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Preliminary Investigation of the Safety of Escalating Cannabinoid Doses in Healthy Dogs

  • Canopy Growth Corporation

Abstract and Figures

Objective: To determine the safety and tolerability of escalating doses of three cannabis oil formulations, containing predominantly CBD, THC, or CBD and THC (1.5:1) vs. placebo in dogs.Design: Randomized, placebo-controlled, blinded, parallel study.Animals: Twenty healthy Beagle dogs (10 males, 10 females).Methods: Dogs were randomly assigned to one of five treatment groups (n = 4 dogs per group balanced by sex): CBD-predominant oil, THC-predominant oil, CBD/THC-predominant oil (1.5:1), sunflower oil placebo, medium-chain triglyceride oil placebo. Up to 10 escalating doses of the oils were planned for administration via oral gavage, with at least 3 days separating doses. Clinical observations, physical examinations, complete blood counts, clinical chemistry, and plasma cannabinoids were used to assess safety, tolerability, and the occurrence of adverse events (AEs). AEs were rated as mild, moderate, or severe/medically significant.Results: Dose escalation of the CBD-predominant oil formulation was shown to be as safe as placebo and safer than dose escalation of oils containing THC (CBD/THC oil or THC oil). The placebo oils were delivered up to 10 escalating volumes, the CBD oil up to the tenth dose (640.5 mg; ~62 mg/kg), the THC oil up to the tenth dose (597.6 mg; ~49 mg/kg), and the CBD/THC oil up to the fifth dose (140.8/96.6 mg CBD/THC; ~12 mg/kg CBD + 8 mg/kg THC). AEs were reported in all dogs across the five groups and the majority (94.9%) were mild. Moderate AEs (4.4% of all AEs) and severe/medically significant AEs (0.8% of all AEs) manifested as constitutional (lethargy, hypothermia) or neurological (ataxia) symptoms and mainly occurred across the two groups receiving oils containing THC (CBD/THC oil or THC oil).Conclusions and clinical significance: Overall, dogs tolerated dose escalation of the CBD oil well, experiencing only mild AEs. The favorable safety profile of 10 escalating doses of a CBD oil containing 18.3–640.5 mg CBD per dose (~2–62 mg/kg) provides comparative evidence that, at our investigated doses, a CBD-predominant oil formulation was safer and more tolerated in dogs than oil formulations containing higher concentrations of THC.
Content may be subject to copyright.
published: 11 February 2020
doi: 10.3389/fvets.2020.00051
Frontiers in Veterinary Science | 1February 2020 | Volume 7 | Article 51
Edited by:
Deirdre P. Campion,
University College Dublin, Ireland
Reviewed by:
Colm B. Collins,
University College Dublin, Ireland
Mario Giorgi,
University of Pisa, Italy
Dana Vaughn
Specialty section:
This article was submitted to
Veterinary Pharmacology and
a section of the journal
Frontiers in Veterinary Science
Received: 29 October 2019
Accepted: 21 January 2020
Published: 11 February 2020
Vaughn D, Kulpa J and Paulionis L
(2020) Preliminary Investigation of the
Safety of Escalating Cannabinoid
Doses in Healthy Dogs.
Front. Vet. Sci. 7:51.
doi: 10.3389/fvets.2020.00051
Preliminary Investigation of the
Safety of Escalating Cannabinoid
Doses in Healthy Dogs
Dana Vaughn*, Justyna Kulpa and Lina Paulionis
Canopy Animal Health, Canopy Growth Corporation, Toronto, ON, Canada
Objective: To determine the safety and tolerability of escalating doses of three cannabis
oil formulations, containing predominantly CBD, THC, or CBD and THC (1.5:1) vs.
placebo in dogs.
Design: Randomized, placebo-controlled, blinded, parallel study.
Animals: Twenty healthy Beagle dogs (10 males, 10 females).
Methods: Dogs were randomly assigned to one of five treatment groups (n=
4 dogs per group balanced by sex): CBD-predominant oil, THC-predominant oil,
CBD/THC-predominant oil (1.5:1), sunflower oil placebo, medium-chain triglyceride oil
placebo. Up to 10 escalating doses of the oils were planned for administration via
oral gavage, with at least 3 days separating doses. Clinical observations, physical
examinations, complete blood counts, clinical chemistry, and plasma cannabinoids were
used to assess safety, tolerability, and the occurrence of adverse events (AEs). AEs were
rated as mild, moderate, or severe/medically significant.
Results: Dose escalation of the CBD-predominant oil formulation was shown to be as
safe as placebo and safer than dose escalation of oils containing THC (CBD/THC oil or
THC oil). The placebo oils were delivered up to 10 escalating volumes, the CBD oil up
to the tenth dose (640.5 mg; 62 mg/kg), the THC oil up to the tenth dose (597.6 mg;
49 mg/kg), and the CBD/THC oil up to the fifth dose (140.8/96.6 mg CBD/THC; 12
mg/kg CBD +8 mg/kg THC). AEs were reported in all dogs across the five groups and
the majority (94.9%) were mild. Moderate AEs (4.4% of all AEs) and severe/medically
significant AEs (0.8% of all AEs) manifested as constitutional (lethargy, hypothermia) or
neurological (ataxia) symptoms and mainly occurred across the two groups receiving oils
containing THC (CBD/THC oil or THC oil).
Conclusions and clinical significance: Overall, dogs tolerated dose escalation
of the CBD oil well, experiencing only mild AEs. The favorable safety profile of 10
escalating doses of a CBD oil containing 18.3–640.5 mg CBD per dose (2–62 mg/kg)
provides comparative evidence that, at our investigated doses, a CBD-predominant oil
formulation was safer and more tolerated in dogs than oil formulations containing higher
concentrations of THC.
Keywords: cannabinoids, CBD—cannabidiol, THC—tetrahydrocannabinol, safety, adverse events, canine
Vaughn et al. Cannabinoid Safety in Dogs
As a result of changing cannabis regulatory frameworks and
social perceptions globally, there is a renewed interest in
the potential therapeutic properties of cannabinoids across
multiple stakeholders, including the veterinary community.
Currently, there are no authorized veterinary drugs containing
cannabinoids in the United States (U.S.) or Canada and state
or federal laws legalizing the use of medical cannabis in
either jurisdiction do not apply to uses in animals (1,2).
Notwithstanding these restrictions, over half (55%) of U.S.-based
veterinarians who responded to a 2018 online survey had clients
inquire weekly or monthly about the use of CBD products in
animals (3). Online surveys also provide data that pet owners in
the U.S. and Canada have purchased cannabis products for their
pets most commonly for the management of pain, inflammation,
and anxiety (4,5). The evidence suggests there is a growing
interest in the potential therapeutic uses of cannabinoids in
companion animals.
While there are existing reviews on the safety and toxicology
of cannabinoids, namely CBD (68) and THC (9), the data
are primarily based on studies conducted in rodents and
humans. Existing data suggest that there are differences in
the metabolism of cannabinoids across species, with different
CBD/THC metabolic profiles observed across rodents, dogs,
monkeys, and humans (1012). Not surprisingly, differences
in the behavioral/physiological effects of cannabinoids across
species have also been reported (11,13).
While minimal, there are published data on the safety
and efficacy of cannabinoids in companion animals. Dogs
have been used in the course of developing the drug safety
profile of CesametTM (nabilone, a synthetic THC; oral) and
Sativex R
(a combination of plant-based CBD and THC; buccal
spray), both approved drugs in the U.S. and/or Canada for
chemotherapy-induced nausea and vomiting (CesametTM), or
spasticity or pain in multiple sclerosis or advanced cancer
(Sativex R
) (14,15). Published studies in dogs also exist on
the pharmacokinetics of CBD (oral; 2–12 mg/kg) or THC
(oral; 1.5 mg/kg) (1619) and on the safety and/or efficacy of
orally administered CBD (17,20,21) or cannabis extracts (11)
for 4–56 weeks.
The primary objective of this study was to determine the
safety of three cannabis oil formulations, predominant in CBD,
THC, or CBD and THC (1.5:1) in dogs. Since a hallmark
dosing strategy for cannabis initiation is to “start low and go
slow” so as to avoid AEs associated with THC (22), a slow
upward dose titration was used. A secondary objective was to
determine blood levels of CBD, THC, and their metabolites,
namely 7-carboxy-CBD (7-COOH-CBD) and 11-hydroxy-THC
(11-OH-THC) at higher dose levels of CBD (>50 mg/kg) and
THC (>30 mg/kg).
Study Design
The study was randomized, placebo-controlled, and blinded.
Twenty-four healthy Beagle dogs were acclimated to study
TABLE 1 | Dose volumes and CBD/THC quantities delivered to dogs across treatment groups.
In medium-chain triglyceride oil In sunflower oil
Dose No. Placebo—MCT oil (n=4) CBD oil (n=4) THC oil (n=4) Dose No. Placebo—SF oil (n=4) CBD/THC oil (n=4)
Vol (mL) Vol (mL) CBD (mg) THC (mg) Vol (mL) CBD (mg) THC (mg) Vol (mL) Vol (mL) CBD (mg) THC (mg)
1 0.5a1 18.3 0.7 1 NDb24.9 1 2.5a2.5 17.6 12.1
2 1a2.5 45.8 1.7 2.5 *b62.3 2 5a5 35.2 24.2
3 2.5 5 91.5 3.5 3.3 * 82.2 3 10 10 70.4 48.3
4 5 7.5 137.3 5.2 4.4 * 109.6 4 15 15 105.6 72.5
5 10 10 183.0 6.9 5.8 * 144.4 5 20 20c140.8 96.6
6 15 15 274.5 10.4 7.7 * 191.7 6 25 - - -
7 20 20 366.0 13.8 10.2 * 254.0 7 30 - - -
8 25 25 457.5 17.3 13.5c* 336.2 8 35 - - -
9 30 30 549.0 20.7 18c* 448.2 9 40 - - -
10 35 35 640.5 24.2 24c* 597.6 10 45 - - -
(-), doses not administered; AE, adverse event; CBD, cannabidiol; MCT, medium-chain triglyceride; ND, not detected; SF, sunflower; THC, delta-9-tetrahydrocannabinol; Vol, volume.
aPlacebo controls were on a dosing schedule such that two placebo doses were administered prior to the start of test formulation dosing. This was to ascertain tolerability to escalating volumes.
bCBD was “not detected” in the cannabinoid analysis (mg/mL) of the THC oil formulation; the symbol (*) indicates that CBD quantities at higher volumes of the formulation are unknown.
cn=3 dogs.
Frontiers in Veterinary Science | 2February 2020 | Volume 7 | Article 51
Vaughn et al. Cannabinoid Safety in Dogs
TABLE 2 | Corresponding range of mg/kg cannabinoid doses achieved in dogs across groups.
CBD oil THC oilaCBD/THC oil
BSN weight rangeb9.9–10.9 kg 11.4–13.3 kg 10.5–12.5 kg
Dose No. CBD (mg/kg) THC (mg/kg) THC (mg/kg) CBD (mg/kg) THC (mg/kg)
1 1.7–1.8 0.06–0.07 1.9–2.2 1.4–1.7 0.97–1.2
2 4.2–4.6 0.16–0.17 4.7–5.5 2.8–3.4 1.9–2.3
3 8.4–9.2 0.32–0.35 6.2–7.2 5.6–6.7 3.9–4.6
4 12.6–13.9 0.48–0.53 8.2–9.6 8.4–10.1 5.8–6.9
5 16.8–18.5 0.63–0.70 10.9–12.7 11.3–13.4 7.7–9.2
6 25.2–27.7 0.95–1.1 14.4–16.8 - -
7 33.6–37.0 1.3–1.4 19.1–22.3 - -
8 42.0–46.2 1.6–1.7 25.3–29.5 - -
9 50.4–55.5 1.9–2.1 33.7–39.3 - -
10 58.8–64.7 2.2–2.4 44.9–52.4 - -
(-), doses not administered; BSN, baseline.
aCBD was not detected in the THC oil formulation; as such, mg/kg CBD dosing not applicable.
bWeight range of dogs and absolute quantity of cannabinoids per dose (Table 1) were used to calculate mg/kg dose.
conditions for 24 days prior to treatment allocation. Twenty
healthy adult purpose-bred Beagle dogs (age range =3.0–7.8
years; weight range =10–14 kg) were randomized to one of
five treatment groups with four dogs per group (two males,
two females): (i) CBD-predominant oil; (ii) THC-predominant
oil; (iii) CBD/THC-predominant oil (1.5:1); (iv) medium-chain
triglyceride (MCT) oil placebo; or (v) sunflower (SF) oil placebo.
Up to 10 escalating doses of the oils were planned for
administration (Table 1), with at least 3 days separating doses.
An absolute quantity of cannabinoids (mg) (Table 1) was
administered to the dogs in each treatment group; as such, the
resultant mg/kg cannabinoid dose slightly varied within each
group due to body weight differences (Table 2).
Two different placebo oils were used since the cannabinoid
oils included either SF or MCT oil as solvents. Moreover,
the amounts delivered across the two placebo oils differed
to match the volumes administered with the cannabinoid
oils. The dosing schedule of the placebo oils was such
that two placebo doses were administered prior to the
start of cannabinoid oil dosing to ascertain tolerability to
increasing volumes.
Treatments were administered to fasted dogs by oral
gavage. Each cannabinoid or placebo oil administration
was followed by a 10 mL water flush to ensure full
uptake. A small wet meatball was given immediately
after dosing to disrupt negative association with repeated
oral gavage. If an animal was observed vomiting within
30 min of test or placebo administration, the dose
was re-administered.
Randomization and Treatment Allocation
Randomization was stratified by sex and conducted using
a random number generator in Microsoft EXCEL R
(Microsoft Corporation, Redmond, WA). Cannabinoid and
placebo oil formulations were also randomly assigned a code
name using a random number generator in Microsoft EXCEL R
2016. Once the dogs were assigned to a group (Groups 1
through 5), the study coordinator randomly allocated each
group to a coded product by drawing lots. All technicians
collecting data and administering the investigational products
were blinded to treatment allocation. All bottles containing
the cannabinoid or placebo oil formulations were over-labeled
with opaque white labels. Information about treatment groups
and their respective treatment conditions were securely kept
in the VivoCore Inc. archive room for the duration of
the study.
Description of Interventions
The cannabinoid oils (CBD-, THC-, or CBD/THC-predominant
oils) and placebo oils (SF or MCT oils) were acquired from
Tweed Inc. (Smiths Falls, ON, Canada) and stored between
19.6 and 21.9C. The cannabis plants used to prepare the
cannabinoid oils were grown indoors under tightly controlled
environmental conditions. Within one lot, all plants were
genetically identical. Upon harvest, plant material was trimmed,
dried, and extracted. Extraction was performed by super-
critical carbon dioxide, and the extracted resin was diluted
with a food-grade oil (SF or MCT oil) to the target
concentration: 18.3 mg/mL CBD in the CBD-predominant
oil, 24.9 mg/mL THC in the THC-predominant oil, and
7.0 mg/mL CBD +4.8 mg/mL THC in the CBD/THC-
predominant oil.
An independent laboratory (RPC, Fredericton, NB) analyzed
the composition of the cannabinoid oil formulations using
validated methods. Levels of phytocannabinoids and terpenes in
the oil formulations are outlined in Table 3. Solvent extraction
and high-performance liquid chromatography with diode-array
detection (HPLC-DAD) were used for cannabinoid analyses
(accuracy: 90–113%; precision: 5.6–12.8%). Solvent extraction
and gas chromatography/mass selective detector (GC-MSD)
were used for terpene analyses (accuracy: 74–106%; relative
standard deviation: 3.2–9.4%).
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Vaughn et al. Cannabinoid Safety in Dogs
TABLE 3 | Select cannabinoid and terpene analysis of the cannabis oil
Constituent CBD oil (with
MCT oil)
THC oil (with
MCT oil)
(with SF oil)
Cannabinoids (mg/mL)a
CBD 18.3 ND 7.0
Delta-9-THC 0.7 24.9 4.8
Delta-9-THCA ND <RL <RL
CBG <RL 2.5 <RL
CBN ND 1.3 <RL
CBC 0.8 1.5 <RL
Terpenes (%) 21 terpenes
below RL
remaining 8
terpenes below
RL (0.01%)c
9 terpenes
below RL
CBC, cannabichromene; CBD, cannabidiol; CBDA, cannabidiolic acid; CBG,
cannabigerol; CBGA, cannabigerolic acid; CBN, cannabinol; MCT, medium-
chain triglyceride; ND, not detectable; RL, reporting limit; SF, sunflower; THC,
tetrahydrocannabinol; THCA, tetrahydrocannabinolic acid.
aRL was 0.5 mg/mL.
bTwenty-one terpenes were specifically measured: alpha pinene, beta pinene, myrcene,
limonene, terpinolene, linalool, terpineol, caryophyllene, humulene, 3-carene, cis-
ocimene, eucalyptol, trans-ocimene, fenchol, borneol, valencene, cis-nerolidol, trans-
nerolidol, guaiol, alpha-bisabolol, sabinene. RL was 0.01%.
cNine terpenes were specifically measured: alpha-pinene, beta-pinene, myrcene,
limonene, terpinolene, linalool, terpineol, caryophyllene, humulene. RL was 0.01%.
Subject Selection
The purpose-bred animals were acquired from a colony at
VivoCore Inc. (Fergus, ON, Canada). The inclusion criteria
for the study were good general health as determined by the
veterinarian; stable weight over a 10-day period preceding
study start and a weight of 9–15 kg; and, under 8 years of
age. Exclusion criteria were pregnant or lactating dogs; use of
medications or supplements during the course of the study;
receipt of cannabinoid or cancer-related therapies in 2 months
preceding study start; receipt of any test substance within a
month prior to study start; existing or a history of cancer, blood-
or immunology-related disease or other chronic morbidity
(including open wounds, psoriatic or allergic skin conditions,
chronic diarrhea, chronic oral gum or tooth disease, or
cardiovascular disease).
Animal Care
The dogs were individually housed in stainless steel metabolic
cages (height, width, depth =75 ×90 ×102 cm) and those in the
same treatment group were exercised together. Environmental
controls for the animal housing area were electronically set to
maintain a temperature of 18.7–26.2C and a 12-h light/dark
cycle. Animals were fed a standard commercial dry canine diet
in stainless steel bowls (Purina ProPlan Savor Adult—Chicken
and Rice Formula) once daily, 7–10 h after dosing. Food was left
for 1 h and the food quantity offered (1.25–2.75 cups) was based
on body weight. Water was available ad libitum in stainless steel
bowls. Upon study completion, animals were returned to their
colony at VivoCore Inc.
Measurable Outcomes
Throughout the study period, food consumption and 24-h
activity (Mini-Mitter R
Actiwatch-64 R
; Mini-Mitter Co., Inc.,
Bend, OR) were measured daily and animal health observations
occurred twice daily. Body weights were collected throughout the
acclimation period, once during the study period, and once upon
study completion. Following administration of the cannabinoid
or placebo oils, animals were monitored up to 9 h post-dose
for body temperature (measured rectally), respiration rate (by
observation), and heart rate (stethoscope). Observations of the
animals were also conducted every 1–3 h post-dosing through
the first 9 h and then at 12 and 24 h. Subjects were observed for
any signs that would not be expected in normal dogs and for
the occurrence of AEs. Experienced veterinary technicians and/or
a licensed veterinarian conducted the clinical observations and
physical assessments.
AEs were rated for severity as (i) mild—activities of daily
living (ADL) not impacted and no intervention indicated; (ii)
moderate—ADL moderately limited (non-invasive intervention
may be indicated); or (iii) severe/medically significant—ADL
significantly limited (23). If one dog in a treatment group
experienced a severe/medically significant AE, no further
treatments were administered to that dog. If two dogs in the same
treatment group experienced severe/medically significant AEs,
subsequent treatments ceased for all dogs in that group.
Blood Collections and Analyses
For analysis of Complete Blood Count (CBC) and clinical
chemistry, 4 mL of blood was drawn by direct venipuncture
from a cephalic or jugular vein; 2 mL was placed into an
evacuated serum separator tube (SST) and another 2 mL
into an evacuated K2EDTA tube. These blood collections
occurred during acclimation (baseline), mid-study (after five
doses of placebo oil, and three doses of cannabinoid oils),
and 7 days following the final dose of the cannabinoid or
placebo oils. Additionally, they occurred 24 h following the
final dose of the cannabinoid oils. With the occurrence of
a severe AE, blood was drawn immediately, and 24 h and 7
days thereafter.
For analysis of CBD, THC, and their metabolites (7-COOH-
CBD and 11-OH-THC), 2 mL of blood was drawn and placed
into an evacuated K2EDTA tube. These blood collections
occurred before and after the ninth dose of the CBD oil and THC
oil (i.e., pre-dose, and at 1, 2, 4, 6, and 24 h post-dose). These
blood collections also occurred 7 days following the final dose of
the cannabinoid or placebo oils.
Blood in the evacuated SSTs was allowed to clot for a
minimum of 30 min but no more than 1 h following collection,
then was centrifuged at 1,525–1,992 relative centrifugal force
(rcf) at 20C for 10 min. K2EDTA tubes were centrifuged at
2,800–3,000 revolutions per minute (rpm) for 10 min at 4C. The
SSTs and K2EDTA tubes were stored at 2 to 8C and on the same
day as blood collection were transported to Antech Diagnostics
(Mississauga, ON) for analysis (CBC and clinical chemistry) or
Frontiers in Veterinary Science | 4February 2020 | Volume 7 | Article 51
Vaughn et al. Cannabinoid Safety in Dogs
further processing. For the K2EDTA tubes intended for analysis
of CBD, THC, and their metabolites, plasma was separated into
two equal aliquots and stored at 80C until shipment on dry ice
to the bioanalytical laboratory for analysis (InterVivo Solutions,
Inc., Mississauga, ON).
CBD, THC, 7-COOH-CBD, and 11-OH-THC were analyzed
by liquid chromatography tandem mass spectrometry (LC-
6500 with an Exion LCTM system, AB
Sciex LP). The analytes CBD, THC and 11-OH-THC were
purchased as analytical reference solutions from Sigma-
Aldrich; 7-COOH-CBD was purchased from Toronto Research
Chemicals. The analytes were chromatographically separated
on a Phenomenex Kinetex Phenyl-Hexyl column (2.1 ×
50 mm, 2.6 µm) using gradient elution (mobile phase A
=0.1% formic acid in water and mobile phase B =0.1%
formic acid in acetonitrile) at a flow rate of 0.4 mL/min.
The mass spectrometer was operated in multiple reaction
monitoring (MRM) mode with a turbo ion spray interface.
Internal standards were deuterated analogs of THC, CBD, and
11-OH-THC (THC-d3, CBD-d3, 11-OH-THC-d3, Toronto
Research Chemicals); paclitaxel was used as the internal standard
for 7-COOH-CBD. All four compounds were analyzed in
one run.
Calibration standards were prepared in blank pooled dog
plasma (with K2EDTA as anticoagulant). Ten calibration
standards over the range of 0.25–2,000 ng/mL (CBD,
THC) or 0.5–2,000 ng/mL (7-COOH-CBD, 11-OH-THC)
were used and included a blank sample (without internal
standard) and a zero sample (with internal standard). Plasma
standards and samples were extracted by the addition of
a solution of 50/50 methanol/acetonitrile containing the
internal standards to precipitate the proteins. A sample batch
consisted of the following: 3 replicates of a system suitability
standard (containing the analyte and internal standard),
calibration standards in ascending order including a blank
sample (without internal standard), a zero sample (with
internal standard), and 10 non-zero standards, the assay
samples, followed by the 3 replicates of the system suitability
sample. Calibration standards bracketed an analysis batch of
>40 samples.
Acceptance criteria for method qualification and sample
analysis were: (1) that at least 75% of the non-zero calibration
standards be included in the calibration curve with all back-
calculated concentrations within ±20% deviation from nominal
concentrations (except for the lower level of quantification,
LLOQ, where ±25% deviation was acceptable), (2) the
correlation coefficient (r) of the calibration curve must be
0.99, and (3) the area ratio variation between the pre-
and post-run injections of the system suitability samples is
within ±25%.
Data Analysis
Measures of central tendency (mean), variability (standard
deviation, standard error of mean), and all figures were generated
by GraphPad Prism version 8.1.2 for Windows, GraphPad
Software, San Diego, California, USA,
Four of 24 dogs evaluated for inclusion into the study were
excluded from study enrollment following the acclimation period
due to recurring loose stool (n=1), recurring ear infections
(n=1), and inadequate maintenance of body weight (n=2).
Therefore, 20 dogs were randomized to treatment groups (with
4 dogs per group). The mean (SD) body weights of each group
at baseline were as follows: MCT oil: 12.2 kg (1.1 kg); CBD oil:
10.3 kg (0.4 kg); THC oil: 12.3 kg (1.0 kg); SF oil: 11.9 kg (1.5 kg);
CBD/THC oil: 11.3 kg (0.9 kg).
Of the cannabinoid oils tested, dosing of the CBD oil had the
least effect on food intake and physical activity. Specifically, food
intake decreased on dosing days as compared to non-dosing days
by 4.6% (MCT oil), 8.1% (CBD oil), 27.9% (THC oil), and 44.7%
(CBD/THC oil), with no changes observed between these periods
with SF oil (data not shown). Dogs were not exercised/socialized
on dosing days and physical activity (measured by Actiwatch-
64 R
) was thus reduced across all groups on dosing days as
compared to non-dosing days by 12.9% (MCT oil), 19.2% (CBD
oil), 19.8% (THC oil), 24.4% (SF oil), and 40.7% (CBD/THC oil)
(data not shown). Despite these changes, body weights remained
stable throughout the study period across the five groups.
Dose Escalation and Subject
The two placebo oils were tested up to 10 escalating volumes
while the CBD oil, THC oil, and CBD/THC oil were tested
up to the tenth, tenth, and fifth dose, respectively; titration to
maximum doses of 640.5 mg CBD (62 mg/kg), 597.6 mg THC
(49 mg/kg), and 140.8/96.6 mg CBD/THC (12 mg/kg CBD +
8 mg/kg THC), respectively, was thus achieved (Tables 1,2). For
the cannabinoid oils, the second cannabinoid dose was 2- to 2.5-
fold greater than the first dose; thereafter, serial doses increased
by 1.2- to 2-fold.
One of four dogs in the THC oil group experienced severe
ataxia at the 7th dose and was discontinued from further dosing.
Two of four dogs in the CBD/THC oil group experienced severe
ataxia and/or lethargy at the fourth or fifth doses (one dog at
the fourth dose and a second dog at the fifth dose) and thus
further dosing ceased for all dogs in this group. No dogs were
discontinued from the CBD oil or placebo oil groups as a result
of AEs.
Adverse Events
AEs were reported in all 20 dogs across the five groups. Of the
total number of AEs observed across the entire study (n=505),
104 AEs occurred in the placebo groups across 10 escalating
volumes (77 AEs with MCT oil and 27 AEs with SF oil), and 401
AEs occurred across the three cannabinoid groups: 80 AEs with
CBD oil (10 doses), 206 AEs with THC oil (10 doses), and 115
AEs with CBD/THC oil (five doses) (Figure 1). The SF oil group
was the placebo control for the CBD/THC oil group, the latter
which was delivered up to five doses; as such, while there were 27
AEs across 10 doses of SF oil, there were 11 AEs across the first
five doses of SF oil (Figure 1).
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Vaughn et al. Cannabinoid Safety in Dogs
FIGURE 1 | Total number and severity (mild, moderate, severe) of AEs experienced across five escalating doses of SF oil placebo (n=4) and CBD/THC oil (n=3 or
4) and 10 escalating doses of MCT oil placebo (n=4), CBD oil (n=4), and THC oil (n=3 or 4). There were no moderate or severe AEs experienced with CBD oil and
SF oil.
Across the three groups receiving cannabinoid oils, the
fewest AEs were reported in the CBD oil group (across 10
doses) as compared to the THC oil group (across 10 doses)
and the CBD/THC oil group (across five doses) (Figure 1).
Compared to dogs receiving the CBD oil, dogs receiving the
THC oil experienced 2.6-fold more total AEs (Figure 1) and,
more specifically, 7-fold more neurological and constitutional
AEs, 5-fold more dermatological AEs, and 3-fold more ocular
and respiratory AEs (Figure 2). The greatest difference between
the CBD oil and THC oil groups with respect to the occurrence
of AEs occurred at the first dose at which point there was a 7-
fold difference in the average number of AEs experienced per
dog (Figure 3). For the remaining nine doses, dogs receiving the
THC oil experienced between a 2- and 3-fold greater number of
AEs per dose vs. dogs receiving the CBD oil (Figure 3). With
respect to the CBD/THC oil group, there was a steep increase
in the average number of AEs per dog at the fifth dose; each
of the three dogs experienced 10 AEs at this dose vs. the other
two cannabinoid oil groups wherein an average of 4.8 AEs (THC
oil group) and 1.5 AEs (CBD oil group) were experienced per
dog (Figure 3). It is noteworthy that the total number of AEs
and the AE profile in the CBD oil group were comparable to
the MCT placebo oil group (Figures 1,2). Moreover, across the
cannabinoid oil groups, at each escalating dose, dogs in the
CBD oil group experienced a lower average number of AEs as
compared to the THC oil group and the CBD/THC oil group
(Figure 3).
The majority of AEs in each of the five groups, and collectively
across all five groups, were mild. Mild AEs accounted for 479 of
the 505 total study AEs (94.9%) (Figure 1). Mild AEs occurred
in all subjects and mainly manifested as gastrointestinal (nausea,
emesis, diarrhea), constitutional (lethargy, hyperesthesia), or
neurological (muscle tremor, ataxia) symptoms (Figure 2). The
proportion of mild AEs that were gastrointestinal in each group
was: 49/75 (65.3%) (MCT oil; 10 doses), 53/80 (66.3%) (CBD oil;
10 doses), 64/203 (31.5%) (THC oil; 10 doses), 9/11 (81.8%) (SF
oil; five doses), 16/94 (17.0%) (CBD/THC oil; five doses). The
proportion of mild AEs that were constitutional or neurological
in each group was: 13/75 (17.3%) (MCT oil; 10 doses), 13/80
(16.3%) (CBD oil; 10 doses), 89/203 (43.8%) (THC oil; 10 doses),
0/11 (SF oil; five doses), 56/94 (59.6%) (CBD/THC oil; five
doses). Thus, across the two placebo groups (SF oil, MCT oil)
and the CBD oil group, a greater proportion of mild AEs were
gastrointestinal vs. constitutional/neurological whereas in the
THC oil and CBD/THC oil groups, a greater proportion of mild
AEs were constitutional/neurological vs. gastrointestinal.
There were no moderate AEs in the CBD oil group at any
of the doses tested. Moderate AEs accounted for 22 of the 505
total study AEs (4.4%) and occurred in 40% of the subjects
(8 of 20 dogs) across three groups: MCT oil (two dogs at
the tenth dose), THC oil (two dogs at the third or seventh
doses), or CBD/THC oil (four dogs across the five doses tested)
(Figure 1). Moderate AEs manifested as constitutional (lethargy,
hypothermia) or neurological (ataxia) symptoms. The most
common moderate AE was hypothermia (rectal temperature
<36.0C), which accounted for 14 of the 22 moderate AEs (64%).
The majority of hypothermia occurrences (13 of 14) occurred
in the CBD/THC oil group, wherein all 4 dogs experienced
hypothermia at four of the five doses tested (excluding the first
dose). The lowest dose of CBD/THC oil at which hypothermia
occurred was at the second dose (35.2/24.2 mg CBD/THC = ∼3
mg/kg CBD and 2 mg/kg THC). The remaining hypothermia
event occurred in the THC oil group at the third dose (82.2 mg
THC = ∼7 mg/kg THC). Indeed, as compared to the other
cannabinoid and placebo oils, a greater decline in the rectal
temperature of dogs occurred following intake of the CBD/THC
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FIGURE 2 | Total number of mild AEs per anatomic category. Mild AEs
accounted for the majority (94.9%) of AEs. (A) Mild AEs across 10 doses of
MCT oil placebo (n=4), CBD oil (n=4), or THC oil (n=3 or 4). (B) Mild AEs
across five doses of SF oil placebo (n=4) or CBD/THC oil (n=3 or 4).
Gastrointestinal =nausea, vomiting, diarrhea, or other (hematemesis or blood
or mucus in stool); Constitutional =lethargy, hyperesthesia, hypothermia, or
other (weight loss, hypertonia, eyebrows raised and no blinking, abnormal
posture, vocalization); Neurological =tremor (including hiccups) or ataxia;
FIGURE 2 | Ocular =mydriasis or other (epiphora, conjunctivitis,
blepharospasm); Dermatological =pruritus or other (skin ulceration, purpura,
alopecia, erythema, granuloma); Respiratory =nasal discharge or
bradypnoea; Cardiovascular =bradycardia; Otic =external ear inflammation;
Genitourinary =urinary incontinence or hematuria.
oil (Figure 4). Moderate AEs were transient and resolved in
3–24 h. Importantly, there were no moderate AEs, including
hypothermia, in the CBD oil group at any of the doses tested.
There were no severe/medically significant AEs in the CBD
oil group at any of the doses tested. Severe AEs accounted for
4 of the 505 total study AEs (0.8%) (Figure 1) and occurred
in 15% of the subjects (3 of 20 dogs) across two groups:
THC oil (one dog at the seventh dose) and CBD/THC oil
(one dog at the fourth dose and a second dog at the fifth
dose). Severe AEs manifested as severe ataxia and/or lethargy
and were transient, resolving in 9–28 h. Plasma levels of CBD,
THC, and their metabolites measured upon observation of
severe AEs were 785 ng/mL THC and 93.9 ng/mL 11-OH-
THC (THC oil group) and 133–296 ng/mL CBD and 99.5–
361 ng/mL THC (CBD/THC oil group). Bloodwork results
from animals experiencing severe AEs revealed abnormalities
(low platelet count, high pancreatic sensitive lipase, high white
blood cell count, high neutrophils, and/or high monocytes)
only in the two dogs administered the CBD/THC oil; these
abnormalities resolved within 24 h. There were no abnormal
physical findings of the dogs on final examinations conducted by
the facility’s veterinarian.
Hematological Changes
Clinical Chemistry and Complete Blood Count
For the cannabinoid oil groups, blood was collected at baseline,
and 24 h and 7 days after the final dose. Overall, hematological
parameters were generally normal for the dogs across these
groups at 24 h and 7 days after the final dose, with a few
exceptions as outlined below.
With respect to changes in clinical chemistry parameters
suggestive of altered liver function, while possibly not clinically
pathologic, we interpreted a notable change to be: (i) at least
a 2-fold increase from baseline to post final dose timepoints
(24 h or 7 days) in total bilirubin or plasma levels of liver
enzymes [alkaline phosphatase (ALP), alanine aminotransferase
(ALT), aspartate aminotransferase (AST), gamma-glutamyl
transpeptidase (GGTP)]; and (ii) the post final dose level (24 h
or 7 days) in the above parameters reached or exceeded the upper
limit of normal. Applying these criteria, one dog in the CBD oil
group and one dog in the CBD/THC oil group experienced 2.9-
fold or 3.6-fold increases in ALP from baseline to 24 h following
the last administered dose, which was the tenth dose (CBD oil) or
the fifth dose (CBD/THC oil), respectively (Table 4). Moreover,
the post final dose level (at 24 h) approached or exceeded the
upper cut-off of normal for ALP. Comparing the 7 days post
final dose ALP levels for these two dogs to the 24-h post final
dose levels showed a downward trend (Table 4). Plasma levels
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FIGURE 3 | Average number (SEM) of AEs per dog per administered dose of oil. (A) Ten doses of MCT oil placebo (n=4), CBD oil (n=4), or THC oil (n=3 or 4)
were administered. (B) Ten doses of SF oil placebo (n=4) and five doses of CBD/THC oil (n=3 or 4) were administered.
FIGURE 4 | Rectal temperature (mean ±SEM) after the 4th dose of the cannabinoid oils or the 6th dose of the placebo oils, measured on the same calendar day. (A)
MCT oil (n=4) vs. CBD oil (n=4; 137.3 mg CBD) vs. THC oil (n=4; 109.6 mg THC). (B) SF oil (n=4) vs. CBD/THC oil (n=4; 105.6/72.5 mg CBD/THC). Rectal
temperature was measured pre-dose (time 0) and 1, 2, 3, 4, 6, and 9h post-dose. The dotted line corresponds to a rectal temperature of 36.0C, below which the
dogs were considered to have hypothermia.
of liver enzymes and total bilirubin were stable in the THC
oil group.
With respect to the remaining CBC and clinical chemistry
parameters, blood collected 24 h following the final dose of the
cannabinoid oils showed only a few abnormalities as based on
laboratory reference ranges. These abnormalities occurred in 1 or
2 dogs in the cannabinoid oil groups and consisted of low creatine
phosphokinase (1 dog in CBD oil group); low amylase, high
sodium, or high pancreatic sensitive lipase (2 dogs in THC oil
group); high pancreatic sensitive lipase (1 dog in the CBD/THC
oil group) (data not shown). All abnormalities resolved 7 days
following the final dose.
Cannabinoids and Their Metabolites
Following intake of the ninth dose of the CBD oil (n=4) or THC
oil (n=3), plasma levels of CBD, THC, and their metabolites
(7-COOH-CBD, 11-OH-THC) were measured 1, 2, 4, 6, and
24 h post-dose; levels of these parameters were also measured
pre-dose (Figure 5).
Intake of the ninth dose of the CBD oil (549.0 mg CBD;
53 mg/kg) led to steady inclines in plasma CBD, 7-COOH-
CBD and THC over the 6-h post-dose period (Figure 5). Levels
(mean/SEM) of CBD and THC at 6 h post-dose were similar to
levels 24 h post-dose [CBD: 334.0 ±193.0 ng/mL (6 h) and 347.0
±204.5 ng/mL (24 h); THC: 10.5 ±6.3 ng/mL (6 h) and 9.8 ±
6.5 ng/mL (24 h)]. In contrast, levels of 7-COOH-CBD were 2-
fold lower at 6 vs. 24 h post-dose (39.1 ±23.0 ng/mL and 82.8 ±
38.4 ng/mL, respectively).
Following intake of the ninth dose of the THC oil (448.2 mg
THC; 37 mg/kg), mean (SEM) plasma THC and 11-OH-
THC reached maximum levels of 69.8 ±28.8 ng/mL (THC, 1 h
post-dose) and 5.9 ±2.7 ng/mL (11-OH-THC, 2 h post-dose),
respectively, with steady declines observed thereafter over the
6-h post-dose period. Mean plasma THC at 6 h post-dose (21.1
±5.1 ng/mL) was similar to its level 24 h post-dose (18.2 ±
7.6 ng/mL). Mean plasma 11-OH-THC at 6 h post-dose (3.7
±1.8 ng/mL) was similar to its level 24 h post-dose (4.5 ±
1.7 ng/mL).
Across the cannabinoid oil groups, cannabinoids and their
metabolites were measured 7 days following the last administered
dose. Seven days following intake of the last (tenth) dose of the
CBD oil (640.5 mg CBD; 62 mg/kg; n=4), CBD was detected
in all four dogs (3.6–31.7 ng/mL) while levels of 7-COOH-CBD
were detected in half the dogs (1.4–1.8 ng/mL) (data not shown).
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TABLE 4 | Clinical chemistry plasma parameters indicative of liver function as measured in healthy Beagle dogs administered cannabinoid oils.
AST (U/L) ALT (U/L) ALP (U/L) GGTP (U/L) Total Bilirubin (µmol/L)
RR =15–66 U/L RR =12–118 U/L RR =5–131 U/L RR =1–12 U/L RR =0.0–5.1 µmol/L
BSN 24 h post FD 7 d post FD BSN 24 h post FD 7 d post FD BSN 24 h post FD 7 d post FD BSN 24 h post FD 7 d post FD BSN 24 h post FD 7 d post FD
Dog 1 23 21 21 21 21 20 44 127a93 3 3 4 2.4 1.6 1.3
Dog 2 24 23 23 23 25 24 80 94 123 3 3 3 3.2 2.2 2.3
Dog 3 21 17 18 29 28 29 43 69 66 6 4 4 2.3 1.7 1.7
Dog 4 25 23 22 24 45 31 48 83 80 4 6 4 2.2 1.1 1.5
Mean (SD) 23.3 (1.7) 21.0 (2.8) 21.0 (2.2) 24.3 (3.4) 29.8 (10.6) 26.0 (5.0) 53.8 (17.6) 93.3 (24.7) 90.5 (24.3) 4.0 (1.4) 4.0 (1.4) 3.8 (0.5) 2.5 (0.5) 1.7 (0.5) 1.7 (0.4)
Dog 1 16 15 13 19 22 20 40 46 49 5 3 3 1.8 1.6 1.4
Dog 2b23 21 19 21 24 20 26 37 27 4 1 5 2.6 2.1 1.8
Dog 3 16 23 18 19 21 23 21 27 29 2 4 4 2.8 2.0 1.7
Dog 4 26 19 20 22 24 23 35 33 39 4 4 2 2.2 1.8 1.8
Mean (SD) 20.3 (5.1) 19.0 (4.0) 17.0 (3.6) 20.3 (1.5) 22.3 (1.5) 22.0 (1.7) 30.5 (8.6) 35.3 (9.7) 39.0 (10.0) 3.8 (1.3) 3.7 (0.6) 3.0 (1.0) 2.4 (0.4) 1.8 (0.2) 1.6 (0.2)
Dog 1 27 18 19 40 42 41 52 189c88 3 3 4 2.5 1.7 2.0
Dog 2d24 21 24 30 32 34 60 96 79 3 3 4 2.0 2.6 1.7
Dog 3 26 24 19 28 24 39 36 55 42 2 3 1 3.7 1.9 2.3
Dog 4 21 19 16 21 66 29 25 41 37 3 5 5 2.6 2.3 2.1
Mean (SD) 24.5 (2.6) 20.3 (3.2) 18.0 (1.7) 29.8 (7.8) 44.0 (21.1) 36.3 (6.4) 43.3 (15.7) 95.0 (81.7) 55.7 (28.1) 2.8 (0.5) 3.7 (1.2) 3.3 (2.1) 2.7 (0.7) 2.0 (0.3) 2.1 (0.2)
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSN, baseline; CBD, cannabidiol; d, days; FD, final dose; GGTP, gamma-glutamyl transpeptidase; h, hours; RR, reference range; SD, standard
deviation; THC, delta-9-tetrahydrocannabinol; U/L, units per liter.
aALP level 2.9-fold higher than baseline and approaching the upper limit of normal (131 U/L).
bThe 7th dose was the last dose due to a severe/medically significant AE with this dose. Calculation of the mean (SD) for all post FD outcomes excluded this dog’s data.
cALP level 3.6-fold higher than baseline and exceeded the upper limit of normal (131 U/L).
dThe 4th dose was the last dose due to a severe/medically significant AE with this dose. Calculation of the mean (SD) for all post FD outcomes excluded this dog’s data. For the remaining dogs in this group, the 5th dose was the
last dose.
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FIGURE 5 | Plasma levels (mean ±SEM) of CBD, THC, and their metabolites (7-COOH-CBD, 11-OH-THC) pre-dose, and at 1, 2, 4, 6, and 24 h following the 9th dose
of (A) CBD oil (549.0mg CBD; n=4) or (B) THC oil (448.2mg THC; n=3). Following exposure to the CBD oil, levels of 11-OH-THC were not detected or were below
the lower level of quantitation in the majority of dogs. Following exposure to the THC oil, there were no detectable levels of CBD or its metabolite (7-COOH-CBD).
Seven days following intake of the last (tenth) dose of the THC
oil (597.6 mg THC; 49 mg/kg; n=3), THC was detected
in all three dogs (2.8–8.2 ng/mL), while 11-OH-THC was not
detected in any dogs (data not shown). Seven days following the
intake of the last (fifth) dose of the CBD/THC oil (140.8/96.6 mg
CBD/THC; 12 mg/kg CBD +8 mg/kg THC; n=3), CBD and
THC were detected in all three dogs (CBD: 8.4–18.8 ng/mL; THC:
6.2–12.2 ng/mL), while 7-COOH-CBD was detected in one of
three dogs (1.4 ng/mL) and 11-OH-THC was not detected in any
of the three dogs (data not shown).
In our study, a CBD-predominant oil consumed via 10 escalating
doses containing 18.3–640.5 mg CBD per dose (2–62 mg/kg)
led to only mild AEs and no moderate or severe AEs. Importantly,
the number and type of AEs that occurred in the CBD oil group
were comparable to the corresponding placebo group (MCT oil).
In both groups, the majority of AEs were gastrointestinal, which
could have been due to discomfort with oral gavage, oil volume,
and/or the MCT oil carrier.
The safety and tolerability of CBD, as determined primarily
in rodents and humans, has been extensively reviewed (68). In
humans, oral doses of CBD ranging from a minimum of 15 or 20
mg/day (24,25) to a maximum of 1,200–1,500 mg/day (2628)
have been well-tolerated, with no significant side effects. In mice,
oral doses ranging from 3 to 100 mg/kg showed no significant
effects on catalepsy (29). In dogs, CBD has shown to be well-
tolerated at doses ranging from 2 to 2.5 mg/kg twice daily for
4 or 12 weeks (17,21) to 5 or 10 mg/kg twice daily for 6 weeks
(20). Indeed, in their critical review report on CBD, the World
Health Organization (WHO) concluded that “CBD is generally
well-tolerated with a good safety profile (. . . ) and relatively low
toxicity” (8).
Previous studies have reported increases in liver enzymes,
specifically ALP, in dogs receiving CBD orally at doses ranging
from 2 mg/kg (twice daily) to 10 mg/kg (twice daily) for
4, 6, or 12 weeks (17,20,21) with increases observed as
early as 2 weeks following treatment initiation (20). In our
study, one dog in the CBD oil group and one dog in the
CBD/THC oil group experienced 2.9- or 3.6-fold increases in
ALP from baseline to 24 h following the tenth dose (CBD
oil) or fifth dose (CBD/THC oil). These changes were not
considered clinically significant by the veterinarian providing
oversight for the study. Elevated liver enzymes with exposure
to cannabis or CBD have also been observed in humans and
rodents. Cross-sectional human studies have shown plasma ALP
to be elevated in habitual daily cannabis users (30,31) with
hepatomegaly also observed (31). Increases in plasma AST, ALT,
and liver-to-body weight ratios were observed in rodents treated
with CBD (oral gavage; 615 mg/kg for 10 days) albeit there
were unremarkable changes in liver enzymes in lower dose
groups (61.5 and 184.5 mg/kg) (32). The potential short- and
long-term effects of CBD on liver function in dogs warrant
further investigation.
Only in the CBD/THC oil group were severe AEs experienced
by more than one dog causing cessation of dosing after the
fifth dose. Researchers have acknowledged that CBD can have
interactions with THC (33) and that CBD is not always a
functional antagonist of THC (34). Indeed, there is evidence
in rodents (3337) and humans (38) that CBD can potentiate,
rather than antagonize, the psychoactive and physiological effects
of THC (e.g., locomotor activity suppression, hypothermia,
hypoactivity). The interaction between these two exogeneous
phytocannabinoids may be pharmacokinetic (CBD modifies the
effect of THC through changes in absorption, distribution,
and/or elimination) or pharmacodynamic (CBD modifies the
effect of THC via additive, synergistic, or antagonistic effects).
The interaction depends on whether CBD is administered
prior to THC (pharmacokinetic interaction more likely) or
concurrently with THC (pharmacodynamic interaction more
likely) (7,34,39) and also on the dose ratio of the compounds (39,
40). Regarding the latter, when CBD/THC are simultaneously
co-administered at a mean (±standard deviation) dose ratio of
8.1 (±11.1), antagonistic effects of CBD on THC have been
observed (a pharmacodynamic interaction) whereas at a ratio of
1.8 (±1.4), CBD has been shown to potentiate the effects of THC
(a pharmacokinetic interaction) (39,41). Our CBD/THC oil had a
CBD/THC dose ratio of 1.5. It therefore follows that the effects of
THC may have been potentiated by CBD via a pharmacokinetic
interaction. CBD is known to be a potent inhibitor of hepatic
drug metabolism (39) by inactivating cytochrome P450 enzymes.
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When co-administered with THC, this effect can delay the
metabolism of THC in the liver (7,34). Notwithstanding that the
levels of other cannabinoids (THCA, CBDA, CBG, CBGA, CBN,
CBC) and terpenes in the CBD/THC oil fell below reporting
limits (0.5 mg/mL for cannabinoids and 0.01% for terpenes),
their potential interaction with CBD and/or THC in the oil
and their contribution to the overall effect of the CBD/THC
oil cannot be precluded (this synergy is often called the
“entourage effect”).
Our data show a clear distinction in AEs associated with a
CBD-predominant oil vs. oils containing higher levels of THC in
that constitutional (lethargy, hyperesthesia, hypothermia)
and neurological (tremor, ataxia) AEs most commonly
occurred in dogs receiving the THC oil or the CBD/THC
oil. Suppression of locomotor activity (hypolocomotion),
catalepsy, and hypothermia have been observed across species
(dogs, cats, rodents, chickens) and associated with exposure
to cannabis, THC, or THC and CBD in combination, but not
CBD alone (33,37,4245). Animal studies have shown that
the production of these effects is dependent on cannabinoid
type 1 (CB1) receptor activation (45). CB1 receptors are located
primarily in central and peripheral neurons and are found
in the highest densities in the neuron terminals of the basal
ganglia, cerebellum, hippocampus neocortex, hypothalamus,
and limbic cortex—areas which, among other functions, are
involved in motor activity, coordination, and sedation (46,47).
THC, a CB1 receptor partial agonist, has a high affinity for
CB1 receptors (48) and is capable of binding and activating
them at orthosteric sites (45,49). In contrast, CBD does not
bind to orthosteric sites of these receptors like THC (49). In
our study, there was a lower proportion of constitutional and
neurological AEs following intake of CBD oil (vs. THC oil and
CBD/THC oil) and no moderate or severe AEs were experienced
by dogs in the CBD oil group. CBD’s lack of interaction with
orthosteric sites of CB1 receptors (49) is a plausible explanation
for the fewer and less severe AEs experienced by dogs receiving
CBD oil.
Plasma levels of CBD, THC, and their metabolites were
highly variable between dogs in the same treatment group
receiving either the ninth dose of CBD oil or THC oil. Others
have also observed high variability in cannabinoid (CBD, THC)
blood concentrations across dogs in single dose pharmacokinetic
studies (16,19) and repeated administration studies (21),
which may be explained by differences in absorption rates or
cannabinoid metabolism across subjects. Following the ninth
dose of the CBD oil (53 mg/kg), maximum plasma CBD levels
achieved across the four dogs in the CBD oil group (62.3–
896.0 ng/mL, at 4, 6, or 24 h post-dose) were comparable to the
range in plasma CBD levels achieved across nine dogs (130–
940 ng/mL) following repeated daily CBD dosing (2.5 mg/kg
twice daily) for 12 weeks (21). With respect to plasma levels
reached following the ninth dose of the THC oil (37 mg/kg),
at 24 h post-dose, mean plasma THC (18.2 ng/mL) and 11-
OH-THC (4.5 ng/mL) across three dogs approximated mean
plasma levels reached by eight dogs receiving a cannabis extract
(2.7 mg/kg THC +2.5 mg/kg CBD) for 56 weeks: 22.0 ng/mL
(THC) and 6.7 ng/mL (11-OH-THC) (11). Thus, it appears that
repeated daily dosing of lower cannabinoid doses can achieve
comparable plasma CBD or THC levels to acutely administered
higher doses.
Contrary to earlier assertions that CBD has low bioavailability
after oral administration to animals, including dogs (18,50),
our study showed circulating plasma CBD and 7-COOH-
CBD in all dogs receiving the ninth dose of CBD oil at all
post-dose timepoints (1, 2, 4, 6, and 24 h). Based on these
results, it appears that a first pass effect through the liver
did not eliminate the systemic availability of CBD following
its oral ingestion. Given the highly lipophilic nature of CBD
(50), its administration in a lipid solvent (MCT oil) in the
present study may have increased its bioavailability. Zgair
et al. (51) showed that co-administration of lipids with oral
CBD increased systematic availability of CBD by almost 3-
fold in rats as compared to lipid-free formulations. Overnight
fasting of the dogs in the present study prior to dosing may
have also improved bioavailability. Lebkowska-Wieruszewska
et al. (19) showed improved cannabinoid (THC) bioavailability
in fasted vs. fed dogs, with a lower Tmax and higher Cmax
achieved for THC in the fasted condition. The approximate
cumulative CBD dose administration from the first to ninth
dose was 2122.9 mg. Detected plasma levels of CBD may also be
reflective of CBD accumulation in plasma with dose escalation
over time.
Fasted dogs receiving the ninth dose of the THC oil
(cumulative THC from first to ninth dose =1653.5 mg) achieved
maximum THC plasma levels at 1-h post-dose. Related findings
are those reported by Lebkowska-Wieruszewska et al. (19) who
calculated median Tmax levels for plasma THC of 1.25 h in
fasted dogs orally dosed with Bedrocan R
(1.5 mg THC/kg). It
is reported in the literature that following oral ingestion of
cannabis, maximum plasma THC levels are reached within 1–
2 h (52). Decreases in plasma THC observed in our study after
1 h are suggestive of the uptake of THC by fat tissues and highly
vascularized tissues, such as the brain and muscle (52). Indeed,
in the THC oil group, the average onset of neurological AEs
(ataxia, tremor) or constitutional AEs (lethargy, hyperesthesia,
hypothermia, hypertonia) was 4 h post-dose (range of onset was
1–24 h).
Both CBD and THC were detected in plasma 1 week following
administration of the final dose of either CBD oil (62 mg/kg;
n=4) or THC oil (49 mg/kg; n=3), at levels ranging from
3.6 to 31.7 ng/mL CBD (CBD oil) and 2.8 to 4.6 ng/mL THC
(THC oil). This finding is relevant to future studies which apply a
crossover design and include a washout period. That quantifiable
levels of CBD were observed one week following dose exposure
is also interesting given that CBD has been reported to have a
relatively rapid elimination in dogs [CBD has been shown to be
bio-transformed in dogs via hydroxylation, carboxylation, and
conjugation (10,18)].
The cannabinoid oils used in this study are proprietary
formulations with relatively high concentrations of CBD
and/or THC and low concentrations of other cannabinoids
and terpenes. Given the multitude of factors that can affect
the proportion of constituents in the cannabis plant (light,
temperature, humidity, soil type during cultivation, plant
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Vaughn et al. Cannabinoid Safety in Dogs
genetics) and a final formulation (extraction procedures used),
our findings are most relevant to our investigated oil-
based formulations and may not be applicable to the safety
of other marketed formulations consisting of a different
profile of cannabinoids and other cannabis constituents (e.g.,
terpenes) and delivered in a different matrix (e.g., not
in an oil formulation). Our study was also a preliminary
safety study and, as such, a small number of animals were
used, which is a limitation. Additional larger studies that
investigate the safety of longer-term cannabinoid dosing in dogs
are needed.
Overall, our study provides novel data that separates
the relative safety and tolerability of dose escalation of
oil formulations predominant in plant-derived CBD,
THC, or CBD and THC in combination (1.5:1) in dogs.
Of the three cannabinoid oil formulations tested, dose
escalation of the CBD-predominant oil formulation was
the most tolerated by dogs up to a maximum dose of
640.5 mg CBD (62 mg CBD/kg) and only mild AEs were
experienced. Novel data on the in vivo metabolism of
CBD vs. THC when delivered at higher dose levels were
generated, which showed that CBD is absorbed more slowly
than THC.
Research on the potential health benefits of CBD in dogs
is beginning to emerge. Existing studies show its potential
as a single therapy for pain reduction in osteoarthritic
dogs (17) or as an adjunct therapy for the reduction in
seizure frequency in dogs with idiopathic epilepsy (21).
Our findings provide support for continuing research
on CBD’s safety profile and potential therapeutic uses in
dogs so that it may be considered a treatment option in
veterinary medicine.
The datasets generated for this study are not publicly available
to allow for commercialization of research findings. Reasonable
requests to access the datasets should be directed to Phil
Shaer (
All animal care and experimental procedures were conducted
under protocols approved by the facility’s Institutional Animal
Care and Use Committee (IACUC) and in accordance with the
Principles of the Animals for Research Act (53) and guidelines of
the Canadian Council on Animal Care (CCAC).
DV and JK were responsible for conception of the study, data
analysis, and provided intellectual input on the manuscript. LP
was responsible for data analysis and interpretation and writing
of the manuscript.
Canopy Animal Health, a division of Canopy Growth
Corporation, financially supported this research. There were no
conditions attached to the allocation of funds for this study.
The authors would like to thank Martha Winhall, DVM
(InterVivo Solutions) for her review and feedback on the
manuscript and Graham Eglit for his input on data analysis.
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Conflict of Interest: DV, JK, and LP are employed by Canopy Animal Health,
which is a division of Canopy Growth Corporation. Staff at VivoCore Inc., and
not the authors, were responsible for study conduct and data collection.
Copyright © 2020 Vaughn, Kulpa and Paulionis. 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
Frontiers in Veterinary Science | 13 February 2020 | Volume 7 | Article 51
... Recent studies in dogs have investigated the short to midterm safety of more moderate levels of CBD. Briefly, CBD concentrations of 2 mg/kg BW daily (23), 2 mg/kg BW twice daily (24, 25), 12 mg/kg BW daily (26), and up to 20 mg/kg daily (27), as well as escalating one-time dosing of CBD up to 62 mg/kg (28), were reportedly well-tolerated when orally administered to dogs. In these studies, some adverse effects were reported but classified as mild; these included gastrointestinal upset, hypersalivation and elevated serum alkaline phosphatase [ALP; (24)(25)(26)28)]. ...
... Briefly, CBD concentrations of 2 mg/kg BW daily (23), 2 mg/kg BW twice daily (24, 25), 12 mg/kg BW daily (26), and up to 20 mg/kg daily (27), as well as escalating one-time dosing of CBD up to 62 mg/kg (28), were reportedly well-tolerated when orally administered to dogs. In these studies, some adverse effects were reported but classified as mild; these included gastrointestinal upset, hypersalivation and elevated serum alkaline phosphatase [ALP; (24)(25)(26)28)]. ...
... As such, alanine transaminase (ALT) was used as a primary measure in this study; ALT is documented to be the gold-standard marker of hepatocellular injury due to its high specificity and sensitivity in comparison to other liver enzymes (30,31). ALP was also included as a secondary measure, as elevation can be indicative of liver injury and raised ALP levels have been previously reported after feeding of CBD to dogs over shorter periods (24,26,28,(32)(33)(34). In addition, a full suite of biochemical and hematological parameters, urinalysis, twice daily observational health and well-being checks, and fortnightly veterinary assessments were performed throughout the study. ...
Full-text available
Cannabidiol (CBD) containing dog food and treats are widely commercially available, mirroring the growing popularity of CBD as a supplement for humans. Despite this, experimental evidence of the safety and efficacy of long-term oral exposure in dogs is lacking. The purpose of this study was to address the gap in knowledge around the longer-term suitability and tolerance of a broad-spectrum CBD (THC-free) distillate in clinically healthy dogs. The study was a randomized, placebo-controlled, and blinded study where one group of twenty dogs received daily CBD capsules at a dose of 4 mg/kg of body weight (BW) for a period of 6 months. The control group of twenty dogs received placebo capsules. A comprehensive suite of physiological health measures was performed throughout the study at baseline, and after 2, 4, 10, 18, and 26 weeks of exposure, followed by 4 weeks of washout. CBD concentrations were measured at the same cadence in plasma, feces and urine. Health measures included biochemistry, hematology, urinalysis, in addition to fortnightly veterinary examinations, twice daily well-being observations, and a daily quality-of-life survey. Biochemistry and hematology showed no clinically significant alterations apart from a transient elevation in alkaline phosphatase (ALP) in just over half of the dogs receiving CBD. This elevation was observed in the absence of concurrent elevations of other liver parameters, and without any adverse effects on health and wellbeing. Furthermore, bone alkaline phosphatase (BALP) was simultaneously elevated with a significant, strong ( r > 0.9) positive correlation between the two measures, suggesting that the elevation of total ALP was at least partly due to the bone-derived isoform. This study provides evidence that a once-daily oral dose of 4 mg CBD/kg BW is well tolerated in clinically healthy dogs for a duration of 6-months.
... • Some panelists would consider joint injections with platelet rich plasma (PRP) or hyaluronic acid (HA)/triamcinolone at this time if a particular joint is refractory to treatment (66-68). • Some panelists would consider cannabinoids at this time with veterinary oversight for close monitoring and appropriate selection of a suitable quality product (69,70). ...
... The existing studies conducted have been product specific, in that the researched product has a specific cannabinoid and terpenoid profile. Unfortunately, this makes it challenging to extrapolate and interpret the results of PK and PD toward other comparable products (69,70,107,111). The safety profile needs further investigation, particularly with regards to causes of liver enzyme elevation and its effects on liver function (107,110). ...
Full-text available
The Canadian consensus guidelines on OA treatment were created from a diverse group of experts, with a strong clinical and/or academic background in treating OA in dogs. The document is a summary of the treatment recommendations made by the group, with treatments being divided into either a core or secondary recommendation. Each treatment or modality is then summarized in the context of available research based support and clinical experience, as the treatment of OA continues to be a multimodal and commonly a multidisciplinary as well as individualized approach. The guidelines aim to help clinicians by providing clear and clinically relevant information about treatment options based on COAST defined OA stages 1–4.
... The rapidly growing market for cannabis-based products and the widespread acceptance of these products as an effective treatment for pets have challenged veterinarians to gather as much scientific data as possible on the use of CBDs (21)(22)(23). Moreover, emerging scientific evidence supports the use of CBDs in dogs and cats (33)(34)(35)(36)(37)(38)(39)(40). ...
... The positive effects observed in our study (improved well-being, greater liveliness, increased activity) were also reported in other studies, in which improved well-being, increased activity, and pain reduction were the most common positive effects (21,23). The adverse effects, such as sedation and/or drowsiness and increased appetite and thirst, reported in our study were also observed by pet owners in other studies (38,39). However, the effects reported in this study are the subjective evaluation of dog and cat owners and should not be interpreted as an evidence-based finding. ...
Full-text available
The aim of this study was to assess the personal experience and attitudes of Slovenian pet owners regarding cannabinoid (CBD) use and to identify the predictors of the first use and reuse of CBDs in dogs and cats. We hypothesized that positive attitudes toward CBDs, postmodern health values, and personal experience would be significant predictors of CBD use in animals. An open online survey targeted randomly selected Slovenian dog and cat owners, regardless of their experience with cannabis products. The questionnaire consisted of six sections related to demographic data and personal experience with CBD use, information about the participant's animal, experience with CBD use in the participant's animal, reasons for not using CBDs in their animal, attitudes toward CBD use in dogs and cats, and postmodern health values. Descriptive statistics were performed to analyze demographics, personal experience with CBD use, and experience with CBD use in dogs and cats. Hierarchical multiple regression using the enter method was performed to analyze the important predictors of CBD use. A total of 408 completed questionnaires were included in the statistical analysis. A substantial proportion (38.5%) of owners had already used CBDs to treat their animal. Positive attitudes and previous personal experience were significant ( p < 0.05) predictors of first use and reuse of CBDs in pets, while postmodern health values were not. In conclusion, the decision to use CBDs for medicinal purposes is based on acquired information and personal experience. Veterinarians should be informed and familiar with CBDs as a treatment option. However, further research is essential to establish the use of CBDs in veterinary medicine. Improved laws and regulations are also needed to ensure that only high-quality medications are prescribed to dogs and cats.
... Additionally, while there have been preliminary investigations into the safety of its use in dogs (Deabold et al., 2019;Gamble et al., 2018;Vaughn et al., 2020), concerns remain regarding the safety of CBD use as it poses potential risks of hepatoxicity and drug interactions (Ewing et al., 2019;Morris et al., 2020;Yamaori et al., 2011). ...
... chemistry in response to short-term CBD supplementation in dogs. At doses ranging from 2 to 65 mg/kg, CBD has been shown to increase serum alkaline phosphatase in dogs as early as 14 d after treatment initiation (Gamble et al., 2018;McGrath et al., 2018;Vaughn et al., 2020). Results from this study concur with these previous findings as serum alkaline phosphatase, though remaining within the IDEXX normal reference range, was increased in the CBD treatment compared with control on day 14 and remained elevated throughout the study. ...
Due to the potential risk for cannabidiol (CBD) to negatively impact the immune system, the objective of the current study was to evaluate the effect of CBD on the canine immune response to immunization with a novel antigen, keyhole limpet hemocyanin (KLH). Thirty-two dogs (22.4 ± 6.3 kg BW) were utilized in a completely randomized design with treatments consisting of 5 mg CBD/kg BW/d and a control administered orally via treats. After a 7-d acclimation to treatments, dogs were immunized with 10 mg/dog of KLH via intramuscular injection into the semimembranosus muscle region, which was repeated in 14 d. Blood samples were collected at baseline and weekly for 28 d after initial KLH immunization for analysis of hematology, serum chemistry, and immunoglobulins. Data were analyzed using the MIXED procedure in SAS including the fixed effects of treatment, day, and the treatment by day interaction. Both primary and secondary KLH immunization produced robust immune responses. Most hematological and serum chemistry variables remained within normal reference ranges for dogs across both treatments throughout the study. Alkaline phosphatase, while within normal reference range and similar between treatments at baseline and on d 7 (P = 0.994 and 0.183, respectively), was elevated for CBD-treated dogs versus control on d 14, 21, and 28 (P = 0.006, 0.027, and 0.014, respectively). Both total and KLH-specific IgG and IgM were similar between treatments throughout the study (P > 0.05), although total IgM peaked earlier in control dogs compared to those receiving CBD. Despite the minor shift in the timing of the total IgM peak, CBD did not appear to exhibit humoral immunosuppressive effects when supplemented at 5 mg/kg BW/d. However, this work does highlight the potential for CBD to alter liver function and the need for further safety evaluations of CBD use in dogs utilizing longer-term studies and multiple CBD doses.
... Soft chews are currently the most popular dosage-form treats available in the marketplace for dogs (52). CBD has a high lipophilicity and its administration in a lipid solvent, such as medium-chain triglycerides oil for example, may increase the bioavailability of CBD (53). In a study in rats, the administration of oral CBD together with lipid compounds increased the bioavailability of CBD by almost 3 times when compared to non-lipid formulations (54). ...
Full-text available
The therapeutic potential of cannabidiol (CBD), a non-psychtropic component of the Cannabis sativa plant, is substantiated more and more. We aimed to determine the pharmacokinetic behavior of CBD after a single dose via intranasal (IN) and intrarectal (IR) administration in six healthy Beagle dogs age 3-8 years old, and compare to the oral administration route (PO). Standardized dosages applied for IN, IR and PO were 20, 100, and 100 mg, respectively. Each dog underwent the same protocol but received CBD through a different administration route. CBD plasma concentrations were determined by ultra-high performance liquid chromatography-tandem mass spectrometry before and at fixed time points after administration. Non-compartmental analysis was performed on the plasma concentration-time profiles. Plasma CBD concentrations after IR administration were below the limit of quantification. The mean area under the curve (AUC) after IN and PO CBD administration was 61 and 1,376 ng/mL * h, respectively. The maximal plasma CBD concentration (C max) after IN and PO CBD administration was 28 and 217 ng/mL reached after 0.5 and 3.5 h (T max), respectively. Significant differences between IN and PO administration were found in the T max (p = 0.04). Higher AUC and C max were achieved with 100 mg PO compared to 20 mg IN, but no significant differences were found when AUC (p = 0.09) and C max (p = 0.44) were normalized to 1 mg dosages. IN administration of CBD resulted in faster absorption when compared to PO administration. However, PO remains the most favorable route for CBD delivery due to its more feasible administration. The IR administration route is not advised for clinical application.
... In a 39-week study with dogs (EMA, 2019), liver weight was increased, with accompanying hepatocyte hypertrophy, at the lowest dose investigated of 10 mg/kg bw per day of Epidyolex ® . In a 28-day dog study with CBD (˃ 95% purity, in MCT oil, 0, 1, 2, 4, 12 mg/kg bw), doses above 2 mg/kg bw per day caused dose-dependent increases in ALP, statistically significant at 12 mg/kg bw (Vaughn et al., 2020). No changes were found for ALT, AST, GGT and bilirubin and pathology was not assessed. ...
Full-text available
The European Commission has determined that cannabidiol (CBD) can be considered as a novel food (NF), and currently, 19 applications are under assessment at EFSA. While assessing these, it has become clear that there are knowledge gaps that need to be addressed before a conclusion on the safety of CBD can be reached. Consequently, EFSA has issued this statement, summarising the state of knowledge on the safety of CBD consumption and highlighting areas where more data are needed. Literature searches for both animal and human studies have been conducted to identify safety concerns. Many human studies have been carried out with Epidyolex®, a CBD drug authorised to treat refractory epilepsies. In the context of medical conditions, adverse effects are tolerated if the benefit outweighs the adverse effect. This is, however, not acceptable when considering CBD as a NF. Furthermore, most of the human data referred to in the CBD applications investigated the efficacy of Epidyolex (or CBD) at therapeutic doses. No NOAEL could be identified from these studies. Given the complexity and importance of CBD receptors and pathways, interactions need to be taken into account when considering CBD as a NF. The effects on drug metabolism need to be clarified. Toxicokinetics in different matrices, the half-life and accumulation need to be examined. The effect of CBD on liver, gastrointestinal tract, endocrine system, nervous system and on psychological function needs to be clarified. Studies in animals show significant reproductive toxicity, and the extent to which this occurs in humans generally and in women of child-bearing age specifically needs to be assessed. Considering the significant uncertainties and data gaps, the Panel concludes that the safety of CBD as a NF cannot currently be established.
Supplements containing Cannabidiol (CBD) are available for horses, however, few studies have been published on their effects on behavior and health parameters. The purpose of this study was to determine if a daily oral supplement containing CBD would cause sedation, ataxia or alterations in other health parameters during administration for 56 days. Twenty clinically healthy adult Thoroughbred horses were housed in stalls. Before treatment was initiated, a complete physical examination, complete blood count (CBC) and biochemical panel were evaluated. In addition, horses were examined for sedation and ataxia using standard scoring systems. Horses were randomly divided into two treatment groups, treated (supplement pellets containing CBD as Hemp Extract, 150 mg) or control (supplement pellets without CBD). Horses were treated daily and sedation and ataxia scores were assigned by two masked observers once weekly for 56 days. Horses were monitored daily for clinical signs or adverse events and body weights were recorded weekly. A CBC and biochemical panel were repeated on days 28 and 56, two hours after administration of the supplement. The supplement was readily consumed by the horses and no adverse effects were seen over the treatment period. Sedation and ataxia scores ranged from 0 to 2 for all horses during the weekly examinations and there was no statistical difference between treatment groups. There were no treatment effects on blood values, including indicators of anemia and blood proteins, liver enzymes, kidney values, electrolytes or calcium. Body weight significantly increased in all horses, by Day 56 compared to Day 0 but no treatment by day effect was noted. The CBD supplement (150 mg) was readily consumed and safe and did not result in changes in mentation, gait, or other health parameters, and no adverse clinical signs were observed during 56 days of oral administration.
The use of complementary and alternative veterinary medicine (CAVM) continues to become more widespread, especially for the management of chronic pain conditions such as canine osteoarthritis. Many patients have comorbidities that preclude traditional medical options, have not adequately responded to conventional therapies, or have owners interested in pursuing a complementary approach. Evidence-based CAVM can serve as a safe and effective adjunct to manage chronic pain conditions. There is growing evidence in the veterinary literature for the use of acupuncture and some herbal supplements in the multimodal management of canine osteoarthritis. The majority of evidence supporting chiropractic is limited to equine and human literature.
The use of cannabis-based products for therapeutic purposes is a reality in the field of animal health. However, although cannabis is considered safe when appropriately used by human patients, cannabis-based products can pose a risk to companion animals such as dogs, depending on their composition or route of administration. Thus, this article discusses aspects of the safety and efficacy of different cannabis-based products in dogs' treatment through an integrative review. The review was systematically performed in Medline (via Pubmed®) and Latin American and Caribbean Health Sciences Literature (LILACS) databases, with period restriction (between 1990 and 2021). The qualified articles (n=19), which met the previously established inclusion criteria, were critically evaluated. Based on the literature review, it is possible to infer safety in the administration of cannabis-based products for the treatment of dogs, especially products rich in cannabidiol (CBD), free or with low concentrations of tetrahydrocannabinol, under the conditions evaluated. In addition, CBD products potentially promote improved quality of life and reduce pain perception in animals affected by canine osteoarthritis. Finally, owing to the lack of large-scale and robust clinical research studies, the performance of clinical trials, considering the individual characteristics of each cannabis-based product (composition, concentration, nature of adjuvants, dosage form, route of administration), is strongly encouraged.
Objective: To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs. Animals: 9 healthy, purpose bred Beagles. Procedures: A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study. Results: Although there were variations in CBD PK variables in dogs receiving CBD alone or in conjunction with PB, significance differences in CBD PK variables were not found. No significant difference was observed in PB PK variables of dogs receiving PB alone or with CBD. During chronic CBD administration, mild gastrointestinal signs were observed in 5 dogs. At daily CBD doses of 10 to 20 mg/kg/d, hypoxia was observed in 5 dogs and increased serum alkaline phosphatase (ALP) activities (range, 301 to 978 U/L) was observed in 4 dogs. A significant increase in ALP activity was observed with chronic administration of CBD during phase 1 between day 0 and day 14. Conclusions and clinical relevance: No significant PK interactions were found between CBD and PB. Dose escalation of CBD or adjustment of PB in dogs is not recommended on the basis of findings of this study.
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The goal of this study was to investigate Cannabidiol (CBD) hepatotoxicity in 8-week-old male B6C3F1 mice. Animals were gavaged with either 0, 246, 738, or 2460 mg/kg of CBD (acute toxicity, 24 h) or with daily doses of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were the allometrically scaled mouse equivalent doses (MED) of the maximum recommended human maintenance dose of CBD in EPIDIOLEX® (20 mg/kg). In the acute study, significant increases in liver-to-body weight (LBW) ratios, plasma ALT, AST, and total bilirubin were observed for the 2460 mg/kg dose. In the sub-acute study, 75% of mice gavaged with 615 mg/kg developed a moribund condition between days three and four. As in the acute phase, 615 mg/kg CBD increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression arrays revealed that CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metabolism pathways and drug metabolizing enzymes. In conclusion, CBD exhibited clear signs of hepatotoxicity, possibly of a cholestatic nature. The involvement of numerous pathways associated with lipid and xenobiotic metabolism raises serious concerns about potential drug interactions as well as the safety of CBD.
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Due to the myriad of laws concerning cannabis, there is little empirical research regarding the veterinary use of cannabidiol (CBD). This study used the Veterinary Information Network (VIN) to gauge US veterinarians' knowledge level, views and experiences related to the use of cannabinoids in the medical treatment of dogs. Participants (n = 2130) completed an anonymous, online survey. Results were analyzed based on legal status of recreational marijuana in the participants' state of practice, and year of graduation from veterinary school. Participants felt comfortable in their knowledge of the differences between Δ9-tetrahydrocannabinol (THC) and marijuana, as well as the toxic effects of marijuana in dogs. Most veterinarians (61.5%) felt comfortable discussing the use of CBD with their colleagues, but only 45.5% felt comfortable discussing this topic with clients. No differences were found based on state of practice, but recent graduates were less comfortable discussing the topic. Veterinarians and clients in states with legalized recreational marijuana were more likely to talk about the use of CBD products to treat canine ailments than those in other states. Overall, CBD was most frequently discussed as a potential treatment for pain management, anxiety and seizures. Veterinarians practicing in states with legalized recreational marijuana were more likely to advise their clients and recommend the use of CBD, while there was no difference in the likelihood of prescribing CBD products. Recent veterinary graduates were less likely to recommend or prescribe CBD. The most commonly used CBD formulations were oil/extract and edibles. These were most helpful in providing analgesia for chronic and acute pain, relieving anxiety and decreasing seizure frequency/severity. The most commonly reported side-effect was sedation. Participants felt their state veterinary associations and veterinary boards did not provide sufficient guidance for them to practice within applicable laws. Recent graduates and those practicing in states with legalized recreational marijuana were more likely to agree that research regarding the use of CBD in dogs is needed. These same groups also felt that marijuana and CBD should not remain classified as Schedule I drugs. Most participants agreed that both marijuana and CBD products offer benefits for humans and expressed support for use of CBD products for animals.
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Background: Cannabidiol is being pursued as a therapeutic treatment for multiple conditions, usually by oral delivery. Animal studies suggest oral bioavailability is low, but literature in humans is not sufficient. The aim of this review was to collate published data in this area. Methods: A systematic search of PubMed and EMBASE (including MEDLINE) was conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans. Results: Of 792 articles retireved, 24 included pharmacokinetic parameters in humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after oromucosal spray, 2–5 days after chronic oral administration, 24 h after i.v., and 31 h after smoking. Bioavailability following smoking was 31% however no other studies attempted to report the absolute bioavailability of CBD following other routes in humans, despite i.v formulations being available. The area-under-the-curve and Cmax increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid formulations. Tmax is reached between 0 and 4 h. Conclusions: This review highlights the paucity in data and some discrepancy in the pharmacokinetics of cannabidiol, despite its widespread use in humans. Analysis and understanding of properties such as bioavailability and half-life is critical to future therapeutic success, and robust data from a variety of formulations is required.
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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.
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Background and purpose: Numerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ9-tetrahydrocannabinol (Δ9-THC), variously reported to be pro- and anti-convulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different Δ9-THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. Experimental approach: Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography-telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats, and treatment-naïve rat, mouse, chicken, dog and human tissue. Key results: Prolonged exposure to cannabis extracts caused spontaneous, generalised seizures, subserved by epileptiform discharges in rats, but not dogs, and produced higher Δ9-THC, but lower 11-hydroxy-THC (11-OH-THC) and CBD, plasma concentrations in rats versus dogs. In the same rats, prolonged exposure to cannabis also impaired cannabinoid type 1 receptor (CB1R)-mediated signalling. Profiling CB1R expression, basal activity, extent of activation and sensitivity to Δ9-THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than a species that did not (dog). Conclusion and implications: Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models.
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Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.
The legal market for recreational and medicinal cannabis for human consumption is growing worldwide. At the same time, marketing of cannabis products for use in pets is expanding. Yet, there is little research exploring the effects of cannabis use in veterinary medicine. This study used an anonymous, online survey to assess Canadian pet owners' reasons for purchasing cannabis products for their dogs, and their perceptions regarding efficacy of these treatments. Owners purchased cannabis products for treatment of pain, inflammation, and anxiety in dogs, and perceived these preparations to be equally or more effective than conventional medications. Most owners reported only minimal side effects in their dogs. Despite indicating comfort in discussing canine cannabis administration with their veterinarian, most owners relied on commercial websites for product information. The main reasons for choosing cannabis products were the ability to use as an adjuvant to other therapies, and the perception of it being a natural substance. Given this information, it is incumbent upon veterinarians to appropriately counsel their clients, and also to advocate for evidence-based studies to evaluate the efficacy of cannabis use in non-human species.
Objective: To assess the effect of oral cannabidiol (CBD) administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with idiopathic epilepsy. Design: Randomized blinded controlled clinical trial. Animals: 26 client-owned dogs with intractable idiopathic epilepsy. Procedures: Dogs were randomly assigned to a CBD (n = 12) or placebo (14) group. The CBD group received CBD-infused oil (2.5 mg/kg [1.1 mg/lb], PO) twice daily for 12 weeks in addition to existing antiepileptic treatments, and the placebo group received noninfused oil under the same conditions. Seizure activity, adverse effects, and plasma CBD concentrations were compared between groups. Results: 2 dogs in the CBD group developed ataxia and were withdrawn from the study. After other exclusions, 9 dogs in the CBD group and 7 in the placebo group were included in the analysis. Dogs in the CBD group had a significant (median change, 33%) reduction in seizure frequency, compared with the placebo group. However, the proportion of dogs considered responders to treatment (≥ 50% decrease in seizure activity) was similar between groups. Plasma CBD concentrations were correlated with reduction in seizure frequency. Dogs in the CBD group had a significant increase in serum alkaline phosphatase activity. No adverse behavioral effects were reported by owners. Conclusions and clinical relevance: Although a significant reduction in seizure frequency was achieved for dogs in the CBD group, the proportion of responders was similar between groups. Given the correlation between plasma CBD concentration and seizure frequency, additional research is warranted to determine whether a higher dosage of CBD would be effective in reducing seizure activity by ≥ 50%.
The aim of this study was to explore the pharmacokinetics of the two main active compounds (THC and CBD) contained in the cannabis oil extract Bedrocan® in fasting and fed dogs. Bedrocan® (20% delta-9-tetrahydrocannabinol [THC] and 0.5% cannabidiol [CBD]) was administered at 1.5 and 0.037 mg/kg THC and CBD, respectively in fasted and fed dogs according to a 2 × 2 cross over study design. The quantification of the two active ingredients was performed by LC/MS. No detectable concentrations of CDB were found at any collection time. THC was quantifiable from 0.5 to 10 h, although there was large inter-subject variability. Fed dogs showed a longer absorption phase (Tmax 5 vs 1.25 h) and lower maximal blood concentration (7.1 vs 24 ng/mL) compared with the fasted group. A larger AUC was found in the fasted group; the relative oral bioavailability in fed animals was 48.22%.
The purpose of this study was to determine the pharmacokinetics of cannabidiol (CBD) in healthy dogs. Thirty, healthy research dogs were assigned to receive 1 of 3 formulations (oral microencapsulated oil beads, oral CBD-infused oil, or CBD-infused transdermal cream), at a dose of 75 mg or 150 mg q12h for 6 wk. Serial cannabidiol plasma concentrations were measured over the first 12 h and repeated at 2, 4, and 6 wk. Higher systemic exposures were observed with the oral CBD-infused oil formulation and the half-life after a 75-mg and 150-mg dose was 199.7 ± 55.9 and 127.5 ± 32.2 min, respectively. Exposure is dose-proportional and the oral CBD-infused oil provides the most favorable pharmacokinetic profile.