CBH Pharma CBD & Pets Research

Because of the lack of International Review Board (IRB) research in certain animal species, we must lean on human research as guidance for future products. Although the human products are not a one to one comparison, insight can be gained from the documented research to form an animal hypothesis.

Addendum – Mammals and the Endocannabinoid System

“The endocannabinoid system has been found to be pervasive in mammalian species. It has also been described in invertebrate species as primitive as the Hydra. Insects, apparently, are devoid of this, otherwise, ubiquitous system that provides homeostatic balance to the nervous and immune systems, as well as many other organ systems. The endocannabinoid system (ECS) has been defined to consist of three parts, which include (1) endogenous ligands, (2) G-protein coupled receptors (GPCRs), and (3) enzymes to degrade and recycle the ligands. Two endogenous molecules have been identified as ligands in the ECS to date. The endocannabinoids are anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol). Two G-coupled protein receptors (GPCR) have been described as part of this system, with other putative GPC being considered. Coincidentally, the phytochemicals produced in large quantities by the Cannabis sativa L plant, and in lesser amounts by other plants, can interact with this system as ligands. These plant-based cannabinoids are termed phytocannabinoids. The precise determination of the distribution of cannabinoid receptors in animal species is an ongoing project, with the canine cannabinoid receptor distribution currently receiving the most interest in non-human animals.”

Question 1. Safety and efficacy of cannabidiol-cannabidiolic acid rich hemp extract in the treatment of refractory epileptic seizures in dogs
AnswerGabriel A. Garcia, Stephanie Kube, Sheila Carrera-Justiz, David Tittle, and Joseph J. Wakshlag

  • Fourteen dogs were examined in a 24-week randomized cross-over study being provided placebo or CBD/CBDA-rich hemp extract treatment at 2 mg/kg orally every 12 h for each 12-week arm of the study. Serum chemistry, complete blood counts, serum anti-seizure medication (ASM) concentrations and epileptic seizure frequency were followed over both arms of the cross-over trial.
  • Epileptic seizure frequency decreased across the population from a mean of 8.0 ± 4.8 during placebo treatment to 5.0 ± 3.6 with CBD/CBDA-rich hemp extract (P = 0.02). In addition, epileptic seizure event days over the 12 weeks of CBD/CBDA-rich hemp treatment were 4.1 ± 3.4, which was significantly different than during the 12 weeks of placebo treatment (5.8 ± 3.1; P =0.02). The number of dogs with a 50% reduction in epileptic activity while on treatment were 6/14, whereas 0/14 had reductions of 50% or greater while on the placebo (P = 0.02).
  • Adverse events were minimal, but included somnolence (3/14) and transient increases in ataxia (4/14) during CBD/CBDA-rich hemp extract treatment; this was not significantly different from placebo.
  • Based on this information, the use of 2 mg/kg every 12 h of a CBD/CBDA-rich hemp extract can have benefits in reducing the incidence of epileptic seizures, when used concurrently with other ASMs.


Question 2. The effect of a mixed cannabidiol and cannabidiolic acid based oil on client-owned dogs with atopic dermatitis
AnswerMelissa Loewinger, Joseph J. Wakshlag, Daniel Bowden, Jeanine Peters-Kennedy, and Andrew Rosenberg

  • To determine if CBD/CBDA is an effective therapy for canine atopic dermatitis (cAD).
  • 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.
  • 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.
  • CBD/CBDA as an adjunct therapy decreased pruritus, and not skin lesions associated with cAD in dogs.
  • CBD may decrease pruritus in canines with atopic der


Question 3. The Effects of Feeding Cannabidiol Oil on Behavior of Stalled Horses
AnswerPaxton L Turner, Kimberly A Guay, Trinette Jones, Lori Cohen, Faith Elwonger, Renata Van Geem, William B Smith

  • The study objective was to determine if a single oral dose of CBD would result in adverse effects in horses. Four mature mares and four mature geldings were used in a randomized-control treatment design. Horses typically housed in paddocks, but not novel to stalling were housed in 11’ X 14’ stalls with cameras to record behavior, feed, and water intake.
  • Stereotypic behaviors such as pawing, cribbing, and aggression were quantified using the Observer XTTM program. Observations were analyzed in R Studio© for analysis of variance (ANOVA). The occurrence of stereotypic behaviors was lower (P = 0.03) in horses given oral CBD. Actions occurred more frequently during feeding sessions, behaviors including aggression and pawing occurred less when horses were given the High dose compared to Control (113 to 26 and 69 to 27) respectively.

Based on results, oral administration of the particular cannabidiol product used in this study may mediate negative behaviors in stalled horses.


Question 4. Cannabidiol in the horse: Effects on movement and reactivity
AnswerA.Draeger, E.Thomas, K.Jones, P.Godwin, A.Davis, S.Porr

  • This project investigated effects of extended CBD treatment on reactivity and movement in horses. Seventeen Quarter Horse geldings were randomly assigned to a control (CON; n = 8) or treatment (TXT; n = 9) group. Treatment horses received a 100 mg oral dose of full-spectrum CBD pellets once daily for 6 wk. Reactivity and movement evaluation occurred pre- and 6 wk post-treatment.
  • Treatment horses received a lower frequency of moderate (3) to high (4, 5) reactivity scores compared with CON (TXT = 24; CON = 37; P = 0.0018). Statistical significance was not observed for IHR, SHR, or FHR. Further investigation is needed to accurately characterize the role of CBD in alterations of equine behavior.


Question 5. Pharmacokinetic Evaluation of a Cannabidiol Supplement in Horses
AnswerMegan R Williams, Todd C Holbrook, Lara Maxwell, Cara H Croft, Michelle M Ientile, Kacey Cliburn

  • The purpose of this study was to describe the pharmacokinetic profile of multiple doses of an orally administered cannabidiol product formulated specifically for horses. A randomized 2-way crossover design was used. Seven horses received 0.35 or 2.0 mg/kg CBD per os every 24 hours for 7 total doses, separated by a 2-week washout.
  • After administration of 0.35 mg/kg of CBD, the Cmax of CBD was 6.6 ± 2.1 ng/mL while Tmax was 1.8 ± 1.2 hour, whereas the Cmax for THC was 0.7 ± 0.6 ng/mL with a Tmax of 2.5 ± 1 hour. After administration of 2.0 mg/kg of CBD, the Cmax of CBD was 51 ± 14 ng/mL with a mean Tmax of 2.4 ± 1.1 hour and terminal phase half-life of 10.4 ± 6 hour, whereas the Cmax of THC was 7.5 ± 2.2 ng/mL with a Tmax of 2.9 ± 1.1 hour.
  • Oral administration of a cannabidiol product at 0.35 mg/kg or 2.0 mg/kg once daily for 7 days was well-tolerated. Based on plasma CBD levels obtained, dose escalation trials in the horse evaluating clinical efficacy at higher mg/kg dose rates are indicated.


Question 6. Evaluation of oral supplementation of cannabidiol (CBD) in horses
AnswerL.Cohen, T.Jones, K.Guay, W.B.Smith, J.Nichols, F.Elwonger

  • The objectives of this study were to determine an appropriate dosage, CBD clearance from the blood, and to evaluate physiological and behavioral effects of a one-time oral dose of CBD in light-breed horses.
  • CBD was reconstituted in olive oil which was fed on a mg/kg basis. Eight horses (4 mares and 4 geldings), were blocked by age and gender. Horses were acclimated to stall environment and feeding methods a week before treatment. One week later, horses were assigned one of 2 treatments: LOW dose (0.3 mg/kg) and HIGH dose (0.6 mg/kg) of a CBD/ol
  • ive oil mixture.Horses receiving HIGH dose had higher (P = 0.005) mean levels of plasma CBD compared with horses receiving LOW dose; with concentrations (2.55 ng/mL and 0.51 ng/ml respectively) peaking at h 4. Feed intake, as a percentage of BW, tended to be higher (P = 0.06) in horses fed the HIGH dose and time of initial meal differed (P = 0.002) with HIGH averaging 271.4 min compared with 135.15 min for LOW).

Overall heart rates tended to be higher (P = 0.07) in LOW horses; however, all heart rates were within normal resting values throughout the collection period. A single dose of orally-administered CBD oil, at either 0.3 mg/kg or 0.6 mg/kg, did not result in abnormal heart rates or feed intake in horses over a 24-h period.

Question 7. Safety and tolerability of escalating cannabinoid doses in healthy cats
AnswerJustyna E Kulpa, Lina J Paulionis, Graham Ml Eglit, and Dana M Vaughn

  • The aim of this study was to determine the safety and tolerability of escalating doses of orally delivered cannabis oils predominant in cannabidiol (CBD), tetrahydrocannabinol (THC), or both CBD and THC in healthy cats.
  • In this placebo-controlled, blinded study, 20 healthy adult cats were randomized to one of five treatment groups (n = 4 per group): two placebo groups (sunflower oil [SF] or medium-chain triglyceride oil [MCT]), or three plant-derived cannabinoid oil groups (CBD in MCT, THC in MCT or CBD/THC [1.5:1] in SF).
  • Titration to maximum doses of 30.5 mg/kg CBD (CBD oil), 41.5 mg/kg THC (THC oil) or 13.0:8.4 mg/kg CBD:THC (CBD/THC oil) was safely achieved in all subjects. All observed adverse events (AEs) were mild, transient and resolved without medical intervention.


Question 8. The Use of Cannabidiol-Rich Hemp Oil Extract to Treat Canine Osteoarthritis-Related Pain: A Pilot Study
AnswerLori Kogan, Peter Hellyer, Robin Downing

  • The objective of this 90-day pilot clinical trial was to  assess the impact of a full-spectrum product containing hemp extract and hemp seed oil on dogs with chronic maladaptive pain. A total of 37 dogs diagnosed with chronic maladaptive pain primarily as a result of osteoarthritis were enrolled in the study.
  •  Of the 32 dogs that completed the study, 30 dogs demonstrated improved pain support. Of the 23 dogs in the study that were taking gabapentin at the time of enrollment, 10 dogs were able to discontinue the gabapentin, and an additional 11 dogs were able to have their daily dose reduced with the addition of the cannabidiol (CBD) oil.
  • The addition of a hemp derived CBD oil appears to positively affect dogs with chronic maladaptive pain by decreasing their pain, thereby improving their mobility and quality of life.

Question 9. Cannabidiol-based natural health products for companion animals (cats and dogs): Recent advances in the management of anxiety, pain, and inflammation
AnswerCindy H J Yu,   H P Vasantha Rupasinghe

  • 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. 
  • 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.

Question 10. Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs
AnswerLauri-Jo Gamble, Jordyn M. Boesch,1 Christopher W. Frye, Wayne S. Schwark, Sabine Mann, Lisa Wolfe, Holly Brown, Erin S. Berthelsen, and Joseph J. Wakshlag

  • 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.
  • 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).
  • This pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and activity in dogs with OA.

Question 11. Pharmacokinetics of single feeding of cannabidiol in cattle: A pilot study
AnswerWarren Edminster, PhD, Honors Executive Director, Thomas Powell, PhD, Committee Member, Laura Ken Hoffman, DVM, Committee Member, Shea Porr, PhD, Advisor, 

  • This study sought to determine the pharmacokinetics of an oral CBD supplement in cattle. 
  • An oral gel cannabinoid-containing product, formulated for equine, designed to be absorbed through mucosal membranes was used in this study. Based upon current knowledge, appearance of cannabinoids in plasma should occur at one-hour post administration and increase to peak concentrations at approximately ten hours.
  • Multiple cannabinoids were detected, which aligned with the guaranteed analysis stated by the manufacturer. Detection of cannabinoids was inconsistent between subjects. Cannabinoids were first detected in plasma at 1-hour post treatment in one subject, and at 12 hours post treatment in the other. Only CBD and 7-hydroxy cannabidiol (CBD-7 acid) were detected during the collection period. 
  • Plasma cannabinoid concentrations were still rising at the end of the collection period, indicating that peak concentrations had yet to be reached. Appearance of cannabinoids in plasma indicated that oral gel cannabinoid product was able to be metabolized and absorbed by the ruminant animal. A half-life of the product was unable to be determined. Future studies should consider expanding sampling numbers and extending collection period.

Question 12. Effect of Cannabidiol (CBD) on Canine Inflammatory Response: An Ex Vivo Study on LPS Stimulated Whole Blood
AnswerEnrico Gugliandolo, Patrizia Licata, Alessio Filippo Peritore, Rosalba Siracusa, Ramona D’Amico, Marika Cordaro, Roberta Fusco, Daniela Impellizzeri, Rosanna Di Paola, Salvatore Cuzzocrea, Rosalia Crupi, and Claudia Dina Interlandi

  • 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.


Question 13. Randomized, placebo-controlled, 28-day safety and pharmacokinetics evaluation of repeated oral cannabidiol administration in healthy dogs
AnswerDana M. Vaughn PhD, Lina J. Paulionis MSc, MHSc, and Justyna E. Kulpa PhD

  • 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.
  • 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.
  • 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.