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
CBD was well tolerated at all doses without serious AEs, but showed gastrointestinal side effects and a strongly food-dependent bioavailability.
Summary
Phase I safety study in healthy subjects, CBD oral 1500–6000 mg (SAD), 750/1500 mg 2x daily (MD); CBD well tolerated, all AEs mild to moderate, no severe/serious events, no study discontinuations; most common AEs: diarrhoea, nausea, headache, somnolence; high-fat meal increased CBD exposure (Cmax and AUCt) by 4,85-fold and 4,2-fold respectively; terminal t½ ~60 h after multiple dosing.
P
PopulationHealthy adult subjects; SAD arm: n=32 (6 per CBD dose group + 8 placebo); MD arm: n=24 (9 per CBD group + 6 placebo); food-effect arm: n=12
I
InterventionHighly purified CBD oral solution; SAD: 1500/3000/4500/6000 mg single dose; MD: 750/1500 mg twice daily over 7 days; food-effect: 1500 mg single dose with high-fat meal
C
ControlPlacebo (SAD and MD arm); fasted condition (food-effect arm)
O
OutcomeCBD well tolerated; all AEs mild to moderate (most common: diarrhoea, nausea, headache, somnolence); no serious AEs/deaths; Cmax increase less than dose-proportional (slope 0,73); high-fat meal increased Cmax 4,85-fold and AUCt 4,2-fold; terminal half-life approx. 60 h under multiple dosing
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 (t<sub>max</sub>) 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 (C<sub>max</sub>) and area under the plasma concentration-time curve from time zero to time t (AUC<sub>t</sub>)] increased in a less than dose-proportional manner (C<sub>max</sub> slope 0.73; AUC<sub>t</sub> 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 C<sub>max</sub> and area under the plasma concentration-time curve over a dosing interval (AUC<sub>τ</sub>), 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. C<sub>max</sub> was 541.2 ng/mL and AUC<sub>τ</sub> was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (C<sub>max</sub> and AUC<sub>t</sub>) by 4.85- and 4.2-fold, respectively; there was no effect of food on t<sub>max</sub> or terminal half-life.<h4>Conclusion</h4>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.