Abrupt withdrawal of cannabidiol (CBD): A randomized trial
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.
Perry MS. Perry MS. Epilepsy Curr. 2019 Mar-Apr;19(2):93-95. doi: 10.1177/1535759719835671. Epilepsy Curr. 2019. PMID: 30955420 Free PMC article.
Ben-Menachem E, Gunning B, Arenas Cabrera CM, VanLandingham K, Crockett J, Critchley D, Wray L, Tayo B, Morrison G, Toledo M. Ben-Menachem E, et al. CNS Drugs. 2020 Jun;34(6):661-672. doi: 10.1007/s40263-020-00726-4. CNS Drugs. 2020. PMID: 32350749 Free PMC article. Clinical Trial.
Perkins D, Butler J, Ong K, Nguyen TH, Cox S, Francis B, Mcintosh M, Lilley B. Perkins D, et al. 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.
Franco V, Perucca E. Franco V, et al. Drugs. 2019 Sep;79(13):1435-1454. doi: 10.1007/s40265-019-01171-4. Drugs. 2019. PMID: 31372958 Review.
Arzimanoglou A, Brandl U, Cross JH, Gil-Nagel A, Lagae L, Landmark CJ, Specchio N, Nabbout R, Thiele EA, Gubbay O, The Cannabinoids International Experts Panel; Collaborators. Arzimanoglou A, et al. Epileptic Disord. 2020 Feb 1;22(1):1-14. doi: 10.1684/epd.2020.1141. Epileptic Disord. 2020. PMID: 32096470 Review.
Dada S, Ellis SLS, Wood C, Nohara LL, Dreier C, Garcia NH, Saranchova I, Munro L, Pfeifer CG, Eyford BA, Kari S, Garrovillas E, Caspani G, Al Haddad E, Gray PW, Morova T, Lack NA, Andersen RJ, Tjoelker L, Jefferies WA. Dada S, et al. Front Immunol. 2023 Feb 22;13:982082. doi: 10.3389/fimmu.2022.982082. eCollection 2022. Front Immunol. 2023. PMID: 36923728 Free PMC article.
Stolar O, Hazan A, Vissoker RE, Kishk IA, Barchel D, Lezinger M, Dagan A, Treves N, Meiri D, Berkovitch M, Kohn E, Heyman E. Stolar O, et al. Front Pharmacol. 2022 Sep 29;13:977484. doi: 10.3389/fphar.2022.977484. eCollection 2022. Front Pharmacol. 2022. PMID: 36249785 Free PMC article.
Kwee CM, van Gerven JM, Bongaerts FL, Cath DC, Jacobs G, Baas JM, Groenink L. Kwee CM, et al. J Psychopharmacol. 2022 Dec;36(12):1299-1314. doi: 10.1177/02698811221124792. Epub 2022 Oct 14. J Psychopharmacol. 2022. PMID: 36239014 Free PMC article. Review.
Pinto JS, Martel F. Pinto JS, et al. Clin Drug Investig. 2022 Nov;42(11):909-919. doi: 10.1007/s40261-022-01205-y. Epub 2022 Oct 1. Clin Drug Investig. 2022. PMID: 36180814 Free PMC article.
EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA); Turck D, Bohn T, Castenmiller J, De Henauw S, Hirsch-Ernst KI, Maciuk A, Mangelsdorf I, McArdle HJ, Naska A, Pelaez C, Pentieva K, Siani A, Thies F, Tsabouri S, Vinceti M, Cubadda F, Frenzel T, Heinonen M, Marchelli R, Neuhäuser-Berthold M, Poulsen M, Prieto Maradona M, Schlatter JR, Trezza V, van Loveren H, Albert O, Dumas C, Germini A, Gelbmann W, Kass G, Kouloura E, Noriega Fernandez E, Rossi A, Knutsen HK. EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), et al. EFSA J. 2022 Jun 7;20(6):e07322. doi: 10.2903/j.efsa.2022.7322. eCollection 2022 Jun. EFSA J. 2022. PMID: 35686177 Free PMC article.