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CBD dosing, safety & pharmacokinetics

SCIENTIFIC REVIEW

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Hazzah, T., André, C.M., Richter, G., & McGrath, S. 2020, ‘Cannabis in Veterinary Medicine: A Critical Review’, AHVMA Journal, vol. 61, pp 17-41
 

CBD Isolate

  • biphasic dose response = a direct relationship between increased dose and efficacy until reaching a point of maximal efficacy. Increasing the dose beyond the level of maximal effect will, however, lead to decreased clinical efficacy as well as increased negative side effects.

 

Full Spectrum CBD products

  • linear dosing curve = 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.

 

Dosing guidelines

  • Because of the possibility of THC sensitivity in cannabis-naive patients and the effects of the biphasic dosing curve, it is ideal to follow a “start low and go slow” dosing regimen—specifically, beginning with very low doses and incrementally increasing the dose every 5 to 7 days based on the patient’s response and tolerance to the product.   The dose is then titrated up to find the clinically effective dose for that specific patient’s condition. 

  • begin dosing at approximately 0.3 mg/kg of CBD BID and incrementally increase the dose over time until efficacy is achieved.

 

  • Most cannabis products are dosed orally at an interval of every 12 hours

  • Depending on the severity of the condition treated (ie, seizures, anxiety, pain), the patient’s tolerance, and the molecular profile of the product, dosing may be implemented every 6 to 8 hours.

 

  • The margin of safety for CBD is so broad, there is little concern for negative side effects with the exception of idiosyncratic responses.

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LITERATURE REVIEW

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Yu CHJ, Rupasinghe HPV 2021, ‘Cannabidiol-based natural health products for companion animals: Recent advances in the management of anxiety, pain, and inflammation’, Research in Veterinary Science, vol. 140, pp.38-46

  

Safety

  • In terms of safety, CBD supplementation in the canine is generally well-tolerated with very few mild adverse events

  • where there are adverse events noted (gastrointestinal, constitutional, and neurological), these closely match that of the placebo.

 

Serum chemistry

  • Upon oral supplementation of CBD, elevated ALP is observed across many studies

    • This may be an indication of hepatic injury and altered function. However, the observed elevation of ALP after CBD administration could also be due to hepatic microsomal enzyme induction by CBD and/or THC without causing actual liver damage.  

 

Cats vs dogs

  • The pharmacokinetics of CBD are different in the two species.

  • There is a significant gap in the literature on the therapeutic use of CBD in cats, with no feline data on anxiety, pain, and inflammation management.  Insufficient information on the safety profile of CBD in cats.

  • To date, only two studies reported CBD pharmacokinetics in healthy cats

    • Deabold, KA, Schwark, WS, Wolf, L & Wakshlag, JJ 2019, ‘Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats’, Animals, vol. 9, pp 832 (SEE SUMMARY BELOW)

      • dose of CBD oil of 2 mg/kg twice daily

    • Kulpa, JE, Paulionis, LJ, Eglit, GM & Vaughn, DM 2021, ‘Safety and tolerability of escalating cannabinoid doses in healthy cats’, Journal of Feline Medicine and Surgery, vol. 23, no. 12, pp. 1162-1175.

      • escalating dose study (2.8 mg/kg – 30.5 mg/kg)

 

  • Both studies reported overall good tolerances of CBD oil in cats, with only mild and rare adverse effects such as hypersalivation, emesis, excessive licking and headshaking during administration and normal liver markers in the majority of the healthy cats studied.

 

There are five studies exploring the CBD pharmacokinetics and safety in dogs

 

  • Bartner et al., 2018.

  • Gamble et al., 2018 

  • McGrath et al., 2018

  • Vaughn, et al., 2020

  • Wakshlag et al., 2020b 

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Lima TM, Santiago NR Alves ECR, Chaves DSA & Visacri MB 2022, ‘Use of cannabis in the treatment of animals: a systematic review of randomized clinical trials’, Animal Health Research Reviews, vol. 23, pp. 25–38.  

 

SYSTEMATIC REVIEW of randomised clinical trials looking at the efficacy or safety of CBD in animals

N= 6 studies were reviewed

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  • Gamble et al, 2018 - OA (see OA page)

  • Briochi et al, 2020 - OA (see OA page)

  • Verrico et al, 2020 - OA (see OA page)

  • Mejia et al, 2020 - OA (see OA page)

  • McGrath et al, 2019 - epilepsy (see Epilepsy page)

  • Corsetti et al, 2021 - behaviour (see Behaviour page)

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  • All studies used cannabidiol (CBD) oil in monotherapy or in combination with other drugs.

  • Studies used CBD at 2 or 2.5 mg /kg BID PO during 4 or 6 weeks, and compared CBD with placebo.

  • CBD was well tolerated with mild adverse effects.

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Bartner, L.R.; McGrath, S.; Rao, S.; Hyatt, L.K.; Wittenburg, L.A. 2018, ‘Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs’, Canadian Journal of Veterinary Research, vol. 82, pp. 178–183

Design: randomised controlled trial

 

Aim: to determine the pharmacokinetics of cannabidiol (CBD) in healthy dogs.

 

Intervention: 30 healthy research dogs, randomly allocated to 3 groups, and given either:  (1) oral microencapsulated oil beads (2) oral CBD-infused oil, or (3) CBD-infused transdermal cream, at a dose of 75 mg or 150 mg q12h for 6 weeks.

 

Results:

  • Pharmacokinetic analysis demonstrated that the oral CBD-infused oil formulation resulted in higher maximal concentrations and systemic exposure than the other 2 formulations

  • the CBD-infused transdermal cream did not reach similar plasma concentrations as the other 2 formulations.

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Gamble L-J, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L, Brown H, Berthelsen ES & Wakshlag JJ 2018, ‘Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs’, Frontiers in Veterinary Science, vol. 5, pp 165.

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Study: randomized, placebo-controlled, owner and veterinarian double-blind, cross-over trial.

 

Sample: 16 client-owned dogs with confirmed OA. 

 

Intervention: dogs were given 2mg/kg of CBD twice daily for 4 weeks

 

Findings:

  • No side effects were reported by owners

  • Serum chemistry showed an increase in ALP during CBD treatment (p < 0.01).

 McGrath, S, Bartner, LR, Rao, S, Kogan, LR, & Hellyer, PW 2018, ‘A report of adverse effects associated with the administration of Cannabidiol in healthy dogs’, Journal of the American Holistic Veterinary Association, vol. 52, pp 34-38.

 

Design: randomised controlled trial

 

Method: 30 healthy Beagle dogs were randomly assigned to receive CBD in the form of (1) microencapsulated oil beads (capsule), (2) CBD-infused oil, or (3) CBD-infused transdermal cream at a dose of 10 mg/kg/day or 20 mg/ kg/day for 6 weeks.

 

Relevant findings:

  • Elevations in serum ALP occurred in some dogs.

  • All of the dogs in the study experienced diarrhoea that was not associated with the formulation or dose of CBD that they received.

  • CBD appeared to be well tolerated in dogs.

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Vaughn, D, Kulpa, J & Paulionis, L 2020, ‘Preliminary investigation of the safety of escalating cannabinoid doses in healthy dogs’, Frontiers in Veterinary Science, vol. 7, pp 51.​

 

Design: Randomized, placebo-controlled, blinded, parallel study.

 

Method:

  • 20 healthy Beagle research dogs (10 males, 10 females)

  • 5 treatment groups

    • (1) CBD-predominant oil,

    • (2) THC-predominant oil,

    • (3) CBD/THC-predominant oil (1.5:1),

    • (4) sunflower oil placebo,

    • (5) medium-chain triglyceride oil placebo.

  • Given up to 10 escalating doses PO, with at least 3 days separating doses.

 

Results:

  • Dose escalation of the CBD-predominant oil 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 (640.5mg; ∼62 mg/kg), the THC oil up to the tenth dose (597.6mg; ∼49 mg/kg), and the CBD/THC oil up to the fifth dose (140.8/96.6mg CBD/THC; ∼12 mg/kg CBD + 8 mg/kg THC).

  • Adverse effects (AEs) were reported in all dogs across the five groups and the majority (94.9%) were mild.

    • AEs mainly occurring in groups receiving oils containing THC

 

Clinical relevance:

  • dose escalation of CBD oil containing 18.3–640.5mg CBD per dose (∼2–62 mg/kg) well tolerated in dogs

Wakshlag, JJ, Schwark, WS, Deabold, KA, Talsma, BN, Cital, S, Lyubimov, A, Iqbal, A & Zakharov, A 2020b, ‘Pharmacokinetics of Cannabidiol, Cannabidiolic acid, delta 9-tetrahydrocannabinol, tetrahydrocannabinolic acid and related metabolites in canine serum after dosing with three oral forms of hemp extract, Frontiers in Veterinary Science, vol. 7, pp 505

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Examined the pharmacokinetics of 3 oral forms of CBD-rich hemp extract, containing near equal CBD:CBDA, and <0.3% of THC/THCA.

  1. CBD/CBDA in an MCT and sesame oil base

  2. CBD/CBDA in a sunflower lecithin and sesame oil base

  3. Soft chew containing CBD/CBDA

 

Method:

  • 6 female research Beagles were each dosed with the 3 oral CBD products at 2 mg/kg, q 12 h for 2 weeks

  • Serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids.

  

Findings:

  •  For all 3 CBD products, the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar.

  • Absorption of CBDA does occur in dogs and is absorbed at least twice as well as CBD in 24-h kinetic examination

  • The quantity of THC and THCA delivered to these dogs was <0.1 mg/kg body weight.  No side effects such as ataxia or somnolence was observed in the dogs in the study at any point during treatment.

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Chicoine, A., Illing, K., Vuong, S., Pinto, K.R., Alcorn, J., Cosford, K., 2020, “Pharmacokinetic and safety evaluation of various oral doses of a novel 1:20 THC:CBD cannabis herbal extract in dogs”, Frontiers in Veterinary Science, vol. 7, 583404.

 

Dogs: 13 healthy Beagle X dogs

 

Intervention:  dogs were given cannabis extract containing a 1:20 ratio of THC: CBD

 

Evaluations of neurological signs, clinical laboratory abnormalities, and other adverse events were performed in 2 study phases:

  1. a multiple-dose phase with 12 dogs receiving five medium doses (5mg CBD/kg bw) at 12 h intervals,

  2. a single low-dose (2mg CBD/kg bw), randomized, blinded, negative controlled study with 13 dogs.

 

 Findings re safety:

  • when high dosages (CBD 10 mg/kg bodyweight) were administered - resulted in neurological signs.  Signs included hyperesthesia (overreaction to normal auditory/visual/tactile stimuli), proprioceptive deficits, head bobbing, torso swaying, ptyalism, urinary incontinence and vomiting

  • lower dosages (2 mg/kg and 5 mg/kg) resulted in a few dogs showing mild neurological deficits such as mydriasis, ataxia, delayed hopping reaction and noise sensitivity

  • Blood counts and biochemistry values remained in reference ranges

 

Findings re pharmacokinetics:

  • Absorption: Absorption after oral administration was rapid, with mean Tmax of approximately 2 h for CBD and THC in all dose groups. The initial rate of depletion in plasma from Tmax until 12 h post-dose (b-phase) was comparable for all cannabinoids, with mean b-phase half-life (T1/2b) of approximately 2 h for CBD, THC, and CBC.

A prolonged elimination phase was observed in all dogs demonstrating quantifiable cannabinoid levels at 48 h (medium- and high-dose groups).  The terminal elimination half-life (T1/2l), derived from plasma samples taken between 12 and 48 h post-dose, ranged from 12 to 24 h, depending on dose group

Deabold, KA, Schwark, WS, Wolf, L & Wakshlag, JJ 2019, ‘Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats, Animals, vol. 9, pp. 832

 

Aim: 12 week dose of full spectrum CBD to show short pharmacokinetic half-lives in dogs and cats

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Method:

  • Animals: 8 Beagle dogs, 8 DSH cats

  • Dosed with 2 mg/kg of full spectrum CBD orally BID for 12 weeks

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Findings:

  • Serum chemistry and CBC results showed no clinically significant alterations (no values exceeded the reference ranges)

    • EXCEPT one cat showed a persistent rise in ALT above the reference range for the duration of the trial.

CATS

  • Cats do appear to absorb or eliminate CBD differently than dogs, showing lower serum concentrations.

  • ADVERSE EVENTS - main adverse effects noted included licking (35.4%) and head shaking (25.2%), respectively. Other adverse events noted were pacing (11.1%), chomping/chewing (6.5%), gagging (2.1%), vomiting food, bile, or hairballs (1.1%), salivating, drooling, or foaming (1.2%), jumping (0.45%), being uncooperative (0.4%), and grimacing (0.4%).  Loose stool was not observed in any of the cats during the study.

DOGS

  • Adverse events - loose stool was the most common adverse event (occurred 3.3% of the time).

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