Crippa JAS, Zuardi AW, Guimarães FS, et al. 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 pandemic: a randomized clinical trial. JAMA Netw Open. 2021;4(8):e2120603.
This study sought to investigate cannabidiol (CBD) therapy’s safety and effectiveness in reducing emotional exhaustion and burnout symptoms in frontline healthcare professionals who work with Covid-19 patients.
Open-label, randomized, controlled trial at a single hospital in Sao Paulo, Brazil
This study randomized 118 Covid-19 pandemic frontline healthcare professionals (n=59 in each arm, 66.9% women, average age 33.6 years old) between June 12, 2020, and November 12, 2020, at a single hospital.
The healthcare workers included doctors, nurses, and physical therapists directly working with Covid-19 patients. The providers were all healthy and between 24 and 60 years old.
Exclusion criteria included providers on medication with potential CBD interaction (not all medication takers were excluded), prior history of adverse reaction to CBD or other phytocannabinoids, Covid-19 high risk group (e.g., diabetes) and pregnancy.
The control arm received standard support therapy (“motivational and instructional videos on low-impact physical exercise plus weekly consultations with psychiatrists who offered psychological support”). The intervention arm received standard support therapy plus 150 mg of cannabidiol (99.6% purity; PurMed Global) in MCT oil twice daily for 28 days.
Study Parameters Assessed
The primary outcome was assessed with the emotional exhaustion subscale of the Maslach Burnout Inventory-Human Services Survey for Medical Personnel. Secondary outcomes of anxiety, depression, and posttraumatic stress disorder (PTSD) were measured with the GAD-7 (7-item Generalized Anxiety Disorder scale), PHQ-9 (9-item Patient Health Questionnaire), and the PTSD checklist (from the DSM-5) respectively. Laboratory analysis and adverse side effects were evaluated for treatment safety.
Primary Outcome Measures
The primary outcome was the efficacy and safety of CBD supplementation in addition to standard of care versus standard of care alone on symptoms of emotional exhaustion and burnout after 28 days.
- 300 mg daily CBD plus standard support therapy was superior to standard support therapy alone for mitigating emotional exhaustion (P=0.08), anxiety (P<0.001), and depression (P<0.001).
- The CBD arm also decreased “burnout syndrome” (ICD-10 criteria) in participants (P=0.08).
- The CBD arm significantly reduced anxiety (significant reduction in participants with GAD-7 scores >9) at 4 weeks (P<0.001).
- The CBD arm significantly reduced depression (reduction of participants with PHQ-9 score >9 points) at 4 weeks (P<0.001).
- The CBD arm experienced similar adverse events as the control group.
- Both groups’ adverse events were predominantly mild and transient.
- The 5 potentially concerning adverse events (see practice implications) resolved with discontinuation of CBD.
- Although adverse events are rare with 300 mg of CBD, providers should monitor liver enzymes periodically upon initial therapy in a fashion similar to initial application of flush niacin.
The Covid-19 pandemic has been emotionally, physically, and financially draining on society. Frontline healthcare workers have experienced excessive stress and emotional overload.1
The study reviewed herein suggests CBD is a viable and relatively safe option for mitigating emotional overload and burnout in healthcare workers. Moreover, CBD demonstrated antianxiolytic and antidepressive benefit to these stressed healthcare providers.
Many potential mechanisms of action could explain the benefits observed. For starters, CBD is an exogenous phytocannabinoid that modulates the endogenous cannabinoids anandamide (AEA), palmitoylethanolamide, (PEA) and oleoylethanolamide (OEA). Endogenous cannabinoids are fat-derived signaling molecules involved in reward, appetite, metabolism, mood, memory, circadian rhythms, and neuroprotection.2,3
This study adds to prior studies in suggesting CBD’s benefits as a neuroendocrine-immune modulator and as a potential ally in helping healthcare workers avoid burnout and emotional exhaustion.
In addition to modulating our endocannabinoids, CBD supports serotonin as a 5-hydroxytryptophan-1A (5HT1A) receptor agonist, acts as a partial agonist at dopamine D2 receptors, and stimulates the anti-inflammatory receptors adenosine A2, glycine, and G-protein–coupled receptor 55 (GPR55).4-8 In animal studies, CBD shows reuptake inhibition of norepinephrine, dopamine, serotonin, gamma aminobutyric acid (GABA), and anandamide.9,10
The dosage of 300 mg of CBD isolate used in this study is a substantial dose and mimics many of the previous benefits in human pilot trials for mood and affect.10 The mechanisms of action of CBD isolate mimic similarities of a “runner’s high,” suggesting CBD isolate may be an uplifting productivity molecule, unlike other phytocannabinoids that can produce intoxicating (eg, THC) or sedating effects (eg, terpenes like myrcene in full spectrum hemp).11
The only severe adverse events in this trial involved 5 participants in the CBD intervention arm. Notably, all of these were transient and resolved upon discontinuation of CBD. Four of the participants showed transient liver enzyme elevations (>3-fold higher than upper normal limit) and one experienced severe pharmacodermia. Generally, CBD has an excellent safety profile.12
The elevated liver enzymes may be due to unique phase I liver metabolism issues in the participants, CBD-drug interactions (10 participants in the trial were on nondisclosed prescriptions), an immune reaction to CBD or the carrier oil used (MCT is often coconut derived), or an unidentified substance in the intervention (CBD purity was 99.6%).
In using CBD with hundreds of patients in clinical practice, I have yet to see elevated liver enzymes with CBD isolate in dosages ranging from 30 to 300 mg. However, our patients are under holistic naturopathic care with many obstacles to healing removed and nutrition and lifestyle supports in place.
The 2 patients we’ve seen with mild hive reactions were related to a coconut allergy (MCT oil carrier) and a beeswax allergy in a CBD topical balm.
Nevertheless, in honoring “First do no harm,” my approach is to titrate 30-60 mg starting dose of cannabidiol until reaching clinical benefit (up to 300 mg) and monitor liver enzymes periodically (at least once within the first month of application).
CBD has helped me personally through the stress and overwhelm of the pandemic. I use 150-300 mg daily, depending on the overwhelm of the day. This study adds to prior studies in suggesting CBD’s benefits as a neuroendocrine-immune modulator and as a potential ally in helping healthcare workers avoid burnout and emotional exhaustion.
Conflict of Interest Disclosure
The author of this review holds positions at companies that manufacture or sell CBD products, including Blue Sky CBD, Apex Energetics, and Roots and Branches Integrative Health Care.
- Iob E, Frank P, Steptoe A, Fancourt D. Levels of severity of depressive symptoms among at-risk groups in the UK during the COVID-19 pandemic. JAMA Netw Open. 2020;3(10):e2026064.
- Pacher, P, Kunos G. Modulating the endocannabinoid system in human health and disease: successes and failures. FEBS J. 2013;280(9):1918-1943.
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- Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037-1043.
- Seeman P. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl Psychiatry. 2016;6(10):e920.
- Mecha M, Feliú A, Iñigo PM, Mestre L, Carrillo-Salinas FJ, Guaza C. 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. 2013;59:141-150.
- Xiong W, Cui T, Cheng K, et al. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med. 2012;209(6):1121-1134.
- Whyte LS, Ryberg E, Sims NA, et al. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A. 2009;106(38):16511-16516.
- Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12(4):699-730.
- Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845-852.
- Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364.
- Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6(4):237-249.