Skip to main content
SpringerLink
Log in

Examination of a New Delivery Approach for Oral Cannabidiol in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Pharmacokinetics Study

  • Original Research
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

Therapeutic effects of cannabidiol (CBD) in specialized populations continue to emerge. Despite supra-physiological dosing being shown to be tolerable in various pathologies, optimization of CBD absorption has obvious benefits for general health and recreational usage. Our objectives were to: (1) to investigate a joint pharmacokinetic-physiological time course of multiple recreational-equivalent (< 100 mg) dosages of oral CBD in young healthy adults and (2) evaluate a newly developed technology (TurboCBD™) for the enhanced delivery of CBD.

Methods

In a double-blinded, placebo-controlled, cross-over design, 12 participants received placebo, generic 45 or 90 mg of CBD, or TurboCBD™ delivery technology capsules on five separate occasions.

Results

Although there were no differences in the 45 mg conditions, circulating CBD levels were higher with the TurboCBD™ 90 mg group at both 90 (+ 86%) and 120 (+ 65%) min compared with the 90 mg control (p < 0.05). Total area under the curve tended to be higher with TurboCBD™ 90 mg compared with 90 mg (10,865 ± 6322 ng ml−1 vs. 7114 ± 2978 ng ml−1; p = 0.088). Only the TurboCBD™ 90 mg dose was elevated greater than placebo at 30 min (p = 0.017) and remained elevated at 4 h (p = 0.002).

Conclusion

Consistent with higher bioavailability, TurboCBD™ 90 mg at the peak CBD concentration was associated with an increase in cerebral perfusion and slight reduction in blood pressure compared with baseline and the 90 mg control. Further studies are needed to establish the mechanisms of action of this technology and to explore the therapeutic potential of acute and chronic dosing on more at-risk populations.

Funding

Lexaria Bioscience Corp.

Trial Registration

ClinicalTrials.gov identifier, NCT03295903.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–20.

    Article  CAS  Google Scholar 

  2. Massi P, Solinas M, Cinquina V, Parolaro D. Cannabidiol as potential anticancer drug. Br J Clin Pharmacol. 2013;75(2):303–12.

    Article  CAS  Google Scholar 

  3. Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94.

    Article  CAS  Google Scholar 

  4. McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiat. 2018;175(3):225–31.

    Article  Google Scholar 

  5. Broyd SJ, van Hell HH, Beale C, Yucel M, Solowij N. Acute and chronic effects of cannabinoids on human cognition—a systematic review. Biol Psychiat. 2016;79(7):557–67.

    Article  CAS  Google Scholar 

  6. Osborne AL, Solowij N, Weston-Green K. A systematic review of the effect of cannabidiol on cognitive function: relevance to schizophrenia. Neurosci Biobehav Rev. 2017;72:310–24.

    Article  CAS  Google Scholar 

  7. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, De Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci. 1990;87(5):1932–6.

    Article  CAS  Google Scholar 

  8. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121–30.

    Article  CAS  Google Scholar 

  9. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of Δ9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66(1):95–105.

    Article  CAS  Google Scholar 

  10. Zuardi AW, Cosme R, Graeff FG, Guimarães F. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993;7(1_suppl):82–8.

    Article  CAS  Google Scholar 

  11. Manini AF, Yiannoulos G, Bergamaschi MM, Hernandez S, Olmedo R, Barnes AJ, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med. 2015;9(3):204–10.

    Article  CAS  Google Scholar 

  12. Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, 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(11):1053–67.

    Article  CAS  Google Scholar 

  13. Atsmon J, Heffetz D, Deutsch L, Deutsch F, Sacks H. Single-dose pharmacokinetics of oral cannabidiol following administration of PTL101: a new formulation based on gelatin matrix pellets technology. Clin Pharmacol Drug Dev. 2018;7(7):751–8.

    Article  CAS  Google Scholar 

  14. Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ, O’Sullivan SE. A systematic review of cannabidiol dosing in clinical populations. Br J Clin Pharmacol. 2019.

  15. Willie CK, Colino FL, Bailey DM, Tzeng YC, Binsted G, Jones LW, et al. Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function. J Neurosci Methods. 2011;196(2):221–37.

    Article  CAS  Google Scholar 

  16. Cole WR, Arrieux JP, Schwab K, Ivins BJ, Qashu FM, Lewis SC. Test–retest reliability of four computerized neurocognitive assessment tools in an active duty military population. Arch Clin Neuropsychol. 2013;28(7):732–42.

    Article  Google Scholar 

  17. Hill AJ, Blundell JE. Nutrients and behaviour: research strategies for the investigation of taste characteristics, food preferences, hunger sensations and eating patterns in man. J Psychiatr Res. 1982;17(2):203–12.

    Article  Google Scholar 

  18. Devinsky O, Cross JH, Wright S. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;377(7):699–700.

    Article  Google Scholar 

  19. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770–804.

    Article  CAS  Google Scholar 

  20. Klawitter J, Sempio C, Morlein S, De Bloois E, Klepacki J, Henthorn T, et al. An atmospheric pressure chemical ionization MS/MS assay using online extraction for the analysis of 11 cannabinoids and metabolites in human plasma and urine. Ther Drug Monit. 2017;39(5):556–64.

    Article  CAS  Google Scholar 

  21. Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu A-X, et al. Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology. 2007;52(4):1079–87.

    Article  CAS  Google Scholar 

  22. Sultan SR, Millar SA, England TJ, O’Sullivan SE. A systematic review and meta-analysis of the haemodynamic effects of cannabidiol. Front Pharmacol. 2017;8:81.

    Article  Google Scholar 

  23. Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L, Guarnieri R, Ferrari L, et al. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology. 2004;29(2):417–26.

    Article  CAS  Google Scholar 

  24. Kiernan JA. Anatomy of the temporal lobe. Epilepsy Res Treat. 2012;2012:176157.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Fisher JP, Hartwich D, Seifert T, Olesen ND, McNulty CL, Nielsen HB, et al. Cerebral perfusion, oxygenation and metabolism during exercise in young and elderly individuals. J Physiol. 2013;591(7):1859–70.

    Article  CAS  Google Scholar 

  26. Iadecola C, Davisson RL. Hypertension and cerebrovascular dysfunction. Cell Metab. 2008;7(6):476–84.

    Article  CAS  Google Scholar 

  27. Stanley CP, Hind WH, Tufarelli C, O’Sullivan SE. Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation. Cardiovasc Res. 2015;107(4):568–78.

    Article  CAS  Google Scholar 

  28. Jadoon KA, Tan GD, O’Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI insight. 2017;2(12).

  29. Moulton PL, Boyko LN, Fitzpatrick JL, Petros TV. The effect of Ginkgo biloba on memory in healthy male volunteers. Physiol Behav. 2001;73(4):659–65.

    Article  CAS  Google Scholar 

  30. Stavro PM, Woo M, Heim TF, Leiter LA, Vuksan V. North American ginseng exerts a neutral effect on blood pressure in individuals with hypertension. Hypertension. 2005;46(2):406–11.

    Article  CAS  Google Scholar 

  31. Rodriguez-Leyva D, Pierce GN. The cardiac and haemostatic effects of dietary hempseed. Nutr Metab. 2010;7(7):32.

    Article  Google Scholar 

  32. Galiègue SM, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232:54–61.

    Article  Google Scholar 

  33. Zhornitsky S, Potvin S. Cannabidiol in humans-the quest for therapeutic targets. Pharmaceuticals (Basel). 2012;5(5):529–52.

    Article  CAS  Google Scholar 

  34. Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3(9):771–84.

    Article  Google Scholar 

  35. Sacerdote P, Martucci C, Vaccani A, Bariselli F, Panerai AE, Colombo A, et al. The nonpsychoactive component of marijuana cannabidiol modulates chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo and in vitro. J Neuroimmunol. 2005;159(1–2):97–105.

    Article  CAS  Google Scholar 

  36. Rong C, Lee Y, Carmona NE, Cha DS, Ragguett RM, Rosenblat JD, et al. Cannabidiol in medical marijuana: research vistas and potential opportunities. Pharmacol Res. 2017;121:213–8.

    Article  CAS  Google Scholar 

  37. Zurier RB, Burstein SH. Cannabinoids, inflammation, and fibrosis. FASEB J. 2016;30(11):3682–9.

    Article  CAS  Google Scholar 

  38. Stanley CP, Hind WH, O’Sullivan SE. Is the cardiovascular system a therapeutic target for cannabidiol? Br J Clin Pharmacol. 2013;75(2):313–22.

    Article  CAS  Google Scholar 

  39. Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28(4):332–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the participants of the study.

Funding

The study was sponsored by Lexaria Bioscience Corp., who also funded the Rapid Service Fees. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Philip N Ainslie acts as a Scientific Advisor for Lexaria Bioscience Corp. Alexander Patrician, Maja Versic-Bratincevic, Tanja Mijackia, Ivana Banic, Mario Marendic, Davorka Sutlović and Željko Dujić declare they have no conflict of interest.

Compliance with Ethics Guidelines

All procedures were performed in accordance with the Ethics Committee at the University of Split School of Medicine and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All participants provided written informed consent prior to completion of any data collection.

Data Availability

The datasets generated and/or analyzed during the current study are not yet publicly available, but are available upon request.

Author information

Authors and Affiliations

  1. Centre for Heart, Lung and Vascular Health, University of British Columbia, 3333 University Way, Kelowna, BC, V1V 1V7, Canada

    Alexander Patrician & Philip N. Ainslie

  2. Department of Toxicology and Pharmacogenetics, University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia

    Maja Versic-Bratincevic & Davorka Sutlović

  3. Department of Integrative Physiology, University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia

    Tanja Mijacika, Ivana Banic & Željko Dujić

  4. Department of Health Studies, University of Split, Ruđera Boškovića 35, 21000, Split, Croatia

    Mario Marendic

  5. Department of Pathology, Forensic Medicine and Citology, University Hospital Centre Split, Spinčićeva 1, 21000, Split, Croatia

    Davorka Sutlović

Authors
  1. Alexander Patrician
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maja Versic-Bratincevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tanja Mijacika
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ivana Banic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mario Marendic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Davorka Sutlović
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Željko Dujić
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Philip N. Ainslie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Patrician.

Additional information

Enhanced Digital Features

To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare.9679580.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patrician, A., Versic-Bratincevic, M., Mijacika, T. et al. Examination of a New Delivery Approach for Oral Cannabidiol in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Pharmacokinetics Study. Adv Ther 36, 3196–3210 (2019). https://doi.org/10.1007/s12325-019-01074-6

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-019-01074-6

Keywords

Search

Navigation