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Low-Dose Naltrexone (LDN)

Updated · 27 sources · Editorial policy

Low-dose naltrexone (LDN) is naltrexone, an opioid-blocking drug, taken at a small fraction of its approved dose, usually around 4.5 mg a day. At the standard 50 mg dose, naltrexone is FDA-approved to treat alcohol dependence and to block the effects of opioids. At low doses it is prescribed off-label for fibromyalgia, Crohn’s disease, multiple sclerosis, long COVID and other conditions.

The most important fact: no low-dose naltrexone product is approved for any condition, and the controlled trials are few and small. A 2026 review of 105 LDN studies found only 15 randomized trials and concluded that early positive results were rarely confirmed by placebo-controlled trials (Gouda et al., Adv Ther 2026). LDN is mostly supplied by compounding pharmacies.

This page summarizes what the naltrexone label, the clinical trials and the systematic reviews report. It is for education only and is not medical advice.

Property Detail
Drug class Opioid receptor antagonist (blocks opioid receptors)
Approved products Naltrexone 50 mg tablets (generics); Vivitrol 380 mg monthly injection; Contrave (naltrexone + bupropion)
Approved uses (standard dose) Alcohol dependence; blocking the effects of opioids; preventing relapse to opioid dependence (Vivitrol)
Low-dose range in studies Typically 0.5–6 mg/day; 4.5 mg/day most common
Route Oral
Half-life (label, 50 mg) Naltrexone ≈4 h; main active metabolite 6-β-naltrexol ≈13 h
LDN status Off-label; not FDA-approved at any low dose; usually compounded
US controlled status Not a controlled substance; DailyMed lists DEA schedule as none (label)
WADA status Not named on the WADA 2026 Prohibited List

What it is

Naltrexone is a synthetic relative of the opioid oxymorphone. Its nitrogen atom carries a cyclopropylmethyl group instead of a methyl group, which removes all opioid-agonist activity and makes it a “pure” antagonist (naltrexone tablet label). It is closely related to naloxone, the opioid-overdose reversal drug.

Naltrexone was first approved in the US in 1984 (Vivitrol label). Off-label low-dose use began in the 1980s in patients with HIV/AIDS, and it later spread to pain, autoimmune and post-infectious conditions (Gouda et al., Adv Ther 2026).

Standard dose vs low dose

Product or use Naltrexone dose Source
Alcohol dependence (tablets) 50 mg once daily Tablet label
Opioid blockade (tablets) 25 mg first dose, then 50 mg/day; label alternatives include 100 mg every other day or 150 mg every third day Tablet label
Vivitrol (extended-release injection) 380 mg intramuscular every 4 weeks Vivitrol label
Contrave (weight management) 32 mg/day naltrexone with 360 mg/day bupropion at full dose Contrave label
Low-dose naltrexone (off-label) Usually 4.5 mg/day; 1–6 mg/day in trials Trials below

At 4.5 mg, LDN is less than a tenth of the standard 50 mg tablet dose.

Proposed low-dose mechanisms

At the standard dose, naltrexone competes with opioids at their receptors. The label states that 50 mg blocks the effects of 25 mg of intravenous heroin for up to 24 hours (tablet label). Two different ideas are offered for why a much lower dose might help in other diseases:

  • Rebound of the body’s own opioids. A short, partial block of opioid receptors may trigger a compensatory rise in endogenous opioids such as met-enkephalin (also called opioid growth factor). This idea comes mainly from mouse studies of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, in which LDN restored serum enkephalin levels and reduced disease signs (Zagon & McLaughlin, Exp Biol Med 2018).
  • Calming immune cells in the nervous system. In rats and in cell lines, naloxone and naltrexone isomers blocked toll-like receptor 4 (TLR4), a receptor that activates microglia (immune cells of the brain and spinal cord), and reversed nerve-injury pain in rats when infused continuously (Hutchinson et al., Eur J Neurosci 2008).

Neither mechanism has been shown to explain a clinical benefit in people. The 2026 review describes the proposed mechanisms as largely theoretical, with little high-quality evidence of relevance to human disease (Gouda et al., Adv Ther 2026).

Pharmacokinetics

The label data come from standard doses (50–200 mg). The label does not describe pharmacokinetics at low doses.

Parameter Value (naltrexone tablet label)
Absorption ≈96% absorbed from the gut
Oral bioavailability 5–40%, due to heavy first-pass metabolism in the liver
Time to peak Within 1 hour (naltrexone and 6-β-naltrexol)
Main active metabolite 6-β-naltrexol
Elimination half-life ≈4 h (naltrexone); ≈13 h (6-β-naltrexol)
Excretion Mainly urine (53–79% of the dose as parent drug and metabolites)
Liver cirrhosis Naltrexone exposure (AUC) ≈5-fold higher in compensated and ≈10-fold higher in decompensated cirrhosis

Approved medical use

The naltrexone tablet label approves 50 mg tablets for the treatment of alcohol dependence and for blocking the effects of opioids taken from outside the body (tablet label). In one 12-week label trial in 104 alcohol-dependent patients, abstention rates were 51% with naltrexone vs 23% with placebo, and relapse was 31% vs 60%.

Vivitrol, a monthly injection, is approved for alcohol dependence in patients who can stop drinking before starting, and for preventing relapse to opioid dependence after detoxification (Vivitrol label).

Contrave (naltrexone extended-release plus the antidepressant bupropion, approved in 2014) is a separate product for long-term weight management in adults with obesity, or overweight with at least one weight-related condition. It carries a boxed warning about suicidal thoughts and behaviors linked to its antidepressant component (Contrave label). It is not low-dose naltrexone, and this page does not cover it further.

None of these products is approved at low doses. LDN is off-label, and its supply is limited mainly to compounding pharmacies (Gouda et al., Adv Ther 2026). Compounded drugs are not FDA-approved, which means FDA does not check their safety, effectiveness or quality before they are sold (FDA).

What the research shows

A daily dose of 4.5 mg is the one used most often (Gouda et al., Adv Ther 2026). Many trials were small crossover studies (each person takes both drug and placebo in turn).

Fibromyalgia

Fibromyalgia has the most LDN trials. Two small early studies from Stanford were positive. Three larger, later trials did not show a meaningful benefit over placebo.

Trial Design, n Dose and duration Main result
Younger & Mackey, Pain Med 2009 Single-blind crossover, 10 women 4.5 mg/day, 8 weeks Over 30% greater symptom reduction than placebo
Younger et al., Arthritis Rheum 2013 Double-blind crossover, 31 women 4.5 mg/day Pain fell 28.8% on LDN vs 18.0% on placebo (P = 0.016); no effect on fatigue or sleep
Bested et al., Pain Rep 2023 Double-blind crossover, 58 patients 4.5 mg/day, 3 weeks per period No difference in fibromyalgia impact score (P = 0.3) or pain ratings (P = 0.4)
Due Bruun et al., Lancet Rheumatol 2024 Double-blind parallel RCT, 99 women 6 mg/day, 12 weeks Pain difference −0.34 points on a 0–10 scale (95% CI −0.95 to 0.27; p = 0.27)
Rodríguez-Freire et al., Eur J Pain 2026 Double-blind parallel RCT, 98 women 4.5 mg/day, 12 months Pain at 3 months: −0.33 on LDN vs −0.64 on placebo (p = 0.236)

A 2024 meta-analysis of 4 trials (222 patients) reported a pain reduction of 0.86 points with LDN (Vatvani et al., Korean J Pain 2024). The Danish trial group later re-analyzed the same trials. They found extraction errors and pooling of different pain scales, and their corrected analysis showed no significant difference in pain between LDN and placebo. A modestly higher rate of patients with at least 30% pain relief remained (odds ratio 2.47, 95% CI 1.10–5.54) (Bruun et al., Korean J Pain 2026).

Crohn’s disease

Most Crohn’s data come from one research group at Penn State, whose lead investigators hold a patent on naltrexone for inflammatory bowel disease (Smith et al., Dig Dis Sci 2011).

Trial Design, n Dose and duration Main result
Smith et al., Am J Gastroenterol 2007 Open-label pilot, 17 adults 4.5 mg/day, 12 weeks 89% responded, 67% reached remission (no placebo group)
Smith et al., Dig Dis Sci 2011 Double-blind RCT, 40 adults enrolled 4.5 mg/day, 12 weeks 70-point drop in disease activity: 88% vs 40% (p = 0.009); endoscopic response 78% vs 28%
Smith et al., J Clin Gastroenterol 2013 Randomized pilot, 14 children 0.1 mg/kg/day, 8 weeks + 8 weeks open-label No serious adverse events; disease activity score fell from 34.2 to 21.7
van de Pol et al., Dig Dis Sci 2026 Double-blind multicenter RCT, 41 adults; stopped early for futility 4.5 mg/day, 12 weeks Endoscopic remission 5.6% vs 18.8% (p = 0.233); clinical remission 22.2% vs 70.0% favoring placebo; less fatigue on LDN

A 2018 Cochrane review pooled the adult and pediatric trials (46 participants). Clinical remission was 30% on LDN vs 18% on placebo, a non-significant difference (RR 1.48, 95% CI 0.42–5.24). The review rated the evidence as low quality and found it insufficient for firm conclusions (Parker et al., Cochrane 2018). The 2026 Dutch trial, independent of the original group, found no benefit for remission.

Multiple sclerosis

Two placebo-controlled crossover trials gave mixed results:

  • UCSF, 2010. 80 people enrolled and 60 completed 8 weeks of 4.5 mg nightly. LDN improved mental-health quality-of-life scores (for example, 3.3 points on the SF-36 mental component, p = 0.04). The authors noted that dropouts and data errors reduced the trial’s statistical power (Cree et al., Ann Neurol 2010).
  • Iran, 2010. 96 people with relapsing-remitting or secondary progressive MS in a 17-week trial. No meaningful differences in pain, energy, emotional well-being or overall quality of life. The authors concluded that efficacy was “under question” (Sharafaddinzadeh et al., Mult Scler 2010).

No trial has tested whether LDN slows MS relapses or disability progression.

Long COVID

As of May 2026, a systematic review found no completed randomized trials of LDN in long COVID. It pooled 4 uncontrolled before-and-after studies (155 people) and found improvements in fatigue, brain fog, sleep, pain and daily function, but rated certainty as low (Byambasuren et al., BMJ Open 2026).

In one of those studies, 52 patients in Dublin were prescribed 1 mg/day for a month and then 2 mg/day. 36 completed the follow-up questionnaire, and 6 of 7 symptom scores improved. There was no placebo group (O’Kelly et al., Brain Behav Immun Health 2022). Uncontrolled designs like this cannot separate a drug effect from natural recovery or placebo response.

A 160-person placebo-controlled trial of LDN for post-COVID fatigue in British Columbia was completed in February 2026. No results had been posted on its registry entry at the time of writing (ClinicalTrials.gov NCT05430152).

Other conditions

The 2026 review also lists single small RCTs in Gulf War illness, lichen planopilaris (a scarring scalp condition), depression and high-grade glioma. In the largest of these, 110 patients with glioma took 4.5 mg/day for 16 weeks alongside chemoradiation, and fatigue and quality of life did not differ from placebo (Gouda et al., Adv Ther 2026). The rest of the evidence for LDN is mostly case reports and uncontrolled series.

Side effects and risks

Tolerability at low dose

In the trials, LDN was well tolerated and side effects were close to placebo rates:

Across 89 placebo-controlled trials of oral naltrexone at any dose (11,194 participants, excluding opioid users), naltrexone did not raise the risk of serious adverse events (RR 0.84, 95% CI 0.66–1.06) (Bolton et al., BMC Med 2019).

Interaction with opioids

Naltrexone blocks opioid painkillers, cough medicines and antidiarrheals. The label contraindicates it in people taking opioid analgesics, people dependent on opioids (including those on methadone or buprenorphine), and people in opioid withdrawal (tablet label). In opioid-dependent people, an antagonist can cause sudden, severe withdrawal that may need hospital care.

The effect of LDN on opioids may also go the other way. In a case report, a man taking LDN for MS became unresponsive after a single 5 mg dose of oxycodone and needed naloxone and an ICU stay. The authors suggest long-term LDN may make people more sensitive to opioids (Leonard et al., Am J Emerg Med 2017). This is one case and has not been studied systematically.

The label also warns that after naltrexone is stopped, people with a history of opioid use may respond to lower opioid doses than before, which raises the risk of overdose.

Liver

Liver injury with naltrexone is dose-related. In a placebo-controlled study at 300 mg/day (the label calls this about five times the recommended dose), 19% (5/26) developed transaminase elevations vs 0% on placebo (tablet label). The label also reports hepatitis cases at standard doses and advises stopping the drug if signs of acute hepatitis appear. The low-dose Crohn’s pilot reported no laboratory abnormalities over 12 weeks.

Mood

The label reports depression, suicidal thoughts and suicide attempts after marketing in people treated for opioid dependence, without a proven causal link. In alcohol trials, new-onset depression occurred in 0–15% on naltrexone vs 0–17% on placebo.

Pregnancy and children

There are no adequate studies of naltrexone in pregnant women. In rats and rabbits, high doses increased early fetal loss. The label states that safety in patients under 18 has not been established (tablet label).

Compounding quality

Because LDN is compounded, the product’s strength and formulation can vary between pharmacies, and the 2026 review notes that inconsistent compounded formulations add uncertainty when comparing studies (Gouda et al., Adv Ther 2026).

Key takeaways

  • Approved at 50 mg, not at low dose. Naltrexone is FDA-approved for alcohol and opioid dependence at 50 mg/day (or 380 mg monthly by injection). LDN at 1–6 mg/day is off-label and usually compounded.
  • The mechanism is a hypothesis. Endorphin rebound and TLR4 blockade come mainly from animal and cell studies and have not been shown to explain benefits in people.
  • Fibromyalgia trials have turned negative. Two small early crossover trials were positive, but three larger trials (58–99 patients) found no meaningful pain benefit over placebo.
  • Crohn’s and MS evidence is small and mixed. A 34–40-person Crohn’s RCT was positive, but a 2026 independent trial was stopped for futility. MS trials showed at most quality-of-life changes.
  • No randomized long COVID results yet. Only uncontrolled before-and-after studies exist; a 160-person RCT has finished but not reported.
  • Usually well tolerated, but it blocks opioids. Side effects in trials resembled placebo, with more vivid dreams and nausea. The naltrexone label contraindicates it with opioid painkillers and in opioid dependence.

Sources

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