Summary
A Canadian clinical trial has found that low-dose naltrexone (LDN) was safe and generally well tolerated but did not work better than placebo for people with post-Covid fatigue syndrome.
In this study, post-Covid fatigue syndrome was defined by the 2015 Institute of Medicine ME/CFS criteria, but with symptoms lasting for at least three months after a Covid-19 infection.
The trial was led by Dr Luis Nacul and run by the University of British Columbia. It was funded by the Canadian Institutes of Health Research (£400,000) and the ME Association Ramsay Research Fund (£132,000).
What did the trial involve?
The study included 160 adults aged 19 to 69 in British Columbia and Ontario. Participants were randomly assigned to receive either LDN (n=81) or a placebo (n=79) for 16 weeks. Neither the participants nor the research team knew who was receiving the active drug.
LDN treatment started at 1 mg a day and increased to a maximum of 4.5 mg a day if tolerated. To determine effectiveness, researchers measured fatigue severity as the primary outcome and also pain, overall ME/CFS symptom severity, daily step count and quality of life.
What were the results?
After 16 weeks, there was no meaningful difference between the LDN and placebo groups in fatigue, pain, overall symptoms, daily steps or quality of life. In other words, LDN did not provide a clear benefit over placebo on any of the outcome measures.
Serious or more severe adverse events were uncommon. They were reported by 5 people (6.2%) in the LDN group and 3 people (3.8%) in the placebo group. The researchers concluded that doses of up to 4.5 mg a day were well tolerated but did not improve fatigue or any of the other outcome measures when compared with placebo.
What does this mean?
This was a well-designed, double-blind, randomised, placebo-controlled trial. This type of study is considered the most reliable way to test whether a treatment has a genuine effect. A placebo comparison is especially important when symptoms vary naturally and when expectations, extra support during a trial or other factors may affect how people feel.
The negative result adds to evidence from other recent studies suggesting that LDN may not be an effective treatment for ME/CFS, Long Covid or Fibromyalgia. It also means that regulatory bodies such as NICE or Health Canada will not approve the use of LDN on the basis of current evidence.
ME/CFS, Long Covid and Fibromyalgia may include subgroups with different or overlapping disease processes. These results do not rule out the possibility that some individuals may benefit from LDN. The trial measured the average effect across the study group and may not have identified a small subgroup that responds differently.
However, the trial did not show a clear benefit of LDN for any of the trial’s participants. The possibility that some people may respond differently is not evidence that such a subgroup exists. To support approval, trials would need to demonstrate a clear benefit over placebo.
Further analysis of the Canadian trial is expected from Dr Nacul and the team early in 2027. This will include MRI data examining whether there were changes in the brain during treatment with LDN or placebo.
If you are taking LDN
The ME Association is not advising anyone to stop taking prescribed LDN suddenly. If you are taking it, discuss the trial findings with the clinician who prescribed it. Ask whether continuing is appropriate and, if stopping is advised, whether the dose should be reduced gradually. Decisions should take account of possible side effects, personal experience and the financial cost of private or off-label treatment.
Why was LDN being studied?
Naltrexone was developed to treat alcohol and opioid dependence. Standard doses are usually 25–50 mg. LDN is generally prescribed at 1–4.5 mg. It has been suggested that low doses might affect endorphins, pain or inflammation in the nervous system, but these proposed benefits have not been proven for ME/CFS, Long Covid or fibromyalgia.
The ME Association Ramsay Research Fund contributed £132,000 to the trial after being approached in January 2025. The funding helped address recruitment challenges and participant follow-up. Most funding came from the Canadian Institutes of Health Research.
It was important to support a well-designed clinical trial because we needed clear evidence that showed if this drug worked for people with ME/CFS. LDN has been around for a long time and has attracted a degree of popularity, but the anecdotal reports of whether it has any benefit are mixed as are the reports of toleration and of side effects.
LDN would not receive regulatory approval unless it can be shown in trials like this one that it has a clear benefit over placebo. Unfortunately, there has been no benefit shown in this trial or in similar trials to date for ME/CFS, Long Covid, or Fibromyalgia.
Why trials like this matter
People with ME/CFS, Long Covid and Fibromyalgia urgently need effective treatments. Claims based on personal experience can be encouraging, but they cannot show reliably whether a treatment works. Carefully controlled trials help patients and clinicians make better-informed choices and avoid overpromising benefits.
Negative findings are still valuable. They can prevent limited research funds, clinical effort and patients’ money from being directed towards treatments that do not show a clear benefit. They also highlight the need for better biological measures and research into disease subgroups, so future treatments can be targeted more effectively.
Recent LDN trial outcomes
- Post-Covid fatigue syndrome (Post-Covid ME/CFS)
The 2026 University of British Columbia trial (described above) was a 16-week, double-blind, randomised, placebo-controlled study involving 160 participants.
LDN was increased to a maximum of 4.5 mg a day. It did not improve fatigue, pain, daily step count or the other main outcomes when compared with placebo. Further details are available from the pre-print results.
- ME/CFS
A five-year United States research project launched in 2026 is examining LDN specifically for ME/CFS. The planned first stage is a dose-finding study involving 100 participants over two years. A second stage randomised controlled trial involving 200 participants is planned for years three to five and will be registered at a later date.
The project also includes MRI research to investigate whether changes in brain inflammation can be detected in people who respond to treatment. As this work is ongoing, it cannot yet show whether LDN is effective for ME/CFS.
- ME/CFS and Long Covid
A 12-week randomised placebo controlled trial was registered by researchers at Griffith University in Australia in September 2024. The study is shown as an active project on the team's website and we've heard today that it is now recruiting. For more information please contact the research team.
- Long Covid
A 2026 systematic review found that evidence came mainly from four observational before-and-after studies involving 155 participants. Because these studies did not include a randomised placebo comparison, they could not provide firm conclusions about effectiveness.
- Fibromyalgia
Two recent placebo-controlled studies have added to the evidence on LDN for fibromyalgia. The INNOVA study, a 12-month randomised, double-blind trial, did not find a clinically meaningful benefit over placebo for its main pain outcomes, although LDN was generally well tolerated.
The FINAL trial also found no statistically significant reduction in pain across the whole study group. It reported a higher rate of at least 30% pain improvement among a subgroup of women, together with improvements in some secondary measures of memory and cognitive problems. These subgroup findings need cautious interpretation and further confirmation.
Earlier small pilot studies reported that some participants experienced improvements in pain, fatigue or sleep. However, small studies without definitive results cannot establish how well LDN works or identify reliably who may respond.
Russell Fleming
Research Manager,
The ME Association
