Low-dose naltrexone use for the management of post-acute sequelae of COVID-19 2023 Bonilla et al

[Andy]

Highlights

• The off-label use of low-dose naltrexone (LDN) is a potential drug intervention for the management of post-COVID conditions.
  
  
• LDN has anti-inflammatory and immunomodulatory properties which may benefit those with PASC where persistent inflammation is the causative pathway.
  
  
• LDN warrants testing in rigorous randomized, placebo-controlled clinical trials.

Abstract

The global prevalence of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) stands at approximately 43 % among individuals who have previously had acute COVID-19. In contrast, in the United States, the National Center for Health Statistics (NCHS) estimates that around 11 % of individuals who have been infected with SARS-CoV-2 go on to experience long COVID. The underlying causes of PASC remains under investigation, and there are no currently established FDA-approved therapies. One of the leading hypotheses for the cause of PASC is the persistent activation of innate immune cells with increase systemic inflammation.

Naltrexone is a medication with anti-inflammatory and immunomodulatory properties that has been used in other conditions that overlap with PASC. We performed a retrospective review of a clinical cohort of 59 patients at a single academic center who received low-dose naltrexone (LDN) off-label as a potential therapeutic intervention for PASC. The use of LDN was associated with a fewer number of symptoms, improved clinical symptoms (fatigue, post-exertional malaise, unrefreshing sleep, and abnormal sleep pattern), and a better functional status. This observation warrants testing in rigorous, randomized, placebo-controlled clinical trials.

Open access, https://www.sciencedirect.com/science/article/pii/S1567576923012912

 

[Evergreen]

Found this thread as the Bonilla et al. paper this thread is about was cited by Charlton et al. 2026 being discussed here as evidence for the use of LDN in long covid.

Bonilla et al.'s study has no control group, so improvement over time could be interpreted as improvement due to LDN. They did acknowledge this, and did something to check it which is good, but no replacement for a control group:

It's important to note that the extent of recovery can vary significantly and often time depend. To mitigate the time factor on recovery in our study population, we compared the effect of LDN in individuals with ≥365 days of symptoms to those with <365 days of symptoms. In this PASC cohort, the duration of symptoms did not affect the clinical response to LDN for the selected symptoms. Therefore, this retrospective EHR review of patients seen in our PASC clinic who received LDN suggests a potential benefit of LDN in some individuals with PASC that warrants further testing in rigorous, randomized, placebo-controlled clinical trials.

They also address the lack of a dose response relationship:

Finally, we did not find a correlation between LDN dose and changes in the seven responsive clinical symptom scores. This finding could be explained by multiple mechanistic pathways proposed in patients with long COVID (micro-clots, persistent virus, and haywire immune system) [3], [4]. However, we cannot exclude the possibility of a placebo effect that could result in either positive or negative response [29]. A larger study of LDN in 160 participants in a randomized parallel group double-blinded placebo-controlled trial is underway [30].

That "larger study" is Nacul's.

Plenty more to discuss but I just wanted to highlight those two aspects.

 

[Jonathan Edwards]

I am ready to believe that LDN might turn out to show some benefit in ME/CFS (but not holding my breath) but I am prepared to bet 97 pints of good beer it has nothing to do with an infinitesimal 'anti-inflammatory' or 'immuno-modulatory' effect.