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The effect of a mixed cannabidiol and cannabidiolic acid based oil on client‐owned dogs with atopic dermatitis

Authors:

Abstract

Background: Cannabidiol (CBD) and cannabidiolic acid (CBDA) are reported to have antinociceptive, immunomodulatory and anti-inflammatory actions. Objectives: To determine if CBD/CBDA is an effective therapy for canine atopic dermatitis (cAD). Animals: Thirty-two privately owned dogs with cAD. Materials and methods: Prospective, randomised, double-blinded, placebo-controlled study. Concurrent therapies were allowed if remained unchanged. Dogs were randomly assigned to receive either 2 mg/kg of an equal mix of CBD/CBDA (n = 17) or placebo for 4 weeks. On Day (D)0, D14 and D28, Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) and pruritus Visual Analog Scale (pVAS) scores were determined by investigators and owners, respectively. Complete blood count, serum biochemistry profiles and cytokine bioassays were performed on serum collected on D0 and D28. Results: There was no significant difference in CADESI-04 from D0 to D14 (p = 0.42) or D28 (p = 0.51) in either group. pVAS scores were significantly lower for the treatment group at D14 (p = 0.04) and D28 (p = 0.01) and a significant change in pVAS from baseline was seen at D14 (p = 0.04) and not D28 (p = 0.054) between groups. There was no significant difference in serum levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein - 1, IL-31 or IL-34 between groups at D0 or D28. Elevated alkaline phosphatase was observed in four of 17 treatment group dogs. Conclusions and clinical relevance: CBD/CBDA as an adjunct therapy decreased pruritus, and not skin lesions associated with cAD in dogs.
Veterinary Dermatology. 20 22; 33:3 29 e77.
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329wileyonlinelibrary.com/journal/vde
ORIGINAL ARTICLE
The effect of a mixed cannabidiol and cannabidiolic acid
based oil on client- owned dogs with atopic dermatitis
MelissaLoewinger1 | Joseph J.Wakshlag2 | DanielBowden1 |
JeaninePeters- Kennedy2 | AndrewRosenberg1
Received: 21 August 2021
|
Accepted: 9 February 2022
DO I: 10 .1111/v de .13 07 7
This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made.
© 2022 The Authors. Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of ESVD and ACVD.
This abstract was presented at the NAVDF on April 22, 2021. This study has not been published previously.
1Animal Dermatology and Allergy
Specialists, Wayne, NJ, USA
2Department of Clinical Sciences, College
of Veterinary Medicine, Cornell University,
Ithaca, NY, USA
Correspondence
Melissa Loewinger, Animal Dermatology
and Allergy Specialists, 82 Newark
Pompton Turnpike, Riverdale, NJ 07457,
USA.
Email: mloewinger@adasvet.com
Funding information
Ellevet Sciences.
Abstract
Background: Cannabidiol (CBD) and cannabidiolic acid (CBDA) are reported
to have antinociceptive, immunomodulatory and anti- inflammatory actions.
Objectives: To determine if CBD/CBDA is an effective therapy for canine
atopic dermatitis (cAD).
Animals: Thirty- two privately owned dogs with cAD.
Materials and methods: Prospective, randomised, double- blinded, placebo-
controlled study. Concurrent therapies were allowed if remained unchanged.
Dogs were randomly assigned to receive either 2 mg/kg of an equal mix of
CBD/CBDA (n=17) or placebo for 4 weeks. On Day (D)0, D14 and D28, Canine
Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI- 04) and
pruritus Visual Analog Scale (pVAS) scores were determined by investiga-
tors and owners, respectively. Complete blood count, serum biochemistry
profiles and cytokine bioassays were performed on serum collected on D0
and D28.
Results: There was no significant difference in CADESI- 04 from D0 to D14
(p = 0.42) or D28 (p= 0.51) in either group. pVAS scores were significantly
lower for the treatment group at D14 (p = 0.04) and D28 (p= 0.01) and a
significant change in pVAS from baseline was seen at D14 (p = 0.04) and
not D28 (p = 0.054) between groups. There was no significant difference in
serum levels of interleukin (IL)- 6, IL- 8, monocyte chemoattractant protein - 1,
IL- 31 or IL- 34 between groups at D0 or D28. Elevated alkaline phosphatase
was observed in four of 17 treatment group dogs.
Conclusions and clinical relevance: CBD/CBDA as an adjunct therapy de-
creased pruritus, and not skin lesions associated with cAD in dogs.
KEYWORDS
acid, atopic, canine, cannabidiol, cannabidiolic, dermatitis, hemp
INTRODUCTION
Canine atopic dermatitis (cAD) is a common inflam-
matory and pruritic allergic skin disease that is charac-
terised by excessive immunoglobulin (Ig)E production
directed against allergens. Due to the multifactorial and
progressive nature of the disease, multimodal and in-
dividualised therapeutic regimens often are indicated.1
Cannabinoids are a unique group of chemical com-
pounds found in Cannabis sativa plants. Cannabidiol
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(CBD) is the predominant nonpsychotropic can-
nabinoid found in the cannabis plant and as such,
CBD- rich plants are classified as hemp rather than
marijuana. Cannabidiolic acid (CBDA) is the precur-
sor carboxylic acid form of CBD, and a recent study
showed similar and possibly better absorption than
CBD in dogs.2
Immunomodulatory and anti- inflammatory actions
of CBD/CBDA in mammals have been reported.3,4
These cannabinoids appear to be well- tolerated and
effective at reducing osteoarthritic pain and seizures
in dogs.2,5 – 8
The G- protein- coupled cannabinoid receptors
(CB1 and CB2) are both expressed in canine kera-
tinocytes, with immunoreactivity to CB1 and CB2
being heightened in atopic dogs compared to healthy
dogs.9 Cannabinoid receptor agonists reduce skin le-
sions and pruritus in atopic dogs, and attenuated in-
flammation in the skin of mice in a model of contact
hypersensitivity.10,11
Cannabidiol does not appear to interact with CB1 or
CB2 receptors directly, yet has been implicated in al-
tering endogenous levels of naturally derived endocan-
nabinoids such as anandamide. CBD also may interact
with other receptor systems in the inflammatory cells
or neurons such as the transient receptor activation
channels (TRPV), adenosine reuptake inhibitor as well
as peroxisome proliferation and activation receptors
(PPAR) based on in vitro and in vivo assessments in
humans and rodents.12– 18
To the best of the authors' knowledge, no studies
investigating the efficacy of CBD/CBDA as a treatment
for cAD have been conducted. The primary objective of
this study was to determine if CBD/CBDA- rich hemp
extract decreased pruritus and cutaneous lesions in
dogs with cAD. Secondary objectives included deter-
mining whether CBD- rich hemp extract caused any
adverse effects through client surveys, routine com-
plete blood counts, serum biochemistry and evaluating
serum cytokines before and after its administration for
28 days.
MATERIALS AND METHODS
Ethics
This study was approved by the Cornell University
Institutional Animal Care and Use Committee (IACUC)
2019 0119.
Dog owners signed a written informed consent form
before inclusion and could withdraw at any time.
Overview
The study was a 4 week, randomised, double- blinded
and placebo- controlled trial. Client- owned dogs were
assigned randomly to a CBD/CBDA group or pla-
cebo group using a computer- based random number
generator.
Enrolment criteria
Client- owned dogs (irrespective of breed, age or sex)
with visible signs of pruritic skin disease and diag-
nosed with cAD based on published guidelines were
enrolled.19 Dogs included in the study met the follow-
ing criteria: (i) current on flea prevention; (ii) confirmed
to not have an adverse food reaction after an 8 weeks
diet trial (hydrolysed or novel protein) with subsequent
negative challenge or if previously confirmed to have
an adverse food reaction were controlled on a diet; (iii)
Canine Atopic Dermatitis Extent and Severity Index,
4th iteration (CADESI- 04) score was >9 and <60; (iv)
pruritus Visual Analog Scale (pVAS) of between 3 and
8cm on a previously validated scale;20 and (v) main-
tained flea prevention throughout study.
Dogs were excluded if: (i) there was clinical evi-
dence of bacterial or fungal skin infections; (ii) systemic
or dermatological causes of pruritus other than cAD
were present; (iii) oral antibiotics were used 7 days
before enrollment or throughout study; (iv) treatment
with lokivetmab or long- acting corticosteroid injec-
tion were used less than 8 weeks before enrollment;
(v) allergen- specific immunotherapy (ASIT) was intro-
duced <52 weeks before enrollment; (vi) administration
of dietary supplements or nutraceuticals was changed
or introduced less than 2 weeks before enrollment; (vii)
oral glucocorticoids, oclacitinib, azole antifungals, ter-
binafine and antihistamine dosing was changed less
than 2 weeks before enrollment; (viii) ciclosporin dosing
was changed less than 8 weeks before enrollment; (ix)
antimicrobial topical protocol was changed less than
2 weeks before enrollment; (x) bathing frequency was
changed less than 2 weeks before enrollment; and (xi)
patient's pre- existing medication regimen changed in
any other way throughout the study.
Study protocol
Dogs were evaluated on the day of enrollment, which
was classified as Day (D)0, D14 and D28. A validated
owner- assessed pVAS was used to determine severity
of pruritus at each evaluation.20 CADESI- 04 was per-
formed at each evaluation.21 Complete blood counts
(CBC) and biochemistry profiles were performed on D0
and D28. Serum from D0 and D28 were collected and
stored at −20°C for cytokine analysis, shipped on dry
ice within 4 months and stored at −80°C until analysis.
All adverse events (AEs) were reported on D14 and
D28. Owners were asked if they thought the treat-
ment was effective at the conclusion of the study in
a standard written survey (see Supporting informa-
tionAppendix S1).
Assessment of efficacy
The outcome measures were the differences in pru-
ritus and lesion severity at D14 and D28 from base-
line. Treatment was considered successful if the
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pVAS and/or CADESI- 04 scores showed a statisti-
cally significant reduction compared with the initial
value at D0 when compared to the placebo group.
We also quantified the reduction in pruritus using
an improvement of ≥2 cm as indicating treatment
success, as has been used in other similar studies,
and additionally we assessed the number of dogs
achieving ≤1.9cm on the scale.10,22,23 Assessment
of treatment effect using these outcome measures
was assessed as responder and nonresponder based
on client exit survey at the end of treatment through
Fisher's exact testing.
Tolerability
Tolerability was assessed by recording AEs and with-
drawals at any time during the study. All AEs that
occurred during the study were recorded by a nonin-
vestigator to maintain blinding on an AE reporting form,
together with their onset, severity and perceived asso-
ciation with the study product.
Study product
The study product was an equal mix of CBD/CBDA
in a sesame oil vehicle (Ellevet) with third- party
analysis of the product showing that it contained ap-
proximately 30 mg/ml CBD, 31 mg/ml CBDA, 1.2mg
Δ9- THC and 1.3mg/ml THCA provided in gelatin cap-
sules in 5, 10, 20 and 30 mg/ml CBD/CBDA incre-
ments for dosing. The placebo was sesame oil- filled
capsules of similar increments. Dogs were admin-
istered CBD/CBDA (approximately 2mg/kg) or pla-
cebo, twice daily with a meal for the entire study
period of 28 days.
Cytokine assays
Serum from all patients at D0 and D28 were analysed
for selected cytokines using commercially available
canine- specific enzyme- linked immunosorbent assay
(ELISA) techniques. Serum levels of interleukin (IL)- 6
and IL- 8 (Luminex Platform, Millipore), monocyte che-
moattractant protein (MCP)- 1(Millipore), and IL- 31 and
IL- 34 (MBS039863, MyBiosource) were evaluated
from serum on D0 and D28. All kits were used accord-
ing to the manufacturers' recommendations, running
each sample in duplicate.
Serum CBD/CBDA concentrations
Analysis was performed using gas chromatography
and mass spectrometry based on previously published
methods for evaluation on stored serum from dogs in
the treatment group that were sent to a contract re-
search laboratory (University of Illinois at Chicago,
Toxicology Laboratory) for validated CBD and CBDA
analysis for D0 and D28 samples.2
Statistical methods
Statistical analysis was performed with a commercially
available software package (JMP 12.0, JMP). All contin-
uous data were assessed utilising a Shapiro– Wilk test
for normality. Considering the majority of our blood cell
count, serum biochemistry and inflammatory cytokine
data were normally distributed, a two- way ANOVA
with repeated measures (ANOVA- RM) was used to
analyse these outcomes, including the fixed effects of
treatment, time, and treatment × time. Pairwise com-
parisons between all time points of both groups were
corrected for multiple comparisons with Tukey's post
hoc tests to examine the interaction of time and treat-
ment variables, and to assess differences between
change from baseline at any time point as they related
to treatment. For ordinal veterinary surgeon and owner
VAS scoring data (CADESI- 04 and pVAS) also were
analysed using ANOVA- RM as ShapiroWilk testing
revealed normality of the data. In addition, a change
from baseline pVAS for both the treatment and placebo
groups was assessed using an unpaired unequal vari-
ance Student's t- test at D14 and D28 to assess signifi-
cant differences between groups. A p- value of <0.05
was defined as significant for all analyses.
Further assessment of the treatment effect was
assessed as responder and nonresponder based on
client exit survey, dogs with ≥2cm reduction in pVAS
during treatment, and a pVAS of ≤1.9cm were deemed
to be normalised through Fisher's exact testing with a
p- value set at 0.05.
Regression analysis was performed on changes over
time in pVAS compared to total CBD/CBDA concentra-
tion in the serum using Pearson's linear regression. A
p- value <0.05 was considered significant. The correla-
tion R values were considered weak if ≤0.3, mild if >0.3
and ≤0.5, moderate if >0.5 and 0.7, and strong if >0.7.
Data graphing was performed using Prism software
(v6, GraphPad Software Inc.).
RESU LTS
Thirty- two dogs were enrolled (Table1). Three dogs
were excluded from the full data analysis: one dog
dropped out after 2 weeks as a result of perceived be-
havioural changes; one dog was withdrawn from the
study as a result of failure of its owner to comply with
consistent antiparasitic prophylaxis; and one dog was
withdrawn as a consequence of a dosing error. Twenty-
nine dogs (17 treatment, 12 placebo) were included in
the complete statistical evaluation. The individual daily
dose for analysed dogs in the treatment group was
4.48 mg/kg daily equally divided in a twice- daily dosing
regimen (range: 3.69– 5.97, median: 4.40).
Pruritus
Mean pVAS (±SD) scores at D0, D14 and D28 in the
treatment group, were 5.5± 1.2, 3.5± 2.0 and 3.3± 2.3,
respectively. Mean pVAS at D0, D14 and D28 in the
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placebo group were 5.6± 1.4, 5.1± 1.7 and 5.0± 2.0,
respectively. The pVAS scores were statistically sig-
nificantly lower for the treatment group at both time
points (D14: p= 0.04, D28: p = 0.01), and a signifi-
cant decrease in pVAS from baseline was seen at D14
(p= 0.04) and not D28 (p = 0.054) when comparing
treatment and placebo groups (Figure1a– c). Using
criteria of ≥2cm improvement to evaluate clinical sig-
nificance, nine of 17 dogs improved at D14 (p=0.003)
when compared to zero of 12 in the placebo group. In
the treatment group, 11 of 17 had a decrease of ≥2cm
at D28 (p=0.022) when compared to two of 17 dogs
improving at D28 in the placebo group. Only three of
12 dogs at D14 achieved a normalised PVAS of
1.9cm
compared to zero of 12 in the placebo group (p=0.25).
Six dogs at D28 in the treatment group achieved a
pVAS of ≤1.9cm, while no dogs in the placebo group
achieved a “normal” score, per derivation of a normal
range of ≤1.9 for the pVAS (p=0.028).24
Ten of 17 treatment group owners answered “yes”
to the question “Did you notice an improvement in
your dog's itch throughout the study?” (Appendix S1).
Only two of 13 placebo group owners answered “yes”
with one dog dropping out before the conclusion of the
study, which was statistically significant (p=0.026).
Lesions
Mean CADESI- 04 scores at D0, D14 and D28 in the
treatment group were 27.8 ± 9.4, 25.3 ± 10.3 and
25.0± 11.0, respectively. Mean scores at D0, D14 and
D28 in the placebo group were 29.0± 8.9, 27.6± 10.4
and 26.3± 13.7, respectively. There was no significant
difference in CADESI- 04 from D0 to D14 (p=0.42) or
D28 (p=0.51) in either group (Figure2a and b).
Cytokines
Cytokine means (±SD) including MCP- 1, IL- 6, IL- 8, IL-
31 and IL- 34 can be found in Table2. There were no
TAB LE 1 Case data for dogs included in the cannabidiol (CBD) treatment study
Dog no. Signalment Group CBD dose (mg/kg) twice daily
1 13 y/o M/N schnoodle CBD 2.2
3 9 y/o M/N English bulldog CBD 2.4
9 9 y/o M/N shih tzu CBD 2.3
11 8 y/o M/N mixed breed CBD 1.9
12 8 y/o M/N goldendoodle CBD 2.2
16 9 y/o F/S shih tzu CBD 2.1
18 10 y/o F/S mixed breed CBD 2 .1
19 4 y/o F/S German shepherd dog CBD 1.9
20 4 y/o M/N mixed breed CBD 2.1
21 3 y/o F/S Labrador retriever CBD 2.1
22 3 y/o M/N shih tzu CBD 2.5
25 7 y/o M/I German shepherd dog CBD 2.1
26 6 y/o M/N Tibetan terrier CBD 2.4
28 3 y/o F/S golden retriever CBD 2.1
30 8 y/o F/S Havanese CBD 3
31 6 y/o M/N Dachshund CBD 3
32 3 y/o F/S French bulldog CBD 2.2
2 1 y/o M/I Labrador retriever PB
4 10 y/o F/S cockapoo PB
5 10 y/o M/N mixed breed PB
7 9 y/o M/N bichon frise PB
8 2 y/o M/N shiba inu PB
10 6 y/o M/I mixed breed PB
13 6 y/o M/I Rottweiler PB
14 5 y/o F/S French bulldog PB
23 3 y/o M/N mixed breed PB
24 2 y/o M/N mixed breed PB
27 5 y/o M/I cane corso PB
29 8 y/o F/S Havanese PB
Note: Dogs 6, 15 and 17 did not complete the study and therefore are not included in this table.
Abbreviations: A, appetite; B, behaviour; L, lethargy; M/I, male intact; M/N, male neutered; PB, placebo; R, regurgitation; S/F, female spayed; y/o, year- old.
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significant differences noted between treatment, time,
or treatment × time for any of the cytokines measured
at D0 and D28 (Table3).
Overall owner satisfaction
In an end of study survey (Appendix S1) with most
questions addressing adverse events, owners were
also asked “Would you use this product in the future
for your dog?” Ten of 17 treatment group owners an-
swered that they would use the product again and
seven of 17 would not. In the placebo group, two of
13 owners answered that they would use the product
again, and 10 of 13 would not, with one dropping out
before the end of the study as a consequence of ad-
verse events and lack of efficacy.
Complete blood count and
serum chemistry
Complete blood count assessment at D0 and D28 (data
not shown) and serum chemistry evaluations (Table2)
revealed no significant changes over time or between
groups for any parameter assessed. Of interest is
that no significant changes in the treatment group or
placebo group were observed for any of the hepatic
enzymes [alanine aminotransferase (ALT), aspartate
aminotransferase (AST) and ALP] before D0 and after
28 days of twice- daily treatment. While not significant,
ALP was elevated outside the reference range in six of
17 treatment group dogs at D28. Two of these six dogs
had elevated ALP at D0 and four dogs had ALP within
the reference range at baseline. ALP that was elevated
FIGURE 1 Dot plots for owner pruritus Visual Analog Scale
(pVAS) scores following treatment with cannabidiol (CBD)/
cannabidiolic acid (CBDA) or placebo. (a) Placebo group at Day
(D)0, D14 and D28. P- values indicate no significance from baseline
scores. (b) treatment group at D0, D14 and D28. Significant
p - values were observed from D0 to D14 (p =0.04) and D0D28
(p =0.01), and not D14– D28 (p =1.0). (c) Mean change in score
from baseline at D14 and D28 in treatment and placebo groups.
Statistical significance was observed when examining change
from baseline pVAS at D14 between treatment and placebo groups
(p =0.04), and not at D28 (p =0.054)
(a)
(b)
(c)
FIGURE 2 Canine Atopic Dermatitis Extent and Severity Index,
4th iteration (CADESI- 04) lesion scoring by veterinary surgeons.
(a) Dot plots at Day (D)0, D14 and D28 in the placebo group. No
statistical significance from baseline or across days of treatment
was observed. (b) Dot plots at D0, D14 and D28 in the treatment
group. No statistical significance from baseline or across days of
treatment was observed
(a)
(b)
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at baseline in one dog from the treatment group de-
creased from 771 to 744 IU/L, and elevated ALP in an-
other dog increased from 336 to 1164 IU/L.
Adverse events
Adverse events are reported in Table1. In the treat-
ment group, AEs included lethargy, defined as loss of
energy (dogs 1,18), behavioural changes (dogs 1, 3, 9,
18, 21, 32), regurgitation (Dog 11), increased flatulence
(Dog 3), and inconsistent appetite (Dog 1). Behavioural
changes reported included: somnolence, sleepiness
(dogs 1, 18), decreased aggression (Dog 9) and in-
creased calmness (dogs 9, 21, 32). Two dogs had in-
creased energy/mobility (dogs 3, 11).
In the placebo group, one dog experienced diarrhoea
and regurgitation (Dog 13). Lethargy and behavioural
changes in one dog led to its exclusion after 14 days
(Dog 6).
Cannabidiol/CBDA concentrations
Sixteen of the 17 dogs that had sufficient serum re-
maining after cytokine analysis had serum CBD/
CBDA analysis. Median cannabidiol serum concentra-
tions after 28 days of treatment was 112 ng/ml (range:
301350 ng/ml). The median CBDA serum level after
28 days of treatment was 48 ng/ml (range 10 168 mg/
ml) (Table1). Further regression statistics examin-
ing combined CBD/CBDA concentration in the serum
compared to decrease in pVAS score at D28 showed a
significant correlation with R=0.53 suggesting a mod-
est correlation with decrease in pVAS score and serum
total CBD/CBDA concentration (p=0.03; Figure3).
DISCUSSION
Results of this study indicated that CBD/CBDA does
not affect lesion severity yet does have a positive ef-
fect on pruritus as an adjunct therapy in some dogs
with cAD.
Using the criterion of ≥2cm improvement in pVAS,
nine of 17 dogs at D14 and 11 of 17 at D28 clinically
and statistically improved in the treatment group,
whereas zero of 12 dogs at D14 and two of 12 at D28
improved in the placebo group. Although there was a
statistically significant decrease in mean pVAS scores
from baseline between groups at D14, there was no
significant difference at D28 even though there was a
TAB LE 2 Mean (±SD) of selected serum chemistry parameters measured at Day (D)0 and D28 for dogs in the placebo and treatment
groups. Significance for treatment, time and treatment × time was set at p≤ 0.05
Parameter (ref. range)
Treatment
D0
Treatment
D28
Placebo
D0
Placebo
D28 Time
P
Treatment
Treatment
× time
Glucose (74– 143 mg/dl) 103± 10 101± 17 104± 12 105± 10 0.92 0.6 0.63
Creatinine (0.5– 1.8mg/dl) 1.0± 0.2 1.0± 0.2 1.0± 0.2 1.1± 0.2 0.46 0.42 0.58
Urea nitrogen (7– 27 mg/dl) 16± 6 16± 7 14.2± 3.0 14.3± 3.4 0.85 0.08 0.96
Phosphorus (2.5– 6.8mg/dl) 3.6± 0.8 3.6± 0.8 4 .1± 0.6 4 .3± 0.7 0.68 <0.01 0.48
Calcium (7.9– 12.0 mg/dl) 10.0± 0.4 9.7± 0.5 9.7± 0.5 9.7± 0.6 0.17 0.24 0.45
Total protein (5.2– 8.2g/dl) 6.9± 0 .6 7± 0.5 6.8± 0.3 7.0± 0.6 0.65 0.84 0.48
Albumin (2.3– 4.0 g/dl) 3.4± 0.2 3.3± 0.3 3.3± 0. 3 3.4± 0.6 0.85 0.68 0.52
Globulin (2.5– 4.5g/dl) 3.6± 0.6 3.6± 0.4 3.5± 0. 3 3.7± 0.3 0.59 0.93 0.78
ALT (10– 125 U/L) 59± 3 5 55± 25 77± 52 5 9± 42 0.26 0.28 0.46
AST (0– 50 U/L) 46± 21 4 0± 14 36± 10 47± 22 0.52 0.93 0.07
ALP (23– 212 U/L) 117± 186 215± 30 3 102± 92 9 6± 79 0.32 0.11 0.27
GGT (0 – 11 U/L) 5± 3 5± 3.7 4.2± 2.8 4.5± 3.5 0.56 0.22 0.89
Bilirubin (0.0– 0.9mg/dl) 0.4± 0.2 0.4± 0.6 0.3± 0 .2 0.5± 0. 8 0.33 0.87 0.75
Cholesterol (110– 320 mg/dl) 242± 57 237± 61 211± 4 9 207± 48 0.76 <0.01 0.98
Abbreviations: ALP, alkaline phosphatase activity; ALT, alanine aminotransferase activity; AST, aspartate aminotransferase activity; GGT, gamma glutamyl
transferase activity.
TAB LE 3 Mean (±SD) serum cytokine measurements at Day (D)0 and D28 including monocyte chemotactic protein- 1 (MCP- 1),
interleukin (IL)- 6, IL- 8, IL- 31 and IL- 34. No significances in treatment, time or treatment × time were noted
Cytokine Treatment D0
Treatment
D28 Placebo D0 Placebo D28 Time
P
Treatment Tre atment × t ime
MCP- 1 (pg/ml) 376.5± 4 04.5 325.8± 215.3 22 8.7± 123.9 258 .4± 147. 8 0.86 0.08 0.51
IL- 6 (pg /ml ) 17.5± 8 .7 17.6± 9 .2 17.9± 17.4 18.1± 17. 4 0.81 0.42 0.94
IL- 8 (pg /ml) 27 78± 293 8 24 97± 2246 1802± 1697 1857± 1715 0.82 0.37 0.61
IL- 31 (pg/ ml ) 3 21.4± 238.4 386 .9± 44 8.4 310.7± 248.5 3 64.3± 2 58.7 0.42 0.75 0.93
IL- 3 4 (p g/m l) 29.3± 28 .4 2 9.2± 28.7 24.6± 10.3 23.6± 11.3 0.71 0.11 0.72
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CAN NABIDIO L FOR ATOPIC DER MATITIS IN D OGS
positive trend. There was a significant difference in af-
firmative answers to the question, “Did you notice an
improvement in your dog's itch throughout the study?”
between groups, supporting a treatment effect.
The pruritus reduction in the treatment group com-
pared to placebo from baseline was observed at both
time points, yet the significant difference shown be-
tween the groups at D14 only could be the result of
several factors. Dogs may develop a tolerance for CBD
over time, as has been seen in mice.25 Due to CBD
potential actions at the TRPV receptor systems, there
may be desensitisation of these receptor systems to
long- term treatment.12,17 In addition, tolerance may be
caused by the hepatic metabolism of CBD induction
of cytochrome p450 enzymes. This may require alter-
ation of the dose to better tailor treatment to effect.
Furthermore, it is recognised that some of the concur-
rent therapies that our population was receiving also
may alter cytochrome p450 enzyme metabolism, fur-
ther complicating the potential synergies between can-
nabinoids. Unfortunately, as a consequence of the low
sample size, this could not be evaluated or elucidated
so further studies are warranted. Based on our regres-
sion statistics, higher serum concentrations appear to
be associated with better clinical effect for the reduc-
tion of pruritus. Serum concentration measurements
may be indicated in the future to determine optimal
dosing regimes.
There was a decrease in pruritus and not
CADESI- 04. In a multicentre, open- label, observational
study using the same scoring methodology, PEA, an
endocannabinoid- like molecule, reduced skin lesions
and pruritus in atopic dogs.10 However, that study's du-
ration was 8 weeks and, furthermore, PEA may have
direct action at the CB1 and CB2 receptors which CBD
does not, leaving this question open regarding CB1/CB2
agonists and cAD resolution. It is possible, however un-
likely, that a longer study duration might be needed for
the study of CBD/CBDA to see true anti- inflammatory
effects. Additionally, CADESI- 04 is less sensitive to
changes in short- term trials because secondary skin
lesions resolve slowly. This also may have contributed
to lack of improvement in skin lesions.26
The lack of improvement in lesions also may be
explained by CBD predominantly affecting the neuro-
logical (endocannabinoid) pathway rather than inflam-
matory cells.12,17,18 Thus, pruritus may be improved
without a change in the cytokine profile that has been
associated with skin lesions in cAD. We found no sig-
nificant change in serum cytokine levels over time,
suggesting that the effects of CBD are through other
mechanistic means of neuronal control rather than
cytokine- driven alterations. Five of the 17 dogs in the
treatment group had reported lethargy or calmness,
and it is possible that neurological status changed due
to the CBD treatment, resulting in reduced perception
or manifestations of pruritus. It is important to note
that serum cytokine concentrations do not necessarily
reflect those in skin lesions, and future studies evaluat-
ing the effects of CBD on skin cytokine concentrations
would be useful.
A secondary objective of this study was to deter-
mine the AEs associated with CBD. Three clinical ther-
apeutic studies in dogs using CBD noted elevations in
serum ALP after therapy.5, 7,2 7 In our study, four dogs in
the treatment group had elevations above the reference
range after receiving CBD for 28 days. The ALP eleva-
tions presumably are due to upregulation of CYP450
enzymes. These elevations have been reported with
prolonged exposure to hemp- derived CBD or cannabis
in humans and were considered adaptive and demon-
strated reversibility.28 Studies in dogs and cats did not
demonstrate significant rises outside normal reference
ranges in any enzymes associated with the hepatobili-
ary system.2,29 A previous study employing the same
product and dose as we used herein showed that
healthy dogs treated twice daily for 3 months showed
no evidence of hepatotoxicity, indicating that CBD at
this dose is probably safe.29
The role of CYP in the metabolism of CBD raises the
question of drug interactions with concomitant medi-
cations. The four dogs on CBD with elevations in ALP
outside the reference range were on concomitant med-
ications, and three were on two or more. Ketoconazole,
fluconazole and ciclosporin are all CYP450 substrates
and oclacitinib and terbinafine are metabolised by the
liver.30 Interaction of CBD with one of these drugs, or
possibly the combination, may be relevant and future
studies are warranted.
Adverse events were considered mild, especially
given that no dogs were withdrawn from the treatment
group. Additionally, the majority of owners whose dogs
were in the treatment group (10 of 17) answered that
they would use the product again, and only two of 13
in the placebo group were willing to continue use. Only
one owner (of Dog 1) in the treatment group cited ad-
verse events as the reason for why he would not use
this product again in their dog, although an improve-
ment in itch was noted. One owner in the placebo
group withdrew from the study as a consequence of
perceived behavioural changes and no resolution of
cAD in their dog.
FIGURE 3 Regression of total cannabidiol (CBD)/ cannabidiolic
acid (CBDA) concentration in serum relative to change in pruritus
Visual Analog Scale (pVAS) score at Day 28 in 16 dogs on CBD- rich
hemp treatment
336
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Veterinary Dermatology
LOEWI NGER Et aL .
The serum CBD concentrations described in this
study were consistent with previously reported values
at approximately 2mg/kg of CBD.5,31 All dogs in the
treatment group had measurable CBD (301350 ng/
ml) and CBDA (10– 169 ng/ml) concentrations after
treatment. The therapeutic level for serum CBD con-
centration is not currently known. The wide range in
individual serum CBD concentrations is similar to three
pharmacokinetic studies examining this product in the
dog.2,5,29 CBD administered to dogs orally in powder
form was reported to have low bioavailability in an early
pharmacokinetics study.32 The absorption in our study
may be greater because of the lipophilic oil- based ve-
hicle and the results cannot be extrapolated to all prod-
ucts marketed as “hemp- rich CBD.”32,33 However, the
interindividual differences observed in our study and
others suggest that serum concentration monitoring
could be useful.2,5,8,29
Limitations of this study include a small sample
size and administration of concomitant therapies. This
study also evaluated only short- term effects, and a
longer study duration is indicated in future studies to
determine long- term effects. Although this was a ran-
domised study, more patients were on concomitant
therapies in the treatment group than in the placebo
group which were beyond our control during randomi-
sation processes during enrollment. These differences
were corrected for statistically, yet this is a limitation of
this study.
CONCLUSIONS
Our results suggest that CBD as an adjunct therapy is
useful in decreasing pruritus in some dogs with cAD.
CBD at 2 mg/kg twice daily was well- tolerated with
minimal AEs.
ACKNOWLEDGEMENTS
The authors would like to thank Ellevet Sciences for
providing funding, CBD/CBDA product and matching
placebos.
CONFLICT OF INTEREST
Andrew Rosenberg serves on the advisory board of
Ellevet Sciences and Joseph J. Wakshlag is currently
the medical director of Ellevet Sciences. The funding
was provided by Ellevet Sciences. Ellevet Sciences
was not involved in the study design, collection, anal-
ysis, interpretation of data, writing or the decision to
submit this article for publication.
AUTHOR CONTRIBUTIONS
Melissa Loewinger:Conceptualization; funding ac-
quisition; investigation; methodology; project adminis-
tration; writing – original draft. Joseph J. Wakshlag:
Data curation; formal analysis; investigation; methodol-
ogy; resources; software; validation; writing – review
and editing. Daniel G. Bowden: Investigation; writ-
ing – review and editing. Jeanine Peters- Kennedy:
Investigation; writing – review and editing. Andrew S.
Rosenberg: Conceptualization; investigation; method-
ology; resources; writing – review and editing.
ORCID
Melissa Loewinger https://orcid.
org/0000-0002-3643-5618
Jeanine Peters- Kennedy https://orcid.
org/0000-0001-9610-9040
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SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of the article at the publisher’s website.
How to cite this article: Loewinger M, Wakshlag
JJ, Bowden D, Peters- Kennedy J, Rosenberg A.
The effect of a mixed cannabidiol and cannabidiolic
acid based oil on client- owned dogs with atopic
dermatitis. Vet Dermatol. 2022;33:329e77.
htt ps://doi.org/10.1111/ vde.13077
Résumé
Contexte - Le cannabidiol (CBD) et l'acide cannabidiolique (CBDA) auraient des actions antinociceptives, immu-
nomodulatrices et anti- inflammatoires.
Objectifs – Déterminer si le CBD/CBDA est une thérapie efficace pour la dermatite atopique canine (cAD).
Animaux – Trente- deux chiens de propriétaires privés atteints de cAD
Matériels et méthodes – Étude prospective, randomisée, en double aveugle, contrôlée versus placebo. Les thé-
rapies concomitantes étaient autorisées si elles restaient inchangées. Les chiens ont été répartis au hasard pour
recevoir soit 2 mg/kg d'un mélange égal de CBD/CBDA (n = 17) soit un placebo pendant quatre semaines. Aux
jours (J)0, J14 et J28, les scores Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI- 04) et
prurit Visual Analog Scale (pVAS) ont été déterminés respectivement par les investigateurs et les propriétaires. Une
formule sanguine complète, des profils biochimiques sériques et des dosages biologiques des cytokines ont été
réalisés sur le sérum prélevé à J0 et J28.
Résultats – Il n'y avait pas de différence significative au CADESI- 04 de J0 à J14 (P = 0,42) ou J28 (P = 0,51) dans
les deux groupes. Les scores pVAS étaient significativement inférieurs pour le groupe de traitement à J14 (P =
0,04) et J28 (P = 0,01) et un changement significatif de la pVAS par rapport à l'inclusion a été observé à J14 (P =
0,04) et non à J28 (P = 0,054) entre les groupes. Il n'y avait pas de différence significative dans les taux sériques
d'interleukine (IL)- 6, IL- 8, protéine chimiotactique des monocytes- 1, IL- 31 ou IL- 34 entre les groupes à J0 ou J28.
Une phosphatase alcaline élevée a été observée chez quatre des 17 chiens du groupe de traitement.
Conclusions et pertinence clinique - Le CBD/CBDA en tant que traitement d'appoint a diminué le prurit, et non
les lésions cutanées associées à la DAC chez les chiens.
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LOEWI NGER Et aL .
Resumen
Introducción- se ha descrito que el cannabidiol (CBD) y el ácido cannabidiólico (CBDA) tienen acciones antinocic-
eptivas, inmunomoduladoras y antiinflamatorias.
Objetivos- determinar si el CBD/CBDA es una terapia eficaz para la dermatitis atópica canina (CAD).
Animales - Treinta y dos perros de propietarios privados con cAD
Materiales y métodos Estudio prospectivo, aleatorio, doble ciego, controlado con placebo. Se permitieron
terapias concurrentes si permanecían sin cambios. Los perros fueron asignados al azar para recibir 2 mg/kg de una
mezcla igual de CBD/CBDA (n = 17) o placebo durante cuatro semanas. En el día (D)0, D14 y D28, los investiga-
dores y los propietarios determinaron las puntuaciones del índice de extensión y gravedad de la dermatitis atópica
canina, cuarta revisión (CADESI- 04) y la escala análoga visual de prurito (pVAS), respectivamente. Se realizaron
hemogramas completos, perfiles bioquímicos séricos y bioensayos de citoquinas en suero obtenido en D0 y D28.
Resultados- no hubo diferencias significativas en CADESI- 04 de D0 a D14 (P = 0,42) o D28 (P = 0,51) en ninguno
de los grupos. Las puntuaciones de pVAS fueron significativamente más bajas para el grupo de tratamiento en D14
(P = 0.04) y D28 (P = 0.01) y se observó un cambio significativo en pVAS desde el inicio en D14 (P = 0.04) y no en
D28 (P = 0.054) entre grupos . No hubo diferencias significativas en los niveles séricos de interleuquina (IL)- 6, IL- 8,
proteína quimioatrayente de monocitos- 1, IL- 31 o IL- 34 entre los grupos en D0 o D28. Se observó fosfatasa alcalina
elevada en cuatro de los 17 perros del grupo de tratamiento.
Conclusiones y relevancia clínica- CBD/CBDA como terapia adjunta disminuyó el prurito y no las lesiones cu-
táneas asociadas con la CAD en perros.
Zusammenfassung
Hintergrund Eine antinozizeptive, immunmodulatorische und entzündungshemmende Wirkung von Cannabidiol
(CBD) und Cannabidiolsäure (CBDA) ist beschrieben.
Ziele Es sollte festgestellt werden, ob CBA/CBDA eine wirksame Therapie für die atopische Dermatitis (cAD)
des Hundes darstellt.
Materialien und Methoden Es handelt sich um eine prospektive, randomisierte, doppelblinde, Plazebo-
kontrollierte Studie. Begleitende Behandlungen waren erlaubt, sofern sie nicht verändert wurden. Die Hunde wur-
den zufällig eingeteilt, um entweder 2 mg/kg einer gleichen Mischung von CBD/CBDA (n = 17) oder Plazebo
vier Wochen lang zu erhalten. Am Tag (D) 0, D14 und D28 wurden mittels Canine Atopic Dermatitis Extent and
Severity Index, 4th iteration (CADESI- 04) bzw Pruritus Visual Analog Scale (pVAS) entsprechende Werte durch
UntersucherInnen bzw BesitzerInnen bestimmt. Es wurden ein großes Blutbild, Serum Biochemie und Zytokin
Assays am Serum, welches an D0 und D28 genommen wurde, durchgeführt.
Ergebnisse Es bestand in keiner der Gruppen ein signifikanter Unterschied des CADESI- 04 zwischen D0 und
D14 (P = 0,42) oder D28 (P = 0,51). pVAS Werte waren in der Behandlungsgruppe am D14 (P = 0,04) und am D28 (P
= 0,01) signifikant niedriger und eine signifikante Veränderung der pVAS Basiswerte zwischen den Gruppen wurde
am D14 (P = 0,04) und nicht am D28 (P = 0,054) gefunden. Es bestand kein signifikanter Unterschied zwischen
den Serumwerten von Interleukin (IL)- 6, IL- 8, Monozyten Chemoattractant Protein- 1, IL- 31 oder IL- 34 zwischen
den Gruppen am D0 oder D28. Es wurden bei Hunden in vier der 17 Behandlungsgruppen erhöhte Werte der
Alkalischen Phosphatase gefunden.
Schlussfolgerungen und klinische Bedeutung CBD/CBDA als Zusatztherapie verminderte den Juckreiz, aber
nicht die Hautveränderungen, die mit cAD bei Hunden einhergehen.
要約
背景 - カンナビジオール (CBD) およびカンナビジオール(CBDA) は抗侵害受容作用免疫調節作用抗炎症作用
すると報告されている。
本研究の目的は、CBD/CBDAが犬アトピー性皮膚炎 (cAD) に対して有効な治療法であかどかを明らかにする
ことであった
被検動物 - cAD を有するオーナー所有犬 32 頭
材料と方法 - 前向き無作為化二重盲検プラセボ対照試験。併用療法は、化がない場合は許可された。犬はCBD/CBDA
の等量混合物2mg/kg(n = 17)たはプラセボのいずれかを4週間投与するよう無作為に割り当てられた。D0、D14およ
D28に犬アトピー性皮膚炎の程度および重症度指数 (CADESI- 04)痒みのビジアナログスケー (pVAS) スコ
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Veterinary Dermatology
CAN NABIDIO L FOR ATOPIC DER MATITIS IN D OGS
アを それ ぞれ 調 査員 い主 定した D 0 とD 2 8 取した血 につ いて、 球数 学プ ロファイル、
・バ
結果 - CADESI- 04のD0からD14(P = 0.42) またはD28(P = 0.51) まいずれの群でも有意差はなかった。pVASスコア
はD14(P = 0.04) およびD28(P = 0.01) で治療群に有意に低く、ベースラインからのpVASの有意変化はD14(P = 0.04) で
見られ、D28(P = 0.054) では認められなかった。インターロイキン (IL)- 6、IL- 8、球走化性タンパク質- 1、IL- 31、IL- 34
血清レベルには、D0とD28で群間に有意な差はなかった。アルカリフォスフターゼの昇が17頭中4頭で観察された。
結論および臨床的意義 - CBD/CBDAを補助療法とて投与することcADに関連する皮膚病変ではなく犬の痒み
させることがで きた
摘要
背景- 据报告, 大麻二醇(CBD)和大麻二酚酸(CBDA)具有镇痛免疫调节和抗炎作用
目的 - 确定CBD/CBDA否是犬特应性皮炎(cAD) 法。
动物- 32只患有cAD 犬。
材料和方 - 性、 机、 盲、安 究。如 , 允许合并治疗将犬随机分配2 mg/kg CBD/CBDA
混合物组(n = 17)或安慰剂组, 持续 4周。在 (D)0天、第 14天和第28, 由研究者和犬主人分别测定犬特应性皮炎程度和
数、第 4(CADESI- 04)和瘙痒视觉模拟量表(pVAS) 分。对 D0D28采集的血清进行全血细胞计数血清生化特
征和细胞因子生物测定
结果- 组中从 D0D14(P = 0.42)D28(P = 0.51)CADESI- 04 。治 D14(P = 0.04)D28(P = 0.01)
pVAS评分显著 降低 , D14(P = 0.04)而非D28(P = 0.01)观察到pVAS相对于基线的显著变化.054) D0D28,
间血清白细胞介素 (IL)- 6IL- 8、单 - 1IL- 31IL- 34 。在 17只治疗组犬的 4只中观
高。
结论和临床相关性– CBD/CBDA作为辅助治疗减少了犬中的瘙痒, 而对cAD 效。
Resumo
Contexto – O canabidiol (CBD) e ácido canabidiólico (CBDA) são relatados como tendo ações antinociceptivas,
imunomoduladoras e anti- inflamatórias.
Objetivos – Determinar se CBD/CBDA é eficaz no tratamento da dermatite atópica canina (CAD)
Animais - Trinta e dois cães de propriedade privada com DAC.
Materiais e métodos - Estudo prospectivo, randomizado, duplo- cego, placebo- controle. As terapias concomi-
tantes foram permitidas se permanecessem inalteradas. Os cães foram divididos aleatoriamente em dois grupos,
o que receberia 2 mg/kg de uma mistura igual de CBD/CBDA (n = 17) ou placebo durante quatro semanas. No
Dia (D) 0, D14 e D28, o Índice de Extensão e Gravidade da Dermatite Atópica Canina, 4ª iteração (CADESI- 04) e
os escores da Escala Visual Analógica de Prurido (pVAS) foram determinados pelos investigadores e proprietários,
respectivamente. Hemograma completo, perfis bioquímicos séricos e ensaios de citocinas foram realizados no
soro coletado em D0 e D28.
Resultados - Não houve diferença significativa no CADESI- 04 de D0 a D14 (P = 0,42) ou D28 (P = 0,51) em nen-
hum dos grupos. Os escores de pVAS foram significativamente menores para o grupo de tratamento no D14 (P =
0,04) e D28 (P = 0,01) e observou- se uma alteração significativa no pVAS do D0 comparado ao D14 (P = 0,04) e não
ao D28 (P = 0,054) entre os grupos. Não houve diferença significativa nos níveis séricos de interleucina (IL)- 6, IL-
8, proteína quimiotática de monócitos- 1, IL- 31 ou IL- 34 entre os grupos em D0 ou D28. Elevação na fosfatase
alcalina foi observada em quatro dos 17 cães do grupo de tratamento.
Conclusões e relevância clínica – CBD e CBDA como uma terapia adjuvante é capaz de reduzir prurido, mas não
lesões cutâneas associadas à DAC em cães.
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