Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2024 May 23.
Published in final edited form as: J Vet Pharmacol Ther. 2021 Oct 17;44(6):967–974. doi: 10.1111/jvp.13026

Plasma and joint tissue pharmacokinetics of two doses of oral cannabidiol oil in guinea pigs (Cavia porcellus)

Alexa P Spittler 1, Joel E Helbling 1, Stephanie McGrath 2, Daniel L Gustafson 2, Kelly S Santangelo 1, Miranda J Sadar 2
PMCID: PMC11114070  NIHMSID: NIHMS1992028  PMID: 34658021

Abstract

Cannabidiol (CBD) has gained widespread popularity as a treatment for osteoarthritis (OA) in pets; however, there is minimal scientific evidence regarding safe and effective dosing. This study determined plasma and tissue pharmacokinetics after oral CBD oil suspension administration in Hartley guinea pigs (Cavia porcellus), which spontaneously develop OA at 3 months of age. Ten, 5-m onth-old, male guinea pigs were randomly assigned to receive 25 (n = 5) or 50 mg/kg (n = 5) CBD oil once orally. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h timepoints. Open-field enclosure monitoring revealed no adverse effects. After euthanasia, stifle cartilage and infrapatellar fat pads were collected to quantitate CBD. CBD concentrations were determined using a validated liquid chromatography-mass spectrometry method, and pharmacokinetic parameters were calculated using noncompartmental analysis. The area under the plasma concentration-versus-time curve was 379.5 and 873.7 h*ng/mL, maximum plasma concentration was 42 and 96.8 ng/mL, time to maximum plasma concentration was 1.6 and 4.8 h, and terminal phase half-life was 8.1 and 10.8 h for the 25 and 50 mg/kg doses, respectively. CBD was detected in joint tissues of all animals. Further studies, including work in female guinea pigs, are needed to determine the efficacy of CBD for OA.

Keywords: cannabidiol, Cavia porcellus, guinea pig, osteoarthritis, pharmacokinetics

1 |. INTRODUCTION

Osteoarthritis (OA) is a degenerative joint disease that commonly causes clinical signs of decreased and painful mobility in geriatric small mammals, particularly guinea pigs (Cavia porcellus) (Bays, 2020; Minarikova et al., 2015). Nonsteroidal anti-inflammatory drugs (NSAIDs) and centrally acting opiate agonists, alone or in combination, are often used to treat clinical signs of pain in this species (Bays, 2020). However, very few studies have evaluated the efficacy of these drugs in guinea pigs (Oliver et al., 2017; Santangelo et al., 2014; Smith et al., 2016), and use of these medications may result in adverse effects (e.g., weight loss, sedation (Oliver et al., 2017), renal, and gastrointestinal injury (Papich, 2008)) that preclude their use. Due to the lack of treatment options, many pet owners are seeking alternative treatments for OA-related pain management.

Cannabidiol (CBD), the nonpsychotropic component of the cannabis plant, has gained widespread popularity over the past several years as a treatment for OA in both human and veterinary medicine (Kogan et al., 2016; Landa et al., 2016). Evidence suggests that CBD exerts anti-inflammatory and pain-modulating effects by acting on the endocannabinoid system, a biochemical signaling system that is thought to play a role in OA pathogenesis and pain control (O’Brien & McDougall, 2018). While pet owners have reported anecdotal success of cannabis products for pain and OA in dogs and cats (Kogan et al., 2016), few scientific reports have been published in veterinary species (Landa et al., 2016). Clinical trials investigating the efficacy and safety of CBD for dogs and cats with OA have found improvements in veterinary assessments of pain and minimal side effects (Deabold et al., 2019; Gamble et al., 2018; Kogan et al., 2020; Martello et al., 2019; Mejia et al., 2021; Verrico et al., 2020). Experimentally, CBD has been shown to have analgesic and anti-inflammatory effects in laboratory mouse and rat models of rheumatoid arthritis (Malfait et al., 2000; Sumariwalla et al., 2004), inflammation (Costa et al., 2004, 2007), and joint degeneration (Hammell et al., 2016; Philpott et al., 2017), but efficacy in guinea pigs with naturally occurring OA has yet to be determined.

The objective of this study was to determine plasma and joint tissue pharmacokinetics and short-term safety of 2 doses of CBD after oral administration in Dunkin Hartley guinea pigs. This guinea pig strain spontaneously develops OA at 3 months of age, making it an attractive model to study OA in both veterinary and human populations. We hypothesized that there would be measurable concentrations of CBD in the plasma and stifle joint tissues, and there would be no short-term adverse effects associated with oral administration.

2 |. MATERIALS AND METHODS

2.1 |. Animals

Ten, 5-month-old, intact male Hartley guinea pigs were used for this study. The mean ± SD body weight was 918.97 ± 79.12 g. All guinea pigs were purchased from a commercial vendor (Charles River Laboratories) with a 2F catheter surgically implanted in the right jugular vein. All guinea pigs were considered to be healthy based on the results of a physical examination and a complete blood cell count (CBC), and serum biochemistry performed prior to the start of the experiment. Animal rooms were maintained at a 12–12 h light–dark cycle, 20–26°C temperature, and 30–70% humidity. Guinea pigs were singly housed in solid bottom cages with corn cob bedding. Red huts and hay cubes were provided for enrichment. Filter-sterilized water and standard laboratory guinea pig pellets were provided ad libitum. All procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee at Colorado State University.

2.2 |. CBD administration and blood sample collection

A 100 mg/mL CBD suspension in almond oil was formulated and provided by Canopy Animal Health. Guinea pigs were randomly assigned (by drawing numbers out of a container) into one of two CBD dosing groups (25 mg/kg or 50 mg/kg). Animals were unfasted prior to CBD dosing. Blood samples were collected from jugular catheters into sodium-heparinized tubes before (time 0) and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h after CBD administration.

Clean techniques were used during all catheter maintenance procedures and blood sample collections. Briefly, a wound clip (which held the catheter in place) was loosened from the skin of the interscapular region, the catheter tubing was minimally exteriorized, and the metal stopper was removed from the end of the catheter. The metal stopper was placed in 0.05% chlorhexidine solution during blood sample collection and rinsed with sterile saline (0.9% NaCl) prior to reinsertion in the catheter. A 26-gauge intravenous catheter without the stylet was inserted into the lumen of the catheter for blood sample collection up to the 12-h sampling timepoint. Blood samples were collected by use of a 3-syringe method (removal of heparin and blood, collection of the sample (0.75 mL), and reinjection of the heparin and blood in the first syringe to the guinea pig, followed by administration of a heparin flush). Heparinized saline solution (4 U/mL) was used for blood collection and flushing of catheters to maintain patency between blood collections. After the catheter was flushed, the catheter was capped between sampling timepoints. When no samples were to be collected within 12 h, the catheter was infused with a heparin lock solution (500 U/mL). After the catheter was flushed, the 26-gauge intravenous catheter was removed, and the metal stopper was reinserted into the catheter. The catheter was replaced into the subcutaneous space, and the wound clip was tightened. For the 24-h timepoint, all guinea pigs were anesthetized in an induction chamber via 5% isoflurane in oxygen. Once under anesthesia, the guinea pigs were maintained on a facemask with 2% isoflurane in oxygen, and blood was collected from the cranial vena cava prior to euthanasia. The blood removed from each guinea pig over the course of the study was calculated to be <10% of each animal’s total blood volume. Collected blood samples were stored on ice until centrifugation (3000 × g for 15 min at 4°C), and all samples were centrifuged within 1 h after collection. Plasma was harvested and stored at −80°C until analysis.

2.3 |. Open-field enclosure monitoring

Guinea pigs’ behavior and voluntary movement were assessed using ANY-maze behavioral tracking software (Stoelting Co.) in a circular plastic bin measuring 45” in diameter and 6” in height. A red hut was placed along the edge of the apparatus in the same location for every recording. Guinea pigs were randomly selected, placed in the center of the apparatus, and allowed to move freely for 14 min. All recordings were performed by the same handlers (APS, JEH). Animals were acclimated to the apparatus for 2 days prior to baseline data collection. As time of day may affect guinea pig behavior and mobility, baseline recordings were performed the day prior to CBD administration from 5:30–7:00 AM, 9:30–11:00 AM, 11:30 AM-1:00 PM, and 3:30–5:00 PM. Subsequent recordings were performed the following day after CBD administration at corresponding time intervals between blood collections to allow for pre- and post-CBD statistical comparisons. The 5:30–7:00 AM recording post-CBD was performed prior to the 24 h blood collection.

2.4 |. Tissue harvest

For tissue collection, animals were anesthetized as previously described and maintained on 5% isoflurane in oxygen for euthanasia. The thoracic cavity was opened, and blood was collected directly from the heart with a 20-gauge butterfly catheter. Collected blood was placed into 0.5 mL ethylenediaminetetraacetic acid (EDTA) microtubes and red top serum collection tubes. After clotting, red top tubes were placed into a centrifuge at 3000 × g for 15 min at 4°C for serum collection. EDTA microtubes and serum aliquots were submitted to the Colorado State University Clinical Pathology Laboratory for CBC and serum biochemical analyses.

After exsanguination, the pelvic limbs were removed at the coxofemoral joint. The stifle joints were exposed by dissecting the quadriceps muscles and reflecting the patella distally. The infrapatellar fat pads (IFP) and articular cartilage with menisci were removed and stored at −80°C until pharmacokinetic analysis.

2.5 |. Pharmacokinetic analysis

Cannabidiol was measured in guinea pig plasma and tissue homogenates using a validated liquid chromatography-tandem mass spectrometry assay (McGrath et al., 2019) carried out in the Pharmacology Laboratory of the Drug Development & Discovery Shared Resource (University of Colorado Cancer Center). Tissue homogenates were generated by homogenizing tissues in high purity deionized water (Milli-Q® Advantage A10 Water Purification System) at a 1:10 ratio (tissue:water). The instrumentation included an Applied Biosystems 3200 Q-TRAP triple quadrupole mass spectrometer coupled to an Agilent 1200 binary pump system and HTC-PAL autosampler. Unknown and quality control (QC) samples were prepared by adding known amounts of CBD (1–1,000 ng/mL) into 100 μL blank plasma or 100 μL of tissue homogenate in a volume of 10 μL prepared in 50/50 acetonitrile and MilliQ H2O. Samples (unknowns, standards, and QCs) were prepared for analysis by mixing 10 μL d3-CBD (1,000 ng/mL, internal standard) and 10 μL 50/50 acetonitrile and MilliQ H2O to unknown samples, followed by 600 μL cyclohexane and vortex mixing for 5 min and centrifugation for 10 min at 13,300 rcf with collection of 500 μL of the resulting supernatant in a microcentrifuge tube. The supernatant was evaporated to dryness on a speed vac and the sample resuspended in 100 μL 50/50 acetonitrile and MilliQ H2O and transferred to HPLC vials with a low volume insert. Sample injection volume was 30 μL (using a 20 μL loading loop), and chromatography was carried out using a Waters Sunfire C18 5 μm column (4.6 × 50 mm) and a solvent system consisting of acetonitrile with 0.1% formic acid (solvent A) and Milli-Q water with 0.1% formic acid (solvent B). CBD and d3-CBD (internal standard) were eluted using a gradient starting at 70% solvent A:30% solvent B for the first 2.0 min and transitioning linearly to 99% solvent A:1% solvent B over a 2-min period and holding until 5.5 min when the original 75% solvent A:25% solvent B was re-established over a 0.5 min period and held for the remainder of the 7.0 min total run time. The mass spectrometer was operated in positive ion mode with an ion spray voltage of 5,500 V and a source temperature of 550°C. Multiple reaction monitoring (MRM) analysis was carried out for CBD by monitoring ion transitions of 315.2 m/z → 193.3 m/z and 315.2 m/z → 259.3 m/z, and for d3-CBD at 318.2 m/z → 196.3 m/z. MRM conditions were optimized using internal algorithms, and both Q1 and Q3 were operated at unit resolution. Assay performance for plasma was monitored using QC samples at 3 concentrations (10, 25, and 100 ng/mL) and showed an accuracy and precision (%CV) of 94.5% ± 3.7% across 3 batches with 26/27 QCs passing with greater than 85% accuracy and a lower limit of quantitation of 1.0 ng/mL. For tissue analysis, assay performance was 95.4% ± 2.7% for QC samples at 3 concentrations (5, 50 and 500 ng/mL) within a single batch and 12/12 QCs showed an accuracy greater than 85% with a lower limit of quantitation of 10 ng/g tissue in the homogenates.

2.6 |. Statistical analysis

Pharmacokinetic parameters were calculated by noncompartmental analysis with Microsoft Excel using equations described for each parameter (Wagner, 1993). The calculation of the terminal slope was performed using the linear portion of the terminal decline in drug concentration. Pharmacokinetic parameters were reported as mean ± standard deviation. Statistical analyses to determine differences before and after CBD administration for CBC and serum biochemistry, as well as enclosure monitoring parameters, were performed using Prism (version 8.4.0, GraphPad Software). Normality was assessed using the D’Agostino–Pearson normality test. Depending on the data distribution, pre- and post-CBC and serum biochemistry parameters were analyzed by either paired t-tests or Wilcoxon matched pairs signed-rank tests. To account for time-of-day effects on mobility and behavior, enclosure monitoring parameters within each time-point (i.e., 9:30 AM pre-CBD vs. 9:30 AM post-CBD) were analyzed by paired t-tests or Wilcoxon matched pairs signed-rank tests as dictated by normality. Correlation was determined using the Spearman coefficient. Significance was set at a value of p < .05.

3 |. RESULTS

3.1 |. Animals

All guinea pigs remained healthy with no clinically apparent adverse effects from drug administration during the study period. Changes in CBCs and serum biochemistries were consistent with minor, but not clinically significant, decreases in blood volume due to serial blood collections. One guinea pig in the 25 mg/kg group removed its catheter just prior to CBD administration. This guinea pig was anesthetized with 3% isoflurane in oxygen with blood collected from the cranial vena cava for all time points except for the 0.25- and 0.5-h samples.

3.2 |. Pharmacokinetic analysis

Plasma concentration-versus-time curves for oral administration of 25 and 50 mg/kg CBD are plotted in Figure 1. Plasma pharmacokinetic parameters for both CBD doses are listed in Table 1. After 24 h, CBD was detected in both the articular cartilage and IFP of stifle joints from all guinea pigs. The dose of CBD was positively correlated with the concentration of CBD in the IFP (r = .6635; p-value = .0476) but not the cartilage (r = .1741; p-value = .6905). Neither the cartilage nor the IFP were correlated with the 24-h plasma concentration of CBD (cartilage, r = .0667, p-value = .8651; IFP, r = .3951, p-value = .2573) or the area under the curve (AUC) (cartilage, r = −.0788, p-value = .8382; IFP, r = .6018, p-value = .0706). Individual guinea pig values of CBD concentrations in plasma, cartilage, and IFP from each dose are shown in Table 2.

FIGURE 1.

FIGURE 1

Open in a new tab

Mean ± SD plasma concentrations of CBD of 10 male guinea pigs that received a single oral dose of CBD at 25 or 50 mg/kg

TABLE 1.

Pharmacokinetic parameters of plasma CBD following a single oral dose of 25 and 50 mg/kg in 10 male guinea pigs

Parameter 25 mg/kg 50 mg/kg
Cmax (ng/mL) 42.0 ± 21.2 96.8 ± 68.4
Tmax (h) 1.6 ± 0.5 4.8 ± 3.0
T1/2λ (h) 8.1 ± 3.0 10.8 ± 7.0
AUC0-inf (ng/mL x h)  379.5 ± 191.9 873.7 ± 296.7
CL/F (L/h/kg) 77.7 ± 30.9 63.8 ± 24.4
MRT (h) 8.6 ± 3.7 11.3 ± 3.1
Vdss/F (L/kg)  693.5 ± 461.9 685.9 ± 191.3
Vdarea/F (L/kg)  912.0 ± 558.0 839.2 ± 318.6
Open in a new tab

Note: Values represent the mean ± SD of 5 animals in each group.

Abbreviations: AUC0-inf, area under the plasma concentration-time curve from 0 to infinity; CL/F, total body clearance of drug from plasma corrected for bioavailability; Cmax, maximum plasma drug concentration; MRT, mean residence time; T1/2λ, terminal phase halflife; Tmax, time to maximum plasma concentration; Vdarea/F, volume of distribution calculated using the AUC method and corrected for bioavailability; Vdss/F, volume of distribution at steady state corrected for bioavailability.

TABLE 2.

Concentration of CBD in the plasma, articular cartilage, and infrapatellar fat pad (IFP) of 10 male guinea pigs 24 h after a single oral dose of 25 and 50 mg/kg CBD

Dose Plasma concentration (ng/mL) Articular cartilage concentration (ng/g) IFP concentration (ng/g)
25 mg/kg 1.2 14 141
7.15 7.06 54.7
4.14 146 151
1.83 75.7 92.9
0.169 72.5 151
Mean ± SD 2.9 ± 2.8 63.05 ± 56.3 118.12 ± 42.8
50 mg/kg 3.89 33.8 225
13.4 58.1 311
15.8 53.6 189
5.2 75.9 136
10.5 185 433
Mean ± SD 9.76 ± 5.2 81.28 ± 59.9 258.8 ± 116.4
Open in a new tab

3.3 |. Open-field enclosure monitoring

To assess potential side effects on activity levels from CBD administration, mobility parameters of guinea pigs were monitored in an open-field apparatus before and after treatment. No significant differences were present in total distance traveled, average speed, or time in red hut between baseline and post-CBD timepoints (Figure 2). Therefore, a single administration of CBD at the provided doses did not appear to alter the animals’ behavior or mobility.

FIGURE 2.

FIGURE 2

Open in a new tab

Longitudinal and before–after graphs representing open-field enclosure monitoring parameters for 10 male guinea pigs that received a single oral dose of 25 or 50 mg/kg CBD. Longitudinal graphs show total distance traveled (a, c), average speed (e, g), and time in red hut (i, k) values from baseline to post-CBD timepoints. Please note that time-of-day variability suggested that statistical comparisons to determine CBD effects were best performed only within corresponding timeframes. Before–after graphs show total distance traveled (b, d), average speed (f, h), and time in red hut (j, l) between pre- and post-CBD timepoints. For these graphs, circles represent pre-CBD values, and squares represent post-CBD values. Each color represents an individual guinea pig

4 |. DISCUSSION

This study describes the plasma and joint tissue pharmacokinetics of 2 doses of an oral oil suspension of CBD in guinea pigs. The doses of 25 and 50 mg/kg used in the current study were selected based on positive results of these doses in a mouse model of rheumatoid arthritis (Malfait et al., 2000). Both doses achieved measurable concentrations of CBD within the plasma of all guinea pigs. Pharmacokinetic analysis demonstrated that the 50 mg/kg dose of CBD oil resulted in approximately double the maximum concentration (Cmax) and systemic exposure (AUC) of the 25 mg/kg dose, suggesting these parameters increase in a dose-dependent manner in guinea pigs. Similarly, human studies have shown Cmax and AUC to be dose-dependent, with Tmax occurring between 1 and 4 h (Millar et al., 2018). Rodent studies have also demonstrated a dose-dependent relationship between CBD and plasma concentrations with transdermal application in rats (Hammell et al., 2016) and both plasma and brain concentrations with intraperitoneal administration in mice (Long et al., 2012).

Oral bioavailability of CBD is reported to be low in both human and animal studies, presumably due to first-pass metabolism (Millar et al., 2018), and may not be the ideal route of administration. However, we chose to evaluate CBD suspended in oil and administered orally, as we believed this to be the most clinically feasible route of administration in this species. A previous study in guinea pigs evaluated the pharmacokinetics of intravenous and transdermal applications of CBD (Paudel et al., 2010). The mean maximum concentration of 1 mg/kg CBD delivered intravenously was 269 ng/mL, which rapidly declined to an average of 33 ng/mL at 1 h and 15 ng/mL at 2 h post-administration, with a mean terminal half-life of 3.5 h. Oral administration of CBD in the current study resulted in lower Cmax and AUC, but higher Tmax and T1/2λ, compared with intravenous administration. Transdermal application in guinea pigs showed low maximum concentrations of 8.6 ng/mL at 38.4 h after administration. Compared with transdermal application, oral administration resulted in higher Cmax and AUC and lower Tmax.

The maximum plasma concentration of both doses of CBD in guinea pigs was relatively low compared with other species after oral administration. Mice administered oral CBD at 20 mg/kg had a Cmax of 129.5 ng/mL at 2 h post- administration (Xu et al., 2019). Cats administered 2 mg/kg of CBD/CBDA-infused fish oil demonstrated similar peak plasma concentrations (43 ng/mL) to guinea pigs receiving a 25 mg/kg dose of CBD oil (Deabold et al., 2019). Dogs have also been shown to have much higher maximum concentrations at significantly lower doses of CBD administered orally. With doses ranging from 1–20 mg/kg, peak plasma concentrations reached 102.3–845.5 ng/mL within 1.5–2.5 h in dogs (Bartner et al., 2018; Deabold et al., 2019; Gamble et al., 2018; Wakshlag et al., 2020). Based on these data, although the therapeutic concentration of CBD is unknown, guinea pigs likely need higher doses and increased frequency of dosing of oral CBD to reach adequate plasma concentrations for therapeutic efficacy. Additionally, it should be noted that horses have shown similarly poor absorption rates of CBD to guinea pigs (Ryan et al., 2021), suggesting hindgut-fermenting species may require unique dosing considerations for oral cannabinoid administration.

Cannabidiol was also detected in both the cartilage and the IFP of the stifle joint, which suggests CBD has the potential to directly exert effects within the joint. Although the dose was positively correlated with the concentration of CBD within the IFP, this was not observed in the cartilage. This is likely due to the avascular nature of cartilage, as well as CBD’s high lipophilicity and preferential accumulation in lipid-rich tissues (Fasinu et al., 2016).

Administration of CBD oil as a single 25 or 50 mg/kg dose produced no adverse effects in guinea pigs. Behavior and activity parameters did not significantly differ from baseline timepoints after CBD administration. Additionally, there were no clinically significant differences in CBC or serum biochemistry parameters after CBD dosing. Studies in dogs have reported increases in alkaline phosphatase (ALP), an indicator of hepatobiliary disease, with repeated administration of CBD (Gamble et al., 2018; McGrath et al., 2018, 2019). Additional studies are still needed in guinea pigs to evaluate long-term safety after repeated dosing.

It is important to note that this study only evaluated pharmacokinetics in male guinea pigs. Due to differences in muscle mass and fat tissue distribution between males and females, pharmacokinetics of CBD may differ between sexes (Fattore & Fratta, 2010). Additionally, isoflurane anesthesia was used to perform a small number of the blood collections in this study, and it is unknown how this impacts the pharmacokinetic parameters of CBD. Further studies would be necessary to determine whether isoflurane anesthesia affects the pharmacokinetics of oral CBD.

The results of this study provide preliminary data for the use of CBD for OA in guinea pigs. This study demonstrated that CBD is absorbed orally and reaches measurable concentrations within the stifle joint tissues in male guinea pigs. Due to low maximum plasma concentrations compared with other species, higher doses and increased frequency of dosing is likely needed to achieve therapeutic efficacy. Further studies are still needed to determine long-term safety, therapeutic doses, and the efficacy of CBD for the treatment of OA in both male and female guinea pigs.

ACKNOWLEDGEMENTS

The authors would like to thank Jordyn Becker and Cassie Seebart for their assistance with data collection. Additionally, we would like to thank the Colorado State University Department of Laboratory Animal Resources for their care of the animals used in this study. This work was supported by the Department of Clinical Sciences at Colorado State University’s College of Veterinary Medicine and Biomedical Sciences. Dr. Spittler was supported by a COHA Translational Fellowship funded by U01 TR002953.

Footnotes

CONFLICT OF INTEREST

The authors declare that they have no conflicts of interest that could influence the work reported in this paper.

ANIMAL WELFARE AND ETHICS STATEMENT

The authors confirm that the ethical policies of the journal have been adhered to. All animal procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals. This study underwent ethical review and was approved by the Colorado State University Institutional Animal Care and Use Committee.

DATA AVAILABILITY STATEMENT

The authors confirm that the data supporting the findings of this study are available within the article.

REFERENCES

  1. Bartner LR, McGrath S, Rao S, Hyatt LK, & Wittenburg LA (2018). Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Canadian Journal of Veterinary Research, 82(3), 178–183. [PMC free article] [PubMed] [Google Scholar]
  2. Bays TB (2020). Geriatric care of rabbits, guinea pigs, and chinchillas. Veterinary Clinics of North America: Exotic Animal Practice, 23(3), 567–593. 10.1016/j.cvex.2020.05.006 [DOI] [PubMed] [Google Scholar]
  3. Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, & Giagnoni G (2004). Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn-Schmiedeberg’s Archives of Pharmacology, 369(3), 294–299. 10.1007/s00210-004-0871-3 [DOI] [PubMed] [Google Scholar]
  4. Costa B, Trovato AE, Comelli F, Giagnoni G, & Colleoni M (2007). The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. European Journal of Pharmacology, 556(1), 75–83. 10.1016/j.ejphar.2006.11.006 [DOI] [PubMed] [Google Scholar]
  5. Deabold KA, Schwark WS, Wolf L, & Wakshlag JJ (2019). Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats. Animals, 9(10), 832. 10.3390/ani9100832 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fasinu PS, Phillips S, ElSohly MA, & Walker LA (2016). Current status and prospects for cannabidiol preparations as new therapeutic agents. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 36(7), 781–796. 10.1002/phar.1780 [DOI] [PubMed] [Google Scholar]
  7. Fattore L, & Fratta W (2010). How important are sex differences in cannabinoid action? British Journal of Pharmacology, 160(3), 544–548. 10.1111/j.1476-5381.2010.00776.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gamble L-J, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L, Brown H, Berthelsen ES, & Wakshlag JJ (2018). Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Frontiers in Veterinary Science, 5. 165. 10.3389/fvets.2018.00165 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hammell DC, Zhang LP, Ma F, Abshire SM, McIlwrath SL, Stinchcomb AL, & Westlund KN (2016). Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. European Journal of Pain (London, England), 20(6), 936–948. 10.1002/ejp.818 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kogan L, Hellyer P, & Downing R (2020). The use of cannabidiol-rich hemp oil extract to treat canine osteoarthritis-related pain: A pilot study. Journal of the American Holistic Veterinary Medical Association, 58, 35–45. [Google Scholar]
  11. Kogan LR, Hellyer PW, & Robinson NG (2016). Consumers’ perceptions of hemp products for animals. Journal of the American Holistic Veterinary Medical Association, 42, 40–48. [Google Scholar]
  12. Landa L, Sulcova A, & Gbelec P (2016). The use of cannabinoids in animals and therapeutic implications for veterinary medicine: A review. Veterinární Medicína, 61(3), 111–122. 10.17221/8762-VETMED [DOI] [Google Scholar]
  13. Long LE, Chesworth R, Huang X-F, Wong A, Spiro A, McGregor IS, Arnold JC, & Karl T (2012). Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. PLoS ONE, 7(4), e34129. 10.1371/journal.pone.0034129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, & Feldmann M (2000). The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proceedings of the National Academy of Sciences of the United States of America, 97(17), 9561–9566. 10.1073/pnas.160105897 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Martello E, Bigliati M, Bisanzio D, Biasibetti E, Dosio F, Pastorino D, De-Nardi M, & Bruni N (2019). Effects on pain and mobility of a new diet supplement in dogs with osteoarthritis: A pilot study. Annals of Clinical and Laboratory Research, 7(2), 304. [Google Scholar]
  16. McGrath S, Bartner LR, Rao S, Kogan LR, & Hellyer PW (2018). A report of adverse effects associated with the administration of cannabidiol in healthy dogs. Journal of the American Holistic Veterinary Medical Association, 52, 34–38. [Google Scholar]
  17. McGrath S, Bartner LR, Rao S, Packer RA, & Gustafson DL (2019). 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. Journal of the American Veterinary Medical Association, 254(11), 1301–1308. 10.2460/javma.254.11.1301 [DOI] [PubMed] [Google Scholar]
  18. Mejia S, Duerr FM, Griffenhagen G, & McGrath S (2021). Evaluation of the effect of cannabidiol on naturally occurring osteoarthritis-associated pain: A pilot study in dogs. Journal of the American Animal Hospital Association, 57, 2. 10.5326/JAAHA-MS-7119 [DOI] [PubMed] [Google Scholar]
  19. Millar SA, Stone NL, Yates AS, & O’Sullivan SE (2018). A systematic review on the pharmacokinetics of cannabidiol in humans. Frontiers in Pharmacology, 9, 1365. 10.3389/fphar.2018.01365 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Minarikova A, Hauptman K, Jeklova E, Knotek Z, & Jekl V (2015). Diseases in pet guinea pigs: A retrospective study in 1000 animals. Veterinary Record, 177(8), 200. 10.1136/vr.103053 [DOI] [PubMed] [Google Scholar]
  21. O’Brien M, & McDougall JJ (2018). Cannabis and joints: Scientific evidence for the alleviation of osteoarthritis pain by cannabinoids. Current Opinion in Pharmacology, 40, 104–109. 10.1016/j.coph.2018.03.012 [DOI] [PubMed] [Google Scholar]
  22. Oliver VL, Athavale S, Simon KE, Kendall LV, Nemzek JA, & Lofgren JL (2017). Evaluation of pain assessment techniques and analgesia efficacy in a female Guinea Pig (Cavia porcellus) model of surgical pain. Journal of the American Association for Laboratory Animal Science, 56(4), 425–435. [PMC free article] [PubMed] [Google Scholar]
  23. Papich MG (2008). An update on nonsteroidal anti-inflammatory drugs (NSAIDs) in small animals. Veterinary Clinics of North America: Small Animal Practice, 38(6), 1243–1266. 10.1016/j.cvsm.2008.09.002 [DOI] [PubMed] [Google Scholar]
  24. Paudel KS, Hammell DC, Agu RU, Valiveti S, & Stinchcomb AL (2010). Cannabidiol bioavailability after nasal and transdermal application: Effect of permeation enhancers. Drug Development and Industrial Pharmacy, 36(9), 1088–1097. 10.3109/03639041003657295 [DOI] [PubMed] [Google Scholar]
  25. Philpott HT, O’Brien M, & McDougall JJ (2017). Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain, 158(12), 2442–2451. 10.1097/j.pain.0000000000001052 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ryan D, McKemie DS, Kass PH, Puschner B, & Knych HK (2021). Pharmacokinetics and effects on arachidonic acid metabolism of low doses of cannabidiol following oral administration to horses. Drug Testing and Analysis, 13, 1305–1317. 10.1002/dta.3028 [DOI] [PubMed] [Google Scholar]
  27. Santangelo KS, Kaeding AC, Baker SA, & Bertone AL (2014). Quantitative gait analysis detects significant differences in movement between osteoarthritic and nonosteoarthritic guinea pig strains before and after treatment with Flunixin Meglumine. Arthritis, 2014, 1–8. 10.1155/2014/503519 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Smith BJ, Wegenast DJ, Hansen RJ, Hess AM, & Kendall LV (2016). Pharmacokinetics and Paw withdrawal pressure in female Guinea Pigs (Cavia porcellus) treated with sustained-release buprenorphine and buprenorphine hydrochloride. Journal of the American Association for Laboratory Animal Science, 55(6), 789–793. [PMC free article] [PubMed] [Google Scholar]
  29. Sumariwalla PF, Gallily R, Tchilibon S, Fride E, Mechoulam R, & Feldmann M (2004). A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis. Arthritis & Rheumatism, 50(3), 985–998. 10.1002/art.20050 [DOI] [PubMed] [Google Scholar]
  30. Verrico CD, Wesson S, Konduri V, Hofferek CJ, Vazquez-Perez J, Blair E, Dunner K, Salimpour P, Decker WK, & Halpert MM (2020). A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. Pain, 161(9), 2191–2202. 10.1097/j.pain.0000000000001896 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wagner JG (1993). Noncompartmental and system analysis. Pharmacokinetics for the Pharmaceutical Scientist (pp. 83–102). Technomic Publishing Company Inc. [Google Scholar]
  32. Wakshlag JJ, Schwark WS, Deabold KA, Talsma BN, Cital S, Lyubimov A, Iqbal A, & Zakharov A (2020). Pharmacokinetics of cannabidiol, cannabidiolic acid, Δ9-tetrahydrocannabinol, tetrahydrocannabinolic acid and related metabolites in canine serum after dosing with three oral forms of hemp extract. Frontiers in Veterinary Science, 7, 505. 10.3389/fvets.2020.00505 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Xu C, Chang T, Du Y, Yu C, Tan X, & Li X (2019). Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model. Environmental Toxicology and Pharmacology, 70, 103202. 10.1016/j.etap.2019.103202 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The authors confirm that the data supporting the findings of this study are available within the article.

RESOURCES