Twenty-Four Hour and One-Week Steady State Pharmacokinetics of Cannabinoids in Two Formulations of Cannabidiol and Cannabidiolic Acid Rich Hemp in Dogs
Main Article Content
Abstract
The aim of this study was to compare the pharmacokinetics of a cannabidiol (CBD) and cannabidiolic acid-rich (CBDA) hemp extract in a sesame oil base and a soft gel capsule formulation. During acute twenty-four hour pharmacokinetic evaluation, maximum serum concentration (Cmax) was higher for all measurable components in the serum (CBD, CBDA, Δ-9-tetrahydrocannabinol [THC] and tetrahydrocannabinolic acid [THCA]) following soft gel administration versus the oil formulation. Similar times of maximal serum concentration (Tmax) were observed with both presentations. Based on the area under the curve, a significant increase in CBDA absorption was observed following soft gel dosing. Whilst comparable, the steady state pharmacokinetic data after one week of twice daily dosing shows an increased concentration of CBDA, with a slightly lower CBD concentration with soft gel administration compared to oil. Although THC and THCA concentrations remain comparably low from both presentations, THCA absorption was superior regardless of formulation. When examining acceptance, soft gels are associated with increased palatability and less rejection of oral dosing with oil. Dogs, and potentially even people, may show increasing tolerance to this soft gel formulation; as such consideration should be given to the ease of administration and superior CBDA absorption with the use of a soft gel formulation of a CBD/CBDA hemp blend.
Article Details
How to Cite
TITTLE, David J. et al.
Twenty-Four Hour and One-Week Steady State Pharmacokinetics of Cannabinoids in Two Formulations of Cannabidiol and Cannabidiolic Acid Rich Hemp in Dogs.
Medical Research Archives, [S.l.], v. 10, n. 7, july 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2907>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i7.2907.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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doi: 10.1212/WNL.0000000000005254
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26. Huntsman RJ, Tang-Wai R, Alcorn J, Vuong S, Acton B, Corley S, et al. Dosage related efficacy and tolerability of cannabidiol in children with treatment-resistant epileptic encephalopathy: Preliminary results of the CARE-E Study. Front Neurol 2019, 10: 716. doi: 10.3389/fneur.2019.00716
27. Pamplona F, Rolim da Silva L, Coan AC. Potential clinical benefits of CBD-rich Cannabis extracts over purified CBD in treatment-resistant epilepsy: Observational data meta-analysis. Front Neurol 2018; 9: 759. doi: 10.3389/fneur.2018.00759
28. Moldzio R, Pacher T, Krewenka C, et al. Effects of cannabinoids Δ9‐tetrahydrocannabinol, Δ9‐tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine 2012; 19(8-9): 819-824. doi: 10.1016/j.phymed.2012.04.002
29. Nadal X, Del Río C, Casano S, Palomares B, Ferreiro‐Vera C, Navarrete C, et al. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol. 2017; 174(23): 4263–4276. doi: 10.1111/bph.14019
2. Gamble LJ, Boesch JM, Frye CW, et al. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Front Vet Sci. 2018; 5: 165. doi: 10.3389/fvets.2018.00165
3. 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 anti-epileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. J Amer Vet Med Assoc. 2019; 254: 1301–8. doi: 10.2460/javma.254.11.1301
4. Kogan L, Hellyer P, Downing R. The use of cannabidiol-rich hemp oil extract to treat canine osteoarthritis-related pain: a pilot study. Amer Vet Holist Med Assoc. 2020; 58: 35–44.
5. Vaughn D, Kulpa J, Paulionis L. Preliminary investigation of the safety of escalating cannabinoid doses in healthy dogs. Front Vet Sci. 2020; 7: 51. doi: 10.3389/fvets.2020.00051
6. Wakshlag, JJ, Schwark, WS, Deabold, KA, et al. Pharmacokinetics of Cannabidiol, Cannabidiolic Acid, Δ9-Tetrahydrocannabinol, Tetrahydrocannabinolic Acid and Related Metabolites in Canine Serum After Dosing With Three Oral Forms of Hemp Extract. Frontiers in Veterinary Science. 2020; 7: 505. doi: 10.3389/fvets.2020.00505
7. Łebkowska-Wieruszewska B, Stefanelli F, Chericoni S, et al. Pharmacokinetics of Bedrocan, a cannabis oil extract, in fasting fed dogs: an explorative study. Res Vet Sci. 2019; 123: 26–8. doi: 10.1016/j.rvsc.2018.12.003
8. Wakshlag JJ, Cital S, Eaton SJ, Prussin R, Hudalla C. Cannabinoid, Terpene, and Heavy Metal Analysis of 29 Over-the-Counter Commercial Veterinary Hemp Supplements. Vet Med (Auckl). 2020; 11: 45-55. doi: 10.2147/VMRR.S248712
9. Hannon MB, Deabold KA, Talsma BN, et al. Serum cannabidiol, tetrahydrocannabinol (THC), and their native acid derivatives after transdermal application of a low-THC Cannabis sativa extract in beagles. J Vet Pharmacol Therap. 2020; 00: 1–4. doi: 10.1111/ jvp.12896
10. Amstutz K, Schwark, WS, Zakharov A, et al. Single dose and chronic oral administration of cannabigerol and cannabigerolic acid-rich hemp extract in fed and fasted dogs: Physiological effect and pharmacokinetic evaluation. J Vet Pharmacol Therap. 2022; 00: 1-10. doi: 10.1111/jvp.13048
11. Eichler M, Spinedi L, Unfer-Grauwiler S, et al. Heat exposure of cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects. Planta Med. 2012; 78: 686–91. doi: 10.1055/s-0031-1298334
12. 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; Jul 22; 11(1): 14948. doi: 10.1038/s41598-021-94212-6
13. Hlozek T, Utti L, Kaderabek L, et al. Pharmacokinetic and behavioural profile of THC, CBD, THC + CBD combination after pulmonary, oral and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. Europ Neuropsychopharm. 2017; 27: 1223–7. doi: 10.1016/j.euroneuro.2017.10.037
14. Nahler G, Grotenhermen F, Zuardi AW, Crippa JAS. A conversion of oral cannabidiol to Delta 9- tetrahydrocannabinol seems not to occur in humans. Cannabis Cann Res. 2017; 2: 81–6. doi: 10.1089/can.2017.0009
15. Birnbaum AK, Karanam A, Marino SE, et al. Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy. Epilepsia. 2019; 60: 1586–92. doi: 10.1111/epi.16093
16. Zgair A, Wong JCM, Lee JB, et al. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines. Am J Transl Res. 2016; 8: 3448–59.
17. Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase 1, randomixed, double-blind, placebo-controlled, single ascending dose, multiple dose and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs. 2018; 32: 1053–67. doi: 10.1007/s40263-018-0578-5
18. McGrath S, Bartner LR, Rao S, Kogan LR and Hellyer PW. A report of adverse effects associated with the administration of cannabidiol in healthy dogs. J Am Holist Vet Med Assoc. 2018; 52: 34–38
19. Pellesi L, Licata M, Verri P, et al. Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH) - a pilot study. European Journal of Clinical Pharmacology 2018; 74, 1427–1436. doi: 10.1007/s00228-018-2516-3
20. Rock EM, Limebeer CL, Parker LA. Effect of cannabidiolic acid and delta 9 tetrahydrocannbinol of carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain. Psychopharm. 2018; 235, 3259–3271. doi: 10.1007/s00213-018-5034-1
21. Takeda S, Misawa K, Yamamoto I, Watanabe K. Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in cannabis. Drug Metabolism and Disposition. 2008; 36, 1917–1921. doi: 10.1124/dmd.108.020909
22. Harvey DJ, Brown NK. Comparative in- vitro metabolism of Cannabinoids. Pharmacol Biochem Behav. 1991; 40: 533-54
23. Whalley BJ, Lin H, Bell L, et al. Species-specific susceptibility to cannabis-induced convulsions. Br J Pharmacol. 2019; 176(10): 1506-1523. doi: 10.1111/bph.14165
24. Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018; 90(14): e1204-e1211.
doi: 10.1212/WNL.0000000000005254
25. Anderson GD, Chan LN. Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products. Clin Pharmacokinet. 2016; 55, 1353–1368. doi: 10.1007/s40262-016-0400-9
26. Huntsman RJ, Tang-Wai R, Alcorn J, Vuong S, Acton B, Corley S, et al. Dosage related efficacy and tolerability of cannabidiol in children with treatment-resistant epileptic encephalopathy: Preliminary results of the CARE-E Study. Front Neurol 2019, 10: 716. doi: 10.3389/fneur.2019.00716
27. Pamplona F, Rolim da Silva L, Coan AC. Potential clinical benefits of CBD-rich Cannabis extracts over purified CBD in treatment-resistant epilepsy: Observational data meta-analysis. Front Neurol 2018; 9: 759. doi: 10.3389/fneur.2018.00759
28. Moldzio R, Pacher T, Krewenka C, et al. Effects of cannabinoids Δ9‐tetrahydrocannabinol, Δ9‐tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine 2012; 19(8-9): 819-824. doi: 10.1016/j.phymed.2012.04.002
29. Nadal X, Del Río C, Casano S, Palomares B, Ferreiro‐Vera C, Navarrete C, et al. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol. 2017; 174(23): 4263–4276. doi: 10.1111/bph.14019