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Safety of CBD and THC in Dogs: What Does the Data Say?

June 23rd 2020

Robert Menardi, DVMDirector, Veterinary Technical and Educational Services

Justyna Kulpa, PhDRegional Research Manager

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6/22/2020

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Safety of CBD and THC in Dogs: What Does the Data Say?

June 23rd 2020

Robert Menardi, DVMDirector, Veterinary Technical and Educational Services

Justyna Kulpa, PhDRegional Research Manager

SAFETY OF CBD & THC IN DOGS:WHAT DOES THE DATA SAY?

Robert Menardi, DVMDirector, Veterinary Technical and Educational Services

Justyna Kulpa, PhDRegional Research Manager

Pet Poison Helpline WebinarJune 23, 2020

C A N O P Y A N I M A L H E A L T H

CANOPY ANIMAL HEALTH (CAH)

• A division of Canopy Growth Corporation (NYSE-CGC)

• Headquartered in both the USA (GA) and Canada (ON)

• Committed to providing veterinarians and pet owners with quality products to advance animal health

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C A N O P Y A N I M A L H E A L T H

CANNABIS SATIVA

• Annual flowering plant historically cultivated as a source of industrial fiber, oil, and for use in religious ceremony and medicine

• Source of cannabinoids, terpenes, flavonoids, alkaloids▶ Over 100 plant-derived cannabinoids have been identified

• There are many varieties of Cannabis sativa with different amounts/proportions of compounds▶ Hemp is a variety of Cannabis with lower THC levels

• <0.3% USA, Canada• <0.2% EU

C A N O P Y A N I M A L H E A L T H

• 1 of over 100 phytocannabinoids

• Primary cannabinoid found in hemp plants

• Being investigated for potential effects on:• Pain• Anxiety• Inflammation• Seizure disorders

OUR AREA OF EXPERTISE: CANNABIDIOL (CBD)

C A N O P Y A N I M A L H E A L T H

3+ Years of Research to Date

↳ 20+ completed studies

↳ Additional studies in progress

• Short term safety• Long term safety• Bioavailability• Pharmacokinetics

• Dosage form• Novel formulations• Synergy/combination

studies• General anxiety• Acute anxiety

• Osteoarthritis• Inflammation• Generalized pain• Quality of life• Seizure disorders

GLOBAL LEADER IN CBD RESEARCH

CAH Canine and Feline Research Areas

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BACKGROUND SCIENCE

C A N O P Y A N I M A L H E A L T H

Cannabidiol (CBD) Delta-9-tetrahydrocannabinol (THC)

CBD AND THC: STRUCTURE VS. FUNCTION

• CBD and THC have similar structures but different functions

C A N O P Y A N I M A L H E A L T H

CBD AND THC: RECEPTOR BINDING

• THC• High binding affinity: CB1>CB2• Intoxicating

• CBD• Does not bind to CB1 at relevant

concentrations• Non-intoxicating

CB1

CB2

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C A N O P Y A N I M A L H E A L T H

CBD1 THC CBD + THC2

# Publications 5 - 1

Dose 2-10 mg/kg, twice daily - CBD: 2.5-25 mg/kg, dailyTHC: 2.7-27 mg/kg, daily

Duration 4 to 12 weeks - 56 weeks

Authors’ conclusions

• Generally well tolerated• Gastrointestinal signs• Increased alkaline

phosphatase (ALP)

-

• Generally well tolerated • Neurological signs (ataxia, tremor,

hypoactivity)• Thin appearance • Gastrointestinal signs• Oro-respiratory signs (placebo?)

1Bartner et al. (2018). Can J Vet Research; 82:178-183 1Gamble et al. (2018). Frontiers in Vet Sci; 5:165 1McGrath et al. (2018). Amer Hol Vet Med Assoc; 52:34-381Deabold et al. (2019). Animals; 9:832 1McGrath et al. (2019). J Am Vet Med Assoc; 254:1301-1308 2Whalley et al. (2017). Brit J Pharmacol; 176:1506-1523

No repeated dose studies comparing CBD vs THC vs CBD+THC in dogs

REPEATED DOSE STUDIES IN DOGS

C A N O P Y A N I M A L H E A L T H

DIFFERENT CLINICAL SIGNS FOLLOWING INGESTION OF THC vs CBD

Figure from: Brutlag and Hommerding (2018). Vet Clin Small Anim;48:1087–1102.

ESCALATING DOSE STUDY

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C A N O P Y A N I M A L H E A L T H

RESEARCH QUESTIONS

• Does the effect of CBD and THC differ in dogs?

• What effect does CBD have on the safety profile of THC?

• How well is dose escalation of CBD and THC, individually and in combination, tolerated in healthy dogs?

C A N O P Y A N I M A L H E A L T H

STUDY DESIGN

• Randomized

• Placebo controlled

• Blinded

• N=20 healthy adult Beagle dogs

• Up to 10 escalating doses of oils delivered by oral gavage to fasted dogs

• ≥ 3 days between doses

• Approved by IACUC and Veterinary Drug Directorate, Health Canada

• Three cannabinoid groups:

• CBD-predominant in MCT oil• THC-predominant in MCT oil• CBD+THC-predominant in sunflower oil

(1.5:1 CBD:THC)

• Two placebo groups:

• Sunflower (SF) oil• Medium-chain triglyceride (MCT) oil

C A N O P Y A N I M A L H E A L T H

mg (total)

DoseCBD oil THC oil CBD+THC oil

CBD THC CBD THC CBD THC

1 18.3 0.7 - 24.9 17.6 12.1

2 45.8 1.7 - 62.3 35.2 24.2

3 91.5 3.5 - 82.2 70.4 48.3

4 137.3 5.2 - 109. 6 105.6 72.5

5 183.0 6.9 - 144.4 140.8 96.6

6 274.5 10.4 - 191.7

7 366.0 13.8 - 254.0

8 457.5 17.3 - 336.2

9 549.0 20.7 - 448.2

10 640.5 24.2 - 597.6

DOSE ESCALATION OF CANNABINOID OILS

• Up to 10 escalating doses of oils delivered by oral gavage to fasted dogs

• ≥ 3 days between doses

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C A N O P Y A N I M A L H E A L T H

mg (total) mg/kg (median)

DoseCBD oil THC oil CBD+THC oil CBD oil THC oil CBD+THC oil

CBD THC CBD THC CBD THC CBD THC CBD THC CBD THC

1 18.3 0.7 - 24.9 17.6 12.1 1.8 0.07 - 2.0 1.6 1.1

2 45.8 1.7 - 62.3 35.2 24.2 4.4 0.17 - 5.1 3.2 2.2

3 91.5 3.5 - 82.2 70.4 48.3 8.9 0.34 - 6.7 6.4 4.4

4 137.3 5.2 - 109. 6 105.6 72.5 13.3 0.50 - 9.0 9.6 6.6

5 183.0 6.9 - 144.4 140.8 96.6 17.8 0.67 - 11.8 12.8 8.8

6 274.5 10.4 - 191.7 26.7 1.0 - 15.7

7 366.0 13.8 - 254.0 35.5 1.3 - 20.8

8 457.5 17.3 - 336.2 44.4 1.7 - 27.6

9 549.0 20.7 - 448.2 53.3 2.0 - 36.7

10 640.5 24.2 - 597.6 62.2 2.3 - 49.0

DOSE ESCALATION OF CANNABINOID OILS

Severe ataxia & lethargy in 1 dog

Severe ataxia & lethargy in 1 dog

Severe ataxia & lethargy in 1 dog

C A N O P Y A N I M A L H E A L T H

MEASURED OUTCOMES

• Clinical observations • Physical examinations• Heart rate• Respiratory rate• Rectal temperature• Body weight• Activity level• Food intake• Hematology (complete blood count,

clinical chemistry)• Plasma cannabinoids

• Adverse event (AE) = any observation outside of ”normal”

• AEs were rated as:

• MILD: Activities of daily living (ADL) not impacted; no intervention

• MODERATE: ADL moderately limited; non-invasive intervention may be indicated

• SEVERE: ADL significantly limited

C A N O P Y A N I M A L H E A L T H

NUMBER/SEVERITY OF ADVERSE EVENTS

• Mild AEs accounted for the majority of all AEs (95%)

• Number of AEs with CBD similar to placebo (MCT oil)

• Moderate & severe AEs occurred in dogs receiving oils containing ↑ THC

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C A N O P Y A N I M A L H E A L T H

DIFFERENTIATING CBD & THC

• Treatment with CBD led to a similar number of AEs, and types of AEs, as placebo (MCT oil)

• Treatment with THC led to 2.6-fold more AEs than CBD

77 AEs

80 AEs

206 AEs

C A N O P Y A N I M A L H E A L T H

DIFFERENTIATING CBD & THC

• Compared to each other category, gastrointestinal (GI) AEs occurred with higher frequency in dogs treated with CBD, THC or MCT oil (placebo)

• Carrier oil?• Oil volume?• Oral gavage?

C A N O P Y A N I M A L H E A L T H

DIFFERENTIATING CBD & THC

• Treatment with THC resulted in more constitutional,neurological, and ocular AEs than treatment with CBD or placebo

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C A N O P Y A N I M A L H E A L T H

GASTROINTESTINAL ADVERSE EVENTS:CBD vs. THC

• CBD and THC had GI effects similar to those of placebo

• GI AEs may be the result of oil volume and/or oral gavage dosing procedure

Other = Hematemesis, or blood or mucus in stool.

C A N O P Y A N I M A L H E A L T H

NEUROLOGICAL ADVERSE EVENTS:CBD vs. THC

• THC associated with 7-fold more neurological AEs than CBD

• Neurological AEs manifested as ataxia and tremor

C A N O P Y A N I M A L H E A L T H

CONSTITUTIONAL ADVERSE EVENTS:CBD vs. THC

• THC associated with 7-fold more constitutional AEs than CBD

• Lethargy and hyperaesthesia were the most common constitutional AEs following THC

Other = Weight loss, hypertonia, eyebrows raised and no blinking, abnormal posture, or vocalization

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C A N O P Y A N I M A L H E A L T H

OCULAR ADVERSE EVENTS:CBD vs. THC

• THC associated with 3-fold more ocular AEs than CBD

• Mydriasis was the most common ocular AE

C A N O P Y A N I M A L H E A L T H

OCULAR ADVERSE EVENTS

• Ocular effects of THC were described in the literature in the 1980s

• Possibly attributable to actions on the sympathetic nervous system / catecholamine release vs direct effects on the eye

C A N O P Y A N I M A L H E A L T H

CBD vs. THC

• At each escalating dose, CBD associated with fewer AEs per dog than THC

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C A N O P Y A N I M A L H E A L T H

CBD vs. THC

• At each escalating dose, CBD associated with fewer AEs per dog than THC

• 1st dose: 7-fold more AEs per dog with ~2 mg/kg THC (THC oil) vs. ~2 mg/kg CBD (CBD oil)

C A N O P Y A N I M A L H E A L T H

CBD vs. THC

• At each escalating dose, CBD associated with fewer AEs per dog than THC

• 1st dose: 7-fold more AEs per dog with ~2 mg/kg THC (THC oil) vs. ~2 mg/kg CBD (CBD oil)

• 2nd to 9th doses: 2- to 3-fold more AEs per dog with THC oil vs. CBD oil

C A N O P Y A N I M A L H E A L T H

THC vs. CBD+THC

• 5th dose: 2-fold more AEs per dog with CBD + THC (~13 mg/kg CBD + 9 mg/kg THC) vs. THC (~12 mg/kg THC) irrespective of lower amount of THC in CBD/THC oil

• Dosing of CBD+THC ceased beyond 5th dose: severe AEs (ataxia, lethargy) experienced by 2 of 4 dogs

• CBD may delay metabolism of THC in liver: pharmacokinetic interaction

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C A N O P Y A N I M A L H E A L T H

Treatment Dose # # events (# dogs)

CBD (mg/kg)

THC (mg/kg)

CBD - - - -

THC 3 1 (1) n/a ~7.3

CBD+THC

2 4 (4) ~3.1 ~2.2

3 2 (2) ~6.2 ~4.3

4 4 (4) ~9.3 ~6.4

5 3 (3) ~12.4 ~8.5

10 / 13 events at THC doses<7.3 mg/kg

HYPOTHERMIA

• CBD+THC resulted in more cases of hypothermia, despite lower doses of THC and CBD

↳ CBD may delay metabolism of THC in the liver via a pharmacokinetic interaction

• CBD+THC was associated with a decrease in rectal temperature

C A N O P Y A N I M A L H E A L T H

C A N O P Y A N I M A L H E A L T H

ALKALINE PHOSPHATASE (ALP)

• Increased (but still within reference range) in one dog in the CBD group

• Elevated (above reference range) in one dog in the CBD+THC group

• Other plasma liver parameters (AST, ALT, GGTP, total bilirubin) were stable and within the reference range for all dogs

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C A N O P Y A N I M A L H E A L T H

ALKALINE PHOSPHATASE ELEVATION AS AN INDICATOR OF LIVER HEALTH?

• Effects of hepatic drug-metabolizing enzyme (DME) induction on clinical pathology markers of hepatobiliary injury and function are not well established.

• Hepatic DME induction is an adaptive response associated with a number of drugs.

• This response can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of DMEs.

C A N O P Y A N I M A L H E A L T H

KEY TAKEAWAYS

• CBD was found to be associated with fewer adverse events, as compared with products containing THC.

► CBD AEs were similar in type/number to those of the placebo.

• Combination of CBD+THC resulted in more AEs than either cannabinoid alone.

► CBD and THC interaction may depend on the relative ratio of each cannabinoid and the dose timing (together or in sequence).

• This study differentiated the safety profiles of CBD, THC and CBD + THC for the first time in a dose escalating study in dogs.

C A N O P Y A N I M A L H E A L T H

DIFFERENT CLINICAL SIGNS FOLLOWING INGESTION OF THC vs CBD

Figure from: Brutlag and Hommerding (2018). Vet Clin Small Anim;48:1087–1102.

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C A N O P Y A N I M A L H E A L T H

CONCLUSIONS

• In this study, orally administered CBD was shown to be as safe as placebo when administered from 2 to 62 mg/kg to dogs over one month.

• Findings from this study provide support for continuing research on the safety and potential therapeutic uses of orally delivered CBD in dogs.

THE CLINICAL PERSPECTIVE

C A N O P Y A N I M A L H E A L T H

THE IMPORTANCE OF HARM REDUCTION

• There are currently no cannabis-based products approved for treatment of any condition. This applies to both CBD and THC.

• Public demand and product availability is increasing rapidly, significantly increasing the potential for deliberate or accidental exposure.

• Regardless of federal or state restrictions, veterinarians should:

• Recognize signs of cannabis toxicity and treat appropriately

• Stay informed of current research, know doses that may cause significant adverse events

• Educate pet owners on safety, risks of administration, and potential drug interactions

Harm reduction does NOT mean prescribing, dispensing, or recommending

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C A N O P Y A N I M A L H E A L T H

POTENTIAL SOURCES OF EXPOSURE• Edibles

• Chocolate• Baked Goods

(brownies, cookies)• Gummies▶ High fat increases

bioavailability

• Dried plant material▶ Variable THC and CBD

content

• Concentrates• Shatter• Wax• Hash oil▶ Concentrated THC!

• Synthetic Cannabinoids• K2, Spice▶ Illegal everywhere!

C A N O P Y A N I M A L H E A L T H

CLINICAL SIGNSTHC

• Neurologic• CNS Depression, Ataxia, Tremors

• Constitutional• Lethargy, Hyperesthesia, Recumbency,

Hypothermia, Irritability• Ocular

• Mydriasis, Epiphora

• Gastrointestinal• Emesis, Nausea, Diarrhea

• Cardiac• Bradycardia

• Urinary• Incontinence

CBD or placebo

• Gastrointestinal• Emesis, Nausea, Diarrhea

• Constitutional (uncommon)• Lethargy, Hyperesthesia

• Neurological (uncommon)• Ataxia, Tremors

• Ocular (uncommon)• Mydriasis

C A N O P Y A N I M A L H E A L T H

• Treatment for THC toxicity is primarily supportive• Induce emesis, activated charcoal for recent ingestion• Monitor heart rate, blood pressure, body temperature• Intravenous fluids for maintenance of BP, hydration• Symptomatic treatment for bradycardia, agitation, seizures, etc. if present

TREATMENT

C A N O P Y A N I M A L H E A L T H

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C A N O P Y A N I M A L H E A L T H

CBD PRODUCTS ARE NOT COMPLETELY WITHOUT RISK• Mislabelled product

• May be adulterated with THC or synthetic cannabinoids

• Contaminated product

• Heavy metals, pesticides, solvents

• Potential drug-drug interactions

• Cytochrome P450 Interactions may affect metabolism of CBD or concurrently administered medications

• Other drugs affecting the endocannabinoid system may result in increased OR decreased blood levels of either drug

THANK YOU

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info@petpoisonhelpline.com

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Blackwell’s Five-Minute Veterinary Consult Clinical Companion:

Small Animal Toxicology 2nd Edition

• Provides concise, bulleted information focused on the most important facts needed when treating a poisoned cat or dog

• Carefully organized for ease of use in an emergency, with important toxicants arranged alphabetically within categories

• Details clinically relevant information on the most common toxicants encountered by small animals

• Presents a wealth of color photographs to aid in plant identification

• Includes 14 new topics to this edition covering cyclosporine A, sleep aids, tacrolimus, bath salts, synthetic marijuana, poisonous lizards, imidacloprid, spring bulbs, and sodium monofluoroacetate

Drs. Lynn Hovda, Ahna Brutlag, Robert Poppenga, Katherine Peterson

www.wiley.com/go/vetPaperback | May 2016 | 960 pages | 978-1-119-03654-8 | $109.99 · CAN $120.99

Pet Poison Helpline is excited to announce our recent expansion into Australia and New Zealand!

Our services are available 24/7 to any veterinary professional in Australia by calling 0011-800-4444-0002 and

New Zealand by calling 00-800-444-0002.

For more information please visit our website:https://www.petpoisonhelpline.com/pphworld

PPH World: Australia & New Zealand

• Full-time CVT/RVT/LVT mid-shift, evening and float, full-time hours available!

• Full-time Non-Certified Technicians/Assistantsevening, full-time hours available!

• Pet Poison Helpline Customer Service Representatives

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Now hiring Relief Licensed and unlicensed veterinary technicians to work flexible schedules!

Learn all the details of our positions and qualifications by visiting our careers page https://www.petpoisonhelpline.com/careers/or emailing careers@safetycall.com.

PPH is Hiring!

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• February 2nd Recorded and available for non-interactive CE credit!

• Essential Oils

• April 7th Recorded and available for non-interactive CE credit!

• Warm Weather Toxins. A Short Review of Timely Woes.

• June 2nd Recorded and available for non-interactive CE credit!

• Management of the Anti-Depressants and Anxiolytic Exposure Patient

• October 6th

• Worst of the Worst: Evaluating the Most Dangerous Toxins for Pets

• November 10th

• Hot Topic TBD

2020 Webinars Announced

Thank you for attending!

CE credit FAQs

1. When will I get my CE certificate?Now! You can download it directly from the On24 platform. Please refer to the green “resource” widget at the bottom of your screen for detailed instructions.

2. I attended the webinar but wasn’t the person who logged in. Can I still get interactive CE credit? Yes. Send your name and email address to info@petpoisonhelpline.com by 1pm central time on June 24th, 2019 (strict deadline).

3. Can I watch the recorded webinar online for CE credit? Yes. You can receive non-interactive CE credit. Go to the “For Vets” page on our website, www.petpoisonhelpline.com for more info.

Comments? Questions? Email us! info@petpoisonhelpline.com

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