Evidence Trace, complete trial record
In plain terms
In plain terms: Low-Dose Naltrexone (LDN) shows early signals in human research but the evidence is limited -- small trials, surrogate endpoints, or not yet independently replicated. It is an emerging area, not yet a proven one.
Low-Dose Naltrexone (LDN)
C
Limited: small, mixed or unreplicated trials
The endpoint this grade is based on: self_report, Graded by use. Fibromyalgia pain: Grade C, one small positive crossover trial against three larger null trials and a pooled analysis with a small effect. Active Crohn's disease: Grade C, one 40-person trial by the patent holders positive on a 70-point activity score fall, with clinical remission not significantly different, against an independent multicenter trial stopped for futility. Replication was attempted at larger scale in both indications and did not confirm the early results.
The evidence as the record states it
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 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. 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.
PMID 21380937 PMID 23359310 PMID 42701992 PMID 29607497 PMID 38258677 PMID 38226027 PMID 42385209 PMID 40540205 PMID 17222320 PMID 19453963 PMID 35001215
Evidence by specific use
Fibromyalgia pain
Grade C
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.
PMID 23359310 PMID 38226027 PMID 38258677 PMID 42385209 PMID 40540205
Active Crohn's disease, induction of response or remission
Grade C
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.
PMID 21380937 PMID 29607497 PMID 42701992
Why Grade C and not Grade B
Grade C reflects early or limited human evidence -- small trials, surrogate endpoints, or preliminary findings not yet independently replicated. The evidence points in a promising direction but does not yet meet the standard for Grade B. A single well-powered, independently replicated trial with a meaningful endpoint would move this to Grade B or higher.
What this grade covers and what it does not
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, because the early trials did show benefit; it is not B, because the larger trials did not. WHAT THIS GRADE DOES NOT COVER: high-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 and single-blind pilots (PMIDs 17222320, 19453963), which are context and carry no letter.
What would move this grade
A well-powered randomized trial with an objective, clinically meaningful primary endpoint and at least one independent replication would support Grade B or higher.
How this was studied
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.
How to track whether this is working
Symptom scales specific to the indication. Prescription only; requires physician management.