A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray

Abstract

Purpose

To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects.

Methods

Twelve subjects took part in this fed–fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC).

Results

Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80–14.91 ng/ml) and lower in 5 subjects (2.81–3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97–9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0–t), AUC(0–inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2–2.5 h. Only mild adverse events were reported.

Conclusions

The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.

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

Fig. 1

References

  1. 1.

    MHRA Public Assessment Report (2012) Nabiximols oromucosal spray (delta-9-tetrahydrocannabinol and cannabidiol)—PL 18024/0009; UK/H/2462/001/DC

  2. 2.

    Porteney R, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT (2012) Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 13(5):438–449

    Article  Google Scholar 

  3. 3.

    Young CA, Nurmikko TJ, Rog DJ, Sanantis N (2005) A randomised controlled trial of Sativex, a cannabis based medicine, in central neuropathic pain due to multiple sclerosis. Program and abstracts of the 2005 Canadian Association of Physical Medicine and Rehabilitation Annual Meeting; Ottawa, Ontario, Canada. Abstract A45

  4. 4.

    Whittle BA, Guy GW, Robson P (2001) Prospects for new cannabis-based prescription medicines. J Cannabis Ther 1(3–4):183–205

    Article  CAS  Google Scholar 

  5. 5.

    Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54(2):161–202

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Pertwee RG (2007) Cannabinoids and multiple sclerosis. Mol Neurobiol 36:45–59

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    FDA Guidance for Industry (2002) Food-effect bioavailability and fed bioequivalence studies. http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126833.pdf Accessed December 2011

  8. 8.

    Foltz RL, McGinnis KM, Chinn DM (1983) Quantitative measurement of delta 9-tetrahydrocannabinol and two major metabolites in physiological specimens using capillary column gas chromatography negative ion chemical ionization mass spectrometry. Biochem MS 10(5):316–323

    CAS  Google Scholar 

  9. 9.

    Goodall CR, Basteyns BJ (1995) A reliable method for the detection, confirmation, and quantitation of cannabinoids in blood. J Anal Tox 19:419–426

    CAS  Google Scholar 

  10. 10.

    Kemp MP, Abukhalaf IK, Manno JE, Manno BR, Alford DD, Abusada GA (1995) Cannabinoids in humans. I. Analysis of delta-9-tetrahydrocannabinol and six metabolites in plasma and urine using GC-MS. J Anal Tox 19:285–291

    CAS  Google Scholar 

  11. 11.

    FDA Guidance for Industry (2001) Bioanalytical method validation issued by the U.S Department of Health and Human Services Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf. Accessed July 2012

  12. 12.

    Miller JC, Miller JN (1992) Statistics for analytical chemistry. Ellis Horwood, New York

    Google Scholar 

  13. 13.

    Lindholm A, Henricsson S, Dahlqvist R (1990) The effect of food and bile acid administration on the relative bioavailability of cyclosporin. Br J Clin Pharmacol 29:541–548

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Charman WN, Porter CJ, Mithani S, Dressman JB (1997) Physicochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci 86:269–282

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Guy GW, Robson PJ (2003) A Phase I, open label, four-way crossover study to compare the pharmacokinetic profiles of a single dose of 20 mg of a Cannabis Based Medicine Extract (CBME) administered on 3 different areas of the buccal mucosa and to investigate the pharmacokinetics of CBME per oral in healthy male and female volunteers (GWPK0112). J Cannabis Ther 3/4:79–120

    Google Scholar 

  16. 16.

    Guy GW, Robson PJ (2003) A Phase I, double blind, three-way crossover study to assess the pharmacokinetic profile of Cannabis Based Medicine Extract (CBME) administered sublingually in variant cannabinoid ratios in normal healthy male volunteers (GWPK0215). J Cannabis Ther 3/4:121–152

    Google Scholar 

  17. 17.

    Patient Information Leaflet (2012) Sativex® Oromucosal Spray. http://www.medicines.org.uk/EMC/medicine/23228/PIL/. Accessed 9 August 2012

  18. 18.

    Gershkovich P, Hoffman A (2007) Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins. Eur J Pharm Sci 32:24–32

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Charman WN, Stella VJ (1992) Lymphatic transport of drug. CRC Press, Boca Raton

    Google Scholar 

Download references

Conflicts of interest

Darren Wilbraham had support from GW Pharmaceuticals Ltd. for the submitted work. Darren Wilbraham was employed by Quintiles, who were contracted to perform the clinical study by GW Pharmaceuticals Ltd. Colin Stott, Linda White, Stephen Wright and Geoffrey Guy are shareholders of GW Pharmaceuticals Ltd.

Author information

Affiliations

Authors

Corresponding author

Correspondence to C. G. Stott.

Additional information

Sativex, a THC/CBD oromucosal spray, does not have an INN. Nabiximols is the US Adopted Name (USAN)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stott, C.G., White, L., Wright, S. et al. A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray. Eur J Clin Pharmacol 69, 825–834 (2013). https://doi.org/10.1007/s00228-012-1393-4

Download citation

Keywords

  • Cannabidiol
  • Cannabinoid
  • Delta-9-tetrahydrocannabinol
  • Endocannabinoid
  • THC/CBD spray
  • Pharmacokinetics