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.
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).
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.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 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.8,12,41–43 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 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.
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.45–48 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
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
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