Patients with long COVID may derive benefits from treatment with fluvoxamine, which has been shown to reduce fatigue and improve quality of life (QoL) in a study. The use of metformin, on the other hand, shows no significant advantage.
“[T]his trial offers support for fluvoxamine in reducing fatigue severity and improving QoL in people with long COVID and should lead to further investigation in a broader, phenotype-informed therapeutic framework,” the investigators said.
A total of 399 adults with fatigue persisting 90 or more days after confirmed SARS-CoV-2 infection were included in this randomized, placebo-controlled, adaptive trial in Brazil. Participants were randomly allocated to receive fluvoxamine (100 mg twice daily), metformin (750 mg twice daily), or matching placebo for 60 days. The primary outcome was change in Fatigue Severity Scale (FSS) score.
Patients with long COVID who received fluvoxamine experienced a significant decrease in fatigue relative to those who received placebo at day 60 (mean difference, ‒0.43, 95 percent credible interval [CrI], ‒0.80 to ‒0.07), with a sustained benefit at day 90 (mean difference, ‒0.58, 95 percent CrI, ‒0.98 to ‒0.16). [Ann Intern Med 2026;doi:10.7326/ANNALS-25-03959]
Likewise, patients treated with fluvoxamine showed improvements in QoL scores with high posterior probability. In contrast, those who received metformin derived no significant benefits.
In terms of safety, adverse events were fewer in the fluvoxamine-treated cohort than the metformin or placebo groups (20.0 percent vs 28.8 percent and 29.7 percent, respectively). Grade ≥3 adverse events rarely occurred across all treatment groups.
“The concordance between the disease-specific fatigue reduction and broader health-related quality-of-life improvement supports the clinical relevance of the observed treatment effects,” the investigators said. “Rather than implying modification of underlying long COVID pathophysiology, the observed benefits may reflect improvements in overall well-being, symptom perception, or functional capacity."
Metformin
These findings do not offer evidence supporting the use of metformin for long COVID fatigue. This is in contrast with a previous study that suggests a reduced risk for developing long COVID symptoms when metformin is administered during acute SARS-CoV-2 infection. [Lancet Infect Dis 2023;23:1119-1129]
Trials of antiviral therapy, such as nirmatrelvir‒ritonavir, have found inconsistent effects on the development of long COVID symptoms, as shown in the STOP-PASC trial. [JAMA Intern Med 2024;184:1024-1034]
In another trial, nicotinamide riboside did not significantly improve cognition, fatigue, sleep, or mood in patients with long COVID when compared with placebo. [EClinicalMedicine 2025;89:103633; BMC Med Res Methodol 2016;16:62]
“These findings [from previous studies] underscore ongoing uncertainty about effective treatment for long COVID and highlight the need for rigorously designed randomized trials,” the investigators said.
“Future trials should incorporate standardized assessments of depression [and] anxiety at baseline and follow-up, alongside inflammatory and metabolic biomarkers, to clarify mechanisms and identify subgroups most likely to benefit,” they said.
The current trial had certain limitations. Firstly, the 90-day follow-up period limits conclusions regarding the durability of treatment effects. Secondly, the focus on fatigue as the primary outcome fails to address other long COVID symptoms.
Fluvoxamine is a selective serotonin reuptake inhibitor with σ-1 receptor agonism that possesses anti-inflammatory properties and has been shown to reduce hospitalization risk in acute COVID-19 across multiple trials. [JAMA 2020;324:2292-2300; Lancet Glob Health 2022;10:e42-e51]
“Its central nervous system activity and immunomodulatory effects offer a possible mechanistic rationale for use in neurocognitive and fatigue-related manifestations of long COVID,” the investigators said. [PLoS One 2024;19:e0300512]