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

Wayne S. Schwark Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY

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 DVM, MS, PhD
and
Joseph J. Wakshlag Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY

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 DVM, PhD, DACVIM, DACVSMR

Abstract

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.

Abstract

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.

PK Studies with CBD in Dogs

In domestic animals to the present, the greatest number of pharmacokinetic (PK) studies with hemp cannabidiol (CBD) have been conducted in dogs. Indeed, the correlation between CBD serum levels and clinical effectiveness 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 first-pass hepatic metabolism or the type of formulation utilized (powder in a gelatin capsule).4

Bartner et al studied the PK of oral forms (microencapsulated oil beads, CBD-infused oil) and a topical 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 subsequent oral studies in dogs. The oil preparations 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 similar doses chronically (6 weeks) to determine adverse effects. 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.

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
Deabold6 Dog Soft chew 1 301 1.4 1.0 1,297 1.4
Chicoine7 Dog 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
Wakshlag8 Dog 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
Tittle9 Dog Soft gel 1 185 1.4 3.4 688 4.4
Dog Oil 1 268 1.1 2.2 693 3.4
Deabold6 Cat 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.

Gamble et al found a dose-dependent absorption 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 substantial CBD absorption (Cmax of 301 ng/mL and 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 elimination 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 redistribution from tissue depots such as adipose tissue. Particularly in the high-dose group, a number of neurological side effects 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; sunflower-lecithin in sesame oil and soft chews).8 There were no significant differences 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 demonstrated no significant differences 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 significant differences 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 palatability 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 several respects. As a species, felines are deficient 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 rejection of orally administered drugs. These considerations 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/fiber base) in dogs and suspended in fish 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 fish oil form in cats. Because cannabinoids are highly lipid soluble, interaction with the fish oil may have diminished systemic absorption. Notably, some of the cats exhibited head shaking and excessive salivation 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 specific 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 examination of adverse effects, measurements of plasma levels of the CBD, THC, and their metabolites were undertaken after the 9th dose of the 11-dose escalating study (at that time 25 mg/kg CBD alone). With regard to CBD, higher Cmax values (236 compared with 43 ng/mL in the Deabold study6) were attributed to the higher dosage and/or the suspending oil (medium-chain triglyceride vs fish 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 effects with higher dosages.

In a more recent study in cats, Wang et al investigated 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 cannabinoids were present in the preparation and were also assayed for PK analysis. Utilizing this formulation, 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 similar 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 predicted by PK analysis. The authors speculated that chronic twice-daily administration may induce cytochrome P-450 systems that enhance the elimination of CBD and other cannabinoids.

PK Studies with CBD in Horses

Dietary considerations and the unique properties 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 cannabinoids 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 determined 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 manner (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 similar to that with a similar dosage in senior horses.13 The authors did not establish whether long-term administration may affect 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 significant which may impact drug testing in competition horses. The authors found no adverse effects 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 fluid concentrations of CBD, utilizing a sunflower oil-lecithin based suspension of CBD.15 Dosages of 1 and 3 mg/kg were administered 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 fluid 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 thoroughbred 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 eicosanoid metabolites (COX-1, COX-2, and LOX) were affected 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.

PK Studies with CBD in Cattle

In cattle and other ruminants, different compartments of the forestomach have unique epithelial absorptive characteristics and pH properties that affect drug absorption. The presence of an abundant microflora, particularly in the rumen, may degrade drugs. Thus, age could have a profound effect on PK results because pre-ruminant calves lack this flora 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 sustained and the average half-life of elimination was 23 hours, which represents a much slower elimination 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 implications 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 product 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 average concentration of CBD was 4 ng/mL, a reflection of the lower dose of CBD compared with the Meyer study cited above.18 Regarding CBDA, the elimination 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 inflammatory biomarkers (cortisol, prostaglandin E2).20 This was correlated with measurable levels of acidic forms of the cannabinoids (especially CBDA) but a lack of significant 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.2123 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 differences 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 ultimate Cmax of CBD.8,32 Bioavailability increased 4-fold between fasted individuals and those administered CBD in conjunction with a high-fat meal. Thus, feeding itself and the nature of the food can profoundly affect CBD PK.

Human PK studies have explored routes of administration other than orally (e.g., intravenous, oromucosal spray, sublingually, nebulization, aerosol inhalation, and smoking).22 Vaporization seems to be an especially effective approach to achieving systemic absorption of CBD.33 Cannabinoid administration 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 vaporized 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 administration other than oral have been explored in animals. Because first-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 application resulted in Cmax levels that were only about one-tenth of that achieved by the oral dosage forms. Similarly, Hannon found minimal blood concentrations 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 diffusion across the aqueous layer of the skin, making this route of administration seemingly ineffective for routine systemic clinical use.

Fernandez-Trapero et al studied the PK of a commercial 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 administration but were low compared with that after oral administration. No neurological or other pharmacological effects were noted with this treatment protocol. Higher plasma levels were found after multiple 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 undertaken, Brioschi et al found that an oral transmucosal CBD preparation (2 mg/kg q 12 hour) enhanced the analgesic effects of other drugs used to treat osteoarthritic pain (non-steroidal anti-inflammatory 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 comparative PK study in dogs after intranasal, rectal, and oral administration.38 Plasma concentrations after rectal administration were undetectable. No significant differences 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 significant systemic levels of CBD or other cannabinoids in animals. While administration by inhalation holds promise, as demonstrated in humans, this route is impractical for routine clinical use in animals.

CBD vs CBDA PKs

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 different oral formulations. Because CBDA itself has pharmacological activity, preparations 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 products in hemp preparations must be taken into consideration when designing dosing regimens because acidic cannabinoids appear to be absorbed better than their decarboxylated neutral counterparts globally.8,12,4143 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 findings across dogs, cats, horses, and cattle suggest that CBDA may be preferably absorbed and suggests that therapeutic dosing of CBDA may be more achievable than CBD when using the oral route.

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)
Wakshlag8 Dog 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
Tittle9 Dog 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.

Metabolism and Elimination of CBD/CBDA

The elimination of all drugs takes place primarily through the phase 1 enteric or hepatic metabolism 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 reaction provides a polar group to increase the potential 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.4548 This has been found to be renally excreted while 7-COOH-CBD undergoes glucuronidation leading to the primarily hepatobiliary excretion of cannabinoids, 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 significantly lower during single and multiple day-dosing assessments suggesting different primary metabolic pathways.8,12,51 Dog ex vivo microsomal assays examining metabolites of CBD show significant hydroxylation of the 6 carbon that suggests fundamental differences in CYP metabolism that is thought to undergo carboxylation as well.52 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 interspecies differences.53 Considering the lack of interest in veterinary species the quantification of these metabolites is difficult 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 pharmacologically active, and further research is necessary to fully understand CBD metabolites in dogs and cats (Figure 1). These minor differences in metabolic byproducts suggest there may be differential CYP metabolism in dogs with preliminary information 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 concentrations (Michael Court, DVM PhD, College of Veterinary Medicine, Washington State University, email report, January 7, 2023). The metabolic fate of CBDA is relatively unknown across all species. It has been postulated 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

Figure 1
Figure 1

Basic phase 1 and 2 metabolism of cannabidiol by species showing probable hydroxylation, carboxylation, and glucuronidation sites in the molecule depending on species.

Citation: American Journal of Veterinary Research 84, 5; 10.2460/ajvr.23.02.0031

CBD and its metabolites are lipophilic and there is evidence of bioaccumulation, particularly in adipose and brain tissues to some extent while the acids such as CBDA appear to undergo less bioaccumulation 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 contaminated 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 significant bioaccumulation while adipose can be a modest repository 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 specific CYP isoenzymes including CYP1A, CYP2B, CYP2D, and CYP3A isoenzymes that are the major CYPs involved in the metabolism of drugs.49 This has been extensively studied in human clinical neurology as it is the primary area of investigation in human medicine providing some evidence that drugs like clonazepam, valproate, and levetiracetam are all affected by CBD administration.56,59,60 That said, recent work assessing the metabolism of phenobarbital in clinical and preclinical studies suggests that this anti-epileptic drug is not affected 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 potassium bromide and zonesimide serum concentrations were not affected 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 significantly inhibit CYP activity would be in the 1 uM and above range, while serum Cmax concentrations 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 influence CYP metabolism; however, further studies are necessary with commonly used veterinary pharmaceuticals to fully understand compatibility, particularly those heavily metabolized by CYP1A, CYP2B, CYP2D, and CYP3A isoenzymes.

Conclusions

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 dosing. This may be due to inherent CYP450 enzymatic differences 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 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 surrounding long-term PKs and optimization of therapeutic levels across all species making this a “One Health” initiative that will benefit humans and animals alike.

Acknowledgments

Dr. Wayne Schwark and Dr. Joseph Wakshlag are both paid consultants for Ellevet Sciences

References

  • 1.

    Gamble L-J, Boesch JM, Frye CW, Schwark WS, Mann S, et al. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Front Vet Sci. 2018;5:165.

    • Search Google Scholar
    • Export Citation
  • 2.

    Potschka H, Bhatti SFM, Tipold A, McGrath S. Cannabidiol in canine epilepsy. Vet J. 2022;6:105913. doi:10.1016/j.tvjl.2022.105913

  • 3.

    Samara E, Bialer M, Mechoulam R. Pharmacokinetics of cannabidiol in dogs. Drug Metab Disp. 1988;16:469473.

  • 4.

    Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4:17701777. doi:10.1002/cbdv.200790152

  • 5.

    Bartner LR, McGrath S, Rao S, Hyatt LK, Wittenburg LA. Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Can J Vet Res. 2018;82:178183.

    • Search Google Scholar
    • Export Citation
  • 6.

    Deabold KA, Schwark WS, Wolf L, Wakshlag JJ. Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats. Animals. 2019;9:832. doi:10.3390/ani9100832

    • Search Google Scholar
    • Export Citation
  • 7.

    Chicoine A, Illing K, Vuong S, Pinto KR, Alcorn J, et al. Pharmacokinetic and safety evaluation of various oral doses of a novel 1:20 THC:CBD cannabis herbal extract in dogs. Front Vet Sci. 2020;7:583404.

    • Search Google Scholar
    • Export Citation
  • 8.

    Wakshlag JJ, Schwark WS, Deabold KA, Talsma BN, Cital S, et al. Pharmacokinetics of cannabidiol, cannabidiolic acid, Δ-9 tetrahydrocannabinol, tetrahydrocannabinolic acid and related metabolites in canine serum after dosing with three oral forms of hemp extract. Front Vet Sci. 2020;7:505.

    • Search Google Scholar
    • Export Citation
  • 9.

    Tittle DJ, Wakshlag JJ, Schwark WS, Lyubimov A, Zakharov A, et al. Twenty-four hour and one-week steady state pharmacokinetics of cannabinoids in two formulations of cannabidiol and cannabidiolic acid rich hemp in dogs. Med Rec Arch. 2022;10:2907.

    • Search Google Scholar
    • Export Citation
  • 10.

    Lascelles BD, Court MH, Hardie EM, Robertson SA. Nonsteroidal anti-inflammatory drugs in cats: a review. Vet Anesthes Analg. 2007;34:228250. doi:10.1111/j.1467-2995.2006.00322.x

    • Search Google Scholar
    • Export Citation
  • 11.

    Kulpa JE, Paulionis IJ, Eglit GM, Vaughn DM. Safety and tolerability of escalating cannabinoid doses in healthy cats. J Fel Med Surg. 2021;23:11621175. doi:10.1177/1098612X211004215

    • Search Google Scholar
    • Export Citation
  • 12.

    Wang T, Zakharov A, Gomez B, Lyubimov A, Trottier NL, et al. Serum cannabinoid 24h and 1 week steady state pharmacokinetic assessment in cats using a CBD/CBDA rich hemp paste. Front Vet Sci. 2022;9:895368.

    • Search Google Scholar
    • Export Citation
  • 13.

    Turner SE, Knych HJ, Adams AA. Pharmacokinetics of cannabidiol in a randomized crossover trial in senior horses. Amer J Vet Res. 2022;83:ajvr.22.02.0028. doi:10.2460/ajvr.22.02.0028

    • Search Google Scholar
    • Export Citation
  • 14.

    Williams MR, Holbrook TC, Maxwell L, Croft CH, Intile MM, et al. Pharmacokinetic evaluation of a cannabidiol supplement in horses. J Equine Vet Sci. 2022;110:103842. doi:10.1016/j.jevs.2021.103842

    • Search Google Scholar
    • Export Citation
  • 15.

    Yocum AF, O’Fallon ES, Gustafson DL, Contino EK. Pharmacokinetics, safety, and synovial fluid concentrations of single- and multiple-dose oral administration of 1 and 3 mg/kg cannabidiol in horses. J Equine Vet Sci. 2022;113:103933. doi:10.1016/j.jevs.2022.103933

    • Search Google Scholar
    • Export Citation
  • 16.

    Ryan D, McKemie DS, Kass PH, Puschner B. Pharmacokinetics and effects on arachidonic metabolism of low doses of cannabidiol following oral administration to horses. Drug Test Anal. 2021;13:13051317. doi:10.1002/dta.3028

    • Search Google Scholar
    • Export Citation
  • 17.

    Schwark WS. Factors that affect drug disposition in food-producing animals during maturation. J Anim Sci. 1992;70:36353644. doi:10.2527/1992.70113635x

    • Search Google Scholar
    • Export Citation
  • 18.

    Meyer K, Hayman K, Baumgartner J, Gorden PJ. Plasma pharmacokinetics of cannabidiol following oral administration of cannabidiol oil to dairy calves. Front Vet Sci. 2022;24:789495.

    • Search Google Scholar
    • Export Citation
  • 19.

    Kleinhenz MD, Magnin G, Lin Z, Griffin J, Kleinhenz KE, et al. Plasma concentrations of eleven cannabinoids in cattle following oral administration of industrial hemp (Cannabis sativa). Sci Rep. 2020;10:12753. doi:10.1038/s41598-020-69768-4

    • Search Google Scholar
    • Export Citation
  • 20.

    Kleinhenz MD, Weederntgomery M, Martin M, Curtis A, Magnin G, et al. Short term feeding of industrial hemp with high cannabidiolic acid (CBDA) content increases lying behavior and reduces biomarkers of stress in inflammation in Holstein steers. Sci Rep. 2022;12:3683. doi:10.1038/s41598-022-07795-z

    • Search Google Scholar
    • Export Citation
  • 21.

    Lucas CJ, Galettas P, Schneider J. The pharmacokinetics and pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018;84:24772482. doi:10.1111/bcp.13710

    • Search Google Scholar
    • Export Citation
  • 22.

    Millar SA, Stone NL, Yates AS, O’Sullivan SE. A systematic review of the pharmacokinetics of cannabidiol in humans. Front Pharmacol. 2018;9:1365.

    • Search Google Scholar
    • Export Citation
  • 23.

    Britch SC, Babalonis S, Walsh SL. Cannabidiol pharmacology and therapeutic targets. Psychopharmacology. 2021;238:928. doi:10.1007/s00213-020-05712-8

    • Search Google Scholar
    • Export Citation
  • 24.

    Hawksworth G, McArdle K. Metabolism ad pharmacokinetics of cannabinoids. In: Guy GW, Whittle BA, Robson PJ, eds. The Medicinal Uses of Cannabis and Cannabinoids. Pharmaceutical Press; 2004:205228.

    • Search Google Scholar
    • Export Citation
  • 25.

    Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42:327360.

  • 26.

    Guy GW, Flint ME. A single centre, placebo-controlled, four period, crossover, tolerability study assessing, pharmacodynamic effects, pharmacokinetic characteristics and cognitive profiles of a single dose of three formulations of Cannabis Based Medicine Extracts (CBMEs) (GWPD9901), plus a two period tolerability study comparing pharmacodynamic effects and pharmacokinetic characteristics of a single dose of a cannabis based medicine extract given via two administration routes (GWPD9901 EXT). J. Cannabis Ther. 2004:3:3577. doi:10.1300/J175v03n03_03

    • Search Google Scholar
    • Export Citation
  • 27.

    Atsmon J, Heffetz D, Deutsch L, Deutsch F, Sacks H. Single-dose pharmacokinetics of oral cannabidiol following administration of PTL101: a new formulation based on gelatin matrix pellets technology. Clin Pharmacol Drug Dev. 2017;7:751758. doi:10.10.1002/cpdd.408

    • Search Google Scholar
    • Export Citation
  • 28.

    Sellers EM, Schoedel K, Bartlett C, Romach M, Russo EB, et al. A multiple-dose, randomized, double-blind, placebo-controlled, parallel-group QT/QTc study to evaluate the electrophysiologic effects of THC/CBD spray. Clin Pharmacol Drug. 2017;2:285294. doi:10.1002/cpdd.36

    • Search Google Scholar
    • Export Citation
  • 29.

    Nadulski T, Pragst F, Weinberg G, Roser P, Schnelle M, et al. Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of D9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract. Ther Drug Monit. 2005:27:799810.

    • Search Google Scholar
    • Export Citation
  • 30.

    Manini AF, Yiannoulos G, Bergamaschi MM, Hernandez S, Olmedo R, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med. 2015:9:204210. doi:10.1097/ADM.0000000000000118

    • Search Google Scholar
    • Export Citation
  • 31.

    Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, et al. Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked cannabis. Neuropsychopharmacology. 2016;41:19741982. doi:10.1038/npp.2015.367

    • Search Google Scholar
    • Export Citation
  • 32.

    Silmore LH, Willmer AR, Capparelli EV, GR Rosania. Food effects on the formulation, dosing, and administration of cannabidiol (CBD) in humans: a systemic review of clinical studies. Pharmacotherapy. 2021:41:405420. doi:10.1002/phar.2512

    • Search Google Scholar
    • Export Citation
  • 33.

    Beregia CL, Spindle TR, Cone EJ, Sholler D, Goffi E, et al. Pharmacokinetic profile of Δ9-tetrahydrocannabinol, cannabidiol and metabolites in blood following vaporization and oral ingestion of cannabidiol products. J Analyt Toxicol. 2022;46: 583591. doi:10.1093/jat/bkab124

    • Search Google Scholar
    • Export Citation
  • 34.

    Spindle TR, Cone EJ, Kuntz D, Mitchell JM, Bigelow GE, et al. Urinary pharmacokinetic profile of cannabinoids following administration of vaporized and oral cannabidiol and vaporized CBD-dominant cannabis. J Analyt Toxicol. 2020;44:109125. doi:10.1093/jat/bkz080

    • Search Google Scholar
    • Export Citation
  • 35.

    Hannon MB, Deabold KA, Talsma BN, Lyubimov A, Iqbal A, et al. Serum cannabidiol, tetrahydrocannabinol (THC), and their native acid derivatives after transdermal application of a low-THC Cannabis sativa extract in beagles. J Vet Pharmacol Ther. 2020;43(5):508511. doi:10.1111/jvp.12896.

    • Search Google Scholar
    • Export Citation
  • 36.

    Fernandez-Trapero M, Perez-Diaz C, Espejo-Porra F, de Lago E, Fernandez-Ruiz J. Pharmacokinetics of Sativex in dogs: towards a potential cannabidiol-based therapy for canine disorders. Biomolecules. 2020;10:279.

    • Search Google Scholar
    • Export Citation
  • 37.

    Brioschi FA, Di Cesare F, Gioeni D, Rabbogliatti V, Ferrari F, et al. Oral transmucosal cannabidiol oil formulation as part of a multimodal analgesic regimen effects on pain relief and quality of life improvement in dogs affected by spontaneous osteoarthritis. Animals. 2020;10(9):1505. doi:10.3390/ani10091505

    • Search Google Scholar
    • Export Citation
  • 38.

    Polidoro D, Temmerman R, Devreese M, Charalambous M, Ham LV, et al. Pharmacokinetics of cannabidiol following intranasal, intrarectal, and oral administration in healthy dogs. Front Vet Sci. 2022;9:899940. doi:10.3389/fvets.2022.899940

    • Search Google Scholar
    • Export Citation
  • 39.

    Formato M, Crescente G, Scognamiglio M, Fiorentino A, Pecoraro MT. S(-)-Cannabidiolic acid, a still overlooked bioactive compound: an introductory review and preliminary research. Molecules. 2020;25:2638. doi:10.3390/molecules25112638

    • Search Google Scholar
    • Export Citation
  • 40.

    Eichler M, Spinedi L, Unfer-Grauwiler S, Bodmer M, Surber C, et al. Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects. Planta Med. 2012;78:686691. doi:10.1055/s-0031-1298334

    • Search Google Scholar
    • Export Citation
  • 41.

    Thomson ACS, McCarrel TM, Lyubimov A, Schwark WS, Mallicote MF, et al. Pharmacokinetics and pharmacodynamics of single-dose enteral cannabidiol in horses (Equus caballus). J Vet Pharmcol Ther. [Submitted for publication]

    • Search Google Scholar
    • Export Citation
  • 42.

    Rooney TA, Carpenter JW, KuKanich B, Gardhouse SM, Magnin GC, et al. Feeding decreases the oral bioavailability of cannabidiol and cannabidiolic acid in hemp oil in New Zealand White rabbits (Oryctolagus cuniculus). Amer J Vet Res. 2002;83(10):ajvr.2022.01.0006. doi:10.2460/ajvr.22.01.0006

    • Search Google Scholar
    • Export Citation
  • 43.

    Amstutz K, Schwark WS, Zakharov A, Gomez B, Lyubimov A, Ellis K, et al. Single dose and chronic oral administration of cannabigerol and cannabigerolic acid-rich hemp extract in fed and fasted dogs: physiological effect and pharmacokinetic evaluation. J Vet Pharmacol Ther. 2022;45:245254. doi:10.1111/jvp.13048

    • Search Google Scholar
    • Export Citation
  • 44.

    Riviere JE. Absorption, distribution, metabolism and elimination. In: Reviere J, Papich M, eds. Veterinary Pharmacology and Therapeutics. 10th ed. Wiley Blackwell; 2018:840.

    • Search Google Scholar
    • Export Citation
  • 45.

    Zendulka O, Dovretelova G, Noskova K, Turjap M, Sulcova A, et al. Cannabinoids and cytochrome p450 interactions. Current Drug Metab. 2016;17:206216. doi:10.2174/1389200217666151210142051

    • Search Google Scholar
    • Export Citation
  • 46.

    Jiang R, Yamaori S, Takeda S, Yammamoto I, Watanabe Z. Identification of cytochrome p450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89:165170. doi:10.1016/j.lfs.2011.05.018

    • Search Google Scholar
    • Export Citation
  • 47.

    Stout SM, Cimino NM. Exogenous cannabinioids as substrates, inhibitors and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Reviews. 2014;46(1):8695. doi:10.3109/03602532.2013.849268

    • Search Google Scholar
    • Export Citation
  • 48.

    Bansal S, Paine MF, Unadkat JD. Comprehensive predictions of cytochrome p450-mediated in vivo cannabinoid-drug interactions based on reversible and time dependent p450 inhibition in human liver microsomes. Drug Metab Dispos. 2022;50(4):351360. doi:10.1124/dmd.121.000734

    • Search Google Scholar
    • Export Citation
  • 49.

    Taylor L, Gidal B, Blakey, G, Tayo B, Morrison G. A phase 1, randomized, double blinded, placebo controlled, single ascending dose, multiple dose and food effect triol on the safety and tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs. 2018;32:10531067. doi:10.1007/s40263-018-0578-5

    • Search Google Scholar
    • Export Citation
  • 50.

    Fabritius M, Staub C, Mangin P, Giroud C. Distribution of free and conjucated cannabinoids in human bile samples. Forens Sci Internat. 2012; 223:114118. doi:10.1016/j.forsciint.2012.08.013

    • Search Google Scholar
    • Export Citation
  • 51.

    Whalley BJ, Lin H, Bell L, Hill T, Patel A, Gray RA, Elizabeth Roberts C, Devinsky O, Bazelot M, Williams CM, Stephens GJ. Species-specific susceptibility to cannabis-induced convulsions. Br J Pharmacol. 2019;176(10):15061523. doi:10.1111/bph.14165

    • Search Google Scholar
    • Export Citation
  • 52.

    Harvey DJ, Samara E, Mechoulam R. Comparative metabolism of cannabidiol in dog, rat and human. Pharm Biochem Behav. 1991;40:523532. doi:10.1016/0091-3057(91)90358-9

    • Search Google Scholar
    • Export Citation
  • 53.

    Harvey DJ, Brown NK. Comparative in vitro metabolism of the cannabinoids. Pharm Biochem Behav. 1991;40:533540. doi:10.1016/0091-3057(91)90359-A

    • Search Google Scholar
    • Export Citation
  • 54.

    Pichini S, Mannocchi G, Gottardi M, Pérez-Acevedo AP, Poyatos L, et al. Fast and sensitive UHPLC-MS/MS analysis of cannabinoids and their acid precursors in pharmaceutical preparations of medical cannabis and their metabolites in conventional and non-conventional biological matrices of treated individual. Talanta. 2020;209:120537. doi:10.1016/j.talanta.2019.120537

    • Search Google Scholar
    • Export Citation
  • 55.

    Spittler AP, Helbling JE, McGrath S, Gustafson DL, Santangelo KS, Sadar MJ. Plasma and joint tissue pharmacokinetics of two doses of oral cannabidiol oil in guinea pigs (Cavia porcellus). J Vet Pharmacol Ther. 2021;44(6):967974. doi:10.1111/jvp.13026

    • Search Google Scholar
    • Export Citation
  • 56.

    Bardhi K, Coates S, Watson CJW, Lazarus P. Cannabinoids and drug metabolizing enzymes: potential for drug-drug interactions and implications for drug safely and efficacy. Exp Rev Clin Pharm. 2022;15(12):14431460. doi:10.1080/17512433.2022.2148655

    • Search Google Scholar
    • Export Citation
  • 57.

    Anderson LL, Low IK, Banister SD, McGregor IS, Arnold JC. Pharmacokinetics of phytocannabinoid acids and anticonvulsant effect of cannabidiolic acid in a mouse model of Dravet syndrome. J Nat Prod. 2019;82(11):30473055. doi:10.1021/acs.jnatprod.9b00600

    • Search Google Scholar
    • Export Citation
  • 58.

    Chakrabarty S, Serum EM, Winders TM, Neville B, Kleinhenz MD, Magnin G, Coetzee JF, Dahlen CR, Swanson KC, Smith DJ. Rapid quantification of cannabinoids in beef tissues and bodily fluids using direct-delivery electrospray ionization mass spectrometry. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2022;39(10):17051717. doi:10.1080/19440049.2022.2107711

    • Search Google Scholar
    • Export Citation
  • 59.

    Ujvary I, Hanus L. Human metabolites of cannabidiol: a review on their formation, biological activity and relevance in therapy. Cannabis Cannabin Res. 2016;1.1:90107. doi:10.1089/can2015.0012

    • Search Google Scholar
    • Export Citation
  • 60.

    Gilmartin CGS, Dowd Z, Parker APJ, Harijan P. Interaction of cannabidiol with other antiseizure medications: a narrative review. Seizure Eur J Epilep. 2021;86:189196. doi:10.1016/j.seizure.2020.09.010

    • Search Google Scholar
    • Export Citation
  • 61.

    Doran CE, McGrath S, Bartner LR, Thomas B, Cribb AE, et al. Drug-drug interaction between cannabidiol and phenobarbital in healthy dogs. Am J Vet Res. 2021;83(1):8694. doi:10.2460/ajvr.21.08.0120

    • Search Google Scholar
    • Export Citation
  • 62.

    McGrath S, Bartner LR, Rao S, Packer RA, Gustafson DL. Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. J Am Vet Med Assoc. 2019;254(11):13011308. doi:10.2460/javma.254.11.1301

    • Search Google Scholar
    • Export Citation
  • 63.

    Garcia GA, Kube S, Carrera-Justiz S, Tittle D, Wakshlag JJ. Safety and efficacy of cannabidiol-cannabidiolic acid rich hemp extract in the treatment of refractory epileptic seizures in dogs. Front Vet Sci. 2022;9:939966. doi:10.3389/fvets.2022.939966

    • Search Google Scholar
    • Export Citation
  • 64.

    Mejia S, Duerr FM, Griffenhagen G, McGrath S. Evaluation of the effect of cannabidiol on naturally occurring osteoarthritis-associated pain: a pilot study in dogs. J Am Anim Hosp Assoc. 2021;57:8190. doi:10.5326/JAAHA-MS-7119

    • Search Google Scholar
    • Export Citation
  • 65.

    Loewinger M, Wakshlag JJ, Bowden D, Peters-Kennedy J, Rosenberg A. The effect of a mixed cannabidiol and cannabidiolic acid based oil on client-owned dogs with atopic dermatitis. Vet Dermatol. 2022;33:329e77. doi:10.1111/vde.13077

    • Search Google Scholar
    • Export Citation
  • Figure 1

    Basic phase 1 and 2 metabolism of cannabidiol by species showing probable hydroxylation, carboxylation, and glucuronidation sites in the molecule depending on species.

  • 1.

    Gamble L-J, Boesch JM, Frye CW, Schwark WS, Mann S, et al. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Front Vet Sci. 2018;5:165.

    • Search Google Scholar
    • Export Citation
  • 2.

    Potschka H, Bhatti SFM, Tipold A, McGrath S. Cannabidiol in canine epilepsy. Vet J. 2022;6:105913. doi:10.1016/j.tvjl.2022.105913

  • 3.

    Samara E, Bialer M, Mechoulam R. Pharmacokinetics of cannabidiol in dogs. Drug Metab Disp. 1988;16:469473.

  • 4.

    Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4:17701777. doi:10.1002/cbdv.200790152

  • 5.

    Bartner LR, McGrath S, Rao S, Hyatt LK, Wittenburg LA. Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Can J Vet Res. 2018;82:178183.

    • Search Google Scholar
    • Export Citation
  • 6.

    Deabold KA, Schwark WS, Wolf L, Wakshlag JJ. Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats. Animals. 2019;9:832. doi:10.3390/ani9100832

    • Search Google Scholar
    • Export Citation
  • 7.

    Chicoine A, Illing K, Vuong S, Pinto KR, Alcorn J, et al. Pharmacokinetic and safety evaluation of various oral doses of a novel 1:20 THC:CBD cannabis herbal extract in dogs. Front Vet Sci. 2020;7:583404.

    • Search Google Scholar
    • Export Citation
  • 8.

    Wakshlag JJ, Schwark WS, Deabold KA, Talsma BN, Cital S, et al. Pharmacokinetics of cannabidiol, cannabidiolic acid, Δ-9 tetrahydrocannabinol, tetrahydrocannabinolic acid and related metabolites in canine serum after dosing with three oral forms of hemp extract. Front Vet Sci. 2020;7:505.

    • Search Google Scholar
    • Export Citation
  • 9.

    Tittle DJ, Wakshlag JJ, Schwark WS, Lyubimov A, Zakharov A, et al. Twenty-four hour and one-week steady state pharmacokinetics of cannabinoids in two formulations of cannabidiol and cannabidiolic acid rich hemp in dogs. Med Rec Arch. 2022;10:2907.

    • Search Google Scholar
    • Export Citation
  • 10.

    Lascelles BD, Court MH, Hardie EM, Robertson SA. Nonsteroidal anti-inflammatory drugs in cats: a review. Vet Anesthes Analg. 2007;34:228250. doi:10.1111/j.1467-2995.2006.00322.x

    • Search Google Scholar
    • Export Citation
  • 11.

    Kulpa JE, Paulionis IJ, Eglit GM, Vaughn DM. Safety and tolerability of escalating cannabinoid doses in healthy cats. J Fel Med Surg. 2021;23:11621175. doi:10.1177/1098612X211004215

    • Search Google Scholar
    • Export Citation
  • 12.

    Wang T, Zakharov A, Gomez B, Lyubimov A, Trottier NL, et al. Serum cannabinoid 24h and 1 week steady state pharmacokinetic assessment in cats using a CBD/CBDA rich hemp paste. Front Vet Sci. 2022;9:895368.

    • Search Google Scholar
    • Export Citation
  • 13.

    Turner SE, Knych HJ, Adams AA. Pharmacokinetics of cannabidiol in a randomized crossover trial in senior horses. Amer J Vet Res. 2022;83:ajvr.22.02.0028. doi:10.2460/ajvr.22.02.0028

    • Search Google Scholar
    • Export Citation
  • 14.

    Williams MR, Holbrook TC, Maxwell L, Croft CH, Intile MM, et al. Pharmacokinetic evaluation of a cannabidiol supplement in horses. J Equine Vet Sci. 2022;110:103842. doi:10.1016/j.jevs.2021.103842

    • Search Google Scholar
    • Export Citation
  • 15.

    Yocum AF, O’Fallon ES, Gustafson DL, Contino EK. Pharmacokinetics, safety, and synovial fluid concentrations of single- and multiple-dose oral administration of 1 and 3 mg/kg cannabidiol in horses. J Equine Vet Sci. 2022;113:103933. doi:10.1016/j.jevs.2022.103933

    • Search Google Scholar
    • Export Citation
  • 16.

    Ryan D, McKemie DS, Kass PH, Puschner B. Pharmacokinetics and effects on arachidonic metabolism of low doses of cannabidiol following oral administration to horses. Drug Test Anal. 2021;13:13051317. doi:10.1002/dta.3028

    • Search Google Scholar
    • Export Citation
  • 17.

    Schwark WS. Factors that affect drug disposition in food-producing animals during maturation. J Anim Sci. 1992;70:36353644. doi:10.2527/1992.70113635x

    • Search Google Scholar
    • Export Citation
  • 18.

    Meyer K, Hayman K, Baumgartner J, Gorden PJ. Plasma pharmacokinetics of cannabidiol following oral administration of cannabidiol oil to dairy calves. Front Vet Sci. 2022;24:789495.

    • Search Google Scholar
    • Export Citation
  • 19.

    Kleinhenz MD, Magnin G, Lin Z, Griffin J, Kleinhenz KE, et al. Plasma concentrations of eleven cannabinoids in cattle following oral administration of industrial hemp (Cannabis sativa). Sci Rep. 2020;10:12753. doi:10.1038/s41598-020-69768-4

    • Search Google Scholar
    • Export Citation
  • 20.

    Kleinhenz MD, Weederntgomery M, Martin M, Curtis A, Magnin G, et al. Short term feeding of industrial hemp with high cannabidiolic acid (CBDA) content increases lying behavior and reduces biomarkers of stress in inflammation in Holstein steers. Sci Rep. 2022;12:3683. doi:10.1038/s41598-022-07795-z

    • Search Google Scholar
    • Export Citation
  • 21.

    Lucas CJ, Galettas P, Schneider J. The pharmacokinetics and pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018;84:24772482. doi:10.1111/bcp.13710

    • Search Google Scholar
    • Export Citation
  • 22.

    Millar SA, Stone NL, Yates AS, O’Sullivan SE. A systematic review of the pharmacokinetics of cannabidiol in humans. Front Pharmacol. 2018;9:1365.

    • Search Google Scholar
    • Export Citation
  • 23.

    Britch SC, Babalonis S, Walsh SL. Cannabidiol pharmacology and therapeutic targets. Psychopharmacology. 2021;238:928. doi:10.1007/s00213-020-05712-8

    • Search Google Scholar
    • Export Citation
  • 24.

    Hawksworth G, McArdle K. Metabolism ad pharmacokinetics of cannabinoids. In: Guy GW, Whittle BA, Robson PJ, eds. The Medicinal Uses of Cannabis and Cannabinoids. Pharmaceutical Press; 2004:205228.

    • Search Google Scholar
    • Export Citation
  • 25.

    Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42:327360.

  • 26.

    Guy GW, Flint ME. A single centre, placebo-controlled, four period, crossover, tolerability study assessing, pharmacodynamic effects, pharmacokinetic characteristics and cognitive profiles of a single dose of three formulations of Cannabis Based Medicine Extracts (CBMEs) (GWPD9901), plus a two period tolerability study comparing pharmacodynamic effects and pharmacokinetic characteristics of a single dose of a cannabis based medicine extract given via two administration routes (GWPD9901 EXT). J. Cannabis Ther. 2004:3:3577. doi:10.1300/J175v03n03_03

    • Search Google Scholar
    • Export Citation
  • 27.

    Atsmon J, Heffetz D, Deutsch L, Deutsch F, Sacks H. Single-dose pharmacokinetics of oral cannabidiol following administration of PTL101: a new formulation based on gelatin matrix pellets technology. Clin Pharmacol Drug Dev. 2017;7:751758. doi:10.10.1002/cpdd.408

    • Search Google Scholar
    • Export Citation
  • 28.

    Sellers EM, Schoedel K, Bartlett C, Romach M, Russo EB, et al. A multiple-dose, randomized, double-blind, placebo-controlled, parallel-group QT/QTc study to evaluate the electrophysiologic effects of THC/CBD spray. Clin Pharmacol Drug. 2017;2:285294. doi:10.1002/cpdd.36

    • Search Google Scholar
    • Export Citation
  • 29.

    Nadulski T, Pragst F, Weinberg G, Roser P, Schnelle M, et al. Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of D9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract. Ther Drug Monit. 2005:27:799810.

    • Search Google Scholar
    • Export Citation
  • 30.

    Manini AF, Yiannoulos G, Bergamaschi MM, Hernandez S, Olmedo R, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med. 2015:9:204210. doi:10.1097/ADM.0000000000000118

    • Search Google Scholar
    • Export Citation
  • 31.

    Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, et al. Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked cannabis. Neuropsychopharmacology. 2016;41:19741982. doi:10.1038/npp.2015.367

    • Search Google Scholar
    • Export Citation
  • 32.

    Silmore LH, Willmer AR, Capparelli EV, GR Rosania. Food effects on the formulation, dosing, and administration of cannabidiol (CBD) in humans: a systemic review of clinical studies. Pharmacotherapy. 2021:41:405420. doi:10.1002/phar.2512

    • Search Google Scholar
    • Export Citation
  • 33.

    Beregia CL, Spindle TR, Cone EJ, Sholler D, Goffi E, et al. Pharmacokinetic profile of Δ9-tetrahydrocannabinol, cannabidiol and metabolites in blood following vaporization and oral ingestion of cannabidiol products. J Analyt Toxicol. 2022;46: 583591. doi:10.1093/jat/bkab124

    • Search Google Scholar
    • Export Citation
  • 34.

    Spindle TR, Cone EJ, Kuntz D, Mitchell JM, Bigelow GE, et al. Urinary pharmacokinetic profile of cannabinoids following administration of vaporized and oral cannabidiol and vaporized CBD-dominant cannabis. J Analyt Toxicol. 2020;44:109125. doi:10.1093/jat/bkz080

    • Search Google Scholar
    • Export Citation
  • 35.

    Hannon MB, Deabold KA, Talsma BN, Lyubimov A, Iqbal A, et al. Serum cannabidiol, tetrahydrocannabinol (THC), and their native acid derivatives after transdermal application of a low-THC Cannabis sativa extract in beagles. J Vet Pharmacol Ther. 2020;43(5):508511. doi:10.1111/jvp.12896.

    • Search Google Scholar
    • Export Citation
  • 36.

    Fernandez-Trapero M, Perez-Diaz C, Espejo-Porra F, de Lago E, Fernandez-Ruiz J. Pharmacokinetics of Sativex in dogs: towards a potential cannabidiol-based therapy for canine disorders. Biomolecules. 2020;10:279.

    • Search Google Scholar
    • Export Citation
  • 37.

    Brioschi FA, Di Cesare F, Gioeni D, Rabbogliatti V, Ferrari F, et al. Oral transmucosal cannabidiol oil formulation as part of a multimodal analgesic regimen effects on pain relief and quality of life improvement in dogs affected by spontaneous osteoarthritis. Animals. 2020;10(9):1505. doi:10.3390/ani10091505

    • Search Google Scholar
    • Export Citation
  • 38.

    Polidoro D, Temmerman R, Devreese M, Charalambous M, Ham LV, et al. Pharmacokinetics of cannabidiol following intranasal, intrarectal, and oral administration in healthy dogs. Front Vet Sci. 2022;9:899940. doi:10.3389/fvets.2022.899940

    • Search Google Scholar
    • Export Citation
  • 39.

    Formato M, Crescente G, Scognamiglio M, Fiorentino A, Pecoraro MT. S(-)-Cannabidiolic acid, a still overlooked bioactive compound: an introductory review and preliminary research. Molecules. 2020;25:2638. doi:10.3390/molecules25112638

    • Search Google Scholar
    • Export Citation
  • 40.

    Eichler M, Spinedi L, Unfer-Grauwiler S, Bodmer M, Surber C, et al. Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects. Planta Med. 2012;78:686691. doi:10.1055/s-0031-1298334

    • Search Google Scholar
    • Export Citation
  • 41.

    Thomson ACS, McCarrel TM, Lyubimov A, Schwark WS, Mallicote MF, et al. Pharmacokinetics and pharmacodynamics of single-dose enteral cannabidiol in horses (Equus caballus). J Vet Pharmcol Ther. [Submitted for publication]

    • Search Google Scholar
    • Export Citation
  • 42.

    Rooney TA, Carpenter JW, KuKanich B, Gardhouse SM, Magnin GC, et al. Feeding decreases the oral bioavailability of cannabidiol and cannabidiolic acid in hemp oil in New Zealand White rabbits (Oryctolagus cuniculus). Amer J Vet Res. 2002;83(10):ajvr.2022.01.0006. doi:10.2460/ajvr.22.01.0006

    • Search Google Scholar
    • Export Citation
  • 43.

    Amstutz K, Schwark WS, Zakharov A, Gomez B, Lyubimov A, Ellis K, et al. Single dose and chronic oral administration of cannabigerol and cannabigerolic acid-rich hemp extract in fed and fasted dogs: physiological effect and pharmacokinetic evaluation. J Vet Pharmacol Ther. 2022;45:245254. doi:10.1111/jvp.13048

    • Search Google Scholar
    • Export Citation
  • 44.

    Riviere JE. Absorption, distribution, metabolism and elimination. In: Reviere J, Papich M, eds. Veterinary Pharmacology and Therapeutics. 10th ed. Wiley Blackwell; 2018:840.

    • Search Google Scholar
    • Export Citation
  • 45.

    Zendulka O, Dovretelova G, Noskova K, Turjap M, Sulcova A, et al. Cannabinoids and cytochrome p450 interactions. Current Drug Metab. 2016;17:206216. doi:10.2174/1389200217666151210142051

    • Search Google Scholar
    • Export Citation
  • 46.

    Jiang R, Yamaori S, Takeda S, Yammamoto I, Watanabe Z. Identification of cytochrome p450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89:165170. doi:10.1016/j.lfs.2011.05.018

    • Search Google Scholar
    • Export Citation
  • 47.

    Stout SM, Cimino NM. Exogenous cannabinioids as substrates, inhibitors and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Reviews. 2014;46(1):8695. doi:10.3109/03602532.2013.849268

    • Search Google Scholar
    • Export Citation
  • 48.

    Bansal S, Paine MF, Unadkat JD. Comprehensive predictions of cytochrome p450-mediated in vivo cannabinoid-drug interactions based on reversible and time dependent p450 inhibition in human liver microsomes. Drug Metab Dispos. 2022;50(4):351360. doi:10.1124/dmd.121.000734

    • Search Google Scholar
    • Export Citation
  • 49.

    Taylor L, Gidal B, Blakey, G, Tayo B, Morrison G. A phase 1, randomized, double blinded, placebo controlled, single ascending dose, multiple dose and food effect triol on the safety and tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs. 2018;32:10531067. doi:10.1007/s40263-018-0578-5

    • Search Google Scholar
    • Export Citation
  • 50.

    Fabritius M, Staub C, Mangin P, Giroud C. Distribution of free and conjucated cannabinoids in human bile samples. Forens Sci Internat. 2012; 223:114118. doi:10.1016/j.forsciint.2012.08.013

    • Search Google Scholar
    • Export Citation
  • 51.

    Whalley BJ, Lin H, Bell L, Hill T, Patel A, Gray RA, Elizabeth Roberts C, Devinsky O, Bazelot M, Williams CM, Stephens GJ. Species-specific susceptibility to cannabis-induced convulsions. Br J Pharmacol. 2019;176(10):15061523. doi:10.1111/bph.14165

    • Search Google Scholar
    • Export Citation
  • 52.

    Harvey DJ, Samara E, Mechoulam R. Comparative metabolism of cannabidiol in dog, rat and human. Pharm Biochem Behav. 1991;40:523532. doi:10.1016/0091-3057(91)90358-9

    • Search Google Scholar
    • Export Citation
  • 53.

    Harvey DJ, Brown NK. Comparative in vitro metabolism of the cannabinoids. Pharm Biochem Behav. 1991;40:533540. doi:10.1016/0091-3057(91)90359-A

    • Search Google Scholar
    • Export Citation
  • 54.

    Pichini S, Mannocchi G, Gottardi M, Pérez-Acevedo AP, Poyatos L, et al. Fast and sensitive UHPLC-MS/MS analysis of cannabinoids and their acid precursors in pharmaceutical preparations of medical cannabis and their metabolites in conventional and non-conventional biological matrices of treated individual. Talanta. 2020;209:120537. doi:10.1016/j.talanta.2019.120537

    • Search Google Scholar
    • Export Citation
  • 55.

    Spittler AP, Helbling JE, McGrath S, Gustafson DL, Santangelo KS, Sadar MJ. Plasma and joint tissue pharmacokinetics of two doses of oral cannabidiol oil in guinea pigs (Cavia porcellus). J Vet Pharmacol Ther. 2021;44(6):967974. doi:10.1111/jvp.13026

    • Search Google Scholar
    • Export Citation
  • 56.

    Bardhi K, Coates S, Watson CJW, Lazarus P. Cannabinoids and drug metabolizing enzymes: potential for drug-drug interactions and implications for drug safely and efficacy. Exp Rev Clin Pharm. 2022;15(12):14431460. doi:10.1080/17512433.2022.2148655

    • Search Google Scholar
    • Export Citation
  • 57.

    Anderson LL, Low IK, Banister SD, McGregor IS, Arnold JC. Pharmacokinetics of phytocannabinoid acids and anticonvulsant effect of cannabidiolic acid in a mouse model of Dravet syndrome. J Nat Prod. 2019;82(11):30473055. doi:10.1021/acs.jnatprod.9b00600

    • Search Google Scholar
    • Export Citation
  • 58.

    Chakrabarty S, Serum EM, Winders TM, Neville B, Kleinhenz MD, Magnin G, Coetzee JF, Dahlen CR, Swanson KC, Smith DJ. Rapid quantification of cannabinoids in beef tissues and bodily fluids using direct-delivery electrospray ionization mass spectrometry. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2022;39(10):17051717. doi:10.1080/19440049.2022.2107711

    • Search Google Scholar
    • Export Citation
  • 59.

    Ujvary I, Hanus L. Human metabolites of cannabidiol: a review on their formation, biological activity and relevance in therapy. Cannabis Cannabin Res. 2016;1.1:90107. doi:10.1089/can2015.0012

    • Search Google Scholar
    • Export Citation
  • 60.

    Gilmartin CGS, Dowd Z, Parker APJ, Harijan P. Interaction of cannabidiol with other antiseizure medications: a narrative review. Seizure Eur J Epilep. 2021;86:189196. doi:10.1016/j.seizure.2020.09.010

    • Search Google Scholar
    • Export Citation
  • 61.

    Doran CE, McGrath S, Bartner LR, Thomas B, Cribb AE, et al. Drug-drug interaction between cannabidiol and phenobarbital in healthy dogs. Am J Vet Res. 2021;83(1):8694. doi:10.2460/ajvr.21.08.0120

    • Search Google Scholar
    • Export Citation
  • 62.

    McGrath S, Bartner LR, Rao S, Packer RA, Gustafson DL. Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. J Am Vet Med Assoc. 2019;254(11):13011308. doi:10.2460/javma.254.11.1301

    • Search Google Scholar
    • Export Citation
  • 63.

    Garcia GA, Kube S, Carrera-Justiz S, Tittle D, Wakshlag JJ. Safety and efficacy of cannabidiol-cannabidiolic acid rich hemp extract in the treatment of refractory epileptic seizures in dogs. Front Vet Sci. 2022;9:939966. doi:10.3389/fvets.2022.939966

    • Search Google Scholar
    • Export Citation
  • 64.

    Mejia S, Duerr FM, Griffenhagen G, McGrath S. Evaluation of the effect of cannabidiol on naturally occurring osteoarthritis-associated pain: a pilot study in dogs. J Am Anim Hosp Assoc. 2021;57:8190. doi:10.5326/JAAHA-MS-7119

    • Search Google Scholar
    • Export Citation
  • 65.

    Loewinger M, Wakshlag JJ, Bowden D, Peters-Kennedy J, Rosenberg A. The effect of a mixed cannabidiol and cannabidiolic acid based oil on client-owned dogs with atopic dermatitis. Vet Dermatol. 2022;33:329e77. doi:10.1111/vde.13077

    • Search Google Scholar
    • Export Citation

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