The ongoing search for effective treatments for long COVID has hit another roadblock. A recently published randomized clinical trial has found that neither metformin, a common diabetes medication, nor ursodeoxycholic acid (UDCA), used to treat liver conditions, significantly improved recovery from post-acute sequelae of SARS-CoV-2 infection (PASC) – commonly known as long COVID. The findings, published in the Annals of Internal Medicine on March 3, 2026, add to the growing body of evidence highlighting the challenges in addressing the complex and varied symptoms experienced by individuals months after the initial COVID-19 infection.
Long COVID, characterized by a wide range of persistent symptoms including fatigue, brain fog, shortness of breath, and muscle pain, affects a substantial portion of those who have been infected with SARS-CoV-2. The lack of proven therapies has led researchers to explore various potential treatments, including repurposing existing drugs. Metformin and UDCA were investigated due to preliminary evidence suggesting potential benefits in mitigating some of the underlying mechanisms thought to contribute to long COVID. Specifically, earlier studies hinted that metformin might reduce the long-term risk when administered during the acute phase of infection, whereas UDCA has shown promise in addressing liver inflammation and metabolic dysfunction, both of which can be observed in some long COVID patients.
Study Details and Methodology
The double-blind, placebo-controlled, randomized clinical trial, registered as KCT0009342 with the Clinical Research Information Service, involved 396 adults in South Korea experiencing symptoms of long COVID. Participants were recruited from two tertiary hospitals between July 2024 and April 2025. To be included in the study, individuals had to have a PASC index score of 12 or greater, indicating a significant symptom burden. Participants were randomly assigned to one of three groups: oral metformin (uptitrated to 1500 mg/day), UDCA (900 mg once daily), or a double placebo, for a period of 14 days. The primary outcome measured was the proportion of participants achieving PASC recovery, defined as a PASC index score of less than 12, at 8 weeks post-intervention.
The demographic profile of the participants revealed a median age of 36 years (interquartile range, 28 to 49 years), with women comprising 72% of the study population. The average time since the initial SARS-CoV-2 infection was 9.8 months (standard deviation, 7.5 months), and the mean baseline PASC score was 19.3 (standard deviation, 5.7). This suggests the participants were experiencing moderate to severe long COVID symptoms at the start of the trial.
Results: No Significant Improvement
The results showed that recovery rates were remarkably similar across all three groups. 63.6% (84 of 132) of participants receiving metformin achieved a PASC recovery, compared to 68.2% (90 of 132) in the UDCA group and 68.2% (90 of 132) in the placebo group. These findings indicate that neither medication provided a statistically significant benefit over placebo in improving long COVID symptoms.
Analysis of changes in PASC scores from baseline to week 8 further supported these conclusions. The mean reduction in PASC scores was −10.05 (95% confidence interval, −11.35 to −8.76) with metformin, −10.62 (95% confidence interval, −11.79 to −9.45) with UDCA, and −10.43 (95% confidence interval, −11.69 to −9.18) with placebo. While both metformin and UDCA showed a numerical reduction in PASC scores, the differences were not statistically significant compared to the placebo group.
Limitations and Future Directions
The study authors acknowledge several limitations. Notably, the findings may not be generalizable to patients with more severe or prolonged cases of long COVID. The study population may not fully represent the diverse range of individuals affected by PASC. The relatively short duration of treatment – only 14 days – may have been insufficient to observe a meaningful effect.
Despite these limitations, the study provides valuable insights into the challenges of treating long COVID. It underscores the need for continued research to identify effective therapies for this debilitating condition. Researchers are currently exploring a variety of other potential treatments, including antiviral medications, immunomodulators, and rehabilitation programs. Understanding the underlying mechanisms driving long COVID is also crucial for developing targeted therapies. The National Institutes of Health (NIH) in the United States, for example, is conducting extensive research through its RECOVER Initiative, a multi-site study investigating the causes, prevention, and treatment of long COVID. Learn more about the RECOVER Initiative here.
The Complexities of Long COVID
Long COVID is not a single disease, but rather a constellation of symptoms that can vary widely from person to person. This heterogeneity makes it difficult to design clinical trials and identify effective treatments. Some patients experience primarily neurological symptoms, such as brain fog and memory problems, while others struggle with cardiovascular or respiratory issues. The underlying causes of long COVID are also not fully understood, but potential mechanisms include persistent viral reservoirs, immune dysregulation, and microclots in the blood vessels. The World Health Organization provides further information on post-COVID-19 condition.
Implications for Patients and Healthcare Providers
The findings from this study, and others like it, emphasize the importance of a holistic approach to managing long COVID. Currently, treatment focuses on symptom management and supportive care. This may include physical therapy, cognitive behavioral therapy, and medications to address specific symptoms such as pain, fatigue, and anxiety.
For patients experiencing long COVID, It’s crucial to work closely with their healthcare providers to develop an individualized treatment plan. Participating in clinical trials is also an option for those who are interested in contributing to research and potentially accessing novel therapies. While a cure for long COVID remains elusive, ongoing research offers hope for the development of effective treatments in the future.
The lack of effective treatments also highlights the critical importance of prevention. Vaccination against COVID-19 remains the most effective way to reduce the risk of both acute infection and long COVID. Public health measures, such as masking and social distancing, can also support to limit the spread of the virus and protect vulnerable populations.
Looking ahead, researchers will need to focus on identifying biomarkers that can predict who is at risk of developing long COVID and tailoring treatments accordingly. Further investigation into the underlying mechanisms driving the condition is also essential. The next steps in research will likely involve larger, more diverse clinical trials and the exploration of combination therapies targeting multiple pathways involved in the pathogenesis of long COVID.
The European Medicines Agency (EMA) is continuously monitoring emerging data on potential treatments for long COVID and will provide guidance to healthcare professionals as fresh evidence becomes available. Stay updated on COVID-19 therapeutics from the EMA.
Key Takeaways:
- A recent clinical trial found that metformin and UDCA did not significantly improve recovery from long COVID symptoms.
- The study involved 396 adults in South Korea with a PASC index score of 12 or greater.
- Neither medication showed a statistically significant benefit over placebo in reducing PASC scores.
- Ongoing research is crucial to identify effective treatments for this complex condition.
The search for answers continues, and the medical community remains committed to finding effective solutions for those struggling with the long-term effects of COVID-19. We encourage readers to share their experiences and perspectives in the comments below. Please consult with your healthcare provider for personalized medical advice.