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Complementary and Alternative Medicine

Efficacy and Safety of Cannabidiol Plus Standard Care vs Standard Care Alone for the Treatment of Emotional Exhaustion and Burnout Among Frontline Health Care Workers During the COVID-19 PandemicA Randomized Clinical Trial

Educational Objective
To identify the key insights or developments described in this article

1 Credit CME

JAMA Network Open

Published Online: August 13, 2021

Original Investigation

Article Information and Disclosures

José Alexandre S. Crippa, PhD^1,2;

Antonio W. Zuardi, PhD^1,2;

Francisco S. Guimarães, PhD^2,3;

Alline Cristina Campos, PhD³;

Flávia de Lima Osório, PhD^1,2;

Sonia Regina Loureiro, PhD¹;

Rafael G. dos Santos, PhD^1,2;

José Diogo S. Souza, MD¹;

Juliana Mayumi Ushirohira, MD, MSc¹;

Julia Cozar Pacheco, RPh¹;

Rafael Rinaldi Ferreira, PhD, RPh³;

Karla Cristinne Mancini Costa, MSc³;

Davi Silveira Scomparin, MSc³;

Franciele Franco Scarante, MSc³;

Isabela Pires-Dos-Santos, VMD³;

Raphael Mechoulam, PhD⁴;

Flávio Kapczinski, PhD^2,5,6;

Benedito A. L. Fonseca, PhD⁷;

Danillo L. A. Esposito, PhD⁷;

Karina Pereira-Lima, PhD^8,9;

Srijan Sen, PhD⁸;

Maristela Haddad Andraus, MSc, RPh¹⁰;

Jaime E. C. Hallak, PhD^1,2;

for the Burnout and Distress Prevention With Cannabidiol in Front-line Health Care Workers Dealing With COVID-19 (BONSAI) Trial Investigators

Author Affiliations

¹Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
²National Institute for Science and Technology–Translational Medicine, São Paulo, Brazil
³Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
⁴Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
⁵Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
⁶Department of Psychiatry, Faculty of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
⁷Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
⁸Department of Psychiatry, University of Michigan Medical School, Ann Arbor
⁹Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil
¹⁰Chromatox Laboratory, São Paulo, Brazil

Burnout and Distress Prevention With Cannabidiol in Front-line Health Care Workers Dealing With COVID-19 (BONSAI) Trial Investigatorsfor the

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Key Points

Question Is cannabidiol (CBD) therapy capable of reducing emotional exhaustion and burnout symptoms among frontline health care professionals working with patients with COVID-19?

Findings In this randomized clinical trial of 120 frontline health care professionals, emotional exhaustion scores were reduced among participants receiving CBD plus standard care compared with those receiving standard care alone. Five participants who received CBD plus standard care experienced serious adverse events, with full recovery after discontinuation.

Meaning The study’s findings suggest that CBD may act as an effective agent for the reduction of emotional exhaustion and burnout symptoms among frontline health care professionals, although it is necessary to balance the benefits with potential undesired effects when making decisions regarding the use of CBD.

Abstract

Importance Frontline health care professionals who work with patients with COVID-19 have an increased incidence of burnout symptoms. Cannabidiol (CBD) has anxiolytic and antidepressant properties and may be capable of reducing emotional exhaustion and burnout symptoms.

Objective To investigate the safety and efficacy of CBD therapy for the reduction of emotional exhaustion and burnout symptoms among frontline health care professionals working with patients with COVID-19.

Design, Setting, and Participants This prospective open-label single-site randomized clinical trial used a 1:1 block randomization design to examine emotional exhaustion and burnout symptoms among frontline health care professionals (physicians, nurses, and physical therapists) working with patients with COVID-19 at the Ribeirão Preto Medical School University Hospital in São Paulo, Brazil. Participants were enrolled between June 12 and November 12, 2020. A total of 214 health care professionals were recruited and assessed for eligibility, and 120 participants were randomized in a 1:1 ratio by a researcher who was not directly involved with data collection.

Interventions Cannabidiol, 300 mg (150 mg twice per day), plus standard care or standard care alone for 28 days.

Main Outcomes and Measures The primary outcome was emotional exhaustion and burnout symptoms, which were assessed for 28 days using the emotional exhaustion subscale of the Brazilian version of the Maslach Burnout Inventory–Human Services Survey for Medical Personnel.

Results A total of 120 participants were randomized to receive either CBD, 300 mg, plus standard care (treatment arm; n = 61) or standard care alone (control arm; n = 59) for 28 days. Of those, 118 participants (59 participants in each arm; 79 women [66.9%]; mean age, 33.6 years [95% CI, 32.3-34.9 years]) received the intervention and were included in the efficacy analysis. In the treatment arm, scores on the emotional exhaustion subscale of the Maslach Burnout Inventory significantly decreased at day 14 (mean difference, 4.14 points; 95% CI, 1.47-6.80 points; partial eta squared [η_p²] = 0.08), day 21 (mean difference, 4.34 points; 95% CI, 0.94-7.73 points; η_p² = 0.05), and day 28 (mean difference, 4.01 points; 95% CI, 0.43-7.59 points; η_p² = 0.04). However, 5 participants, all of whom were in the treatment group, experienced serious adverse events: 4 cases of elevated liver enzymes (1 critical and 3 mild, with the mild elevations reported at the final 28-day assessment) and 1 case of severe pharmacodermia. In 2 of those cases (1 with critical elevation of liver enzymes and 1 with severe pharmacodermia), CBD therapy was discontinued, and the participants had a full recovery.

Conclusions and Relevance In this study, CBD therapy reduced symptoms of burnout and emotional exhaustion among health care professionals working with patients during the COVID-19 pandemic. However, it is necessary to balance the benefits of CBD therapy with potential undesired or adverse effects. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings.

Trial Registration ClinicalTrials.gov Identifier: NCT04504877

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Article Information

Accepted for Publication: June 1, 2021.

Published: August 13, 2021. doi:10.1001/jamanetworkopen.2021.20603

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Crippa JAS et al. JAMA Network Open.

Corresponding Author: José Alexandre S. Crippa, PhD, Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Terceiro Andar, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, Brazil, CEP 14049-900 (jcrippa@fmrp.usp.br).

Author Contributions: Drs Zuardi and Guimarães had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Crippa, Zuardi, Guimarães, Osório, Loureiro, Souza, Ushirohira, Pacheco, Mechoulam, Hallak.

Acquisition, analysis, or interpretation of data: Crippa, Zuardi, Campos, dos Santos, Souza, Ushirohira, Pacheco, Rinaldi Ferreira, Mancini Costa, Scomparin, Scarante, Pires-Dos-Santos, Kapczinski, Fonseca, Esposito, Pereira-Lima, Sen, Andraus, Hallak.

Drafting of the manuscript: Crippa, Zuardi, Campos, Osório, dos Santos, Ushirohira, Pacheco, Rinaldi Ferreira, Mancini Costa, Scomparin, Scarante, Pires-Dos-Santos, Hallak.

Critical revision of the manuscript for important intellectual content: Crippa, Zuardi, Guimarães, Campos, Osório, Loureiro, dos Santos, Souza, Ushirohira, Pacheco, Mechoulam, Kapczinski, Fonseca, Esposito, Pereira-Lima, Sen, Andraus, Hallak.

Statistical analysis: Crippa, Zuardi, Guimarães, Campos, Rinaldi Ferreira, Mancini Costa, Scomparin, Scarante, Pires-Dos-Santos, Esposito.

Obtained funding: Crippa, Hallak.

Administrative, technical, or material support: Crippa, Campos, Osório, Loureiro, Souza, Ushirohira, Pacheco, Rinaldi Ferreira, Mancini Costa, Scomparin, Scarante, Pires-Dos-Santos, Andraus, Hallak.

Supervision: Crippa, Campos, Osório, Pacheco, Kapczinski, Hallak.

Conflict of Interest Disclosures: Dr Crippa reported receiving grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo and the Instituto Nacional de Ciência e Tecnologia Translational em Medicina and personal fees from the Conselho Nacional de Desenvolvimento Científico e Tecnológico and Salomão e Zoppi Serviços Médicos e Participações during the conduct of the study and receiving travel support and personal fees from BioSynthesis Pharma Group; serving as a member of the international advisory board of the Australian Centre for Cannabinoid Clinical and Research Excellence, National Health and Medical Research Council; being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs); and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. Dr Zuardi reported receiving grants from the Instituto Nacional de Ciência e Tecnologia Translational em Medicina and personal fees from the Conselho Nacional de Desenvolvimento Científico e Tecnológico during the conduct of the study, being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs), and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. Dr Guimarães reported receiving grants from Prati-Donaduzzi, being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs), and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. Dr Campos reported having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. Dr dos Santos reported receiving grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico during the conduct of the study. Dr Ushirohira reported receiving personal fees from Ribeirão Preto Medical School, University of São Paulo, during the conduct of the study. Dr Mechoulam reported being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs) outside the submitted work. Dr Kapczinski reported receiving grants from the Canada Foundation for Innovation, the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Mitacs, and the Stanley Medical Research Institute; personal fees from Aché Laboratorios Farmaceuticos, Daiichi Sankyo, and Janssen-Cilag; and being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs) outside the submitted work. Ms Andraus reported receiving technical support from Salomao Zoppi Serviços Medicos e Participações during the conduct of the study and personal fees from Laboratório Chromatox outside the submitted work. Dr Hallak reported receiving grants from Prati-Donaduzzi, travel support and personal fees from BioSynthesis Pharma Group, being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs), and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grant 2020/12110-9 from the Fundação de Amparo à Pesquisa do Estado de São Paulo; grant 2008/09009-2 from the Instituto Nacional de Ciência e Tecnologia Translational em Medicina; a grant from the Global Priorities in Cannabinoid Research Excellence Program, University Global Partnership Network (Dr Crippa); funding via research fellowships from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Drs Crippa, Hallak, de Lima Osório, Loureiro, Campos, and Zuardi); in-kind donations of cannabidiol from PurMed Global; and donated services (dosing plasma levels of cannabidiol) from Laboratório Chromatox.

Role of the Funder/Sponsor: The funding organizations 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 manuscript; and decision to submit the manuscript for publication.

Group Members: Information on the Burnout and Distress Prevention With Cannabidiol in Front-line Health Care Workers Dealing With COVID-19 (BONSAI) trial investigators appears in Supplement 3.

Additional Contributions: We thank PurMed Global (Delray Beach, Florida) for donating cannabidiol and Salomão e Zoppi Serviços Médicos e Participações (São Paulo, Brazil) and Laboratório Chromatox (São Paulo, Brazil) for dosing plasma levels of cannabidiol at no cost. We also thank the following members of the data and safety monitoring board for their commitment and responsiveness: Antonio Carlos dos Santos, MD, PhD, of the Department of Medical Imaging, Haematology, and Clinical Oncology, University of São Paulo (São Paulo, Brazil); Fábio Carmona, MD, PhD, of the Department of Pediatrics, University of São Paulo (São Paulo, Brazil); and Osvaldo Takayanagui, MD, PhD, of the Department of Health Sciences, University of São Paulo (São Paulo, Brazil). None of the contributors received compensation for their assistance.

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