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
- PMID: 30374683
- PMCID: PMC6223703
- DOI: 10.1007/s40263-018-0578-5
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
Erratum in
-
Correction to: 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. 2019 Apr;33(4):397. doi: 10.1007/s40263-019-00617-3. CNS Drugs. 2019. PMID: 30830575 Free PMC article.
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](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6223703/bin/40263_2018_578_Fig1_HTML.gif)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6223703/bin/40263_2018_578_Fig2_HTML.gif)
![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6223703/bin/40263_2018_578_Fig3_HTML.gif)
Similar articles
-
A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers.Eur J Drug Metab Pharmacokinet. 2020 Oct;45(5):575-586. doi: 10.1007/s13318-020-00624-6. Eur J Drug Metab Pharmacokinet. 2020. PMID: 32409982 Free PMC article. Clinical Trial.
-
A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects.Epilepsia. 2020 Feb;61(2):267-277. doi: 10.1111/epi.16419. Epub 2020 Feb 3. Epilepsia. 2020. PMID: 32012251 Free PMC article. Clinical Trial.
-
A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal Impairment.Clin Pharmacokinet. 2020 Jun;59(6):747-755. doi: 10.1007/s40262-019-00841-6. Clin Pharmacokinet. 2020. PMID: 31802404 Free PMC article. Clinical Trial.
-
Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers.Curr Pharm Des. 2012;18(32):4966-79. doi: 10.2174/138161212802884780. Curr Pharm Des. 2012. PMID: 22716148 Review.
-
Tiotropium bromide. A review of its use as maintenance therapy in patients with COPD.Treat Respir Med. 2004;3(4):247-68. doi: 10.2165/00151829-200403040-00005. Treat Respir Med. 2004. PMID: 15350163 Review.
Cited by
-
Pharmacokinetics behavior of four cannabidiol preparations following single oral administration in dogs.Front Vet Sci. 2024 Apr 25;11:1389810. doi: 10.3389/fvets.2024.1389810. eCollection 2024. Front Vet Sci. 2024. PMID: 38725584 Free PMC article.
-
Determination of Δ9-tetrahydrocannabinol, 11-nor-carboxy-Δ9-tetrahydrocannabinol and cannabidiol in human plasma and urine after a commercial cannabidiol oil product intake.Forensic Toxicol. 2024 Apr 9. doi: 10.1007/s11419-024-00686-0. Online ahead of print. Forensic Toxicol. 2024. PMID: 38592642
-
Pharmacokinetic of two oral doses of a 1:20 THC:CBD cannabis herbal extract in cats.Front Vet Sci. 2024 Feb 23;11:1352495. doi: 10.3389/fvets.2024.1352495. eCollection 2024. Front Vet Sci. 2024. PMID: 38585296 Free PMC article.
-
Influence of short-term chronic oral cannabidiol application on muscle recovery and performance after an intensive training protocol - a randomized double-blind crossover study.J Int Soc Sports Nutr. 2024 Dec;21(1):2337252. doi: 10.1080/15502783.2024.2337252. Epub 2024 Apr 4. J Int Soc Sports Nutr. 2024. PMID: 38572744 Free PMC article.
-
Cannabinoid-Induced Inhibition of Morphine Glucuronidation and the Potential for In Vivo Drug-Drug Interactions.Pharmaceutics. 2024 Mar 18;16(3):418. doi: 10.3390/pharmaceutics16030418. Pharmaceutics. 2024. PMID: 38543313 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases