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Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International It’s too early to tell whether CBD helps against Covid-19 — but researchers worry that won’t stop CBD makers. David Aronoff, MD, discusses an early study on CBD and on how to address interested patients

Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response

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Abstract

The rapid spread of COVID-19 underscores the need for new treatments. Here we report that cannabidiol (CBD), a compound produced by the cannabis plant, inhibits SARS-CoV-2 infection. CBD and its metabolite, 7-OH-CBD, but not congeneric cannabinoids, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after cellular infection, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD induces interferon expression and up-regulates its antiviral signaling pathway. A cohort of human patients previously taking CBD had significantly lower SARSCoV-2 infection incidence of up to an order of magnitude relative to matched pairs or the general population. This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection.

Summary sentence:

Cannabidiol from the cannabis plant has potential to prevent and inhibit SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19), a pandemic that has overtaken the world during the past year. SARS-CoV-2, related to severe acute respiratory syndrome-related coronavirus (SARS-CoV), is the seventh species of coronavirus known to infect people. These coronaviruses, which include SARS-CoV, 229E, NL63, OC43, HKU1, and MERS-CoV cause a range of symptoms from the common cold to more severe pathologies ( 1 ). Despite recent vaccine availability, SARS-CoV-2 is still spreading rapidly ( 2 ), highlighting the need for alternative treatments, especially for populations with limited access to vaccines. To date, few therapies have been identified that block SARS-CoV-2 replication and viral production.

SARS-CoV-2 is a positive-sense single-stranded RNA (+ssRNA) enveloped virus composed of a lipid bilayer and four structural proteins that drive viral particle formation. The spike (S), membrane (M), and envelope (E) are integral proteins of the virus membrane and serve to drive virion budding, while also recruiting the nucleocapsid (N) protein and the viral genomic RNA into nascent virions. Like SARS-CoV, SARS-CoV-2 primarily enters human cells by the binding of the viral S protein to the angiotensin converting enzyme 2 (ACE2) receptor ( 3 – 5 ), after which the S protein undergoes proteolysis by transmembrane protease, serine 2 (TMPRSS2) or other proteases into two non-covalently bound peptides (S1, S2) that facilitate viral entry into the host cell. The N-terminal S1 binds the ACE2 receptor, and the C-terminal S2 mediates viral-cell membrane fusion following proteolytic cleavage by TMRSS2 or other proteases. Depending upon the cell type, viral entry can also occur after ACE2 binding, independent of proteolytic cleavage ( 6 – 8 ). Following cell entry, the SARS-CoV-2 genome is translated into two large polypeptides that are cleaved by two viral proteases, MPro and PLPro ( 9 , 10 ), to produce 15 proteins, in addition to the synthesis of subgenomic RNAs that encode another 10 accessory proteins plus the 4 structural proteins. These proteins enable viral replication, assembly, and budding. In an effort to suppress infection by the SARS-CoV-2 beta-coronavirus as well as other evolving pathogenic viruses, we tested the antiviral potential of a number of small molecules that target host stress response pathways.

One potential regulator of the host stress and antiviral inflammatory responses is cannabidiol (CBD), a member of the cannabinoid class of natural products ( 11 ). CBD is produced by Cannabis sativa (Cannabaceae; marijuana/hemp). Hemp refers to cannabis plants or materials derived thereof that contain 0.3% or less of the psychotropic tetrahydrocannabinol (THC) and typically have relatively high CBD content. By contrast, marijuana refers to C. sativa materials with more than 0.3% THC by dry weight. THC acts through binding to the cannabinoid receptor, and CBD potentiates this interaction ( 12 ). Despite numerous studies and many typically unsubstantiated claims related to CBD-containing products, the biology of CBD itself is unclear and specific targets are mostly unknown ( 11 ). However, an oral solution of CBD is an FDA-approved drug, largely for the treatment of epilepsy ( 13 ). Thus, CBD has drug status, is viable as a therapeutic, and cannot be marketed as a dietary supplement in the United States ( 11 ). Although limited, some studies have reported that certain cannabinoids have antiviral effects against hepatitis C virus (HCV) and other viruses ( 14 ).

RESULTS

To test the effect of CBD on SARS-CoV-2 replication, we pretreated A549 human lung carcinoma cells expressing exogenous human ACE-2 receptor (A549-ACE2) for 2 hours with 0–10 μM CBD prior to infection with SARS-CoV-2. After 48 hours, we monitored cells for expression of the viral spike protein (S). For comparison, we also treated cells over a similar dose range with an MLK inhibitor (URMC-099) previously implicated as an antiviral for HIV ( 12 ) and KPT-9274, a PAK4/NAMPT inhibitor ( 13 ) that our analysis suggested might reverse many changes in gene expression caused by SARS-CoV-2. All three inhibitors potently inhibited viral replication under non-toxic conditions with EC50s ranging from 0.2–2.1 μM ( Fig. 1A ). CBD inhibited SARS-CoV-2 replication in Vero E6 monkey kidney epithelial cells as well (fig. S1A). No toxicity was observed at the effective doses (fig. S1B). We also determined that CBD suppressed replication of a related beta-coronavirus, mouse hepatitis virus (MHV), under non-toxic conditions with an EC50 of ~5 μM using A549 cells that express the MHV receptor (A549-MHVR), indicating the potential for more broader viral efficacy (fig. S1C,D).

(A) A549 cells with ACE2 overexpression (A549-ACE2) were treated with indicated doses of CBD, KPT-9274, or URMC-099 followed by infection with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.5 for 48 hours. The cells were stained for spike protein and the percentage of cells expressing the spike protein in each condition was plotted. EC50 values are indicated. (B) The 1 H qNMR spectra of CBD from a reference material and CBD samples from three different suppliers A, B, and C. (C) A549-ACE2 cells were treated with indicated doses of CBD from three different suppliers followed by infection with SARS-CoV-2 at an MOI of 0.5 for 48 hours. The cells were stained for spike protein and the percentage of cells expressing the spike protein in each condition was plotted. EC50 values are indicated.

When isolated from its source plant, natural non-synthetic CBD is typically extracted along with other cannabinoids, representing the unavoidable residual complexity of natural products. To verify that CBD is indeed responsible for the viral inhibition, we analyzed a CBD reference standard as well as CBD from three different sources for purity using 100% quantitative NMR (qNMR). These sources included two chemical vendors (Suppliers A and B) and one commercial vendor that used natural materials (Supplier C). The striking congruence between the experimental 1 H NMR and the recently established quantum-mechanical HiFSA ( 1 H Iterative Full Spin Analysis) profiles observed for all materials confirmed that 1) the compounds used were indeed CBD with purities of at least 97% ( Fig. 1B ) and 2) congeneric cannabinoids were not present at levels above 1.0% ( 11 ). Analysis of these different CBD preparations in the viral A549-ACE2 infection assay showed similar EC50s with a range from 0.6–1.8 μM likely reflecting the intrinsic biological variability of the assay ( Fig. 1C ). No toxicity was observed for any of the CBD preparations at the doses used to inhibit viral infection (fig. S1 E–G).

CBD is often consumed as part of a C. sativa extract, particularly in combination with psychoactive THC enriched in marijuana plants. We therefore determined whether congeneric cannabinoids, especially analogues with closely related structures and polarities produced by the hemp plant, are also capable of inhibiting SARS-CoV-2 infection. Remarkably, only CBD was a potent agent, while limited or no antiviral activity was exhibited by the structurally closely related congeners that share biosynthesis pathways and form the biogenetically determined residual complexity of CBD purified from C. sativa: THC, cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabichromene (CBC), or cannabigerol (CBG) ( Fig. 2 A – B ; see Methods). None of these compounds were toxic to the A549-ACE2 cells in the dose range of interest (fig. S2). Notably, combining CBD with THC (1:1) significantly suppressed CBD efficacy consistent with competitive inhibition by THC.

(A) A549-ACE2 cells were treated with indicated doses of various cannabinoids or a CBD/THC 1:1 mixture followed by infection with SARS-CoV-2 at an MOI of 0.5 for 48 hours. The cells were stained for spike protein and the percentage of cells expressing the spike protein in each condition was plotted. All cannabinoids tested were isolated from a hemp extract as described in Methods. (B) Chemical structures of cannabinoids and 7-OH CBD. (C) A549-ACE2 cells were treated with indicated doses of 7-OH CBD followed by infection with the SARS-CoV-2 at an MOI of 0.5. The cells were stained for spike protein and the percentage of cells expressing the spike protein in each condition was plotted. Representative data of CBD from Figure 1C (Supplier A) is used for comparison. EC50 values are indicated.

CBD is rapidly metabolized in the liver and gut into two main metabolites, 7-carboxy-cannabidiol (7-COOH-CBD) and 7-hydroxy-cannabidiol (7-OH-CBD). Although the levels of 7-COOH-CBD are 40-fold higher than 7-OH-CBD in human plasma, 7-OHCBD is the active ingredient for the treatment of epilepsy ( 14 ). Like CBD but unlike the other cannabinoids, 7-OH-CBD effectively inhibited SARS-CoV-2 replication in A549-ACE2 cells (EC50 3.6 μM; Fig. 2C ) and was non-toxic to cells (fig. S2H). Analysis of blood plasma levels in healthy patients taking FDA-approved CBD (Epidiolex ® ) shows a maximal concentration (Cmax) for CBD in the nM range whereas 7-OH-CBD had a Cmax in the μM range, similar to that observed in cultured cells ( 15 ). These results suggest that CBD itself is not present at the levels needed to effectively inhibit SARS-CoV-2 in people. By contrast, the plasma concentrations of its metabolite 7-OH-CBD, whose Cmax can be increased several-fold by co-administration of CBD with a high-fat meal, are sufficient to potentially inhibit SARS-CoV-2 infection in humans ( 15 ).

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CBD could be acting to block viral entry to host cells or at later steps following infection. As CBD was shown to decrease ACE2 expression in some epithelial cells including A549 ( 16 ), we first determined whether CBD suppressed the SARS-CoV-2 receptor in our A549-ACE2 overexpressing cells. No decrease in ACE2 expression was observed ( Fig. 3A ). Furthermore, analysis of lentiviruses pseudotyped with either the SARS-CoV-2 spike protein or the VSV glycoprotein ( 17 ) showed that antibody to the spike protein effectively blocked viral infection of the SARS-CoV-2, but not VSV-G expressing viruses. However, 10 μM CBD only partially inhibited cell entry by spike-expressing virus, suggesting that other mechanisms were largely responsible for its antiviral effects ( Fig. 3B , and figs. S3 A and B). By contrast, antibodies to the spike protein effectively blocked viral infection of the SARS-CoV-2 but not VSV-G expressing viruses. Consistent with this, CBD was also effective at inhibiting SARS-CoV-2 spike protein expression in host cells even 2 hours after infection in the presence of antibodies to the spike protein to prevent reinfection during this time period ( Fig. 3C , ​ ,D). D ). To assess whether CBD might be preventing viral protein processing by the viral proteases Mpro or PLpro, we assayed their activity in vitro (fig. S4). CBD did not affect the activity of either protease, raising the possibility that CBD targets host cell processes.

(A) Immunoblots of ACE2 protein expression from A549-ACE2 cell lysates either untreated or treated with vehicle or CBD at indicated doses (n=3). Blots were probed with antibodies against ACE2 and tubulin. ACE2 protein expression levels were normalized to the tubulin signal within each sample. ACE2 expression levels were plotted relative to untreated samples. Expression levels were compared to vehicle by one-way ANOVA. (B) 293T-ACE2 cells were infected by spike or VSV-G pseudovirus for 72 hours with the indicated doses of CBD treatment, and the percentage of infected cells plotted. (C) A549-ACE2 cells were either pre-treated or not with 10 μM CBD for 2 hours, then infected with SARS-CoV-2 at an MOI of 0.5 for 2 hours. Cells were then treated with 10 μM CBD or DMSO for 16 hours with the spike neutralizing antibody to prevent reinfection. Spike positive cells were quantified and normalized to the virus-infected only sample. (D) Validation of neutralizing antibody efficacy. 400 pfu of SARS-CoV-2 virus was incubated with or without 100 μM of neutralizing antibody for 1 hour. A549-ACE2 cells were treated with the mixture for 16 hours and Spike positive cells were quantified.

Consistent with this interpretation, RNA-seq analysis of infected A549-ACE2 cells treated with CBD for 24 hours shows a striking suppression of SARS-CoV-2-induced changes in gene expression. CBD effectively eradicated viral RNA expression in the host cells, including RNA coding for spike, membrane, envelope and nucleocapsid proteins ( Figs. 4 A and ​ andB). B ). Both SARS-CoV-2 and CBD each induced significant changes in cellular gene expression, including a number of transcription factors (figs. S5 and S6). Principal component analysis of host cell RNA shows almost complete reversal of viral changes but, rather than returning to a normal cell state, the CBD+virus infected cells resemble those treated with CBD alone ( Fig. 4C ). Clustering analysis using Metascape reveals some interesting patterns and associated themes ( Fig. 4D , figs. S7, and S8). For example, viral induction of genes associated with chromatin modification and transcription (Cluster 1) is reversed by CBD although CBD alone has no effect. Similarly, viral inhibition of genes associated with ribosomes and neutrophils (Cluster 3) is largely reversed by CBD, but the drug alone has no effect. This contrasts with Clusters 5 and 6 where CBD alone induces strong activation of genes associated with the host stress response. Together these results suggest that CBD acts to prevent viral protein translation and associated cellular changes.

A549-ACE2 cells were infected with SARS-CoV-2 at MOI of 3 with or without CBD treatment at 10 μM for 24 hours. RNA-seq was performed as described in Methods. (A) Heatmap of relative levels of SARS-CoV-2 genes from the RNA-seq samples. (B) Expression levels of SARS-CoV-2 spike and nucleocapsid genes. Percent expression level changes for genes from infected cells compared to cells infected and CBD treated are indicated for each gene. (C) Principal component analysis (PCA) of RNA-seq data showing control (veh_mock), SARS-CoV-2 infected (veh_infect), CBD-treated (CBD_mock), and SARS-CoV-2 infected plus CBD treated (CBD_infect) samples. The first and second principal components (PC1 and PC2) of each sample are plotted. (D) Heatmap of normalized expression levels of 5,000 most variable genes across all RNA-seq samples, clustered into 6 groups based on differential expression between treatment conditions.

One potential mechanism by which CBD could suppress viral infection and promote degradation of viral RNA is through induction of the interferon signaling pathway. Interferons are among the earliest innate immune host responses to pathogen exposure ( 18 ). SARS-CoV-2 infection suppresses the interferon signaling pathway ( 19 ) ( Fig. 5A , and fig. S9). Some genes that are induced by CBD in both the absence and presence of the virus include receptors for interferons beta and gamma as well as mediators of the signaling pathway such as STATs 1 and 2 ( Fig. 5A and fig. S10). Other genes in the pathway like OAS1, an interferon-induced gene that leads to activation of RNase L and RNA degradation ( 20 ), are not significantly induced by CBD unless in the presence of the virus ( Fig. 5A and fig. S11). These latter results are consistent with the possibility that CBD lowers the effective viral titer sufficiently to enable normal host activation of the interferon pathway. At the same time, CBD effectively reverses viral induction of cytokines that can lead to the deadly cytokine storm at later stages of infection ( Fig. 5B ). Collectively, these results suggest that CBD inhibits SARS-CoV-2 infection in part by activating the interferon pathway leading to degradation of viral RNA and subsequent viral-induced changes in host gene expression, including cytokines.

(A) Heatmap of normalized expression levels of genes from the Interferon Response Canonical Pathway for all RNA-seq samples including control (veh_mock), SARS-CoV-2 infected (veh_infect), CBD-treated (CBD_mock), and SARS-CoV-2 infected plus CBD treated (CBD_infect) samples. Hierarchical clustering was applied to the genes. (B) Heatmap of normalized expression levels of GO Cytokine Activity genes which were up-regulated by the viral infection but down-regulated by CBD treatment for all RNA-seq samples as described in (A).

Given that CBD preparations containing substantial amounts of CBD are taken by a large number of individuals, we examined whether CBD exposure might correlate to a decreased risk of SARS-CoV-2 infection. Analysis of over 93,000 patients tested for SARS-CoV-2 at the University of Chicago Medical Center showed that 10.0% tested positive overall, but only 5.7% of the ~400 who had any cannabinoid in their medical record tested positive ( Fig. 6 ). Patients taking CBD versus other cannabinoids had an even lower rate of testing positive (1.2% in 85 CBD patients versus 7.1% in 113 patients taking other cannabinoids, p=0.08). This finding that patients taking other cannabinoids had less protection against viral infection is consistent with our cell culture studies. Since multiple potential confounding factors could explain these findings, including age, race, clinical morbidities, and sex, we matched 82 patients who were prescribed oral, FDA-approved CBD (Epidiolex ® ) before COVID-19 testing to patients who had no indication of taking any cannabinoids but had comparable other characteristics including similar demographic characteristics, clinical comorbidities, and records of other medications in the two years before COVID-19 testing (table S1). Of the patients prescribed oral CBD before their COVID-19 test, the most common morbidity categories were hypertension and conditions with immunosuppression. Strikingly, only 1.2% of the patients prescribed CBD contracted SARS-CoV-2 whereas 12.2% of the matched, non-cannabinoid patients tested positive (p=0.009), suggesting a potential reduction in SARS-CoV-2 infection risk of approximately an order of magnitude.

Associations between reported cannabinoid medication use and COVID-19 test results among adults tested at the University of Chicago Medicine (total n=93,565). P*: p-values of percent positivity of the specified patient population compared to percent positivity of all patients (10% COVID-19 positive among 93,565 patients). Middle right: 85 patients took CBD before their COVID test date. Upper right: 82 of the 85 patients took FDA-approved CBD (Epidiolex ® ) and were matched to 82 of the 93,167 patients (Matched Controls) with a nearest neighbor propensity score model that scored patients according to their demographics and their recorded diagnoses and medications from the two years before their COVID-19 test. P-values were calculated using Fisher’s exact test two-sided.

DISCUSSION

Our results suggest that CBD can block SARS-CoV-2 infection at early stages of infection, and CBD administration is associated with a lower risk of SARS-CoV-2 infection in humans. Furthermore, the active compound in patients is likely to be 7-OH-CBD, the same metabolite implicated in CBD treatment of epilepsy. The substantial reduction in SARS-CoV-2 infection risk of approximately an order of magnitude in patients who took FDA-approved CBD highlights the potential efficacy of this drug in combating SARS-CoV-2 infection. Finally, the ability of CBD to inhibit replication of MHV raises the possibility that CBD may have efficacy against new pathogenic viruses arising in the future.

One mechanism contributing to the antiviral activity of CBD is the induction of the interferon pathway both directly and indirectly following activation of the host immune response to the viral pathogen. In fact, interferons have been tested clinically as potential treatments for COVID-19 ( 21 ). Importantly, CBD also suppresses cytokine activation in response to viral infection, reducing the likelihood of immune cell recruitment and subsequent cytokine storms within the lungs and other affected tissues. These results complement previous findings suggesting that CBD suppresses cytokine production in recruited immune cells such as macrophages ( 22 ). Thus, CBD has to the potential not only to act as an antiviral agent at early stages of infection but also to protect the host against an overactive immune system at later stages.

However, several issues require close examination before CBD can be considered or even explored as a therapeutic for COVID-19 ( 11 ). Although many CBD formulations are available on the market, they vary vastly in quality, the amount of CBD, and their pharmacokinetic properties after oral administration, which are mostly unknown. CBD is quite hydrophobic and forms large micellar structures that are trapped and broken down in the liver, thereby limiting the amount of drug available to other tissues after oral administration. The inactive carriers have a significant impact on clinically obtainable concentrations. As CBD is widely sold as a preparation in an edible oil, we analyzed flavored commercial hemp oils and found a CBD content of only 0.30% in a representative sample (fig. S12). The purity of CBD and, in particular, the composition of the materials labelled as CBD are also important, especially in light of our findings suggesting that other cannabinoids such as THC might act to counter CBD antiviral efficacy. This essentially eliminates the feasibility of marijuana serving as an effective source of antiviral CBD, in addition to issues related to its legal status. Finally, other means of CBD administration such as vaping and smoking raise concerns about potential lung damage.

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Future studies to explore the optimal means of CBD delivery to patients along with clinical trials will be needed to fully test the promise of CBD as a therapeutic to block SARS-CoV-2 infection. As the clearance rates for CBD in plasma are substantially lower in humans than mice, we would suggest moving to clinical trials rather than doing preclinical studies in animal models ( 15 ). We advocate carefully designed placebo-controlled clinical trials with known concentrations and highly-characterized formulations in order to define CBD’s role in preventing and treating early SARS-CoV-2 infection. The necessary human in vivo concentration and optimal route and formulation remain to be defined. We strongly caution against the urge to take CBD in presently available formulations as a preventative or treatment therapy at this time, especially without the knowledge of a rigorous randomized clinical trial with this natural product ( 23 ).

Supplementary Material

Supplement 1

ACKNOWLEDGEMENTS

We thank the members of the SARS-CoV-2 host response team in Chicago for stimulating discussions and support with particular thanks to Julian Solway, Rick Morimoto, Nissim Hay, Anne Sperling, HuanHuan Chen, Raphael Lee, Raymond Roos, Shannon Elf, Alexander Muir, Gokhan Mutlu, Jay Pinto, Steven White, Nickolai Dulin, Ray Moellering, Viswanathan Natarajan, Leonitis Platanias, Karen Ridge and HuanHuan Chen. We thank Dominique Missiakas for facilitating access to the University of Chicago Howard Taylor Ricketts Facility by providing protocols and trained scientists. We also thank Nicole Rosner and Kathleen Cagney for proposing and facilitating analysis of clinical data, and Mark Ratain for consideration of pharmacokinetic issues. We thank the University of Chicago Genomics Facility (RRID:SCR_019196) especially Sandhiya Arun and Pieter Faber, for their assistance with RNA sequencing. Finally, we would like to acknowledge the University of Chicago Vice Provost for Research, Karen Kim, and the Dean of the Biological Sciences Division, Kenneth Polonsky, for their steadfast support.

Funding:

This work was supported by:

BIG Vision grant from the University of Chicago (M.R.R.)

National Institutes of Health grant R01 GM121735 (M.R.R.)

National Institutes of Health grant R01 CA184494 (M.R.R.)

National Institutes of Health grant R01 AI137514 (G.R.)

National Institutes of Health grant R01 AI127518 (G.R.)

National Institutes of Health grant R01 AI134980 (G.R.)

National Institutes of Health grant R01 CA219815 (S.A.O.)

National Institutes of Health grant R35 GM119840 (B.C.D)

National Institutes of Health grant P30 CA014599 (University of Chicago Comprehensive Cancer Center Support grant)

Competing interests:

Five of the authors (MRR, GR, LCN, DY and JMM) filed a provisional patent entitled “Method of use of Cannabidiol as an antiviral agent”. Receipt of the provisional patient was acknowledged by the USPTO on November 30, 2020. S.A.O. is a cofounder and consultant at OptiKira., L.L.C. (Cleveland, OH).

Footnotes

Data and materials availability: All data, code, and materials used in the analysis will be available in some form to any researcher for purposes of reproducing or extending the analysis except when limited by materials transfer agreements (MTAs). Raw and processed RNA-seq data will be deposited into the GEO database.

Materials and Methods

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It’s too early to tell whether CBD helps against Covid-19 — but researchers worry that won’t stop CBD makers

T he scientists stressed the caveats that early-stage research demands: the compounds they had studied showed hints — in cells in lab dishes and in animals — of being able to combat the coronavirus. Definite answers could only come from clinical trials.

But the compounds were CBD and other marijuana and hemp derivatives, so the news took off. Kimmel and Colbert cracked jokes. The studies received coverage in outlets from Fox News to The Daily Beast.

The latest hubbub is an example of both the promise of cannabinoids — components of cannabis — as potential therapies, but also the hype around them, which can far outpace the evidence that they work. It’s left researchers and consumer advocates scrambling to warn people that patients shouldn’t be turning to over-the-counter products or recreational marijuana in hopes that it might protect them from Covid-19.

“We don’t want people running out taking random cannabinoids,” said Marsha Rosner of the University of Chicago, the senior author of one of the new studies.

The research also presents a new challenge for the Food and Drug Administration, which is already struggling to police the rapidly growing CBD market. While the agency has said CBD makers can’t market their products as medical treatments without conducting a clinical trial and submitting an application to the agency, few companies have actually invested in conducting those trials. Instead, companies have tried to tiptoe around the FDA rules by selling their products as dietary supplements and making only modest claims. Experts fear that the FDA’s job will only get harder with the increased hype around cannabinoids and Covid-19.

“These kinds of studies are what these companies look for to promote their products — that’s the scary part,” said Jeanette Contreras, director of health policy at the National Consumers League, which runs a campaign called Consumers for Safe CBD. “This gives them more fuel to make false claims about their products.”

Related: The FDA is finalizing its long-awaited rules for CBD

R osner and her team were initially skeptical that CBD could have any potential effect for Covid-19. They thought that if there was going to be any benefit, it might be in the late-stage illness that occurs when the immune response to the virus goes into hyperdrive.

But then they found something that surprised them: While CBD couldn’t block the virus from entering human epithelial cells in lab dishes, it prevented the pathogen from hijacking the cell’s internal Xerox machines to make copies of itself. It also lowered viral levels in infected mice.

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Rosner and her team’s paper was published in Science Advances this month, soon after researchers in Oregon reported in the Journal of Natural Products that two chemicals found in hemp, CBGA and CBDA, could bind to the virus’ spike protein and thus prevent it from infecting cells in lab dishes.

Together, the two studies earned attention for the suggestion that cannabinoids might have a role to play in the pandemic.

But since the work was published, Rosner has been trying to inject caveats and nuances into the discussion around CBD for Covid.

As she emphasizes: experiments in mice and cells in lab dishes regularly seem like breakthroughs, whether for Covid-19 or just about any other ailment. But only rarely do they go on to demonstrate any actual effectiveness in human trials.

Outside researchers also noted that the two papers reported sometimes opposing results for how cannabinoids interacted with the coronavirus, indicating that any potential effect needs to be further studied.

“These are the seeds of our knowledge related to how cannabinoids might interact with the SARS-Cov-2 virus,” said Ziva Cooper, the director of the UCLA Cannabis Research Initiative. “We have a long way to go.”

Related: A spate of new class-action lawsuits threaten the CBD industry. Will they force Washington to act?

T he new studies are adding to the FDA’s existing CBD headache, too.

The agency has already grappled with companies trying to use early research into CBD and Covid-19 to promote their products — it has sent 13 official warning letters demanding that companies stop selling their CBD products as Covid-19 treatments.

Some of those companies did not explicitly call their products cures, but instead included outside research on their websites that could lead consumers to believe CBD was a proven treatment for Covid-19, STAT found when it reviewed the FDA’s warning letters. Other companies explicitly noted that their product was not a treatment for Covid-19 but suggested, for example, that “ the best thing you can do is boost your immune system.”

This has been a long-running issue with CBD, which the FDA regulates the same way it does other prescription drugs. That means anything with CBD in it must go through the agency’s rigorous approval process if companies want to suggest it can treat or cure anything at all.

Few companies have been willing to invest the time and effort needed to actually get a CBD drug through the regulatory odyssey. Instead, most market their products as dietary supplements in hopes that the FDA will not crack down on their individual products.

Related: The company behind the first-ever CBD-based drug is now eyeing everything from multiple sclerosis to autism

Research is hard for other reasons, too. Just a few years ago, researching cannabidiol was heavily restricted because of marijauna’s legal status, and the trials are still hard to conduct — one researcher called the system a “nightmare.”

That means there’s hardly any infrastructure or investment into actually testing whether CBD has an impact on Covid-19.

In fact, there’s still not much late-stage clinical research into whether CBD really does much of anything at all.

“The status quo is challenging,” said Lowell Schiller, the former co-lead of the FDA’s CBD working group. “When we see potentially promising research coming out of the laboratory setting, where are the dollars coming from to do the kind of rigorous clinical research that we need to genuinely understand whether there’s a there there ?”

It’s an open question whether new trials looking at cannabinoids and Covid will take off. Scientists have hypothesized that CBD or other cannabinoids might have some role to play against Covid-19 for much of the pandemic, but a STAT review of clinicaltrials.gov identified just seven trials that have tested CBD as a therapy for Covid-19, the majority of which are early-stage studies that would not produce the type of results necessary to conclude whether CBD can help combat the pandemic.

Rosner said she and her colleagues have been in touch with various companies about clinical trials, but so far, nothing’s set up. “Our hope is we can get some traction in the near future,” she said.

Related: These four companies are betting big on CBD-based prescription drugs

Richard van Breemen, a professor of medicinal chemistry at Oregon State University and one of the scientists involved with the other paper, told the Boston Globe this month that he expected data from clinical trials later this year. He did not respond to a question from STAT about whether clinical trials based on his team’s research had started or when they might.

Not all clinical trials are created equally, either — a fact that has dogged scientists’ efforts to test potential Covid-19 treatments. Going back to the heady days of hydroxychloroquine mania, dozens of trials of different treatments were launched based on preclinical hope, but they were ultimately too small or too poorly designed to come up with definite answers. The pileup of unhelpful U.S. clinical trials stands in stark contrast to something like the Recovery trial out of the United Kingdom, where a cohesive strategy and a national health system led to clear findings about treatments like dexamethasone (which worked) and convalescent plasma (which didn’t).

“It’s not just, is there a clinical trial, but what kind of clinical trial?” Rosner said, adding that her team was hoping to conduct a rigorous trial.

Trending Now: Pfizer isn’t sharing Covid vaccines with researchers for next-gen studies

In the meantime: Rosner is urging consumers not to go buy CBD to try to prevent Covid-19. For one, it’s not clear the products available at convenience stories contain pure CBD, or at what levels. The clinical trial Rosner envisions would test a pharmaceutical-grade CBD — something like the FDA-approved Epidiolex, an epilepsy treatment.

There’s another reason why people shouldn’t smoke marijuana or pop an edible and think it might be helping protect them from Covid-19, Rosner added: While her team reported an effect from CBD, the scientists found that the added presence of THC — the component of marijuana that makes people high — counteracted whatever benefits CBD may provide.

“The last thing we would like to see is for someone to say, ‘I’m going to go out and take CBD,’ and say, ‘I’m not going to get vaccinated, I’m not going to get boosted, I’m going to take off my mask,’” she said.

So, Your Patient Just Asked About CBD for COVID-19?

— David Aronoff, MD, discusses an early study on CBD and on how to address interested patients

by Emily Hutto, Associate Video Producer January 28, 2022

In this video, David Aronoff, MD, chair of the department of medicine at Indiana University School of Medicine in Indianapolis, discusses a recent study testing cannabidiol (CBD) against COVID-19 in the lab and in mice, and how to guide patients seeking treatment for COVID-19.

The following is a transcript of his remarks:

If a patient were to come to me and ask about the use of CBD oil to prevent COVID-19 or reduce the severity of it, I would say that right now, that approach is not ready for prime time. There are other, better ways that we know are safe and very effective to prevent COVID-19 and reduce the severity if someone gets ill. So wear your mask, socially distance, get vaccinated, and if you get symptomatically ill with COVID, let a healthcare professional know, because you may be eligible for things like monoclonal antibodies or new medications like Paxlovid [nirmatrelvir/ritonavir] or repurposed medicines like fluvoxamine [Luvox]. But it’s really important to engage with a licensed healthcare professional if you’re sick with COVID-19.

These investigators thought that there may be some anti-inflammatory effects of CBD, and that might be useful to suppress some of the inflammation that can occur in patients who have COVID-19. But the investigators found a surprising result, which is that CBD and one of its active metabolites didn’t really have too much of an effect on the inflammatory response of the epithelial cells they were studying. But rather, and curiously, the CBD seemed to block the replication of the SARS CoV-2 virus in the respiratory epithelial cells.

This really led the investigators to dig deeper into trying to understand whether the effect they were seeing was specific to CBD or could be found in other compounds that may be also identified in marijuana and to try to drill down on mechanisms through which CBD could be limiting SARS CoV-2 replications in epithelial cells.

And finally, based on what they found in vitro, they wanted to know if there were any correlates of this compound being used in humans that may show some promise for reducing the risk of COVID-19 and even went as far as doing an interventional study in mice to look at the impact of CBD on reducing the severity of SARS COVID-2 infection in a mouse model.

While this study is really interesting and promising, we don’t yet have data in humans that show that we can use CBD oil in therapeutic ways to prevent COVID-19 or reduce the severity of COVID-19. And really what we need is an actual randomized placebo-controlled, double-blind study, which is now regularly being done to look at therapeutic and preventive strategies for COVID-19. Right now, the best we can say about CBD oil is that it’s a promising idea. But until we have properly controlled studies, we don’t actually know how effective or not this is in humans.

Even the human component of the study that was just published, although it was retrospective, which has its limitations, it was looking at essentially medical-grade CBD oil used in the treatment of people who have severe seizure disorders. So we really don’t know how commercially-available, easy-to-get CBD preparations might perform in protecting people from COVID-19.

Emily Hutto is an Associate Video Producer & Editor for MedPage Today. She is based in Manhattan.

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