceptive ataxia, and euthanasia. Interestingly, there were 2 dogs with ataxia that were both in the CBD group, and one of these dogs had improvement in ataxia after CBD discontinuation. One of the placebo dogs was given CBD oil during the final stages of the study (oops!), so only 16 dogs had data included in the study analysis. While a variety of breeds were represented, mixed breed dogs were most prevalent. The dogs were primarily males (11 neutered, 2 intact) with 3 spayed females, and a total mean body weight of 29 kg. The majority of dogs had generalized seizures, with a smaller number that had both focal and generalized in each group. A total of 3 dogs were on phenobarbital alone, and 3 dogs took a combination of phenobarbital, potassium bromide, and levetiracetam. Other dogs were on various combinations of one of these drugs and/or zonisamide.

So, what’s the dope? (Get it!) Perhaps the most exciting finding was that the dogs in the CBD group did have a significantly lower median for the monthly average seizures after treatment! The median dropped by 33%, from an average of 4 seizures per month to 2.7 seizures per month, in the CBD group. There was no change in the placebo group, with a median average of 2 seizures per month before and after the study. However, before we get too excited and run off to start all of our patients on CBD, it is important to note that the actual number of “responders” per group did not differ. Remember that at least a 50% reduction in seizure frequency was required for a dog to be classified as a responder, and in this study, each group had 2 responders. Interestingly, the authors found a negative correlation between mean CBD plasma levels and the percent change in mean seizure frequency. In other words, the higher the plasma CBD level, the greater the reduction of mean monthly seizures. Dogs in the CBD group also had higher increases in alkaline phosphatase (ALP) during the study period as compared to the placebo group. No significant differences in phenobarbital or bromide levels were noted between groups during the study, nor were there differences in the behavioral parameters that were assessed. The authors discuss a variety of limitations of this study, including the small sample size, lack of definitive evidence for selected dosing regimen, and the dependency on clients for accurate recording of seizure activity.

So what can we take away from this VETgirl podcast? Well, we are certainly at the very early stages of investigating CBD and its potential utility in veterinary medicine. This study is an interesting first look at potential anticonvulsant properties of CBD in dogs with idiopathic epilepsy. While CBD did not reduce the number of dogs that, by definition, responded to therapy, it did significantly reduce the monthly seizure frequency. This begs the question, which of these is the more clinically relevant parameter? As veterinarians, we are treating individual patients, and our goal with seizure management cases is to at least achieve this 50% goal in seizure reduction. VETgirl’s take? The evidence from this study may not mean that we will rush to add CBD oil to our AED regimens on epileptic dogs. However the decrease in seizure frequency between groups provides some promise that perhaps there could be a role for CBD in the future or on a case-by-case basis. Certainly more studies are needed to clarify dosing regimens and further investigate the safety and efficacy of such therapies. Perhaps a higher dose would have been more effective in producing responders to therapy, particularly given the correlation between plasma CBD and seizure frequency. Lastly, given that two dogs in the CBD group developed ataxia, alerting owners to this as a potential side effect should be considered.

References:
1. McGrath S, Bartner L, Rao S, et al. 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. J Am Vet Med Assoc 2019;254(11):1301-1308.
2. Podell M, Volk HA, Berendt M, et al. 2015 ACVIM small animal consensus statement on seizure management in dogs. J Vet Intern Med 2016;30:477–490.
3. US Department of Health and Human Services. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. Accessed Feb 13, 2019.

Abbreviations:
AED – Antiepileptic drug
ALP – Alkaline phosphatase
CBD – Cannabidiol
THC – Tetrahydrocannibinol

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