Abstract

Importance: Owing to its anti-inflammatory properties and antiviral “in vitro” effect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cannabidiol (CBD) has been proposed as a potential treatment for coronavirus disease 2019 (COVID-19).
Objective: To investigate the safety and efficacy of CBD for treating patients with mild to moderate COVID-19.
Design: Randomized, parallel-group, double-blind, placebo-controlled clinical trial conducted between July 7 and October 16, 2020, in two sites in Brazil.
Setting: Patients were recruited in an emergency room.
Participants: Block randomized patients (1:1 allocation ratio—by a researcher not directly involved in data collection) with mild and moderate COVID-19 living in Ribeirão Preto, Brazil, seeking medical consultation, and those who voluntarily agreed to participate in the study.
Interventions: Patients received 300 mg of CBD or placebo added to standard symptomatic care during 14 days.
Main Outcome and Measure: The primary outcome was reduction or prevention of the deterioration in clinical status from mild/moderate to severe/critical measured with the COVID-19 Scale or the natural course of the resolution of typical clinical symptoms. Primary study outcome was assessed on days 14, 21, and 28 after enrollment.
Results: A total of 321 patients were recruited and assessed for eligibility, and 105 were randomly allocated either in CBD (n=49) or in placebo (n=42) group. Ninety-one participants were included in the analysis of efficacy. There were no baseline between-group differences regarding disease severity (χ2=0.025, p=0.988) and median time to symptom resolution (12 days [95% confidence interval, CI, 6.5–17.5] in the CBD group, 9 days [95% CI, 4.8–13.2] in the placebo group [χ2=1.6, p=0.205 by log-rank test]). By day 28, 83.3% in the CBD group and 90.2% in the placebo group had resolved symptoms. There were no between-group differences on secondary measures. CBD was well tolerated, producing mostly mild and transient side effects (e.g., somnolence, fatigue, changes in appetite, lethargy, nausea, diarrhea, and fever), with no significant differences between CBD and placebo treatment groups.
Conclusions and Relevance: Daily administration of 300 mg CBD for 14 days failed to alter the clinical evolution of COVID-19. Further trials should explore the therapeutic effect of CBD in patients with severe COVID-19, possibly trying higher doses than the used in our study. Trial Registration: ClinicalTrials.gov identifier NCT04467918 (date of registration: July 13, 2020).

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Cite this article as: Crippa JAS, Pacheco JC, Zuardi AW, Guimarães FS, Campos AC, Osório FL, Loureiro SR, dos Santos RG, Souza JDS, Ushirohira JM, Ferreira RR, Mancini Costa KC, Scomparin DS, Scarante FF, Pires-Dos-Santos I, Mechoulam R, Kapczinski F, Fonseca BAL, Esposito DLA, Passos ADC, Dal Fabbro AL, Bellissimo-Rodrigues F, Arruda E, Scarpelini S, Andraus MH, Nather Junior JC, Wada DT, Koenigkam-Santos M, Santos AC, Busatto Filho G, Hallak JEC; for the Cannabidiol for COVID-19 Patients (CANDIDATE) Trial Investigators (2022) Cannabidiol for COVID-19 patients with mild to moderate symptoms (CANDIDATE study): a randomized, double-blind, placebo-controlled clinical trial, Cannabis and Cannabinoid Research 7:5, 658–669, DOI: 10.1089/can.2021.0093.

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cover image Cannabis and Cannabinoid Research
Cannabis and Cannabinoid Research
Volume 7Issue Number 5October 2022
Pages: 658 - 669
PubMed: 34619044

History

Published online: 12 October 2022
Published in print: October 2022
Published ahead of print: 7 October 2021

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Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
National Institute for Science and Technology—Translational Medicine, São Paulo, Brazil.
Julia Cozar Pacheco
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Antonio W. Zuardi
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
National Institute for Science and Technology—Translational Medicine, São Paulo, Brazil.
Francisco S. Guimarães
National Institute for Science and Technology—Translational Medicine, São Paulo, Brazil.
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Alline Cristina Campos
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Flávia de Lima Osório
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
National Institute for Science and Technology—Translational Medicine, São Paulo, Brazil.
Sonia Regina Loureiro
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Rafael G. dos Santos
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
National Institute for Science and Technology—Translational Medicine, São Paulo, Brazil.
José Diogo S. Souza
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Juliana Mayumi Ushirohira
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Rafael Rinaldi Ferreira
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Karla Cristinne Mancini Costa
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Davi Silveira Scomparin
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Franciele Franco Scarante
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Isabela Pires-Dos-Santos
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Raphael Mechoulam
Department of Medicinal Chemistry and Natural Products, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Flávio Kapczinski
National Institute for Science and Technology—Translational Medicine, São Paulo, Brazil.
Department of Psychiatry and Behavioural Neurosciences, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
Graduate Program in Psychiatry and Behavioral Sciences, Department of Psychiatry, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Benedito A.L. Fonseca
Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Danillo L.A. Esposito
Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Afonso Dinis Costa Passos
Department of Social Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Amaury Lelis Dal Fabbro
Department of Social Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Fernando Bellissimo-Rodrigues
Department of Social Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Eurico Arruda
Department of Cell and Molecular Biology, and Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Sandro Scarpelini
Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Maristela Haddad Andraus
Chromatox Laboratory Ltda., São Paulo, Brazil.
Julio Cesar Nather Junior
Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Danilo Tadao Wada
Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Marcel Koenigkam-Santos
Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Antonio Carlos Santos
Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Geraldo Busatto Filho
Laboratory of Psychiatric Neuroimaging (LIM 21), Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Jaime E.C. Hallak
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
National Institute for Science and Technology—Translational Medicine, São Paulo, Brazil.

Notes

*
Address correspondence to: José Alexandre S. Crippa, PhD, Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, 3900, Ribeirão Preto, São Paulo CEP 14049-900, Brazil, [email protected]

Authors' Contributions

J.A.S.C., A.W.Z., F.S.G., F.L.O., A.C.C., S.R.L., and J.E.C.H. designed the study, and J.A.S.C. and R.G.S. wrote the report. J.A.S.C., A.W.Z., F.S.G., F.L.O., A.C.C., J.C.P., and J.E.C.H. coordinated the study, and A.W.Z., F.S.G., and A.C.C. analyzed the data. R.R.F., K.C.M.C., D.S.S., I.P.-.D.-S., F.F.S., and A.C.C. designed, performed, and analyzed the cytokines plasma levels. All authors critically revised the report or contributed important intellectual content.

Author Disclosure Statement

J.A.S.C. is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE)—National Health and Medical Research Council (NHMRC). J.A.S.C. and J.E.C.H. have received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. J.A.S.C., J.E.C.H., F.K., F.S.G., A.W.Z., and R.M. are coinventors of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; R.M., A.W.Z., F.K., J.E.C.H. F.S.G., J.A.S.C., A. Breuer). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson's disease, and anxiety disorders.” J.A.S.C., J.E.C.H., F.S.G., A.C.C., and A.W.Z. are coinventors of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on September 16, 2016 (BR 112018005423-2). The other authors declare that they have no conflicts of interest.

Funding Information

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and by the Instituto Nacional de Ciência e Tecnologia Translational em Medicina (INCT-TM; CNPq/FAPESP; 465458/2014-9; 2014/50891-1). J.A.S.C. received a grant from the University Global Partnership Network (UGPN)—Global Priorities in Cannabinoid Research Excellence Program. J.A.S.C., J.E.C.H., F.L.O., S.R.L., A.C.C., and A.W.Z. are recipients of CNPq research fellowships. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

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