Drug Metab Dispos / May-Jun 1988;16(3):469-72 / Pharmacokinetics of cannabidiol in dogs / E Samara 1, M Bialer, R Mechoulam / Affiliations expand / PMID: 2900742
Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Recent studies have shown that CBD has a high protective index, comparable to that of phenobarbital and phenytoin. Because CBD has been reported to possess both anticonvulsant and antiepileptic activity, its pharmacokinetics were studied in dogs after the administration of two iv doses (45 and 90 mg) and one oral dose (180 mg) to dogs.
After iv administration, CBD was rapidly distributed, followed by a prolonged elimination. It has a terminal half-life of 9 hr. CBD plasma levels declined in a triphasic fashion. The total body clearance of CBD was 17 liters/hr (after the 45-mg dose) and 16 liters/hr (after the 90-mg dose). This clearance value, after its normalization to blood clearance using mathematical equations, approaches the value of the hepatic blood flow; the extraction ratio in the liver is 0.74. CBD was observed to have a large volume of distribution, approximately 100 liters. In the dose range of 45 to 90 mg, the increase in the AUC was proportional to the dose, a fact that indicates that the pharmacokinetic profile of CBD in this dose range was not dose dependent. In three of the six dogs studied, CBD could not be detected in the plasma after oral administration. In the other three, the oral bioavailability ranged from 13 to 19%. The results of this study show that CBD is barely absorbed after oral administration to dogs. This low bioavailability may be due to a first pass effect.
Front Vet Sci / 2018 Jul 23;5:165. doi: 10.3389/fvets.2018.00165. eCollection 2018. / Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs / Lauri-Jo Gamble 1, Jordyn M Boesch 1, Christopher W Frye 1, Wayne S Schwark 2, Sabine Mann 3, Lisa Wolfe 4, Holly Brown 5, Erin S Berthelsen 1, Joseph J Wakshlag 1 / Affiliations expand / PMID: 30083539 PMCID: PMC6065210 DOI: 10.3389/fvets.2018.00165
Objectives: The objectives of this study were to determine basic oral pharmacokinetics, and assess safety and analgesic efficacy of a cannabidiol (CBD) based oil in dogs with osteoarthritis (OA).
Methods: Single-dose pharmacokinetics was performed using two different doses of CBD enriched (2 and 8 mg/kg) oil. Thereafter, a randomized placebo-controlled, veterinarian, and owner blinded, cross-over study was conducted. Dogs received each of two treatments: CBD oil (2 mg/kg) or placebo oil every 12 h. Each treatment lasted for 4 weeks with a 2-week washout period. Baseline veterinary assessment and owner questionnaires were completed before initiating each treatment and at weeks 2 and 4. Hematology, serum chemistry and physical examinations were performed at each visit. A mixed model analysis, analyzing the change from enrollment baseline for all other time points was utilized for all variables of interest, with a p ≤ 0.05 defined as significant. Results: Pharmacokinetics revealed an elimination half-life of 4.2 h at both doses and no observable side effects. Clinically, canine brief pain inventory and Hudson activity scores showed a significant decrease in pain and increase in activity (p < 0.01) with CBD oil. Veterinary assessment showed decreased pain during CBD treatment (p < 0.02). No side effects were reported by owners, however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment (p < 0.01). Clinical significance: This pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and activity in dogs with OA.
Science Newsfrom research organizations /CBD clinical trial results on seizure frequency in dogs 'encouraging' / Date:May 21, 2019 / Source:Colorado State University
Summary:Scientists have found in a small study that 89 percent of dogs who received CBD in the clinical trial had a reduction in the frequency of seizures. Nine dogs were treated with CBD, while seven in a control group were treated with a placebo.See the study
Animals (Basel) / 2020 Aug 26;10(9):1505. doi: 10.3390/ani10091505. 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 / Federica Alessandra Brioschi 1, Federica Di Cesare 2, Daniela Gioeni 1, Vanessa Rabbogliatti 3, Francesco Ferrari 3, Elisa Silvia D'Urso 4, Martina Amari 3, Giuliano Ravasio 1 / Affiliations expand / PMID: 32858828 PMCID: PMC7552307 DOI: 10.3390/ani10091505
The aim of this study was to evaluate the efficacy of oral transmucosal (OTM) cannabidiol (CBD), in addition to a multimodal pharmacological treatment for chronic osteoarthritis-related pain in dogs.
Twenty-one dogs were randomly divided into two groups: in group CBD (n = 9), OTM CBD (2 mg kg-1 every 12 h) was included in the therapeutic protocol (anti-inflammatory drug, gabapentin, amitriptyline), while in group C (n = 12), CBD was not administered. Dogs were evaluated by owners based on the Canine Brief Pain Inventory scoring system before treatment initiation (T0), and one (T1), two (T2), four (T3) and twelve (T4) weeks thereafter. Pain Severity Score was significantly lower in CBD than in C group at T1 (p = 0.0002), T2 (p = 0.0043) and T3 (p = 0.016). Pain Interference Score was significantly lower in CBD than in C group at T1 (p = 0.0002), T2 (p = 0.0007) and T4 (p = 0.004). Quality of Life Index was significantly higher in CBD group at T1 (p = 0.003). The addition of OTM CBD showed promising results. Further pharmacokinetics and long-term studies in larger populations are needed to encourage its inclusion into a multimodal pharmacological approach for canine osteoarthritis-related pain.
Animals (Basel). 2021 Mar; 11(3): 892. Published online 2021 Mar 20. doi: / 10.3390/ani11030892 / PMCID: PMC8003882PMID: 33804793 / Cannabis, Cannabidiol Oils and Tetrahydrocannabinol—What Do Veterinarians Need to Know? / Nancy De Briyne,1,* Danny Holmes,2 Ian Sandler,3 Enid Stiles,3 Dharati Szymanski,4 Sarah Moody,1 Stephan Neumann,5 and Arturo Anadón6 / Luis Antunes, Academic Editor
As cannabis-derived products have become more available, veterinarians are seeing more cases of toxicosis. In addition, animal owners are having an increasing interest in using these products for their pets.
This review looks at the situation in Europe and North America, the different types of cannabis and cannabis-derived products with historical examples of use in animals, and the cannabis industry. The existing regulatory framework for use in humans and animals as medicines and/or supplements was examined. Finally, a review of the clinical indications for which medicinal cannabis is authorised, a discussion of toxicosis, and recommendations and warnings around medical cannabis use are presented.
Am J Vet Res / . 2021 May;82(5):405-416. doi: 10.2460/ajvr.82.5.405. / Randomized, placebo-controlled, 28-day safety and pharmacokinetics evaluation of repeated oral cannabidiol administration in healthy dogs / Dana M Vaughn, Lina J Paulionis, Justyna E Kulpa / PMID: 33904801 DOI: 10.2460/ajvr.82.5.405
Objective: To determine the safety and pharmacokinetics of various doses of plant-derived cannabidiol (CBD) versus placebo following repeated oral administration. Animals: 20 healthy adult Beagles.
Procedures: In a randomized, blinded, placebo-controlled trial, dogs were randomized to 5 groups balanced in body weight and sex (n = 4 dogs/group) and received a CBD (1, 2, 4, or 12 mg/kg; from cannabis extract) or placebo oil formulation PO once daily for 28 days. Outcome variables were assessed through daily health observations, veterinary examinations, CBC, and serum biochemical analysis. Blood samples were collected at various time points to estimate 24-hour pharmacokinetic profiles of CBD and selected metabolites (7-carboxy-CBD and 7-hydroxy-CBD). Results: Repeated CBD administration was well tolerated by dogs, with no clinically important changes in measured safety outcomes. Veterinary examinations revealed no clinically important abnormal findings. Adverse events were mild in severity. Relative to placebo administration, CBD administration at 12 mg/kg/d resulted in more gastrointestinal adverse events (mainly hypersalivation) and significantly higher serum alkaline phosphatase activity. Total systemic exposure to CBD increased on a dose-dependent basis following both acute (first dose) and chronic (28 days) administration. Within each CBD dose group, repeated administration increased total systemic exposure to CBD 1.6- to 3.3-fold. The 24-hour trough plasma CBD concentrations were also dose dependent, with a steady state reached following 2 weeks of administration. Conclusions and clinical relevance: Repeated, daily oral administration of the CBD formulation led to dose-dependent increases in total systemic exposure to CBD and 24-hour trough plasma concentrations in healthy dogs. These findings could help guide dose selection.
Front Vet Sci / . 2021 Apr 29;8:645667. doi: 10.3389/fvets.2021.645667. eCollection 2021. / Feeding Cannabidiol (CBD)-Containing Treats Did Not Affect Canine Daily Voluntary Activity / Elizabeth M Morris 1, Susanna E Kitts-Morgan 2, Dawn M Spangler 2, Jessica Gebert 2, Eric S Vanzant 1, Kyle R McLeod 1, David L Harmon 1 / Affiliations expand / PMID: 33996972 PMCID: PMC8118201 DOI: 10.3389/fvets.2021.645667
Growing public interest in the use of cannabidiol (CBD) for companion animals has amplified the need to elucidate potential impacts. The purpose of this investigation was to determine the influence of CBD on the daily activity of adult dogs.
Twenty-four dogs (18.0 ± 3.4 kg, 9 months-4 years old) of various mixed breeds were utilized in a randomized complete block design with treatments targeted at 0 and 2.5 mg (LOW) and at 5.0 mg (HIGH) CBD/kg body weight (BW) per day split between two treats administered after twice-daily exercise (0700-0900 and 1,700-1,900 h). Four hours each day [1,000-1,200 h (a.m.) and 1,330-1,530 h (p.m.)] were designated as times when no people entered the kennels, with 2 h designated as Quiet time and the other 2 h as Music time, when calming music played over speakers. Quiet and Music sessions were randomly allotted to daily a.m. or p.m. times. Activity monitors were fitted to dogs' collars for continuous collection of activity data. Data were collected over a 14-day baseline period to establish the activity patterns and block dogs by activity level (high or low) before randomly assigning dogs within each block to treatments. After 7 days of treatment acclimation, activity data were collected for 14 days. Data were examined for differences using the MIXED procedure in SAS including effects of treatment, day, session (Quiet or Music), time of day (a.m. or p.m.), and accompanying interactions. CBD (LOW and HIGH) did not alter the total daily activity points (P = 0.985) or activity duration (P = 0.882). CBD tended (P = 0.071) to reduce total daily scratching compared with the control. Dogs were more active in p.m. sessions than in a.m. sessions (P < 0.001). During the p.m. session, dogs receiving HIGH tended (P = 0.091) to be less active than the control (CON). During the a.m. and p.m. sessions, CBD reduced scratching compared with CON (P = 0.030). CBD did not affect the activity duration during exercise periods (P = 0.143). These results indicate that, when supplemented with up to 4.5 mg CBD/kg BW/day, CBD does not impact the daily activity of adult dogs, but may exert an antipruritic effect.
Front Vet Sci. 2020; 7: 569565. Published online 2020 Sep 22. doi: 10.3389/fvets.2020.569565 / PMCID: PMC7537661PMID: 33195551 / The Impact of Feeding Cannabidiol (CBD) Containing Treats on Canine Response to a Noise-Induced Fear Response Test / Elizabeth M. Morris,1 Susanna E. Kitts-Morgan,2 Dawn M. Spangler,2 Kyle R. McLeod,1 Joao H. C. Costa,1 and David L. Harmon1,*
Interest is increasing regarding use of Cannabidiol (CBD) in companion animals due to anecdotal evidence of beneficial behavioral and health effects. The purpose of this investigation was to evaluate the influence of CBD on behavioral responses to fear-inducing stimuli in dogs.
Sixteen dogs (18.1 ± 0.2 kg) were utilized in a replicated 4 × 4 Latin square design experiment with treatments arranged in a 2 × 2 factorial, consisting of control, 25 mg CBD, trazodone (100 mg for 10–20 kg BW, 200 mg for 20.1–40 kg BW), and the combination of CBD and trazodone. A fireworks model of noise-induced fear was used to assess CBD effectiveness after 7 d of supplementation. Each test lasted a total of 6 min and consisted of a 3 min environmental habituation phase with no noise and a 3 min noise phase with a fireworks track. Plasma was collected 1 h before, immediately after, and 1 h following testing for cortisol analysis. Behaviors in each 3 min block were video recorded, and heart rate (HR) sensors were fitted for collection of HR and HR variability parameters. Research personnel administering treats and analyzing behavioral data were blinded as to the treatments administered. Data were tested for normality using the UNIVARIATE procedure in SAS, then differences examined using the MIXED procedure with fixed effects of treatment, period, time, and treatment x time interaction. Inactivity duration and HR increased during the first minute of the fireworks track compared with 1 min prior (P < 0.001 and P = 0.011, respectively), indicating the fireworks model successfully generated a fear response. Trazodone lowered plasma cortisol (P < 0.001), which was unaffected by CBD (P = 0.104) or the combination with CBD (P = 0.238). Neither CBD nor trazodone affected the duration of inactivity (P = 0.918 and 0.329, respectively). Trazodone increased time spent with tail relaxed (P = 0.001). CBD tended to increase HR (P = 0.093) and decreased the peak of low- and high-frequency bands (LF and HF, P = 0.011 and 0.022, respectively). These results do not support an anxiolytic effect of CBD in dogs given 1.4 mg CBD/kg BW/d.
Can Vet J / . 2022 Apr;63(4):423-426. / Effects of cannabidiol without delta-9-tetrahydrocannabinol on canine atopic dermatitis: A retrospective assessment of 8 cases / Chie Mogi 1, Masanori Yoshida 1, Koji Kawano 1, Takaaki Fukuyama 1, Toshiro Arai 1 / Affiliations expand / PMID: 35368394 PMCID: PMC8922375 (available on 2022-07-01)
Objective: We aimed to examine the effects of cannabidiol (CBD)-containing hemp oil without delta-9-tetrahydrocannabinol (THC) as a supplemental treatment for canine atopic dermatitis (CAD), as well as its adverse effects, and effects on concurrent drug use in dogs.
Animal: In this retrospective case series, 8 dogs with CAD were diagnosed by veterinary dermatologists certified by the Japanese Society of Veterinary Dermatology. Procedure: The medical records of dogs supplemented with CBD-containing hemp oil were evaluated with respect to signalment, physical examination, plasma C-reactive protein concentrations, pharmacologic management, the CAD Extent and Severity Index (4th iteration), and the Pruritus Visual Analog Scale. Results: Overall, CBD, used as a supplement in combination with other drugs, was well-tolerated over a wide dose range and decreased the occurrence of pruritus in dogs with CAD when ingested twice a day. Conclusion: This study provides the first report of supplementation with CBD without THC that was effective in controlling pruritic behavior in dogs with CAD. Clinical relevance: Further controlled studies are required to investigate the dose range, efficacy, and safety. Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.
Animals (Basel) / . 2019 Oct 19;9(10):832. doi: 10.3390/ani9100832. / Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats / Kelly A Deabold 1, Wayne S Schwark 2, Lisa Wolf 3, Joseph J Wakshlag 4 / Affiliations expand / PMID: 31635105 PMCID: PMC6826847 DOI: 10.3390/ani9100832
The use of CBD-rich hemp products is becoming popular among pet owners with no long-term safety data related to consumption in adult dogs and cats. The purpose of this study was to determine the single-dose oral pharmacokinetics of CBD, and to provide a preliminary assessment of safety and adverse effects during 12-week administration using a hemp-based product in healthy dogs and cats.
Eight of each species were provided a 2 mg/kg total CBD concentration orally twice daily for 12 weeks with screening of single-dose pharmacokinetics in six of each species. Pharmacokinetics revealed a mean maximum concentration (Cmax) of 301 ng/mL and 43 ng/mL, area under the curve (AUC) of 1297 ng-h/mL and 164 ng-h/mL, and time to maximal concentration (Tmax) of 1.4 h and 2 h, for dogs and cats, respectively. Serum chemistry and CBC results showed no clinically significant alterations, however one cat showed a persistent rise in alanine aminotransferase (ALT) above the reference range for the duration of the trial. In healthy dogs and cats, an oral CBD-rich hemp supplement administered every 12 h was not detrimental based on CBC or biochemistry values. Cats do appear to absorb or eliminate CBD differently than dogs, showing lower serum concentrations and adverse effects of excessive licking and head-shaking during oil administration.
Res Vet Sci / . 2021 Nov;140:38-46. doi: 10.1016/j.rvsc.2021.08.001. Epub 2021 Aug 8. / Cannabidiol-based natural health products for companion animals: Recent advances in the management of anxiety, pain, and inflammation / Cindy H J Yu 1, H P Vasantha Rupasinghe 2 / Affiliations expand / PMID: 34391060 DOI: 10.1016/j.rvsc.2021.08.001
Recent advances in cannabidiol (CBD) use in canines and felines for anxiety management, pain management, and anti-inflammatory effects were reviewed using a literature search conducted with the following keywords: CBD, anxiety, inflammation, pain, dogs, cats, and companion animals. For decades, research on CBD has been hindered due to the status of cannabis (C. sativa L.) as an illicit drug. Limited safety data show that CBD is well-tolerated in dogs, with insufficient information on the safety profile of CBD in cats.
Upon oral supplementation of CBD, elevation in liver enzymes was observed for both dogs and cats, and pharmacokinetics of CBD are different in the two species. There is a significant gap in the literature on the therapeutic use of CBD in cats, with no feline data on anxiety, pain, and inflammation management. There is evidence that chronic osteoarthritic pain in dogs can be reduced by supplementation with CBD. Furthermore, experiments are required to better understand whether CBD has an influence on noise-induced fear and anxiolytic response. Preliminary evidence exists to support the analgesic properties of CBD in treating chronic canine osteoarthritis; however, there are inter- and intra-species differences in pharmacokinetics, tolerance, dosage, and safety of CBD. Therefore, to validate the anxiety management, pain management, and anti-inflammatory efficacy of CBD, it is essential to conduct systematic, randomized, and controlled trials. Further, the safety and efficacious dose of CBD in companion animals warrants investigation.
Front Vet Sci / . 2022 Apr 28;9:892306. doi: 10.3389/fvets.2022.892306. eCollection 2022. / A Case Report of Subcutaneously Injected Liposomal Cannabidiol Formulation Used as a Compassion Therapy for Pain Management in a Dog / Yael Shilo-Benjamini 1 2, Ahuva Cern 1, Daniel Zilbersheid 1, Atara Hod 1, Eran Lavy 2, Dinorah Barasch 3, Yechezkel Barenholz 1 / Affiliations expand / PMID: 35573415 PMCID: PMC9097221 DOI: 10.3389/fvets.2022.892306
A 14-year-old intact mixed breed dog (26 kg) was submitted for a novel cannabidiol (CBD) analgesic treatment. The dog was cachectic and had a testicular neoplasia, hip and elbow osteoarthritis and severe cervical pain. Analgesic treatment included canine osteoarthritic supplement, robencoxib and gabapentin.
An additional liposomal CBD injectable formulation at 5 mg/kg was administered subcutaneously between the shoulder blades. The dog was monitored using an activity monitoring collar (PetPace), owner wellbeing questionnaire (Canine Brief Pain Inventory; CBPI), pain interactive visual analog scale (iVAS), blood work and CBD plasma concentrations. A week from the injection and up to 3 weeks afterwards the dog had improved CBPI and iVAS pain scores, and increased collar activity scores. CBD was quantified in plasma for 28 days. Due to disease progression, further difficulty to rise and walk, and relapse to pain after 3 weeks, the owners requested a second liposomal CBD injection, which was performed 4 weeks following the first injection using 3 mg/kg dose. Two days later, the dog was found dead in the yard under direct sun, while environmental temperature was 37°C. Major findings on necropsy revealed evidence of heat stroke and severe cervical disc protrusion with spinal hematoma, none related to liposomal CBD. In conclusion, subcutaneous liposomal CBD produced quantifiable CBD plasma concentrations for 28 days and may be an effective additional treatment as part of multimodal pain management in dogs.
Sci Rep / . 2022 Mar 7;12(1):3683. doi: 10.1038/s41598-022-07795-z. / Short term feeding of industrial hemp with a high cannabidiolic acid (CBDA) content increases lying behavior and reduces biomarkers of stress and inflammation in Holstein steers / Michael D Kleinhenz 1, Mikaela Weeder 2, Shawnee Montgomery 3, Miriam Martin 3, Andrew Curtis 3, Geraldine Magnin 3 4, Zhoumeng Lin 3 4 5, Jason Griffin 6, Johann F Coetzee 7 8 / Affiliations expand / PMID: 35256692 PMCID: PMC8901777 DOI: 10.1038/s41598-022-07795-z
Industrial hemp (IH) is defined as Cannabis sativa containing < 0.3% delta-9 tetrahydrocannabinol (THC) and was legalized in the 2018 Farm Bill. The impact of cannabinoids in IH fed to livestock, especially after repeat exposure, has not been thoroughly investigated. Sixteen male castrated Holstein cattle weighting (± SD) 447 ± 68 kg were enrolled onto the study.
Cattle were allocated into two treatment groups either receiving IH (HEMP, n = 8) or a control (CNTL, n = 8). Cattle in the HEMP group were fed 25 g IH mixed in 200 g of grain once a day for 14 days to target a daily dose of 5.5 mg/kg of cannabidiolic acid (CBDA). Behavior was continuously monitored with accelerometers and blood samples were collected at predetermined time points for plasma cannabinoid, serum cortisol, serum haptoglobin, liver enzymes, serum amyloid A, and prostaglandin E2 concentrations. The HEMP group spent a mean 14.1 h/d (95% CI 13.6-14.6 h/d) lying compared to the 13.4 h/d (95% CI 12.9-13.8 h/d) for the CNTL cattle (P = 0.03). Cortisol concentrations in the HEMP group were lower than the CNTL group (P = 0.001). Cattle in the HEMP group demonstrated an 8.8% reduction in prostaglandin E2 concentrations from baseline compared to a 10.2% increase from baseline observed in the CNTL group. No differences for haptoglobin or serum amyloid A were observed. These results suggest that feeding IH with a high CBDA content for 14 days increases lying behavior and decreases biomarkers of stress and inflammation in cattle.
Randomized Controlled Trial Pain / . 2020 Sep 1;161(9):2191-2202. doi: 10.1097/j.pain.0000000000001896. / A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain / Chris D Verrico 1 2, Shonda Wesson 3, Vanaja Konduri 4, Colby J Hofferek 4, Jonathan Vazquez-Perez 4, Emek Blair 5, Kenneth Dunner Jr 6, Pedram Salimpour 7, William K Decker 4 8 9, Matthew M Halpert 4 / Affiliations expand / PMID: 32345916 PMCID: PMC7584779 DOI: 10.1097/j.pain.0000000000001896
Over the last 2 decades, affirmative diagnoses of osteoarthritis (OA) in the United States have tripled due to increasing rates of obesity and an aging population. Hemp-derived cannabidiol (CBD) is the major nontetrahydrocannabinol component of cannabis and has been promoted as a potential treatment for a wide variety of disparate inflammatory conditions.
Here, we evaluated CBD for its ability to modulate the production of proinflammatory cytokines in vitro and in murine models of induced inflammation and further validated the ability of a liposomal formulation to increase bioavailability in mice and in humans. Subsequently, the therapeutic potential of both naked and liposomally encapsulated CBD was explored in a 4-week, randomized placebo-controlled, double-blinded study in a spontaneous canine model of OA. In vitro and in mouse models, CBD significantly attenuated the production of proinflammatory cytokines IL-6 and TNF-α while elevating levels of anti-inflammatory IL-10. In the veterinary study, CBD significantly decreased pain and increased mobility in a dose-dependent fashion among animals with an affirmative diagnosis of OA. Liposomal CBD (20 mg/day) was as effective as the highest dose of nonliposomal CBD (50 mg/day) in improving clinical outcomes. Hematocrit, comprehensive metabolic profile, and clinical chemistry indicated no significant detrimental impact of CBD administration over the 4-week analysis period. This study supports the safety and therapeutic potential of hemp-derived CBD for relieving arthritic pain and suggests follow-up investigations in humans are warranted.
Front Vet Sci / . 2022 Jan 24;9:789495. doi: 10.3389/fvets.2022.789495. eCollection 2022. / Plasma Pharmacokinetics of Cannabidiol Following Oral Administration of Cannabidiol Oil to Dairy Calves / Kelsey Meyer 1, Kristen Hayman 1, James Baumgartner 2, Patrick J Gorden 1 / Affiliations expand / PMID: 35141311 PMCID: PMC8818876 DOI: 10.3389/fvets.2022.789495
Cannabidiol (CBD), the non-psychotropic component of cannabis, has drawn increased interest amongst some medical professionals for its potential therapeutic effects. Human and canine work has been done to describe CBD where it is already widely used, however, little is known about the effects of CBD in livestock species.
The purpose of this descriptive study was to determine the pharmacokinetics (PK) of CBD in calves after a single oral exposure to CBD oil. Seven male Holstein calves received a single oral dose of 25 mg/mL CBD oil to achieve 5 mg/kg dose of CBD. Blood samples were collected for 48 (h) after dosing. The CBD geometric mean maximum concentration of 0.05 ug/mL was reached 7.5 h after administration. The geometric mean half-life was 23.02 h. Cannabidiol administered orally to cattle is slowly absorbed and has an extended elimination half-life compared to other species.
Front Vet Sci / . 2020 Feb 11;7:51. doi: 10.3389/fvets.2020.00051. eCollection 2020. / Preliminary Investigation of the Safety of Escalating Cannabinoid Doses in Healthy Dogs / Dana Vaughn 1, Justyna Kulpa 1, Lina Paulionis 1 / Affiliations expand / PMID: 32118071 PMCID: PMC7029731 DOI: 10.3389/fvets.2020.00051
Objective: To determine the safety and tolerability of escalating doses of three cannabis oil formulations, containing predominantly CBD, THC, or CBD and THC (1.5:1) vs. placebo in dogs. Design: Randomized, placebo-controlled, blinded, parallel study.
Animals: Twenty healthy Beagle dogs (10 males, 10 females). Methods: Dogs were randomly assigned to one of five treatment groups (n = 4 dogs per group balanced by sex): CBD-predominant oil, THC-predominant oil, CBD/THC-predominant oil (1.5:1), sunflower oil placebo, medium-chain triglyceride oil placebo. Up to 10 escalating doses of the oils were planned for administration via oral gavage, with at least 3 days separating doses. Clinical observations, physical examinations, complete blood counts, clinical chemistry, and plasma cannabinoids were used to assess safety, tolerability, and the occurrence of adverse events (AEs). AEs were rated as mild, moderate, or severe/medically significant. Results: Dose escalation of the CBD-predominant oil formulation was shown to be as safe as placebo and safer than dose escalation of oils containing THC (CBD/THC oil or THC oil). The placebo oils were delivered up to 10 escalating volumes, the CBD oil up to the tenth dose (640.5 mg; ~62 mg/kg), the THC oil up to the tenth dose (597.6 mg; ~49 mg/kg), and the CBD/THC oil up to the fifth dose (140.8/96.6 mg CBD/THC; ~12 mg/kg CBD + 8 mg/kg THC). AEs were reported in all dogs across the five groups and the majority (94.9%) were mild. Moderate AEs (4.4% of all AEs) and severe/medically significant AEs (0.8% of all AEs) manifested as constitutional (lethargy, hypothermia) or neurological (ataxia) symptoms and mainly occurred across the two groups receiving oils containing THC (CBD/THC oil or THC oil). Conclusions and clinical significance: Overall, dogs tolerated dose escalation of the CBD oil well, experiencing only mild AEs. The favorable safety profile of 10 escalating doses of a CBD oil containing 18.3-640.5 mg CBD per dose (~2-62 mg/kg) provides comparative evidence that, at our investigated doses, a CBD-predominant oil formulation was safer and more tolerated in dogs than oil formulations containing higher concentrations of THC.
J Equine Vet Sci / . 2022 Jun;113:103933. doi: 10.1016/j.jevs.2022.103933. Epub 2022 Mar 18. / Pharmacokinetics, Safety, and Synovial Fluid Concentrations of Single- and Multiple-Dose Oral Administration of 1 and 3 mg/kg Cannabidiol in Horses / Alicia F Yocom 1, Elsbeth S O'Fallon 1, Daniel L Gustafson 1, Erin K Contino 2 / Affiliations expand / PMID: 35307550 DOI: 10.1016/j.jevs.2022.103933
Cannabidiol (CBD) products are widely marketed to horse owners, trainers, and veterinarians and are readily available to the consumer despite minimal pharmacokinetic or safety data being available. The objectives of this study were to determine the plasma pharmacokinetics, short-term safety, and synovial fluid levels of CBD following oral administration in horses.
A prospective, randomized, controlled study design was used. Twelve horses were administered sunflower lecithin oil-based CBD at either 1 mg/kg (Group 1) or 3 mg/kg (Group 2) for a 24-hour pharmacokinetic study. Horses then received 0.5 mg/kg (Group 1) or 1.5 mg/kg (Group 2) CBD q12 PO for 6 weeks, with steady state and elimination sampling performed up to 96 hours post-final dose. Synovial fluid CBD concentrations were evaluated at 12 and 24 hours, and 5 weeks. Horses were monitored daily and clinicopathologic parameters were evaluated. Mean ± SD Cmax and tmax were 4.3 ± 2.1 ng/ml and 4.1 ± 4.1 hours, and 19.9 ± 15.6 ng/ml and 5.0 ± 3.7 hours for Groups 1 and 2, respectively. CBD was detectable in synovial fluid in 8/12 horses during steady state. Mild hypocalcemia was seen in all horses and elevated liver enzymes were observed in 8/12 horses, but these changes improved or normalized within 10 days after the final CBD dose. CBD had dose-dependent, but variable, oral bioavailability at 1 mg/kg and 3 mg/kg daily dosing and was consistently detectable at steady state in synovial fluid at the higher dose. Further investigation is needed to establish clinically effective doses.
Res Vet Sci / . 2021 Nov;140:38-46. doi: 10.1016/j.rvsc.2021.08.001. Epub 2021 Aug 8. / Cannabidiol-based natural health products for companion animals: Recent advances in the management of anxiety, pain, and inflammation / Cindy H J Yu 1, H P Vasantha Rupasinghe 2 / Affiliations expand / PMID: 34391060 DOI: 10.1016/j.rvsc.2021.08.001
Recent advances in cannabidiol (CBD) use in canines and felines for anxiety management, pain management, and anti-inflammatory effects were reviewed using a literature search conducted with the following keywords: CBD, anxiety, inflammation, pain, dogs, cats, and companion animals. For decades, research on CBD has been hindered due to the status of cannabis (C. sativa L.) as an illicit drug.
Limited safety data show that CBD is well-tolerated in dogs, with insufficient information on the safety profile of CBD in cats. Upon oral supplementation of CBD, elevation in liver enzymes was observed for both dogs and cats, and pharmacokinetics of CBD are different in the two species. There is a significant gap in the literature on the therapeutic use of CBD in cats, with no feline data on anxiety, pain, and inflammation management. There is evidence that chronic osteoarthritic pain in dogs can be reduced by supplementation with CBD. Furthermore, experiments are required to better understand whether CBD has an influence on noise-induced fear and anxiolytic response. Preliminary evidence exists to support the analgesic properties of CBD in treating chronic canine osteoarthritis; however, there are inter- and intra-species differences in pharmacokinetics, tolerance, dosage, and safety of CBD. Therefore, to validate the anxiety management, pain management, and anti-inflammatory efficacy of CBD, it is essential to conduct systematic, randomized, and controlled trials. Further, the safety and efficacious dose of CBD in companion animals warrants investigation.
Randomized Controlled Trial Can J Vet Res / . 2018 Jul;82(3):178-183. / Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs / Lisa R Bartner 1, Stephanie McGrath 1, Sangeeta Rao 1, Linda K Hyatt 1, Luke A Wittenburg 1 / Affiliations expand / PMID: 30026641 PMCID: PMC6038832
The purpose of this study was to determine the pharmacokinetics of cannabidiol (CBD) in healthy dogs. Thirty, healthy research dogs were assigned to receive 1 of 3 formulations (oral microencapsulated oil beads, oral CBD-infused oil, or CBD-infused transdermal cream), at a dose of 75 mg or 150 mg q12h for 6 wk.
Serial cannabidiol plasma concentrations were measured over the first 12 h and repeated at 2, 4, and 6 wk. Higher systemic exposures were observed with the oral CBD-infused oil formulation and the half-life after a 75-mg and 150-mg dose was 199.7 ± 55.9 and 127.5 ± 32.2 min, respectively. Exposure is dose-proportional and the oral CBD-infused oil provides the most favorable pharmacokinetic profile.
Drug Test Anal / . 2021 Jul;13(7):1305-1317. doi: 10.1002/dta.3028. Epub 2021 Mar 31. / Pharmacokinetics and effects on arachidonic acid metabolism of low doses of cannabidiol following oral administration to horses / Declan Ryan 1, Dan S McKemie 1, Philip H Kass 2, Birgit Puschner 3, Heather K Knych 1 4 / Affiliations expand / PMID: 33723919 DOI: 10.1002/dta.3028
The increasing availability of cannabidiol (CBD) and anecdotal reports of its anti-inflammatory effects has garnered it much interest in the equine industry. The objectives of the current study were to (1) describe the pharmacokinetics of oral CBD in exercising thoroughbreds, (2) characterize select behavioral and physiologic effects, and (3) evaluate effects on biomarkers of inflammation using an ex vivo model.
This study was conducted in a randomized balanced 3-way crossover design with a two-week washout period between doses. Horses received a single oral dose (0.5, 1, and 2 mg/kg) of CBD suspended in sesame oil. Blood and urine samples were collected prior to and for 72 hr post drug administration. Additional blood samples collected at select time points were challenged ex vivo with calcium ionophore or lipopolysaccharide to induce eicosanoid production. Drug, metabolite, and eicosanoid concentrations were determined using LC-MS/MS. Cannabidiol was well tolerated with no significant behavioral, gastrointestinal, or cardiac abnormalities observed. CBD was readily absorbed, with parent drug detected in blood at all time points. The carboxylated and hydroxylated metabolites predominated in serum and urine, respectively. The terminal half-life for CBD was 10.7 ± 3.61, 10.6 ± 3.84 and 9.88 ± 3.53 for 0.5, 1, and 2 mg/kg. Although the effects were mixed, results of eicosanoid analysis suggest CBD affects COX-1, COX-2 and LOX at the doses studied here. Results of this study coupled with previous reports in other species, suggest further study of CBD in horses is warranted before its use as an anti-inflammatory can be recommended.
J Vet Pharmacol Ther / . 2021 Nov;44(6):967-974. doi: 10.1111/jvp.13026. Epub 2021 Oct 17. / 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 / Affiliations expand / PMID: 34658021 DOI: 10.1111/jvp.13026
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-month-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.
Vet Dermatol / . 2022 May 29. doi: 10.1111/vde.13077. Online ahead of print. / The effect of a mixed cannabidiol and cannabidiolic acid based oil on client-owned dogs with atopic dermatitis / Melissa Loewinger 1, Joseph J Wakshlag 2, Daniel Bowden 1, Jeanine Peters-Kennedy 2, Andrew Rosenberg 1 / Affiliations expand / PMID: 35644533 DOI: 10.1111/vde.13077
Background: Cannabidiol (CBD) and cannabidiolic acid (CBDA) are reported to have antinociceptive, immunomodulatory and anti-inflammatory actions. Objectives: To determine if CBD/CBDA is an effective therapy for canine atopic dermatitis (cAD).
Animals: Thirty-two privately owned dogs with cAD. Materials and methods: Prospective, randomised, double-blinded, placebo-controlled study. Concurrent therapies were allowed if remained unchanged. Dogs were randomly assigned to receive either 2 mg/kg of an equal mix of CBD/CBDA (n = 17) or placebo for 4 weeks. On Day (D)0, D14 and D28, Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) and pruritus Visual Analog Scale (pVAS) scores were determined by investigators and owners, respectively. Complete blood count, serum biochemistry profiles and cytokine bioassays were performed on serum collected on D0 and D28. Results: There was no significant difference in CADESI-04 from D0 to D14 (p = 0.42) or D28 (p = 0.51) in either group. pVAS scores were significantly lower for the treatment group at D14 (p = 0.04) and D28 (p = 0.01) and a significant change in pVAS from baseline was seen at D14 (p = 0.04) and not D28 (p = 0.054) between groups. There was no significant difference in serum levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein - 1, IL-31 or IL-34 between groups at D0 or D28. Elevated alkaline phosphatase was observed in four of 17 treatment group dogs. Conclusions and clinical relevance: CBD/CBDA as an adjunct therapy decreased pruritus, and not skin lesions associated with cAD in dogs.
Anim Health Res Rev / . 2022 Jun 15;1-14. doi: 10.1017/S1466252321000189. Online ahead of print. / Use of cannabis in the treatment of animals: a systematic review of randomized clinical trials / Tácio de Mendonça Lima 1, Nathania Rodrigues Santiago 2, Elaine Cristina Ramos Alves 3, Douglas Siqueira de Almeida Chaves 1, Marília Berlofa Visacri 4 / Affiliations expand / PMID: 35703023 DOI: 10.1017/S1466252321000189
Cannabis is used in the treatment of several human conditions; however, its use is still less explored in veterinary medicine. This systematic review aims to summarize the evidence of efficacy and safety of the use of cannabis for the treatment of animal disease. A literature search was performed for studies published until 16 March 2021 in five databases.
Randomized clinical trials (RCTs) that reported the efficacy or safety of cannabis in the treatment of animal disease were included. The RoB 2 Tool was used to assess the risk of bias. A total of 2427 records were identified, of which six studies fully met the eligibility criteria. RCTs were conducted in dogs with osteoarthritis (n = 4), with epilepsy (n = 1), and with behavioral disorders (n = 1). All studies used cannabidiol (CBD) oil in monotherapy or in combination with other drugs. Studies used CBD at 2 or 2.5 mg kg-1 twice daily (n = 4), orally (n = 5), during 4 or 6 weeks (n = 3), and compared CBD with placebo (n = 5). CBD significantly reduced pain and increased activity in dogs with osteoarthritis (n = 3). Moreover, CBD significantly reduced the frequency of seizures in dogs with epilepsy (n = 1) and the aggressive behavior of dogs (n = 1). Although promising results were identified, studies were heterogeneous and presented risks of bias that required caution in the interpretation of findings. Therefore, there was some evidence to support the use of CBD in dogs with osteoarthritis to reduce pain and increased activity, but limited evidence against epilepsy and behavioral problems. In addition, CBD was well tolerated with mild adverse effects. More RCTs with high quality of evidence are needed, including greater numbers of animal subjects, additional species, and clear readout measures to confirm these findings.
Am J Vet Res / . 2021 Nov 1;83(1):86-94. doi: 10.2460/ajvr.21.08.0120. / Drug-drug interaction between cannabidiol and phenobarbital in healthy dogs / Caitlin E Doran 1, Stephanie McGrath 1, Lisa R Bartner 1, Breonna Thomas 1, Alastair E Cribb 2, Daniel L Gustafson 1 / Affiliations expand / PMID: 34727050 DOI: 10.2460/ajvr.21.08.0120
Objective: To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs. Animals: 9 healthy, purpose bred Beagles.
Procedures: A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study. Results: Although there were variations in CBD PK variables in dogs receiving CBD alone or in conjunction with PB, significance differences in CBD PK variables were not found. No significant difference was observed in PB PK variables of dogs receiving PB alone or with CBD. During chronic CBD administration, mild gastrointestinal signs were observed in 5 dogs. At daily CBD doses of 10 to 20 mg/kg/d, hypoxia was observed in 5 dogs and increased serum alkaline phosphatase (ALP) activities (range, 301 to 978 U/L) was observed in 4 dogs. A significant increase in ALP activity was observed with chronic administration of CBD during phase 1 between day 0 and day 14. Conclusions and clinical relevance: No significant PK interactions were found between CBD and PB. Dose escalation of CBD or adjustment of PB in dogs is not recommended on the basis of findings of this study.
Biopharm Drug Dispos / . 1990 Dec;11(9):785-95. doi: 10.1002/bdd.2510110906. / Pharmacokinetics of urinary metabolites of cannabidiol in the dog / E Samara 1, M Bialer, D J Harvey / Affiliations expand / PMID: 2271754 DOI: 10.1002/bdd.2510110906
The pharmacokinetics of cannabidiol (CBD) and six of its urinary metabolites was investigated in dogs. CBD was administered intravenously to three dogs, and urine was collected at specified time intervals over a period of 30 h.
The apparent terminal half-life of CBD calculated from the slope of the sigma minus plot was significantly shorter (2 h) than the half-life of CBD calculated from plasma data (8 h), and the apparent terminal half-life of the metabolites was similar to that of the CBD calculated from plasma data, indicating that the elimination of these metabolites was formation rate limited. The time course of the metabolite excretion could be divided into two phases: the first phase contained mainly monohydroxy metabolites, and the second phase contained mainly metabolites with a carboxylic acid moiety in their side-chain.
Front Vet Sci / . 2019 Jan 10;5:338. doi: 10.3389/fvets.2018.00338. eCollection 2018. / US Veterinarians' Knowledge, Experience, and Perception Regarding the Use of Cannabidiol for Canine Medical Conditions / Lori Kogan 1, Regina Schoenfeld-Tacher 2, Peter Hellyer 1, Mark Rishniw 3 / Affiliations expand / PMID: 30687726 PMCID: PMC6338022 DOI: 10.3389/fvets.2018.00338
Due to the myriad of laws concerning cannabis, there is little empirical research regarding the veterinary use of cannabidiol (CBD). This study used the Veterinary Information Network (VIN) to gauge US veterinarians' knowledge level, views and experiences related to the use of cannabinoids in the medical treatment of dogs.
Participants (n = 2130) completed an anonymous, online survey. Results were analyzed based on legal status of recreational marijuana in the participants' state of practice, and year of graduation from veterinary school. Participants felt comfortable in their knowledge of the differences between Δ9-tetrahydrocannabinol (THC) and marijuana, as well as the toxic effects of marijuana in dogs. Most veterinarians (61.5%) felt comfortable discussing the use of CBD with their colleagues, but only 45.5% felt comfortable discussing this topic with clients. No differences were found based on state of practice, but recent graduates were less comfortable discussing the topic. Veterinarians and clients in states with legalized recreational marijuana were more likely to talk about the use of CBD products to treat canine ailments than those in other states. Overall, CBD was most frequently discussed as a potential treatment for pain management, anxiety and seizures. Veterinarians practicing in states with legalized recreational marijuana were more likely to advise their clients and recommend the use of CBD, while there was no difference in the likelihood of prescribing CBD products. Recent veterinary graduates were less likely to recommend or prescribe CBD. The most commonly used CBD formulations were oil/extract and edibles. These were most helpful in providing analgesia for chronic and acute pain, relieving anxiety and decreasing seizure frequency/severity. The most commonly reported side-effect was sedation. Participants felt their state veterinary associations and veterinary boards did not provide sufficient guidance for them to practice within applicable laws. Recent graduates and those practicing in states with legalized recreational marijuana were more likely to agree that research regarding the use of CBD in dogs is needed. These same groups also felt that marijuana and CBD should not remain classified as Schedule I drugs. Most participants agreed that both marijuana and CBD products offer benefits for humans and expressed support for use of CBD products for animals.
Environ Toxicol Pharmacol / . 2019 Aug;70:103202. doi: 10.1016/j.etap.2019.103202. Epub 2019 May 30. / Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model / Chen Xu 1, Tanran Chang 2, Yaqi Du 3, Chaohui Yu 4, Xin Tan 2, Xiangdong Li 5 / Affiliations expand / PMID: 31173966 DOI: 10.1016/j.etap.2019.103202
Cannabidiol (CBD) exhibits significant efficacy in mental and inflammatory diseases. Several studies have recently reported on the rapid antidepressant-like effects of CBD, suggesting that CBD is a potential anti-depressant or anti-stress drug. However, CBD is mainly administered orally or by inhalation with poor bioavailability, resulting in high costs. We aim to explore the efficacy of long-term periodic administration of CBD in chronic mild stress (CMS) via two routes and its pharmacokinetics. We treated ICR mice with CBD administered orally and intravenously and then determined the kinetic constants.
A single bolus intravenous injection of CBD resulted in a half-life of 3.9 h, mean residence time of 3.3 h, and oral bioavailability of about 8.6%. The antidepressant-like effects of periodically administered CBD on the chronic mild stress mouse model are evaluated. Results demonstrated that such treatment at a high dose of 100 mg/kg CBD (p.o.) or a low dose of 10 mg/kg CBD (i.v.), elicited significant antidepressant-like behavioral effects in forced swim test, following increased mRNA expression of brain-derived neurotrophic factor (BDNF) and synaptophysin in the prefrontal cortex and the hippocampus. Our findings are expected to provide a reference for the development of intravenous antidepressant formulations of CBD.
Sci Rep / . 2021 Feb 2;11(1):2773. doi: 10.1038/s41598-021-82439-2. / Cannabis sativa L. may reduce aggressive behaviour towards humans in shelter dogs / Sara Corsetti 1, Simona Borruso 2, Livia Malandrucco 3, Valentina Spallucci 4, Laura Maragliano 3, Raffaella Perino 3, Pietro D'Agostino 5, Eugenia Natoli 3 / Affiliations expand / PMID: 33531559 PMCID: PMC7854708 DOI: 10.1038/s41598-021-82439-2
Among the phytocomplex components of Cannabis sativa L., cannabidiol (CBD) has a recognised therapeutic effect on chronic pain. Little is known about the veterinary use of CBD in dogs. Even less is known on the effects of CBD on dog behaviour, especially in shelters. The purpose of this study was to determine if CBD affects stress related behaviour in shelter dogs.
The sample consisted of 24 dogs divided into two groups that were created by assigning the dogs alternately: 12 dogs were assigned to the treatment group and 12 to the control group. Extra virgin olive oil, titrated to 5% in CBD was given to treated group; the placebo consisted of olive oil only, dispensed daily for 45 days. Behavioural data were collected using the 'focal animal' sampling method with 'all occurrences' and '1/0' methods for 3 h: before (T0), after 15 days (T1), after 45 days of treatment (T2) and after 15 days from the end of the treatment (T3). Treated dogs showed reduced aggressive behaviour toward humans following the treatment (Friedman Test: χ2 = 13.300; df = 3; N = 12; p = .004; adj. sig. p = 0.027), but the difference in the decrease of aggressive behaviour between the two groups was not significant (Mann-Whitney U test, T2-T0: Z = - 1.81; N = 24; p = 0.078). Other behaviours indicative of stress, such as displacing activities and stereotypes, did not decrease. Despite some non-significant results, our findings suggest that it is worth doing more research to further investigate the effect of CBD on dog behaviour; this would be certainly valuable because the potential for improving the welfare of dogs in shelters is priceless.
Eur J Pain / . 2016 Jul;20(6):936-48. doi: 10.1002/ejp.818. Epub 2015 Oct 30. / Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis / D C Hammell 1, L P Zhang 2, F Ma 2, S M Abshire 2, S L McIlwrath 2, A L Stinchcomb 1, K N Westlund 2 / Affiliations expand / PMID: 26517407 PMCID: PMC4851925 DOI: 10.1002/ejp.818
Background: Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic and has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels.
Methods: This study examined efficacy of transdermal CBD for reduction in inflammation and pain, assessing any adverse effects in a rat complete Freund's adjuvant-induced monoarthritic knee joint model. CBD gels (0.6, 3.1, 6.2 or 62.3 mg/day) were applied for 4 consecutive days after arthritis induction. Joint circumference and immune cell invasion in histological sections were measured to indicate level of inflammation. Paw withdrawal latency (PWL) in response to noxious heat stimulation determined nociceptive sensitization, and exploratory behaviour ascertained animal's activity level. Results: Measurement of plasma CBD concentration provided by transdermal absorption revealed linearity with 0.6-6.2 mg/day doses. Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. PWL recovered to near baseline level. Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNFα) revealed dose-dependent reductions of pro-inflammatory biomarkers. Results showed 6.2 and 62 mg/day were effective doses. Exploratory behaviour was not altered by CBD indicating limited effect on higher brain function. Conclusions: These data indicate that topical CBD application has therapeutic potential for relief of arthritis pain-related behaviours and inflammation without evident side-effects.
Front Vet Sci / . 2021 Jul 16;8:685606. doi: 10.3389/fvets.2021.685606. eCollection 2021. / Alteration of the Canine Metabolome After a 3-Week Supplementation of Cannabidiol (CBD) Containing Treats: An Exploratory Study of Healthy Animals / Elizabeth M Morris 1, Susanna E Kitts-Morgan 2, Dawn M Spangler 2, Ibukun M Ogunade 3, Kyle R McLeod 1, David L Harmon 1 / Affiliations expand / PMID: 34336977 PMCID: PMC8322615 DOI: 10.3389/fvets.2021.685606
Despite the increased interest and widespread use of cannabidiol (CBD) in humans and companion animals, much remains to be learned about its effects on health and physiology. Metabolomics is a useful tool to evaluate changes in the health status of animals and to analyze metabolic alterations caused by diet, disease, or other factors. Thus, the purpose of this investigation was to evaluate the impact of CBD supplementation on the canine plasma metabolome.
Sixteen dogs (18.2 ± 3.4 kg BW) were utilized in a completely randomized design with treatments consisting of control and 4.5 mg CBD/kg BW/d. After 21 d of treatment, blood was collected ~2 h after treat consumption. Plasma collected from samples was analyzed using CIL/LC-MS-based untargeted metabolomics to analyze amine/phenol- and carbonyl-containing metabolites. Metabolites that differed - fold change (FC) ≥ 1.2 or ≤ 0.83 and false discovery ratio (FDR) ≤ 0.05 - between the two treatments were identified using a volcano plot. Biomarker analysis based on receiver operating characteristic (ROC) curves was performed to identify biomarker candidates (area under ROC ≥ 0.90) of the effects of CBD supplementation. Volcano plot analysis revealed that 32 amine/phenol-containing metabolites and five carbonyl-containing metabolites were differentially altered (FC ≥ 1.2 or ≤ 0.83, FDR ≤ 0.05) by CBD; these metabolites are involved in the metabolism of amino acids, glucose, vitamins, nucleotides, and hydroxycinnamic acid derivatives. Biomarker analysis identified 24 amine/phenol-containing metabolites and 1 carbonyl-containing metabolite as candidate biomarkers of the effects of CBD (area under ROC ≥ 0.90; P < 0.01). Results of this study indicate that 3 weeks of 4.5 mg CBD/kg BW/d supplementation altered the canine metabolome. Additional work is warranted to investigate the physiological relevance of these changes.
Vet Sci / . 2021 Sep 4;8(9):185. doi: 10.3390/vetsci8090185. / Effect of Cannabidiol (CBD) on Canine Inflammatory Response: An Ex Vivo Study on LPS Stimulated Whole Blood / Enrico Gugliandolo 1, Patrizia Licata 1, Alessio Filippo Peritore 2, Rosalba Siracusa 2, Ramona D'Amico 2, Marika Cordaro 3, Roberta Fusco 2, Daniela Impellizzeri 2, Rosanna Di Paola 2, Salvatore Cuzzocrea 2 4, Rosalia Crupi 1, Claudia Dina Interlandi 1 / Affiliations expand / PMID: 34564578 PMCID: PMC8473042 DOI: 10.3390/vetsci8090185
The use of cannabidiol (CBD) for animal species is an area of growing interest, for example for its anti-inflammatory and immuno-modulating properties, even though all of its biological effects are still not fully understood, especially in veterinary medicine. Therefore, the aim of this study was to investigate the anti-inflammatory and immuno-modulating properties of CBD for the first time directly in canine inflammatory response.
We used an ex vivo model of LPS-stimulated whole dog blood. We stimulated the whole blood from healthy dogs with LPS 100 ng/mL for 24 h in the presence or not of CBD 50 and 100 μg/mL. We observed a reduction in IL-6 and TNF-α production from the group treated with CBD, but non-altered IL-10 levels. Moreover, we also observed from the CBD-treated group a reduction in Nf-κB and COX-2 expression. In conclusion, we demonstrated for the first time the anti-inflammatory and immuno-modulating properties of CBD directly in dogs' immune cells, using a canine ex vivo inflammatory model. The results obtained from these studies encourage further studies to better understand the possible therapeutic role of CBD in veterinary medicine.
J Small Anim Pract / . 2022 Apr 6. doi: 10.1111/jsap.13500. Online ahead of print. / Identification of canine osteoarthritis using an owner-reported questionnaire and treatment monitoring using functional mobility tests / A Wright 1, D M Amodie 1, N Cernicchiaro 2, B D X Lascelles 3, A M Pavlock 4, C Roberts 5, D J Bartram 1 / Affiliations expand / PMID: 35385129 DOI: 10.1111/jsap.13500
Objectives: To investigate the diagnostic value of an owner-completed canine osteoarthritis screening checklist to help identify previously undiagnosed osteoarthritis cases, and assess their response to carprofen treatment by monitoring pain and functional mobility.
Materials and methods: Dogs (n=500) whose owners reported ≥1 positive response to the osteoarthritis checklist were examined to identify dogs with previously undiagnosed osteoarthritis. Eligible dogs (n=133) were evaluated for pain and video mobility analysis by Helsinki Chronic Pain Index and visual analogue scale scores, respectively, following carprofen treatment, administered for 30 days (n=95) or up to 120 days (n=38). Dogs were filmed at clinics performing activities (walking, jogging, sitting/lying, walking up and down stairs), and scored at days 0, 30 and 120 using visual analogue scale by an independent blinded expert. Results: A diagnosis of osteoarthritis was confirmed by a veterinarian in 38% (188 of 500) of dogs. Balance of sensitivity and specificity across the original group of nine screening questions was optimised to approximately 88 and 71%, respectively, after elimination of three questions. Pain measured by Helsinki Chronic Pain Index and functional mobility improved over time in response to treatment with carprofen. Mean ability scores for activities significantly improved between days 0 and 30 for walking, jogging, sitting/lying and walking down stairs, and days 0 and 120 for sitting/lying and walking up stairs. Clinical significance: More osteoarthritis cases were identified in study dogs than previous prevalence estimates, indicating the screening checklist's potential to help identify for further evaluation cases that could otherwise remain undiagnosed. Improvements in function were demonstrated after carprofen treatment.
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