key: cord-0961543-j3irhdgd authors: Herrera-Gomez, P.; Echeveri-Catano, L. F.; Ruiz Colorado, Y. A.; Giraldo Galeano, S.; Velez van Meerbeke, A. title: Cannabis potential effects to prevent or attenuate SARS-COV2 contagion date: 2022-04-05 journal: nan DOI: 10.1101/2022.03.31.22273181 sha: 726c05789749cd553245e35ca725c600cf2b0d53 doc_id: 961543 cord_uid: j3irhdgd Medical cannabis has gained an exponential interest in recent years. Therapeutic targets have been broadened from specific applications over pain control, chemotherapy side effects, treatment-resistant epilepsies and multiple sclerosis, among others. Several in vitro and animal studies, along with few human controlled studies, suggest cannabinoids have a potential therapeutic role over medical conditions comporting inflammatory mechanisms. Given the tremendous world-wide impact of the COVID-19 pandemic, research efforts are converging towards the use of cannabinoids to attenuate severe or fatal forms of the disease. The present survey aims to explore possible correlations between cannabis use, either recreational or medical, over the presence of SARS-COV-2 contagion, along with the symptoms severity. 4026 surveys were collected via electronic form. Results suggest a relation between any type of cannabis use and a lower risk of SARS-COV-2 contagion (p=0,004; OR=0,689, IC95% 0,534-0,889). Despite several methodological limitations, the present survey steps up the urge to expand our understanding on cannabinoids potential use on human controlled studies, that can better arm us in the fight against the current COVID-19 pandemic. Cannabinoids have been regarded as a possible therapeutic clue for the SARS-COV-2 pandemic. Even though, till date there is limited evidence towards a specific therapeutic role for cannabinoids on viral infections 1 . Cannabinoids anti-inflammatory mechanisms have been only explored during recent years, mainly tested in vitro, in vivo, animals and computational settings 2,3 . Comparatively, human controlled studies are still scarce 4 . THC and CBD anti-inflammatory effects are highly suspected given their therapeutic potential use in diverse conditions having a physio pathological core around inflammation and immune cells 1, [5] [6] [7] . Based on available literature, it is reasonable to think that cannabinoids may play multiple therapeutic roles in front of SARS-COV2 contagion, as well as on other viral infections. These perspectives embrace a potential preventive role through replication inhibition mechanisms, and a direct therapeutic role linked to a possible modulation of angiotensin converting enzyme 2 (ACE2) 8-10 and cytokines cascades 11 , both related to the most severe and fatal SARS-COV-2 issues 3 . The present survey aims to explore possible correlations between cannabis use, either recreational or medical, over the presence of SARS-COV-2 contagion, along with the symptom's severity. We carried out a cross-sectional study through a self-administered online survey among a non-probabilistic sample in Colombia. The survey remained online from 1 st to 30 th of November, 2020. We calculated sample size with an expected frequency of 50%, an acceptable error of 5%, and a design effect of 1 for a population survey, of a minimum sample size of 384 participants. Sampling was obtained with a virtual snowball method, by posting the survey All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273181 doi: medRxiv preprint in social media groups and contacts (WhatsApp©, Telegram®, Facebook®) asking to answer and share the link with multiple contacts. We did not use any imputation method after trying to collect the information. After giving their agreement, participants were allowed to answer the survey: After completing the scheduled data collection, a visual inspection was conducted to verify the database completion. A semi-automated procedure was applied to homogenize outputs. Statistical analyses were conducted on IBM SPSS Statistics for Mac, Version 26.0. Data distribution was checked to verify sphericity, skewness and kurtosis. Parametric analysis (univariate and bivariate analysis) through Chi-square test and risk estimation were conducted. This research is supported by the Ethics Committee from Universidad Tecnologica de Pereira (Comité de Bioética de la Universidad Tecnologica de Pereira), who gave the ethical approval (# 52-28062). Once participants entered the survey link, they were explicitly told that participation is voluntary and data gathered will be processed anonymously and solely for investigative purposes. Participants were not asked to give their name or any contact information. Results 4026 surveys were collected through an online questionnaire. Three participants did not fill the age information. Data obtained was retained to apply statistical analysis. The mean age was 34.9 years (SD 11.6; min 18, max 86). 2272 participants declared any type of cannabis All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273181 doi: medRxiv preprint use (56,4%); 727 (18,4%) declared confirmed SARS-COV-2 contagion by test or by highly suggestive symptoms. Among those participants under the category SARS-CoV2 positive or suspected infection, 10,3% were cannabis users, and 7,8% were non consumers. Referring to the type of medicinal cannabis employed, participants mainly declared the use of uncontrolled preparations like topical ointments (67,9%), followed by Cannabis sativa oil (43,9%) and hemp mother tincture (12,4%) . 341 participants declared recreational and medical use jointly (See Table 1 for full data). 62% of participants declared having had low or mild intensity symptoms, 6% required hospitalization and 0,83% required ICU management. (See Figure 1 and 2 for full data description). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The present study found that there is a significant statistical association between any type of cannabis use and a lower risk of SARS-COV-2 contagion (p=0,004; OR=0,689, IC95% 0,534-0,889). No other relations nor associations were found in the population survey. Despite the estimated sample size declared in Methodology (N=384), total data obtained from online surveys was used to complete the statistical analysis (N=4026). Given the conditions declared about the non-probabilistic sampling, the association found in the statistical analysis only can be suggested, not assured, due to selection bias. Another limitation is the absence of data in regard to doses quantification and biomarkers of endocannabinoid response in individuals consuming cannabis having SARS-CoV2 positive or suspected infection, in order to compare effects among different populations, dosing quantification, doses-response relation, biological and sociodemographic characteristics. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. Cytokine release syndrome is triggered by internalization of ACE2 and activation of angiotensin 2, which in turns activates the expression of KB nuclear factor, increasing proinflammatory cytokines (IL-6, TNFα, IL-1β, and IL-10). Among the main described effects, there is a blood pressure elevation and impaired lung function 13 . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273181 doi: medRxiv preprint been proposed as a possible molecule having the capacity to downregulate NLRP3/Caspase-1/IL-1β and IL-18 pathway 14 . It has been suggested that high-cannabidiol sativa extracts are able to down-regulate the expression of the two key receptors for SARS-CoV-2 in several models of human epithelia 17 . The CB2 receptor agonists, is the main therapeutic target of cannabinoids, including immunomodulation effects, blocking virus entry and viral replication inhibition. When CB2 receptor is activated, it occurs specific proteins downward regulation (ACE2 and TMPRSS), thus preventing the SARS-CoV-2 invasion, which in turn, blocks viral replication, inhibits the migration of macrophages, and promotes the change of the proinflammatory phenotype of macrophages (M2) triggered by infection, towards anti-inflammatory phenotype characterized by release of IL10 and TGF-b. Virus replication can be prevented by the malfunction of different Ca2+-dependent enzyme complexes implicated in inflammatory processes, including transglutaminases, calpains, and matrix metalloproteinases. The CB1 receptor agonists induced by Anandamide (AEA) and 2-arachidonoylglycerol (2-AG), can inhibit Ca2+ ions release, stabilizing function of Ca2+dependent proteins and changing signal transduction 18. In spite of the promising studies describing anti-inflammatory and antioxidative properties 15, 16 , there is still a long way ahead to fully grasp the phytocannabinoids pharmacological properties. Particular attention must be paid in regard to potential adverse effects, depending on specific phytocannabinoids, the type of extract or compounds, and the administration pathway. For instance, even if their incidence is low, CBD-mediated impairment of immune response may increase the risk of pneumonia, viral infection or boosting of an already existing one 19 . Other considerations should be taken with those patients having hepatic enzymes alterations, like those exposed to antiepileptic or retroviral medications 20 . Further research is always needed, even though available reports on medical cannabis keep on throwing lights on their enormous therapeutic potentials, with a particular hope as a powerful tool to cope with our global health challenge in front of the COVID-19 pandemic and its lasting post-infections effects. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273181 doi: medRxiv preprint Cannabinoids and the Coronavirus Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches Cannabidiol Modulates Cytokine Storm in Acute Respiratory Distress Syndrome Induced by Simulated Viral Infection Using Synthetic RNA Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders Looking Back at Cannabis Research Non-Cannabinoid Metabolites of Cannabis sativa L. with Therapeutic Potential Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2 Characterization of the cytokine storm reflects hyperinflammatory endothelial dysfunction in COVID-19 Potentials of plant-based substance to inhabit and probable cure for the covid-19 The Immunopathology of COVID-19 and the Cannabis Paradigm Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1 signaling suppression in Caco-2 cell line The Therapeutic Potential of Cannabis in Counteracting Oxidative Stress and Inflammation Oxidative stress and inflammation in schizophrenia The potential of cannabidiol in the COVID-19 pandemic Cannabinoids for sars-cov-2 and is there evidence of their therapeutic efficacy? Potential Adverse Drug Events and Drug-Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity Serious adverse effects of cannabidiol (CBD): a review of randomized controlled trials No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted