Cannabidiol for COVID-19 Patients with Mild to Moderate Symptoms (CANDIDATE Study): A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
José Alexandre S Crippa, Julia Cozar Pacheco, Antonio W Zuardi, Francisco S Guimarães, Alline Cristina Campos, Flávia De Lima Osório, Sonia Regina Loureiro, Rafael G Dos Santos, José Diogo S Souza, Juliana Mayumi Ushirohira, Rafael Rinaldi Ferreira, Karla Cristinne Mancini Costa, Davi Silveira Scomparin, Franciele Franco Scarante, Isabela Pires-Dos-Santos, Raphael Mechoulam, Flávio Kapczinski, Benedito A L Fonseca, Danillo L A Esposito, Afonso Dinis Costa Passos, Amaury Lelis Dal Fabbro, Fernando Bellissimo-Rodrigues, Eurico Arruda, Sandro Scarpelini, Maristela Haddad Andraus, Julio Cesar Nather Junior, Danilo Tadao Wada, Marcel Koenigkam-Santos, Antonio Carlos Santos, Geraldo Busatto Filho, Jaime E C Hallak
Cannabis and Cannabinoid Research, doi:10.1089/can.2021.0093
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 Ribeira ˜o 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 (v 2 = 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,
References
Anil, Shalev, Vinayaka, Cannabis compounds exhibit antiinflammatory activity in vitro in COVID-19-related inflammation in lung epithelial cells and pro-inflammatory activity in macrophages, Sci Rep
Bergamaschi, Queiroz, Chagas, Cannabidiol reduces the anxiety induced by simulated public speaking in treatmentnaı ¨ve social phobia patients, Neuropsychopharmacology
Biali, Broers, Besson, Cannabinoids and COVID-19, Med Cannabis Cannabinoids
Byrareddy, Mohan, SARS-CoV2 induced respiratory distress: can cannabinoids be added to anti-viral therapies to reduce lung inflammation?, Brain Behav Immun
Campos, Brant, Miranda, Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria, Neuroscience
Campos, Ferreira, Guimara, Fs, Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors, J Psychiatr Res
Campos, Ortega, Palazuelos, The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system, Int J Neuropsychopharmacol
China, National Health Commission of the People's Republic of China
Crippa, Guimara ˜es, Campos, Translational investigation of the therapeutic potential of cannabidiol (CBD): toward a new age, Front Immunol
Crippa, Pacheco, Zuardi, Guimara ˜es, Campos et al., for the Cannabidiol for COVID-19 Patients (CANDIDATE) Trial Investigators (2021) Cannabidiol for COVID-19 patients with mild to moderate symptoms (CANDIDATE study): a randomized, double-blind, placebo-controlled clinical trial, Cannabis and Cannabinoid Research X:X
Dong, Tang, Wang, The role of imaging in the detection and management of COVID-19: a review, IEEE Rev Biomed Eng
Dos-Santos-Pereira, ˜es, Bel, Cannabidiol prevents LPS-induced microglial inflammation by inhibiting ROS/ NF-jB-dependent signaling and glucose consumption, Glia
Esposito, Pesce, Seguella, The potential of cannabidiol in the COVID-19 pandemic, Br J Pharmacol
Fu, Kong, Wang, The clinical implication of dynamic neutrophil to lymphocyte ratio and D-dimer in COVID-19: a retrospective study in Suzhou China, Thromb Res
Jimeno, Ventura, Castellano, Prognostic implications of neutrophil-lymphocyte ratio in COVID-19, Eur J Clin Invest
Khodadadi, Salles, ´l, Jarrahi, Cannabidiol modulates cytokine storm in acute respiratory distress syndrome induced by simulated viral infection using synthetic RNA, Cannabis Cannabinoid Res
Long, Zeng, Zhang, Short-term outcomes of COVID-19 and risk factors for progression, Eur Respir J
Mabou Tagne, Pacchetti, Sodergren, Cannabidiol for viral diseases: hype or hope? Cannabis Cannabinoid, Res
Malinowska, Baranowska-Kuczko, Kicman, Opportunities, challenges and pitfalls of using cannabidiol as an adjuvant drug in COVID-19, Int J Mol Sci
Masataka, Anxiolytic effects of repeated cannabidiol treatment in teenagers with social anxiety disorders, Front Psychol
Mecha, Feliu, ˜igo, Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors, Neurobiol Dis
Moreno, Desousa, Souza, Factor structure, reliability, and item parameters of the Brazilian-Portuguese version of the GAD-7 questionnaire, Temas Psicol
Oso, Vilela Mendes, Crippa, Study of the discriminative validity of the PHQ-9 and PHQ-2 in a sample of Brazilian women in the context of primary health care, Perspect Psychiatr Care
Pacheco, Souza, Hallak, Cannabidiol as a treatment for mental health outcomes among health care workers during the coronavirus disease pandemic, J Clin Psychopharmacol
Raj, Park, Cho, Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches, Int J Biol Macromol
Richardson, Hirsch, Narasimhan, Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area, JAMA
Salles, ´l, Khodadadi, Jarrahi, Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome, J Cell Mol Med
Sonego, Prado, Vale, Cannabidiol prevents haloperidolinduced vacuos chewing movements and inflammatory changes in mice via PPARc receptors, Brain Behav Immun
Stamps, Bartoshuk, Heilman, A brief olfactory test for Alzheimer's disease, J Neurol Sci
Suryavanshi, Kovalchuk, Kovalchuk, Cannabinoids as key regulators of inflammasome signaling: a current perspective, Front Immunol
Vuolo, Abreu, Michels, Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma, Eur J Pharmacol
Zanelati, Biojone, Moreira, Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT 1A receptors, Br J Pharmacol
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