Background and Purpose: Cannabis is the third most commonly used psychoactive substance of abuse, yet it also receives considerable attention as a potential therapeutic drug. Therefore, it is essential to fully understand the actions of cannabis in the human brain. The olfactory neuroepithelium (ON) represents an interesting surrogate model to study the effects of drugs in the brain, since it is closely related to the central nervous system, and sensory olfactory neurons are continually regenerated from populations of stem/progenitor cells that undergo neurogenesis throughout life. Experimental Approach: In this study, we used ON cells from chronic cannabis users and healthy control subjects to assess alterations in relevant cellular processes, and to identify changes in functional proteomic pathways due to cannabis consumption. Key Results: The ON cells from cannabis users exhibited alterations in the expression of proteins that were related to the cytoskeleton, cell proliferation and cell death, as well as, changes in proteins implicated in cancer, gastrointestinal and neurodevelopmental pathologies. Subsequent studies showed cannabis provoked an increase in cell size and morphological alterations evident through β-Tubulin III staining, as well as, enhanced beta-actin expression and a decrease in the ability of ON cells to undergo cell attachment, suggesting abnormalities of the cytoskeleton and cell adhesion system. Furthermore, these cells proliferated more and underwent less cell death. Conclusion and Implications: Our results indicate that cannabis may alter key processes of the developing brain, some of which are similar to those reported in mental disorders like DiGeorge syndrome, schizophrenia and bipolar disorder.

AIM: Immune response hyperactivation is critical in the progression of coronavirus disease (COVID-19). We studied the effect of the pre-exposure to disease-modifying antirheumatic drugs (DMARDs) that decrease immunological responses on the incidence of COVID-19 symptoms to explore therapeutic approaches in its early stages. METHODS: Multicentre retrospective cohort study including 2,494 patients with inflammatory diseases recruited from 14 primary care centres in Barcelona (Spain). The primary outcome was the presence of confirmed or highly suspected COVID-19 (hsCOVID-19) symptoms reported during March 2020 at primary care or hospital emergency department. Multivariable Poisson regression models were fitted to estimate hsCOVID-19 symptoms relative risk (RR) adjusted by comorbidities. RESULTS: Biological (RR=0.46, CI95%=0.31-0.67) and synthetic (RR=0.62, CI95%=0.43-0.91) DMARDs used in immunomediated inflammatory diseases diminished the incidence of symptomatic cases of hsCOVID-19. Striking sex differences were revealed. Protective effects of anti-TNFα pre-exposure (RR=0.50, CI95%=0.33-0.75) were higher in women (RR=0.33, CI95%=0.17-0.647), whereas anti-IL6/12/17/23 compounds pre-exposure (RR=0.47, CI95%=0.24-0.92) produced slightly higher protective effects in men (RR=0.44, CI95%=0.15-1.68). Pre-exposure to low glucocorticoid doses also revealed sex differences decreasing the incidence of hsCOVID-19 symptoms predominantly in women (RR=0.72, CI95%=0.42-1.22). A merely protective effect of pre-exposure to chloroquine/hydroxychloroquine (RR 0.76, CI95%=0.36-1.62) was observed. CONCLUSION: We identified specific DMARDs with different immune-depressor mechanisms that decrease hsCOVID-19 symptoms with striking sex differences. These results underline the potential interest of starting clinical trials with anti-TNFα compounds in women to evaluate their efficacy in minimizing disease progression in the early stages of COVID-19.

BACKGROUND AND PURPOSE: Immune response hyperactivation is critical in the progression of coronavirus disease (COVID-19). We studied the effect of the pre-exposure to disease-modifying antirheumatic drugs (DMARDs) that decrease immunological responses on the incidence of COVID-19 symptoms to explore therapeutic approaches in its early stages. EXPERIMENTAL APPROACH: Multicentre retrospective cohort study including 2,494 patients with inflammatory diseases recruited from 14 primary care centres in Barcelona (Spain). The primary outcome was the presence of confirmed or highly suspected COVID-19 (hsCOVID-19) symptoms reported during March 2020 at primary care or hospital emergency department. Multivariable Poisson regression models were fitted to estimate hsCOVID-19 symptoms relative risk (RR) adjusted by comorbidities. KEY RESULTS: Biological (RR=0.46, CI95%=0.31-0.67) and synthetic (RR=0.62, CI95%=0.43-0.91) DMARDs used in immunomediated inflammatory diseases diminished the incidence of symptomatic cases of hsCOVID-19. Striking sex differences were revealed. Protective effects of anti-TNFα pre-exposure (RR=0.50, CI95%=0.33-0.75) were higher in women (RR=0.33, CI95%=0.17-0.647), whereas anti-IL6/12/17/23 compounds pre-exposure (RR=0.47, CI95%=0.24-0.92) produced slightly higher protective effects in men (RR=0.44, CI95%=0.15-1.68). Pre-exposure to low glucocorticoid doses also revealed sex differences decreasing the incidence of hsCOVID-19 symptoms predominantly in women (RR=0.72, CI95%=0.42-1.22). A merely protective effect of pre-exposure to chloroquine/hydroxychloroquine (RR 0.76, CI95%=0.36-1.62) was observed. CONCLUSIONS AND IMPLICATIONS: We identified specific DMARDs with different immune-depressor mechanisms that decrease hsCOVID-19 symptoms with striking sex differences. These results underline the potential interest of starting clinical trials with anti-TNFα compounds in women to evaluate their efficacy in minimizing disease progression in the early stages of COVID-19.