Effect of low-dose naltrexone for long COVID: a systematic review and meta-analysis.

OBJECTIVE

Long covid is a debilitating chronic condition, and the effect of low-dose naltrexone (LDN) on its symptoms is unclear. We aimed to determine the effectiveness of LDN on symptoms of long covid.

DESIGN

Systematic review and meta-analysis.

DATA SOURCES: PubMed, Embase and Cochrane Library for published studies; ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) for registered ongoing studies were searched through 5 May 2026.

ELIGIBILITY CRITERIA: We included randomised controlled trials and pre-post studies of patients with long covid reporting on fatigue, quality of life, cognitive symptoms or function and other long covid symptoms.

DATA EXTRACTION AND SYNTHESIS: Two independent reviewers used standardised methods to search, screen and select included studies. Risk of bias was assessed using the Newcastle-Ottawa Scale. Meta-analysis was conducted using random effects models.

RESULTS

Of 397 titles and abstracts screened, no randomised controlled trials were identified. Four observational pre-post studies from the USA and Ireland (n=155) met inclusion criteria. LDN doses varied from 1 mg/day to 6 mg/day. Pooled pre-post analyses showed moderate effects for reducing fatigue (Hedges' g=-0.74; 95% CI -1.11 to -0.37; p<0.001), brain fog (Hedges' g=-0.53; 95% CI -1.01 to -0.05; p=0.03) and improving sleep quality (Hedges' g=-0.60; 95% CI -0.91 to -0.30; p=0.0001), and large effects for pain (Hedges' g=-0.93; 95% CI -1.29 to -0.57; p<0.001) and daily functioning (Hedges' g=-0.93; 95% CI -1.29 to -0.57; p<0.0001) in favour of LDN. Heterogeneity ranged from 0% to 62%. No serious adverse events were reported in the two studies that assessed safety.

CONCLUSION

Limited evidence from small pre-post studies suggests LDN may improve fatigue, cognition, sleep, pain and functioning in long covid. However, certainty of evidence is low. Well-powered trials are needed to confirm efficacy, determine dosing and duration and identify subgroups most likely to benefit.

TRIAL REGISTRATION: https://doi.org/10.17605/OSF.IO/C2VKX.