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Frontiers in veterinary science2024; 11; 1356463; doi: 10.3389/fvets.2024.1356463

Pharmacokinetics and tolerability of single-dose enteral cannabidiol and cannabidiolic acid rich hemp in horses (Equus caballus).

Abstract: The pharmacokinetics and tolerability of cannabinoids and their metabolites were determined in eight horses after enteral administration of a commercial CBD/CBDA-rich hemp oil product. Each horse was administered 2 mg/kg or 8 mg/kg CBD/CBDA or no treatment in a randomized cross-over design. Serial serum samples collected over 48 h were analyzed by high performance liquid chromatography with tandem mass spectrometry. Plasma chemistry analysis was performed at 0 h and 24 h. Vital parameters, pedometry, and blinded mentation and gait evaluations were recorded at intervals up to 24 h. Manure production and gastrointestinal transit time were tracked for 48 h after oil administration. The median maximal concentration of CBD and CBDA were 5.2 and 36.95 ng/mL in the 2 mg/kg group, respectively; and 40.35 and 353.56 ng/mL in the 8 mg/kg group. The median half-life of elimination was not calculated for the 2 mg/kg CBD treatment due to lack of time points above the lower quantifiable limit beyond the Cmax while it was 7.75 h in the 8 mg/kg group. CBDA absorption was biphasic. Pharmacokinetic parameters for tetrahydrocannabinol, tetrahydrocannabinolic acid, cannabigerolic acid, and 7-carboxy cannabidiol are also reported. No significant differences in any of the measured tolerability parameters were demonstrated between treatment groups. Single-dose enteral administration of CBD/CBDA-rich hemp extract up to 8 mg/kg does not appear to produce neurologic, behavioral, or gastrointestinal effects in horses.
Publication Date: 2024-04-12 PubMed ID: 38681854PubMed Central: PMC11047043DOI: 10.3389/fvets.2024.1356463Google Scholar: Lookup
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  • Journal Article

Summary

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This study examines the effects and tolerability of hemp oil containing CBD (Cannabidiol) and CBDA (Cannabidiolic acid) in horses and determines its pharmacokinetics, which is the movement of drugs within the body. The results indicated that the hemp oil did not negatively affect the horses’ behavior, nervous system or gastrointestinal functions, even at high dosages.

Study Design

  • The experiment involved eight horses who were administered either doses of 2mg/kg or 8mg/kg of the CBD/CBDA-rich hemp oil, or given no treatment at all. This was done in a randomized cross-over design, which helps to eliminate potential bias and increase reliability of the results.
  • Blood samples were collected from the horses over a 48-hour period and analysed using high performance liquid chromatography with tandem mass spectrometry – a highly sensitive, precise method for detecting substances in samples.
  • The researchers also conducted plasma chemistry analysis (which assesses the concentration of certain substances in the blood plasma) at the 0 hour and 24 hours marks.
  • Several parameters, including vital signs, movement patterns and mental and physical state were observed and recorded at intervals up to 24 hours.
  • The horses’ manure production and gastrointestinal transit time (the amount of time it takes for food to pass through the digestive system) were also tracked for 48 hours after the administration of the oil.

Findings

  • The observations revealed that the concentration (ng/mL) of CBD and CBDA in the horses’ bodies varied depending on the dose. It was higher in the 8mg/kg group compared to the 2mg/kg group.
  • The elimination half-life (time it takes for the concentration of the drug to decrease by half in the body) for the 2mg/kg CBD treatment could not be determined due to lack of time points above the lower quantifiable limit beyond the maximum concentration, while it was 7,75 hours in the 8mg/kg group.
  • The absorption of CBDA was observed to be biphasic, meaning it had two phases – an initial rapid absorption phase followed by a slower elimination phase.
  • Pharmacokinetic parameters for other substances including tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabigerolic acid (CBGA), and 7-carboxy cannabidiol (7-COOH CBD) were also reported.
  • Importantly, no significant differences were found in any of the measured tolerability parameters across the different treatment groups. This suggests that the CBD/CBDA-rich hemp oil did not produce adverse effects on the horses’ neurologic, behavioural, or gastrointestinal states.

Implications

  • This research suggests that single-dose enteral administration of CBD/CBDA-rich hemp extract up to 8mg/kg does not appear to have negative impacts on horses.
  • However, the authors do not specify the therapeutic implications or potential uses of these findings. Further research may provide clarity on how this dosage can be used to treat conditions in horses, and whether it may be applicable or safe for other animals or humans.

Cite This Article

APA
Thomson ACS, McCarrel TM, Zakharov A, Gomez B, Lyubimov A, Schwark WS, Mallicote MF, Portela DA, Bisiau AL, Wakshlag JJ. (2024). Pharmacokinetics and tolerability of single-dose enteral cannabidiol and cannabidiolic acid rich hemp in horses (Equus caballus). Front Vet Sci, 11, 1356463. https://doi.org/10.3389/fvets.2024.1356463

Publication

ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 11
Pages: 1356463
PII: 1356463

Researcher Affiliations

Thomson, Alexander C S
  • Department of Comparative, Population, and Diagnostic Medicine, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
McCarrel, Taralyn M
  • Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
Zakharov, Alexander
  • Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, United States.
Gomez, Beatriz
  • Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, United States.
Lyubimov, Alex
  • Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, United States.
Schwark, Wayne S
  • Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States.
Mallicote, Martha F
  • Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
Portela, Diego A
  • Department of Comparative, Population, and Diagnostic Medicine, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
Bisiau, Amber L
  • Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
Wakshlag, Joseph J
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States.

Conflict of Interest Statement

JW and WS are paid consultants of Ellevet Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

This article includes 44 references
  1. Elphick MR. The evolution and comparative neurobiology of endocannabinoid signalling. Philos Trans R Soc Lond Ser B Biol Sci (2012) 367:3201–15.
    doi: 10.1098/rstb.2011.0394pmc: PMC3481536pubmed: 23108540google scholar: lookup
  2. Howlett AC. The cannabinoid receptors. Prostaglandins Other Lipid Mediat (2002) 68-69:619–31.
    doi: 10.1016/S0090-6980(02)00060-6pubmed: 12432948google scholar: lookup
  3. Basavarajappa BS. Critical enzymes involved in endocannabinoid metabolism. Protein Pept Lett (2007) 14:237–46.
    doi: 10.2174/092986607780090829pmc: PMC1939815pubmed: 17346227google scholar: lookup
  4. di Marzo V, Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics (2015) 12:692–8.
    doi: 10.1007/s13311-015-0374-6pmc: PMC4604172pubmed: 26271952google scholar: lookup
  5. Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol (2004) 143:247–50.
    doi: 10.1038/sj.bjp.0705920pmc: PMC1575333pubmed: 15313881google scholar: lookup
  6. Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem (1995) 232:54–61.
  7. Brioschi FA, di Cesare F, Gioeni D, Rabbogliatti V, Ferrari F, D’Urso ES. 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. Animals (2020) 10:1505.
    doi: 10.3390/ani10091505pmc: PMC7552307pubmed: 32858828google scholar: lookup
  8. Coelho JC, Duarte N, Bento da Silva A, Bronze MR, Mestrinho LA. Placebo-controlled trial of daily oral cannabidiol as adjunctive treatment for cats with chronic gingivostomatitis. Animals (2023) 13:2716.
    doi: 10.3390/ani13172716pmc: PMC10487179pubmed: 37684980google scholar: lookup
  9. Gamble L-J, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Front Vet Sci (2018) 5:165.
    doi: 10.3389/fvets.2018.00165pmc: PMC6065210pubmed: 30083539google scholar: lookup
  10. McGrath S, Bartner LR, Rao S, Packer RA, Gustafson DL. 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. J Am Vet Med Assoc (2019) 254:1301–8.
    doi: 10.2460/javma.254.11.1301pubmed: 31067185google scholar: lookup
  11. Kleinhenz MD, Weeder M, Montgomery S, Martin M, Curtis A, Magnin G. Short term feeding of industrial hemp with a high cannabidiolic acid (CBDA) content increases lying behavior and reduces biomarkers of stress and inflammation in Holstein steers. Sci Rep (2022) 12:3683.
    doi: 10.1038/s41598-022-07795-zpmc: PMC8901777pubmed: 35256692google scholar: lookup
  12. Campos AC, Moreira FA, Gomes FV, del Bel EA, Guimarães FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond Ser B Biol Sci (2012) 367:3364–78.
    doi: 10.1098/rstb.2011.0389pmc: PMC3481531pubmed: 23108553google scholar: lookup
  13. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol (2008) 153:199–215.
    doi: 10.1038/sj.bjp.0707442pmc: PMC2219532pubmed: 17828291google scholar: lookup
  14. Bisogno T, Hanuš L, de Petrocellis L, Tchilibon S, Ponde DE, Brandi I. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol (2001) 134:845–52.
    doi: 10.1038/sj.bjp.0704327pmc: PMC1573017pubmed: 11606325google scholar: lookup
  15. Gobira PH, Vilela LR, Gonçalves BDC, Santos RPM, de Oliveira AC, Vieira LB. Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: possible role of the mTOR pathway and reduction in glutamate release. Neurotoxicology (2015) 50:116–21.
    doi: 10.1016/j.neuro.2015.08.007pubmed: 26283212google scholar: lookup
  16. Suryavanshi SV, Kovalchuk I, Kovalchuk O. Cannabinoids as key regulators of inflammasome signaling: a current perspective. Front Immunol (2021) 11:613613.
    doi: 10.3389/fimmu.2020.613613pmc: PMC7876066pubmed: 33584697google scholar: lookup
  17. Court MH, Mealey KL, Burke NS, Jimenez TP, Zhu Z, Wakshlag JJ. Cannabidiol and cannabidiolic acid: preliminary in vitro evaluation of metabolism and drug-drug interactions involving canine cytochrome P-450, UDP-glucuronosyltransferase, and P-glycoprotein. Vet Pharmacol Ther (2024) 47:1–13.
    doi: 10.1111/jvp.13403pubmed: 37469115google scholar: lookup
  18. Takeda S, Misawa K, Yamamoto I, Watanabe K. Cannabidiolic acid as a selective Cyclooxygenase-2 inhibitory component in Cannabis. Drug Metab Dispos (2008) 36:1917–21.
    doi: 10.1124/dmd.108.020909pubmed: 18556441google scholar: lookup
  19. Philpot LM, Ebbert JO, Hurt RT. A survey of the attitudes, beliefs and knowledge about medical cannabis among primary care providers. BMC Fam Pract (2019) 20:17.
    doi: 10.1186/s12875-019-0906-ypmc: PMC6341534pubmed: 30669979google scholar: lookup
  20. Kondrad E, Reid A. Colorado family physicians’ attitudes toward medical marijuana. J Am Board Family Med (2013) 26:52–60.
    doi: 10.3122/jabfm.2013.01.120089pubmed: 23288281google scholar: lookup
  21. Ryan D, McKemie DS, Kass PH, Puschner B, Knych HK. Pharmacokinetics and effects on arachidonic acid metabolism of low doses of cannabidiol following oral administration to horses. Drug Test Anal (2021) 13:1305–17.
    doi: 10.1002/dta.3028pubmed: 33723919google scholar: lookup
  22. Yocom AF, O’Fallon ES, Gustafson DL, Contino EK. Pharmacokinetics, safety, and synovial fluid concentrations of single-and multiple-dose oral administration of 1 and 3 mg/kg cannabidiol in horses. J Equine Vet (2022) 113:103933.
    doi: 10.1016/j.jevs.2022.103933pubmed: 35307550google scholar: lookup
  23. Williams MR, Holbrook TC, Maxwell L, Croft CH, Ientile MM, Cliburn K. Pharmacokinetic evaluation of a cannabidiol supplement in horses. J Equine Vet (2022) 110:103842.
    doi: 10.1016/j.jevs.2021.103842pubmed: 34923070google scholar: lookup
  24. Turner SE, Knych HK, Adams AA. Pharmacokinetics of cannabidiol in a randomized crossover trial in senior horses. Am J Vet Res (2022) 83:ajvr.22.02.0028.
    doi: 10.2460/ajvr.22.02.0028pubmed: 35895770google scholar: lookup
  25. Sánchez de Medina A, Serrano-Rodríguez JM, Díez de Castro E, García-Valverde MT, Saitua A, Becero M. Pharmacokinetics and oral bioavailability of cannabidiol in horses after intravenous and oral administration with oil and micellar formulations. Equine Vet J (2023) 55:1094–103.
    doi: 10.1111/evj.13923pubmed: 36624043google scholar: lookup
  26. Eichler F, Poźniak B, Machnik M, Schenk I, Wingender A, Baudisch N. Pharmacokinetic modelling of orally administered cannabidiol and implications for medication control in horses. Front Vet Sci (2023) 10:1234551.
    doi: 10.3389/fvets.2023.1234551pmc: PMC10445762pubmed: 37621871google scholar: lookup
  27. Deabold KA, Schwark WS, Wolf L, Wakshlag JJ. Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats. Animals (2019) 9:832.
    doi: 10.3390/ani9100832pmc: PMC6826847pubmed: 31635105google scholar: lookup
  28. Anderson LL, Etchart MG, Bahceci D, Golembiewski TA, Arnold JC. Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations. Sci Rep (2021) 11:14948.
    doi: 10.1038/s41598-021-94212-6pmc: PMC8298633pubmed: 34294753google scholar: lookup
  29. Sano H, Martin-Flores M, Santos LCP, Cheetham J, Araos JD, Gleed RD. Effects of epidural morphine on gastrointestinal transit in unmedicated horses. Vet Anaesth Analg (2011) 38:121–6.
  30. Grubb TL, Kurkowski D, Sellon DC, Seino KK, Coffey T, Davis JL. Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals. J Vet Pharmacol Ther (2019) 42:26–36.
    doi: 10.1111/jvp.12715pubmed: 30242851google scholar: lookup
  31. Crockett J, Critchley D, Tayo B, Berwaerts J, Morrison G. A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects. Epilepsia (2020) 61:267–77.
    doi: 10.1111/epi.16419pmc: PMC7065230pubmed: 32012251google scholar: lookup
  32. Silmore LH, Willmer AR, Capparelli EV, Rosania GR. Food effects on the formulation, dosing, and administration of cannabidiol (CBD) in humans: a systematic review of clinical studies. Pharmacotherapy: the journal of human pharmacology and drug. Therapy (2021) 41:405–20.
    doi: 10.1002/phar.2512pmc: PMC8485703pubmed: 33583102google scholar: lookup
  33. Rock EM, Limebeer CL, Parker LA. Effect of cannabidiolic acid and ∆9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain. Psychopharmacology (2018) 235:3259–71.
    doi: 10.1007/s00213-018-5034-1pubmed: 30225659google scholar: lookup
  34. Vigli D, Cosentino L, Pellas M, de Filippis B. Chronic treatment with Cannabidiolic acid (CBDA) reduces thermal pain sensitivity in male mice and rescues the hyperalgesia in a mouse model of Rett syndrome. Neuroscience (2021) 453:113–23.
  35. Wang T, Zakharov A, Gomez B, Lyubimov A, Trottier NL, Schwark WS. Serum cannabinoid 24 h and 1 week steady state pharmacokinetic assessment in cats using a CBD/CBDA rich hemp paste. Front Vet Sci (2022) 9:895368.
    doi: 10.3389/fvets.2022.895368pmc: PMC9355628pubmed: 35937287google scholar: lookup
  36. Godfrey KR, Arundel PA, Dong Z, Bryant R. Modelling the double peak phenomenon in pharmacokinetics. IFAC Proc (2009) 42:127–32.
  37. Weitschies W, Bernsdorf A, Giessmann T, Zschiesche M, Modess C, Hartmann V. The talinolol double-peak phenomenon is likely caused by presystemic processing after uptake from gut lumen. Pharm Res (2005) 22:728–35.
    doi: 10.1007/s11095-005-2588-5pubmed: 15906167google scholar: lookup
  38. Mirfazaelian A, Mahmoudian M. A simple pharmacokinetics subroutine for modeling double peak phenomenon. Biopharm Drug Dispos (2006) 27:119–24.
    doi: 10.1002/bdd.492pubmed: 16400712google scholar: lookup
  39. Baggot J. Bioavailability and bioequivalence of veterinary drug dosage forms, with particular reference to horses: an overview. J Vet Pharmacol Ther (1992) 15:160–73.
  40. Duijkeren E, Vulto AG, van Oldruitenborgh-Oosterbaan MMS, Kessels BG, van Miert AS, Breukink HJ. Pharmacokinetics of trimethoprim/sulphachlorpyridazine in horses after oral, nasogastric and intravenous administration. J Vet Pharmacol Ther (1995) 18:47–53.
  41. Watkins PB, Church RJ, Li J, Knappertz V. Cannabidiol and abnormal liver chemistries in healthy adults: results of a phase I clinical trial. Clin Pharmacol Ther (2021) 109:1224–31.
    doi: 10.1002/cpt.2071pmc: PMC8246741pubmed: 33022751google scholar: lookup
  42. Nadal X, del Río C, Casano S, Palomares B, Ferreiro-Vera C, Navarrete C. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol (2017) 174:4263–76.
    doi: 10.1111/bph.14019pmc: PMC5731255pubmed: 28853159google scholar: lookup
  43. Eichler F, Ehrle A, Machnik M, Jensen KC, Wagner S, Baudisch N. Behavioral observations, heart rate and cortisol monitoring in horses following multiple oral administrations of a cannabidiol containing paste (part 2/2). Front Vet Sci (2024) 10:1305873.
    doi: 10.3389/fvets.2023.1305873pmc: PMC10791836pubmed: 38234983google scholar: lookup
  44. Cunha RZ, Felisardo LL, Salamanca G, Marchioni GG, Neto OI, Chiocchetti R. The use of cannabidiol as a novel treatment for oral stereotypic behaviour (crib-biting) in a horse. Vet Anim Sci (2023) 19:100289.
    doi: 10.1016/j.vas.2023.100289pmc: PMC9941357pubmed: 36824298google scholar: lookup

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