Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses.

The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time.

Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results.

Importance: Deficient (ie, <20 ng/mL) or insufficient (ie, 20 to <30 ng/mL) 25-hydroxyvitamin D (also known as calcifediol) levels are more common in Black individuals than White individuals and are associated with increased coronavirus disease 2019 (COVID-19) risk. Whether COVID-19 risk is associated with differences in vitamin D levels of 30 ng/mL or greater is not known. Objective: To examine whether COVID-19 test results are associated with differences in vitamin D levels of 30 ng/mL or greater, including for White individuals and for Black individuals. Design, Setting, and Participants: This retrospective cohort study was conducted at an academic medical center in Chicago, Illinois. Participants included individuals with data on vitamin D level within 365 days before COVID-19 testing, which was conducted from March 3 to December 30, 2020. Data were analyzed from September 11, 2020, to February 5, 2021. Exposures: The last vitamin D level before COVID-19 testing was categorized as less than 20 ng/mL (ie, deficient), 20 to less than 30 ng/mL (ie, insufficient), 30 to less than 40 ng/mL, or 40 ng/mL or greater. Treatment was defined by vitamin D type and dose 14 days before COVID-19 testing and treatment changes after last vitamin D level. Main Outcomes and Measures: The main outcome was a positive result for COVID-19 in polymerase chain reaction testing. Multivariable analyses tested whether previously measured vitamin D level was associated with having test results positive for COVID-19 in White individuals and in Black individuals, controlling for months and treatment changes since the vitamin D level was measured, as well as demographic characteristics and comorbidity indicators. Results: A total of 4638 individuals (mean [SD] age 52.8 [19.5] years; 3205 [69%] women) had data for a vitamin D level within 1 year before COVID-19 testing, including 2288 (49%) Black individuals, 1999 (43%) White individuals, and 351 individuals (8%) who were another race/ethnicity (eg, Asian, Mideast Indian, >1 race). Stratified by vitamin D level, 1251 individuals (27%) had less than 20 ng/mL, 1267 individuals (27%) had 20 to less than 30 ng/mL, 1023 individuals (22%) had 30 to less than 40 ng/mL, and 1097 individuals (24%) had 40 ng/mL or greater. Lower vitamin D levels were more common in Black individuals (<20 ng/mL: 829 of 2288 Black individuals [36%]) than White individuals (<20 ng/mL: 315 of 1999 White individuals [16%]). A total of 333 individuals (7%) had test results positive for COVID-19, including 102 White individuals (5%) and 211 Black individuals (9%). Multivariate analysis controlling for time since last vitamin D level measurement was used to estimate the outcomes associated with levels 14 days before COVID-19 testing. A positive test result for COVID-19 was not significantly associated with vitamin D levels in White individuals but was associated with vitamin D levels in Black individuals (compared with ≥40 ng/mL: <20 ng/mL incidence rate ratio [IRR], 2.55 [95% CI, 1.26-5.15]; P = .009; 20 to <30 ng/mL IRR, 1.69 [95% CI, 0.75-3.84]; P = .21; 30 to <40 ng/mL IRR, 2.64 [95% CI, 1.24-5.66]; P = .01). Stratified by vitamin D level, estimated COVID-19 positivity rates in Black individuals were 9.72% (95% CI, 6.74%-13.41%) for individuals with a vitamin D level less than 20 ng/mL, 6.47% (95% CI, 3.33%-10.28%) for individuals with a vitamin D level of 20 to less than 30 ng/mL, 10.10% (95% CI, 6.00%-15.47%) for individuals with a vitamin D level of 30 to less than 40 ng/mL, and 3.82% (95% CI, 1.78%-6.68%) for individuals with a vitamin D level of 40 ng/mL or higher. Multivariate analysis in individuals with a vitamin D level of 30 ng/mL or greater found that the IRR of a positive COVID-19 test result was 0.97 (95% CI, 0.94-0.99; P = .008) per 1-ng/mL increase in vitamin D overall and 0.95 (95% CI, 0.91-0.98; P = .003) per 1-ng/mL increase in vitamin D in Black individuals. Conclusions and Relevance: In this single-center retrospective cohort study, COVID-19 risk increased among Black individuals with vitamin D level less than 40 ng/mL compared with those with 40 ng/mL or greater and decreased with increasing levels among individuals with levels greater than 30 ng/mL. No significant associations were noted for White individuals. Randomized clinical trials should examine whether increasing vitamin D level to greater than 40 ng/mL affects COVID-19 risk.

Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results.

Importance: Vitamin D treatment has been found to decrease the incidence of viral respiratory tract infection, especially in patients with vitamin D deficiency. Whether vitamin D is associated with coronavirus disease 2019 (COVID-19) incidence is unknown. Objective: To examine whether the last vitamin D status before COVID-19 testing is associated with COVID-19 test results. Design, Setting, and Participants: This retrospective cohort study at an urban academic medical center included patients with a 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol level measured within 1 year before being tested for COVID-19 from March 3 to April 10, 2020. Exposures: Vitamin D deficiency was defined by the last measurement of 25-hydroxycholecalciferol less than 20 ng/mL or 1,25-dihydroxycholecalciferol less than 18 pg/mL before COVID-19 testing. Treatment changes were defined by changes in vitamin D type and dose between the date of the last vitamin D level measurement and the date of COVID-19 testing. Vitamin D deficiency and treatment changes were combined to categorize the most recent vitamin D status before COVID-19 testing as likely deficient (last level deficient and treatment not increased), likely sufficient (last level not deficient and treatment not decreased), and 2 groups with uncertain deficiency (last level deficient and treatment increased, and last level not deficient and treatment decreased). Main Outcomes and Measures: The outcome was a positive COVID-19 polymerase chain reaction test result. Multivariable analysis tested whether vitamin D status before COVID-19 testing was associated with testing positive for COVID-19, controlling for demographic and comorbidity indicators. Results: A total of 489 patients (mean [SD] age, 49.2 [18.4] years; 366 [75%] women; and 331 [68%] race other than White) had a vitamin D level measured in the year before COVID-19 testing. Vitamin D status before COVID-19 testing was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Overall, 71 participants (15%) tested positive for COVID-19. In multivariate analysis, testing positive for COVID-19 was associated with increasing age up to age 50 years (relative risk, 1.06; 95% CI, 1.01-1.09; P = .02); non-White race (relative risk, 2.54; 95% CI, 1.26-5.12; P = .009), and likely deficient vitamin D status (relative risk, 1.77; 95% CI, 1.12-2.81; P = .02) compared with likely sufficient vitamin D status. Predicted COVID-19 rates in the deficient group were 21.6% (95% CI, 14.0%-29.2%) vs 12.2%(95% CI, 8.9%-15.4%) in the sufficient group. Conclusions and Relevance: In this single-center, retrospective cohort study, likely deficient vitamin D status was associated with increased COVID-19 risk, a finding that suggests that randomized trials may be needed to determine whether vitamin D affects COVID-19 risk.