A new study shows that an FDA-approved, pharmaceutical-grade formulation of CBD has an antiviral effect in human lung cells and mice, and shows a significant negative association with COVID infection in human patients. It’s too early to tell whether CBD helps against Covid-19 — but researchers worry that won’t stop CBD makers.
Researchers recommend clinical trials for CBD to prevent COVID-19 based on promising animal data
An interdisciplinary team of researchers from the University of Chicago has found evidence that cannabidiol (CBD), a product of the cannabis plant, can inhibit infection by SARS-CoV-2 in human cells and in mice.
The study, published on January 20, 2022, in Science Advances, found CBD showed a significant negative association with SARS-CoV-2 positive tests in a national sample of medical records of patients taking the FDA-approved drug for treating epilepsy. The researchers now say that clinical trials should be done to determine whether CBD could eventually be used as a preventative or early treatment for COVID-19. They caution, however, that the COVID-blocking effects of CBD come only from a high purity, specially formulated dose taken in specific situations. The study’s findings do not suggest that consuming commercially available products with CBD additives that vary in potency and quality can prevent COVID-19.
Scientists have been looking for new therapies for people infected by the coronavirus and emerging variants, especially those who lack access to vaccines, as the pandemic continues across the country and world and as breakthrough infections become more common.
CBD: An unexpected avenue for fighting COVID-19
The idea to test CBD as a potential COVID-19 therapeutic was serendipitous. “CBD has anti-inflammatory effects, so we thought that maybe it would stop the second phase of COVID infection involving the immune system, the so-called ‘cytokine storm.’ Surprisingly, it directly inhibited viral replication in lung cells,” said Marsha Rosner, PhD, Charles B. Huggins Professor in the Ben May Department of Cancer Research and a senior author of the study.
To see this effect, the researchers first treated human lung cells with a non-toxic dose of CBD for two hours before exposing the cells to SARS-CoV-2 and monitoring them for the virus and the viral spike protein. They found that, above a certain threshold concentration, CBD inhibited the virus’ ability to replicate. Further investigation found that CBD had the same effect in two other types of cells and for three variants of SARS-CoV-2 in addition to the original strain.
CBD did not affect the ability of SARS-CoV-2 to enter the cell. Instead, CBD was effective at blocking replication early in the infection cycle and six hours after the virus had already infected the cell.
Like all viruses, SARS-CoV-2 affects the host cell by hijacking its gene expression machinery to produce more copies of itself and its viral proteins. This effect can be observed by tracking virus-induced changes in cellular RNAs. High concentrations of CBD almost completely eradicated the expression of viral RNAs. It was a completely unexpected result.
“We just wanted to know if CBD would affect the immune system,” Rosner said. “No one in their right mind would have ever thought that it blocked viral replication, but that’s what it did.”
The researchers showed that the mechanism by which CBD blocks SARS-CoV-2 replication involves CBD activation of one of the host cell stress responses and generation of interferons, an antiviral cell protein.
Real world data: Patients taking CBD test positive for COVID-19 at lower rates
The researchers wanted scientific data to show that CBD prevents viral replication in live animals. The team showed pretreatment with CBD for one week prior to infection with SARS-CoV-2 suppressed infection both in the lung and the nasal passages of mice. “These results provide major support for a clinical trial of CBD in humans,” said Rosner.
And the success of CBD wasn’t limited to the laboratory: An analysis of 1,212 patients from the National COVID Cohort Collaborative revealed that patients taking a medically prescribed oral solution of CBD for the treatment of epilepsy tested positive for COVID-19 at significantly lower rates than a sample of matched patients from similar demographic backgrounds who were not taking CBD.
The potential for CBD to treat patients recently exposed to or infected by SARS-CoV-2 does not precede the first lines of defense against COVID-19, which are to get vaccinated and follow existing public health guidelines for masking in indoor spaces and social distancing. But the published results offer a potential new therapeutic, something still needed as the pandemic rages on.
“A clinical trial is necessary to determine whether CBD is really effective at preventing or suppressing SARS-CoV-2 infection, but we think this may have potential as a prophylactic treatment,” said Rosner. “Maybe you’re in a hot spot or you think you might have been exposed or you’ve just tested positive — that’s where we think CBD might have an effect.”
Not your dispensary’s CBD
The research team emphasized that the COVID-blocking effects of CBD were confined strictly to high purity, high concentrations of CBD. Closely related cannabinoids such as CBDA, CBDV and THC, the psychoactive element enriched in marijuana plants, did not have the same power. In fact, combining CBD with equal amounts of THC actually reduced the efficacy of CBD.
“Going to your corner bakery and buying some CBD muffins or gummy bears probably won’t do anything,” said Rosner. “The commercially available CBD powder we looked at, which was off the shelf and something you could order online, was sometimes surprisingly of high purity but also of inconsistent quality. It is also hard to get into an oral solution that can be absorbed without the special, FDA-approved formulation,” Rosner said.
Furthermore, CBD use is not without potential risks. It appears to be extremely safe when consumed in food or drink, but methods of use such as vaping can have negative side effects, including potential damage to the heart and lungs. It’s also not well studied in certain populations, such as pregnant people, and so should be used only under the supervision of a physician and with caution.
While the study’s results are exciting, additional study is needed to determine the precise dosing of CBD that is effective at preventing SARS-CoV-2 infection in humans as well as its safety profile and any potential side effects.
“We are very eager to see some clinical trials on this subject get off the ground,” Rosner said. “Especially as we are seeing that the pandemic is still nowhere near the end — determining whether this generally safe, well-tolerated, and non-psychoactive cannabinoid might have anti-viral effects against COVID-19 is of critical importance.”
Rosner was also pleased that this research project was a case study in the power of scientific collaboration by bringing together a highly interdisciplinary group of researchers. Senior authors listed on the paper came from three different research universities and from departments as diverse as microbiology, molecular engineering, cancer biology and chemistry.
“This was truly a team-science effort, and that’s something that really excites me,” said Rosner. “From clinicians to David Meltzer’s group who did the patient analysis to virologists like Glenn Randall, and it goes on and on. This is the way science should be carried out.”
The study, “Cannabidiol Inhibits SARS-CoV-2 Replication through Induction of the Host ER Stress and Innate Immune Responses,” was supported by a BIG Vision grant from the University of Chicago, the National Institutes of Health (R01 GM121735, R01 CA184494, R01 AI137514, R01 AI127518, R01 AI134980, R01 CA219815, R35 GM119840, P30 CA014599), and the Harry B. and Leona M Helmsley Charitable Trust. Additional authors include Long Chi Nguyen, Dongbo Yang, Thomas J. Best, Nir Drayman, Adil Mohamed, Christopher Dann, Diane Silva, Lydia Robinson-Mailman, Andrea Valdespino, Letícia Stock, Eva Suárez, Krysten A. Jones, Saara-Anne Azizi, James Michael Millis, Bryan C. Dickinson, Savaş Tay, Scott A. Oakes, and David O. Meltzer of the University of Chicago; Vlad Nicolaescu, Haley Gula, and Glenn Randall of UChicago and Argonne National Laboratory; Divayasha Saxena, Jon D. Gabbard, Jennifer K. Demarco, William E. Severson, Charles D. Anderson, and Kenneth E. Palmer of the University of Louisville; Shao-Nong Chen, Takashi Ohtsuki, John Brent Friesen, and Guido F. Pauli of the University of Illinois at Chicago; and the National COVID Cohort Collaborative Consortium.
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.
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.”
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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.
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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.
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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.