Regarding the epilepsy study specifically, it is important work because we are constantly searching for an effective anticonvulsant drug to treat epilepsy in dogs. The drugs we currently have available frequently cause intolerable side effects or do not work well enough to control the seizures. Therefore, if CBD does prove to be an effective anticonvulsant, this would affect thousands of dogs worldwide.”
Without studies and regulations, many of the CBD products on the market are untested and unregulated. When asked if pet owners should be wary of these products, Dr. McGrath said, “Yes, the lack of regulation is of great concern. Not knowing the exact constituents and quantities of those constituents in a particular product is scary, especially with the knowledge that at certain doses, THC can be toxic to dogs. Hopefully, this market will change in the future.”
Why Studies on CBD & Dog Seizures Matter
She explained, “The study is testing CBD on dogs with epilepsy in a controlled research setting. The dogs enrolled in the study are randomly assigned to receive either a placebo or the CBD oil for 12 weeks and then, after a 4-week washout period, receive the opposite drug for an additional 12 weeks. The researchers and the owners are blinded as to which drug is given in each half of the study.”
The AKCCHF’s CBD study could be the first published, large-scale study to examine the effects of CBD on seizure activity in dogs. “This clinical trial is important for several reasons,” Dr. McGrath shared. “Generally speaking, the science supporting CBD use in veterinary medicine is lacking. There is abundant anecdotal evidence, but very few, if any, well-executed research studies.
AKCCHF Epilepsy Initiative
It can sometimes feel like there is nothing we can do to help our dogs, especially with diseases like epilepsy. That is part of what makes the AKCCHF studies so exciting. Dr. Brown suggested two ways owners and enthusiasts can help:
The interest in cannabis preparations in the treatment of epilepsies, particularly drug refractory childhood epilepsies, has skyrocketed in recent years. Marijuana and other cannabis products with moderate to high THC content utilized primarily for recreational purposes are generally unsuitable for this indication, not only because evidence for an anti-seizure activity of THC is equivocal and risk of seizure aggravation cannot be excluded,101 but also because THC is associated with many undesired effects, including addiction liability, psychiatric disorders, cognitive and motor impairment125–127 and, possibly, also cardiovascular toxicity.128 The maturing brain is also more vulnerable to the adverse of effects of marijuana,126,129,130 and there is evidence of THC impairing structural and functional connectivity during brain development.126,129,130 Discontinuation of THC after prolonged exposure can also lead to withdrawal manifestations131,132 and cases have been reported of seizure exacerbation after marijuana cessation in people with epilepsy.133
In preclinical studies, CBD has been found to be active in a variety of seizures models, including seizures induced by maximal electro-shock39–41 and by pentylentetrazole in rats and mice,42–44 audiogenic seizures in rats45 and seizures induced by 3-mercaptopropionic acid, bicuculline, picrotoxin, cocaine and isoniazid (but not strychnine) in mice.39,45,46 In addition, CBD shows protective activity in pilocarpine models of temporal lobe seizures and in the penicillin and cobalt models of focal seizures in rats,47–49 and increases the afterdischarge threshold while reducing afterdischarge amplitude and duration in electrically evoked kindled seizures in rats.50 CBD also inhibits epileptiform potentials induced by a Mg 2+ -free medium and 4-amino-pyridine in hippocampal brain slices.42
Recently, the anticonvulsant profile of CBD was re-evaluated using a refocused screening protocol developed by the National Institute of Neurological Disorders and Stroke (NINDS)-funded Epilepsy Therapy Screening Program.41 In this investigation, CBD given intra-peritoneally (i.p.) produced a dose-dependent protection against maximal electroshock-induced seizures in mice (ED50 83.5 mg/kg) and rats (ED50 88.9 mg/kg), and was also found to be effective in the 6 Hz 44 mA seizure model (ED50 164 mg/kg), and in the corneal kindling model (ED50 119 mg/kg) in mice. These effects were observed at doses that did not cause motor impairment. No protection, however, was attained in the lamotrigine-resistant amygdala kindled rat at doses up to 300 mg/kg.
CBD is highly bound to plasma proteins (> 99%)63 and is extensively metabolized by cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2C19,66 and glucuronyltransferases.67 The major metabolic pathway involves hydroxylation and oxidation at C-7, followed by further hydroxylation in the pentyl and propenyl groups.68 The major oxidized metabolite identified is cannabidiol-7-oic acid containing a hydroxyethyl side chain. The elimination of CBD follows a biphasic pattern, with an initial half-life of about 6 hours which partly reflects distributive processes. Because of its very high lipophilic properties, CBD distributes extensively into tissues, from which it is slowly released, resulting in a late-phase terminal half-life of about 24 hours.63 In a safety and pharmacokinetic study in patients with Dravet syndrome, 27 children aged 4 to 10 years received CBD doses of 5, 10 or 20 mg/kg/day in addition to pre-existing antiepileptic drugs (AEDs).69 On treatment day 22, exposures to CBD and its major metabolites were found to increase dose-proportionally.
Double-blind trials in Lennox-Gastaut syndrome
The history of human use of the Cannabis plant goes back to the dawn of mankind. The plant, which originated in Central Asia or in the foothills of the Himalayas, was initially cultivated in China for fiber and seed production, and in India for resin production.1 For many centuries, European and East Asian societies have used mostly Cannabis strains containing low amounts (< 1% dry weight) of the psychoactive principle 9-Δ-tetrahydrocannabidiol (THC), and their main utilization was for fiber and food. Conversely, African, Middle-Eastern, South Asian, and Southeast Asian societies have used cannabis primarily for its psychoactive properties, with strains from these regions often containing 5–10% THC.1
Overall the results of these trials demonstrate that at dosages of 10 to 20 mg/kg/day CBD is superior to placebo in reducing the frequency of drop seizures in patients with Lennox-Gastaut syndrome. Published reports, however, provide no information on concomitant therapies, and most notably whether, and to what extent, the clinical improvement on CBD therapy could be related to elevation in serum concentrations of other medications, most notably clobazam and N-desmethylclobazam.
Compared with THC, CBD shows a better defined anticonvulsant profile in animal models considered to be predictive of efficacy against focal and generalized seizures. Moreover, CBD is largely devoid of adverse psychoactive effects, and is considered to lack the abuse liability associated with THC-containing products.134 In the last decade, this has led to an increasing use of CBD-enriched extracts as a potential treatment for epilepsy, particularly in children. Improvement in seizure control, often associated with additional benefits on sleep and behaviour, have been reported in a sizeable proportion of cases,87 but interpretation of these data is made difficult by the uncontrolled nature of the observations. Additionally, as discussed in this article, there are concerns about the quality and variability of many of the products used,98 particularly because cannabis treatment is often initiated spontaneously by patients or caregivers without adequate medical supervision.105
Pharmacological profile in experimental models of seizures and epilepsy
The list is not exhaustive and not all reported actions may be relevant to anti-seizure activity.
In the second trial, 225 patients with Lennox-Gastaut syndrome (mean age 16 years, median number of drop seizures per month at baseline 85) were randomised to three groups and allocated to two doses of CBD (10 or 20 mg/kg/day) or placebo.124 Enrolled patients were receiving a median of 3 concomitant AEDs. Duration of the trial was 14 weeks (2-week titration and 12-week maintenance). The reduction in monthly frequency of drop seizures was significantly greater in the CBD 20 mg/kg group (42%) and 10 mg/kg group (37%) than in the placebo group (17%; p = 0.0047 and 0.0016, respectively, Fig. 4 ). The proportion of patients with a ≥ 50% decrease in drop seizure frequency was also significantly greater in the 20 and 10 mg/kg groups (40% and 36%, respectively) than in the placebo group (15%; p = 0.0006 and p = 0.0030, respectively). Total seizures were also significantly reduced in both CBD groups compared with placebo. Adverse events were reported in 94% of patients allocated to 20 mg/kg, 84% of those allocated to 10 mg/kg, and 72% of placebo patients, the most common being somnolence and decreased appetite. Serious treatment-related adverse events occurred in five patients in the 20 mg/kg group, two patients in the 10 mg/kg group, and no patients on placebo patients. Some elevations in transaminases were seen. Of 212 completers, 99% entered an open-label extension study.