Implications of Cannabis and Cannabinoid Use in COVID-19: Scoping Review

to identify and synthesize studies on the effects of cannabis use and its relation with SARS-CoV-2, as well as the therapeutic possibilities of using cannabinoids in the prevention and treatment of COVID-19.

Methods:

scoping review, in the BVS, PubMed, SCIELO, CINAHL, SCOPUS, Web of Science, MedNar, CAPES and ProQuest databases, with no language restriction and year limitation. Narrative synthesis was performed.

Results:

cannabis use causes changes in the respiratory and vascular system, it reduces the production of cytokines, which affects the users’ immune system, increasing the susceptibility to infection and progression of COVID-19. However, studies have suggested the use of cannabinoids in the prophylaxis and treatment of COVID-19, due to their anti-inflammatory effect.

Conclusions:

the use of inhaled cannabis increases the progression and severity of the infection. On the other hand, the benefits of cannabinoids seem promising to modulate the immune system, but it needs further studies.

Descriptors:
Marijuana Use; Cannabis; Coronavirus Infections; Mental Health; Nursing

Title	Year/Country	Design/objective	Outcomes of studies on the effects of cannabis use and its relationship with SARS-COV2 and the therapeutic possibilities of cannabinoids in the prevention and treatment of COVID-19	Methodological quality
Cannabis in the Time of Coronavirus Disease 2019: The Yin and Yang of the Endocannabinoid System in Immunocompetence(¹⁶16 Sexton M. Cannabis in the Time of Coronavirus Disease 2019: The Yin and Yang of the Endocannabinoid System in Immunocompetence. J Altern Complement Med. 2020;26(6):444-8. https://doi.org/10.1089/acm.2020.0144 https://doi.org/10.1089/acm.2020.0144... )	2020 USA	Opinion article Objective: To assess whether Phytocannabinoids can be useful or harmful to immune competence in the context of the current COVID-19 pandemic.	• The chronic use of inhaled cannabis can increase coughing, sputum production, wheezing, reduced lung function, and can cause respiratory illnesses. These changes reduce the effectiveness of the response to infection, increasing the risk of rapid progression to hypoxia; • Cannabis users showed systemic reduction in cytokine production; • The endogenous cannabinoid signaling system (ECS) mediates several immunosuppressive effects, including inhibition of immune cell proliferation, migration and antibody production, induction of apoptosis, and suppression of cytokines; • CBD has been perceived as a potential treatment for COVID-19 due to its anti-inflammatory effects.	High
Cannabinoids and the Coronavirus(²⁰20 Hill KP. Cannabinoids and the Coronavirus. Med Cannabis Cannabinoids. 2020;5(2):118-120. https://doi.org/10.1089/can.2020.0035 https://doi.org/10.1089/can.2020.0035... )	2020 USA	Opinion article Objective: To identify the benefits and risks of cannabinoids with regard to Covid-19.	• SARS-CoV-2 triggers excessive production of cytokines, resulting in hyperinflammation. CBD could possibly be part of the treatment, associated with non-steroidal anti-inflammatory drugs and other medications that act on the immune system, with the aim of reducing the overproduction of these substances.	High
Cannabidiol Modulates Cytokine Storm in Acute Respiratory Distress Syndrome Induced by Simulated Viral Infection Using Synthetic RNA(²¹21 Khodadadi H, Salles ÉL, Jarrahi A, Chibane F, Costigliola V, Yu JC, et al. Cannabidiol Modulates Cytokine Storm in Acute Respiratory Distress Syndrome Induced by Simulated Viral Infection Using Synthetic RNA. Cannabis Cannabinoid Res. 2020;5(3):197-201. https://doi.org/10.1089/can.2020.0043 https://doi.org/10.1089/can.2020.0043... )	2020 USA	Experimental study with animal model. N=15 mice. Objective: To assess whether CBD can reduce cytokine storm and treat acute respiratory distress syndrome.	• The treatment with CBD reversed the inflammatory indices and partially reestablished the body’s homeostasis; • It reduced the expression of interleukin (IL)-6 and decreased the presence of neutrophils in the lung and blood; • It increased the presence of lymphocytes, reduced the number of neutrophils and monocytes, as well as the level of pro-inflammatory cytokines.	High
Cerebrovascular and neurological dysfunction under the threat of COVID-19: Is there a comorbid role for smoking and vaping?(²⁷27 Archie SR, Cucullo L. Cerebrovascular and neurological dysfunction under the threat of COVID-19: Is there a comorbid role for smoking and vaping? Int J Mol Sci. 2020;21(11). https://doi.org/10.3390/ijms21113916 https://doi.org/10.3390/ijms21113916... )	2020 USA	Review article. N=9 studies Objective: To summarize the possible role of smoking and vaporization in cerebrovascular and neurological dysfunction in patients with COVID-19.	• The use of inhaled cannabis can deteriorate the condition of patients with COVID-19, due to airway inflammation, being a risk factor for the development of neurological disorders, due to the harmful effect on the cerebrovascular system.	Moderate
The potential of Cannabidiol in the COVID-19 pandemic(³⁰30 Esposito G, Pesce M, Seguella L, Sanseverino W, Lu J, Corpetti C, et al. The potential of cannabidiol in the COVID-19 pandemic. Br J Pharmacol. 2020;177(21):4967-70. https://doi.org/10.1111/bph.15157 https://doi.org/10.1111/bph.15157... )	2020 Italy	Opinion article Objective: To identify effective drugs in the new coronavirus disease 2019 (COVID - 19).	• Cannabis sativa extracts with a high content of cannabinoid (CB) are able to reduce the expression of the two main receptors for the installation of SARS-CoV-2 infection: the angiotensin 2 converting enzyme and the serine protease 2 enzymes; • CBD exerts a wide range of immunomodulatory and anti-inflammatory effects, smoothing the uncontrolled production of cytokines in acute lung injury, acting as a regulator of fibroblast/myofibroblast activation .and improving lung function in recovered patients.	High
Acute inflammation and pathogenesis of SAR-CoV-2 infection: cannabidiol as a potential anti-inflammatory treatment(²⁸28 Costiniuk CT, Jenabian MA. Acute inflammation and pathogenesis of SARS-CoV-2 infection: Cannabidiol as a potential anti-inflammatory treatment? Cytokine Growth Factor Rev. 2020;53:63-65. https://doi.org/10.1016/j.cytogfr.2020.05.008 https://doi.org/10.1016/j.cytogfr.2020.0... )	2020 Canada	Opinion article Objective: To assess Cannabidiol’s potential to attenuate excessive inflammation.	• CBs can suppress immune and inflammatory activation by reducing the production of cytokines, suggesting potential to modulate excessive inflammation; • Cannabis use was associated with a reduction in pro-inflammatory monocytes, a reduction in CD4 and CD8 T lymphocyte cells, in addition to tumor necrosis factor alpha (TNF-α), IL-10 and IL-producing antigen-presenting cells 12, compared to non-cannabis users.	Moderate
Cannabinoid receptor type 2: a possible target in SARS-CoV-2 (CoV-19) infection?(³⁴34 Rossi F, Tortora C, Argenziano M, di Paola A, Punzo F. Cannabinoid receptor type 2: a possible target in SARS-CoV-2 (CoV-19) infection? Int J Mol Sci. 2020;21(11). https://doi.org/10.3390/ijms21113809 https://doi.org/10.3390/ijms21113809... )	2020 Italy	Opinion article Objective: To assess whether the CB2 receptor can be a therapeutic target in the COVID-19 pandemic emergency.	• Endocannabinoid CB2 receptor stimulation is known to limit the release of pro-inflammatory cytokines, change the macrophage phenotype to the M2 anti-inflammatory type, and enhance the immune modulating properties of cells; • For these reasons, it is hypothesized that the CB2 receptor may be a therapeutic target in cases of COVID-19 infection, playing a role in preventing and/or influencing the development and severity of the disease.	Moderate
Opioids/cannabinoids as potential therapeutic approach in COVID-19 patients(³⁵35 Tahamtan A, Tavakoli-Yaraki M, Salimi V. Opioids/cannabinoids as a potential therapeutic approach in COVID-19 patients. Expert Rev Respir Med. 2020;14(10):965-967. https://doi.org/10.1080/17476348.2020.1787836 https://doi.org/10.1080/17476348.2020.17... )	2020 Iran	Opinion article Objective: To assess the use of opioids/cannabinoids in the context of COVID-19.	• CB2 stimulation could control the inflammatory cascade caused by SARS-CoV-2 infection, considering its ability to reduce the exacerbated production of pro-inflammatory cytokines; • Considering this scenario, its use can be very beneficial in the exacerbated containment of the inflammatory response in patients with COVID-19.	High
Cannabis for COVID-19: can cannabinoids quell the cytokine storm?(³¹31 Onaivi ES, Sharma V. Cannabis for COVID-19: Can cannabinoids quell the cytokine storm? Future Sci OA. 2020;6(8). https://doi.org/10.2144/fsoa-2020-0124 https://doi.org/10.2144/fsoa-2020-0124... )	2020 USA	Opinion article Objective: To assess the potential of the pharmacological immunomodulatory effects of cannabinoids that are constituents of the cannabis plant.	• CBs are effective in suppressing the immune system, having immunoregulatory and anti-inflammatory properties, resulting from the activation of CB1 and CB2 receptors; • ECS mediates immunosuppression through cytokine suppression; inhibition of immune cell proliferation, migration and antibody production, allowing control of viral pathogenesis; • The phytocannabinoids, tetrahydrocannabinol (THC) and CBD, have been shown to reduce the exacerbated production of inflammatory cytokines through their immunoregulatory properties.	High
Letter to the Editor: Possible Drug-Drug Interactions Between Cannabinoids and Candidate COVID-19 Drugs(³⁶36 Land MH, MacNair L, Thomas BF, Peters EN, Bonn-Miller MO. Letter to the editor: possible drug-drug interactions between cannabinoids and candidate COVID-19 drugs. Cannabis Cannabinoid Res. 2020;5(4):340-343. https://doi.org/10.1089/can.2020.0054 https://doi.org/10.1089/can.2020.0054... )	2020 USA	Opinion article Objective: Early identification of possible interactions between cannabinoids and drugs that can be used to treat COVID-19.	• The interaction of some CBs with certain medications can be extremely serious, potentially causing hepatocellular damage and sedation; • The immunosuppressive effects associated with CBD can trigger a primary and/or secondary infectious condition, resulting in a worse prognosis in patients with COVID-19; • A recent in vitro study showed that CBD can antagonize some effects of dexamethasone, replacing its anti-inflammatory potential, when used concomitantly.	High
Genetic Liability to Cannabis Use Disorder and COVID-19 Hospitalization(²⁹29 Hatoum AS, Morrison CL, Winiger EA, Johnson EC, Agrawal A, Bogdan R. Genetic liability to cannabis use disorder and COVID-19 hospitalization. medRxiv. 2020[cited 2021 Jan 03]. https://doi.org/10.1101/2020.11.15.20229971 https://doi.org/10.1101/2020.11.15.20229... )	2020 USA	Quasi-experimental. Cannabis Use Disorder (N case = 14 080, N control = 343 726) and hospitalization for COVID-19 (N case = 6 492, N population control = 1 012 809). Objective: To identify whether genomic responsibility for cannabis use disorder can contribute to severe presentation of COVID-19.	• The heavy and/or problematic use of cannabis associated with the genetic factor for cannabis use disorder may increase the severity of COVID-19 due to respiratory complications; • The formulation of strategies to reduce heavy cannabis use is recommended to mitigate risks in relation to COVID-19.	High
In search of preventive strategies: novel high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues(³²32 Wang B, Kovalchuk A, Li D, Ilnytskyy Y, Kovalchuk I, Kovalchuk O. In search of preventative strategies: novel high-CBD cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues. Aging (Albany NY). 2020;12(22):22425. https://doi.org/10.18632/aging.202225 https://doi.org/10.18632/aging.202225... )	2020 Canada	Experimental study. N=23 Objective: To assess whether C. sativa extracts with high CBD content can be used to down-regulate ACE2 expression in COVID-19 target tissues.	• By using artificial 3D human tissue models, it was observed that Cannabis sativa extracts with high content of CBD can decrease the expression of angiotensin-converting enzyme (ACE2) in coronavirus target tissues, suggesting the importance of these extracts in prevention of COVID-19; • These results cannot be extrapolated to the effects of cannabis smoking.	High
Coronavirus Disease-2019 Treatment Strategies Targeting Interleukin-6 Signaling and Herbal Medicine(³³33 Dzobo K, Chiririwa H, Dandara C, Dzobo W. Coronavirus disease-2019 treatment strategies targeting interleukin-6 signaling and herbal medicine. OMICS. 2020;25(1):13-22. https://doi.org/10.1089/omi.2020.0122 https://doi.org/10.1089/omi.2020.0122... )	2021 South Africa	Review article. N=15 studies Objective: To map therapeutic strategies by blocking the cytokine storm	• The search for potential strategies to target IL-6 signaling in the treatment of COVID-19 patients, such as: tocilizumab (decreases cytokine release), IL-6 signaling inhibitors (pacritinib, ruxolitinib and tofacitinib), bone marrow-derived exosomes, and dexamethasone; • Another plausible strategy is the use of natural compounds with the ability to inhibit virus entry into host cells; • Among them is Cannabis sativa, which is a plant known for containing anti-inflammatory compounds such as CB, CBD and terpenes.	Moderate

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[1] Corresponding author: Caroline Figueira Pereira E-mail: pereiracf@usp.br