Why this trial exists
Children and adolescents with Long COVID are currently facing two realities. Many receive no treatment at all. Others are given medications developed for adults or borrowed from other conditions, without research showing if or how those medications work in children with Long COVID specifically. Families and doctors are often forced to make hard decisions with very little information.
The pediatric low-dose naltrexone (LDN) trial within RECOVER-TLC is one of the first studies designed to change that. It is testing LDN directly in children and adolescents with Long COVID, starting at a dose of 1.5 mg and slowly increasing to 4.5 mg if the child is doing well.
Researchers are testing LDN because earlier studies and doctors’ experience suggest it may help with Long COVID symptoms. This trial looks at how children and teens respond to the medication, whether it helps, and whether it is safe and well tolerated.
Questions about dosing
Concerns have been raised about whether children with Long COVID may be more sensitive to medication and may benefit from starting at a lower dose than 1.5 mg or increasing more slowly. These concerns are based primarily on patient experience and clinical observations in the adult Long COVID and ME/CFS communities, where even low doses have reportedly triggered stronger side effects, post-exertional symptom flares, or ‘crashes’ in some patients.
Long Covid Families looked closely at these concerns. We reviewed the pediatric evidence and the trial protocol. Below is what the research shows about LDN in children, how this trial is set up, and where we stand on the design.
How the trial works
Dosing schedule
The trial starts LDN at 1.5 mg. If a child is tolerating it well, the dose increases to 3.0 mg the following week, then 4.5 mg the week after. The protocol also allows for a slower pace if a child needs more time at a given dose.
Dose decisions
The research team monitors each child’s symptoms and side effects during the trial. If the medication is not well tolerated, the dose can be lowered, paused, or stopped. A child who cannot tolerate a higher dose can stay at a lower one.
Based on real-world pediatric prescribing
The dosing approach in this trial matches how doctors already prescribe low dose naltrexone for children with Long COVID. The trial tests that approach in a more structured, closely monitored setting.
If a child stops the medication
If a child stops taking the medication, they do not automatically leave the study. They can continue follow up visits so researchers can still include their outcomes in the study results.
How medication is made
Outside of research studies, low dose naltrexone is often prepared by specialized pharmacies, which can sometimes lead to small differences in the amount of medication from one dose to the next.
For RECOVER-TLC, the medication is made specifically for the trial using stricter manufacturing standards. This helps make sure children receive a consistent, verified amount of medication throughout the study.
Why RECOVER selected 1.5 mg
The study team weighed concerns about medication sensitivity in children before settling on 1.5 mg. Two factors drove the decision.
First, there is limited research on ultra low doses of naltrexone below 1.5 mg.
Second, doses below 1.5 mg could not be made reliably enough to meet the trial’s quality standards. Naltrexone reacts to water and temperature, which makes it harder to ensure every dose contains the same amount of medication.
Available pediatric data also helped guide the decision.
What early pediatric data shows
A 2026 preprint study by Villatoro and colleagues followed 62 children and adolescents with Long COVID who were prescribed LDN. Many were prescribed LDN for symptoms that included post exertional malaise, or PEM. PEM is a worsening of symptoms after physical, mental, or emotional activity. It can happen right away or be delayed.
More than half of the children in the study, 56.5%, had PEM as an ongoing symptom. Many also had fatigue, brain fog, and autonomic symptoms, such as problems with heart rate, dizziness, or temperature regulation. This was not a low symptom group.
Most (75%) continued using LDN. Sixteen patients stopped taking LDN due to the following:
- 7 because it was not helping
- 3 because their symptoms improved
- 4 because of side effects (6% of the total group of 62 children)
- 2 for reasons that were not reported
One line from the Villatoro paper has been cited as a reason to be concerned: “Medication discontinuation was attributed to perceived lack of benefit (43.8%) or side effects (25.0%).”
At first glance, that sounds like 25% of all 62 children had to stop LDN because of side effects. However, those percentages apply only to the 16 children who had already discontinued taking LDN. That is, 25% means 4 of 16 children discontinued taking LDN. Of the total group of 62 children, only 4, or about 6%, stopped because of side effects from LDN.
That rate is consistent with what clinicians often see when using other medications to treat chronic illness in children and does not, on its own, suggest an unusual pattern of harm.
Side effects, PEM, and trial safeguards
Looking at the full cohort of 62 children, 71% reported no adverse effects from LDN. Among those who did report side effects, the most common were vivid dreams and insomnia, each affecting 9.7% of patients. The study did not report worsening PEM as a side effect or as a documented reason children stopped the medication.
The trial has a clear plan for managing side effects. Participants track symptoms throughout the study using a remote diary, and the research team monitors changes in fatigue, energy, mood, sleep, and post-exertional malaise. If a child has worrisome side effects, the dose can be lowered, paused, or stopped. To reduce the risk of vivid dreams and insomnia, children will take the medication in the morning with breakfast.
An independent safety board also reviews the trial data throughout the study. If they see a pattern that concerns them, they can change the protocol or stop the trial.
Dropout rates and trial validity
A separate concern has been raised that the LDN trial could see unusually high dropout rates because of medication intolerance. This matters because high dropout rates can threaten the validity of a clinical trial, especially when children leave before researchers can measure the study’s main outcomes. Many researchers view dropout rates approaching or exceeding 20% as a concern.
In this study, stopping the medication is not the same as dropping out. Children who stop taking LDN are encouraged to remain in the trial for follow-up visits so their outcomes and any side effects are still captured.
Some have worried that side effects could cause many children to stop the medication. The available pediatric evidence does not suggest that. In the Villatoro Long COVID cohort, only about 6 percent of patients stopped LDN due to side effects. Most reported no side effects at all, and the medication was described as generally well tolerated.
This pattern matches what other pediatric studies have found. Studies in Crohn’s disease and chronic pain have similarly described LDN as generally well tolerated by children, with relatively low rates of discontinuation due to side effects. Those conditions share some symptoms with pediatric Long COVID, including abdominal pain, fatigue, and muscle or joint pain.
The study design was also informed by the pediatric use of naltrexone in autism spectrum disorder, another population known to be sensitive to medication side effects. In those studies, naltrexone has been used safely at doses much higher than those used in RECOVER-TLC. This evidence contributed to the broader pediatric safety context considered during trial development.
Taken together, these data do not support the idea that LDN typically causes unusually high rates of children stopping because of side effects.
How community shaped this work
As part of forming our position on RECOVER-TLC, Long Covid Families looked at how community perspectives were included during trial development and whether that input was reflected in the final study design.
Good research starts with the people living with the condition, and their input needs to be built in from the beginning. The trial included community participation throughout protocol development. A strategic working group brought together pediatric clinicians, pharmacology experts, parents of children with Long COVID, and community advocates.
Community members then reviewed and commented on a public synopsis of the protocol, and that feedback led to concrete changes in the study design. Those changes included additions to neurocognitive assessment, measures related to post-exertional malaise, expanded subgroup analyses (including for POTS, dysautonomia, ME/CFS, and MCAS), greater accessibility supports, and additional study procedures.
Long Covid Families has been involved in the LDN trial since early in its development. Members participated in the RECOVER-TLC workshop, and the president of Long Covid Families joined as a panelist.
Not all recommendations could be implemented. Final decisions reflected scientific, manufacturing, and safety constraints.
Our position
The Long COVID community holds diverse perspectives on research priorities and trial design. We offer this analysis as part of an ongoing conversation about how best to serve children.
Treatment decisions for children with Long COVID should be grounded in research that directly includes them. Adult experience and evidence from related conditions can help guide research, but they should not override emerging data from children with Long COVID themselves.
The RECOVER-TLC LDN trial is based on current pediatric research. This includes how LDN is being used and tolerated in children with Long COVID, and how it has been used in children with related conditions.
Long Covid Families supports the RECOVER-TLC LDN trial as an important and appropriately designed study for children with Long COVID. Our position is based on the available evidence and on input from families of children with Long COVID, along with clinicians and researchers with expertise in pediatric Long COVID and ME/CFS.
Sources
- Information on RECOVER‑TLC trial design, dosing, titration, safety monitoring, and family‑facing procedures was provided by RECOVER‑TLC principal investigators, pediatric researchers, and clinicians.
- Bell, M. L., Kenward, M. G., Fairclough, D. L., & Horton, N. J. (2013). Differential dropout and bias in randomised controlled trials: When it matters and when it may not. BMJ, 346, e8668.
- Ewig, C. L. Y., Wong, K. S., Chan, P. H., Leung, T. F., & Cheung, Y. T. (2022). Chronic medication use and factors associated with polypharmacy among outpatient pediatric patients. Journal of Pediatric Pharmacology and Therapeutics, 27(6), 537–544.
- Smith, J. P., Field, D., Bingaman, S. I., Evans, R., & Mauger, D. T. (2013). Safety and tolerability of low‑dose naltrexone therapy in children with moderate to severe Crohn’s disease: A pilot study. Journal of Clinical Gastroenterology, 47(4), 339–345.
- Stancil, S. L., et al. (2021). Developmental considerations for the use of naltrexone in children and adolescents. Journal of Pediatric Pharmacology and Therapeutics, 26(7), 675–695.
- Theriault, C., Oyelola, O., & Zempsky, W. T. (2023). The efficacy of low‑dose naltrexone in pediatric chronic pain: A retrospective analysis. The Journal of Pain. Advance online publication.
- U.S. Food and Drug Administration. (n.d.). Compounding and the FDA: Questions and answers. U.S. Food and Drug Administration.
- Villatoro, C., Yonts, A. B., Barter, T., Mohandas, S., & Malone, L. A. (2026). Low dose naltrexone prescribing practices for children and adolescents with long COVID [Preprint]. medRxiv.
