WASHINGTON — People with long COVID reported significantly better functioning and symptom improvements after taking low-dose naltrexone, according to a small retrospective cohort study.
Symptom burdens declined among 230 adults with long COVID from baseline to more than 3 months after receiving a low-dose naltrexone prescription off-label for the condition. The average seven-symptom composite score dropped by an estimated annual change of 5.1 points (95% CI -7.69 to -2.52, P<0.001) from a baseline average of 20 after adjustment for other factors. Number of symptoms declined by a mean annual change of -2.4 (95% CI -3.94 to -0.94, P=0.001).
As self-reported symptoms slid, self-reported functional status rose. The adjusted mean annual change to patients’ functional stage scores was -0.32 (95% CI -0.57 to -0.07, P=0.011) on a scale from 1-5, reported Brandon Aflak, JD, CNA, a fellow at Stanford University in California.
“Although these findings are encouraging, this observational study design does limit causal inference,” Aflak said in a presentation at the IDWeek annual meeting. “Randomized, placebo-controlled trials are needed to establish the safety and efficacy of low-dose naltrexone for long COVID, and to determine its potential role in clinical management.”
There are no FDA-approved therapies for long COVID, and various treatments including anti-inflammatories and antihistamines have fizzled in clinical trials. In one study of nirmatrelvir-ritonavir (Paxlovid), the active treatment group failed to outperform the placebo group, where 33-70% of the recipients showed improvements in exercise, cognitive, and autonomic domains after 3 months.
Although definitions differ, the National Academies of Sciences, Engineering, and Medicine defines long COVID as an infection-associated chronic condition that happens after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state affecting at least one organ system.
A 2022 survey found that 6.9% of U.S. adults reported ever having had long COVID and 3.4% had it that year.
Naltrexone is an opioid antagonist approved by the FDA to treat opioid use disorder and alcohol use disorder and to treat obesity when given in combination with bupropion (Contrave). Low-dose naltrexone below the approved 50-100 mg dosages has been used off-label for multiple sclerosis, fibromyalgia, Crohn’s disease, and pain management. Naltrexone might have anti-inflammatory and immunomodulatory effects in long COVID, Aflak noted.
For their study, the investigators analyzed patient electronic health records from the Stanford Long COVID Clinic from 2023 to December 2025. Patients included in the analysis were adults with laboratory-confirmed SARS-CoV-2 infection and persistent symptoms at least 90 days after infection. They had to have had at least two clinic visits: a baseline visit before taking naltrexone, and at least one follow-up visit while on the drug.
Median patient age was 45.4 years, 67% were female. Most patients were fully vaccinated for COVID-19 (85.2%) and had been infected with an Omicron variant (70.9%). Median time from COVID-19 infection to naltrexone start was 606 days, initial median number of symptoms was 12, and patients’ initial seven-symptom median composite score was 20. The median final naltrexone dose was 4 mg.
More than half of patients reported reduced daily activity from long COVID (55.7%), with another 24.3% reporting struggles with normal daily activities, and 8.3% reporting that they were incapacitated and bedridden.
Patients saw significant improvements across a range of individual symptoms, with adjusted mean annual changes as follows:
- Fatigue: -0.90 (95% CI -1.36 to -0.44, P<0.001)
- Brain fog: -1.27 (95% CI -1.84 to -0.69, P<0.001)
- Unrefreshing sleep: -1.06 (95% CI -1.59 to -0.53, P<0.001)
- Difficulty sleeping: -1.01 (95% CI -1.63 to -0.39, P=0.001)
- Post-exertional malaise: -1.44 (95% CI -2.11 to -0.77, P<0.001)
Patients didn’t see significant improvements in headache or lightheadedness.
Aflak acknowledged that the study’s lack of a control group as a comparison creates concerns that natural progression of long COVID or concurrent treatments could confound some of the observations.
