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

Lesley Taylor, Barry Gidal, Graham Blakey, Bola Tayo, Gilmour Morrison, Lesley Taylor, Barry Gidal, Graham Blakey, Bola Tayo, Gilmour Morrison

Abstract

Background: A formal single ascending and multiple dose pharmacokinetic (PK) trial of cannabidiol (CBD) oral solution was required to determine the safety and tolerability of CBD, the maximum tolerated dose, and to examine the effect of food on CBD PK parameters.

Objective: This trial assessed the safety, tolerability and PK of CBD oral solution in healthy adult volunteers, as well as the effect of food on CBD PK parameters.

Methods: The study consisted of three arms: single ascending dose (1500, 3000, 4500 or 6000 mg CBD [n = 6 per group]/placebo [n = 8; 2 per CBD dose group]), multiple dose (750 or 1500 mg CBD [n = 9 per group]/placebo [n = 6; 3 per CBD dose group] twice daily), and food effect (1500 mg CBD single dose [n = 12]). All subjects completed all trial arms and were analyzed as planned.

Results: CBD was generally well tolerated. Diarrhea, nausea, headache, and somnolence were the most common adverse events (AEs) across all trial arms, with an increased incidence of some gastrointestinal and nervous system disorder AEs (most notably diarrhea and headache) apparent in subjects taking CBD compared with placebo. All AEs were of mild or moderate severity; none were severe or serious. There were no deaths or discontinuations in the trial. After single oral doses, CBD appeared rapidly in plasma; time to maximum plasma concentration (tmax) was approximately 4-5 h. The major circulating metabolite was 7-carboxy-CBD, then parent CBD, 7-hydroxy-CBD (active metabolite), and 6-hydroxy-CBD (a relatively minor metabolite). Plasma exposure to CBD [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to time t (AUCt)] increased in a less than dose-proportional manner (Cmax slope 0.73; AUCt slope 0.64). Oral clearance of CBD was high (1111-1909 L/h) and apparent volume of distribution was large (20,963-42,849 L). CBD reached steady state after approximately 2 days, with moderate accumulation (1.8- to 2.6-fold) after 750 and 1500 mg CBD twice daily. After 7 days, a twofold increase in CBD dose resulted in 1.6- and 1.9-fold increases in geometric mean Cmax and area under the plasma concentration-time curve over a dosing interval (AUCτ), respectively. CBD elimination was multiphasic; the terminal elimination half-life was approximately 60 h after 750 and 1500 mg CBD twice daily; and effective half-life estimates ranged from 10 to 17 h. Cmax was 541.2 ng/mL and AUCτ was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (Cmax and AUCt) by 4.85- and 4.2-fold, respectively; there was no effect of food on tmax or terminal half-life.

Conclusion: CBD was generally well tolerated. Most AEs were mild in severity; none were severe or serious. The safety and PK profile support twice-daily administration of CBD.

Conflict of interest statement

Lesley Taylor, Gilmour Morrison and Bola Tayo are employed by GW Research Ltd and have shares in the company. Graham Blakey and Barry Gidal have received consultancy fees from GW Research Ltd.

Figures

Fig. 1
Fig. 1
Single ascending CBD dose (1500, 3000, 4500 or 6000 mg) geometric mean plasma concentration-time profiles for CBD and its major metabolites (semi-logarithmic scale; pharmacokinetic set). 6-OH-CBD 6-hydroxy-cannabidiol, 7-OH-CBD 7-hydroxy-cannabidiol, 7-COOH-CBD 7-carboxy-cannabidiol, CBD cannabidiol
Fig. 2
Fig. 2
Multiple CBD dose (1500 mg) geometric mean plasma concentration-time profiles for CBD and its major metabolites (semi-logarithmic scale; pharmacokinetic set). 6-OH-CBD 6-hydroxy-cannabidiol, 7-OH-CBD 7-hydroxy-cannabidiol, 7-COOH-CBD 7-carboxy-cannabidiol, CBD cannabidiol
Fig. 3
Fig. 3
Geometric mean and individual (expressed as dose normalized) Cmax (a) and AUC∞ (b) of CBD for the fasted and fed state following a single 1500 mg dose of CBD (pharmacokinetic set). AUC∞ area under the concentration-time curve from time zero to infinity, CBD cannabidiol, Cmax maximum measured plasma concentration

References

    1. Devinsky O, Cross JH, Laux L, et al. Cannabidiol in Dravet Syndrome Study Group. Trial of Cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–2020. doi: 10.1056/NEJMoa1611618.
    1. 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.
    1. Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018;378(20):1888–1897. doi: 10.1056/NEJMoa1714631.
    1. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085–1096. doi: 10.1016/S0140-6736(18)30136-3.
    1. Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12(4):699–730. doi: 10.1007/s13311-015-0377-3.
    1. Henstridge CM, Balenga NA, Kargl J, et al. Minireview: recent developments in the physiology and pathology of the lysophosphatidylinositol-sensitive receptor GPR55. Mol Endocrinol. 2011;25(11):1835–1848. doi: 10.1210/me.2011-1197.
    1. Sylantyev S, Jensen TP, Ross RA, Rusakov DA. Cannabinoid and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci USA. 2013;110(13):5193–5198. doi: 10.1073/pnas.1211204110.
    1. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172(3):737–753. doi: 10.1111/bph.12944.
    1. Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89(5–6):165–170. doi: 10.1016/j.lfs.2011.05.018.
    1. Zendulka O, Dovrtělová G, Nosková K, et al. Cannabinoids and cytochrome P450 interactions. Curr Drug Metab. 2016;17(3):206–226. doi: 10.2174/1389200217666151210142051.
    1. Mazur A, Lichti CF, Prather PL, et al. Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. Drug Metab Dispos. 2009;37(7):1496–1504. doi: 10.1124/dmd.109.026898.
    1. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86–95. doi: 10.3109/03602532.2013.849268.
    1. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–1251. doi: 10.1111/epi.13060.
    1. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586–1592. doi: 10.1111/epi.13852.
    1. Zuardi AW, Morais SL, Guimarães FS, Mechoulam R. Antipsychotic effect of cannabidiol. J Clin Psychiatry. 1995;56(10):485–486.
    1. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6(4):237–249. doi: 10.2174/157488611798280924.
    1. Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57(10):1617–1624. doi: 10.1111/epi.13499.
    1. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment resistant epilepsy: an open-label interventional trial. The Lancet Neurology. 2016;15:270–278. doi: 10.1016/S1474-4422(15)00379-8.
    1. Whalley BJ, Stott C, Gray RA. The human metabolite of cannabidiol, 7-hydroxy-cannabidiol, but not 7-carboxy-cannabidiol, is anticonvulsant in the maximal electroshock threshold test (MEST) in mouse [abstract no. 1.435]. AES Conference; 2017.
    1. Boxenbaum H, Battle M. Effective half-life in clinical pharmacology. J Clin Pharmacol. 1995;35(8):763–766. doi: 10.1002/j.1552-4604.1995.tb04117.x.
    1. Gidal BE, Clark AM, Anders B, Gilliam F. The application of half-life in clinical decision making: comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate. Epilepsy Res. 2017;129:26–32. doi: 10.1016/j.eplepsyres.2016.10.020.
    1. Moghimipour E, Ameri A, Handali S. Absorption-enhancing effects of bile salts. Molecules. 2015;20(8):14451–14473. doi: 10.3390/molecules200814451.

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