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Safety and efficacy of cannabidiol-cannabidiolic acid rich hemp extract in the treatment of refractory epileptic seizures in dogs

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The use of cannabidiol (CBD) in childhood refractory seizures has become a common therapeutic approach for specific seizure disorders in human medicine. Similarly, there is an interest in using CBD, cannabidiolic acid (CBDA) or cannabinoid-rich hemp products in the treatment of idiopathic epilepsy in dogs. We aimed to examine a small cohort in a pilot investigation using a CBD and CBDA-rich hemp product for the treatment of refractory epileptic seizures in dogs. Fourteen dogs were examined in a 24-week randomized cross-over study being provided placebo or CBD/CBDA-rich hemp extract treatment at 2 mg/kg orally every 12 h for each 12-week arm of the study. Serum chemistry, complete blood counts, serum anti-seizure medication (ASM) concentrations and epileptic seizure frequency were followed over both arms of the cross-over trial. Results demonstrated that besides a mild increase in alkaline phosphatase, there were no alterations observed on routine bloodwork at 2, 6, and 12 weeks during either arm of the study. Epileptic seizure frequency decreased across the population from a mean of 8.0 ± 4.8 during placebo treatment to 5.0 ± 3.6 with CBD/CBDA-rich hemp extract ( P = 0.02). In addition, epileptic seizure event days over the 12 weeks of CBD/CBDA-rich hemp treatment were 4.1 ± 3.4, which was significantly different than during the 12 weeks of placebo treatment (5.8 ± 3.1; P =0.02). The number of dogs with a 50% reduction in epileptic activity while on treatment were 6/14, whereas 0/14 had reductions of 50% or greater while on the placebo ( P = 0.02). No differences were observed in serum zonisamide, phenobarbital or bromide concentrations while on the treatment across groups. Adverse events were minimal, but included somnolence (3/14) and transient increases in ataxia (4/14) during CBD/CBDA-rich hemp extract treatment; this was not significantly different from placebo. This further indicates that providing CBD/CBDA-rich hemp extract during refractory epilepsy (only partially responsive to ASM), in conjunction with other ASM appears safe. Based on this information, the use of 2 mg/kg every 12 h of a CBD/CBDA-rich hemp extract can have benefits in reducing the incidence of epileptic seizures, when used concurrently with other ASMs.
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TYPE Original Research
PUBLISHED 29 July 2022
DOI 10.3389/fvets.2022.939966
OPEN ACCESS
EDITED BY
Luisa De Risio,
Linnaeus Veterinary Limited,
United Kingdom
REVIEWED BY
Fabio Stabile,
Southfields Veterinary Specialists,
United Kingdom
Berta São Braz,
University of Lisbon, Portugal
*CORRESPONDENCE
Gabriel A. Garcia
gabrielagarcia@ufl.edu
SPECIALTY SECTION
This article was submitted to
Comparative and Clinical Medicine,
a section of the journal
Frontiers in Veterinary Science
RECEIVED 09 May 2022
ACCEPTED 04 July 2022
PUBLISHED 29 July 2022
CITATION
Garcia GA, Kube S, Carrera-Justiz S,
Tittle D and Wakshlag JJ (2022) Safety
and ecacy of
cannabidiol-cannabidiolic acid rich
hemp extract in the treatment of
refractory epileptic seizures in dogs.
Front. Vet. Sci. 9:939966.
doi: 10.3389/fvets.2022.939966
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©2022 Garcia, Kube, Carrera-Justiz,
Tittle and Wakshlag. This is an
open-access article distributed under
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original author(s) and the copyright
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original publication in this journal is
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academic practice. No use, distribution
or reproduction is permitted which
does not comply with these terms.
Safety and ecacy of
cannabidiol-cannabidiolic acid
rich hemp extract in the
treatment of refractory epileptic
seizures in dogs
Gabriel A. Garcia1*, Stephanie Kube2, Sheila Carrera-Justiz1,
David Tittle3and Joseph J. Wakshlag3
1Department of Clinical Sciences, University of Florida College of Veterinary Medicine, Gainesville,
FL, United States, 2Veterinary Neurology and Pain Management Center of New England, Walpole,
MA, United States, 3Ellevet Sciences, South Portland, ME, United States
The use of cannabidiol (CBD) in childhood refractory seizures has become
a common therapeutic approach for specific seizure disorders in human
medicine. Similarly, there is an interest in using CBD, cannabidiolic acid (CBDA)
or cannabinoid-rich hemp products in the treatment of idiopathic epilepsy
in dogs. We aimed to examine a small cohort in a pilot investigation using a
CBD and CBDA-rich hemp product for the treatment of refractory epileptic
seizures in dogs. Fourteen dogs were examined in a 24-week randomized
cross-over study being provided placebo or CBD/CBDA-rich hemp extract
treatment at 2 mg/kg orally every 12 h for each 12-week arm of the study.
Serum chemistry, complete blood counts, serum anti-seizure medication
(ASM) concentrations and epileptic seizure frequency were followed over
both arms of the cross-over trial. Results demonstrated that besides a mild
increase in alkaline phosphatase, there were no alterations observed on
routine bloodwork at 2, 6, and 12 weeks during either arm of the study.
Epileptic seizure frequency decreased across the population from a mean
of 8.0 ±4.8 during placebo treatment to 5.0 ±3.6 with CBD/CBDA-rich
hemp extract (P=0.02). In addition, epileptic seizure event days over the
12 weeks of CBD/CBDA-rich hemp treatment were 4.1 ±3.4, which was
significantly dierent than during the 12 weeks of placebo treatment (5.8 ±
3.1; P=0.02). The number of dogs with a 50% reduction in epileptic activity
while on treatment were 6/14, whereas 0/14 had reductions of 50% or greater
while on the placebo (P=0.02). No dierences were observed in serum
zonisamide, phenobarbital or bromide concentrations while on the treatment
across groups. Adverse events were minimal, but included somnolence
(3/14) and transient increases in ataxia (4/14) during CBD/CBDA-rich hemp
extract treatment; this was not significantly dierent from placebo. This
further indicates that providing CBD/CBDA-rich hemp extract during refractory
epilepsy (only partially responsive to ASM), in conjunction with other ASM
Frontiers in Veterinary Science 01 frontiersin.org
Garcia et al. 10.3389/fvets.2022.939966
appears safe. Based on this information, the use of 2 mg/kg every 12 h of a
CBD/CBDA-rich hemp extract can have benefits in reducing the incidence of
epileptic seizures, when used concurrently with other ASMs.
KEYWORDS
dog, seizure, cannabidiol, cannabidiolic acid, phenobarbital, zonisamide
Introduction
Since the 1970’s or earlier, cannabinoids have been found to
have anti-epileptic effects in animal seizure models (1). These
anti-epileptic findings also show that the effects of cannabinoids
were separate from the psychotropic and excitatory effects of
19-tetrahydrocannabidiol (THC) and that CBD exhibited a
lack of central nervous system excitation (1, 2). Following the
approval of a highly purified CBD formulation, licensed in
humans1specifically for the treatment of seizures associated
with Dravet Syndrome, Lennox-Gastaut Syndrome and more
recently Tuberous Sclerosis Complex, there has been a resurgent
interest in the use of CBD for various forms of epileptic activity
in various species (3–5).
In their review article, Franco et al. summate that no
one mechanism appears to be solely responsible for the anti-
epileptic action of CBD (6). Goerl et al. explored the growing
evidence that CBD alone does not solely contribute to the
anti-epileptic properties seen in the use of such preparations
(4). They concluded from their study that hemp extracts
containing increased levels of CBDA also demonstrated similar
anticonvulsant activity in a mouse epilepsy model; the presence
of minor cannabinoids alongside CBDA augmented potency,
providing further conceptual evidence of the “entourage
effect” (4).
The pharmacokinetics, safety and efficacy of a blend of
a CBD/CBDA-rich hemp extract in osteoarthritic dogs at 2
mg/kg in an oil b ase provided orally every 12 h, have been
previously demonstrated (7). Previous work describes CBD
and CBD/CBDA-rich hemp extract administration being safe
at doses between 2 and 10 mg/kg body weight provided as
an orally administered oil (8, 9). Other studies have found
mild adverse events associated with the administration of CBD
to dogs; these gastrointestinal signs were attributed to the
medium-chain triglyceride oil base of the product rather than
the cannabinoids (3).
Various studies in both humans and animals, have
demonstrated epileptic seizure reduction following
1 Epidiolex, Full (2020) Prescribing Information. Greenwich Biosciences
Inc., Carlsbad https://www.epidiolex.com/sites/default/files/pdfs/VV-MED-
03633_EPIDIOLEX_(Cannabidiol)_USPI.pdf (accessed November 23,
2021).
administration of CBD alongside commonly prescribed
ASM (10, 11). Furthermore, McGrath et al. found a significant,
thirty-three percent reduction in epileptic seizure days (seizure
days being defined as one or more events during the day
to account for cluster seizures) in dogs administered CBD,
compared to baseline reported seizure events. Two of nine
dogs in the treatment group showed a fifty percent or greater
reduction in epileptic seizure events (11).
Drug-to-drug interactions between various ASM and
CBD have been explored in numerous studies and review
articles in both humans and animals (3, 6, 10–12). CBD
is metabolized in the liver and the gastrointestinal tract,
via cytochrome P450 (CYP) isoenzymes (13). These enzymes
are also involved in the metabolism of many ASMs, and
so some interaction or inhibition of metabolism could be
anticipated (14). Conversely, McGrath et al. found no significant
difference in serum phenobarbital or bromide concentration
with concurrent CBD administration, during their study
period (11). Additionally, Gaston et al. did report interaction
between some commonly used ASMs and CBD in human
studies with increased serum concentrations of topiramate and
zonisamide, although no information is currently available in
veterinary medicine (14). No effects on serum concentrations
of phenobarbital, levetiracetam, or pregabalin in humans have
been noted (14). This concurs with Doran et al. who found no
variation in canine phenobarbital serum concentration with co-
administration of CBD-rich hemp, further clarifying that CBD-
rich hemp when treating concomitantly with phenobarbital
may not need to be monitored more frequent during co-
administration (3).
Dose-related somnolence and sedation is a commonly
reported side effect of CBD administration (10, 14) and is
of greater magnitude in human patients receiving the ASM,
clobazam. McGrath et al. found no evidence of increased
sedation in their canine study cohort; however there were 2 dogs
that discontinued the study due to ataxia in the CBD-rich hemp
group (11).
The aim of this study was two-fold: (1) determine
whether CBD/CBDA rich hemp extract can help control canine
refractory epileptic seizure patients who are only partially
responsive to commonly utilized ASMs and (2) determine
the adverse events of this treatment through owner survey,
physical examination, serum biochemistry and ASM serum
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Garcia et al. 10.3389/fvets.2022.939966
concentration evaluation during treatment in a 3 month cross
over blinded clinical trial.
Materials and methods
Study participants
The protocol for clinical research was approved by the
University of Florida Institutional Animal Care and Use
Committee (UF-0056-2019) that included two study sites
[University of Florida Small Animal Hospital (UFSAH) and the
Veterinary Neurology and Pain Management Center of New
England (VNPMCNE)] which began in September of 2019 and
terminated in June of 2021. Prior to enrolment, all clients were
provided with a client consent form outlining the study and the
expectations during the research protocol.
Inclusion/exclusion criteria
All dogs initially enrolled (n=10) in the study had prior
magnetic resonance imaging (MRI) and cerebral spinal fluid
(CSF) analysis for infectious or structural lesions. Dogs had
complete blood counts, serum chemistry, pre and post-feeding
bile acids, thyroid hormone assessment and urinalysis to rule
out other metabolic issues as defined by the International
Veterinary Task Force level II confidence (15). All dogs from
this cohort had been treated for over a year and remained
only partially responsive to common highest tolerable doses of
ASM yet still having at least one epileptic event per month as
criteria for enrolment (15). Dogs must have been on the current
medications over the past 3 months with no new additions
of ASM during the time, prior to enrolment. For all dogs, no
new medications could be added throughout the study period,
but alterations in phenobarbital or potassium bromide dosing
could occur, based on adverse events reported by the owner
(i.e., ataxia, excessive lethargy, or somnolence) or blood work
abnormalities (i.e., outside or reference range when monitoring
ASM, adverse hepatic, or renal parameter alterations). All
dogs were required to be negative for infectious disease titers
including all tick-borne diseases, toxoplasma and neospora, as
well as Dirofilaria Immitis. All dogs involved in the study could
not have endocrine issues or organ dysfunction, other than
concomitant osteoarthritis issues and could be on non-steroidal
anti-inflammatories and non-hemp based nutraceuticals, but
owners were informed that the regimen could not be altered over
the 6-month study period.
After initial enrolment, the enrolment criteria was modified
to increase dog numbers as there were patients identified that
had been on ASM for long duration (over 1 year) and showed
no bloodwork or urinalysis abnormalities indicating metabolic
issues, yet the owners were resistant to general anesthesia for
MRI and CSF assessment and were enrolled based on level 1
confidence of the International Veterinary Epilepsy Task Force
(15). Therefore, five dogs without MRI or CSF assessment with
presumed idiopathic epilepsy were enrolled from one institution
(UFSAH). The attending neurologist was confident were these
dogs had signalments of at least a 1-year duration of refractory
epileptic events (one ore more epileptic events per month) that
were being managed on highest tolerable doses ASMs with only
partial responses.
Study design
This study was designed as a randomized placebo blinded
cross over, where dogs were randomized into placebo or
CBD/CBDA-rich hemp treatment for 3 months, using a random
number generator (Randomizer Smartphone App); and then
switched after 3 months with no washout period. Treatment
consisted of a hemp derived cannabinoid therapy in sesame seed
oil. The oil suspension was utilized to make 10, 25, and 50 mg
capsules to be dispensed. Cannabinoid analysis of the product
was 30 mg/mL of CBD, 31 mg/mL of CBDA, 1.2 mg/mL THC,
1.3 mg/mL tetrahydrocannabinolic acid (THCA), 1 mg/mL
of cannabichromene and 1.2 mg/mL of cannabichromic acid.
Placebo was formulated similarly utilizing the same volume of
sesame oil in comparable capsules. All placebo bottles were lined
with a thin layer of cannabinoid depleted terpenes, to provide the
same odor upon opening the bottle to aid in blinding owners to
the treatment vs. placebo and were provided capsules that would
equate to the same number of capsules that were provided from
the treatment phase. For the CBD/CBDA-rich hemp extract oil,
patients were dosed with variations in numbers of capsules as
close to 2 mg/kg body weight every 12 h; medications were
dispensed to provide enough supply to be sufficient between
each 6 week study visit, so that medication residuals could be
assessed for compliance.
Complete blood counts, serum
chemistry, and ASM concentrations
Dogs were re-evaluated at 2, 6, and 12 weeks of each arm
of the cross-over study. At these time points, blood was drawn
to evaluate the complete blood counts, serum biochemistry and
serum ASMs, including zonisamide, phenobarbital and bromide
between 10 a.m. and 4 p.m. after morning dosing before arrival
to the clinic. Serum phenobarbital and bromide concentrations
were evaluated at the University of Florida Veterinary Clinical
Pathology Department, whilst serum zonisamide was evaluated
at the Auburn University Veterinary Diagnostic Laboratory.
A serum biochemistry including sodium, potassium, chloride,
phosphorus, calcium, magnesium, albumin, total protein,
globulin, cholesterol, glucose, alanine aminotransferase (ALT),
aspartate amino transferase (AST), alkaline phosphatase (ALP),
bilirubin, urea nitrogen and creatinine was evaluated at each
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time point. Complete blood counts including white blood
cell, red blood cells, hematocrit, hemoglobin, neutrophil,
lymphocyte, platelet, eosinophil, and basophil counts were
performed at the University of Florida Veterinary Clinical
Pathology Department.
Owner adverse event and epileptic
seizure diary
At the initial visit, owners were provided with a epileptic
seizure diary to log events and cluster activity (i.e., a cluster
of seizures on a single day which is reported as seizure days)
including the date and time that the event was recognized
and any interventions, such as diazepam or oral ASM dosing
beyond the typical regimen. At the end of the 12-week period,
the diary was given to the investigators and the owners were
provided a second diary to utilize for the next 12-week period
of the cross-over design. For each diary the total number
of seizure events were tallied over the 3 month period and
considering some dogs displayed cluster seizures as separate
epileptic events over a period of time in a single day we
also recorded seizure days similar to a prior study examining
CBD-rich hemp use in dogs with idiopathic epilepsy (11). In
addition, success of treatment as a reduction of 50% in seizure
activity was also examined as an outcome that is considered
clinically significant (11). At the end of each 12-week treatment
period, the owners were provided with a survey that utilized
a Likert scale for a series of questions related to adverse
events including diarrhea/vomiting, appetite, thirst/urination,
lethargy/somnolence, ataxia and anxiety behaviors. A similar
scale was used related to seizure severity, seizure frequency
and overall control of seizures during both 12-week periods of
placebo and treatment (see Supplementary material).
Statistical analysis and record screening
Power analysis was performed based on prior pilot work
examining CBD use in dogs with a median of 4 seizures,
that decreased to 2.7 over the duration of the study; a
standard deviation estimate of 1.3 seizures per month resulted
in a presumed population of 16 dogs necessary to establish
significance (11). Initially candidate records were screened based
on MRI and CSF analysis being negative for structural or
inflammatory disease, at the UFSAH and the VNPCNE.
Eight dogs were identified based on records at UFSAH and
solicited, of which only 6 were initially screened at baseline
examination, while 5 dogs at VNPCNE were screened and
enrolled. Of these 11 candidates originally enrolled, only 1
dog discontinued from protocol within the first week, due
to compliance issues (dog resistant to medicating) while
initially taking the treatment medication. All 10 remaining
dogs completed the protocol by the summer of 2020. The
recent pandemic has however, prevented adequate enrolment,
alongside client hesitance to perform anesthesia for MRI and
CSF collection. This led to increasing enrolment to 5 more dogs
that had idiopathic refractory epilepsy with at least 1 epileptic
seizure per month, between June of 2020 and June of 2021. All of
these dogs had partial response to ASM for over 1-year duration,
without confirmation by MRI and CSF, and no alterations in
treatment protocols within the prior 3 months of treatment.
Four of the 5 dogs were recruited and completed the study. The
remaining dog completed the study, but it was later found that
phenobarbital was instituted at the initiation of the study, so the
data were removed from the analysis. Hence, 14 dogs completed
the protocols with adequate data for analysis.
Statistical analysis was performed with a commercially
available software package (JMP 11.0; Cary NC, USA). All data
were assessed utilizing a Shapiro-Wilk test, and residual plots
were examined to determine normality. When normality was
rejected, the data was log transformed before analysis utilizing
a mixed model analysis of variance. Cross-over study variables
included in the model were: fixed effects of treatment, time,
sequence of treatments, treatment ×time, as well as random
effects of the observation period, period nested within dog, time
point nested within period nested within dog. Tukey’s tests were
performed post-hoc on any significant effects of time, treatment
or time ×treatment to assess differences. A p-value of <0.05 was
determined to be significant for all analyses.
Epileptic seizure incidence data from the diaries was
collected and enumerated as a total quantity of seizures in a
12 week period of time, with cluster events counted as separate
events for seizure frequency tabulation; and total number of
seizure days (to account for cluster seizures as a daily event)
were recorded for both placebo and CBD/CBDA-rich hemp
treatment. The total seizure numbers and seizure days during
each 3-month period were assessed for normality and a Student’s
T-Test was performed, with a p-value for significance set at p
<0.05. As ordinal data, the 3-month owner survey questions
related to severity, frequency and overall seizure management
for placebo vs. CBD/CBDA-rich hemp oil treatment periods
was collected and assessed utilizing a non-parametric Wilcoxon
signed-rank test, with a p-value set at p<0.05. For adverse
events (diarrhea, vomiting, ataxia, urination frequency, appetite,
and somnolence/lethargy, anxiety) when a score over the 3
month period was shown to increase to a score of 4 or 5
suggesting an increase in adverse events, then it was classified
as a patient with an adverse event; vs. scores of 3 or less
which were classified as no adverse event. These data were
assessed using a Fisher’s exact test to determine if there were
any significant differences, when comparing the placebo and
CBD/CBDA-rich hemp oil treatment groups with a p-value set
at p<0.05. In addition, responders with a 50% reduction in
epileptic seizure events and days of seizures were also evaluated
using a Fisher’s exact test to determine significance between
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TABLE 1 Complete blood count means and standard deviations at baseline, 2, 6, and 12 weeks of CBD/CBDA-rich hemp oil vs. placebo (n=14) in a
randomized cross over clinical trial.
Parameter (reference range) Baseline 2 wk 6 wk 12 wk P Tx P Time PTx*time
WBC (K/uL) Placebo 8.71 ±2.29 8.71 ±1.90 8.95 ±2.08 8.81 ±2.17 0.68 0.74 0.86
Treatment 9.00 ±2.51 8.92 ±2.84 9.21 ±2.63
RBC (M/uL) Placebo 6.56 ±0.69 6.65 ±0.81 6.51 ±0.74 6.64 ±1.17 0.75 0.64 0.13
Treatment 6.42 ±0.78 6.66 ±0.82 6.48 ±0.81
Hemoglobin (g/dL) Placebo 16.2 ±1.7 16.6 ±1.7 18.6 ±8.1 16.1 ±2.12 0.41 0.36 0.57
Treatment 16.0 ±1.8 16.6 ±1.8 16.6 ±1.9
Hematocrit (%) Placebo 47.1 ±4.8 48.1 ±4.9 47.7 ±4.2 47.1 ±6.6 0.33 0.6 0.29
Treatment 46.1 ±5.1 48.1 ±5.4 46.7 ±4.8
Platelet (K/uL) Placebo 370 ±132 389 ±129 413 ±141 408 ±161 0.1 0.61 0.66
Treatment 385 ±146 373 ±128 366 ±115
Neutrophil (K/uL) Placebo 5.57 ±1.69 5.58 ±1.76 5.84 ±1.66 5.66 ±2.22 0.04 0.82 0.80
Treatment 5.95 ±2.23 5.91 ±2.59 5.79 ±1.59
Lymphocyte (K/uL) Placebo 1.84 ±0.72 1.91 ±0.67 1.92 ±0.72 1.84 ±0.60 0.02 0.96 0.96
Treatment 1.81 ±0.79 1.75 ±0.65 1.81 ±0.73
Monocyte (K/uL) Placebo 0.41 ±0.24 0.42 ±0.20 0.39 ±0.16 0.46 ±0.20 0.51 0.29 0.31
Treatment 0.47 ±0.19 0.44 ±0.25 0.43 ±0.22
Eosinophil (K/uL) Placebo 0.88 ±0.70 0.74 ±0.47 0.78 ±0.51 0.81 ±0.62 0.15 0.37 0.48
Treatment 0.72 ±0.56 0.77 ±0.53 1.10 ±1.22
Basophil (K/uL) Placebo 0.02 ±0.01 0.04 ±0.04* 0.02 ±0.01 0.02 ±0.01 0.61 <0.01 0.84
Treatment 0.05 ±0.08* 0.02 ±0.02 0.02 ±0.02
P-values for treatment, time and treatment over time show no treatment effects.
placebo and CBD/CBDA-rich hemp treatments with a p-value
set at p<0.05.
Results
Animals and recruitment
Of the 14 dogs, the median age at enrolment was 6.3 years
(range 2.9–9.7 years). All dogs were neutered and included 3
females and 11 males. The median body weight at enrolment
was 31.3 kg (range 4.2–40.9 kg). Breeds of dogs represented
in this study were: 6 mixed breeds, 2 Labrador Retrievers,
2 Labradoodles, 1 Siberian Husky, 1 Chihuahua, 1 Golden
Retriever and 1 German Shepherd.
Complete blood count and serum
chemistry
Complete blood counts and serum chemistry evaluations
were performed on all dogs at each time point except for one
dog from the VNPCoNE location, whose bloodwork was not
performed due to a logistical error related to shipment while
on placebo at week 12. All other time points were evaluated in
the mixed model analysis of variance. All data were normally
distributed, except for AST, ALT, and ALP which were log-
transformed before analysis. Complete blood counts showed no
treatment effects for any cell type evaluated over the course
of both placebo or CBD/CBDA-rich hemp extract treatments
(Table 1). There was a time effect showing a significant rise in
basophils at week 2 of both placebo and CBD/CBDA-rich hemp
extract treatment (P<0.05).
Serum chemistry evaluations showed no significant changes
for any serum electrolyte (sodium, potassium, chloride,
phosphorus, calcium, or magnesium) over time or treatment
(data not shown). Hepatic parameters (AST, ALP, bilirubin,
cholesterol, glucose, albumin, and total protein) showed no
significant alterations over time with treatment. Although no
alterations in ALP could be deduced statistically over time
between the groups there was a global treatment effect for ALP
concentrations (Table 2;Figure 1). Renal parameters (creatinine,
urea nitrogen) showed no significant changes over time or with
treatment (Table 2).
Anti-seizure medication and serum
concentrations
All dogs were on 3 or more ASMs consistently for 3
months before enrolment. Thirteen dogs were receiving
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TABLE 2 Serum chemistr y hepatic and renal parameter means and standard deviations at baseline, 2, 6, and 12 weeks of CBD/CBDA-rich hemp oil
vs. placebo treatment (n=14) in a randomized cross over clinical trial.
Parameter (ref/range) Baseline 2 wk 6 wk 12 wk P Tx P Time P Tx*time
AST (U/L) Placebo 28 ±16 29 ±15 30 ±17 39 ±34 0.63 0.63 0.59
Treatment 30 ±18 27 ±15 26 ±9
ALT (U/L) Placebo 76 ±106 69 ±72 70 ±76 113 ±166 0.50 0.95 0.78
Treatment 63 ±47 54 ±37 43 ±22
ALP (U/L) Placebo 362 ±299 446 ±377 465 ±423 542 ±577 <0.01 0.56 0.20
Treatment 664 ±879 707 ±699 617 ±561
Bilirubin (mg/dL) Placebo 0.2 ±0.1 0.2 ±0.1 0.2 ±0.1 0.2 ±0.1 0.13 0.90 0.98
Treatment 0.2 ±0.1 0.2 ±0.1 0.2 ±0.1
Glucose (mg/dL) Placebo 104 ±13 99 ±12 104 ±31 103 ±7 0.88 0.36 0.84
Treatment 98 ±9 98 ±12 101 ±12
Cholesterol (mg/dL) Placebo 234 ±84 251 ±90 229 ±80 219 ±54 0.96 0.25 0.64
Treatment 242 ±77 227 ±63 256 ±70
Albumin (g/dL) Placebo 2.8 ±0.4 2.8 ±0.4 2.9 ±0.3 2.8 ±0.4 0.41 0.45 0.28
Treatment 2.8 ±0.3 2.9 ±0.3 2.8 ±0.4
Globulin (G/dL) Placebo 2.8 ±0.3 3.1 ±0.4 3.1 ±0.4 3.2 ±0.5 0.75 0.29 0.18
Treatment 3.0 ±0.4 3.1 ±0.4 3.1 ±0.4
Urea nitrog. (mg/dL) Placebo 16.2 ±2.6 16.8 ±4.4 16.7 ±4.0 16.8 ±4.7 0.81 0.17 0.54
Treatment 14.9 ±5.8 18.1 ±4.6 18.2 ±3.1
Total protein (g/dL) Placebo 5.6 ±0.5 5.9 ±0.5 5.9 ±0.5 6.0 ±0.7 0.33 0.30 0.13
Treatment 5.8 ±0.5 6.0 ±0.5 5.9 ±0.4
Creatinine (mg/dL) Placebo 0.9 ±0.2 1.0 ±0.2 1.0 ±0.3 0.9 ±0.3 0.56 0.28 0.80
Treatment 1.0 ±0.3 1.0 ±0.3 1.0 ±0.2
P-values for treatment, time and treatment over time show no treatment effects except for ALP where a global treatment effect was noted.
FIGURE 1
Log serum ALP activity shown over 12 weeks in both
CBD/CBDA-rich hemp oil and placebo treatment phases of the
study. No dierences were observed across time or between
groups at any time point, however there is a global treatment
eect with slightly elevated ALP concentrations (P<0.01).
potassium bromide; 11 dogs, zonisamide; 9 dogs were on
phenobarbital; 13 on levetiracetam and one dog, topiramate
(Supplementary Table 1). Alterations in medications were
allowed during the protocol, yet few were observed. Potassium
bromide was increased for one dog while on placebo and for
one dog while on the CBD/CBDA-rich hemp oil. No dogs
receiving zonisamide or levetiracetam had alterations in dosing
throughout the 24-week study. Three dogs had phenobarbital
decreased during the treatment phase, with one dog increasing
the dose during the placebo phase, and one dog decreasing the
dose during the placebo phase. One of the dogs receiving a
lower dose during the treatment phase was maintained on the
lower dose during the placebo phase.
Serum concentrations of ASMs were measured at each time
point throughout the study. Serum zonisamide concentrations
were assessed at all time points for 11 dogs, with the
exception of 2 dogs, whose serum concentrations were not
run at week 2. This was due to lack of serum for one
dog; the second dog’s serum was lost on shipment to the
diagnostic laboratory. Serum zonisamide concentrations were
not significantly different based on treatment or time, and
no alterations due to treatment over time (Table 3). Serum
phenobarbital concentrations were assessed on all 9 dogs being
administered phenobarbital, except for one dog at week 12
during placebo treatment, due to logistical error regarding
submission. Serum phenobarbital concentrations were not
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TABLE 3 Serum concentrations of anti-seizure medications [ASM; potassium bromide (KBr), phenobarbital, zonisamide] that were co- administered
with CBD/CBDA-rich hemp oil vs. placebo treatment measured at baseline, 2, 6, and 12 weeks.
Serum ASM conc. Treatment Baseline Week 2 Week 6 Week 12 P Tx P Time P Tx*time
KBr (mg/mL) Placebo 1.2 ±0.6 1.4 ±0.6 1.4 ±0.6 1.3 ±0.6 0.39 0.79 0.10
(n=13) Treatment 1.2 ±0.6 1.3 ±0.6 1.5 ±0.5
Phenobarbital (ug/dL) Placebo 27.8 ±7.8 30.1 ±4.2 31.1 ±3.2 29.0 ±4.2 0.88 0.90 0.33
(n=9) Treatment 28.8 ±4.9 27.7 ±4.8 31.5 ±7.2
Zonisamide (ug/mL) Placebo 35.8 ±21.0 30.8 ±12.7 36.4 ±16.4 37.6 ±17.3 0.83 0.77 0.37
(n=11) Treatment 38.4 ±14.9 34.8 ±14.3 36.3 ±16.3
No significant differences were observed.
significantly different based on treatment, or over time and no
alterations due to treatment over time (Table 3). Serum bromide
concentrations were assessed on all 13 dogs being administered
potassium bromide, except for one dog at week 12 during
placebo treatment due to lack of serum, and week 2 for one dog
due to serum loss during shipment to the diagnostic laboratory.
Serum bromide concentrations were not significantly different
based on treatment, or over time and no alterations due to
treatment over time (Table 3).
Seizure control assessment
Epileptic seizure events (as recorded by owners) were tallied
over each 3-month period of time and the mean and standard
deviations were calculated. Epileptic seizure events were all
generalized in nature and no focal/partial seizures. The mean
number of epileptic seizures during the placebo phase was 8.0 ±
4.8, while the mean number of seizures during the CBD/CBDA-
rich hemp oil was 5.0 ±3.6 (P=0.02; Figure 2A). Mean epileptic
seizure days in the control group over the 12-week period
were 5.8 ±3.1 and 4.1 ±3.4 in the CBD/CBDA-rich hemp
oil group (P=0.02; Figure 2B). When assessed for a clinically
significant 50% decrease in seizures between the two groups,
the placebo group was 50% lower for 0 of 14 dogs, while 6 of
14 showed a 50% reduction in epileptic seizure events whilst on
rich CBD/CBDA-rich hemp oil; this was statistically significant
(P=0.02). Similarly when assessing number of dogs with a 50%
reduction in epileptic seizure days between groups, 0 of 14 in
the placebo group showed a 50% reduction, while this level of
reduction was seen in 5 of 14 in the CBD/CBDA-rich hemp oil
group (P=0.04).
Owner assessments and adverse events
Owner Likert scores for seizure control and adverse events
were collected for all respondents, except for one owner who did
not provide the survey due to loss of contact at study end. The
Likert scores were then compared between the two treatment
FIGURE 2
Mean seizure activity over 12-weeks of CBD/CBDA-rich hemp
oil vs. placebo compared to placebo. (A) Epileptic seizure
numbers recorded by owners during treatment using an
encapsulated CBD/CBDA-rich hemp oil (2 mg/kg every 12 h) vs.
placebo treatment. Asterisk indicates a significant dierence (P
=0.02). (B) Total days of seizure activity over the 12 week period
using an encapsulated CBD/CBDA-rich hemp oil vs. placebo
treatment. Asterisk indicates a significant dierence (P=0.02).
phases for 13 of the 14 dogs enrolled. The average Likert score
for owner perceived improvement in frequency of seizures was a
median of 3 (no change; range 2–5) during the treatment phase.
The median was 3 (no change; range 1–5) during the placebo
phase, which was not significant (P=0.41). Owner perception
of improvement in severity for the CBD/CBDA-rich hemp oil
treatment revealed a median value of 4 (a little improvement:
range 2–5) and placebo median response was 3 (no change;
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Garcia et al. 10.3389/fvets.2022.939966
TABLE 4 Adverse event report at end of 12 weeks of CBD/CBDA-rich
hemp oil vs. placebo treatment.
Adverse events13 Placebo Treatment Fisher’s
respondents exact
Increased appetite 0 3 p=0.22
Increased GI signs (vomit/diarrhea) 0 2 p=0.48
Increased thirst/urination 3 2 p=1.0
Increased ataxia 1 4 p=0.32
Increased anxiety 3 2 p=1.0
Increased lethargy/somnolence 1 3 p=0.59
Fisher’sexact testing showed no significan t differences between groups.
range 1–5); this was not considered significant (P=0.12).
Further overall client assessment for overall epileptic seizure
management revealed a median score of 4 (a little improvement;
Range 2–5) while for placebo the median was 3 (no change;
range 1–5) which showed no significant differences between the
phases of treatment (p=0.16).
Adverse events associated with increases in anxiety,
vomiting or diarrhea, lethargy/somnolence, appetite, urination
or thirst, and ataxia were assessed through Fisher’s exact testing
and found that for each of these potential adverse events
associated with CBD/CBDA rich hemp vs. placebo, that there
were no significant increases in these adverse events (Table 4).
Discussion
The major finding of our study is the statistically significant
reduction in epileptic seizure frequency, as well as number
of epileptic seizure days, as assessed through diaries kept by
owners. Of course, unlike humans where precise accounts are
likely, for dogs there may be seizures missed and unaccounted
for. Usually, however, an episode can be determined by postictal
activities or inappropriate soiling of surroundings, particularly
since these were dog owners who were managing chronic
epilepsy for over a year and were astute to behavioral changes.
The epileptic seizure events in this population of dogs ranged
from 3 to 14 seizures with a mean of 8 seizures over the 12-week
study using placebo, which decreased to a mean of 5 seizures
with a range of 0–12 events over the 12 weeks of treatment.
A recent measure of successful treatment has been defined as
a seizure free period of >3 times the longest pre-treatment
interictal interval, which cannot be fully assessed as retrospective
epileptic seizure diaries were not collected. Rather the epileptic
seizure events during CBD/CBDA-rich hemp oil treatment was
compared to the placebo treatment phase, whereby two dogs
of the 14 dogs showed a 3-fold reduction in epileptic seizure
events compared to placebo, as a full response (15). Another
measure of partial success in the treatment of seizures is a
50% or greater reduction in seizure activity which is often
reported in human literature and some veterinary literature
(11, 16, 17). This would be defined as a partial response to an
ASM (15), and is considered clinically significant. We found
that a 50% reduction was observed in 6 of the 14 dogs during
CBD/CBDA-rich hemp oil vs. placebo. If we examine dogs on
CBD/CBDA-rich hemp oil treatment for both a 50% reduction
in epileptic seizure frequency and epileptic seizure days 40%
of the patient population displayed minimally a partial response.
These findings are very similar to the pilot study performed by
McGrath et al. using a dose of 2.5 mg/kg of CBD oil orally every
12 h (11), while our study used a similar hemp extract dosing at
1 mg/kg of CBD and 1 mg/kg of CBDA as an equal mix orally
every 12 h.
CBD treatment has been well studied in both humans and
rodents, showing reductions in seizure activity, particularly in
various childhood conditions including Dravet’s syndrome and
Lennox- Gastaut syndrome (16–18). The current FDA approved
CBD product (Epidiolex) is used at a dose of 10–20 mg/kg,
which is 10 times higher than doses that have now been utilized
in dogs with partial responses. The difference in response
between dogs may be related to the utilization of a whole hemp
extract rich in CBD, vs. a purified CBD compound. Additionally,
the formulation used in our study contains significant amounts
of CBDA which has been shown to have anti-convulsant and
anti-seizure activity in rodent models when delivered orally once
per day (4); there is relatively sparse information regarding
its use in humans, short of a pharmaceutical company trial
suggesting efficacy of CBDA when provided orally once a day.2
CBDA is similar to CBD in its overall actions at neurological
targets such as the glycine receptor, transient receptor
potential villinoid and ankyrin receptors (TRPV, TRPA) and
5-hydroxytrapamine 1A receptors (5HT1A) with less known
about CBDAs ability to interact with the equilibrative nucleoside
transporter activity (19, 20). In humans, the pharmacokinetics of
CBDA appear to be superior to CBD and have been examined
in human clinical trials. Rodent model trials have shown that
CBDA has similar efficacy in reducing seizure activity as CBD as
a single molecule or blended as a 1:9 mixture of CBDA:CBD and
taken at a total dose of 100 mg/kg (see text footnote 2). Mouse
studies examining brain concentrations of CBDA suggest that it
may not have the same nervous system penetration as CBD (4),
due to the acidic form being less able to cross the blood brain
barrier, while still displaying efficacy in a mouse model of Dravet
Syndrome (21). Regardless, it seems to have similar activity and
CBDA is known to be a superior agonist for the 5HT1A receptor
(22, 23). The examination of CBDA as an anticonvulsant is in
its infancy and further studies are necessary, yet it does seem
to provide similar efficacy in dogs, to primary CBD-rich hemp
treatment alone.
2 GW Pharmaceuticals, World Intellectual Property Organization,
Patents Number; WO2017/025712 A1. International Publication Date—
February 16th, 2017.
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Garcia et al. 10.3389/fvets.2022.939966
The whole hemp extract utilized in our study also contains
small amounts of THC and THCA. THCA is the carboxylic
acid form of THC which is found in the Cannabis sativa
and is retained during extraction of the product used in
this study. Primary preclinical rodent models have found
benefit in providing THCA as a neuroprotective molecule for
various degenerative diseases, including models of Parkinson’s
and Huntington’s disease related pathologies (24, 25). THCA
is non-psychotropic and sparsely studied regarding clinical
investigation as a THC related molecule. Interestingly, prior
examination of the pharmacokinetics in dogs has revealed that
when equal small portions of THC and THCA are provided
to dogs, there is a far more robust absorption of THCA than
THC by 10-fold (9). Serum concentrations when providing
0.15 mg/kg of THCA reached between 20 and 30 ng/mL in
the bloodstream while THC was 2–5 ng/mL (9). The ability of
THCA to reach the central nervous system has yet to be reported,
but THCA appears to have variable effects on rodent seizure
models and improvements in Huntington’s disease models, as
well as potent anti-inflammatory activity; this may be due to its
interaction with the peroxisomal proliferation receptor system
that modulates the inflammatory response (24, 25).
As a whole hemp extract, the cannabinoids may be able
to act synergistically with the minor cannabinoids and other
components (terpenes and flavonoids) to augment the response
to the major cannabinoids CBD and CBDA. This is known as
“the entourage effect” (26, 27). There is mounting evidence that
constituent compounds within CBD-rich hemp extracts have
efficacy as anti-epileptics and that dosing can be significantly
decreased from CBD isolates (26, 27). A recent study examining
children with refractory epilepsy showed that there were similar
responses when using CBD-rich whole hemp extract with a
CBD:THC ratio of 20:1, at a total dose of 5–6 mg/kg per
day. Four of the 7 children examined had a 50% reduction in
seizure frequency and all of these respondents displayed serum
concentrations of CBD in the 15–25 ng/mL. When administered
10–12 mg/kg of cannabinoid rich hemp extract three of these
4 patients became seizure free, with steady state concentrations
in the blood being between 52 and 124 ng/mL (26). A more
recent meta-analysis of observational studies utilizing CBD-rich
hemp products, as compared to purified CBD isolate products,
showed similar response rates of 35–40% with a 50% reduction
in seizure frequency. The average daily dose administered was 6
mg/kg of CBD-rich hemp, vs. 25 mg/kg when using CBD isolate
products. This further clarifies the validity of possible “entourage
effects” observed when using whole hemp extracts, whereby a
lower dose can be useful (27).
The use of CBD or CBD-rich hemp extracts can both lead
to physiological changes; most notably an alteration in hepatic
metabolism and increases in either ALT or ALP activity in
dogs (7, 11). In a prior study examining the ALP activity over
12 weeks in dogs treated with a CBD-rich hemp extract for
refractory epilepsy, a 2–4-fold increase in ALP serum enzyme
activity was shown, suggesting potential alterations to hepatic
drug metabolism (11). This rise can also be observed with ASMs
like phenobarbital in dogs (28), hence examination of hepatic
parameters are of utmost importance when using any ASM.
Interestingly, we found no treatment over time effects when
using CBD/CBDA-rich hemp extract, but there was a significant
treatment effect overall suggesting mild to modest rises in
ALP activity. It must be noted that 9 dogs in this study were
receiving phenobarbital treatment which predisposed them to
elevations; when examining the average increase, it was 150–
200 U/L which was suggestive of limited increases. Additionally,
these alterations were within 2 weeks of initiating treatment
and remained static for the 3 months of treatment. No other
treatment effects were observed across serum chemistry or
complete blood count assessment during the 12-week trial when
compared to placebo.
In line with the ALP rise, there is expected to be some
alterations in either induction or inhibition of the CYP enzyme
system that is involved in the metabolism of drugs like
phenobarbital and zonisamide (12, 14, 29, 30). In humans
and rodents, the primary CYP known to be influenced
by CBD administration are CYP3A4 and CYP2D19; these
may not be identical in dogs considering the metabolites of
CBD are dramatically different (29–32). This however, does
not negate the need to understand whether CBD/CBDA-rich
hemp alters the serum concentrations of these commonly
prescribed ASM’s. When measuring both phenobarbital and
zonisamide concentrations over the 12-week period, there were
no differences when compared to placebo treatment for 12
weeks. This suggests that CBD/CBDA-rich hemp does not
affect the metabolism of these drugs or potassium bromide
treatment when administered together. It must also be noted
that two of the dogs did have increases in their potassium
bromide dosing during the trial, one during the CBD/CBDA-
rich hemp oil treatment phase and one during the placebo
treatment phase, which can take up to 3 months to observe
consistent changes in serum bromide concentrations. The
small number of dogs needing alterations in their ASMs, and
lack of this occurring in only one group, gives merit to the
idea that CBD/CBDA-rich hemp treatment is not significantly
affecting serum ASM concentrations. This lack of influence
on serum ASMs concentrations is further corroborated in a
recent publication by Doran et al., showing that neither CBD
or phenobarbital concentrations differed when dogs were on 1
month of phenobarbital treatment, suggesting that these non-
psychotropic cannabinoids can be administered together safely
in epileptic dogs (3).
Owners were surveyed at the end of each 12-week phase of
the study for improvements in severity, frequency and overall
management of seizures. Surprisingly, owners did not find any
improvement in frequency but did feel that the severity of
seizures was improved on treatment. Overall management was
slightly improved, with median Likert score improvements from
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Garcia et al. 10.3389/fvets.2022.939966
a median of 3 for placebo to slightly improved (median score of
4) on treatment. The seizure frequency observed from diaries
were likely influenced by recall bias, which is a factor that
cannot be controlled in survey research. More importantly, no
dogs were discontinued from the study due to adverse events
related to the use of CBD/CBDA-rich hemp use over the 12-
week period, other than an initial drop out due to difficulty
in administering this particular product to the dog which may
have been due to the typical hemp odor or the larger than
usual number of capsules needed for this large dog. The results
of adverse events when compared between groups assessed
statistically showed no difference; however it must be noted
that three owners reported somnolence and four reported a
mild increase in ataxia while on the CBD/CBDA-rich hemp
oil capsules. Increases in somnolence or lethargy was reported
in only one dog while on the placebo capsules, and only one
dog reported to be mildly more ataxic on the placebo. Other
events, such as gastrointestinal disturbances were self-limiting
and mild in nature with two dogs experiencing this during
the CBD/CBDA-rich hemp oil treatment phase, and 3 dogs
showing mild increases in appetite during the CBD/CBDA-rich
oil treatment phase of the trial. Overall, the reported adverse
events are comparable to that observed in larger human clinical
trials regarding appetite, somnolence and ataxia (16–18). These
are changes that should be monitored or discussed with clients
interested in pursuing CBD-rich hemp treatment for epileptic
seizure management (16–18).
A major limitation of any study with a small sample size of
this nature is our inability to control consistent dosing; this is
under the control of the client without confirmation of daily
dosing. There was control to some extent by dispensing the
initial 6 weeks of treatment or placebo and then asking about
relative needs to complete the trial. This facilitated dispensing
for the next few weeks, where owners did suggest that they
were nearly out of capsules, allowing us to assume relatively
regular twice daily dosing. Measuring serum cannabinoids at
intervals would have allowed for better assessment of this factor
and would have allowed for regression statistics to be run on
the CBD serum concentrations to clinical response. McGrath
et al. have suggested that responders in their study tended to
have higher CBD levels on spot check after 12 weeks, inferring
that there may be some benefit in monitoring serum CBD or
other cannabinoid concentrations to better utilize CBD-rich
hemp extracts clinically, much like other ASMs (11). At the time
of initiating the study, there were no laboratories performing
serum analysis of any cannabinoid other than CBD. Considering
the product being tested contained other cannabinoids (namely
CBDA) we felt that any assessment would be incomplete;
therefore serum was not saved for future analysis. In addition,
although this study suggests potential benefits for some dogs,
the unique nature of this CBD/CBDA-rich hemp product cannot
be extrapolated to other products. This is due to the unique
nature of the CBD/CBDA blend, which is rare to find in the
current cannabinoid nutraceutical market for dogs. The specific
CBD/CBDA blend utilized in this study is readily available
throughout the United States (Ellevet) with a current expansion
project throughout the European Union, to include Greece,
Germany, Netherlands, France and Spain. The same active
product is freely available in the United Kingdom, marketed as a
human preparation (Ellevance), due to current United Kingdom
legislative restrictions on the provision of CBD based products
to animals.
In conclusion, there appears to be a population of
dogs that respond favorably to CBD/CBDA-rich hemp
products for epileptic seizure reduction similar to other
human, dog and rodent data. It must be noted that these
benefits are observed as a multi-modal approach to ASM
treatment and cannot be extrapolated to using CBD/CBDA-
rich hemp as a single agent, due to a lack of studies. More
importantly, the use of a CBD/CBDA-rich hemp does not
appear to alter the hepatic metabolism of other ASMs,
namely phenobarbital, zonisamide or potassium bromide
during this 3 month period of treatment. Furthermore, the
serum chemistry and complete blood count profiles across
the 12-week trial period on treatment were no different
than the placebo treatment phase, with the exception of
a mild rise in serum alkaline phosphatase. Regardless, it
is prudent to follow routine bloodwork to assess hepatic
enzymes particularly when other ASMs, that are known to
commonly cause increases in ALT and ALP concentrations, are
being administered.
Data availability statement
The raw data supporting the conclusions of this article will
be made available by the authors, without undue reservation.
Ethics statement
The animal study was reviewed and approved by University
of Florida IACUC. Written informed consent was obtained
from the owners for the participation of their animals in
this study.
Author contributions
GG and SK were the genesis of the idea, study design, data
collection, initial analysis, and manuscript preparation/review.
SC-J was involved in data collection, analysis, and manuscript
preparation/review. DT and JW were involved in data analysis
and manuscript review. All authors contributed to the article and
approved the submitted version.
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Garcia et al. 10.3389/fvets.2022.939966
Funding
GG received a grant from Ellevet Sciences to complete the
clinical trial outlines in the manuscript and is an Advisory Board
Member at Ellevet Sciences. Ellevet Sciences was not involved in
the study design, collection, analysis, interpretation of data, the
writing of this article or the decision to submit it for publication.
Conflict of interest
Author GG received a grant from Ellevet Sciences to
complete the clinical trial outlines in the manuscript and is an
Advisory Board Member at Ellevet Sciences. Authors JW and
DT are consultants at Ellevet Sciences and also serve as advisory
board members at Ellevet Sciences.
The remaining authors declare that the research was
conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict
of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be
found online at: https://www.frontiersin.org/articles/10.3389/
fvets.2022.939966/full#supplementary-material
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... The results revealed a statistically lower SF during the CBD/CBDA-rich hemp treatment phase with six dogs experiencing at least 50 % reduction in SF compared to the placebo phase and no dogs showing at least 50 % reduction in SF. Adverse events observed during treatment were somnolence and ataxia in three and four dogs, respectively (Garcia et al., 2022). A small scale case series supported a decrease in SF with CBD in three dogs with IE Tier I (Mogi and Fukuyama, 2019). ...
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In the last decade, nutrition has gained interest in the management of canine idiopathic epilepsy (IE) based on growing scientific evidence. Diets can serve their functions through many pathways. One potential pathway includes the microbiota-gut-brain axis, which highlights the relationship between the brain and the intestines. Changing the brain’s energy source and a number of dietary sourced anti-inflammatory and neuroprotective factors appears to be the basis for improved outcomes in IE. Selecting a diet with anti-seizure effects and avoiding risks of proconvulsant mediators as well as interference with anti-seizure drugs should all be considered in canine IE. This literature review provides information about preclinical and clinical evidence, including a systematic evaluation of the level of evidence, suggested mechanism of action and interaction with anti-seizure drugs as well as pros and cons of each potential dietary adaptation in canine IE.
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The anticonvulsant effect of cannabidiol (CBD), which has been confirmed by findings from animal models and human trials, has attracted the interest of veterinary practitioners and dog owners. Moreover, social media and public pressure has sparked a renewed awareness of cannabinoids, which have been used for epilepsy since ancient times. Unfortunately, at this moment veterinarians and veterinary neurologists have difficulty prescribing cannabinoids because of the paucity of sound scientific studies. Pharmacokinetic studies in dogs have demonstrated a low oral bioavailability of CBD and a high first-pass effect through the liver. Administering CBD in oil-based formulations and/or with food has been shown to enhance the bioavailability in dogs, rats and humans. Tolerability studies in healthy dogs and dogs with epilepsy have demonstrated that CBD was safe and well tolerated with only mild to moderate adverse effects. In this context, it should be noted that the quality of available CBD varies widely, underscoring the importance of pharmaceutical quality and its control. One clinical trial in dogs with drug-resistant idiopathic epilepsy failed to confirm a difference in response rates between the CBD group and the placebo group, while in another cross-over trial a ≥ 50% reduction in epileptic seizure frequency was found in six of 14 dogs in the treatment phase, a reduction that was not observed during the placebo phase. Based on the current state of knowledge it is not possible to provide clear-cut recommendations for the use of CBD in canine epilepsy. Randomized controlled canine trials with large sample sizes are needed to determine the range of therapeutic plasma concentrations, develop evidence-based dosing regimens, determine the efficacy of cannabidiol in drug-refractory epilepsy, and explore potential associations between treatment effects and different etiologies, epilepsy types, and drug combinations.
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Cannabidiol (CBD)-rich hemp extract use is increasing in veterinary medicine with little examination of serum cannabinoids. Many products contain small amounts of Δ9-tetrahydrocannabinol (THC), and precursor carboxylic acid forms of CBD and THC known as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). Examination of the pharmacokinetics of CBD, CBDA, THC, and THCA on three oral forms of CBD-rich hemp extract that contained near equal amounts of CBD and CBDA, and minor amounts (<0.3% by weight) of THC and THCA in dogs was performed. In addition, we assess the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) to better understand the pharmacokinetic differences between three formulations regarding THC and CBD, and their metabolism. Six purpose-bred female beagles were utilized for study purposes, each having an initial 7-point, 24-h pharmacokinetic study performed using a dose of 2 mg/kg body weight of CBD/CBDA (~1 mg/kg CBD and ~1 mg/kg CBDA). Dogs were then dosed every 12 h for 2 weeks and had further serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectroscopy (LC-MS/MS). Regardless of the form provided (1, 2, or 3) the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar, with only Form 2 generating enough data above the lower limit of quantitation to assess pharmacokinetics of THC. CBDA and THCA concentrations were 2- to 3-fold higher than CBD and THC concentrations, respectively. The 1- and 2-week steady-state concentrations were not significantly different between the two oils or the soft chew forms. CBDA concentrations were statistically higher with Form 2 than the other forms, showing superior absorption/retention of CBDA. Furthermore, Form 1 showed less THCA retention than either the soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the quantitation limit of the assay for nearly all samples. Overall, these findings suggest CBDA and THCA are absorbed or eliminated differently than CBD or THC, respectively, and that a partial lecithin base provides superior absorption and/or retention of CBDA and THCA.
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Cannabidiolic acid (CBDA) is the main phytocannabinoid in fiber and seed-oil hemp (Cannabis sativa L.) plants, but its potential health-related capabilities have been masked for years by a greater scientific interest towards its neutral derivative cannabidiol (CBD). This review aims to collect from the literature and critically discuss all the information about this molecule, starting from its biosynthesis, and focusing on its bioactivity, as an anti-inflammatory, anti-emetic, anti-convulsant, and anti-cancerogenic drug. Furthermore, in the awareness that, despite its multiple bioactive effects, currently poor efforts have been made to achieve its reliable purification, herein, we propose a relatively simple, fast, and inexpensive procedure for its recovery from pollen of industrial hemp cultivars. Spectroscopic and spectrometric techniques allowed us to unequivocally identify pure isolated CBDA and to distinguish it from the constitutional isomer tetrahydrocannabinolic acid (THCA-A).
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Cannabis sativa produces a complex mixture of many bioactive molecules including terpenophenolic compounds known as phytocannabinoids. Phytocannabinoids come in neutral forms (e.g., Δ⁹-tetrahydrocannabinol, THC; cannabidiol, CBD; etc.) or as acid precursors, which are dominant in the plant (e.g., Δ⁹-tetrahydrocannabinolic acid, THCA; cannabidiolic acid, CBDA; etc.). There is increasing interest in unlocking the therapeutic applications of the phytocannabinoid acids; however, the present understanding of the basic pharmacology of phytocannabinoid acids is limited. Herein the brain and plasma pharmacokinetic profiles of CBDA, THCA, cannabichromenic acid (CBCA), cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA), and cannabigerovarinic acid (CBGVA) were examined following intraperitoneal administration in mice. Next it was examined whether CBDA was anticonvulsant in a mouse model of Dravet syndrome (Scn1aRX/+ mice). All the phytocannabinoid acids investigated were rapidly absorbed with plasma tmax values of between 15 and 45 min and had relatively short half-lives (<4 h). The brain–plasma ratios for the acids were very low at ≤0.04. However, when CBDA was administered in an alternate Tween 80-based vehicle, it exhibited a brain–plasma ratio of 1.9. The anticonvulsant potential of CBDA was examined using this vehicle, and it was found that CBDA significantly increased the temperature threshold at which the Scn1aRX/+ mice had a generalized tonic-clonic seizure.
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Objective: To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs. Animals: 9 healthy, purpose bred Beagles. Procedures: A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study. Results: Although there were variations in CBD PK variables in dogs receiving CBD alone or in conjunction with PB, significance differences in CBD PK variables were not found. No significant difference was observed in PB PK variables of dogs receiving PB alone or with CBD. During chronic CBD administration, mild gastrointestinal signs were observed in 5 dogs. At daily CBD doses of 10 to 20 mg/kg/d, hypoxia was observed in 5 dogs and increased serum alkaline phosphatase (ALP) activities (range, 301 to 978 U/L) was observed in 4 dogs. A significant increase in ALP activity was observed with chronic administration of CBD during phase 1 between day 0 and day 14. Conclusions and clinical relevance: No significant PK interactions were found between CBD and PB. Dose escalation of CBD or adjustment of PB in dogs is not recommended on the basis of findings of this study.
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The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam. This article is part of the special issue on ‘Cannabinoids’.
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Objective Cannabidiol is efficacious as an adjunctive treatment in children with epilepsy associated with Dravet and Lennox-Gastaut syndromes. As its role is currently adjunctive, we reviewed the interactions of cannabidiol with other antiseizure medications (ASMs). Methods A search of Cochrane, Pubmed and Embase databases from January 2015 to April 2020 was performed. All original research papers discussing interactions between cannabidiol and ASMs were included. Bibliographies of review articles were searched to identify further papers. Adverse events and side effects were excluded. Results Cannabidiol interacts with ASMs through both pharmacokinetic and pharmacodynamic mechanisms. Thirty studies were identified (eighteen observational cohort studies, two randomised-control trials, three case reports/series, three animal studies, two briefing reports, an analysis of cohort data and a clinical trial simulation). There is potential for pharmacokinetic interactions between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam. An animal study identified that the brain concentration of ASMs may be altered while the serum concentration remains the same. Conclusion Pharmacokinetic and pharmacodynamic interactions exist between cannabidiol and ASMs. The cytochrome p450 system in particular has been implicated in pharmacokinetic interactions, although not exclusively. The existing literature is limited for some ASMs by studies having relatively small cohorts. As increasing numbers of patients use cannabidiol, specialists need to monitor closely for interactions clinically and with blood levels when required.
Article
Introduction: Pharmaceutically purified oral cannabidiol (CBD) has been recently approved by the US Food and Drug Administration and European Medicines Agency as treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), which are severe and difficult-to-treat developmental and epileptic encephalopathies with onset in early childhood. Areas covered: This review will critically review the pharmacokinetic properties of CBD, the interactions with antiseizure and non-antiseizure medications, and the main tolerability and safety issues to provide guidance for its use in everyday practice. Expert opinion: CBD is metabolized in the liver and can influence the activity of enzymes involved in drug metabolism. The best characterized drug-drug interaction is between CBD and clobazam. The most common adverse events include somnolence, gastrointestinal discomfort, and increase in serum transaminases. High-grade purified CBD oral solution represents an effective therapeutic option in patients with DS and LGS. The findings cannot be extrapolated to other cannabis-based products, synthetic cannabinoids for medicinal use and non-medicinal cannabis and CBD derivatives.
Article
Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States and as EPIDYOLEX from the EU agency) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy. Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).