A letter describes the human evidence, not the product, the manufacturer, or the intervention's worth.
Grade C: human trials exist, but they are small, mixed or not yet repeated. This is not a finding that it does not work. How to read a grade →
See the full evidence record →Low-Dose Naltrexone (LDN)
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How this letter has changedLatest: October 2026 · Corrected.
The record held C on two pilots presented as trials, one small positive crossover A trial design in which each participant receives both the treatment and the comparison, one after the other, and serves as their own control., one patent-holders' Crohn's trial and a null glioma trial listed as if supportive. Three larger fibromyalgia trials were null on pain (Bested et al., Pain Rep, 2023; PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 38226027; Due Bruun et al., Lancet Rheumatol, 2024; PMID 38258677; Rodriguez-Freire et al., Eur J Pain, 2026; PMID 42385209), the independent Crohn's trial was stopped for futility (van de Pol et al., Dig Dis Sci, 2026; PMID 42701992), the Cochrane review found clinical remission not significant (Parker et al., 2018; PMID 29607497), and the 2025 pooled analysis (Hegde et al., PMID 40540205) found more adverse events than placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received.. Smith et al. 2007 (PMID 17222320) and Younger and Mackey 2009 (PMID 19453963) are relabeled as pilots, Peters et al. 2022 (PMID 35001215) as null, and the narrative review (Li et al., Int Immunopharmacol, 2018; PMID 29885638) is removed from the grade support. The Smith and Zagon patent (PMID 21380937) is stated beside the Crohn's letter. Both indications are C under the rule's own words, a replication The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away. that failed; the headline stays C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).PMID 17222320 PMID 19453963 PMID 21380937 PMID 29607497 PMID 29885638 PMID 35001215 PMID 38226027 PMID 38258677 PMID 40540205 PMID 42385209 PMID 42701992
Every change to a letter on this site is dated and published. The full evidence log →
Low-dose naltrexone uses a small fraction of the usual dose of a drug for addiction. For fibromyalgia pain, one small early study was positive, but three larger studies found no benefit. For Crohn's disease, one small study by people holding a patent on it was positive. A larger outside study was stopped because it was not working.
Opioid receptor antagonist · Immunomodulator · Prescription only
Naltrexone is an opioid antagonist, FDA-approved at 50mg for opioid and alcohol dependence. At roughly one tenth of that dose it produces a brief, transient blockade of opioid receptors that is hypothesized to upregulate endogenous endorphins and dampen neuroinflammation. Small human RCTs Randomized controlled trial: people are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect. support a symptom benefit in fibromyalgia and Crohn's disease. No human trial has tested it against a longevity, mortality, or healthspan endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score..
Why this gradeGrade C, small or unreplicated trials. The reasoning, and what the grade does not cover.
Grade C in both named indications, and the C now rests on larger trials than the record previously cited. Fibromyalgia: one small positive crossover (Younger et al., 2013; PMID 23359310; 31 women) followed by three larger trials null on pain (Bested et al., 2023; PMID 38226027; Due Bruun et al., Lancet Rheumatol, 2024; PMID 38258677; Rodriguez-Freire et al., 2026; PMID 42385209), with a pooled analysis finding a small effect that predates the 12-month trial (Hegde et al., 2025; PMID 40540205). Crohn's disease: one 40-person trial by investigators holding a patent on the use, positive on a 70-point activity-score fall and endoscopic response with clinical remission not significantly different (Smith et al., 2011; PMID 21380937; Parker et al., Cochrane, 2018; PMID 29607497), and an independent multicenter trial stopped for futility (van de Pol et al., 2026; PMID 42701992). The written rule places a failed replication at C, not D on Route 2 Human randomized trials have been run and did not show benefit on the stated outcome. One of the two routes to the lowest letter on EBL's scale., because the early trials did show benefit; it is not B, because the larger trials did not.
WHAT THIS GRADE DOES NOT COVERhigh-grade glioma, where the one trial was null on quality of life and fatigue (Peters et al., 2022; PMID 35001215); long COVID, multiple sclerosis or any other indication, where no randomized trial is cited; people taking opioid analgesics, whose effect naltrexone blocks; and the open-label Everyone in the trial knows which treatment they are receiving, so expectations can shape the results, especially for symptoms people report themselves. and single-blind pilots (PMIDs 17222320, 19453963), which are context and carry no letter.
A grade describes the human evidence for a named use. It is not advice, and it is not a judgment on any individual prescription. How the letters are decided →
As studiedDose, form, population and duration for every use.
Naltrexone 4.5 mg by mouth once daily, usually at night, in the fibromyalgia and Crohn's trials; the FINAL fibromyalgia trial used 6 mg. A compounded dose, roughly a tenth of the 50 mg tablet approved for opioid and alcohol dependence.
A grade describes the intervention that was tested. Where the product on the shelf differs from it, this says so.
The trial that would change this grade.
A positive trial of this shape, supported by further trials, would move this entry to B.
Why the current trials fall short
Each use already has one small positive trial followed by larger or independent trials that did not confirm it. In fibromyalgia, three larger trials found no benefit on pain. In Crohn's disease, the independent multicenter trial was stopped early for futility. A new trial would raise the letter only if it is positive and large enough that, taken together with the trials that found nothing, the benefit still holds.
Why people believe itFour human sources; four published case reports of benefit; two reports of harm.
The case for low-dose naltrexone is that a tiny dose, about a tenth of the dose used to treat addiction, briefly blocks the body's opioid receptors, and supporters believe this calms inflammation. It is cheap, usually well tolerated and widely prescribed off label, and the first small trials in fibromyalgia and Crohn's disease were positive before larger ones were not.
What supporters point to, and what each source actually shows. None of it is enough to move this letter higher; the trial described above under Evidence wanted is what would.
- Human study, no comparison groupIn 17 adults with active Crohn's disease who took low-dose naltrexone for 12 weeks, 89 percent responded and 67 percent went into remission. There was no comparison group, so it cannot show how many would have improved anyway. PMID 17222320
- Human trial, a different useIn a crossover trial in 80 people with multiple sclerosis, 60 of whom finished, 8 weeks of low-dose naltrexone improved several mental health quality-of-life scores. A different use, scored by the patients themselves. A second multiple sclerosis trial, in 96 people, found no difference in quality of life. PMID 20695007
- Population study, not a trialIn Norway's national prescription records, 256 people with inflammatory bowel disease who kept taking low-dose naltrexone were dispensed steroid drugs less often in the two years after starting. People who choose a treatment and stay on it differ from people who stop, so this cannot show the drug caused the change. PMID 29385430
- Population study, not a trialIn the same Norwegian records, people with rheumatoid or seropositive arthritis who kept taking it used 13 percent less of their other arthritis and pain medicines over the next year. The same limit applies: it is not a trial. PMID 30763385
A case report describes what happened to one or a few patients. It cannot show the treatment caused the change, and reports of success are published more often than reports of failure.
- One patient with severe fibromyalgia who had not responded to standard drugs improved on 4.5 mg a day and stayed improved over two years of follow-up. One patient, with no comparison. PMID 40491623
- A 60-year-old with fibromyalgia and severe depression went into remission of both within 10 weeks. Low-dose naltrexone was given together with a higher dose of trazodone and with psychotherapy, so the report cannot say which of the three helped. PMID 35386139
- A fibromyalgia case report whose title proposes low-dose naltrexone as a treatment option. No abstract is indexed, so its findings are not summarized here. PMID 22480625
- A letter describing a child with Crohn's disease of the duodenum treated with low-dose naltrexone. No abstract is indexed, so the outcome is not summarized here. PMID 20014017
- A 66-year-old man on long-term opioid painkillers went into severe opioid withdrawal, with agitation, confusion and a dangerous buildup of acid in the blood, after a first 1 mg dose. Even a low dose blocks opioid painkillers. PMID 40929607
- A man taking low-dose naltrexone for multiple sclerosis became unresponsive after a single 5 mg dose of oxycodone and needed naloxone and a night in intensive care. The authors suggest that long-term use may make the body more sensitive to opioid painkillers. PMID 28410920
Searched PubMed, October 2026: 64 case report record(s) returned. Of the 64 records, three describe fibromyalgia and one describes Crohn's disease, the two uses graded here; they are listed above. Two describe harm and are listed below. The other 58 concern uses not graded here: 14 Hailey-Hailey disease, 14 other skin conditions, 11 other chronic pain conditions, 9 cancer and 10 other conditions, among them Sjogren's syndrome, chronic fatigue and immune disorders. Several mention low-dose naltrexone only as one of many treatments given together.
Naltrexone is FDA-approved at 50mg for opioid and alcohol use disorder. The low-dose regimen discussed here (roughly 1.5 to 4.5mg) is off-label, is not FDA-approved for any inflammatory or longevity indication, and is typically compounded because no commercial low-dose product exists. Concurrent opioid use is an absolute contraindication A condition or medication that makes a treatment unsafe or unsuitable for a particular person. because naltrexone will precipitate withdrawal. EBL presents the published human evidence for educational purposes only. Nothing on this page is medical advice or a recommendation to seek a prescription. It is a decision for a qualified physician who knows your full clinical picture.
Every human RCT of LDN measures a disease or symptom outcome: fibromyalgia pain, Crohn's disease activity, cancer-related quality of life. None measures aging, mortality, or healthspan. The longevity use is an extrapolation from anti-inflammatory and immune-modulating effects, not a tested outcome.
The strongest studies are small, often single-center pilot or crossover designs with a few dozen participants. The signal in fibromyalgia and Crohn's is real and placebo-controlled, but the total human evidence base is thin and has not been confirmed in large multicenter trials.
The anti-aging case rests on transient opioid blockade upregulating endorphins and quieting microglial and neuroinflammatory activity. This is biologically plausible and consistent with the inflammatory-condition data, but plausibility is not a demonstrated longevity benefit.
The human evidenceSix papers, each linked to its PubMed record.
A small placebo-controlled crossover RCT in women with fibromyalgia. Low-dose naltrexone reduced daily pain compared with placebo and was well tolerated. This is the most cited controlled trial in the LDN literature and the strongest single data point for a genuine drug effect, but the endpoint is fibromyalgia pain, not any aging outcome.
A randomized, placebo-controlled trial in adults with active Crohn's disease. Naltrexone improved clinical response and promoted mucosal healing on endoscopy compared with placebo. A rigorous small trial with an objective endpoint, and the clearest evidence of an anti-inflammatory effect in humans. Again, a disease outcome rather than a longevity outcome.
The original single-blind crossover pilot in fibromyalgia that generated the hypothesis later tested in the 2013 RCT. A very small study, useful as the origin of the signal rather than as confirmatory evidence.
An earlier open-label pilot in Crohn's disease reporting symptom improvement. Open-label and uncontrolled, so it is supporting context for the 2011 randomized trial rather than independent proof.
A placebo-controlled trial testing low-dose naltrexone for quality of life in high-grade glioma patients. Included here for completeness as another controlled human study. It does not establish a longevity benefit and is outside the inflammatory conditions where the signal is strongest.
A review of the proposed mechanisms behind LDN in immune-related disease, including transient opioid receptor blockade, endorphin rebound, and toll-like receptor 4 modulation on microglia. A review, not a trial, so it informs the rationale rather than the grade.
The dosing used in practice comes from the trial protocols and clinician experience, not from a powered dose-finding study. Because no commercial low-dose tablet exists, LDN is compounded.
LDN is generally well tolerated at these doses and requires far less monitoring than most prescription longevity compounds. A prescriber should still confirm the essentials:
LDN is off-label and compounded.
Because there is no commercial low-dose product and the use is off-label, LDN requires a prescriber comfortable with the evidence and a compounding pharmacy. Many primary care physicians are unfamiliar with the protocol.
EBL's clinical practitioner network includes physicians experienced with off-label Rx evaluation who will review your full clinical picture, confirm there is no opioid conflict, and monitor appropriately. EBL helps you arrive at that conversation prepared.
Educational use only · Not medical advice · Prescription medication · Consult a qualified clinician
As studied, and the trials
Younger et al. (Arthritis Rheum, 2013; PMID 23359310): 31 women, crossover, pain 28.8 percent lower against 18.0 percent on placebo. Three larger trials were null on pain: Bested et al. (2023; PMID 38226027; 58 patients, crossover), the FINAL trial (Due Bruun et al., Lancet Rheumatol, 2024; PMID 38258677; 99 women, 6 mg) and INNOVA (Rodriguez-Freire et al., 2026; PMID 42385209; 98 women, 12 months). Hegde et al. (2025; PMID 40540205) pool a small fibromyalgia effect (d -0.34) before INNOVA reported. One small positive crossover and three larger nulls is a replication that failed, which the written rule places at C; self-report would cap it at B in any case.
As studied, and the trials
Smith et al. (Dig Dis Sci, 2011; PMID 21380937): 40 adults, 4.5 mg for 12 weeks; a 70-point activity-index fall in 88 against 40 percent and endoscopic response in 78 against 28 percent, while clinical remission was not significantly different (Parker et al., Cochrane, 2018; PMID 29607497; 30 against 18 percent); the investigators hold a patent for naltrexone in inflammatory bowel disease, stated beside the letter. van de Pol et al. (Dig Dis Sci, 2026; PMID 42701992): the independent multicenter trial, stopped for futility, with clinical remission lower on naltrexone than placebo. One positive trial by the patent holders and an independent null: a failed replication, C.
Read the grade that matches your goal. How EBL grades by use →
Primary evidenceEleven papers, each linked to its PubMed record.
FIBROMYALGIA. Younger et al. (Arthritis Rheum, 2013; PMID 23359310): randomized double-blind crossover, 31 women, 4.5 mg nightly; daily pain fell 28.8 percent against 18.0 percent on placebo, with better mood and life satisfaction and no change in fatigue or sleep. Bested et al. (Pain Rep, 2023; PMID 38226027): randomized crossover, 58 patients, 4.5 mg; no clinically relevant difference on the Fibromyalgia Impact Questionnaire or pain ratings. Due Bruun et al. (Lancet Rheumatol, 2024; PMID 38258677), the FINAL trial: 99 women, 6 mg for 12 weeks; pain fell 1.3 points on naltrexone and 0.9 on placebo, a difference of 0.34 (95% CI -0.95 to 0.27), not superior. Rodriguez-Freire et al. (Eur J Pain, 2026; PMID 42385209), INNOVA: 98 women, 4.5 mg for 12 months; pain change -0.33 against -0.64 on placebo, no difference on any secondary outcome. Hegde et al. (Curr Pain Headache Rep, 2025; PMID 40540205): meta-analysis A study that pools the numbers from several trials into one combined estimate. of seven randomized trials; no overall pain effect across chronic pain conditions, a small fibromyalgia effect (d -0.34) in a pooling that predates INNOVA, and more adverse events than placebo (incidence rate ratio 1.4). CROHN'S DISEASE. Smith et al. (Dig Dis Sci, 2011; PMID 21380937): 40 adults with active disease, 4.5 mg for 12 weeks; a 70-point fall in the Crohn's Disease Activity Index in 88 against 40 percent and an endoscopic response in 78 against 28 percent; the investigators hold a patent for naltrexone in inflammatory bowel disease, NIH-funded. Parker et al. (Cochrane, 2018; PMID 29607497): two small trials, 46 participants; clinical remission 30 against 18 percent, not significant, low-quality evidence. van de Pol et al. (Dig Dis Sci, 2026; PMID 42701992): independent multicenter Dutch trial in 7 hospitals, 41 adults, 4.5 mg for 12 weeks, stopped for futility; endoscopic remission 5.6 against 18.8 percent, clinical remission 22 against 70 percent on placebo. PILOTS AND OTHER INDICATIONS. Smith et al. (Am J Gastroenterol, 2007; PMID 17222320) is an open-label single-arm pilot in 17 patients and Younger and Mackey (Pain Med, 2009; PMID 19453963) a single-blind pilot in 10 women; neither is a randomized controlled trial People are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect.. Peters et al. (2022; PMID 35001215): randomized trial in high-grade glioma, 110 patients; no effect on quality of life or fatigue, a different indication. Grade C in both named indications: early small positive trials followed by larger null trials, which the written rule calls mixed evidence or a failed replication.
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