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A One Health perspective on comparative cannabidiol and cannabidiolic acid pharmacokinetics and biotransformation in humans and domestic animals


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The goal of pharmacokinetic (PK) studies is to provide a basis for appropriate dosing regimens with novel therapeutic agents. With a knowledge of the desired serum concentration for optimum pharmacological effect, the amount and rate of drug administration can be tailored to maintain that concentration based on the 24-hour PK modeling (eg, every 24 hours, every 12 hours) to achieve therapeutic ranges. This dosing and PK information are tailored to maintain that concentration. Typically, these optimum serum concentrations pertain across species. Single-dose PK modeling provides fundamental parameters to suggest dosing regimes. Multiple-dose PK studies provide information on steady-state serum levels to assure that desired therapeutic levels are maintained during chronic administration. Clinical trials using dosing suggested by these PK determinations provide proof that the compound is producing the desired therapeutic effect. A number of PK studies with cannabinoids in humans and domestic animals have been conducted with the goal of determining appropriate clinical use with these plant-derived products. The following review will focus on the PK of cannabidiol (CBD) and the lesser-known precursor of CBD, cannabidiolic acid (CBDA). Although Δ9-tetrahydrocannabinol (THC) has profound pharmacological effects and may be present at variable and potentially violative concentrations in hemp products, PK studies with THC will not be a major consideration. Because, in domestic animals, hemp-CBD products are usually administered orally, that route will be a focus. When available, PK results with CBD administered by other routes will be summarized. In addition, the metabolism of CBD across species appears to be different in carnivorous species compared with omnivorous/herbivorous species (including humans) based on current information, and the preliminary information related to this will be explained with the therapeutic implication being addressed in Currents in One Health by Ukai et al, JAVMA, May 2023.
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American Journal of Veterinary Research 1
Currents in One Health
Leading at the intersection of
animal, human, and environmental health
PK Studies with CBD in Dogs
In domestic animals to the present, the great-
est number of pharmacokinetic (PK) studies with
hemp cannabidiol (CBD) have been conducted in
dogs. Indeed, the correlation between CBD serum
levels and clinical eectiveness in conditions such
as seizure disorders and osteoarthritis is established
in canine patients.1,2 Initial PK studies with CBD in
dogs showed an extremely low bioavailability (0% to
19%) with some dogs showing no serum levels after
oral administration.3 This may be due to rst-pass
hepatic metabolism or the type of formulation uti-
lized (powder in a gelatin capsule).4
Bartner et al studied the PK of oral forms (micro-
encapsulated oil beads, CBD-infused oil) and a topi-
cal preparation (CBD-infused transdermal cream)
in dogs.5 Oral dosage levels of CBD were 10 and
20 mg/kg, which is higher than that used in sub-
sequent oral studies in dogs. The oil preparations
A One Health perspective on comparative cannabidiol
and cannabidiolic acid pharmacokinetics and
biotransformation in humans and domestic animals
Wayne S. Schwark, DVM, MS, PhD1, and Joseph J. Wakshlag, DVM, PhD, DACVIM, DACVSMR2*
1Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY
2Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY
*Corresponding author: Dr. Wakshlag (
Received February 13, 2023
Accepted March 1, 2023
resulted in a higher maximal serum concentration
(Cmax) and area under the curve (AUC; see Table 1)
with both oral doses than in the report cited above.3
As a follow-up, the drugs were administered in simi-
lar doses chronically (6 weeks) to determine adverse
eects. The Cmax levels after the 6-week period were
similar to that after a single dose, indicating that
there were no alterations in elimination rate with
chronic administration.
Gamble et al found a dose-dependent absorp-
tion of CBD in a CBD/CBDA-rich hemp mixture. Oral
administration of the mixture in oil (1 and 4 mg/kg
CBD, as the 2 mg/kg and 8 mg/kg dose contained an
equal amount of cannabidiolic acid [CBDA], which
was not assessed pharmacokinetically) resulted in
median Cmax levels of 102 and 591 ng/mL and AUCs
of 376 and 2,658 ng·h/mL.1 This group subsequently
reported a PK study with oral 1 mg/kg CBD in a
CBD/CBDA soft chew preparation and found sub-
stantial CBD absorption (Cmax of 301 ng/mL and
The goal of pharmacokinetic (PK) studies is to provide a basis for appropriate dosing regimens with novel therapeu-
tic agents. With a knowledge of the desired serum concentration for optimum pharmacological eect, the amount
and rate of drug administration can be tailored to maintain that concentration based on the 24-hour PK modeling
(eg, every 24 hours, every 12 hours) to achieve therapeutic ranges. This dosing and PK information are tailored to
maintain that concentration. Typically, these optimum serum concentrations pertain across species. Single-dose PK
modeling provides fundamental parameters to suggest dosing regimes. Multiple-dose PK studies provide information
on steady-state serum levels to assure that desired therapeutic levels are maintained during chronic administration.
Clinical trials using dosing suggested by these PK determinations provide proof that the compound is producing the
desired therapeutic eect. A number of PK studies with cannabinoids in humans and domestic animals have been
conducted with the goal of determining appropriate clinical use with these plant-derived products. The following
review will focus on the PK of cannabidiol (CBD) and the lesser-known precursor of CBD, cannabidiolic acid (CBDA).
Although Δ9-tetrahydrocannabinol (THC) has profound pharmacological eects and may be present at variable and
potentially violative concentrations in hemp products, PK studies with THC will not be a major consideration. Because,
in domestic animals, hemp-CBD products are usually administered orally, that route will be a focus. When available,
PK results with CBD administered by other routes will be summarized. In addition, the metabolism of CBD across
species appears to be dierent in carnivorous species compared with omnivorous/herbivorous species (including
humans) based on current information, and the preliminary information related to this will be explained with the
therapeutic implication being addressed in Currents in One Health by Ukai et al, JAVMA, May 2023.
Unauthenticated | Downloaded 03/29/23 05:00 PM UTC
an AUC of 1,297 ng·h/mL), indicating a somewhat
greater absorption with the soft chew formulation.6
Chicoine et al administered a cannabis herbal
extract containing a 1:20 ratio of Δ9-THC:CBD
orally in doses of 2, 5, and 10 mg/kg CBD to fasted
dogs. There was an apparent dose-dependent
increase in Cmax and AUC (Table 1).7 In contrast to
previous studies, there was an initial rapid elimina-
tion based on a half-life of elimination time (T1/2;
approximately 2 hours) and a slower second phase
of elimination with half-lives of up to 24 hours. The
authors speculated this may be related to a redis-
tribution from tissue depots such as adipose tis-
sue. Particularly in the high-dose group, a number
of neurological side eects were observed, which
may be attributed to the tetrahydrocannabinol
(THC) content.
Wakshlag et al reported the PK of CBD and a
number of other cannabinoid and cannabinoid
metabolites after administration of 1 mg/kg CBD
in 3 formulations (medium-chain triglyceride in
sesame oil; sunower-lecithin in sesame oil and
soft chews).8 There were no signicant dierences
between the formulations in CBD PK (Table 1).
Examination of steady-state serum levels after 1
and 2 weeks of daily q 12 hour administration dem-
onstrated no signicant dierences in CBD levels
between the formulations. In a study to determine
the acceptance of a soft gel vs an oil formulation of
a commercial CBD/CBDA-rich hemp blend in dogs,
no signicant dierences in PK parameters were
found with CBD (1 mg/kg) in a single dose study
or in steady state after q 12 hour administration for
1- or 2-week periods.9 The generally greater palat-
ability and acceptance of the soft gel formulation
and the similar PK results suggested that this may
be a superior formulation for clinical use compared
with the oil formulation.
PK Studies with CBD in Cats
Regarding drug therapy, cats are unique in sev-
eral respects. As a species, felines are decient in
the ability to glucuronidate drugs which can lead to
accumulation and toxicity unless dosage regimes are
tailored to account for this characteristic.10 Cats are
discriminating eaters, which may lead to the rejec-
tion of orally administered drugs. These consider-
ations may impact the interpretation of PK studies in
cats. In an initial cat study, Deabold et al compared
the single-dose PK of CBD-rich hemp (50:50 mixture
of CBD:CBDA) in dogs and cats. Fasted animals were
orally administered 2 mg/kg in the form of soft chews
(glycerol/starch/ber base) in dogs and suspended
in sh oil in cats.6 Results indicated that there was an
apparent decrease in the ability of cats to absorb CBD
compared with dogs. The mean Cmax of CBD in dogs
was 7-fold greater than in cats (301 vs 43 ng/mL) and
AUC was 8 times greater in dogs than cats (1,297 vs
164 ng·h/mL) (Table 1). The authors suggested this
may be related to the matrix of drug suspension in
the sh oil form in cats. Because cannabinoids are
highly lipid soluble, interaction with the sh oil may
have diminished systemic absorption. Notably, some
of the cats exhibited head shaking and excessive sal-
ivation that may have indicated rejection of a portion
of the dose. Thus, optimum therapeutic levels may
not be obtained in cats as opposed to dogs utilizing
these specic formulations.
CBD preparations
Kulpa et al studied the safety of 11 escalating
oral doses of cannabinoids in oil (CBD alone, THC
alone, or a combination of CBD/THC) in healthy
cats.11 While the goal of the study was the exami-
nation of adverse eects, measurements of plasma
levels of the CBD, THC, and their metabolites were
Table 1—Averages for single dose oral CBD PK data in small animals.
Reference Species Del. matrix Dose (mg/kg) Cmax (ng/mL) Tmax (h) T1/2 el. (h) AUC (ng·h/mL) MRT (h)
Bartner5* Dog Oil 10 635 ND 3.3 136 3.6
Dog Nano-emulsion 10 346 ND 1.6 98 5.9
Dog Oil 20 846 ND 2.1 298 6.0
Dog Nano-emulsion 20 578 ND 1.9 163 5.5
Gamble1# Dog Oil 1 102 1.5 4.2 367 5.6
Dog Oil 4 591 2 4.2 2,658 5.6
Deabold6Dog Soft chew 1 301 1.4 1.0 1,297 1.4
Chicoine7Dog Herbal extract 2 213 2.1 2.5 692 ND
Dog Herbal extract 5 838 1.9 2.6 2,433 ND
Dog Herbal extract 10 1,868 2.3 2.3 5,883 ND
Wakshlag8Dog MCT + Oil 1 145 1.5 4.1 635 5.2
Dog Lecithin + Oil 1 124 2.0 4.4 683 6.5
Dog Soft chew 1 226 2.5 3.8 826 5.3
Tittle9Dog Soft gel 1 185 1.4 3.4 688 4.4
Dog Oil 1 268 1.1 2.2 693 3.4
Deabold6Cat Oil 1 43 2.0 1.5 164 3.5
Kulpa11 Cat Oil 25 236 ND ND ND ND
Wang12 Cat Paste 1.37 282 2.0 2.1 909 3.8
AUC = area under the serum concentration curve; CBD = cannabidiol; Cmax = maximum serum/plasma concentration;
MCT = medium chain triglyceride; MRT = mean residence time; PK = pharmacokinetics; T1/2 el = elimination half-life; Tmax = time
of maximum serum concentration; ND = not determined.
*AUC expressed as µg-min/mL #data expressed as median values; #data reported as medians.
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undertaken after the 9th dose of the 11-dose esca-
lating study (at that time 25 mg/kg CBD alone).
With regard to CBD, higher Cmax values (236 com-
pared with 43 ng/mL in the Deabold study6) were
attributed to the higher dosage and/or the suspend-
ing oil (medium-chain triglyceride vs sh oil).
Interestingly, the CBD/THC combination resulted
in higher CBD Cmax (483 vs 236 ng/mL), suggesting
that the presence of THC enhanced the absorption
of CBD. Other PK parameters were not reported. The
study found a number of adverse gastrointestinal
and neurological eects with higher dosages.
In a more recent study in cats, Wang et al investi-
gated the 24-hour and 1-week steady-state PK with
a CBD/CBDA rich hemp paste.12 A unique matrix
of palatable drug suspension consisting, in part, of
soy oil, dextrose, and chicken liver was used as the
carrier in this study. Minor amounts of other can-
nabinoids were present in the preparation and were
also assayed for PK analysis. Utilizing this formula-
tion, much better absorption was apparent than
in the feline studies cited above. Similar doses of
CBD/CBDA resulted in a 6-fold higher CBD Cmax than
in the Deabold study6 (282 vs 43 ng/mL) and a simi-
lar Cmax of CBD was achieved (282 vs 256 ng/mL)
with an 18 times lower dose of CBD than in the Kulpa
article (Table 1).11 The absolute steady state achieved
after 1 week of administration was less than that pre-
dicted by PK analysis. The authors speculated that
chronic twice-daily administration may induce cyto-
chrome P-450 systems that enhance the elimination
of CBD and other cannabinoids.
PK Studies with CBD in Horses
Dietary considerations and the unique proper-
ties of the equine gastrointestinal tract (hindgut
fermentation) may impact cannabinoid PK. As in
ruminants (see below), the presence of forage and
pH variations may impact absorption of the canna-
binoids compared with simple stomached animals
like dogs and cats. Turner et al conducted a PK study
with the oral administration of 2 mg/kg CBD (in soy
oil) in senior horses.13 True bioavailability was deter-
mined by comparison of AUC with IV administration
(0.1 mg/kg in DMSO). Bioavailability was found to be
low (8%) which was comparable with that previously
reported in dogs. An average Cmax of 18.5ng/mL was
seen after 2.5 hours. A longer half-life (7.2 hours)
was akin to that in ruminants (see below).
Williams et al administered 2 doses (0.35 and
2 mg/kg daily for 7 days) of a commercially available
equine CBD supplement. PK determinations were
performed after the last day of administration. Serum
levels appeared to increase in a dose-dependent man-
ner (Cmax of 6.6 ng/mL with 0.35 mg/kg vs 51 ng/mL
with the 2 mg/kg/day dose).14 The terminal half-life
was prolonged (10.4 hours) and was in the range sim-
ilar to that with a similar dosage in senior horses.13
The authors did not establish whether long-term
administration may aect PK (eg, by cytochrome
P450 induction) because PK determinations were not
undertaken on day 1 of administration. THC levels
were also measured and were found to be signicant
which may impact drug testing in competition horses.
The authors found no adverse eects with these
2 levels of CBD and suggested that higher dosages of
CBD may be required to elicit clinical responses.
Yocom et al explored the single dose 24-hour
PK, safety, and synovial uid concentrations of CBD,
utilizing a sunower oil-lecithin based suspension
of CBD.15 Dosages of 1 and 3 mg/kg were adminis-
tered orally after feeding a small meal. Horses were
then treated twice daily with either 0.5 or 1.5 mg/
kg for 6 weeks and steady-state plasma levels were
determined. There was a dose-dependent increase
in plasma levels (Cmax of 4.3 and 19.9 ng/mL with
the 0.5 and 3 mg/kg dose, respectively). Elimination
half-lives ranged from 8.8 to 14.3 hours. Steady-state
Cmax levels after 6-week treatment were compared
with those with single-dose CBD administration,
indicating no apparent alteration in PK. Synovial
uid levels of CBD up to 7 to 8 ng/mL were detected
but this was not consistently observed in all horses.
This may have implications for the use of CBD for the
management of osteoarthritic pain in horses.
Ryan et al administered 3 doses of CBD (0.5, 1,
and 2 mg/kg) in sesame oil to exercising thorough-
bred horses.16 Levels of CBD were detected for up to
48 hours but Cmax values were low.
Elimination half-lives were comparable with the
3 doses (9.9 to 10.7 hours). Although the results
were inconsistent, there was evidence that eico-
sanoid metabolites (COX-1, COX-2, and LOX) were
aected by these levels of CBD. The results of these
studies in horses are summarized (Table 2).
Table 2—Averages for single-dose oral CBD PKs of CBD in large animals.
Reference Species Del. matrix Dose (mg/kg) Cmax (ng/mL) Tmax (h) T1/2 el. (h) AUC (ng·h/mL) MRT (h)
Meyer18 Calves Oil 5 50 7.5 23 950 35
Kleinhenz19 Calves Hemp 0.5 4 ND ND ND ND
Turner13 Horse Oil 2 18 2.5 7 132 ND
Williams14 Horse Hemp pellets 0.35 7 1.8 ND 42 156
Horse Hemp pellets 2 51 2.4 10 330 153
Yocum15 Horse Lecithin-oil 1 4.3 4.1 14.8 73 13.5
Horse Lecithin-oil 3 19.9 5 8.5 186 10.5
Ryan16 Horse Oil 0.5 1.2 10.7 ND ND ND
Horse Oil 1 2.9 10.6 ND ND ND
Horse Oil 2 6.1 9.9 ND ND ND
See Table 1 for key.
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PK Studies with CBD in Cattle
In cattle and other ruminants, dierent com-
partments of the forestomach have unique epithe-
lial absorptive characteristics and pH properties that
aect drug absorption. The presence of an abundant
microora, particularly in the rumen, may degrade
drugs. Thus, age could have a profound eect on PK
results because pre-ruminant calves lack this ora
until post-weaning.17 Meyer et al studied the plasma
PK of CBD in 19-day-old (pre-ruminant) calves after
oral administration of 5 mg/kg of an oil formulation.
CBD was absorbed, reaching a Cmax of 50 ng/mL with
an average Tmax of 7 hours.18 The absorption was sus-
tained and the average half-life of elimination was
23 hours, which represents a much slower elimina-
tion rate than in simple-stomached animals. The level
of plasma CBD was still appreciable at 48 hours, the
last point of plasma collection. This may have impli-
cations for withdrawal times in edible tissues.
Kleinhenz et al administered CBDA (an acidic
precursor of CBD) rich hemp to 10-month-old calves
at a dosage of 5 mg/kg.19 CBD content in this prod-
uct was very low (delivering a dosage of 0.6 mg/
kg). While CBDA absorption was adequate to allow
PK calculations (Cmax of 73 ng/mL), CBD levels were
only detectable in 2 of 8 calves and in those the aver-
age concentration of CBD was 4 ng/mL, a reection
of the lower dose of CBD compared with the Meyer
study cited above.18 Regarding CBDA, the elimina-
tion half-life was 14 hours, comparable with that
of CBD in Meyer et al18 and suggests cannabinoids
per se may be eliminated slowly in cattle. Notably,
these animals were considerably older than the CBD
study cited above and this may impact cannabinoid
absorption. Feeding of this CBDA-rich preparation
for a 2-week period was found to induce behavioral
changes (increased recumbency) and a reduction of
circulating inammatory biomarkers (cortisol, pros-
taglandin E2).20 This was correlated with measurable
levels of acidic forms of the cannabinoids (especially
CBDA) but a lack of signicant CBD serum levels.
The results of these PK studies and comparison with
data in horses are shown in Table 2.
PK Studies with CBD in Humans
Data on the PK of oral CBD in people have
recently been reviewed. Reports include those where
CBD was administered alone or in a combination of
CBD/THC.21–23 A wide diversity of oral formulations
were used in these studies (capsules, drops, and
solutions) and in a wide range of doses. For the most
part, studies were conducted in healthy adult male
and female volunteers but gender-related dierences
in PK were not explored. As in animals (see above),
bioavailability after oral administration of CBD in
people is low. Amounts varying from 6%24 to 13% to
16% were reported.25 Generally, dose-dependent PK
(Cmax and AUC) was found after oral administration
of CBD in adult humans (see below). Tmax was found
to occur 1–4 hours after administration and half-
lives of elimination varied widely but were typically
within the 2–4 hour range reported in dogs and cats
(see Table 1).22,26,27
Administration of oral CBD doses lower than
those examined in animals cited above (5–60 mg/
adult that would be equivalent to less than 1 mg/
kg for a 70 kg adult) resulted in plasma Cmax levels
below 5 ng/mL and AUCs below 50 ng·hr/mL).28,29
When dosages comparable with those reported in
animal studies (400–800 mg total dose or 5–10 mg/
kg for a 70 kg individual), Cmax values ranged from
80–220 ng/mL, which is in the range of that found
in dogs and cats administered similar oral doses.30,31
As reported in animals, CBD administration with
food increased the rate of absorption and the ulti-
mate Cmax of CBD.8,32 Bioavailability increased 4-fold
between fasted individuals and those administered
CBD in conjunction with a high-fat meal. Thus, feed-
ing itself and the nature of the food can profoundly
aect CBD PK.
Human PK studies have explored routes of
administration other than orally (e.g., intravenous,
oromucosal spray, sublingually, nebulization, aero-
sol inhalation, and smoking).22 Vaporization seems
to be an especially eective approach to achieving
systemic absorption of CBD.33 Cannabinoid admin-
istration by inhalation exhibits a similar PK to that
attained after IV administration.25 Inhaled CBD was
found to have a bioavailability several-fold higher
than after oral administration.21 The apparent
increased bioavailability of CBD by inhalation has led
to the development of products that deliver vapor-
ized Cannabis products by this route.34
Alternate Routes of CBD
Administration in Animals
Because oral bioavailability of CBD is low (0%
to 19%) in dogs,3 the PK of routes of administra-
tion other than oral have been explored in animals.
Because rst-pass hepatic metabolism may be a
major contributor to decreasing oral bioavailability,
routes of administration that bypass this site have
particular interest. In their PK study in dogs, Bartner
et al also examined a group wherein CBD was applied
topically to the ear pinnae.5 This transdermal appli-
cation resulted in Cmax levels that were only about
one-tenth of that achieved by the oral dosage forms.
Similarly, Hannon found minimal blood concentra-
tions of CBD and CBDA after topical application of
4 mg/kg q 12 hour of a CBD/CBDA-rich extract for
periods of up to 2 weeks.35 The hydrophobic nature
of the cannabinoids apparently limits diusion across
the aqueous layer of the skin, making this route of
administration seemingly ineective for routine sys-
temic clinical use.
Fernandez-Trapero et al studied the PK of a com-
mercial preparation of phytocannabinoids (Sativex,
GW Pharmaceuticals) administered via a sublingual
spray in adult dogs.36 Peak plasma levels (Cmax =
15 ng/mL) were attained 2 hours after administra-
tion but were low compared with that after oral
administration. No neurological or other pharma-
cological eects were noted with this treatment
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protocol. Higher plasma levels were found after mul-
tiple than single sublingual doses which, the authors
speculated could be due to an accumulation in and
subsequent release from fat depots.
Although no PK determinations were under-
taken, Brioschi et al found that an oral transmuco-
sal CBD preparation (2 mg/kg q 12 hour) enhanced
the analgesic eects of other drugs used to treat
osteoarthritic pain (non-steroidal anti-inammatory
drugs, amitryptyline, and gabapentin) in canine
patients. However, this transmucosal application is
suspect because dogs will naturally swallow orally
applied products.37 Polidoro et al performed a com-
parative PK study in dogs after intranasal, rectal, and
oral administration.38 Plasma concentrations after
rectal administration were undetectable. No signi-
cant dierences in Cmax or AUC values were detected
between the oral or intranasal routes but the authors
concluded that oral administration was preferable
based on the convenience of administration. Studies
such as these indicate that, to date, there is no ideal
alternative route to oral administration to achieve
signicant systemic levels of CBD or other canna-
binoids in animals. While administration by inhala-
tion holds promise, as demonstrated in humans, this
route is impractical for routine clinical use in animals.
As summarized (Table 3), CBDA, the precursor
of CBD in hemp, is generally absorbed to a greater
extent after oral administration. This is seen across
species and with dierent oral formulations. Because
CBDA itself has pharmacological activity, prepara-
tions containing CBDA may reinforce the actions of
CBD.39 Furthermore, there is evidence that CBDA
may enhance the gastrointestinal absorption of
CBD.40 Thus, the presence of acidic precursor prod-
ucts in hemp preparations must be taken into con-
sideration when designing dosing regimens because
acidic cannabinoids appear to be absorbed better
than their decarboxylated neutral counterparts glob-
ally.8,12,41–43 This examination of CBDA absorption
across many domestic species is being established
and has yet to be examined in the human literature to
any appreciable degree. These novel ndings across
dogs, cats, horses, and cattle suggest that CBDA
may be preferably absorbed and suggests that ther-
apeutic dosing of CBDA may be more achievable
than CBD when using the oral route.
Metabolism and
Elimination of CBD/CBDA
The elimination of all drugs takes place primar-
ily through the phase 1 enteric or hepatic metabo-
lism that often includes the cytochrome p450 system
(CYP) leading to hydroxylation and carboxylation to
the increased polarization of compounds for renal
excretion. In conjunction, this initial phase 1 reac-
tion provides a polar group to increase the poten-
tial for phase II glucuronidation that occurs through
UDP glucuronidation pathways resulting in primarily
hepatobiliary elimination of many compounds from
foods to pharmacological agents consumed daily.44
The hepatic metabolism of cannabinoids is relatively
well deciphered in rodents and humans; whereby,
the CYP2 (CYP2B6, CYP2C19, and CYP2D6) and
CYP3 (CYP3A4, CYP3A5) isoenzymes appear to
metabolize CBD to 7-OH-CBD (and lesser degree
6-OH CBD) and eventually 7-COOH-CBD with serum
levels increasing to very high concentrations in the
bloodstream in the range often well over 1,000 ng/
mL during chronic use, with smaller amounts of 6
and 4 hydroxylation occurring in these species.45–48
This has been found to be renally excreted while
7-COOH-CBD undergoes glucuronidation leading
to the primarily hepatobiliary excretion of cannabi-
noids, in general.49,50
In horses this appears to be a primary means of
metabolism which may be why serum concentrations
of CBD in horses appear to be similar to humans at
typical dosing regimens between 1–3 mg/kg, leading
to lower than expected serum CBD concentrations.
Thus far, in dogs and cats, the serum concentrations
of 7-COOH CBD are signicantly lower during single
and multiple day-dosing assessments suggesting dif-
ferent primary metabolic pathways.8,12,51 Dog ex vivo
microsomal assays examining metabolites of CBD
show signicant hydroxylation of the 6 carbon that
suggests fundamental dierences in CYP metabolism
that is thought to undergo carboxylation as well.52
Table 3—Comparison of PK parameters with oral CBD and CBDA
Reference Species Del. matrix CBD dose
(mg/kg) CBDA dose
(mg/kg) CBD Cmax
(ng/mL) CBD AUC
(ng·h/mL) CBDA Cmax
(ng/mL) CBDA AUC
(ng·h /mL)
Wakshlag8Dog MCT + Oil 1 1 145 635 383 1,018
Dog Lecithin + Oil 1 1 124 683 386 1,619
Dog Soft chew 1 1 226 826 510 1,407
Tittle9Dog Soft gel 1 1 268 688 1826 2,786
Dog Oil 1 1 184 693 923 2,161
Wang12 Cat Paste 1.37 1.13 282 909 1,011 2,639
Thomson41 Horse Oil 1 1 6 37 46 425
Kleinhenz19 Bovine Hemp 0.6 5 4 ND 73 ND
Rooney42 Rabbit Oil 15 16.4 30 180 2,573 12,286
CBDA = cannabidiolic acid.
See Table 1 for remainder of key.
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In cats, a single cat’s hepatic microsomes were
assessed in a comparative study showing the CBD CYP
metabolism occurs at both the 6 and 4 sites in hepatic
microsomal preparations further suggesting inter-
species dierences.53 Considering the lack of inter-
est in veterinary species the quantication of these
metabolites is dicult because standards for 4 and
6 hydroxylation and carboxylation metabolites are not
available commercially to perform standard curves for
PK studies; therefore, the extent of this metabolism as
major metabolites is currently unknown.
In human medicine, it has been established
that the major 7 carboxylated metabolite of CBD
appears to be inactive.49 Currently, it is unknown as
to whether the metabolites of CBD in dogs are phar-
macologically active, and further research is neces-
sary to fully understand CBD metabolites in dogs
and cats (Figure 1). These minor dierences in met-
abolic byproducts suggest there may be dierential
CYP metabolism in dogs with preliminary informa-
tion suggesting that CYP1A metabolism may be a
primary means of CBD metabolism in dogs, while
CYP2 isoenzyme metabolism may be a secondary
pathway for metabolism at relatively high concentra-
tions (Michael Court, DVM PhD, College of Veterinary
Medicine, Washington State University, email report,
January 7, 2023). The metabolic fate of CBDA is rela-
tively unknown across all species. It has been postu-
lated that the native 3' carboxylation may make CBDA
a good substrate for direct glucuronidation similar to
THC glucuronidation found at high concentrations in
human serum after oral cannabis decoction, yet has
not been examined regarding CBDA metabolism.50,54
CBD and its metabolites are lipophilic and there
is evidence of bioaccumulation, particularly in adi-
pose and brain tissues to some extent while the acids
such as CBDA appear to undergo less bioaccumu-
lation in brain tissue, yet are still present, albeit at
lower concentrations than CBD.55,56 Recent work in
Guinea pigs examining adipose and cartilage tissues
shows that the bioaccumulation of CBD does occur
primarily in the patellar fat pad and much less so in
cartilage.57 Work in beef cows examining contami-
nated hempseed cake also shows CBD and CBDA in
liver and kidney tissue at low concentrations lower
than what was found in plasma, suggesting similarly
to people that organs do not show signicant bioac-
cumulation while adipose can be a modest reposi-
tory for cannabinoids to some extent.58
Potential CYP Inhibition
and Drug Interactions
There is extensive work performed in humans
and rodents to better understand if CBD and its
metabolites have the ability to inhibit specic CYP
isoenzymes including CYP1A, CYP2B, CYP2D, and
CYP3A isoenzymes that are the major CYPs involved
in the metabolism of drugs.49 This has been exten-
sively studied in human clinical neurology as it is the
primary area of investigation in human medicine pro-
viding some evidence that drugs like clonazepam,
valproate, and levetiracetam are all aected by CBD
administration.56,59,60 That said, recent work assessing
the metabolism of phenobarbital in clinical and pre-
clinical studies suggests that this anti-epileptic drug
is not aected when dogs are administered between
1–20 mg/kg body weight of CBD once or twice a
day.61,62 Another recent study suggests that potas-
sium bromide and zonesimide serum concentrations
were not aected by doses of 2 mg/kg of CBD/CBDA
equal mix provided twice a day for 12 weeks.63
Although CBD has the potential to inhibit CYP
drug metabolism in many of the liver microsomal
systems examined the concentrations necessary
to signicantly inhibit CYP activity would be in the
1 uM and above range, while serum Cmax concentra-
tions observed in most studies suggest that serum
CBD is usually below or near this threshold.62,64,65
Therefore, the current dosing recommendations
observed in many studies are unlikely to heavily
inuence CYP metabolism; however, further studies
are necessary with commonly used veterinary phar-
maceuticals to fully understand compatibility, partic-
ularly those heavily metabolized by CYP1A, CYP2B,
CYP2D, and CYP3A isoenzymes.
A few concepts surrounding PKs from a One
Health perspective are becoming increasingly clear.
Firstly, CBD absorption and retention appear to be
superior in dogs and cats as they can often achieve
over 100 ng/mL as a Cmax while humans and horses
are often 10-fold lower when utilizing similar dos-
ing. This may be due to inherent CYP450 enzymatic
dierences between species and it is becoming
increasingly evident that the typical metabolite
7 COOH-CBD found in humans and horses appears to
be a secondary metabolite in dogs and cats. Second,
in veterinary species, the absorption of CBDA, and
generally all of the acidic forms of cannabinoids,
appears to be absorbed and retained at a higher
Figure 1—Basic phase 1 and 2 metabolism of cannabi-
diol by species showing probable hydroxylation, car-
boxylation, and glucuronidation sites in the molecule
depending on species.
Unauthenticated | Downloaded 03/29/23 05:00 PM UTC
level than CBD suggesting that further work in this
area is warranted because it may be easier to reach
therapeutic levels and there is a dearth of information
regarding CBDA in the human literature. There is still a
tremendous amount of research to be done surround-
ing long-term PKs and optimization of therapeutic
levels across all species making this a “One Health
initiative that will benet humans and animals alike.
Dr. Wayne Schwark and Dr. Joseph Wakshlag are both
paid consultants for Ellevet Sciences
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Full-text available
Objective: To determine the pharmacokinetics of a solution containing cannabidiol (CBD) and cannabidiolic acid (CBDA), administered orally in 2 single-dose studies (with and without food), in the domestic rabbit (Oryctolagus cuniculus). Animals: 6 healthy New Zealand White rabbits. Procedures: In phase 1, 6 rabbits were administered 15 mg/kg CBD with 16.4 mg/kg CBDA orally in hemp oil. In phase 2, 6 rabbits were administered the same dose orally in hemp oil followed by a food slurry. Blood samples were collected for 24 hours to determine the pharmacokinetics of CBD and CBDA. Quantification of plasma CBD and CBDA concentrations was determined using a validated liquid chromatography-mass spectrometry (LC-MS) assay. Pharmacokinetics were determined using noncompartmental analysis. Results: For CBD, the area under the curve extrapolated to infinity (AUC)0-∞ was 179.8 and 102 hours X ng/mL, the maximum plasma concentration (Cmax) was 30.4 and 15 ng/mL, the time to Cmax (tmax) was 3.78 and 3.25 hours, and the terminal half-life (t1/2λ) was 7.12 and 3.8 hours in phase 1 and phase 2, respectively. For CBDA, the AUC0-∞ was 12,286 and 6,176 hours X ng/mL, Cmax was 2,573 and 1,196 ng/mL, tmax was 1.07 and 1.12 hours, and t1/2λ was 3.26 and 3.49 hours in phase 1 and phase 2, respectively. Adverse effects were not observed in any rabbit. Clinical relevance: CBD and CBDA reached a greater Cmax and had a longer t1/2λ in phase 1 (without food) compared with phase 2 (with food). CBDA reached a greater Cmax but had a shorter t1/2λ than CBD both in phase 1 and phase 2. These data may be useful in determining appropriate dosing of cannabinoids in the domestic rabbit.
Full-text available
The aim of this study was to compare the pharmacokinetics of a cannabidiol (CBD) and cannabidiolic acid-rich (CBDA) hemp extract in a sesame oil base and a soft gel capsule formulation. During acute twenty-four hour pharmacokinetic evaluation, maximum serum concentration (Cmax) was higher for all measurable components in the serum (CBD, CBDA, Δ-9-tetrahydrocannabinol [THC] and tetrahydrocannabinolic acid [THCA]) following soft gel administration versus the oil formulation. Similar times of maximal serum concentration (Tmax) were observed with both presentations. Based on the area under the curve, a significant increase in CBDA absorption was observed following soft gel dosing. Whilst comparable, the steady state pharmacokinetic data after one week of twice daily dosing shows an increased concentration of CBDA, with a slightly lower CBD concentration with soft gel administration compared to oil. Although THC and THCA concentrations remain comparably low from both presentations, THCA absorption was superior regardless of formulation. When examining acceptance, soft gels are associated with increased palatability and less rejection of oral dosing with oil. Dogs, and potentially even people, may show increasing tolerance to this soft gel formulation; as such consideration should be given to the ease of administration and superior CBDA absorption with the use of a soft gel formulation of a CBD/CBDA hemp blend.
Full-text available
The use of cannabidiol (CBD) in childhood refractory seizures has become a common therapeutic approach for specific seizure disorders in human medicine. Similarly, there is an interest in using CBD, cannabidiolic acid (CBDA) or cannabinoid-rich hemp products in the treatment of idiopathic epilepsy in dogs. We aimed to examine a small cohort in a pilot investigation using a CBD and CBDA-rich hemp product for the treatment of refractory epileptic seizures in dogs. Fourteen dogs were examined in a 24-week randomized cross-over study being provided placebo or CBD/CBDA-rich hemp extract treatment at 2 mg/kg orally every 12 h for each 12-week arm of the study. Serum chemistry, complete blood counts, serum anti-seizure medication (ASM) concentrations and epileptic seizure frequency were followed over both arms of the cross-over trial. Results demonstrated that besides a mild increase in alkaline phosphatase, there were no alterations observed on routine bloodwork at 2, 6, and 12 weeks during either arm of the study. Epileptic seizure frequency decreased across the population from a mean of 8.0 ± 4.8 during placebo treatment to 5.0 ± 3.6 with CBD/CBDA-rich hemp extract ( P = 0.02). In addition, epileptic seizure event days over the 12 weeks of CBD/CBDA-rich hemp treatment were 4.1 ± 3.4, which was significantly different than during the 12 weeks of placebo treatment (5.8 ± 3.1; P =0.02). The number of dogs with a 50% reduction in epileptic activity while on treatment were 6/14, whereas 0/14 had reductions of 50% or greater while on the placebo ( P = 0.02). No differences were observed in serum zonisamide, phenobarbital or bromide concentrations while on the treatment across groups. Adverse events were minimal, but included somnolence (3/14) and transient increases in ataxia (4/14) during CBD/CBDA-rich hemp extract treatment; this was not significantly different from placebo. This further indicates that providing CBD/CBDA-rich hemp extract during refractory epilepsy (only partially responsive to ASM), in conjunction with other ASM appears safe. Based on this information, the use of 2 mg/kg every 12 h of a CBD/CBDA-rich hemp extract can have benefits in reducing the incidence of epileptic seizures, when used concurrently with other ASMs.
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Objective: To determine the pharmacokinetics, bioavailability, and pharmacological effects of cannabidiol (CBD) in senior horses. Animals: 8 university-owned senior horses. Procedures: In this randomized, crossover study, horses were assigned to receive either a single oral dose of 2 mg/kg CBD in oil or a single IV dose of 0.1 mg/kg CBD in DMSO between August 10 and September 4, 2020. Blood samples were collected before and then 0.5, 1, 4, 8, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 264 hours after CBD administration. Serum biochemical analyses and CBCs were performed. Plasma concentrations of CBD and its metabolites were determined with the use of liquid chromatography-tandem mass spectrometry. Results: Concentrations of CBD and metabolites (7-COH CBD and 7-COOH CBD) were detected in all plasma samples up to 8 hours after dosing (oral and IV), with 7-COOH CBD being the most predominant metabolite. Pharmacokinetic results for CBD oral dosing at 2 mg/kg were mean ± SD half-life of 7.22 ± 2.86 hours, maximum concentration of 18.54 ± 9.80 ng/mL, and time to maximum concentration of 2.46 ± 1.62 hours. For both oral and IV administrations, 7-COOH CBD did not fall below the limit of quantification for the times reported. Oral bioavailability for CBD was 7.92%. There was no meaningful effect of CBD on results for CBC, serum biochemical analyses, or vital signs for any horse. Clinical relevance: Pharmacokinetics and bioavailability of CBD in senior horses were determined, and there were no adverse effects of administering either the oral or IV dose of CBD evaluated.
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Hemp based cannabinoids have gained popularity in veterinary medicine due to the potential to treat pain, seizure disorders and dermatological maladies in dogs. Cat owners are also using hemp-based products for arthritis, anxiety and neoplastic disorders with no studies assessing hemp cannabinoids, namely cannabidiol efficacy, for such disorders. Initial twenty-four pharmacokinetic and chronic dosing serum concentration in cats are sparse. The aim of our study was to assess 8 cats physiological and 24 h and 1-week steady state pharmacokinetic response to a cannabidiol (CBD) and cannabidiolic acid (CBDA) rich hemp in a palatable oral paste. Using a standard dose of paste (6.4 mg/CBD + CBDA 5.3 mg/gram) across 8 cats weighing between 4.2 and 5.4 kg showed an average maximal concentration of CBD at 282.0 ± 149.4 ng/mL with a half-life of ~2.1 ± 1.1 h, and CBDA concentrations of 1,011.3 ± 495.4 ng/mL with a half-life of ~2.7 ± 1.4 h, showing superior absorption of CBDA. After twice daily dosing for 1 week the serum concentrations 6 h after a morning dosing showed that the acidic forms of the cannabinoids were approximately double the concentration of the non-acidic forms like CBD and Δ9- tetrahydrocannabinol (THC). The results of this study compared to two other recent studies suggest that the absorption in this specific paste product may be superior to oil bases used previously, and show that the acidic forms of cannabinoids appear to be absorbed better than the non-acidic forms. More importantly, physical and behavioral examinations every morning after dosing showed no adverse events related to neurological function or behavioral alterations. In addition, bloodwork after 1 week of treatment showed no clinically significant serum biochemical alterations as a reflection of hepatic and renal function all remaining within the reference ranges set by the diagnostic laboratory suggesting that short-term treatment was safe.
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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.
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Background: Cannabidiol (CBD) and cannabidiolic acid (CBDA) are reported to have antinociceptive, immunomodulatory and anti-inflammatory actions. Objectives: To determine if CBD/CBDA is an effective therapy for canine atopic dermatitis (cAD). Animals: Thirty-two privately owned dogs with cAD. Materials and methods: Prospective, randomised, double-blinded, placebo-controlled study. Concurrent therapies were allowed if remained unchanged. Dogs were randomly assigned to receive either 2 mg/kg of an equal mix of CBD/CBDA (n = 17) or placebo for 4 weeks. On Day (D)0, D14 and D28, Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) and pruritus Visual Analog Scale (pVAS) scores were determined by investigators and owners, respectively. Complete blood count, serum biochemistry profiles and cytokine bioassays were performed on serum collected on D0 and D28. Results: There was no significant difference in CADESI-04 from D0 to D14 (p = 0.42) or D28 (p = 0.51) in either group. pVAS scores were significantly lower for the treatment group at D14 (p = 0.04) and D28 (p = 0.01) and a significant change in pVAS from baseline was seen at D14 (p = 0.04) and not D28 (p = 0.054) between groups. There was no significant difference in serum levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein - 1, IL-31 or IL-34 between groups at D0 or D28. Elevated alkaline phosphatase was observed in four of 17 treatment group dogs. Conclusions and clinical relevance: CBD/CBDA as an adjunct therapy decreased pruritus, and not skin lesions associated with cAD in dogs.
Introduction Cannabis is an increasingly popular recreational and medicinal drug in the USA. While cannabis is still a Schedule 1 drug federally, many states have lifted the ban on its use. With its increased usage, there is an increased potential for potential drug-drug interactions (DDI) that may occur with concomitant use of cannabis and pharmaceuticals. Area covered This review focuses on the current knowledge of cannabis induced DDI, with a focus on pharmacokinetic DDI arising from enzyme inhibition or induction. Phase I and phase II drug metabolizing enzymes, specifically cytochromes P450, carboxylesterases, and uridine-5’-diphosphoglucuronosyltransferases, have historically been the focus of research in this field, with the much of the current knowledge of the potential for cannabis to induce DDI within these families of enzymes coming from in vitro enzyme inhibition studies. Together with a limited number of in vivo clinical studies and in silico investigations, current research suggests that cannabis exhibits the potential to induce DDI under certain circumstances. Expert opinion Based upon the current literature, there is a strong potential for cannabis-induced DDI among major drug-metabolizing enzymes.
The anticonvulsant effect of cannabidiol (CBD), which has been confirmed by findings from animal models and human trials, has attracted the interest of veterinary practitioners and dog owners. Moreover, social media and public pressure has sparked a renewed awareness of cannabinoids, which have been used for epilepsy since ancient times. Unfortunately, at this moment veterinarians and veterinary neurologists have difficulty prescribing cannabinoids because of the paucity of sound scientific studies. Pharmacokinetic studies in dogs have demonstrated a low oral bioavailability of CBD and a high first-pass effect through the liver. Administering CBD in oil-based formulations and/or with food has been shown to enhance the bioavailability in dogs, rats and humans. Tolerability studies in healthy dogs and dogs with epilepsy have demonstrated that CBD was safe and well tolerated with only mild to moderate adverse effects. In this context, it should be noted that the quality of available CBD varies widely, underscoring the importance of pharmaceutical quality and its control. One clinical trial in dogs with drug-resistant idiopathic epilepsy failed to confirm a difference in response rates between the CBD group and the placebo group, while in another cross-over trial a ≥ 50% reduction in epileptic seizure frequency was found in six of 14 dogs in the treatment phase, a reduction that was not observed during the placebo phase. Based on the current state of knowledge it is not possible to provide clear-cut recommendations for the use of CBD in canine epilepsy. Randomized controlled canine trials with large sample sizes are needed to determine the range of therapeutic plasma concentrations, develop evidence-based dosing regimens, determine the efficacy of cannabidiol in drug-refractory epilepsy, and explore potential associations between treatment effects and different etiologies, epilepsy types, and drug combinations.
Hempseed cake is a byproduct of hempseed oil extraction and is potentially a useful source of protein and fiber for use in ruminant diets. However, data are lacking on the appearance and/or clearance of cannabinoids in tissues of animals fed hempseed cake. To this end, a rapid method for quantifying cannabinol (CBN), cannabidiol (CBD), cannabinolic acid (CBNA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA) in cattle tissues, plasma, and urine was developed using rapid screen electrospray ionization mass spectrometry (RS-ESI-MS). Regression coefficients of matrix-matched standard curves ranged from 0.9946 to >0.9999 and analyte recoveries averaged from 90.2 ± 15.5 to 108.7 ± 18.7% across all compounds. Limits of detection and quantification ranged from 0.05 to 2.79 ng · mL-1 and 0.17 to 9.30 ng · mL-1, respectively, while the inter-day relative standard deviation ranged from 5.1 to 15.1%. Rapid screening electrospray ionization mass spectrometry (RS-ESI-MS) returned no false positives for any cannabinoid in plasma, urine, and tissue (liver, skeletal muscle) samples from 6 non-dosed control animals (n = 90 samples; of which 72 samples were plasma or urine and 18 samples were tissues). Across-animal cannabinoid concentrations measured in 32 plasma samples of cattle dosed with ground hemp were quantified by RS-ESI-MS; analytical results correlated well (r2 = 0.963) with independent LC-MS/MS analysis of the same samples.