A Report Of Adverse Effects Associated With The .

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Used with permission of the Journal of the American Holistic Veterinary Medical Association(JAHVMA). Article first appeared in Volume 52, Fall Issue, 2018.Scientific ReportA Report of Adverse EffectsAssociated With the Administration ofCannabidiol in Healthy DogsStephanie McGrath*, DVM, MS, Lisa R. Bartner, DVM, MS,Sangeeta Rao, BVSc, MVSc, PhD, Lori R. Kogan, PhD, Peter W. Hellyer, DVM, MS* Corresponding author, Email: [email protected], Phone: 970-297-5000DEPARTMENT OF CLINICAL SCIENCESColorado State University300 West Drake Road,Fort Collins, ColoradoABBREVIATIONSCBC — cannabichromene (for Table 1)CBD — cannabidiolCBG — cannabigerolCBN — cannabinolLLOQ — lower limit of quantificationTHC — delta-9-tetrahydrocannabinolAbstractCannabis-based therapies have been used for centuriesfor various medicinal purposes. They have recentlygained recognition as an effective treatment for medicalconditions in humans; and, as such, awareness is increasingamong veterinarians and pet owners. However, side effects,pharmacokinetics, and efficacy in dogs are not known. Thepurpose of this study was to determine the tolerability ofcannabidiol (CBD) by healthy dogs. We hypothesized thatCBD would be tolerated in a healthy population ofdogs. A group of 30 healthy Beagle dogs were randomlyassigned to receive CBD in the form of microencapsulatedoil beads (capsule), CBD-infused oil, or CBD-infusedtransdermal cream at a dose of 10 mg/kg/day or 20 mg/kg/day for 6 weeks. Complete blood counts, chemistry34AHVMA Journal Volume 52 Fall 2018panels, urinalysis, and bile acids were performed at 0, 2,4, and 6 weeks. Elevations in serum ALP occurred in somedogs. All of the dogs in the study experienced diarrhea thatwas not associated with the formulation or dose of CBDthat they received. CBD appeared to be well tolerated indogs. However, a more extensive safety study is necessary todetermine if there are long-term effects of CBD on the liverand an association with diarrhea.IntroductionCannabis has been used as a medicinal remedy for centuriesfor the treatment of numerous ailments, including cancer,nausea, irritable bowel syndrome, epilepsy, amyotrophiclateral sclerosis, Parkinson’s disease, dementia, glaucoma,

anxiety, depression, and sleep disorders (1–5). However,there is a paucity of published scientific reports on the safety,pharmacokinetics, or efficacy of cannabis use in human andveterinary medicine (1, 2, 6–8).on blood work, or current treatment with medication. Ofthe 31 dogs assessed, 30 met the inclusion criteria and wereenrolled in the study, and 1 dog was excluded because ofblood work abnormalities.Cannabis sativa is a strain of cannabis plant that containsover 104 different cannabinoids including the mostfamiliar delta-9-tetrahydrocannabinol (THC) andcannabidiol (CBD) (1, 2). THC is the primary psychoactivecannabinoid that is responsible for the “high” experiencedwith cannabis use. There is evidence that certain doses oforal THC in dogs are associated with adverse effects, (2, 9,10). Hemp is a cannabis plant that contains less than 0.3percent THC on a dry-weight basis but is abundant in thenon-psychotropic compound CBD (1, 2). The potentialmedicinal value of CBD makes hemp a promising remedyfor use in veterinary medicine (11–14).All of the dogs enrolled in the study were transported to anon-site research facility. They were either housed in a singlerun or shared a run with 1 other dog. The dogs were fed amaintenance diet once daily, had their runs cleaned twicedaily, received CBD treatments twice daily, had a generalhealth assessment twice daily, and had interactions with thestaff for socialization and exercise once daily. All dogs receiveda complete physical examination by a veterinarian weekly.The CBD for this study was formulated from hemp plantscertified by a third-party company in the state of Colorado.A random number generator was used to assign each dogto 1 of 3 CBD delivery methods: Group 1 had CBD-infusedtransdermal cream applied to the pinnae, Group 2 receivedoral CBD-microencapsulated oil beads (capsule), and Group3 received oral CBD-infused oil. Each of these groups weresplit into 2 subgroups of 5 dogs each. “Subgroup a” received10 mg/kg/day of CBD, and “subgroup b” received 20 mg/kg/day of CBD. For the 6 weeks of the study, the dogsreceived CBD twice daily following a small meal.To the authors’ knowledge, there are no published studiesevaluating the safety and side effects of CBD in dogs. Thisstudy aimed to determine how healthy canine patients wouldtolerate CBD at higher doses than would be anticipated forclinical use. Since there is no established canine dosage,doses for this study were extrapolated from those reported inhuman clinical studies. The majority of human studies useddosages between 2–5 mg/kg per day, but some reportedusing up to 600 mg per day (15, 16). In this study, the dogswere administered 10 or 20 mg/kg/day.The purpose of this study was to record any short-termeffects of CBD in healthy dogs. The hypothesis was thatno clinically relevant adverse events would occur; but ifthere were any subclinical effects, they would occur in adose dependent manner.At weeks 2, 4, and 6, CBCs, chemistry panels, pre- andpostprandial bile acid assays, and urinalyses wererun on samples collected from each dog. The resultsfrom the pre- and postprandial bile acid tests wereused to determine if the effect of CBD on cytochromeP450 activity in dogs was similar to that in humans. Inhumans, phytocannabinoids are extensively metabolizedby hepatic cytochrome P450 enzymes; but CBD is also apotent inhibitor of cytochrome P450 enzymes (16).Materials and MethodsStatistical analysisThis study was approved by Colorado State University’sInstitutional Animal Care and Use Committee (protocolID: 15-5782A; approval date: February 19, 2016). A group of31 healthy intact male research Beagle dogs were evaluatedfor the study. All dogs were 4–5 years old and weighed anaverage of 13 kg (range 9.5–16.2 kg). The dogs had physicalexaminations by either a board-certified neurologist or aneurology resident, and laboratory tests, including CBCs,chemistry panels, urinalyses, and pre- and postprandial bileacid assays. Conditions for exclusion from the study includedcomorbidity with a poor prognosis, significant abnormalitiesClinically significant results were recorded as binary dataindicating the presence or absence of the clinical outcome.Contingency tables were constructed for each of theanalyses; and the Fisher's exact test was used to evaluatethe significance of association between the formulations ateach time point, and between the time points within eachformulation for both doses of CBD. A P value of 0.05 wasused to determine statistical significance. No statistics couldbe performed when all the subjects were in 1 group. SAS v9.4 software (SAS Institute Inc.) was used to analyze the data.ResultsAHVMA Journal Volume 52 Fall 201835

The actual concentration of CBD in the cream, capsules,and oils was determined and compared to the concentrationstated on the labels (see Table 1). All 3 formulationscontained less CBD than indicated on the label. Thevariability was 10% for the CBD-infused transdermal creamand CBD-infused oil (6% for the CBD-infused transdermalcream, 9% for the 150 mg/mL CBD-infused oil, and 3%for the 75 mg/mL CBD-infused oil). However, there wasconsiderable variation between the CBD concentration inthe capsules and the amount stated on the label (28% forthe 50 mg/capsule and 31% for the 25 mg/capsule).Throughout the 6-week study period, gastrointestinal upsetwas the most frequently recorded adverse clinical sign. All ofthe dogs in the study developed diarrhea, and 6/30 (20%)dogs had single episodes of vomiting. The dogs that vomitedwere in the groups that received CBD orally in the form ofcapsules or oil, but it was determined that there was nocorrelation between the episodes of vomiting and the dose orformulation of CBD. The episodes of diarrhea were suspectedto be secondary to the CBD treatments, but dietary variation,including treats, and stress from being housed in a new facilitycould not be ruled out as contributing factors. At the onsetof diarrhea, metronidazole therapy was initiated under thedirection of the laboratory animal veterinarians and withapproval of the authors. All dogs responded well to treatmentwith metronidazole. Each dog’s weight was evaluated weeklyand remained stable for the duration of the study.Erythematous pinnae was the second most common adverseclinical sign reported at week 2 and 4. A mild erythematousreaction of the pinnae occurred in 11 dogs (36%), 9 ofwhom belonged to the group that received the transdermalcream; 4 of those received the 10kg/day dose and 5 of thosereceived the 20 mg/kg/day dose. From the groups receivingthe transdermal formulation, all but 1 of the dogs developederythematous pinnae. At week 2 and week 4, it was notedthat 1 dog from each group that received 10mg/kg/day ofCBD orally had also developed erythematous pinnae.Other abnormal clinical signs included ocular discharge in10/30 dogs (33%), nasal discharge in 10/30 dogs (33%),salivary staining of the feet or ventral abdomen in 5/30(17%), intermittent, spontaneously prolapsed glands ofthe nictitans in 2/30 dogs (6%), transient elevated bodytemperature (104.2 F) in 1/30 dogs (33%), and mild,weight-bearing lameness in 5/30 (17%) dogs. Otherobservations included salivation during administration ofthe CBD-infused oil formulations at both concentrations.The above findings were not necessarily attributed to CBDadministration.There were no clinically significant abnormalities detectedon CBCs or fasting and postprandial bile acid tests for any ofthe dogs during the 6-week study period.At some time during the 6 weeks, 15 dogs (50%) had transientepisodes of either isosthenuria (USG 1.020), hyposthenuria(USG 1.008), and/or proteinuria (either 1 proteinwith USG 1.020 or 2 protein with USG 1.020). Otherurinalysis parameters were considered unremarkable. Therewere no correlations between the urinalysis results and CBDdose, formulation, or time in the study.Table 1. Calculated cannabinoid concentration of the products(transdermal cream, capsule, and oil) used in the study.Calculated ConcentrationCBD annabichromene (CBC)100 mg/mLCBD Cream103.08.12Below LLOQ1.922.2850 mg Capsule36.00.250.990.83Below LLOQ25 mg Capsule17.20.140.550.38Below LLOQ150 mg/mLCBD Oil36.011.6Below LLOQ3.113.4875 mg/mLCBD Oil77.64.99Below LLOQ1.501.7736AHVMA Journal Volume 52 Fall 2018The only clinically significant bloodworkabnormality detected during the 6 weekstudy was elevation of alkaline phosphataseenzyme (ALP) activity in 11 dogs (36%). Asignificant elevation was defined as equalto or more than a 2-fold increase from thehigh end of the Colorado State University(CSU) laboratory reference range (140IU/L). A few dogs (3/30, 10%) hadclinically significant elevations in ALP afteronly 2 weeks of receiving 1 of the oral CBDformulations. At 4 and 6 weeks, significantincreases in ALP values were detected in 1dog that received 10 mg/kg/day of CBD

from microencapsulated oil beads and CBD-infused oil, andin all but 1 of the dogs that received 20 mg/kg/day of CBDfrom microencapsulated oil beads and CBD-infused oil. Atweeks 4 and 6, significant differences were apparent betweenthe ALP values of the dogs given microencapsulated oilbeads and CBD-infused oil formulations at 20 mg/kg/day.No animals receiving the CBD-infused transdermal creamformulation had elevations in ALP activity. (Figure 1).DiscussionThis study is the first to assess the safety of transdermal andoral CBD use in healthy dogs. Overall, the product was welltolerated clinically. However, clinically significant adverseeffects, particularly diarrhea and elevations in serum ALP levels,are noteworthy and warrant further discussion and research.All dogs experienced mild diarrhea during the study. Theoverall incidence of diarrhea increased over the durationof the study, but no correlation was made between diarrheaand the formulation or dose of CBD received by the dogs.Although the diarrhea improved in most dogs once restricteddiets and treatment with metronidazole were initiated, somedogs had persistent soft, formed stool. Factors that mighthave contributed to the prevalence of diarrhea includestress related to relocating the dogs to new housing, sharingenclosures, and diet.Even though all the dogs were transitioned to a consistentadult maintenance dog food, they did received various treatsduring socialization, enrichment, and other daily activities.Mild diarrhea has been reported as an uncommon adverseevent in 6-19% of human patients treated with CBD, butcannabis has still been used extensively for the managementof inflammatory bowel disease (15, 19, 20)A mild erythematous reaction of the pinnae occurred in11 dogs (36%). The incidence of erythematous pinnae wasgreater for the dogs treated with CBD-infused transdermalcream than for those receiving the microencapsulated oilbeads and CBD-infused oil formulations. For most of thedogs, this adverse reaction appeared a week after startingthe application of the cream. Possible explanations for thisreaction may be related to the carrier, the quantity applied,and the contact time prior to absorption.Serum ALP values that were double the normal referencerange accepted by CSU (140 IU/L) were consideredto be clinically significant. The dogs that received themicroencapsulated oil beads and CBD-infused oil had dosedependent elevations of serum ALP apparent at 4 and 6weeks. There was no evidence of short-term hepatotoxicitysince fasting and postprandial bile acids remained normalfor all the dogs throughout the study. However, the potentialf o r l o n g - t e r m liver toxicity was not evaluated inthis study. Theobser vation ofALP elevationswarrantsserialmonitoringofliverenzymesF