Effect of low dose naltrexone for long covid: a systematic review

BackgroundLong 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. MethodsWe searched PubMed, Embase, and Cochrane Library for published studies; ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform for registered ongoing studies from inception to 1 May 2025. Eligible studies were randomised controlled trials or pre-post studies in patients with long covid reporting on fatigue, quality of life, cognition, or other symptoms. Risk of bias was assessed by Newcastle-Ottawa scale. ResultsOf 226 titles and abstracts screened, no randomised controlled trials were identified. Four observational pre-post studies from USA and Ireland (n=155) met inclusion criteria. LDN doses varied from 1mg/d to 6 mg/d. Pooled analyses showed moderate effects for reducing fatigue (Hedges g= -0.74; 95% CI [-1.11, -0.37]; p<0.001), brain fog (Hedges g= - 0.53; 95%CI [-1.01, -0.05]; p=0.03), and improving sleep quality (Hedges g= -0.60; 95%CI [-0.91, -0.30]; p=0.0001), and large effects for pain (Hedges g= -0.93; 95%CI [-1.29, -0.57]; p<0.001) and daily functioning (Hedges g= -0.93; 95%CI [-1.29, -0.57]; p<0.0001) in favour of LDN. Heterogeneity ranged from 0% to 62%. Risk of bias was assessed as low in all four studies. No serious adverse events were reported in the two studies that assessed safety. ConclusionLimited 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 urgently needed to confirm efficacy, determine dosing and duration, and identify subgroups most likely to benefit. Protocol registrationOpen Science Framework https://doi.org/10.17605/OSF.IO/C2VKX