Low-Dose Naltrexone (LDN)

What low-dose naltrexone is

Naltrexone blocks opioid receptors. In Germany it is approved as a 50 mg tablet to support abstinence after opioid or alcohol dependence. LDN uses the same active substance in a fraction of this amount; there is no ready-made medicinal product for it, and the pharmacy prepares it as a compounded medicine on a doctor’s prescription.

The interest is understandable: many people with chronic pain or long COVID have few effective options, and LDN is inexpensive and usually well tolerated. That is exactly why a close look at what the controlled studies show is worthwhile.

How it works

There are two explanatory approaches. The first: at a low dose, naltrexone occupies the opioid receptors only briefly, and the body responds with a counter-regulation and more endogenous endorphins. The second: LDN dampens inflammatory signals in the microglia, the immune cells of the nervous system, independently of the opioid receptors (Younger 2014).

Both approaches are plausible and have been investigated in the lab, but have not been directly measured in humans. The mechanism alone does not yet imply a benefit in a particular disease.

What the studies show

Younger 2013: the study where much of it began

Younger and colleagues gave 31 women with fibromyalgia, double-blind and in alternating order, 4.5 mg of naltrexone daily or placebo and had them record their pain daily. Pain fell more on LDN (28.8 versus 18.0 percent, p = 0.016). Response was defined as less pain plus less fatigue or fewer sleep problems; this was achieved by 32 percent on LDN and 11 percent on placebo (p = 0.05). The authors themselves called for larger parallel-group studies.

FINAL 2024: 99 women, no difference in pain

The Danish FINAL trial randomized 99 women with fibromyalgia to 6 mg of naltrexone or placebo, 12 weeks, double-blind. Pain fell in both groups, by 1.3 and 0.9 points; the difference of 0.34 points was not significant (p = 0.27). No one was lost to the analysis. The authors saw a possible advantage for memory problems and recommended investigating this further (Due Bruun 2024).

INNOVA 2026: one year of follow-up

The Spanish INNOVA trial gave 98 women with fibromyalgia 4.5 mg of LDN or placebo in addition to their existing treatment and followed them for 12 months. After 3 months, pain fell by 0.33 points on LDN and by 0.64 points on placebo; the difference was not significant (p = 0.236). After 6 and 12 months there was also no clinically relevant advantage, but LDN was well tolerated (Rodríguez-Freire 2026).

Long COVID: so far only before-and-after studies

A systematic review with a search up to May 2026 found not a single randomized trial, but four before-and-after studies from the US and Ireland with 155 people in total. In these, fatigue, pain and brain fog decreased and sleep improved. Without a control group, this cannot be separated from the natural course and the placebo effect; the authors rate the certainty of the conclusion as low (Byambasuren 2026).

The large review: 105 studies

A 2026 review evaluated 105 studies in humans, including 15 randomized ones, ranging from pain to autoimmune diseases to bowel and skin diseases. Its conclusion: early positive findings from uncontrolled studies were rarely confirmed in placebo-controlled trials. LDN is safe, inexpensive and well tolerated, it says, and can have a pragmatic place in treatment-resistant cases if its experimental status is discussed openly (Gouda 2026).

Where the data stop

• A robust pain effect in fibromyalgia. The small early studies and the meta-analysis show an advantage, the two largest randomized trials do not.
• A benefit in long COVID. So far there are only before-and-after studies without a control group. Whether LDN achieves more there than time and expectation is open.
• A benefit in autoimmune diseases in general. For Crohn’s disease there is a signal from a study with 34 adults; for many other diseases for which LDN is recommended, there are only case reports and small feasibility studies.
• The mechanism of action in humans. Endorphin counter-regulation and microglia dampening are hypotheses. Direct measurements in humans that confirm one of them are lacking.

Status, approval and legal

In Germany, naltrexone is prescription-only. It is approved as a 50 mg tablet to support abstinence in alcohol dependence and after opioid dependence, embedded in a treatment program.

For the low dose there is neither a ready-made medicinal product nor an approved indication. LDN is prescribed by doctors as a compounded medicine and prepared in the pharmacy; any use in fibromyalgia, long COVID or autoimmune diseases is off-label. No dosage can be derived from this; it belongs in the doctor’s prescription.

Safety

In the controlled studies LDN was well tolerated: side effects occurred about as often as under placebo, and serious side effects were rare and not more frequent. Vivid dreams and nausea were somewhat more frequent (Vatvani 2024).

The most important point is the interaction with opioids. Naltrexone blocks their effect; according to the summary of product characteristics of the approved 50 mg tablet, it must not be used in people receiving opioid painkillers or other opioid-containing medicines, and not in opioid dependence without completed withdrawal, because withdrawal symptoms may then occur. It is also not indicated in severe liver or kidney disease. Anyone taking painkillers from this group should coordinate LDN with a doctor.

Sources

• Younger J et al., Arthritis Rheum 2013 – low-dose naltrexone in fibromyalgia, double-blind crossover study with 31 women
• Younger J et al., Clin Rheumatol 2014 – LDN as a possible anti-inflammatory agent in the nervous system via microglia, review
• Due Bruun K et al., Lancet Rheumatol 2024 – FINAL, 6 mg naltrexone versus placebo in 99 women with fibromyalgia, RCT
• Rodríguez-Freire C et al., Eur J Pain 2026 – INNOVA, LDN versus placebo over 12 months in 98 women with fibromyalgia, RCT
• Vatvani AD et al., Korean J Pain 2024 – meta-analysis, 4 RCTs with 222 fibromyalgia patients
• Parker CE et al., Cochrane Database Syst Rev 2018 – LDN for induction of remission in Crohn’s disease, 2 RCTs with 46 participants
• Byambasuren O et al., BMJ Open 2026 – LDN in long COVID, systematic review: no RCTs, 4 before-and-after studies with 155 people
• Gouda AHK et al., Adv Ther 2026 – Low-Dose Naltrexone: What is the Evidence? Review of 105 studies, including 15 RCTs
• Summary of product characteristics, Naltrexon-HCl neuraxpharm 50 mg film-coated tablets – indications and contraindications
• German Prescription Drugs Ordinance (AMVV), Annex 1 – naltrexone prescription-only