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Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs


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Objectives: The objectives of this study were to determine basic oral pharmacokinetics, and assess safety and analgesic efficacy of a cannabidiol (CBD) based oil in dogs with osteoarthritis (OA). Methods: Single-dose pharmacokinetics was performed using two different doses of CBD enriched (2 and 8 mg/kg) oil. Thereafter, a randomized placebo-controlled, veterinarian, and owner blinded, cross-over study was conducted. Dogs received each of two treatments: CBD oil (2 mg/kg) or placebo oil every 12 h. Each treatment lasted for 4 weeks with a 2-week washout period. Baseline veterinary assessment and owner questionnaires were completed before initiating each treatment and at weeks 2 and 4. Hematology, serum chemistry and physical examinations were performed at each visit. A mixed model analysis, analyzing the change from enrollment baseline for all other time points was utilized for all variables of interest, with a p ≤ 0.05 defined as significant. Results: Pharmacokinetics revealed an elimination half-life of 4.2 h at both doses and no observable side effects. Clinically, canine brief pain inventory and Hudson activity scores showed a significant decrease in pain and increase in activity (p < 0.01) with CBD oil. Veterinary assessment showed decreased pain during CBD treatment (p < 0.02). No side effects were reported by owners, however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment (p < 0.01). Clinical significance: This pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and activity in dogs with OA.
Content may be subject to copyright.
published: 23 July 2018
doi: 10.3389/fvets.2018.00165
Frontiers in Veterinary Science | 1July 2018 | Volume 5 | Article 165
Edited by:
Troy N. Trumble,
University of Minnesota Twin Cities,
United States
Reviewed by:
Gareth Edward Zeiler,
University of Pretoria, South Africa
Joao Henrique Neves Soares,
Virginia Tech, United States
Joseph J. Wakshlag
Specialty section:
This article was submitted to
Veterinary Surgery and
a section of the journal
Frontiers in Veterinary Science
Received: 25 February 2018
Accepted: 02 July 2018
Published: 23 July 2018
Gamble L-J, Boesch JM, Frye CW,
Schwark WS, Mann S, Wolfe L,
Brown H, Berthelsen ES and
Wakshlag JJ (2018)
Pharmacokinetics, Safety, and Clinical
Efficacy of Cannabidiol Treatment in
Osteoarthritic Dogs.
Front. Vet. Sci. 5:165.
doi: 10.3389/fvets.2018.00165
Pharmacokinetics, Safety, and
Clinical Efficacy of Cannabidiol
Treatment in Osteoarthritic Dogs
Lauri-Jo Gamble 1, Jordyn M. Boesch 1, Christopher W. Fr ye 1, Wayne S. Schwark2,
Sabine Mann 3, Lisa Wolfe 4, Holly Brown 5, Erin S. Berthelsen 1and Joseph J. Wakshlag 1
1Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States, 2Department
of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States, 3Department of
Population Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States, 4Proteomic and
Metabolomic Facility, Colorado State University, Fort Collins, CO, United States, 5Metzger Animal Hospital, State College,
PA, United States
Objectives: The objectives of this study were to determine basic oral pharmacokinetics,
and assess safety and analgesic efficacy of a cannabidiol (CBD) based oil in dogs with
osteoarthritis (OA).
Methods: Single-dose pharmacokinetics was performed using two different doses
of CBD enriched (2 and 8 mg/kg) oil. Thereafter, a randomized placebo-controlled,
veterinarian, and owner blinded, cross-over study was conducted. Dogs received each
of two treatments: CBD oil (2 mg/kg) or placebo oil every 12 h. Each treatment lasted
for 4 weeks with a 2-week washout period. Baseline veterinary assessment and owner
questionnaires were completed before initiating each treatment and at weeks 2 and 4.
Hematology, serum chemistry and physical examinations were performed at each visit.
A mixed model analysis, analyzing the change from enrollment baseline for all other time
points was utilized for all variables of interest, with a p0.05 defined as significant.
Results: Pharmacokinetics revealed an elimination half-life of 4.2 h at both doses and no
observable side effects. Clinically, canine brief pain inventory and Hudson activity scores
showed a significant decrease in pain and increase in activity (p<0.01) with CBD oil.
Veterinary assessment showed decreased pain during CBD treatment (p<0.02). No
side effects were reported by owners, however, serum chemistry showed an increase in
alkaline phosphatase during CBD treatment (p<0.01).
Clinical significance: This pharmacokinetic and clinical study suggests that 2 mg/kg
of CBD twice daily can help increase comfort and activity in dogs with OA.
Keywords: cannabidiol, CBD oil, hemp, canine, osteoarthritis, pharmacokinetic
Routine nonsteroidal anti-inflammatory drug (NSAID) treatments, though efficacious, may not
provide adequate relief of pain due to osteoarthritis (OA) and might have potential side effects
that preclude its use, particularly in geriatric patients with certain comorbidities, such as kidney
or gastrointestinal pathologies (14). In a systematic review of 35 canine models of OA and
29 clinical trials in dogs, treatment with NSAIDs caused adverse effects in 35 of the 64 (55%)
Gamble et al. Cannabidiol and Osteoarthritis in Dogs
studies, most commonly being gastro-intestinal signs (3).
Although other pharmacological agents are advocated, such as
gabapentin or amantadine, there is little evidence regarding their
efficacy in dogs with chronic or neuropathic pain related to OA.
Recent medical interest in alternative therapies and modalities for
pain relief has led many pet owners to seek hemp related products
rich in cannabinoids.
The endocannabinoid receptor system is known to play a
role in pain modulation and attenuation of inflammation (5
7). Cannabinoid receptors (CB1 and CB2) are widely distributed
throughout the central and peripheral nervous system (810) and
are also present in the synovium (11). However, the psychotropic
effects of certain cannabinoids prevent extensive research into
their use as single agents for pain relief (5,12). The cannabinoids
are a group of as many as 60 different compounds that may
or may not act at CB receptors. One class of cannabinoids,
cannabidiol (CBD), may actually be an allosteric non-competitive
antagonist of CB receptors (13). In lower vertebrates, CBD is also
reported to have immunomodulatory (14), anti-hyperalgesic (15,
16), antinociceptive (17,18), and anti-inflammatory actions (5,
19), making it an attractive therapeutic option in dogs with OA.
Currently there are several companies distributing nutraceutical
derivatives of industrial hemp, rich in cannabinoids for pets, yet
little scientific evidence regarding safe and effective oral dosing
The objectives of this study were to determine: (1) single-
dose oral pharmacokinetics, (2) short-term safety, and (3)
efficacy of this novel CBD-rich extract, as compared to
placebo, in alleviating pain in dogs with OA. Our underlying
hypotheses were that appropriate dosing of CBD-rich oil would
safely diminish perceived pain and increase activity in dogs
with OA.
CBD Oil and Protocols Approval
The industrial hemp used in this study was a proprietary
hemp strain utilizing ethanol and heat extraction with the final
desiccated product reconstituted into an olive oil base containing
10 mg/mL of CBD as an equal mix of CBD and carboxylic
acid of CBD (CBDa), 0.24 mg/mL tetrahydrocannabinol
(THC), 0.27 mg/mL cannabichromene (CBC), and 0.11 mg/mL
cannabigerol (CBG); all other cannabinoids were less than
0.01 mg/mL. Analysis of five different production runs using
a commercial analytical laboratory (MCR Laboratories,
Framingham, MA) show less than a 9% difference across batches
for each of the detected cannabinoids listed above. The study was
performed after the Cornell University institutional animal care
and use committee (IACUC) approved the study following the
guidelines for animal use according to the IACUC. Client owned
dogs were enrolled after informed consent in accordance with
the Declaration of Helsinki.
Abbreviations: CBD, cannabidiol; CB, cannabinoid; CBDa, carboxylic acid of
CBD; THC, tetrahydrocannabinol; CBC, cannabichromene; CBG, cannabigerol;
CBPI, Canine Brief Pain Inventory.
An initial investigation into single-dose oral pharmacokinetics
was performed with 4 beagles (3.5–7 years, male castrated, 10.7–
11.9 kg). Each dog received a 2 mg/kg and an 8 mg/kg oral
dosage of CBD oil, with a 2-week washout period between
each experiment. The dogs were fed 2 h after dosing. Physical
examination was performed at 0, 4, 8, and 24 h after dosing.
Attitude, behavior, proprioception, and gait were subjectively
evaluated at each time point during free running/walking
and navigation around standard traffic cones (weaving). Five
milliliters of blood was collected at time 0, 0.5, 1, 2, 4, 8, 12,
and 24 h after oil administration. Blood samples were obtained
via jugular venipuncture and transferred to a coagulation tube
for 20 min. Samples were centrifuged with a clinical centrifuge at
3,600 ×g for 10 min; serum was removed and stored at 80C
until analysis using liquid chromatography-mass spectrometry
(LC-MS) at Colorado State University Core Mass Spectrometry
Extraction of CBD From Canine Serum and
Mass Spectrometry Analysis
CBD was extracted from canine serum using a combination of
protein precipitation and liquid-liquid extraction using n-hexane
as previously described (20), with minor modifications for
microflow ultra-high pressure liquid chromatography (UHPLC).
Briefly, 0.05 mL of canine serum was subjected to protein
precipitation in the presence of ice-cold acetonitrile (80% final
concentration), spiked with deuterated CBD as the internal
standard (0.06 mg/mL, CDB-d3 Cerilliant, Round Rock, T X,
USA). 0.2 mL of water was added to each sample prior to the
addition of 1.0 mL of hexane to enhance liquid-liquid phase
separation. Hexane extract was removed and concentrated to
dryness under laboratory nitrogen. Prior to LC-MS analysis,
samples were resuspended in 0.06 mL of 100% acetonitrile.
A standard curve using the CBD analytical standard was
prepared in canine serum non-exposed to CBD and extracted
as above. Cannabidiol concentration in serum was quantified
using a chromatographically coupled triple-quadropole mass
spectrometer (UHPLC-QQQ-MS) using similar methods as
previously described (21).
CDB Serum Concentration Data Analysis
From the UHPLC-QQQ-MS data, peak areas were extracted for
CBD detected in biological samples and normalized to the peak
area of the internal standard CBD-d3, in each sample using
Skyline (22) as well as an in-house R Script (
CBD concentrations were calculated to nanograms per mL of
serum as determined by the line of regression of the standard
curve (r2=0.9994, 0–1,000 ng/mL). For this assay, the limits of
detection (LOD) and limits of quantification (LOQ) represent the
lower limits of detection and quantification for each compound
in the matrix of this study (23,24). Pharmacokinetic variables
were estimated by means of non-compartmental analysis,
utilizing a pharmacokinetic software package (PK Solution,
version 2.0, Montrose, CO, USA).
Frontiers in Veterinary Science | 2July 2018 | Volume 5 | Article 165
Gamble et al. Cannabidiol and Osteoarthritis in Dogs
Inclusion and Exclusion Criteria for the
Clinical Trial
The study population consisted of client-owned dogs presenting
to Cornell University Hospital for Animals for evaluation and
treatment of a lameness due to OA. Dogs were considered for
inclusion in the study if they had radiographic evidence of
OA, signs of pain according to assessment by their owners,
detectable lameness on visual gait assessment and painful
joint(s) on palpation. Each dog had an initial complete blood
count ([CBC] Bayer Advia 120, Siemens Corp., New York,
NY, USA) and serum chemistry analysis (Hitachi 911, Roche
Diagnostics, Indianapolis, IN, USA) performed to rule out any
underlying disease that might preclude enrolment. Elevations
in alkaline phosphatase (ALP), alanine aminotransferase (ALT),
and aspartate aminotransferase (AST) were allowed if prior
hepatic ultrasound was deemed within normal limits except
for potential non-progressive nodules (possible hepatic nodular
hyperplasia). All owners completed a brief questionnaire to
define the affected limb(s), duration of lameness, and duration
of analgesic or other medications taken. All dogs underwent
radiographic examination of affected joints and a radiologist
confirmed the presence or absence of OA, and excluded the
presence of concomitant disease that might preclude them from
enrolment (i.e., lytic lesions).
During the trial, dogs were only allowed to receive NSAIDs,
fish oil, and/or glucosamine/chondroitin sulfate without any
change in these medications for 4 weeks prior to or during
the 10-week study period as standard of care for the disease
process. Other analgesic medications used, such as gabapentin
and tramadol, were discontinued at least 2 weeks prior to
enrolment. Dogs were excluded if they had evidence of renal,
uncontrolled endocrine, neurologic, or neoplastic disease, or
were undergoing physical therapy. Every dog was fed its regular
diet with no change allowed during the trial.
Clinical Trial
The study was a randomized, placebo-controlled, owner and
veterinarian double-blind, cross-over trial. Dogs received each
of two treatments in random order (Randomizer iPhone
Application): CBD, 2 mg/kg every 12 h, or placebo (an equivalent
volume of olive oil with 10 parts per thousands of anise oil and 5
parts per thousands of peppermint oil to provide a similar herbal
smell) every 12 h. Each treatment was administered for 4 weeks
with a 2-week washout period in between treatments. Blood was
collected to repeat complete blood counts and chemistry analysis
at weeks 2 and 4 for each treatment.
At each visit, each dog was evaluated by a veterinarian based
on a scoring system previously reported (25) as well as by its
owner (canine brief pain inventory [CBPI], Hudson activity
scale) before treatment initiation and at weeks 2 and 4 thereafter
Statistical Analysis
Initial power analysis was performed to assess number of
dogs needed for this study as a cross over design with
a power set 0.80 and alpha of 0.05 using prior data
suggesting a baseline CBPI or Hudson score change of
15 points (two tailed) with a standard deviation of
20. When calculated it was assumed that 14 dogs would
be necessary to find differences in outcomes of interest
Statistical analysis was performed with a commercially
available software package (JMP 12.0, Cary, NC, USA). All
continuous data were assessed utilizing a Shapiro–Wilk test for
normality. Considering a majority of our blood, serum and
scoring data were normally distributed a mixed model analysis
was used to analyze these outcomes, including the fixed effects
of treatment, time, sequence of treatment assignment, gender,
age, NSAID usage, treatment ×time; as well as random effects
of observation period, period nested within dog, time point
nested within period nested within dog to account for the
hierarchical nature of data in a cross-over design as well as
repeated measurements for each dog. For ordinal veterinary
scoring data a similar linear mixed model was used, but
differences from baseline were first calculated to approximate
a normal distribution to meet assumptions for a mixed model
analysis. Residual diagnostics of all final models showed that
residuals were normally distributed and fulfilled the assumption
of homoscedasticity, and assumptions where therefore met. This
statistical modeling approach allowed for adequate control of
hierarchical data structure necessary in a cross-over design,
as well as for the performance of easily interpretable time
×treatment Tukey post-hoc comparisons that were our main
interest, as compared to an ordinal logistical regression (30,
31). To control for baseline differences and therefore the
possible difference in relative change in CBPI pain, and activity
interference assessments and Hudson scoring across dogs, the
initial CPBI or Hudson Scores were included for these analyses
as a covariate. 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.
Ap-value of less than 0.05 was defined as the significance
Pharmacokinetics demonstrated that CBD half-life of
elimination median was 4.2 h (3.8–6.8 h) for the 2 mg/kg dose,
and 4.2 h (3.8–4.8 h) for the 8 mg/kg dose (Table 1). Median
maximal concentration of CBD oil was 102.3 ng/mL (60.7–
132.0 ng/mL; 180 nM) and 590.8 ng/mL (389.5–904.5 ng/mL;
1.2 uM) and was reached after 1.5 and 2 h, respectively, for 2
and 8 mg/kg doses. No obvious psychoactive properties were
observed on evaluation at any time point during the 2 and
8 mg/kg doses over 24 h. These results led to dosing during the
clinical trial at 2 mg/kg body weight every 12 h, due the cost
prohibitive nature of 8 mg/kg dosing for most larger patients, the
impractical nature of more frequent dosing, the volume of oil
necessary and anecdotal reports surrounding 0.5-2 mg/kg dosing
recommended by other vendors.
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Gamble et al. Cannabidiol and Osteoarthritis in Dogs
TABLE 1 | Serum pharmacokinetic of single oral dosing (2 mg and 8mg/kg) of CBD oil in dogs.
Cmax (ng/mL) Tmax (h) T1/2 elim (h) AUC 0-t (ng-hr/mL) MRT (h)
DOSE (2 mg/kg)
Dog 1 61 1 4.4 183 6.0
Dog 2 132 1 3.9 351 4.2
Dog 3 102 2 3.8 382 5.1
Dog 4 101 2 6.8 437 9.1
Median (Range) 102 (61–132.0) 1.5 (1.0–2.0) 4.2 (3.8–6.8) 367 (183–437) 5.6 (4.2–9.1)
DOSE (8 mg/kg)
Dog 1 499 2 3.8 2,928 5.7
Dog 2 389 1 4.8 1,753 7.0
Dog 3 905 2 4.2 3,048 5.1
Dog 4 682 2 4.1 2,389 5.2
Median (Range) 591 (389–905) 2.0 (1.0–2.0) 4.2 (3.8–4.8) 2,658 (1,753–3,048) 5.6 (5.1–7.0)
Cmax, maximum concentration; Tmax, time of maximum concentration; T1/2 el, half-life of elimination; AUC 0-t, area under the curve (time 0–24 h); MRT, median residence time.
Dogs Included in the Clinical Trial
Twenty-two client-owned dogs with clinically and
radiographically confirmed evidence of osteoarthritis were
recruited. Sixteen of these dogs completed the trial and were
included in the analyses; their breed, weight, age, sex, worse
affected limb, radiographic findings, use of NSAIDs and
sequence of treatments are summarized in Table 2. Dogs
were removed due to osteosarcoma at the time of enrolment,
gastric torsion (placebo oil), prior aggression issues (CBD
oil), pyelonephritis/kidney insufficiency (CBD oil), recurrent
pododermatitis (placebo oil), and diarrhea (placebo oil).
Clinical Trial
CBPI and Hudson change from baseline scores showed a
significant decrease in pain and increase in activity (p<0.01)
at week 2 and 4 during CBD treatment when compared to
baseline week 0, while no other statistical significances were
observed across treatment in this cross-over design (Table 3).
Lameness as assessed by veterinarians showed an increase from
baseline in lameness with age (p<0.01), whereas NSAID use
(p=0.03) reduced lameness scores. Veterinary pain scores
showed a decrease from baseline in dogs on NSAIDs (p<0.01).
CBD oil resulted in a decrease in pain scores when compared to
baseline on evaluation at both week 2 and week 4 (p<0.01 and
p=0.02, respectively), and week 2 CBD oil treatment was lower
than baseline placebo treatment (p=0.02) and week 4 placebo
treatment (p=0.02). No other veterinary pain comparisons were
statistically significant. No changes were observed in weight-
bearing capacity when evaluated utilizing the veterinary lameness
and pain scoring system (Table 3).
Chemistry analysis and CBC were performed at each visit.
No significant change in the measured CBC values was noted
in either the CBD oil or placebo treated dogs (data not shown).
Serum chemistry values were not different between placebo
compared to CBD oil (Table 4), except for alkaline phosphatase
(ALP) which significantly increased over time from baseline
by week 4 of CBD oil treatment (p<0.01); with nine of
the 16 dogs showing increases over time (Figure 1). Glucose
was increased in dogs receiving the placebo oil at each time
point (p=0.04) and creatinine levels increased over time in
both dogs receiving CBD oil and those receiving placebo oil
(p<0.01); though all values remained within reference ranges.
Other notable significances in serum chemistry values were
associated with primarily age or NSAID use. An increase in
age was associated with significantly higher blood urea nitrogen
(BUN; p<0.01), calcium (p=0.01), phosphorus (p<0.01),
alanine aminotransferase (ALT; p=0.03), alkaline phosphatase
(ALP; p=0.01), gamma glutamyltransferase (GGT; p=0.02),
globulin (p=0.02), and cholesterol (p<0.01) values. NSAID use
was associated with significantly higher BUN (p=0.003), and
creatinine (p=0.017), and significant decreases in total protein
(p<0.001) and serum globulin (p<0.001).
To date, an objective evaluation of the pharmacokinetics of a
commercially available industrial hemp product after oral dosing
in dogs is absent. This study showed that the terminal half-
life of oral CBD, as the most abundant cannabinoid in this
specific preparation when in an oil base, was between 4 and 5 h,
suggesting it was bioavailable with a dosing schedule of 2 mg/kg
at least twice daily. This half-life was shorter than a previous
report after intravenous (1.88–2.81 and 3.75–5.63 mg/kg) and
oral (7.5–11.25 mg/kg) administration (32). In the intravenous
study, CBD distribution was rapid, followed by prolonged
elimination with a terminal half-life of 9 h. When examining
prior oral CBD bioavailability it was determined to be low and
highly variable (0–19% of dose) with three dogs showing no
absorption. This may be due to the first pass effect in the liver,
and the product was not in an oil base, but a powder within
a gelatin capsule being a different delivery vehicle (32). After
initially seeing no neurological effects at the 2 mg/kg dose a
8 mg/kg dose was chosen to assess the potential neurological
effects since mistaken overdosing can occur clinically, and a
higher dose might have been necessary since the prior study
showed poor absorption. Although our dogs were fasted the
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Gamble et al. Cannabidiol and Osteoarthritis in Dogs
TABLE 2 | Characteristics of dogs enrolled in a placebo-controlled study investigating the effects of CBD on osteoarthritis.
Breed Weight (kg) Age (years) Sex Radiographic findings and OA localization NSAID
Rottweiler 35.3 10 FS - Moderate, intracapsular swelling with moderate osteophytosis, left stifle Carprofen
(2.1 mg/kg BID)
Mix 30.6 13 MC - Moderate-to-severe, right-shoulder osteoarthrosis; mild, left-shoulder
- Moderate-to-severe, bilateral hip osteoarthrosis
Mix 27.2 9 FS - Moderate medial coronoid remodeling
(with fragmentation on the right) and bilateral elbow osteoarthrosis
Mix 30.5 14 MC - Moderate enthesiopathies on right carpus; mild, left-antebrachiocarpal
- Bilateral moderate coxofemoral osteoarthrosis
Mix 23.5 10 FS - Moderate bilateral stifle osteoarthrosis and moderate intracapsular
(2.2 mg/kg)
Mix 28.1 10 FS - Moderate bilateral elbow osteoarthrosis
- Moderate left-stifle osteoarthrosis with intracapsular swelling
(0.1 mg/kg
English Bulldog 25.2 8 MC - Severe osteoarthrosis, left elbow
- Moderate intracapsular swelling and mild osteoarthrosis, right stifle
(2 mg/kg BID)
German Shorthaired Pointer 21.5 14 FS - Moderate bilateral elbow osteoarthrosis Carprofen
(2.4 mg/kg BID)
Labrador Retriever 26.1 13 FS - Bilateral severe stifle osteoarthrosis due to cranial cruciate ligament
(0.1 mg/kg SID)
Mix 18.2 13 FS - Bilateral moderate elbow osteoarthrosis and medial epicondylitis Meloxicam
(0.1 mg/kg SID)
Mix 22 9 FS - Moderate, stifle osteoarthrosis with moderate intracapsular swelling None
Bernese Mountain Dog 50 3 M - Bilateral severe elbow osteoarthritis, medial coronoid disease, and medial
(2 mg/kg SID)
Belgian Malinois 25.1 9 FS - Severe bilateral elbow osteoarthrosis
- Bilateral moderate hip osteoarthrosis
(2 mg/kg BID)
Mix 28.6 13 FS - Severe bilateral elbow osteoarthritis
- Severe bilateral hip osteoarthritis
Border Collie 22 14 MC - Severe thoracolumbosacral osteophytosis
- Multifocal carpal enthesiophytes
Beagle 17.6 5 MC - Mild left elbow osteoarthrosis, with possible medial coronoid disease
- Moderate-to-severe bilateral stifle osteoarthrosis
FS, female spayed; MC, male castrated; Mix, mixed breed; SID, once daily; BID, twice daily.
delivery vehicle was olive oil which is a food item. The
absorption may be greater and more consistent because of the
oil-based vehicle which may be due to the lipophilic nature
of CBD, hence delivery with food may be preferable (32,33).
As previously demonstrated, CBD biotransformation in dogs
involves hydroxylation, carboxylation and conjugation, leading
to relatively rapid elimination suggesting a more frequent dosing
schedule (34). The dosing schedule of twice per day was chosen
due to the practical nature of this dosing regimen even though
the elimination is well within a three or four time a day dosing
regimen. Our hope was that the lipophilic nature of CBD would
allow for a steady state over time, and future studies examining
24 h pharmacokinetics with different dosing regimens with larger
numbers of dogs, and steady state serum pharmacokinetics after
extended treatment in a clinical population are sorely needed.
The main objective of this study was to perform an owner
and veterinary double-blinded, placebo-controlled, cross-over
study to determine the efficacy of CBD oil in dogs affected by
OA. Despite our small sample size, short study duration and
heterogeneity of OA signs, CBPI and Hudson scores showed that
CBD oil increase comfort and activity in the home environment
for dogs with OA. Additionally, veterinary assessments of
pain were also favorable. Although a caregiver placebo effect
should be considered with subjective evaluations by owners
and veterinarians (35), the cross-over design limits confounding
covariates since each dog serves as its own control. Our statistical
model controlled for the possible effect of treatment sequence.
The lack of a placebo effect in our study may be due to
nine of the 16 owners being intimately involved in veterinary
medical care, all of whom have an understanding of the placebo
effect making them more cognizant of improvements when
providing feedback. In addition, there was a noticeable decrease
in Hudson scores and rise in CBPI scores during the initiation
placebo treatment suggesting a potential carry over effect of
CBD treatment indicating that a longer washout period might
be indicated in future studies. This carry over effect may have
resulted in some improved perceptions at the initiation of the
placebo treatment which were eliminated by week 4 of placebo
treatment, underscoring the importance of longer term steady
state PK studies in dogs.
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Gamble et al. Cannabidiol and Osteoarthritis in Dogs
TABLE 3 | Canine Brief Pain Inventory (Pain and Activity questions) and Hudson Scale mean and standard deviation; lameness, weight-bearing and pain scores median
and ranges at each time for cannabidiol (CBD) and placebo oils.
CBD oil Placebo oil
Week 0 Week 2 Week 4 Week 0 Week 2 Week 4
CBPI Pain (0–40) 21 ±8 14 ±6* 14 ±8* 17 ±7 19 ±9 19 ±9
CBPI activity interference (0–60) 35 ±15 25 ±15* 26 ±14* 27 ±15 29 ±15 31 ±16
Hudson (0–110) 54 ±13 67 ±15* 67 ±10* 65 ±14 64 ±16 60 ±19
Veterinary lameness§ 3 (1–4) 3 (1–4) 3 (1–4) 3 (2–4) 3 (2–4) 3 (1–4)
Veterinary pain R3 (3–4) 3 (2–4)* 3 (1–4)* 3 (2–4)** 3 (2–4) 3 (2–4)**
Veterinary weight-bearing =2 (1–3) 2 (1–3) 2 (1–3) 2 (1–3) 2 (1–3) 2 (1–3)
*Represents significant difference (p <0.05) from baseline week 0 of CBD treatment. **Represents significant differences (p <0.05) from week 2 of CBD oil treatment. §Lameness was
scored as follows: 1 =no lameness observed/walks normally, 2 =slightly lame when walking, 3 =moderately lame when walking, 4 =severely lame when walking, 5 =reluctant to rise
and will not walk more than 5 paces. RPain on palpation was scored as follows: 1 =none, 2 =mild signs, dog turns head in recognition, 3 =moderate signs, dog pulls limb away, 4=
severe signs, dog vocalizes or becomes aggressive, 5 =dog will not allow palpation. =Weight-bearing was scored as follows: 1 =equal on all limbs standing and walking, 2 =normal
standing, favors affected limb when walking, 3 =partial weight-bearing standing and walking, 4 =partial weight-bearing standing, non-weight-bearing walking, 5 =non-weight-bearing
standing and walking.
TABLE 4 | Serum chemistry values of dogs receiving CBD or placebo oils.
Reference CBD oil Placebo oil
Week 0 Week 2 Week 4 Week 0 Week 2 Week 4
Sodium 145–153 mEq/L 149 ±3 149 ±2 149 ±1 149 ±1 149 ±2 149 ±2
Potassium 4.1–5.6 mEq/L 4.9 ±0.3 4.9 ±0.5 4.9 ±0.3 4.8 ±0.4 4.9 ±0.4 4.9 ±0.3
Chloride 105–116 mEq/L 110 ±3 109 ±3 109 ±2 110 ±2 110 ±2 110 ±2
SUN 10–32 mg/dL 20 ±9 20 ±7 20 ±6 19 ±6 21 ±7 19 ±6
Creatinine 0.6–1.4 mg/dL 1.0 ±0.3 1.1 ±0.3* 1.0 ±0.3* 0.9 ±0.3 1.0 ±0.3* 1.0 ±0.3*
Calcium 9.3–11.4 mg/dL 10.4 ±0.5 10.4 ±0.4 10.3 ±0.4 10.4 ±0.6 10.4 ±0.4 10.4 ±0.4
Phosphorus 2.9–5.2 mg/dL 3.8 ±0.8 3.9 ±0.8 3.9 ±0.6 4.0 ±0.7 3.9 ±0.6 4.0 ±0.5
Magnesium 1.4–2.2 mg/dL 1.8 ±0.2 1.8 ±0.2 1.8 ±0.2 1.8 ±0.1 1.8 ±0.1 1.8 ±0.1
Glucose 63–118 mg/dL 92 ±9 89 ±9 92 ±9 97 ±10* 93 ±8 97 ±10*
ALT 20–98 U/L 93 ±86 93 ±88 114 ±119 90 ±89 222 ±606 166 ±284
AST 14–51 U/L 31 ±8 33 ±13 34 ±16 30 ±8 56 ±99 45 ±34
ALP 17–111 U/L 160 ±212 238 ±268 323 ±407* 204 ±287 186 ±287 175 ±248
GGT 0–6 U/L 4 ±3 3 ±2 3 ±2 3 ±2 4 ±6 5 ±4
Bilirubin 0.0–0.2 mg/dL 0.1 ±0.1 0.0 ±0.1 0.1 ±0.1 0.0 ±0.1 0.0 ±0.1 0.0 ±0.1
Total protein 5.3–7.0 g/dL 6.3 ±0.4 6.4 ±0.5 6.3 ±0.4 6.3 ±0.4 6.3 ±0.4 6.3 ±0.4
Albumin 3.1–4.2 g/dL 3.7 ±0.2 3.7 ±0.2 3.7 ±0.2 3.7 ±0.2 3.7 ±0.2 3.7 ±0.2
Globulin 1.9–3.6 g/dL 2.6 ±0.3 2.6 ±0.4 2.6 ±0.4 2.6 ±0.4 2.6 ±0.4 2.6 ±0.4
Cholesterol 138–332mg/dL 291 ±64 301 ±62 302 ±62 295 ±71 300 ±71 308 ±83
CK 48–260 U/L 148 ±81 147 ±59 134 ±61 139 ±57 158 ±80 168 ±105
Data presented at mean +standard deviations. Asterisk (*) indicates significantly different (p <0.05) serum concentration from baseline week 0 CBD treatment. SUN , serum urea
nitrogen; ALT, alanine animotranferase; AST, aspartate animotransferase; ALP, alkaline phosphatase; GGT, gamma glutamyl transferase; CK, creatine kinase.
There was no significant difference in subjective veterinary
lameness score and weight-bearing capacity throughout the
study. Kinetic data was obtained from these dogs (data not
shown), however 11 of the 16 dogs had significant bilateral
disease (stifle, coxofemoral, or elbow) making evaluation of peak
vertical force or symmetry tenuous at best. Unilateral disease in
any of the aforementioned joints would be ideal to study the
kinetic effects of this or similar extracts for pain relief leading
to better objective outcomes. The population we used in our
investigation was representative of dogs presenting in a clinical
setting for management of OA and represents the typical OA
Currently, NSAIDs are the primary treatment for OA and
are associated with negative effects on the gastrointestinal tract
and glomerular filtration (2). In the current study, no significant
difference was noted in BUN, creatinine, or phosphorus between
dogs treated with the CBD oil vs. the placebo oil, while
NSAID treatment resulted in a higher creatinine concentration.
A mild rise in creatinine from baseline was noted in both
groups at weeks 2 and 4, the hydration status of the dogs was
Frontiers in Veterinary Science | 6July 2018 | Volume 5 | Article 165
Gamble et al. Cannabidiol and Osteoarthritis in Dogs
FIGURE 1 | Box-and-whisker plot of serum alkaline phosphatase (ALP) activity
at each time for treatment and placebo oils. Box represents the mean and 25th
and 75th percentile and the whiskers represent the 99th and 1st percentiles.
*Indicates a significant difference (p<0.05) from week 0 CBD treatment.
unknown; however changes in albumin sodium, and chloride
were unchanged suggesting euhydration, and all creatinine
values remained within the reference interval. Increased ALP
activity is fairly sensitive for hepatobiliary changes in this age
group, but not specific. Increased ALP activity noted in nine
dogs in the CBD treatment group may be an effect of the
hemp extract attributed to the induction of cytochrome p450
mediated oxidative metabolism of the liver (reported previously
with prolonged exposure to cannabis) (3638). Other causes
of cholestasis, increased endogenous corticosteroid release from
stress, or a progression of regenerative nodular hyperplasia of
the liver cannot be ruled out. Without concurrent significant
rise in ALT in the CBD treatment to support hepatocellular
damage, or biopsy for further clarification, the significance is
uncertain. As such, it may be prudent to monitor liver enzyme
values (especially ALP) while dogs are receiving industrial hemp
products until controlled long term safety studies are published.
A recent survey reported that pet owners endorse hemp
based treats and products because of perceived improvement
in numerous ailments, as hemp products were moderately to
very helpful medicinally (39). Some of the conditions thought
to be relieved by hemp consumption were: pain, inflammation,
anxiety and phobia, digestive system issue, and pruritus (39).
One immunohistochemical study suggested that cannabinoids
could protect against the effects of immune-mediated and
inflammatory allergic disorders in dogs (40) whereas another
uncontrolled study suggested that CBD has anticonvulsant
and anti-epileptic properties in dogs (41). The apparent
analgesic effect of the industrial hemp based oil observed
in the present study may be attributable to downregulation
of cylooxygenase enzymes, glycine interneuron potentiation,
transient receptor potential cation receptor subfamily V1
receptor agonism (peripheral nerves), and/or g-protein receptor
55 activation (immune cells), influencing nociceptive signaling
and/or inflammation (14,42,43).
The industrial hemp product used in this study is a proprietary
strain-specific extract of the cannabinoids outlined in the
methods with relatively high concentrations of CBD and lesser
quantities of other cannabinoids as well as small amounts of
terpenes that may have synergistic effects often termed the
“entourage effect.” This brings to light that fact that different
strains of cannabis produce differing amounts of CBD and other
related cannabinoids making the results of this study specific
to this industrial hemp extract that may not translate to other
available products due to differing cannabinoid concentrations
in this largely unregulated market.
In conclusion, this particular product was shown to be
bioavailable across the small number of dogs examined in the PK
portion of the study, and dogs with OA receiving this industrial
hemp extract high in CBD (2 mg/kg of CBD) were perceived to
be more comfortable and active. There appear to be no observed
side effects of the treatment in either the dogs utilized in the PK
study at 2 and 8 mg/kg, or dogs undergoing OA treatment for
a month duration. There were some dogs with incidental rises
in alkaline phosphatase that could be related to the treatment.
Further long-term studies with larger populations are needed to
identify long-term effects of CBD rich industrial hemp treatment,
however short term effects appear to be positive.
L-JG was responsible for data analysis and interpretation,
drafting of the manuscript and approval of the submitted
manuscript. JB was responsible for the conception of the study
and manuscript writing and revisions. CF was responsible for
acquisition of data and manuscript revision. WS was responsible
for pharmacokinetic evaluation and revision of the manuscript.
SM was responsible for statistical analysis, data analysis and
revision of the manuscript. LW was responsible for laboratory
work including liquid chromatography-mass spectrometry. HB
was responsible for interpretation of the blood work and
manuscript revision. EB was responsible for acquisition of data,
and data analysis. JW was responsible for the conception of study,
supervised data collection, statistical analysis, and manuscript
Ellevet LLC supported this research with a grant to Cornell
University to study this product.
The authors would like to thank Renee C. Staffeld and Danny
Sack for data entry. The present study was financially supported
by ElleVet Sciences, Portland, Maine.
Frontiers in Veterinary Science | 7July 2018 | Volume 5 | Article 165
Gamble et al. Cannabidiol and Osteoarthritis in Dogs
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Conflict of Interest Statement: The 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.
Copyright © 2018 Gamble, Boesch, Frye, Schwark, Mann, Wolfe, Brown, Berthelsen
and Wakshlag. This is an open-access article distributed under the terms of
the Creative Commons Attribution License (CC BY). The use, distribution or
reproduction in other forums is permitted, provided the original author(s) and the
copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
Frontiers in Veterinary Science | 9July 2018 | Volume 5 | Article 165
... Studies into the potential for CBD use in treating canine conditions are limited. Dogs with osteoarthritis were perceived to be more comfortable and mobile with decreased pain scores following oral CBD administration compared those without [6,17]. Carry over effect was also found with significant CBD effect 14 days after dosage ceased [6]. ...
... Knowledge of dosage method, efficacy and safety is deficit. Some suggest the bioavailable half-life of CBD in oil carrier form to be 4.2 hours [17] or 1hr from maximum concentration being at 1.4 hrs. on fasted dogs [20]. This would suggest a limit of CBD affect, which could be due to limiting endogenous factors [11,21]. ...
... Quantification of prevalence has not yet been determined in the UK. CBD has been perceived to be well tolerated by dogs [17][18][19]24]. More understanding of tolerance and possible intoxication is needed, and no studies exist for knowledge of long-term dosage or effects. ...
This research aims to give insight into to the opinions, experiences, and ideas of stakeholders of the veterinary industry regarding current use and integration of cannabidiol (CBD) into canine veterinary care in the UK. Including identifying and evaluating indications, demand and barriers from the perspective of stakeholders of the industry. Semi-structured interviews were conducted with 3 veterinary surgeons, 2 veterinary physiotherapists and 4 owner participants. Grounded theory was used in combination with thematic analysis to identify trends. Results suggested a positive current use of CBD for canines including first-hand experience by all owners. All experiences were positive with no adverse reactions reported. Identified barriers included stigma, lack of research, and issues with product standardization and dosage. Demand for CBD was high by all owners and interest was indicated by professionals. However, professionals expressed reservations more prevalently with the unknown pharmacokinetics of CBD, whereas owners expressed confidence and lower perceived risk. This research is a preliminary investigation into canine focused veterinary CBD use in the UK. Veterinary consumer opinion is also explored where there is currently little existing.
... Previous non-clinical studies have shown that oral administration of CBD in rats improved thermal and mechanical hypersensitivity and reduced inflammation in a model of chronic inflammation [14]. Gamble et al. in their study on the analgesic efficacy of CBD oil treatment demonstrated that it can help increase comfort and increase activity in dogs with osteoarthritis (OA) [15,16]. The purpose of this study was to evaluate the anticonvulsant effect in a model of seizures induced by the administration of electric shocks to mice for acute treatment with 3 vegetable oils from Cannabis sativa having different concentrations in CB [17] and without pesticide content [18] . ...
... et al., 2015) Com a utilização dos óleos full spectrum é notória uma ativação mais eficaz do sistema endocanabinóide devido ao "efeito comitiva", sendo assim é obtido um efeito terapêutico Multiplicidade dad Ciências da Saúde, Volume 3 altamente eficaz em comparação com o óleo isolado de CBD, que para reproduzir o mesmo efeito seria necessária uma dose quatro vezes maior de canabidiol.(GALLILY et al., 2015) Além da associação do óleo de Cannabis a medicamentos opióides, tendo em vista que os compostos da planta têm efeito potencializador em vários medicamentos devido à inibição da enzima citocromo P-450, responsável pela degradação dos medicamentos no organismo, aumentando o tempo de duração desses fármacos, influenciando positivamente os resultados do tratamento do animal(GAMBLE et al., 2018).Em situação de dor crônica em um pós-cirúrgico, por exemplo, os animais que utilizarem o óleo de Cannabis integral, associado às medicações que foram passadas pelo veterinário, não necessitariam de altas dosagens medicamentosas devido a potencialização farmacológica ocasionada pelo efeito do óleo, sem contar com a analgesia e propriedades anti-inflamatória, antibactericida, antimetastática, entre outras várias propriedades estudadas e são proporcionadas pelos compostos das plantas Cannabis sp. (GAMBLE et al., 2018) A tabela 1 representa os resultados de alguns estudos experimentais analisados e selecionados por meio dos critérios de inclusão da revisão integrativa, estando presente elementos como número de animais utilizados no estudo, o ano de sua realização e a posologia do composto a base de Cannabis sp. ...
... Hemp has a fairly wide range of uses, ranging from cosmetology to the food and pet food industry. The cannabidiol (CBD) present in their inflorescences has many pharmacological effects, including anxiolytic, sedative, anti-epileptic, anti-inflammatory, analgesic, anti-emetic, anti-diabetic and anti-ischemic effects [53][54][55]. All these effects can be convincingly explained by observations about the mechanism of action of CBD. ...
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Hemp is a high-value crop that originated in Central Asia and is a historic but emerging cultivated plant. It may be grown for fiber, food, paper making, textiles, and therapeutic reasons. In the 21st century, market interest in hemp and its products has notably increased because seed portions can be utilized in the agri-food business, the woody component of the stem can be used in green buildings, the outer layer of the stems can be used in the textile industry, and the extraction of bioactive components from roots can play a vital role in the pharmacological industries. Hemp has recently been demonstrated to be a viable alternative for economies built on synthetic materials by the food, pharmaceutical, textiles, paper, building, and energy industries, among others. As a result, the goal of this study is to assemble the significant advancements in hemp, as well as to identify research gaps and research direction opportunities. The hemp plant will be provided more encouragement to be grown and be used. Many applications of hemp may be pushed to the next level for both producing a green environment and profit. A strong vision and a well-defined plan will pave the path for the discovery of new technologies and concepts.
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Many dogs experience stress when separated from their caregivers, as well as when traveling in vehicles. Pet owners employ various approaches to managing these issues, from training, to giving medications and supplements, often with mixed results. Cannabidiol (CBD) can alleviate stress and anxiety in humans but the effect it has on canine stress is less well-documented. The present study aimed to understand the impact of being left alone and traveling in a car on measures of canine stress, and establish whether a single dose of a tetrahydrocannabinol (THC)-free CBD distillate could positively influence any measures of stress. In a blinded, parallel design study, a population of dogs were either left alone in a familiar room (n = 21) or underwent a short car journey (n = 19). A range of physiological and behavioral measures were collected pre, during and post-test. Significant changes in several stress-related measures (serum cortisol, mean ear temperature, heart rate, heart rate variability, whining and a stressed/anxious behavioral factor) were observed from baseline to test, with the car journey test paradigm eliciting a more pronounced stress response overall. The mitigating effect of CBD treatment varied by measure and test, with some indicating a significant reduction in canine stress compared to the placebo group. Additional research is required to fully understand the complex effect of CBD on canine wellbeing.
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Objective: To determine the pharmacokinetics of 8 cannabinoids and 5 metabolites after oral administration of single and multiple doses of a cannabidiol (CBD)-cannabidiolic acid (CBDA)-rich hemp extract to orange-winged Amazon parrots (Amazona amazonica) as well as to evaluate the extract's adverse effects. Animals: 12 birds. Procedures: Based on pilot studies, a single-dose study based on 30/32.5 mg/kg of cannabidiol/cannabidiolic acid of a hemp extract was administered orally to 8 fasted parrots, and 10 blood samples were collected over 24 hours after administration. After a 4-week washout period, the hemp extract was administered orally to 7 birds at the previous dose every 12 hours for 7 days, and blood samples were collected at the previous time points. Cannabidiol, Δ9-tetrahydrocannabinol, cannabinol, cannabichromene, cannabigerol, cannabidiolic acid, cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, and 5 specific metabolites were measured by liquid chromatography-tandem/mass-spectrometry, and pharmacokinetic parameters were calculated. Adverse effects and changes in the plasma biochemistry and lipid panels were evaluated. Results: Pharmacokinetic parameters for cannabidiol, cannabidiolic acid, Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabinolic acid, and the metabolite 11-hydroxy-9-tetrahydrocannabinol were established. For the multiple-dose study, cannabidiol/cannabidiolic acid mean Cmax was 337.4/602.1 ng/mL with a tmax of 30 minutes and a terminal half-life of 8.6/6.29 hours, respectively. No adverse effects were detected during the multidose study. The predominant metabolite was 11-hydroxy-9-tetrahydrocannabinol. Clinical relevance: Twice daily oral administration of the hemp extract based on 30 mg/kg/32.5 mg/kg of cannabidiol/cannabidiolic acid was well tolerated and maintained plasma concentrations considered to be therapeutic in dogs with osteoarthritis. Findings suggest different cannabinoid metabolism from mammals.
Cannabidiol (CBD) is a non-psychotropic phytocannabinoid of the plant Cannabis sativa L. CBD is increasingly being explored as an alternative to conventional therapies to treat health disorders in dogs and cats. Mechanisms of action of CBD have been investigated mostly in rodents and in vitro and include modulation of CB1, CB2, 5-HT, GPR, and opioid receptors. In companion animals, CBD appears to have good bioavailability and safety profile with few side effects at physiological doses. Some dog studies have found CBD to improve clinical signs associated with osteoarthritis, pruritus, and epilepsy. However, further studies are needed to conclude a therapeutic action of CBD for each of these conditions, as well as for decreasing anxiety and aggression in dogs and cats. Herein, we summarize the available scientific evidence associated with the mechanisms of action of CBD, including pharmacokinetics, safety, regulation, and efficacy in ameliorating various health conditions in dogs and cats.
The projected market value of the UK CBD industry looks to hit £1 billion by 2025. The statistics for its safety in animals are not easily obtainable. Many owners could be, and are suspected to be, using CBD products without a veterinary prescription. Many are using CBD as a ‘natural’ alternative, it is important to question and explore this relatively new trend to assess if natural really does mean safe and benign, and importantly if there is enough evidence base to warrant its use in veterinary medicine.
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Background and objectives: Cannabinoid receptors (CB1R/CB2R) are known to play important roles in pain transmission. In this study, we investigated the effects of continuous intrathecal infusion of CB1/2R agonists in the L5/6 spinal nerve ligation pain model. Methods: Under isoflurane anesthesia, rats received nerve ligation and intrathecal catheter connected to an infusion pump. After surgery, saline (1 μL/h), CB1/2R agonist WIN55,212-2, CB1R agonist ACEA, or CB2R agonist AM1241 (1 μmol/h) was given intrathecally for 7 days. The mechanical and thermal sensitivities of rat hindpaw were determined by von Frey hair and radiant heat tests. The expression of CB1/2R and protein levels of CB1/2R, Iba1, glial fibrillary acidic protein, and tumor necrosis factor α were examined by immunofluorescence study and Western blotting. Results: On postligation day 7, rats that received WIN55,212-2, ACEA or AM1241 had significantly higher mean withdrawal thresholds (6.8, 8.4, and 10.2 g) and latencies (6.3, 7.3, and 9.1 seconds) than did saline-treated rats (1.7 g, 2.2 seconds). Cannabinoid receptors were expressed not only in IB4 (isolectin B4) and CGRP (calcitonin gene-related peptide) dorsal root ganglion neurons, their central terminals, and peripheral axons, but also in neurons, microglia, and astrocytes in spinal cord. Cannabinoid receptor agonists enhanced nerve ligation-induced up-regulation of cannabinoid receptor in spinal cord and dorsal root ganglion. Treatment with WIN55,212-2 or AM1241, but not ACEA, markedly reduced nerve ligation-induced up-regulation of Iba1, glial fibrillary acidic protein, and tumor necrosis factor α in spinal cord. Conclusions: Continuous intrathecal infusion of CB1/2R agonists elicits antinociception in the pain model. The mechanisms might involve their actions on neurons and glial cells. CB2R, but not CB1R, seems to play an important role in the regulation of nerve injury-induced neuroinflammation.
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Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word "cannabidiol". Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington's disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150-600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed.
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Objective: To determine the optimal method for use of the Canine Brief Pain Inventory (CBPI) to quantitate responses of dogs with osteoarthritis to treatment with carprofen or placebo. Animals: 150 dogs with osteoarthritis. Procedures: Data were analyzed from 2 studies with identical protocols in which owner-completed CBPIs were used. Treatment for each dog was classified as a success or failure by comparing the pain severity score (PSS) and pain interference score (PIS) on day 0 (baseline) with those on day 14. Treatment success or failure was defined on the basis of various combinations of reduction in the 2 scores when inclusion criteria were set as a PSS and PIS ≥ 1, 2, or 3 at baseline. Statistical analyses were performed to select the definition of treatment success that had the greatest statistical power to detect differences between carprofen and placebo treatments. Results: Defining treatment success as a reduction of ≥ 1 in PSS and ≥ 2 in PIS in each dog had consistently robust power. Power was 62.8% in the population that included only dogs with baseline scores ≥ 2 and 64.7% in the population that included only dogs with baseline scores ≥ 3. Conclusions and clinical relevance: The CBPI had robust statistical power to evaluate the treatment effect of carprofen in dogs with osteoarthritis when protocol success criteria were predefined as a reduction ≥ 1 in PIS and ≥ 2 in PSS. Results indicated the CBPI can be used as an outcome measure in clinical trials to evaluate new pain treatments when it is desirable to evaluate success in individual dogs rather than overall mean or median scores in a test population.
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Objective: To determine efficacy of a single intra-articular injection of an autologous platelet concentrate for treatment of osteoarthritis in dogs. Design: Randomized, controlled, 2-center clinical trial. Animals: 20 client-owned dogs with osteoarthritis involving a single joint. Procedures: Dogs were randomly assigned to a treatment or control group. In all dogs, severity of lameness and pain was scored by owners with the Hudson visual analog scale and the University of Pennsylvania Canine Brief Pain Inventory, respectively, and peak vertical force (PVF) was determined with a force platform. Dogs in the treatment group were then sedated, and a blood sample (55 mL) was obtained. Platelets were recovered by means of a point-of-use filter and injected intra-articularly within 30 minutes. Control dogs were sedated and given an intra-articular injection of saline (0.9% NaCl) solution. Assessments were repeated 12 weeks after injection of platelets or saline solution. Results: Dogs weighed between 18.3 and 63.9 kg (40.3 and 140.6 lb) and ranged from 1.5 to 8 years old. For control dogs, lameness scores, pain scores, and PVF at week 12 were not significantly different from pretreatment values. In contrast, for dogs that received platelet injections, lameness scores (55% decrease in median score), pain scores (53% decrease in median score), and PVF (12% increase in mean PVF) were significantly improved after 12 weeks, compared with pretreatment values. Conclusions and clinical relevance: Results suggested that a single intra-articular injection of autologous platelets resulted in significant improvements at 12 weeks in dogs with osteoarthritis involving a single joint.
Endocannabinoids (ECs) represent a class of endogenous, small molecules that bind and activate the G-protein coupled EC receptors. They are involved in a variety of fundamental biological processes and are associated with many disease states. Endocannabinoids are often present in complex matrices and at low concentrations, complicating their measurement. Here we describe a highly sensitive method for the quantitation of the following ECs in serum: N-arachidonoylethanolamine (anandamide), N-oleoylethanolamine, N-palmitoylethanolamine, 2-arachidonoylglycerol, and its inactive isomer 1-arachidonoylglycerol. On-line sample trapping coupled with separation via microflow liquid chromatography and detection by tandem quadrupole mass spectrometry results in the necessary sensitivity for accurate quantitation of ECs in less than 50μL of serum, without the need for off-line solid phase extraction. Limits of quantitation between 1.2 and 13.4pg/mL were achieved, representing a significant increase in sensitivity compared to previous methods using analytical flow rates. An additional benefit of microflow chromatography is the reduction of solvent consumption by more than two orders of magnitude. The experimental utility of the assay is demonstrated through the analysis of serum from hibernating bears to assess seasonal changes in circulating EC concentrations.
There has been increased interest in the medical use of cannabinoids in recent years, particularly in the predominant natural cannabinoids, cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC). The aim of the current study was to develop a sensitive and reliable method for the quantification of CBD and THC in rat plasma. A combination of protein precipitation using cold acetonitrile and liquid-liquid extraction using n-hexane was utilised to extract CBD and THC from rat plasma. Samples were then evaporated and reconstituted in acetonitrile and 30μL was injected into an HPLC system. Separation was achieved using an ACE C18-PFP 150mm×4.6mm, 3μm column at 55°C with isocratic elution using a mobile phase consisting of acetonitrile-water (62:38, v/v) at 1mL/min for 20min. Both cannabinoids, as well as the internal standard (4,4-dichlorodiphenyltrichloroethane, DDT) were detected at 220nm. Our new method showed linearity in the range of 10-10,000ng/mL and a lower limit of quantification (LLOQ) of 10ng/mL for both cannabinoids, which is comparable to previously reported LC-MS/MS methods. Inter- and intra-day precision and accuracy were below 15% RSD and RE, respectively. To demonstrate the suitability of the method for in vivo studies in rats, the assay was applied to a preliminary pharmacokinetic study following IV bolus administration of 5mg/kg CBD or THC. In conclusion, a simple, sensitive, and cost-efficient HPLC-UV method for the simultaneous determination of CBD and THC has been successfully developed, validated and applied to a pharmacokinetic study in rats. Copyright © 2015 Elsevier B.V. All rights reserved.
The quality of life for dogs with osteoarthritis can often be improved with nonsteroidal anti-inflammatory drugs (NSAIDs); however, the number of adverse drug events associated with NSAID use reported to the Federal Drug Administration Center for Veterinary Medicine is higher than that for any other companion animal drug. Of those events, adverse renal reactions are the second most reported. NSAIDs produce pharmacologic effects via inhibition of cyclooxygenase (COX), which decreases production of prostanoids. Prostaglandins are synthesized by both the COX-1 and COX-2 enzymes in the healthy kidney and influence renal blood flow, glomerular filtration rate, renin release, and Na excretion. There are important species differences in the renal expression of COX-1 and COX-2. For example, dogs have higher basal levels of COX-2 expression in the kidney compared with humans. In addition, in dogs with chronic kidney disease, an increase in COX-2 expression occurs and synthesis of prostaglandins shifts to the COX-2 pathway. For those reasons, NSAIDs that target COX-2 may be expected to adversely affect renal function in dogs, especially dogs with chronic kidney disease. The purpose of this review was to evaluate the literature to report the renal effects of NSAIDs in dogs.
The aim of this systematic review was to identify, assess, and critically evaluate the quality of evidence of nonsteroidal anti-inflammatory drug (NSAID)-induced adverse effects in dogs. Original prospective studies published in peer-reviewed journals in English (1990-2012) that reported data on the safety of NSAIDs administration in dogs were searched. For each study, design type (I, II, III, or IV) and assessment of quality (+, Ø, -) were rated. For each drug, quantity and consistency rating (***, **, *) and strength of evidence (high, moderate, low, or extremely low) were identified and evaluated. The strength of evidence was defined in terms of how applicable and relevant the conclusions were to the target population. Sixty-four studies met the inclusion criteria. Thirty-five (55%) research studies and 29 (45%) clinical trials were identified. A high strength of evidence existed for carprofen, firocoxib, and meloxicam; moderate for deracoxib, ketoprofen, and robenacoxib; and low for etodolac. Quality and consistency rating were as follows: carprofen (***/***), deracoxib (**/***), etodolac (*/unable to rate), firocoxib (***/**), ketoprofen (**/***), meloxicam (***/***), and robenacoxib (**/**), respectively. Adverse effects were detected in 35 studies (55%) and commonly included vomiting, diarrhea, and anorexia. Three studies (5%) reported a power analysis related to adverse effects of ≥80%. In randomized, placebo-controlled, blinded studies (n = 25, 39%), the incidence of adverse effects was not statistically different between treated and control dogs. Finally, most studies were not appropriately designed to determine the safety of NSAIDs, and involved a healthy nongeriatric population of research dogs.