This article is part of Harvard Medical School continuous coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.
For the past year and a half, the COVID-19 pandemic has continued to sweep the world, fueled in part by new variants and the uneven distribution of vaccines. Hundreds of thousands of new COVID-19 cases and thousands of new deaths continue to be reported worldwide every day, creating a need for drugs that can fight the disease caused by SARS-CoV-2.
Now, new research led by researchers from Harvard Medical School and Boston Children’s Hospital points to a well-known and widely available drug called disulfiram (marketed as Antabuse) as a possible treatment for COVID-19
In the retrospective study, published October 28 in PLOS ONE, patients taking disulfiram for alcoholism were less likely to become infected with SARS-CoV-2, and those who did become infected were less likely to die from COVID-19 than those who didn’t take the drug.
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The researchers caution that since the study was observational, it cannot establish a cause-and-effect relationship between disulfiram and disease development. However, they say the results are encouraging enough to warrant further research and clinical trials.
The exact mechanism of the drug against SARS-CoV-2 is not yet known, but researchers have hypothesized that it may prevent the virus from taking hold by interfering with an enzyme it needs to replicate.
In addition, disulfiram may attenuate the symptoms of severe COVID-19 by inhibiting a protein involved in hyperinflammation. If the effect of disulfiram against SARS-CoV-2 is confirmed, it could become a useful tool against the virus.
A pandemic twist
In the spring of 2020, SARS-CoV-2 quickly spread around the world, and it quickly became apparent that the most serious – and deadliest – symptoms of COVID-19 are caused by an intense inflammatory response to the virus.
At the same time, Judy Lieberman, HMS professor of pediatrics at Boston Children’s, and Hao Wue, de Asa and Patricia Springer, professor of structural biology at the Blavatnik Institute at HMS, explored whether disulfiram, an oral drug commonly prescribed for alcoholism, could be reused to treat inflammation.
In May 2020 they published a study in mice showing that disulfiram reduced inflammation caused by sepsis by blocking a key protein involved in the process.
Realizing that their research could be relevant to inflammation linked to COVID-19, the duo reached out to: Chris Sander, professor in residence of cell biology at HMS.
“They approached me and asked, can you find computational evidence on whether this drug works against COVID-19?” remembers Sander. “I just thought, the world is going to break here, let’s do something useful. I wanted to help them take their research one step further.”
Sander sprang into action, working with Lieberman and Wu to assemble a team of epidemiologists and public health experts, including Nathanael Fillmore and Nhan Do of the Boston VA Cooperative Studies Program Center. The researchers used computational techniques to analyze a large database of clinical data from the national health care system of Veterans Affairs.
The analysis included 944,127 veterans who had at least one SARS-CoV-2 test between February 2020 and February 2021; of these, 2,233 had been prescribed disulfiram for alcoholism.
Veterans who took disulfiram had a 34 percent lower incidence of SARS-CoV-2 infection than those who were not. In addition, no one died on disulfiram infected with the virus, compared with 3 percent of those infected and not on the drug.
“There is some evidence that disulfiram not only reduces the incidence of SARS-CoV-2 infection, but may actually reduce the number of deaths,” Sander said.
However, he noted that the study, which is retrospective, can only establish an association between disulfiram and SARS-CoV-2 — and so the findings need to be confirmed in randomized clinical trials.
A small randomized phase 2 clinical trial of disulfiram in patients with moderate COVID-19 is nearing completion and another is underway. The authors hope the study will motivate large international Phase 3 trials of the drug.
Noting that it would be unrealistic to give the drug as a preventive measure, they are particularly interested in how patients hospitalized with severe COVID-19 fare on disulfiram.
The researchers would also like to further investigate the mechanism underlying the effect of disulfiram against SARS-CoV-2. One possibility is that the drug inhibits a key protease that SARS-CoV-2 needs to replicate, preventing the virus from spreading in cells.
“That is a plausible mechanism, but needs to be confirmed with further research. It is a work in progress’, says Sander.
Disulfiram can also suppress hyperinflammation — which can cause breathing problems in patients with severe COVID-19 — by inhibiting a protein called gasdermin D that is needed for this inflammatory response.
If disulfiram does indeed reduce SARS-CoV-2 infection and death from COVID-19, it could become part of a growing arsenal in the global fight against the disease.
The drug is FDA-approved and has been prescribed as a treatment for alcoholism for more than 60 years. It is safe, cheap, trusted by doctors and widely used in many countries.
“This is a great candidate for a repurposed drug,” Sander said. “It could be easily made available worldwide if we can prove that it has a positive effect on patients with COVID-19.”
The work was supported by the British Heart Foundation (RG/4/32218), the VA Cooperative Studies Program, the VA Boston Healthcare System, the National Institute of Arthritis and Musculoskeletal and Skin Disease (K23AR069127), Dana-Farber Cancer Institute, Harvard Medical School and the National Institutes of Health.