Rationale: The rationale of this study was to assess occurrence of withdrawal symptoms induced by abrupt cessation of cannabidiol (CBD) after prolonged administration in healthy volunteers.
Methods: Thirty volunteers were randomized to receive 750 mg of a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL; Epidiolex® in the United States and Epidyolex® in Europe) twice daily (b.i.d.) for 4 weeks (Part 1) followed by 2 weeks of 750 mg b.i.d. CBD (Part 2, Arm 1) or matched placebo (Part 2, Arm 2). All volunteers completed the Cannabis Withdrawal Scale (CWS) and the 20-item Penn Physician Withdrawal Checklist (PWC-20) on days -1, 21, 28, 31, 35, 42, and at follow-up.
Results: Median CWS and PWC-20 scores slightly decreased from Part 1 to Part 2. Median CWS scores ranged from 0.0 to 4.0 (out of a possible 190) in Arm 1 and 0.0 to 0.5 in Arm 2. Median PWC-20 scores were 0.0 (out of a possible 60) in both arms. Twenty-nine (97%) volunteers in Part 1 reported all-causality treatment-emergent adverse events (AEs); the most commonly reported was diarrhea (63%). In Part 2, Arm 1, 6 (67%) volunteers reported all-causality AEs; the most commonly reported was diarrhea (44%). In Part 2, Arm 2, 9 (75%) volunteers reported all-causality AEs; the most commonly reported was headache (58%). Nine volunteers withdrew because of AEs in Part 1; 1 withdrew in Part 2, Arm 2, because of an AE that began in Part 1. Four severe AEs were reported in Part 1; the remainder were mild or moderate. No serious AEs were reported.
Conclusion: In healthy volunteers, no evidence of withdrawal syndrome was found with abrupt discontinuation of short-term treatment with CBD.
Keywords: Cannabidiol; Cannabinoid; Drug withdrawal; Epilepsy; Seizure.
Copyright © 2020 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of competing interest All authors met the International Committee of Medical Journal Editors authorship criteria. Neither honoraria nor payments were made for authorship. Lesley Taylor was an employee of GW Research Ltd. at the time the work was completed. Julie Crockett is an employee of GW Research Ltd. and has share options in the company. Bola Tayo is an employee of GW Research Ltd. and owns shares in the company. Daniel Checketts is an employee of GW Research Ltd. Kenneth Sommerville was an employee of Greenwich Biosciences, Inc. at the time the work was completed.
Don't Fear the Reefer-Evidence Mounts for Plant-Based Cannabidiol as Treatment for Epilepsy.Epilepsy Curr. 2019 Mar-Apr;19(2):93-95. doi: 10.1177/1535759719835671. Epilepsy Curr. 2019. PMID: 30955420 Free PMC article.
Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial.Clin Ther. 2007 Sep;29(9):2068-79. doi: 10.1016/j.clinthera.2007.09.013. Clin Ther. 2007. PMID: 18035205 Clinical Trial.
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 Nov;32(11):1053-1067. doi: 10.1007/s40263-018-0578-5. CNS Drugs. 2018. PMID: 30374683 Free PMC article. Clinical Trial.
Adjunctive Cannabidiol in Patients with Dravet Syndrome: A Systematic Review and Meta-Analysis of Efficacy and Safety.CNS Drugs. 2020 Mar;34(3):229-241. doi: 10.1007/s40263-020-00708-6. CNS Drugs. 2020. PMID: 32040850 Review.
Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy.Drugs. 2019 Sep;79(13):1435-1454. doi: 10.1007/s40265-019-01171-4. Drugs. 2019. PMID: 31372958 Review.