Received: 21 August 2021 | Accepted: 9 February 2022
DOI: 10.1111/vde.13077
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 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.
K E YWORDS
acid, atopic, canine, cannabidiol, cannabidiolic, dermatitis, hemp
INTRODUCTION
Canine atopic dermatitis (cAD) is a common inflammatory
and pruritic allergic skin disease that is characterised
by excessive immunoglobulin (Ig)E production
directed against allergens. Due to the multifactorial and
progressive nature of the disease, multimodal and individualised
therapeutic regimens often are indicated.1
Cannabinoids are a unique group of chemical compounds
found in Cannabis sativa plants. Cannabidiol
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LOEWINGER et al.
(CBD) is the predominant nonpsychotropic cannabinoid
found in the cannabis plant and as such,
CBD-rich
plants are classified as hemp rather than
marijuana. Cannabidiolic acid (CBDA) is the precursor
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 keratinocytes,
with immunoreactivity to CB1 and CB2
being heightened in atopic dogs compared to healthy
dogs.9 Cannabinoid receptor agonists reduce skin lesions
and pruritus in atopic dogs, and attenuated inflammation
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 altering
endogenous levels of naturally derived endocannabinoids
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 determining
whether CBD-rich
hemp extract caused any
adverse effects through client surveys, routine complete
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 placebo
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 diagnosed
with cAD based on published guidelines were
enrolled.19 Dogs included in the study met the following
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) maintained flea prevention throughout study. Dogs were excluded if: (i) there was clinical evidence 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 injection were used less than 8 weeks before enrollment; (v) allergen-specific immunotherapy (ASIT) was introduced <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, terbinafine 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 performed 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 treatment was effective at the conclusion of the study in a standard written survey (see Supporting information Appendix S1). Assessment of efficacy The outcome measures were the differences in pruritus and lesion severity at D14 and D28 from baseline. Treatment was considered successful if the 13653164, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vde.13077 by CochraneItalia, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 331 Veterinary Dermatology CANNABIDIOL FOR ATOPIC DERMATITIS IN DOGS pVAS and/or CADESI-04 scores showed a statistically 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 withdrawals at any time during the study. All AEs that occurred during the study were recorded by a noninvestigator to maintain blinding on an AE reporting form, together with their onset, severity and perceived association 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 approximately 30 mg/ml CBD, 31 mg/ml CBDA, 1.2 mg Δ9-THC and 1.3 mg/ml THCA provided in gelatin capsules in 5, 10, 20 and 30 mg/ml CBD/CBDA increments for dosing. The placebo was sesame oil-filled capsules of similar increments. Dogs were administered CBD/CBDA (approximately 2 mg/kg) or placebo, 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 chemoattractant protein (MCP)-1( Millipore), and IL-31 and IL-34 (MBS039863, MyBiosource) were evaluated from serum on D0 and D28. All kits were used according 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 research 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 continuous 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 comparisons 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 treatment 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 Shapiro–Wilk 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 variance Student’s t-test at D14 and D28 to assess significant 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 concentration in the serum using Pearson’s linear regression. A p-value <0.05 was considered significant. The correlation 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.).
RESULTS
Thirty-two
dogs were enrolled (Table 1). Three dogs
were excluded from the full data analysis: one dog
dropped out after 2 weeks as a result of perceived behavioural
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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LOEWINGER et al.
placebo group were 5.6 ± 1.4, 5.1 ± 1.7 and 5.0 ± 2.0,
respectively. The pVAS scores were statistically significantly
lower for the treatment group at both time
points (D14: p = 0.04, D28: p = 0.01), and a significant
decrease in pVAS from baseline was seen at D14
(p = 0.04) and not D28 (p = 0.054) when comparing
treatment and placebo groups (Figure 1a–c).
Using
criteria of ≥2 cm improvement to evaluate clinical significance,
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 (Figure 2a and b).
Cytokines
Cytokine means (±SD) including MCP-1,
IL-6,
IL-8,
IL-31
and IL-34
can be found in Table 2. There were no
TABLE 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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CANNABIDIOL FOR ATOPIC DERMATITIS IN DOGS
significant differences noted between treatment, time,
or treatment × time for any of the cytokines measured
at D0 and D28 (Table 3).
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 answered
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 adverse
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 (Table 2)
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 D0–D28
(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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LOEWINGER et al.
at baseline in one dog from the treatment group decreased
from 771 to 744 IU/L, and elevated ALP in another
dog increased from 336 to 1164 IU/L.
Adverse events
Adverse events are reported in Table 1. In the treatment
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 increased
calmness (dogs 9, 21, 32). Two dogs had increased
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 remaining
after cytokine analysis had serum CBD/
CBDA analysis. Median cannabidiol serum concentrations
after 28 days of treatment was 112 ng/ml (range:
30–1350
ng/ml). The median CBDA serum level after
28 days of treatment was 48 ng/ml (range 10 168 mg/
ml) (Table 1). Further regression statistics examining
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 modest
correlation with decrease in pVAS score and serum
total CBD/CBDA concentration (p = 0.03; Figure 3).
DISCUSSION
Results of this study indicated that CBD/CBDA does
not affect lesion severity yet does have a positive effect
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
TABLE 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 ± 35 55 ± 25 77 ± 52 59 ± 42 0.26 0.28 0.46
AST (0–50
U/L) 46 ± 21 40 ± 14 36 ± 10 47 ± 22 0.52 0.93 0.07
ALP (23–212
U/L) 117 ± 186 215 ± 303 102 ± 92 96 ± 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 ± 49 207 ± 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.
TABLE 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 Treatment × time
MCP-1
(pg/ml) 376.5 ± 404.5 325.8 ± 215.3 228.7 ± 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) 2778 ± 2938 2497 ± 2246 1802 ± 1697 1857 ± 1715 0.82 0.37 0.61
IL-31
(pg/ml) 321.4 ± 238.4 386.9 ± 448.4 310.7 ± 248.5 364.3 ± 258.7 0.42 0.75 0.93
IL-34
(pg/ml) 29.3 ± 28.4 29.2 ± 28.7 24.6 ± 10.3 23.6 ± 11.3 0.71 0.11 0.72
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CANNABIDIOL FOR ATOPIC DERMATITIS IN DOGS
positive trend. There was a significant difference in affirmative
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 compared
to placebo from baseline was observed at both
time points, yet the significant difference shown between
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 alteration
of the dose to better tailor treatment to effect.
Furthermore, it is recognised that some of the concurrent
therapies that our population was receiving also
may alter cytochrome p450 enzyme metabolism, further
complicating the potential synergies between cannabinoids.
Unfortunately, as a consequence of the low
sample size, this could not be evaluated or elucidated
so further studies are warranted. Based on our regression
statistics, higher serum concentrations appear to
be associated with better clinical effect for the reduction
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 duration
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 unlikely,
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 neurological
(endocannabinoid) pathway rather than inflammatory
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 significant
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 evaluating
the effects of CBD on skin cytokine concentrations
would be useful.
A secondary objective of this study was to determine
the AEs associated with CBD. Three clinical therapeutic
studies in dogs using CBD noted elevations in
serum ALP after therapy.5,7,27 In our study, four dogs in
the treatment group had elevations above the reference
range after receiving CBD for 28 days. The ALP elevations
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 demonstrated
reversibility.28 Studies in dogs and cats did not
demonstrate significant rises outside normal reference
ranges in any enzymes associated with the hepatobiliary
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 medications.
The four dogs on CBD with elevations in ALP
outside the reference range were on concomitant medications,
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 adverse
events as the reason for why he would not use
this product again in their dog, although an improvement
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
13653164, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vde.13077 by CochraneItalia, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
336 |
Veterinary Dermatology
LOEWINGER 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 (30–1350
ng/
ml) and CBDA (10–169
ng/ml) concentrations after
treatment. The therapeutic level for serum CBD concentration
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
vehicle
and the results cannot be extrapolated to all products
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 randomised
study, more patients were on concomitant
therapies in the treatment group than in the placebo
group which were beyond our control during randomisation
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, analysis,
interpretation of data, writing or the decision to
submit this article for publication.
AUTHOR CONTRIBUTIONS
Melissa Loewinger:Conceptualization; funding acquisition;
investigation; methodology; project administration;
writing –original
draft. Joseph J. Wakshlag:
Data curation; formal analysis; investigation; methodology;
resources; software; validation; writing –review
and editing. Daniel G. Bowden: Investigation; writing
–review
and editing. Jeanine Peters-Kennedy:
Investigation; writing –review
and editing. Andrew S.
Rosenberg: Conceptualization; investigation; methodology;
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;33:329–e77.
https://doi.org/10.1111/vde.13077
Résumé
Contexte -Le
cannabidiol (CBD) et l’acide cannabidiolique (CBDA) auraient des actions antinociceptives, immunomodulatrices
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 thérapies
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.
13653164, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vde.13077 by CochraneItalia, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
e76 |
Veterinary Dermatology
LOEWINGER et al.
Resumen
Introducción-se
ha descrito que el cannabidiol (CBD) y el ácido cannabidiólico (CBDA) tienen acciones antinociceptivas,
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 investigadores
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 cutáneas
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 wurden
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酸 (CBDA) は、抗侵害受容作用、免疫調節作用、抗炎症作用を
有すると報告されている。
目的 –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るかどうかを明らかにする
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、変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) ま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および
D28に、犬アトピー性皮膚炎の程度および重症度指数 (CADESI-04)
、痒みのビジュアルアナログスケール (pVAS) スコ
13653164, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vde.13077 by CochraneItalia, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| e77
Veterinary Dermatology
CANNABIDIOL FOR ATOPIC DERMATITIS IN DOGS
アをそれぞれ調査員、飼い主が決定した。D0とD28に採取した血清について、全血球数、血清生化学プロファイル、サイト
カイン・バイオアッセイ法を実施した。
結果 -CADESI-
04
のD0からD14(P = 0.42) またはD28(P = 0.51) まで、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
、単球走化性タンパク質-1
、IL-31
、IL-34
の
血清レベルには、D0とD28で群間に有意な差はなかった。アルカリフォスファターゼの上昇が17頭中4頭で観察された。
結論および臨床的意義 -CBD/
CBDAを補助療法として投与することで、cADに関連する皮膚病変ではなく、犬の痒みを
減少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是否是犬特应性皮炎(cAD)的有效疗法。
动物-32
只患有cAD的私家犬。
材料和方法-
前瞻性、随机、双盲、安慰剂对照研究。如果保持不变, 允许合并治疗。将犬随机分配至2 mg/kg CBD/CBDA等
混合物组(n = 17)或安慰剂组, 持续4周。在第(D)0天、第14天和第28天, 由研究者和犬主人分别测定犬特应性皮炎程度和
严重指数、第4版(CADESI-04)
和瘙痒视觉模拟量表(pVAS)评分。对D0和D28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-
两组中从D0至D14(P = 0.42)或D28(P = 0.51)的CADESI-04
无显著差异。治疗组在D14(P = 0.04)和D28(P = 0.01)
的pVAS评分显著降低, 在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) 。D0或D28时, 组
间血清白细胞介素(IL)-6
、IL-8
、单核细胞趋化蛋白-1
、IL-31
或IL-34
水平无显著差异。在17只治疗组犬的4只中观察到碱性磷
酸酶升高。
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相关的皮肤病变无效。
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 concomitantes
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 nenhum
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.
13653164, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vde.13077 by CochraneItalia, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
