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Pharmacokinetics of Cannabidiol in Dogs. E. Samara, M. Bialer, R. Mechoulam. Drug Metabolism and Disposition. May 1988,16(3):469-472. Quote: 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 [six] 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.

Cannabinoid treats as adjunctive therapy for pets: gaps in our knowledge. Alexandra Greb, Birgit Puschner. Toxicology Communications. March 2018; doi: 10.1080/24734306.2018.1434470. Quote: Cannabidiol (CBD)-infused pet treats are becoming a huge market for pet owners as they turn to this supplement for a non-traditional therapeutic option. However, CBD's short-term or long-term effects on companion animals remain largely unknown. We conducted a targeted literature search about the mechanism, efficacy, and safety of these treats in order to highlight the gaps in knowledge of CBD products. This communication elucidates some of the common misperceptions regarding CBD pet treats, and proposes suggestions for further research based on the status of knowledge in this field. With the emergence of these treats and identified gaps in knowledge, the veterinary research community needs to determine the pharmacokinetic parameters for short- and long-term duration and conduct rigorous clinical trials to assess CBD's and other cannabinoids' impact on various diseases.

Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects. Laura M. Dryburgh, Nanthi S. Bolan, Christopher P.L. Grof, Peter Galettis, Jennifer Schneider, Catherine J. Lucas, Jennifer H. Martin. Brit. J. Clin. Pharm. June 2018; doi: 10.1111/bcp.13695. Quote: There has been a resurgence in interest and use of the cannabis plant for medical purposes. However, an in-depth understanding of plant contaminants and toxin effects on stability of plant compounds and human bioavailability is needed. This systematic review aims to assess current understanding of the contaminants of cannabis and their effect on human health, leading to the identification of knowledge gaps for future investigation. A systematic search of seven indexed biological and biomedical databases and the Cochrane library was undertaken from inception up to December 2017. A qualitative synthesis of filtered results was undertaken after independent assessment for eligibility by two reviewers. The common cannabis contaminants include microbes, heavy metals and pesticides. Their direct human toxicity is poorly quantified but include infection, carcinogenicity, reproductive and developmental impacts. Cannabis dosing formulations and administration routes affect the transformation and bioavailability of contaminants. ... Firstly, cannabis is able to remove heavy metals from substrate soils and deposit these in its tissues, by virtue of its bioaccumulative capacity. ... Although there have not been any major reports on heavy metal uptake by medicinal cannabis, there have been a number of studies on the uptake of heavymetals by industrial hemp (Cannabis sativa L.). This indicates that the cannabis plant is very efficient in the uptake of heavy metals from contaminated sites and can be considered as a potential candidate for phytoremediation of contaminated soils. ... There may be important pharmacokinetic interactions between the alkaloid active ingredients of cannabis (i.e. phytocannabinoids) and contaminants but these are not yet identified nor quantified. There is significant paucity in the literature describing the prevalence and human impact of cannabis contaminants. Advances in the availability of cannabis globally warrant further research in this area, particularly when being used for patients.

Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Lisa R. Bartner, Stephanie McGrath, Sangeeta Rao, Linda K. Hyatt, Luke A. Wittenburg. Can. J. Vet. Res. July 2018;82(3):178-183. Quote: 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. ... Bioavailability of CBD has been reported to be low when given orally to both dogs and humans, presumably due to high first-pass effect through the liver. Our hypothesis was that a transdermal route of administration would avoid first-pass effect from the liver. Although bioavailability could not be determined in this cohort of dogs, we demonstrated that the CBD-infused transdermal cream did not reach similar plasma concentrations as the other 2 formulations. In general, transdermal absorption may be incomplete because of diffusion barriers, such as thickness of the skin of the pinnae or absorptivity of the CBD-infused transdermal cream. Since CBD is highly lipophilic, it accumulates within the stratum corneum of human and rodent skin and does not penetrate deeper skin layers. Pharmacokinetic analysis demonstrated that the CBD-infused oil formulation resulted in higher maximal concentrations (Cmax) and systemic exposure (area under the curve; AUC) than the other 2 formulations (Table II). The oil formulation had the smallest amount of inter-individual variability in plasma CBD concentrations. This may be due, at least in part, to having less variation in the formulation. Regardless of cause, lower measurable plasma levels of CBD were evident in the CBD-infused transdermal cream group than in the groups given either of the other 2 formulations.

Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Lauri-Jo Gamble, Jordyn M. Boesch, Christopher W. Frye, Wayne S. Schwark, Sabine Mann, Lisa Wolfe, Holly Brown, Erin S. Berthelsen, Joseph J. Wakshlag. Front. Vet. Sci. July 2018; doi: 10.3389/fvets.2018.00165. Quote: 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. ... Twenty-two client-owned dogs with clinically and radiographically confirmed evidence of osteoarthritis were recruited. Sixteen of these dogs completed the trial and were included in the analyses. ... 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. In conclusion, this particular product was shown to be bioavailable across the small number of dogs examined in the PK portion of the study, and dogs with OA receiving this industrial hemp extract high in CBD (2mg/kg of CBD) were perceived to be more comfortable and active. There appear to be no observed side effects of the treatment in either the dogs utilized in the PK study at 2 and 8mg/kg, or dogs undergoing OA treatment for a month duration. There were some dogs with incidental rises in alkaline phosphatase that could be related to the treatment. Further long-term studies with larger populations are needed to identify long-termeffects of CBD rich industrial hemp treatment, however short term effects appear to be positive.

A Report of Adverse Effects Associated With the Administration of Cannabidiol in Healthy Dogs. Stephanie McGrath, Lisa R. Bartner, Sangeeta Rao, Lori R. Kogan, Peter W. Hellyer. AHVMA J. September 2018;52(Fall):34-38. Quote: Cannabis-based therapies have been used for centuries for various medicinal purposes. They have recently gained recognition as an effective treatment for medical conditions in humans; and, as such, awareness is increasing among veterinarians and pet owners. However, side effects, pharmacokinetics, and efcacy in dogs are not known. The purpose of this study was to determine the tolerability of cannabidiol (CBD) by healthy dogs. We hypothesized that CBD would be tolerated in a healthy population of dogs. A group of 30 healthy Beagle dogs were randomly assigned to receive CBD in the form of microencapsulated oil beads (capsule), CBD-infused oil, or CBD-infused transdermal cream at a dose of 10 mg/kg/day or 20 mg/ kg/day for 6 weeks. Complete blood counts, chemistry panels, urinalysis, and bile acids were performed at 0, 2, 4, and 6 weeks. Elevations in serum ALP occurred in some dogs. ... Serum ALP values that were double the normal reference range accepted by CSU (140 IU/L) were considered to be clinically signicant. The dogs that received the microencapsulated oil beads and CBD-infused oil had dose-dependent elevations of serum ALP apparent at 4 and 6 weeks. There was no evidence of short-term hepatotoxicity since fasting and postprandial bile acids remained normal for all the dogs throughout the study. However, the potential for long-term liver toxicity was not evaluated in this study. The observation of ALP elevations warrants serial monitoring of liver enzymes and bile acids for patients being treated with CBD. Subsequent studies need to consider potential drug interactions that may occur if CBD is used clinically. ... All of the dogs in the study experienced diarrhea that was not associated with the formulation or dose of CBD that they received. CBD appeared to be well tolerated in dogs. However, a more extensive safety study is necessary to determine if there are long-term effects of CBD on the liver and an association with diarrhea.

Pharmacokinetics of Bedrocan®, a cannabis oil extract, in fasting and fed dogs: An explorative study. Beata Łebkowska-Wieruszewska, Fabio Stefanelli, Silvio Chericoni, Helen Owen, Amnart Poapolathep, Andrzej Lisowski, Mario Giorgi. Res. Vet. Sci. April 2019; doi: 10.1016/j.rvsc.2018.12.003. Quote: The aim of this study was to explore the pharmacokinetics of the two main active compounds (THC and CBD) contained in the cannabis oil extract Bedrocan® in fasting and fed dogs. ... Six healthy, intact female, adult (5–7 years) Labrador dogs were used. ... Bedrocan® (20% delta-9-tetrahydrocannabinol [THC] and 0.5% cannabidiol [CBD]) was administered at 1.5 and 0.037mg/kg THC and CBD, respectively in fasted and fed dogs according to a 2×2 cross over study design. The quantification of the two active ingredients was performed by LC/MS. No detectable concentrations of CDB were found at any collection time. ... This is unsurprising given its low concentration in the Bedrocan® formulation and the reported low oral bioavailability of this compound in dogs (below 20%; Samara et al., 1988). ... THC was quantifiable from 0.5 to 10h, although there was large inter-subject variability. Fed dogs showed a longer absorption phase (Tmax 5 vs 1.25h) and lower maximal blood concentration (7.1 vs 24ng/mL) compared with the fasted group. A larger AUC was found in the fasted group; the relative oral bioavailability in fed animals was 48.22%.

Effects on Pain and Mobility of a New Diet Supplement in Dogs with Osteoarthritis: A Pilot Study. Elisa Martello, Mauro Bigliati, Donal Bisanzio, Elena Biasibetti, Franco Dosio, Daniela Pastorino, Massimo De Nardi, Natascia Bruni. Annals Clinical & Lab. Res. April 2019; doi: 10.21767/2386-5180.100304. Quote: In this study, we have evaluated the efficacy of a new diet supplement in reducing chronic pain and improving mobility in a group of 10 dogs with Osteoarthritis (OA). OA is a common debilitating condition affecting humans and animals. Tablets containing a preparation of natural ingredients (Cannabidiol (CBD)-rich fraction, Boswellia serrata Roxb. in a Phytosome® delivery form and Cucumis melo L. extract) were administered for 30 days. Veterinary evaluations were performed and owners filled questionnaires on chronic pain (Helsinki chronic pain index HCPI) three times during the study. The product was well tolerated and owners reported a good palatability and ease of administration. In terms of effectiveness, results of a Generalized Linear Mixed Model (GLMM) on HCPI highlighted a significant reduction of pain scores at the end of the study. Based on our observations, our new dietary supplement has beneficial effects in dogs with OA after the treatment.

Cannabis in Veterinary Medicine: Cannabinoid Therapies for Animals. Joshua A. Hartsel, Kyle Boyar, Andrew Pham, Robert J. Silver, Alexandros Makriyannis. R. C. Gupta et al. (eds.), Nutraceuticals in Veterinary Medicine. May 2019; doi: 10.1007/978-3-030-04624-8_10. Quote: The use of cannabis for animal species is an area of growing interest, largely due to the therapeutic benefits being observed for humans and animals in the era of cannabis legalization. The close relationship humans have with their pets and other veterinary species has led to a renewed interest in the possibility and promise of cannabis to treat similar health issues in the animal community. This chapter explores the literature available on cannabis, its interactions with the endocannabinoid system, and how animal species interact with various formulations and cannabis treatments. A brief overview of the biology, chemistry, and history of cannabis is discussed with the relevance to veterinary species in mind. The pharmacologically active components are discussed with both anecdotal and objective, evidencebased, and clinical data.

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. Stephanie McGrath, Lisa R. Bartner, Sangeeta Rao, Rebecca A. Packer, Daniel L. Gustafson. J. Am. Vet. Med. Assn. June 2019; doi: 10.2460/javma.254.11.1301. Quote: Objective: To assess the effect of oral cannabidiol (CBD) administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with idiopathic epilepsy. Design: Randomized blinded controlled clinical trial. Animals: 26 client-owned dogs with intractable idiopathic epilepsy [none being cavalier King Charles spaniels]. Procedures: Dogs were randomly assigned to a CBD (n = 12) or placebo (14) group. The CBD group received CBD-infused oil (2.5 mg/kg [1.1 mg/lb], PO) twice daily for 12 weeks in addition to existing antiepileptic treatments, and the placebo group received noninfused oil under the same conditions. Seizure activity, adverse effects, and plasma CBD concentrations were compared between groups. Results: 2 dogs in the CBD group developed ataxia and were withdrawn from the study. After other exclusions, 9 dogs in the CBD group and 7 in the placebo group were included in the analysis. Dogs in the CBD group had a significant (median change, 33%) reduction in seizure frequency, compared with the placebo group. However, the proportion of dogs considered responders to treatment (≥ 50% decrease in seizure activity) was similar between groups. Plasma CBD concentrations were correlated with reduction in seizure frequency. Dogs in the CBD group had a significant increase in serum alkaline phosphatase activity. ... Serum ALP activity increased significantly from weeks 0 to 12 in dogs in the CBD group, compared with activity in dogs in the placebo group. This increase, observed in all 9 dogs in the CBD group, was likely due to the induction of CYP isoenzymes in the liver. ... This inhibition may be linked to adverse effects from coadministration of common AEDs, such as potentiation of benzodiazepines and phenobarbital. Thus, although the clinical importance of the increase in serum ALP activity observed in the present study remains unknown, other considerations involving drug interactions are of importance. No measurement of serum bile acids concentrations was performed, which would have helped elucidate whether any functional changes to the liver had occurred after 12 weeks of CBD treatment. ... No adverse behavioral effects were reported by owners. ... A limitation of the study reported here was the small sample size, which made the clinical importance of the observed data difficult to interpret. Given the results, a larger randomized blinded controlled clinical trial involving a higher dose of CBD is warranted. Another limitation inherent to clinical trials involving dogs with epilepsy is the reliance on dog owners for recording outcomes such as seizure frequency. Some seizures could have been missed if they were nocturnal or the owner was absent; however, because owners were unaware of which treatment their dogs received, there was no reason to believe that any bias introduced by misclassification of seizure frequency would be different between treatment groups. ... Conclusions & Clinical Relevance: Although a significant reduction in seizure frequency was achieved for dogs in the CBD group, the proportion of responders was similar between groups. Given the correlation between plasma CBD concentration and seizure frequency, additional research is warranted to determine whether a higher dosage of CBD would be effective in reducing seizure activity by ≥ 50%.

Evaluation of the Effect of Cannabidiol on Osteoarthritis-Associated Pain in Dogs — A Pilot Study. S. Mejia, F.M. Duerr, S. McGrath. Vet. Comp. Orthop. Traumatol. July 2019; doi: 10.1055/s-0039-1692272. Quote: Introduction: There is a lack of research evaluating the efficacy of cannabidiol (CBD) for treatment of osteoarthritis-associated pain using objective outcome measures. This pilot study was designed to evaluate the effect of CBD on pain associated with canine osteoarthritis. Materials and Methods: Client-owned dogs with radiographically confirmed osteoarthritis were enrolled in this prospective, double-blinded, crossover, placebo-controlled study. Outcome measures included serum chemistry, weekly total activity counts (AC), clinical metrology instruments (CMI), and objective gait analysis (OGA). Baseline data were acquired for four weeks prior to initiation of the first treatment. Patients were randomly allocated to either placebo or oral CBD oil treatment for the first six weeks, then treated for the subsequent six weeks with the opposite treatment. Results: Twenty-three dogs, medium-large breed dogs, were enrolled. Fourteen dogs displayed elevation in liver enzymes associated with CBD treatment. Significant differences between treatment groups were identified for several CMI and OGA time point comparisons. However, there was a lack of consistency amongst the different outcome measures. Discussion/Conclusion: This pilot study identified differences in some outcome measures suggesting that CBD may benefit dogs with osteoarthritis-associated pain. However, adequately powered studies with a larger sample size are needed to confirm this suggestion. Further evaluation of the clinical implications of the observed liver enzyme elevation, particularly with long-term administration, is necessary.

Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats. Kelly A. Deabold, Wayne S. Schwark, Lisa Wolf, Joseph J.Wakshlag. Animals. October 2019; doi: 10.3390/ani9100832. Quote: 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. ... The dogs were o ered ElleVet Mobility Chews (ElleVet Sciences; Portland, ME, USA) at a dose of 2 mg/kg twice daily for 84 days. Small chews contained 10 mg of CBD as a 50% mix of CBD (5 mg per chew) and CBDA (CBDA—5 mg per chew). Large soft chews containing approximately 15 mg of CBD (equal mix of CBD/CBDA) were also used in the study. When necessary, a combination of large and small chews were used or partitioned in half to reach the appropriate dose for 84 days. All dogs had been fasted from the prior day and were not fed until 8 h after the initial dosing. ... All 6 dogs were dosed with soft chews at a dose of 2 mg/kg CBD/CBDA at 6 am in the morning. In all but one dog the entire dose was consumed, where it was realized the dog did not consume a portion of the dose at time 0 and was thus dropped form the experimental pharmacokinetic data set. ... In our opinion oral dosing with CBD in an oil base may enhance absorption, and may have been enhanced further in this study by inclusion in a food matrix. We have no explanation for our finding that elimination of CBD in the present work was significantly faster than in our previous study. This brings into question the potential for therapeutic uses at our current dosing of 2 mg/kg twice a day (4 mg per day) and whether this may be enough to achieve therapeutic concentrations of CBD. ... In this uncontrolled preliminary study dosing of 2 mg/kg twice daily as an even mixture of CBD and CBDA showed no abnormalities in weekly physical examinations, nor any evidence of organ dysfunction as assessed by blood parameters. The canine CBD-infused chews showed no ALP elevations, with no ALP values falling outside the reference range (5–131 U/L) for any dog in the study. ... 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.

Preliminary investigation of the safety of escalating cannabinoid doses in healthy dogs. Dana Vaughn, Justyna Kulpa, Lina Paulionis. Front. Vet. Sci. February 2020; doi: 10.3389/fvets.2020.00051. Quote: 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). ... Contrary to earlier assertions that CBD has low bioavailability after oral administration to animals, including dogs (18, 50), our study showed circulating plasma CBD and 7-COOH-CBD in all dogs receiving the ninth dose of CBD oil at all post-dose timepoints (1, 2, 4, 6, and 24 h). Based on these results, it appears that a first pass effect through the liver did not eliminate the systemic availability of CBD following its oral ingestion. Given the highly lipophilic nature of CBD (50), its administration in a lipid solvent (MCT oil) in the present study may have increased its bioavailability. Zgair et al. (51) showed that co-administration of lipids with oral CBD increased systematic availability of CBD by almost 3-fold in rats as compared to lipid-free formulations. Overnight fasting of the dogs in the present study prior to dosing may have also improved bioavailability. Lebkowska-Wieruszewska et al. (19) showed improved cannabinoid (THC) bioavailability in fasted vs. fed dogs, with a lower Tmax and higher Cmax achieved for THC in the fasted condition. The approximate cumulative CBD dose administration from the first to ninth dose was 2122.9 mg. Detected plasma levels of CBD may also be reflective of CBD accumulation in plasma with dose escalation over time. ... 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.

Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders. María Fernández-Trapero, Carmen Pérez-Díaz, Francisco Espejo-Porras, Eva de Lago, Javier Fernández-Ruiz. Biomolecules. February 2020; doi: 10.3390/biom10020279. Quote: The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study,adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, [6] Beagle dogs [3 males and 3 females] received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), ∆9-tetrahydrocannabinol (∆9-THC) and its metabolite 11-hydroxy-∆9-THC. Maximal plasma concentrations of both ∆9-THC (Cmax = 18.5 ng/mL) and CBD (Cmax = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (∆9-THC: Cmax = 24.5 ng/mL; CBD: Cmax = 15.2 ng/mL). 11-hydroxy-∆9-THC, which is mainly formed in the liver from ∆9-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and ∆9-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1–2 h and suggested progressive accumulation after the multiple dose treatment.

The Use of Cannabidiol-Rich Hemp Oil Extract to Treat Canine Osteoarthritis-Related Pain: A Pilot Study. Lori Kogan, Peter Hellyer, Robin Downing. AHVMA J. March 2020;58(Spring):42-45. Quote: 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 mal adaptive pain. A total of 37 dogs diagnosed with chronic maladaptive pain primarily as a result of osteoarthritis were enrolled in the study. The dogs were given an initial physical examination that included systematic pain palpation, mapping of pain patterns, informal gait analysis, metabolic profile, and owner interview. The same palpa tions and mappings were performed during each biweekly assessment to identify trends, chart progress, and inform dose adjustments. ... Among these 30 dogs, the dose of CBD needed to achieve a positive effect ranged from 0.3 up to 4.12 mg/kg BID. The 2 dogs in the study requiring the highest dose of the CBD product were both Cavalier King Charles spaniels (not related to one another), and neither of these dogs experienced any changes/elevations in liver enzymes. It is unclear why some patients responded to a very small dose of the CBD product (0.3 mg/kg per dose), whereas the majority required dosing in the range of 1 to 2 mg/kg per dose. ... The metabolic parameters were repeated at the end of 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. Conclusion: 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. The reduction in gabapentin dose may be the result of changes in analgesia and/or sedation with the addition of the hemp oil extract.

Cannabinoid, Terpene, and Heavy Metal Analysis of 29 Over-the-Counter Commercial Veterinary Hemp Supplements. Joseph J Wakshlag, Stephen Cital, Scott J. Eaton, Reece Prussin, Christopher Hudalla. Vet. Med. (Auckl). April 2020; doi: 10.2147/VMRR.S248712. Quote: Purpose: The use of veterinary low tetrahydrocannabinol (THC) Cannabis sativa (ie, hemp) products has increased in popularity for a variety of pet ailments. Low-THC Cannabis sativa is federally legal for sale and distribution in the USA, and the rise in internet commerce has provided access to interested consumers, with minimal quality control. Materials and methods: We performed an internet word search of "hemp extract and dog" or "CBD product and dog" and analyzed 29 products that were using low-THC Cannabis sativa extracts in their production of supplements. All products were tested for major cannabinoids including cannabidiol (CBD), ∆9-tetrahydrocannabinol (THC), cannabigerol (CBG), and other minor cannabinoids, as well as their carboxylic acid derivatives (CBDA, THCA, CBGA) using an ISO/IEC 17025 certified laboratory. Products were also tested for major terpenes and heavy metals to understand constituents in the hemp plants being extracted and distributed. Results: All products were below the federal limit of 0.3% THC with variable amounts of CBD (0-88 mg/mL or g). Only two products did not supply a CBD or total cannabinoid concentration on their packaging or website, while 22/29 could supply a certificate of analysis (COA) from a third-party laboratory. Ten of the 27 products were within 10% of the total cannabinoid concentrations of their label claim with a median concentration of 93% of claims (0-154%). Heavy metal contamination was found in 4/29 products, with lead being the most prevalent contaminant (3/29). Conclusion: The products analyzed had highly variable concentrations of CBD or total cannabinoids with only 18 of 29 being appropriately labeled according to current FDA non-medication, non-dietary supplement or non-food guidelines. Owners and veterinarians wanting to utilize CBD-rich Cannabis sativa products should be aware of low-concentration products and should obtain a COA enabling them to fully discuss the implications of use and calculated dosing before administering to pets.

Critical aspects affecting cannabidioloral bioavailability and metabolic elimination, and related clinical Lmplications. Emilio Perucca1, Meir Bialer. CNS Drugs. June 2020; doi: 10.1007/s40263-020-00741-5. Quote: This article provides a critical appraisal of the available evidence concerning clinical exposure to orally administered cannabidiol (CBD), with special reference to factors affecting gastrointestinal absorption, presystemic elimination, and susceptibility to metabolic drug interactions. Although detailed studies have not been published, the available data suggest that the absolute bioavailability of CBD after oral dosing under fasting conditions is approximately 6%, and increases fourfold when the medication is co-administered with a high-fat meal. Based on measurements of CBD plasma exposure after oral dosing and a 6% absolute oral bioavailability estimate, the actual clearance of CBD in adults can be inferred to be in the order of 67 L/h, which is similar to the value of 74 ± 14 L/h (mean ± standard deviation) determined after intravenous injection of a 20-mg dose of deuterium-labeled CBD in five healthy subjects. Assuming that the CBD blood-to-plasma ratio is about 1, as in the case of tetrahydrocannabinol (THC), and that CBD metabolism takes place virtually entirely in the liver, it can be estimated that about 70 to 75% of an orally absorbed dose of CBD can be removed by hepatic metabolism before reaching the systemic circulation, and additionally CBD gastrointestinal absorption is incomplete. A formulation with improved biopharmaceutical properties could increase the extent of CBD absorption about fourfold (i.e., to the level achieved with the currently available formulations co-administered with a high-fat meal) and minimize the influence of food effects on CBD bioavailability. There is also potential for favoring the absorption of CBD through the enteric lymphatic system, thereby reducing the extent of presystemic hepatic elimination. Evidence that CBD can behave as a high hepatic clearance compound also has implications when predicting the magnitude of drug–drug interactions affecting CBD metabolism. These considerations have important clinical relevance, particularly with respect to the objective of minimizing pharmacokinetic variability and consequent intra- and interindividual differences in therapeutic response and susceptibility to adverse effects.

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, Federica Di Cesare, Daniela Gioeni, Vanessa Rabbogliatti, Francesco Ferrari, Elisa Silvia D’Urso, Martina Amari, Giuliano Ravasio. Animals. August 2020; doi: 10.3390/ani10091505. Quote: 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.

Pharmacokinetics of Cannabidiol, Cannabidiolic Acid, △9-Tetrahydrocannabinol, Tetrahydrocannabinolic Acid and Related Metabolites in Canine Serum After Dosing With Three Oral Forms of Hemp Extract. Joseph J. Wakshlag, Wayne S. Schwark, Kelly A. Deabold, Bryce N. Talsma, Stephen Cital, Alex Lyubimov, Asif Iqbal, Alexander Zakharov. Front. Vet. Sci. September 2020; doi: 10.3389/fvets.2020.00505. Quote: Cannabidiol (CBD)-rich hemp extract use is increasing in veterinary medicine with little examination of serum cannabinoids. Many products contain small amounts of Δ9-tetrahydrocannabinol (THC), and precursor carboxylic acid forms of CBD and THC known as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). Examination of the pharmacokinetics of CBD, CBDA, THC, and THCA on three oral forms of CBD-rich hemp extract that contained near equal amounts of CBD and CBDA, and minor amounts (<0.3% by weight) of THC and THCA in dogs was performed. In addition, we assess the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) to better understand the pharmacokinetic differences between three formulations regarding THC and CBD, and their metabolism. Six purpose-bred female beagles were utilized for study purposes, each having an initial 7-point, 24-h pharmacokinetic study performed using a dose of 2 mg/kg body weight of CBD/CBDA (~1 mg/kg CBD and ~1 mg/kg CBDA). Dogs were then dosed every 12 h for 2 weeks and had further serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectroscopy (LC-MS/MS). Regardless of the form provided (1, 2, or 3) the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar, with only Form 2 generating enough data above the lower limit of quantitation to assess pharmacokinetics of THC. CBDA and THCA concentrations were 2- to 3-fold higher than CBD and THC concentrations, respectively. The 1- and 2-week steady-state concentrations were not significantly different between the two oils or the soft chew forms. CBDA concentrations were statistically higher with Form 2 than the other forms, showing superior absorption/retention of CBDA. Furthermore, Form 1 showed less THCA retention than either the soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the quantitation limit of the assay for nearly all samples. Overall, these findings suggest CBDA and THCA are absorbed or eliminated differently than CBD or THC, respectively, and that a partial lecithin base provides superior absorption and/or retention of CBDA and THCA. ... Overall, this study is the first to show that CBDA and THCA are readily absorbed and retained in dogs with some differences observed in CBDA absorption and/or retention depending on the medium used to deliver the oral treatment. The finding of mid dosing concentrations of 75 ng/mL of CBD and CBDA or greater suggests potential for therapeutic use when delivered at 1 mg/kg body weight for each of these cannabinoids with food. A more interesting finding is the retention of THCA in the serumof between 10 and 25 ng/mL. The exact functions of CBDA and THCA physiologically suggest similar therapeutic benefits to CBD that may have the potential to work synergistically with CBD. These synergistic properties known as the “entourage effect” are currently thought to be the primary reason that lower CBD whole hemp extract dosing can be therapeutic when compared to purified CBD (40, 41). Although the hemp extract product used in this study appears to be generally safe, the results of this study cannot be translated to other products due to differences in variable absorption dependent on carrier oils, and cannabinoid and terpene profiles. This fact makes recommendations of CBD-rich hemp products globally tenuous, and veterinarians should become versed on products available before using them clinically.

A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. Chris D. Verrico, Shonda Wesson, Vanaja Konduri, Colby J. Hofferek, Jonathan Vazquez-Perez, Emek Blair, Kenneth Dunner Jr, Pedram Salimpour, William K. Decker, Matthew M. Halpert. Pain. September 2020; doi: 10.1097/j.pain.0000000000001896. Quote: Quote: 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. 

Pharmacokinetic and Safety evaluation of various oral doses of a novel 1:20 THC:CBD cannabis herbal extract in dogs. Alan Chicoine, Kate Illing, Stephanie Vuong, K. Romany Pinto, Jane Alcorn, Kevin Cosford. Front. Vet. Sci. September 2020; doi: 10.3389/fvets.2020.583404. Quote: Objective: To determine the pharmacokinetics (PK) and safety of various oral doses of a Cannabis herbal extract (CHE) containing a 1:20 ratio of Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) in 13 healthy Beagle-cross dogs. Methods: Single-dose PK was assessed after oral administration of CHE at low, medium, or high doses [2, 5, or 10 mg CBD and 0.1, 0.25, or 0.5 mg THC per kg of body weight (bw), respectively; n = 6 per group]. Dogs were monitored for adverse events for up to 48 h post-dose. Evaluations of neurological signs, clinical laboratory abnormalities, and other adverse events were performed in two separate study phases: a multiple-dose phase with 12 dogs receiving five medium doses (5 mg CBD/kg bw) at 12 h intervals, and a single low-dose (2 mg CBD/kg bw), randomized, blinded, negative controlled study with 13 dogs. Results: Cannabinoids CBD, THC, CBC, and metabolites 6-OH-CBD, 7-OH-CBD, 11-OH-THC, and THC-COOH were quantified in plasma. CBD and THC were rapidly absorbed (mean Tmax of 1.9–2.3 h) and initially depleted rapidly (mean CBD T1/2β of 2.3–2.6 h). A prolonged elimination phase (mean CBD T1/2λ of 13.3–24.4 h) was observed. CBD and THC concentrations increased in a dose-dependent (non-linear) manner, with disproportionally greater cannabinoid exposure relative to the dose increase. Neurological signs (hyperesthesia or proprioceptive deficits) were noted in five of six dogs in the high-dose group, but only occasionally or rarely in the medium- and low-dose groups, respectively. Presence and severity of clinical signs correlated with plasma cannabinoid concentrations. Dogs appeared to develop a tolerance to cannabinoid effects after multiple CHE doses, with fewer neurological signs noted after the final (fifth) vs. first dose. No clinically meaningful changes in blood count or chemistry values occurred after multiple CHE doses. Clinical Significance: Dogs tolerated the 1:20 THC:CBD formulation well at low and medium doses, but clinically meaningful neurological signs were observed at high doses. Because of non-proportional increases in plasma cannabinoid concentrations with increasing doses, as well as potential differences in CHE product composition and bioavailability, the possibility of adverse events and dose regimen consistency should be discussed with dog owners.

Cannabis in Veterinary Medicine: A Critical Review. Trina Hazzah, Casara Andre, Gary Richter, Stephanie McGrath. AHVMA J. December 2020;61:17. Quote: This article is intended to provide the veterinary community with a concise, understandable, and clinically relevant review of cannabis medicine in companion animals. Included are descriptions of the structure and function of the endocannabinoid system (ECS), outlines of the pharmacologic effects of biologically active compounds produced by the cannabis plant (phytocannabinoids, terpenoids, flavonoids), potential clinical uses and toxicities, relevant legal updates, and an overview of the most relevant veterinary research. The ECS is a complex neuromodulatory signaling system that regulates multiple systems throughout the body and is often up-regulated or down-regulated in times of disease. Many cannabis-derived molecules have been shown to have multiple therapeutic benefits, including anti-inflammatory, analgesic, antineoplastic, anxiolytic, and anticonvulsant properties, through a variety of mechanisms. Although some of the naturally occurring compounds produced by the cannabis plant work in concert with the ECS, others have a unique pharmacology that produces important physiologic effects via ECS-independent mechanisms. Cannabis science is still in its infancy, and the research up to this point has centered around cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC). It is essential for veterinary practitioners to understand that the cannabis plant does not consist of a single therapeutic agent but rather a heterogeneous blend of a multitude of compounds. ... Dosing: Considerations for dosing cannabis in the veterinary patient are multifactorial and, to an extent, somewhat unique compared to other drugs and botanicals. Most pharmaceuticals follow a familiar pharmacokinetics (PK) pattern by demonstrating a linear dosing curve and thus displaying a direct linear relationship between increasing dose and increased efficacy until a maximum level of efficacy is reached. Dosing above this point of maximal effect may lead to an increase in negative side effects with little to no increase in therapeutic value.

Cannabis, Cannabidiol Oils and Tetrahydrocannabinol — What Do Veterinarians Need to Know? Nancy De Briyne, Danny Holmes, Ian Sandler, Enid Stiles, Dharati Szymanski, Sarah Moody, Stephan Neumann , Arturo Anadón. Animals. March 2021; doi: 10.3390/ani11030892. Quote: 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. ... CBD is highly lipophilic, which raises concerns over potential long-term tissue build-up and toxicity. ... THC is highly lipophilic and readily distributes to the brain and other fatty tissues following absorption. ... The low bioavailability of CBD is due to an extensive first pass or presystemic metabolism in the liver in which CBD and its metabolites are mostly excreted via the kidneys. The presystemic metabolism restrains the systemic exposure (i.e., CBD is greatly reduced before it reaches the systemic circulation). ... In dogs, the onset of clinical signs in cases of marijuana toxicosis typically occurs within 30–90 min of exposure and can last up to 96 h.

Evaluation of the Effect of Cannabidiol on Naturally Occurring Osteoarthritis-Associated Pain: A Pilot Study in Dogs. Sebastian Mejia, Felix Michael Duerr, Gregg Griffenhagen, Stephanie McGrath. J. Am. Anim. Hosp. Assn. March 2021; doi: 10.5326/JAAHA-MS-7119. Quote: The objective of this study was to provide preliminary data describing the safety and effect of cannabidiol (CBD) for symptom relief of canine osteoarthritis-associated pain in a clinical setting using objective outcome measures. Twenty-three client-owned dogs with naturally occurring osteoarthritis of appendicular joints completed this prospective, double-blinded, crossover, placebo-controlled study. Baseline data were acquired for 4 wk, followed by random allocation to either placebo or CBD treatment for 6 wk, followed by 6 wk with the opposite treatment. Outcome measures included objective gait analysis, activity counts (via accelerometry) and clinical metrology instruments. There were no differences noted between groups at any time point for any of the recorded outcome measures. Adverse events associated with CBD administration included elevation in liver enzymes (n = 14) and vomiting (n = 2). ... The pilot data from this study do not support the use of CBD as a symptom-relieving agent for canine OA.

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. Am. J. Vet. Res. May 2021; doi: 10.2460/ajvr.82.5.405. Quote: 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. ... Analysis of all CBC and serum biochemical analytes evaluated in the present study indicated that the only abnormality was an increase in serum ALP activity that appeared to be dose related in some dogs. Such an increase in dogs receiving CBD has been observed by others5,6,8,9 as early as 2 weeks following treatment initiation (10 or 20 mg/kg/d).5 The increases in ALP values in the present study, observed as early as 1 week (12 mg/kg) or 2 weeks (2 and 4 mg/kg) after CBD administration began, changed to decreases following 2 weeks of administration in all 3 groups, suggesting an adaptive response. ... The origin of any increases in serum ALP activity (ie, liver, bone, or corticosteroid hormones), the potential role of CYP induction in these increases, and whether these increases are associated with hepatobiliary insult also warrant further investigation. ... 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 & 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.

Detecting and quantifying marijuana metabolites in serum and urine of 19 dogs affected by marijuana toxicity. Alyson H. Fitzgerald, Yuntao Zhang, Scott Fritz, William H. Whitehouse, Tamera Brabson, Lisa Pohlman, Natalia Cernicchiaro, Caroline Tonozzi, Steve Ensley. J. Vet. Diagnosic Investigation, July 2021: doi: 10.1177/10406387211027227. Quote: Veterinarians diagnose marijuana toxicity based on clinical signs and history, or in conjunction with an over-the-counter (OTC) human urine drug screen. With the legalization of recreational marijuana use becoming more prevalent in the United States, a more accurate test to aid in the diagnosis of canine marijuana toxicity is needed. We collected urine and serum samples from 19 dogs with confirmed or suspected marijuana toxicosis from multiple veterinary hospitals and analyzed them with a novel UPLC-MS/MS method. Calibrations from 0.1 to 100 ng/mL and QC materials were prepared. Samples were extracted, purified, and eluted with solid-phase extraction. Urine samples were tested with an OTC human urine drug screen. The limit of detection (LOD) and lower limit of quantification (LLOQ) ranges for marijuana metabolites in serum were 0.05–0.25 ng/mL and 0.1–0.5 ng/mL, respectively. In urine, the LOD and LLOQ ranges for the metabolites were 0.05–0.1 ng/mL and 0.1–0.5 ng/mL, respectively. In serum, median and range of metabolite concentrations (ng/mL) detected included: THC, 65.0 (0.14–160); 11-OH-Δ9-THC, 4.78 (1.15–17.8); 11-nor-9-carboxy-Δ9-THC, 2.18 (0.71–7.79); CBD, 0.28 (0.11–82.5); and THC-glucuronide, 2.05 (0.72–18.3). In the 19 urine samples, metabolite: creatinine (ng: mg) values detected included: THC, 0.22 (0.05–0.74); 11-OH-Δ9-THC, 0; 11-nor-9-carboxy-Δ9-THC, 1.32 (0.16–11.2); CBD, 0.19 (0.12–0.26); THC-COOH-glucuronide, 0.08 (0.04–0.11); and THC-glucuronide, 0.98 (0.25–10.7). Twenty of 21 urine samples tested negative for THC on the urine drug screen. All 19 serum samples contained quantifiable concentrations of THC using our novel UPLC-MS/MS method. Utilizing a UPLC-MS/MS method can be a useful aid in the diagnosis of marijuana toxicosis in dogs, whereas using an OTC human urine drug test is not a useful test for confirming marijuana exposure in dogs because of the low concentration of THC-COOH in urine.

Drug-drug interaction between cannabidiol and phenombarbital in healthy dogs. Caitlin E. Doran, Stephanie McGrath, Lisa R. Bartner, Breonna Thomas, Alastair E. Cribb, Daniel L. Gustafson. Am. J. Vet. Res. January 2022; doi: 10.2460/ajvr.21.08.0120. Quote: 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 & 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.

Single dose and chronic oral administration of cannabigerol and cannabigerolic acid-rich hemp extract in fed and fasted dogs: Physiological effect and pharmacokinetic evaluation. Kara Amstutz, Wayne S. Schwark, Alexander Zakharov, Beatriz Gomez, Alex Lyubimov, Karolynn Ellis, Kurt P. Venator, Joseph J. Wakshlag. Vet. Pharm. & Therapeutics. February 2022; doi: 10.1111/jvp.13048. Quote: The use of cannabinoids in veterinary medicine has been increasing exponentially recently and there is little information regarding the pharmacokinetics of cannabinoids except for cannabidiol (CBD) and tetrahydrocannabinol (THC), with even more sparse information related to their native acid forms found in cannabis. Cannabigerol (CBG) is the precursor molecule to cannabinoid formation in the cannabis plant which may have medicinal properties as well, yet there are no publications related to CBG or the native cannabigerolic acid (CBGA) in companion animal species. The aim of this study was to investigate similar dosing of CBG and CBGA from hemp plants that have been used for cannabidiol pharmacokinetic studies. ... This is the first pharmacokinetic serum assessment of CBG and CBGA using an infused sesame oil that contained a mixture of 30 mg/ml CBG and 30 mg/ml CBGA given orally to dogs. ... Six intact male beagles all 2 years of age weighing between 18.6 and 22.2 kilograms body weight ... underwent the fasted treatment trial for a two-week period. ... After Day 14 of treatment, the dogs were allowed 2 weeks of washout. After this washout period, dogs began a 2-week period of similar treatment in the fed state ... . Administration in the fed and fasted state was performed to better understand absorption and retention of these unique hemp-derived cannabinoids in dogs. Results suggest that when providing a hemp-derived CBG/CBGA formulation in equal quantities, CBGA is absorbed approximately 40-fold better than CBG regardless of being given to fed or fasted dogs. After twice daily dosing for two weeks at 2 mg/kg in the fasted and then fed state, no differences in the mean serum CBG (5 ng/ml) or CBGA (250 ng/ml) serum concentrations were observed between states. Importantly, physical examination, complete blood counts, and serum chemistry evaluations over the two weeks suggest no adverse events during this short-term dosing trial.

Antibacterial activity of cannabis extract (Cannabis sativa L. subsp. indica (Lam.)) against canine skin infection bacterium Staphylococcus pseudintermedius. Jareerat Aiemsaarda, Ranee Singh, Glenn N. Borlace, Bungorn Sripanidkulchai, Peera Tabboon, Eakachai Thongkham. Sci. Asia, February 2022; doi: 10.2306/scienceasia1513-1874.2022.053. Quote: Superficial bacterial skin infections caused by Staphylococcus pseudintermedius are common in dogs. The cannabis plant has shown potential antibacterial effects, but there is limited information about anti-S. pseudintermedius activity. This study investigated the antibacterial activity of the ethanolic extract and the topical formulations of Cannabis sativa L. subsp. indica (Lam.) against 23 S. pseudintermedius isolates obtained from canine pyoderma using broth microdilution and time-kill assays. The cannabis extract’s minimum inhibitory concentrations for 50% (MIC50) and 90% (MIC90) of the tested S. pseudintermedius isolates were 6.25 and 12.50 µg/ml, respectively. The MIC for S. pseudintermedius ATCC 49051 was 6.25 µg/ml. The time-kill test revealed that the bactericidal effect of the cannabis extract was time- and not concentration-dependent. Topical formulations containing 0.5, 1, 2, 5, and 10% w/w cannabis extract showed limited in vitro antimicrobial activity in the time-kill test. Only the formulations with cannabis extract of 10% and 5% w/w could reduce the number of viable S. pseudintermedius ATCC 49051 by more than 3-log10 (99.9%) at 6 and 24 h, respectively. This study demonstrated that the cannabis extract has a good potential to be developed as an antibacterial agent against S. pseudintermedius. However, a clinical trial should be conducted to determine its in vivo therapeutic efficacy.

Effects of cannabidiol without delta-9-tetrahydrocannabinol on canine atopic dermatitis: a retrospective assessment of 8 cases. Chie Mogi, Masanori Yoshida, Koji Kawano, Takaaki Fukuyama, Toshiro Arai. Can. Vet. J. April 2022;63(4):423-426. Quote: 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 [none being cavaliers] 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. ... We administered a 10% CBD-containing broad-spectrum hemp oil (Mary’s Tails Hemp Extract Tincture; Mary’s Nutritionals, Denver, Colorado, USA) to the 8 dogs with CAD for at least 8 wk. Each dog received oral administrations q12h for the entire study period at a dose of 0.14 to 1.43 mg/kg/d. These CBD products were certified to not contain THC. ... According to the CBD manufacturer’s information, all dogs were started at a dose of approximately 0.07 to 0.25 mg/kg of body weight twice daily. During the testing period, the dose was increased depending on the skin condition of each dog and the observed response at 0.125 mg/kg. The dose was increased if no apparent change was observed with the previous dose. Concomitant medications were allowed during the study period, and their doses could be maintained or reduced by the certified dermatologist on Day 0. ... No adverse events were reported following ingestion of the CBD oil. Improvements were noticed in each dog, as described in the following paragraphs. Due to the absence of a control group, we could not conclude whether the improvements were caused fully or in part by the CBD. The CADESI values decreased in 5 dogs, remained unchanged in 1 dog, and increased in 1 dog. The PVAS values decreased in 7 dogs but increased in 1 dog. ... In the present study, improvements in pruritic behavior were observed in all dogs, which may have been related to the use of CBD. However, the lack of a control group is one of the main limitations of this study, which restricted the conclusions regarding the efficacy of CBD. ... 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. ... Although the number of cases was limited, we tested a new treatment method with the aim of examining the safety of combining a CBD supplement with therapeutic drugs, with a lack of adverse events following administration of CBD. Furthermore, there was a decrease in the frequency of concomitant medication use and an improvement in quality of life and symptoms, suggesting that a new approach using supplementary CBD could improve the quality of life for dogs as well as their owners. ... 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.

The effect of a mixed cannabidiol and cannabidiolic acid based oil on client-owned dogs with atopic dermatitis. Melissa Loewinger, Joseph J. Wakshlag, Daniel Bowden, Jeanine Peters-Kennedy, Andrew Rosenberg. Vet. Derm. May 2022; doi:10.1111/vde.13077. Quote: 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.

Pharmacokinetics of Cannabidiol Following Intranasal, Intrarectal, and Oral Administration in Healthy Dogs. Dakir Polidoro, Robin Temmerman, Mathias Devreese, Marios Charalambous1, Luc Van Ham, Ine Cornelis, Bart J. G. Broeckx, Paul J. J. Mandigers, Andrea Fischer, Jan Storch, Sofie F. M. Bhatti. Front. Vet. Sci. June 2022; doi: 10.3389/fvets.2022.899940. Quote: The therapeutic potential of cannabidiol (CBD), a non-psychtropic component of the Cannabis sativa plant, is substantiated more and more. We aimed to determine the pharmacokinetic behavior of CBD after a single dose via intranasal (IN) and intrarectal (IR) administration in six healthy Beagle dogs age 3–8 years old, and compare to the oral administration route (PO). Standardized dosages applied for IN, IR and PO were 20, 100, and 100 mg, respectively. Each dog underwent the same protocol but received CBD through a different administration route. CBD plasma concentrations were determined by ultra-high performance liquid chromatography-tandem mass spectrometry before and at fixed time points after administration. Non-compartmental analysis was performed on the plasma concentration-time profiles. Plasma CBD concentrations after IR administration were below the limit of quantification. The mean area under the curve (AUC) after IN and PO CBD administration was 61 and 1,376 ng/mL*h, respectively. The maximal plasma CBD concentration (Cmax) after IN and PO CBD administration was 28 and 217 ng/mL reached after 0.5 and 3.5 h (Tmax), respectively. Significant differences between IN and PO administration were found in the Tmax (p = 0.04). Higher AUC and Cmax were achieved with 100 mg PO compared to 20 mg IN, but no significant differences were found when AUC (p = 0.09) and Cmax (p = 0.44) were normalized to 1 mg dosages. IN administration of CBD resulted in faster absorption when compared to PO administration. However, PO remains the most favorable route for CBD delivery due to its more feasible administration. The IR administration route is not advised for clinical application.

Safety and efficacy of cannabidiol-cannabidiolic acid rich hemp extract in the treatment of refractory epileptic seizures in dogs. Gabriel A. Garcia1, Stephanie Kube, Sheila Carrera-Justiz, David Tittle, Joseph J. Wakshlag. Front. Vet. Sci. July 2022; doi: 10.3389/fvets.2022.939966. Quote: The use of cannabidiol (CBD) in childhood refractory seizures has become a common therapeutic approach for specific seizure disorders in human medicine. Similarly, there is an interest in using CBD, cannabidiolic acid (CBDA) or cannabinoid-rich hemp products in the treatment of idiopathic epilepsy in dogs. We aimed to examine a small cohort in a pilot investigation using a CBD and CBDA-rich hemp product for the treatment of refractory epileptic seizures in dogs. 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. Results demonstrated that besides a mild increase in alkaline phosphatase, there were no alterations observed on routine bloodwork at 2, 6, and 12 weeks during either arm of the study. 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). No differences were observed in serum zonisamide, phenobarbital or bromide concentrations while on the treatment across groups. 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. This further indicates that providing CBD/CBDA-rich hemp extract during refractory epilepsy (only partially responsive to ASM), in conjunction with other ASM appears safe. 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.

Long-term daily feeding of cannabidiol is well-tolerated by healthy dogs. Sophie Bradley, Scott Young, Anne Marie Bakke, Lucy Holcombe, Daniel Waller, Alysia Hunt, Kathleen Pinfold, Phillip Watson, Darren W. Logan. Front. Vet. Sci. September 2022; doi: 10.3389/fvets.2022.977457. Quote: Cannabidiol (CBD) containing dog food and treats are widely commercially available, mirroring the growing popularity of CBD as a supplement for humans. Despite this, experimental evidence of the safety and efficacy of long-term oral exposure in dogs is lacking. The purpose of this study was to address the gap in knowledge around the longer-term suitability and tolerance of a broad-spectrum CBD (THC-free) distillate in clinically healthy dogs. The study was a randomized, placebo-controlled, and blinded study where one group of twenty dogs received daily CBD capsules at a dose of 4 mg/kg of body weight (BW) for a period of 6 months. The control group of twenty dogs received placebo capsules. A comprehensive suite of physiological health measures was performed throughout the study at baseline, and after 2, 4, 10, 18, and 26 weeks of exposure, followed by 4 weeks of washout. CBD concentrations were measured at the same cadence in plasma, feces and urine. Health measures included biochemistry, hematology, urinalysis, in addition to fortnightly veterinary examinations, twice daily well-being observations, and a daily quality-of-life survey. Biochemistry and hematology showed no clinically significant alterations apart from a transient elevation in alkaline phosphatase (ALP) in just over half of the dogs receiving CBD. This elevation was observed in the absence of concurrent elevations of other liver parameters, and without any adverse effects on health and wellbeing. Furthermore, bone alkaline phosphatase (BALP) was simultaneously elevated with a significant, strong (r > 0.9) positive correlation between the two measures, suggesting that the elevation of total ALP was at least partly due to the bone-derived isoform. This study provides evidence that a once-daily oral dose of 4 mg CBD/kg BW is well tolerated in clinically healthy dogs for a duration of 6-months.

Pharmacokinetics of cannabidiol following single oral and oral transmucosal administration in dogs. Giorgia della Rocca1,2 Fabiola Paoletti3 Maria Beatrice Conti1,2* Roberta Galarini3 Elisabetta Chiaradia1 Monica Sforna1 Cecilia Dall'Aglio1 Angela Polisca1 Alessandra Di Salvo. Front. Vet. Sci. January 2023; doi: 10.3389/fvets.2022.1104152. Quote: Introduction: In the last few years, different formulations containing cannabidiol (CBD) were tested with regard to its efficacy on chronic pain, refractory epilepsy, anxiety, aggressive behavior and atopic dermatitis in dogs. CBD is generally administered orally, but its low bioavailability, probably due to a first-pass metabolism, represents a great limitation. The aim of this study was to evaluate if CBD bioavailability increases after oral transmucosal administration (OTM) compared to oral treatment. Methods: Twelve dogs diagnosed with mild chronic pain were enrolled in the study and treated once orally or OTM (6 dogs/group) with a pure CBD in oil formulation at a dosing rate of 1 mg/kg b.w. ... A 10% formulation of CBD in MTC oil was used in the present study to permit the administration of reduced volumes of solution considering the dogs' weight range, thus avoiding losses outside the mouth when given OTM (16). Moreover, besides preventing the oxidative degradation and the decrease of cannabinoid's concentration better than other oils (24), MTC oil is flavorless, limiting ptyalism and vomiting (16). When given orally, CBD oil was mixed with a small amount of dry food to facilitate the administration of the drug and as a food bolus is reputed to enhance the gastrointestinal absorption of very lipophilic substances such as CBD. ... At prefixed time points, blood samples were collected to define CBD plasma concentrations vs. time profiles, and the main pharmacokinetics parameters were obtained by non-compartmental model. Results: CBD Cmax, Tmax, terminal half-life and AUC0−t were 206.77 ± 167 and 200.33 ± 158.33 ng/mL, 2.17 ± 0.98 and 1.92 ± 1.11 h, 2.67 ± 0.53 and 2.62 ± 0.64 h, 647.51 ± 453.17, and 536.05 ± 370.21 h*ng/mL, following oral and OTM administration, respectively. No significant difference in pharmacokinetic parameters were observed between treatments. Discussion: The OTM administration did not increase cannabidiol bioavailability compared to oral treatment. The almost perfectly superimposable mean plasma concentrations of cannabidiol following the two treatments suggests that CBD is not able to be adsorbed by the oral mucosa or that its absorption is very scarce, and that CBD is swallowed and absorbed in the gastrointestinal tract. ... Conclusions: ... Contrarily to our expectations, the OTM administration of a pure CBD oil did not increase its bioavailability compared to oral administration. The development of innovative formulations able to enhance a fast penetration of CBD in the systemic circulation through the oral mucosa is therefore desirable.

Scientific Validation of Cannabidiol for Management of Dog and Cat Diseases. Isabella Corsato Alvarenga, Kiran S. Panickar, Hannah Hess, Stephanie McGrath. Annu. Rev. Anim. Biosci. February 2023; doi: 10.1146/annurev-animal-081122-070236. Quote: Cannabidiol (CBD) is a non-psychotropic phytocannabinoid of the plant Cannabis sativa L. CBD is increasingly being explored as an alternative to conventional therapies to treat health disorders in dogs and cats. Mechanisms of action of CBD have been investigated mostly in rodents and in vitro and include modulation of CB1, CB2, 5-HT, GPR, and opioid receptors. In companion animals, CBD appears to have good bioavailability and safety profile with few side effects at physiological doses. Some dog studies have found CBD to improve clinical signs associated with osteoarthritis, pruritus, and epilepsy. However, further studies are needed to conclude a therapeutic action of CBD for each of these conditions, as well as for decreasing anxiety and aggression in dogs and cats. Herein, we summarize the available scientific evidence associated with the mechanisms of action of CBD, including pharmacokinetics, safety, regulation, and efficacy in ameliorating various health conditions in dogs and cats. ... Whether CBD is effective in reducing epileptic episodes in dogs with IE is inconclusive, and to date there are more clinical reports than controlled clinical studies.

The clinical use of cannabidiol and cannabidiolic acid–rich hemp in veterinary medicine and lessons from human medicine. Masayasu Ukai, Stephanie McGrath, Joseph Wakshlag. J. Amer. Vet. Med. Assn. March 2023; doi: 10.2460/javma.23.02.0064. Quote: The endocannabinoid system (ECS) is an integral neuromodulatory system involved in neuronal development, synaptic plasticity, and homeostasis regarding immunity, as well as brain and other physiological functions such as anxiety, pain, metabolic regulation, and bone growth. Cannabis is a plant that contains exogenous cannabinoids, which have the potential for profound interplay within the ECS as enzymatic inhibitors or receptor-mediated interactions. Activation of cannabinoid receptors leads to various intracellular signaling processes that are involved in cellular functions, but those interactions are diverse due to different affinities of each cannabinoid with relevant receptors. Among the exogenous cannabinoids, cannabidiol (CBD) has drawn attention due to its potential anticancer, antiangiogenic, anti-inflammatory, and antiseizure properties using in vitro and in vivo models. Although scientific evidence is limited in dogs, there appears to be cautious optimism regarding the utilization of CBD in conjunction with other therapeutics for a range of disorders. This review will primarily focus on current scientific research on the efficacy of CBD on seizure, anxiety, osteoarthritis, and atopic dermatitis, following a brief discussion of endo- and exogenous cannabinoids, ECS, their molecular mechanism, and potential side effects in veterinary medicine. Cannabinoid pharmacology and pharmacokinetics will be addressed in the companion Currents in One Health by Schwark and Wakshlag, AJVR, May 2023. ... Conclusions: Although the use of cannabinoids, particularly CBD products, is in its infancy in veterinary medicine, there appears to be cautious optimism regarding its utilization concurrently with other therapeutics for a range of disorders including epileptic seizure control, pain associated with osteoarthritis, and atopic dermatitis. There is currently no appreciable evidence that CBD products have utility in the treatment of situational or chronic anxiety in dogs. Drug interactions have been poorly elucidated across veterinary species with emerging evidence that many of the current antiepileptic drugs do not seem to be a major concern in dogs.

A One Health perspective on comparative cannabidiol and cannabidiolic acid pharmacokinetics and biotransformation in humans and domestic animals. Wayne S. Schwark, Joe Wakshlag. Am. J. Vet. Res. March 2023; doi: 10.2460/ajvr.23.02.0031. Quote: The goal of pharmacokinetic (PK) studies is to provide a basis for appropriate dosing regimens with novel therapeutic agents. With a knowledge of the desired serum concentration for optimum pharmacological effect, the amount and rate of drug administration can be tailored to maintain that concentration based on the 24-hour PK modeling (eg, every 24 hours, every 12 hours) to achieve therapeutic ranges. This dosing and PK information are tailored to maintain that concentration. Typically, these optimum serum concentrations pertain across species. Single-dose PK modeling provides fundamental parameters to suggest dosing regimes. Multiple-dose PK studies provide information on steady-state serum levels to assure that desired therapeutic levels are maintained during chronic administration. Clinical trials using dosing suggested by these PK determinations provide proof that the compound is producing the desired therapeutic effect. A number of PK studies with cannabinoids in humans and domestic animals have been conducted with the goal of determining appropriate clinical use with these plant-derived products. The following review will focus on the PK of cannabidiol (CBD) and the lesser-known precursor of CBD, cannabidiolic acid (CBDA). Although Δ9-tetrahydrocannabinol (THC) has profound pharmacological effects and may be present at variable and potentially violative concentrations in hemp products, PK studies with THC will not be a major consideration. Because, in domestic animals, hemp-CBD products are usually administered orally, that route will be a focus. When available, PK results with CBD administered by other routes will be summarized. In addition, the metabolism of CBD across species appears to be different in carnivorous species compared with omnivorous/herbivorous species (including humans) based on current information, and the preliminary information related to this will be explained with the therapeutic implication being addressed in Currents in One Health by Ukai et al, JAVMA, May 2023. ... Conclusions: A few concepts surrounding PKs from a One Health perspective are becoming increasingly clear. Firstly, CBD absorption and retention appear to be superior in dogs and cats as they can often achieve over 100 ng/mL as a Cmax while humans and horses are often 10-fold lower when utilizing similar dosing. This may be due to inherent CYP450 enzymatic differences between species and it is becoming increasingly evident that the typical metabolite 7 COOH-CBD found in humans and horses appears to be a secondary metabolite in dogs and cats. Second, in veterinary species, the absorption of CBDA, and generally all of the acidic forms of cannabinoids, appears to be absorbed and retained at a higher level than CBD suggesting that further work in this area is warranted because it may be easier to reach therapeutic levels and there is a dearth of information regarding CBDA in the human literature. There is still a tremendous amount of research to be done surrounding long-term PKs and optimization of therapeutic levels across all species making this a “One Health” initiative that will benefit humans and animals alike.

Pharmacokinetics, efficacy, and safety of cannabidiol in dogs: an update of current knowledge. Alessandra Di Salvo, Maria Beatrice Conti, Giorgia della Rocca. Front. Vet. Sci. June 2023; doi: 10.3389/fvets.2023.1204526. Quote: In the last 5 years, interest has grown in using phytocannabinoids, particularly cannabidiol (CBD), in veterinary medicine to treat several pathologies, including pain, epilepsy, anxiety, nausea, anorexia, skin lesions, and even some types of cancer, among others. Indeed, due to a positive perception of CBD use, many pet owners are increasingly requesting this option to relieve their pets, and many veterinarians are exploring this possibility for their patients. Besides the widespread empiric use of CBD in pets, the research is trying to obtain proof of its efficacy and lack of adverse effects and to know its pharmacokinetics to define an appropriate posology. This review summarizes all data published so far about the canine pharmacokinetics, efficacy, and tolerability of CBD and cannabidiolic acid (CBDA). Despite a certain number of available pharmacokinetic studies, the kinetic profile of CBD has yet to be fully known, probably because of the very different experimental conditions. In terms of efficacy, most studies have tested CBD’ ability to relieve osteoarthritic pain. In contrast, few studies have evaluated its role in epilepsy, behavioral disorders, and skin lesions. From obtained results, some evidence exists supporting the beneficial role of CBD. Nevertheless, the limited number of published studies and the occurrence of bias in almost all require caution in interpreting findings. From tolerability studies, CBD’ side effects can be classified as mild or unremarkable. However, studies were prevalently focused on short- to medium-term treatment, while CBD is usually employed for long-term treatment. Further studies are warranted to define better whether CBD could be a valid adjunct in canine treatment.

 Therapeutic efficacy and pharmacokinetics of liposomal-cannabidiol injection: a pilot clinical study in dogs with naturally-occurring osteoarthritis. Yael Shilo-Benjamini, Eran Lavy, Nadav Yair, Joshua Milgram, Daniel Zilbersheid, Atara Hod, Dinorah Barasch, Wiessam Abu Ahmad, Ahuva Cern, Yechezkel Barenholz. Front. Vet. Sci. August 2023; doi: 10.3389/fvets.2023.1224452. Quote: Introduction: Osteoarthritis is a common disease in dogs resulting in chronic pain and decreased wellbeing. Common analgesics such as non-steroidal antiinflammatories may fail to control pain and can produce major adverse effects. Study objectives were to evaluate pharmacokinetics, therapeutic efficacy, and safety of subcutaneous liposomal-cannabidiol (CBD) as an additional analgesic therapy in dogs suffering from naturally-occurring osteoarthritis. Methods: Six such dogs were recruited following ethics approval and owner consent. Dogs were administered a single subcutaneous injection of 5 mg/kg liposomal-CBD. Plasma concentrations of CBD, blood work, activity monitoring collar data, wellbeing questionnaire (owners) and pain scoring (veterinarian) were performed at baseline and monitored up to six weeks following intervention. Data overtime were compared with baseline using linear-regression mixed-effects. Pvalue was set at 0.05. Results: CBD plasma concentrations were observed for 6 weeks; median (range) peak plasma concentration (Cmax) was 45.2 (17.8–72.5) ng/mL, time to Cmax was 4 (2–14) days and half-life was 12.4 (7.7–42.6) days. Median (range) collar activity score was significantly increased on weeks 5–6; from 29 (17–34) to 34 (21–38). Scores of wellbeing and pain evaluations were significantly improved at 2–3 weeks; from 69 (52–78) to 53.5 (41–68), and from 7.5 (6–8) to 5.5 (5–7), respectively. The main adverse effect was minor local swelling for several days in 5/6 dogs. Conclusion: Liposomal-CBD administered subcutaneously produced detectable CBD plasma concentrations for 6 weeks with minimal side effects and demonstrated reduced pain and increased wellbeing as part of multimodal pain management in dogs suffering from osteoarthritis. Further placebo-controlled studies are of interest.

Efficacy and safety of cannabidiol for the treatment of canine osteoarthritis: a systematic review and meta-analysis of animal intervention studies. Chanthawat Patikorn, Osot Nerapusee, Kumpanart Soontornvipart, Kanta Lawonyawut, Kachapong Musikpodok, Kanisorn Waleethanaphan, Puree Anantachoti. Front. Vet. Sci. September 2023; doi: 10.3389/fvets.2023.1248417. Quote: Introduction: Canine osteoarthritis (OA) is a degenerative disease with chronic inflammation of internal and external joint structures in dogs. Cannabis spp. contains cannabidiol (CBD), a substance known for various potential indications, such as pain relief and anti-inflammatory in various types of animals, including dogs with OA. As CBD is increasingly in the spotlight for medical use, we aimed to perform a systematic review and meta-analysis to evaluate the efficacy and safety of CBD in treating canine OA. Methods: We searched PubMed, Embase, Scopus, and CAB Direct for animal intervention studies investigating the effects of CBD for canine OA from database inception until February 28, 2023. Study characteristics and findings were summarized. A risk of bias in the included studies was assessed. Meta-analyses were performed using a random-effects model to estimate the effects of CBD on pain scores (0–10), expressed as mean difference (MD) and 95% confidence interval (95% CI). Certainty of evidence was assessed using GRADE. Results: Five articles were included, which investigated the effects of CBD in 117 dogs with OA. All studies were rated as having a high risk of bias. CBD products varied substantially, i.e., oral full-spectrum CBD oil in four studies, and isolated CBD oil and liposomal CBD oil in another study. Treatment duration varied from 4–12 weeks. Meta-analyses of three studies found that, in dogs with OA, treatment with oral full-spectrum CBD oil may reduce pain severity scores (MD; −0.60, 95% CI; −1.51 to 0.31, I2 = 45.64%, p = 0.19) and pain interference scores (MD; −1.52, 95% CI; −3.84 to 0.80, I2 = 89.59%, p = 0.20) but the certainty of evidence was very low. CBD is generally considered safe and well-tolerated in the short-run, with few mild adverse events observed, such as vomiting and asymptomatic increase in alkaline phosphatase level. Conclusion: CBD is considered safe for treating canine OA. CBD may reduce pain scores, but the evidence is very uncertain to conclude its clinical efficacy. High-quality clinical trials are needed to further evaluate the roles of CBD in canine OA.

Cannabidiol plasma determination and pharmacokinetics conducted at beginning, middle and end of long-term supplementation of a broad-spectrum hemp oil to healthy adult dogs. Isabella Corsato Alvarenga, Daniel Gustafson, Krista Banks, Kim Wilson, Stephanie McGrath. Front. Vet. Sci. September 2023; doi: 10.3389/fvets.2023.1279926. Quote: Introduction: Veterinary hemp products containing cannabidiol (CBD) and negligible psychoactive (THC) have increased popularity since hemp (with <0.3% THC) was removed from schedule 1 substances under the Controlled Substances Act in 2018. This was accompanied by increased CBD research, mostly on the short-term safety and efficacy for inflammatory and neurological conditions. It is imperative to understand how CBD is metabolized or accumulated in the body long-term, thus the goal of the present work was to determine monthly plasma CBD concentrations, as well as changes in pharmacokinetic (PK) parameters in chronically dosed dogs. Methods: The study was a masked, placebo-controlled, randomized design. Six adult beagles were assigned to placebo, 5 and 10 mg/kg/day CBD treatment groups. Dogs received oral oil treatment once daily for 36 weeks. Blood was collected once every 4 weeks pre- and postprandially for CBD plasma determination (at 0 and 2h). Pharmacokinetics were conducted at 0, 18 and 36 weeks. Pharmacokinetics and monthly CBD plasma data of dogs who received CBD were analyzed as repeated measures over time using a mixed model, with significance at α=0.05. Results: Average plasma CBD at 5 and 10 mg/kg were 97.3 ng/mL and 236.8 ng/mL pre-prandial, 341 ng/mL and 1,068 ng/mL postprandial, respectively. PK parameters suggested CBD accumulation over time, with significant increases in Cmax and AUC at both the 18 and 36-week timepoints. Cmax and AUC were dose proportional. Half-life demonstrated large inter-individual variations and increased (p<0.05) at weeks 18 and 36 compared to baseline. Volume of distribution was not affected by time or treatment, while MRT increased, and clearance decreased over time (p<0.05). Conclusions and clinical importance: Chronic administration of CBD to healthy adult dogs led to a dose-proportional accumulation in the body for 36 weeks, which was confirmed by an increased half-life, total exposure, mean residence time and plasma peak. Our data also suggests that CBD plasma levels may have less daily variation if administered twice daily.

Dermatological evaluation in dogs with atopic dermatitis treated with full-spectrum high cannabidiol oil: a pre study part 1. Carollina Mariga1, Ana Lűcia Souza Silva Mateus, Ângela Isabel dos Santos Dullius, Ana Paula da Silva, Mariana Martins Flores, Andrě Vasconcelos Soares, Erik Amazonas, Saulo Tadeu Lemos Pinto Filho. Front. Vet. Sci. October 2023; doi: 10.3389/fvets.2023.1285384. Quote: Introduction: Dermatological consultations represent a great part of the small animal medical clinic routine. Canine atopic dermatitis (CAD) is a common skin disease that affects a significant amount of dogs, making it a relevant consideration in clinical practice. The role of the endocannabinoid system on skin homeostasis has been described and its deregulation contributes to dermatopathies. Its function in specialized skin cells reveals an expressive therapeutic potential. Due to the difficulties and the growing scientific evidence of the therapeutic benefits of cannabis on animals, this work aimed to evaluate the anti-inflammatory effects of cannabis-derived oil in the treatment of CAD. Methods: Fourteen canines [none were cavaliers] diagnosed with CAD were divided into two groups: T: full spectrum high cannabidiol (CBD) cannabis oil, 2,5 mg/kg; and C: control group (treated with olive oil alone). The effectiveness was evaluated based on the degree of pruritus, dermatological evaluation (CADESI-4) and histopathological evaluation of the skin including mast cell count. Results: Despite the theoretical basis, there were no significant results obtained between the compared treatments. Discussion: Thus, it can be concluded that although full spectrum high cannabinoids therapy presents a promising approach to immunological diseases, further research is required in order to establish the actual effective cannabinoid ratio within the myriad possible combinations and for multi-target therapy of CAD.

Tolerability of long-term cannabidiol supplementation to healthy adult dogs. Isabella Corsato Alvarenga, Kim M. Wilson, Stephanie McGrath. J. Vet. Intern. Med. November 2023; doi: 10.1111/jvim.16949. Quote: Background: Cannabidiol (CBD) has therapeutic potential in companion animals. Shorter-term studies have determined that CBD is well tolerated in dogs with mild adverse effects and an increase in alkaline phosphatase (ALP) activity. There is need to assess CBD's long-term tolerability. Hypothesis: Determine the long-term tolerability of CBD administered PO to healthy dogs for 36 weeks at dosages of 5 and 10 mg/kg body weight (BW)/day. Our hypothesis was that CBD would be well tolerated by dogs. Methods: Eighteen healthy adult beagle dogs were randomly assigned to 3 groups of 6 each that received 0, 5, or 10 mg/kg BW/day CBD PO. Dogs were adapted to their housing for 3 weeks and received treatment for 36 weeks once daily with food. Adverse events (AEs) were recorded daily. Blood biochemistry profiles were monitored every 4 weeks. Data were analyzed as repeated measures over time using a mixed model, with significance at α = 0.05. Results: The 0 and 5 mg/kg treatment groups had similar fecal scores, and the 10 mg/kg treatment group had higher frequency of soft feces. No other significant AEs were noted. An increase (P < .0001) in ALP activity occurred in groups that received CBD. Remaining blood variables were within reference range. Conclusions and Clinical Importance: Chronic administration of CBD in healthy dogs at 5 mg/kg was better tolerated than 10 mg/kg, and both dosages caused an increase in ALP activity. Although our data does not indicate hepatic damage, it is recommended to monitor liver function in dogs receiving CBD chronically.

The efficacy and safety of cannabidiol as adjunct treatment for drug-resistant idiopathic epilepsy in 51 dogs: A double-blinded crossover study.. Aaron J. Rozental, Brooke G. Weisbeck, Isabella Corsato Alvarenga, Daniel L. Gustafson, Breonna R. Kusick, Sangeeta Rao, Lisa R. Bartner, Stephanie McGrath. J. Vet. Intern. Med. November 2023; doi: 10.1111/jvim.16912. Quote: Background: Approximately 30% of dogs with idiopathic epilepsy (IE) are drug-resistant. Recent studies have suggested cannabidiol (CBD) may be an effective anticonvulsant in dogs with IE. Objective: To evaluate the addition of CBD to antiseizure drugs (ASDs) on seizure frequency and to report adverse events in dogs with drug-resistant IE. Animals: Fifty-one dogs. Dogs having at least 2 seizures per month while receiving at least 1 ASD were included in the trial. Methods: Double-blinded placebo-controlled crossover study. The 5mg/kg/day dosage met futility requirements after 12 dogs, and a dosage of 9mg/kg/day was used in the next 39 dogs. Dogs were randomly assigned to receive CBD or placebo for 3 months, with a 1-month washout period between oils. Total numbers of seizures and seizure days were recorded. Diagnostic testing was performed periodically throughout the trial. Results: At the 9mg/kg/day dose, the decrease in total seizure frequency was significant compared with placebo. A 24.1% decrease in seizure days occurred in dogs receiving CBD and a 5.8% increase occurred in dogs receiving placebo (P≤.05). No significant difference was found in the number of responders (≥50% decrease in total seizures or seizure days). Liver enzyme activities increased at both dosages. Decreased appetite and vomiting were more common in the CBD phase (P ≤.05). Conclusions and Clinical Importance: Cannabidiol decreased total seizures and seizure days compared to placebo when administered to dogs PO at 9mg/kg/day. Liver enzymes should be monitored with administration of CBD in dogs.

Safety study of cannabidiol products in healthy dogs. William Bookout, Margitta Dziwenka, Margitta Dziwenka, Kaiti Valm, Jennifer Kovacs-Nolan. Front. Vet. Sci. March 2024; doi: 10.3389/fvets.2024.1349590. Quote: The tolerability of different cannabinoids given orally to dogs was evaluated in a randomized, non-blinded, negative controlled, parallel design 90-day repeat dose study with a 14-day recovery period. Healthy beagles (16 males and 16 females) were randomized into four treatment groups and treated with either medium chain triglyceride oil as the control or one of the following: broad spectrum cannabidiol, broad spectrum cannabidiol with cannabigerol, or broad spectrum cannabidiol with cannabidiolic acid at 5 mg total cannabinoids/kg body weight/day. Animals were observed daily with detailed clinical examinations conducted weekly. Animals were monitored for an additional 2 weeks after dosing. Body weights, food consumption and clinical pathology evaluations were included in the study. Cannabinoids were well tolerated when healthy male and female beagles were dosed for 90 consecutive days. Annual post-market surveillance data for hemp-derived supplement products sold for use in dogs from 2010 to 2023 (partial year) shows that the rate per 1 million administrations sold is 2.10 for adverse events and 0.01 for serious adverse events. Based on the results of this study, other published studies, and data from extensive post-market surveillance, hemp-derived cannabinoids are well tolerated in healthy dogs at a dose of 5 mg/kg body weight/day.

Pharmacokinetics behavior of four cannabidiol preparations following single oral administration in dogs. Sasithorn Limsuwan, Natthaporn Phonsatta, Atikorn Panya, Rathapon Asasutjarit, Natthasit Tansakul. Front. Vet. Sci. April 2024; doi: 10.3389/fvets.2024.1389810. Quote: Cannabidiol (CBD) is a natural phytochemical agent and one of the most abundant found in Cannabis sativa. It is known to exhibit pharmacological properties on various condition such as relieving-inflammation, pain, epilepsy, and anxiety effect. There has been an increasing trend globally in the use of CBD as a supplement in pets. Consequently, there are various CBD products being marketed that are specifically available for pets. Veterinarians and pet owners are concerned that following ingestion, different CBD formulations may result in a CBD level circulating in the blood that may affect the safe use and efficacy of CBD in pets. Several pharmacokinetics studies in animals have been mainly conducted with an oily form of CBD. To date, there is a lack of data regarding direct comparisons in animals among the CBD plasma kinetic profiles from an oral administration of the various preparation forms. Therefore, the current study evaluated and compared the plasma CBD levels from a single oral administration using four different CBD preparations—liquid (an oil-based form, a nanoemulsion form, or a water-soluble form) or a semi-solid form (as CBD mixed in a treat) in dogs. In total, 32 healthy, crossbreed dogs were randomly assigned into 4 groups and treated according to a 1-period, 4-treatment parallel-design. The three liquid forms were dosed at 5 mg/kg body weight, while the single semi-solid form was given at 50 mg/treat/dog. The results showed that the CBD plasma profile from the administration of a water-soluble form was comparable to that of the oil-based group. The nanoemulsion-based form tended to be rapidly absorbed and reached its peak sooner than the others. However, the CBD in all preparations reached the maximum plasma concentration within 3 h post-dose, with an average range of 92–314 μg/L. There were significant differences among certain parameters between the liquid and semi-solid forms. This was the first study to provide pharmacokinetics data regarding CBD in water soluble, nanoemulsion-based, and semi-solid forms for dogs as companion animals. The current data should facilitate the scrutiny of CBD plasma profiles based on different formulations via an oral route in dogs.

Cannabidiol plus krill oil supplementation improves chronic stifle osteoarthritis in dogs: A double-blind randomized controlled trial. K. Soontornvipart, P. Wongsirichatchai, A. Pongphuwanun, K. Chatdarong, S. Vimolmangkang. Vet. J. August 2024; doi: 10.1016/j.tvjl.2024.106227. Quote: Osteoarthritis (OA) is the most common orthopedic disorder characterized by chronic inflammation and pain in dogs and cats. Cannabis spp. contains cannabidiol (CBD), a substance with pain relief and anti-inflammatory properties in different animals including dogs with OA. The use of CBD supplements has been increasingly intertwining in veterinary medicine. This study aimed to evaluate the clinical efficacy of CBD + krill oil-supplemented biscuit against canine OA. In total, 30 dogs with stifle OA were randomized and divided into the placebo, krill oil, and CBD + krill oil groups. The Canine Brief Pain Inventory questionnaire was used to evaluate the efficacy of each treatment against pain. Stifle temperature was monitored to identify degrees of stifle inflammation. Two and one dogs in the placebo group were excluded from the study due to worsening lameness and increased pain interference score (PIS) and pain severity score (PSS) at days 14 and 28, respectively. The PIS and PSS scores of the krill oil and CBD + krill oil groups gradually and significantly improved after two weeks of treatment. The CBD + krill oil group had better PIS and PSS scores than the placebo and krill oil groups. However, there was no statistically significant difference in the PIS and PSS scores between the krill oil and CBD + krill oil groups. The stifle temperature of the three groups at different periods did not significantly differ. In conclusion, CBD + krill oil supplements are safe against canine OA. CBD can reduce pain and inflammation. Highlights: • CBD + krill oil-supplemented biscuit significantly reduced pain and inflammation in OA dogs. • Krill oil or CBD + krill oil biscuits both reduced pain, with the latter showing slightly better results. • No side effects were observed when giving the dog the CBD + krill oil-supplemented biscuit.