Medications · Metabolic & weight

Low-Dose Naltrexone (LDN)

Naltrexone at compounded micro-doses for off-label use.

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Low-Dose Naltrexone (LDN) molecular structure (Opioid antagonist (low-dose))

Why this needs to be personal

Why Personalized Low-Dose Naltrexone (LDN)

Low-dose naltrexone is the cleanest example of why compounding exists at all. The FDA reviewed naltrexone at 50 mg orally and 380 mg as a monthly depot, doses chosen to produce near-complete opioid receptor blockade for substance-use disorder. The clinical use case for LDN, transient receptor antagonism plus TLR4 modulation in fibromyalgia, Crohn's disease, and multiple sclerosis, runs at 1.5 to 4.5 mg, roughly one-tenth to one-thirtieth of the approved strength. No manufacturer makes that pill. The trial doses behind LDN were not calibrated for your weight, your sleep architecture, your tolerance for vivid dreams during initiation, or whether your prescriber wants to start you at 0.5 mg and walk up over six weeks. They were calibrated for the average patient in a 31-person crossover at Stanford or an 80-person MS trial in San Francisco.

That entire dose range, 0.5, 1, 1.5, 3, and 4.5 mg, only exists because a compounding pharmacy makes it. The molecule is the same naltrexone hydrochloride the FDA reviewed, weighed out at a fraction of the commercial strength and capsuled to the prescriber's titration plan. A compounder can step a sensitive patient up by 0.5 mg increments instead of jumping to 4.5 mg, can switch to a sublingual troche or transdermal cream when a patient cannot tolerate the oral capsule, and can produce a dye-free, lactose-free preparation for patients with the relevant sensitivities. None of that is available off a manufacturer's shelf because the manufacturer's shelf does not carry this dose at all.

This is the older arrangement: a prescriber who knows the patient writes the order, a licensed pharmacist prepares it for that named patient, and the preparation reflects the clinical decision rather than a marketing SKU. Modern state inspection and pharmacist review keep it honest.

In brief

Low-Dose Naltrexone (LDN) Explained

Low-dose naltrexone, or LDN, is a small dose of an older medicine called naltrexone 17. The standard naltrexone pill is 50 mg and is used to help people with opioid or alcohol use disorder. LDN is much smaller, usually 1 to 4.5 mg, taken as a compounded capsule once a day, often at bedtime. There is no commercial low-dose pill on the U.S. market, so LDN is always made up to order by a compounding pharmacy.

Doctors prescribe LDN off-label for conditions where the immune system or nerves are overactive, most often fibromyalgia, Crohn's disease, and multiple sclerosis, but also complex regional pain syndrome, certain autoimmune skin conditions, and chronic fatigue states. The evidence is strongest in fibromyalgia and Crohn's, where small randomized trials have shown improvements in pain and disease activity 256. Larger trials are still missing, so LDN is best thought of as a reasonable add-on for selected patients rather than a first-line treatment.

At a glance

Quick Facts About Low-Dose Naltrexone (LDN)

Category
Opioid receptor antagonist at sub-therapeutic dose
Active ingredient
Naltrexone hydrochloride at compounded micro-doses of 0.5, 1, 1.5, 3, or 4.5 mg, typically one-tenth to one-twentieth of the 50 mg FDA-approved oral strength
FDA-approved branded forms (at 50 mg)
ReVia (naltrexone HCl 50 mg oral tablet, FDA-approved 1984 for opioid use disorder; 1995 for alcohol use disorder) and Vivitrol (naltrexone extended-release 380 mg intramuscular suspension, FDA-approved 2006 for alcohol use disorder, 2010 for opioid use disorder)
Compounded dosing range
Oral 0.5, 4.5 mg once daily (typically at bedtime); 4.5 mg is the most-studied dose in fibromyalgia and Crohn's disease trials
Evidence posture
Small randomized trials and pilot studies support a Tier 2 (well-studied) posture for fibromyalgia and Crohn's disease. Other indications (multiple sclerosis, CRPS, autism, inflammatory skin disease) are emerging or case-level. No phase III program supports LDN in any indication.
FDA-approval status
Naltrexone HCl is FDA-approved as a 50 mg oral tablet and a 380 mg intramuscular depot for opioid- and alcohol-use disorders. The low-dose (≤5 mg) preparation is not FDA-approved for any indication, there is no commercial low-dose product on the U.S. market.
Compounded under
503A, patient-specific prescription only. Because no commercial product exists at the 0.5, 4.5 mg strength range, LDN is inherently a compounded preparation rather than a copy of a manufactured drug.
Important compounding caution
Low-dose naltrexone is not 'essentially a copy' of the manufactured 50 mg tablet, the dose is approximately 10, 100× lower and the therapeutic rationale (transient opioid receptor antagonism, glial TLR4 modulation) is mechanistically distinct from full-dose opioid blockade. The compounded preparation should not be conflated with the FDA-approved 50 mg or 380 mg products.

Prescription review

Patient-Specific Prescription Only

Low-Dose Naltrexone (LDN) on this page is a 503A compounded preparation. Every dose is made on a prescription, for a named patient, by a licensed pharmacist. It is not a stocked, mass-manufactured product.

  • Made to order, not off a shelf. No batch sits in a warehouse waiting for buyers. Your prescription is what triggers the prep.
  • Named-patient label. The bottle carries your name. The batch records carry your prescription.
  • Dose, strength, and route chosen for you. A prescriber who knows your chart decides what gets compounded, not a manufacturer who set the strength for a trial population.
  • Licensed pharmacist on the hook. A real person, with a license that can be pulled, signs off on every prep. State inspectors check the facility.
  • Compounded drugs are not FDA-approved. They should not be evaluated using branded-drug trial data. Availability varies by state and prescribed medication.
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Real medicine, not gray market

How This Differs from a Research-Use-Only Website

A research-use-only website ships a vial from a warehouse. There is no prescription, no pharmacist, no facility inspection, and no way to recall the product if something is wrong with it. If the vial is mislabeled, contaminated, or under-potent, there is nobody whose license is at stake.

A 503A compounding pharmacy is the other thing. Your doctor writes the prescription. A licensed pharmacist, whose name is on the label, prepares the medicine in a facility the state inspects. If something goes wrong, there is a person and a license on the hook, and a documented chain of custody on every lot. That accountability is what makes it safe.

What it is

What is Low-Dose Naltrexone (LDN)?

Naltrexone is a small-molecule competitive antagonist at mu-, kappa-, and (to a lesser extent) delta-opioid receptors. As a drug substance it was synthesized in the 1960s and FDA-approved as a 50 mg oral tablet in 1984 for the treatment of opioid use disorder; the indication was extended to alcohol use disorder in 1995. A long-acting 380 mg intramuscular depot (Vivitrol) was approved in 2006 (alcohol use disorder) and 2010 (opioid use disorder). At those doses naltrexone produces near-complete and sustained opioid receptor blockade 25.

Low-dose naltrexone (LDN) refers to compounded oral preparations at 0.5, 4.5 mg once daily, approximately 1/10th to 1/100th the dose used for substance-use disorder. There is no commercial low-dose naltrexone product approved by the FDA 2526. LDN is therefore inherently a compounded preparation, typically dispensed as oral capsules at 0.5, 1, 1.5, 3, or 4.5 mg strengths, occasionally as troches or transdermal cream where the prescriber documents an oral-route limitation 1720.

The clinical rationale for LDN was developed by Bernard Bihari and colleagues beginning in the mid-1980s, originally in the context of HIV/AIDS-era immune dysregulation, and was subsequently extended to autoimmune, inflammatory, and chronic pain conditions 17320 25. Modern off-label use is heaviest in fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome, with case-level reports across a broader autoimmune and inflammatory disease catalog.

How it works

How Low-Dose Naltrexone (LDN) Works

Class
Opioid antagonist (low-dose)
First studied
1980s LDN research
Common forms
Capsule, micro-dose strengths
Compounding category
503A, patient-specific prescription

Two distinct mechanisms are proposed for low-dose naltrexone, and both are likely operative. The first is transient mu-opioid receptor antagonism with rebound up-regulation of endogenous opioid tone. At 4.5 mg orally, naltrexone occupies central mu-opioid receptors for approximately 4, 6 hours before clearing; the brief blockade is hypothesized to trigger a compensatory increase in endogenous opioid ligand (β-endorphin, met-enkephalin) production and in receptor density that persists after the drug has cleared, producing a net pro-analgesic, anti-inflammatory state 317 4.

The second mechanism is non-stereoselective antagonism of Toll-like receptor 4 (TLR4) on microglia and other innate-immune cells 11. Hutchinson and colleagues demonstrated in 2008 that both naloxone and naltrexone (and their non-opioid-binding R-isomers) reverse neuropathic pain in rodent models through a mechanism that does not require opioid receptor binding, and traced the effect to direct antagonism of TLR4-mediated glial cell activation. Because activated microglia release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) implicated in centrally-mediated chronic pain and autoimmune symptomatology, TLR4 antagonism provides a mechanistic basis for LDN's reported effects on fibromyalgia, multiple sclerosis, and inflammatory bowel disease that is independent of the opioid receptor pathway 4.

Research history

Low-Dose Naltrexone (LDN) Research History

Bernard Bihari, a New York City neurologist, originated the low-dose naltrexone clinical concept in the mid-1980s in the context of HIV/AIDS-era investigation of immune-modulating agents 1720. Early Bihari case-series work in HIV and in autoimmune conditions remained largely outside the peer-reviewed literature, but established the empiric 1.5, 4.5 mg once-nightly oral dosing schedule that has been carried into every subsequent randomized trial. Brown and Panksepp (2009) 20 consolidated the early clinical rationale into the Medical Hypotheses literature.

The first contemporary randomized fibromyalgia evidence was published by Younger and Mackey (2009) at Stanford 1, an open-label, single-site pilot in 10 women that established feasibility, tolerability, and a substantial within-subject pain-score signal. The follow-on randomized, double-blind, placebo-controlled crossover trial 2 2 reported a 28.8% reduction in fibromyalgia pain on 4.5 mg LDN versus 18.0% on placebo and demonstrated greater symptom-day responder rates with LDN. The Younger review (Clin Rheumatol 2014) 3 consolidated the mechanism and clinical evidence as it stood at the time. Parkitny and Younger (2017) 4 extended the fibromyalgia work mechanistically by demonstrating reductions in serum IL-1β, IL-6, and TNF-α after 8 weeks of LDN treatment.

Crohn's disease evidence was developed by the Smith group at Penn State Children's Hospital. Smith et al. (2007, Am J Gastroenterol) 5 reported an open-label pilot in 17 adults with active Crohn's disease showing reductions in CDAI on 4.5 mg LDN. The randomized, double-blind, placebo-controlled adult trial 6 6 demonstrated 78% clinical response and 33% endoscopic mucosal healing on LDN versus 28% and 8% on placebo respectively. A 2013 pediatric pilot in adolescents 7 established tolerability and a within-subject CDAI signal in younger patients. The 2014 Cochrane review (Segal et al.) 8 characterized the body of evidence as low-certainty but consistent across small RCTs.

Multiple sclerosis evidence comprises two small randomized trials. Sharafaddinzadeh et al. (2010, Mult Scler) 9 randomized 96 Iranian adults with relapsing-remitting or secondary-progressive MS to 4.5 mg LDN or placebo for 17 weeks and reported significant improvement in the mental health domain of MSQOL-54. Cree et al. (2010, Ann Neurol) 10 randomized 80 U.S. adults with MS in a single-center crossover and reported improvement in self-reported quality of life on LDN. Raknes and Småbrekke (2017) 2324 performed observational pharmacoepidemiology in Norway following a 2013 surge in LDN prescribing, documenting reduced use of co-medications including immunomodulators in MS prescribers.

The fibromyalgia evidence base broadened substantially between 2020 and 2024. Bruun-Plesner and colleagues at the University of Southern Denmark conducted a dose-response investigation in 2020 31, examining 1.0, 2.0, 3.0, 4.0, 4.5, and 6.0 mg dosing in 25 women with fibromyalgia and identifying 3.88 mg as the modal effective dose. Their group then ran the largest LDN-fibromyalgia randomized trial to date, Due Bruun et al. (2024, Lancet Rheumatology) 32, comparing naltrexone 6 mg once daily to placebo in 99 women over 12 weeks; the trial's primary outcome (between-group difference in pain on a 0, 10 NRS at week 12) did not reach statistical significance, although the LDN arm showed a numerically larger improvement and significantly better memory-domain scores on the FIQR. The Driver and D'Souza (2023) 33 enterprise-wide retrospective analysis at Mayo Clinic, 14 years, 115 LDN-treated patients across fibromyalgia and other chronic pain conditions, reported a 65% symptomatic improvement rate and identified body-pain extent and prior opioid exposure as predictors of discontinuation. Partridge et al. (2023) 35 systematic literature review and Vatvani et al. (2024) 34 systematic review with meta-analysis and trial-sequential analysis both concluded that the fibromyalgia LDN evidence direction is consistent with benefit but that available trials are underpowered to confirm a robust effect, and called for further multi-center RCTs.

Crohn's disease evidence was extended by the Lie et al. (2018, J Transl Med) 36 observational cohort in the Netherlands, an IBD-patient audit that reported clinical benefit and tolerability in adults with active Crohn's disease and ulcerative colitis treated with 4.5 mg LDN at the Erasmus MC IBD center. Parker et al. (2018) 37 published the Cochrane systematic review update on LDN for induction of remission in Crohn's disease, replacing the 2014 Segal review with expanded analysis but reaching a similar low-certainty-but-consistent conclusion across the small-trial corpus.

Multiple sclerosis evidence was extended by Gironi et al. (2008, Mult Scler) 38, a 40-patient pilot trial of LDN in primary progressive MS, the first prospective LDN-MS trial and a precursor to the Sharafaddinzadeh and Cree randomized work, which reported tolerability and modest signal on quality-of-life and spasticity outcomes over 6 months. Complex regional pain syndrome evidence was consolidated by Soin et al. (2021, Pain Physician) 39 in a systematic literature review that supplemented the Chopra and Cooper case series with additional small-case reports.

Single-indication studies are reported across complex regional pain syndrome 1239, psoriasis vulgaris 14, systemic sclerosis pruritus 16, Hailey-Hailey disease 40, and inflammatory dermatologic conditions more broadly 15. Albers et al. (2017, JAMA Dermatol) 40 reported sustained clearance of recalcitrant Hailey-Hailey lesions in three patients treated with 3.0, 4.5 mg LDN, the first peer-reviewed evidence in this rare autosomal-dominant acantholytic disease, and the Ekelem 2019 systematic review consolidates the broader dermatologic case-level literature. Roy et al. (2015) 13 systematically reviewed opioid antagonists including low-dose naltrexone in autism spectrum conditions and concluded the evidence did not support efficacy at the core-symptom level. Trofimovitch and Baumrucker (2019) 19 consolidated the LDN evidence for chronic non-malignant pain in a palliative care pharmacology update. Patten et al. (2018) 18 reviewed safety and efficacy across fibromyalgia, MS, and Crohn's. Cabanas et al. (2019) 21 and (2021) 43 and Eaton-Fitch et al. (2022) 22 reported mechanistic and pilot clinical evidence for LDN in myalgic encephalomyelitis/chronic fatigue syndrome via a TRPM3 ion channel restoration mechanism in natural killer cells; Bolton et al. (2020) 44 independently published a case-level chronic fatigue syndrome response to 4.5 mg LDN. The post-acute-COVID literature emerged with O'Kelly et al. (2022) 41, a 38-patient interventional pre-post study of 1.0, 4.5 mg LDN over 2 months that demonstrated improvement in WHO long-COVID symptom-score domains, followed by Bonilla et al. (2023) 42, a 59-patient Stanford retrospective cohort that reported symptom improvement in fatigue, post-exertional malaise, and pain-domain scores over 2 months of LDN. Toljan and Vrooman (2018) 17 and the Leiber and Parker (2025, Cureus) scoping review 45 provide the most recent comprehensive utilization syntheses across the full indication catalog.

Timeline

Low-Dose Naltrexone (LDN) Timeline

  1. 1984 FDA approves naltrexone HCl 50 mg oral tablet (ReVia) for opioid use disorder 25
  2. Mid-1980s Bernard Bihari develops the low-dose (≤4.5 mg) clinical concept in HIV/AIDS-era immune-modulation work in New York City; case-series-level evidence accumulates outside the peer-reviewed literature 1720
  3. 1995 FDA extends naltrexone HCl 50 mg oral indication to alcohol use disorder 25
  4. 2006 FDA approves naltrexone extended-release injectable suspension 380 mg (Vivitrol) for alcohol use disorder 26
  5. 2007 Smith et al 5. (Am J Gastroenterol) publish first open-label pilot of LDN 4.5 mg in adults with active Crohn's disease, reduction in CDAI in 17 patients
  6. 2008 Hutchinson et al 11. (Eur J Neurosci) demonstrate non-stereoselective reversal of neuropathic pain by naloxone and naltrexone via Toll-like receptor 4 antagonism on microglia, mechanistic foundation independent of opioid receptor binding
  7. 2009 Younger and Mackey (Pain Med) publish open-label fibromyalgia pilot at Stanford, 10 women, single-blind crossover, ~30% reduction in fibromyalgia symptom score on 4.5 mg LDN 1
  8. 2009 Brown and Panksepp (Med Hypotheses) consolidate LDN clinical rationale across disease-prevention and quality-of-life applications 20
  9. 2010 FDA expands Vivitrol indication to opioid use disorder 26
  10. 2010 Sharafaddinzadeh et al 9. (Mult Scler) publish RCT of 4.5 mg LDN in 96 Iranian adults with multiple sclerosis, improvement in MSQOL-54 mental health domain at 17 weeks
  11. 2010 Cree et al 10. (Ann Neurol) publish 8-week crossover RCT of LDN in 80 U.S. adults with MS, improvement in self-reported quality of life
  12. 2011 Smith et al 6. (Dig Dis Sci) publish randomized double-blind placebo-controlled adult Crohn's trial of 4.5 mg LDN, 78% clinical response and 33% endoscopic mucosal healing vs 28% and 8% on placebo
  13. 2011 Frech et al 16. (Int J Rheumatol) report case series of LDN for pruritus in systemic sclerosis
  14. 2013 Younger et al 2. (Arthritis Rheum) publish randomized double-blind placebo-controlled crossover trial of 4.5 mg LDN in 31 women with fibromyalgia, 28.8% reduction in pain on LDN vs 18.0% placebo; greater responder rates
  15. 2013 Smith et al 7. (J Clin Gastroenterol) publish open-label pediatric Crohn's pilot in 12 adolescents, tolerability established and CDAI reduction observed
  16. 2013 Chopra and Cooper (J Neuroimmune Pharmacol) report case series of LDN in complex regional pain syndrome, symptom and function improvement in 2 patients 12
  17. 2014 Segal et al 8. (Cochrane Database Syst Rev) review LDN for induction of remission in Crohn's disease, low-certainty evidence of benefit across the small-RCT corpus
  18. 2014 Younger et al 3. (Clin Rheumatol) publish comprehensive review of LDN as a novel anti-inflammatory for chronic pain, consolidates mechanism (opioid rebound plus TLR4 glial modulation) and clinical evidence
  19. 2015 Roy et al 13. (J Intellect Disabil Res) publish systematic review of opioid antagonists in autism spectrum conditions, no consistent evidence for core symptom efficacy at LDN-range doses
  20. 2017 Parkitny and Younger (Biomedicines) demonstrate reduction in serum IL-1β, IL-6, and TNF-α after 8 weeks of LDN in women with fibromyalgia, human pharmacodynamic support for the TLR4/glial mechanism 4
  21. 2017 Raknes and Småbrekke (Pharmacoepidemiol Drug Saf) document an unprecedented surge in LDN prescribing in Norway after national media coverage, patient and prescriber characteristics and dispense patterns 23
  22. 2017 Raknes and Småbrekke (PLoS One), quasi-experimental analysis of medication-use change among new LDN users with multiple sclerosis, demonstrating reduced co-medication use 24
  23. 2018 Toljan and Vrooman (Med Sci) publish comprehensive review of LDN therapeutic utilization across autoimmune, inflammatory, and chronic pain conditions 17
  24. 2018 Patten et al 18. (Pharmacotherapy) review safety and efficacy of LDN in chronic pain and inflammation across multiple sclerosis, fibromyalgia, and Crohn's disease
  25. 2018 Bridgman and Bruce-Brand (JAAD Case Rep) report psoriasis vulgaris response to LDN in a single-patient case 14
  26. 2019 Ekelem et al 15. (JAMA Dermatol) systematic review of LDN in chronic inflammatory dermatologic conditions, small-study evidence for Hailey-Hailey disease, lichen planopilaris, and psoriasis
  27. 2019 Trofimovitch and Baumrucker (Am J Hosp Palliat Care) consolidate LDN evidence for chronic non-malignant pain in a palliative-care pharmacology update 19
  28. 2019 Cabanas et al 21. (Front Immunol) demonstrate that naltrexone restores impaired TRPM3 ion channel function in natural killer cells from ME/CFS patients, mechanistic basis for an emerging chronic-fatigue-syndrome indication
  29. 2022 Eaton-Fitch et al 22. (J Transl Med) extend the TRPM3/NK-cell pharmacodynamic finding in ME/CFS
  30. 2008 Gironi et al 38. (Mult Scler) publish 40-patient pilot trial of LDN in primary progressive multiple sclerosis, first prospective LDN-MS trial; tolerability and modest QoL signal over 6 months
  31. 2017 Albers et al 40. (JAMA Dermatol) report sustained clearance of recalcitrant Hailey-Hailey disease in three patients on 3.0, 4.5 mg LDN, first peer-reviewed dermatologic case series in this autosomal-dominant acantholytic disease
  32. 2018 Lie et al 36. (J Transl Med) publish observational cohort of LDN in inflammatory bowel disease at the Erasmus MC IBD center, clinical benefit and tolerability in active Crohn's disease and ulcerative colitis
  33. 2018 Parker et al 37. (Cochrane Database Syst Rev) publish updated Cochrane systematic review of LDN for induction of remission in Crohn's disease, replacing the 2014 Segal review with expanded analysis
  34. 2020 Bruun-Plesner et al 31. (Pain Med) publish dose-response investigation of LDN in fibromyalgia across 1.0, 6.0 mg; identifies 3.88 mg as the modal effective dose in 25 women
  35. 2020 Bolton et al 44. (BMJ Case Rep) publish case-level evidence of 4.5 mg LDN response in chronic fatigue syndrome
  36. 2021 Cabanas et al 43. (Front Immunol) consolidate the TRPM3/NK-cell mechanism and clinical rationale for LDN in ME/CFS
  37. 2021 Soin et al 39. (Pain Physician) publish systematic literature review of LDN in complex regional pain syndrome, consolidating case-series evidence
  38. 2022 O'Kelly et al 41. (Brain Behav Immun Health) publish 38-patient interventional pre-post study of 1.0, 4.5 mg LDN in long COVID over 2 months, improvement in WHO long-COVID symptom-score domains
  39. 2023 Driver and D'Souza (Biomedicines) publish 14-year enterprise-wide Mayo Clinic retrospective analysis of LDN in 115 patients across fibromyalgia and other chronic pain, 65% symptomatic improvement rate; identifies predictors of treatment success and discontinuation 33
  40. 2023 Bonilla et al 42. (Int Immunopharmacol) report 59-patient Stanford retrospective cohort of LDN for post-acute sequelae of COVID-19, improvement in fatigue, post-exertional malaise, and pain-domain scores over 2 months
  41. 2023 Partridge et al 35. (Heliyon) publish systematic literature review of LDN clinical efficacy in fibromyalgia and putative pathophysiological mechanisms
  42. 2024 Due Bruun et al 32. (Lancet Rheumatol) publish 99-women randomized placebo-controlled trial of naltrexone 6 mg in fibromyalgia, primary pain outcome did not reach significance; significant FIQR memory-domain improvement on LDN
  43. 2024 Vatvani et al 34. (Korean J Pain) publish systematic review and meta-analysis of LDN in fibromyalgia with trial-sequential analysis, consistent direction of effect; trial-sequential analysis indicates further RCTs are needed for definitive conclusion
  44. 2025 Leiber and Parker (Cureus) publish scoping review of LDN therapeutic uses and efficacy across the full indication catalog 45

Natural role

Biological Role of Low-Dose Naltrexone (LDN)

Naltrexone occupies endogenous opioid receptor systems that, at physiological tone, modulate pain, mood, immune function, and visceral homeostasis. The mu-opioid receptor system is engaged by β-endorphin from POMC neurons and by exogenous opioid agonists; the kappa-opioid system is engaged by dynorphin and contributes to dysphoric and aversive states; the delta-opioid system is engaged by enkephalins and contributes to mood-regulatory and analgesic tone. Naltrexone is a competitive antagonist at all three receptors with highest affinity at mu.

Beyond the canonical opioid receptor system, naltrexone (and its R-enantiomer, which does not bind opioid receptors) antagonizes Toll-like receptor 4 (TLR4) on microglia and other innate-immune cells 11. TLR4 sits at the interface between innate immunity and central pain processing, its activation by endogenous danger-associated molecular patterns or by lipopolysaccharide drives a pro-inflammatory glial transcriptional program that has been implicated in fibromyalgia central sensitization, multiple sclerosis disease activity, and neuropathic pain states. The dual mechanism (transient opioid antagonism plus TLR4 glial modulation) is the leading current account of why low-dose naltrexone has clinical signal across an otherwise heterogeneous catalog of conditions 3174.

Clinical contexts studied

Clinical Contexts for Low-Dose Naltrexone (LDN)

Opioid use disorder (full-dose naltrexone, FDA-approved) fda approved

FDA-approved at 50 mg orally (ReVia) and 380 mg intramuscularly (Vivitrol). This is the molecule's labeled indication, not the low-dose use described elsewhere in this brief.

Naltrexone HCl 50 mg orally once daily and naltrexone extended-release injectable suspension 380 mg every 4 weeks are FDA-approved for the prevention of relapse to opioid dependence after opioid detoxification 2526. The labeled mechanism is complete and sustained mu-opioid receptor blockade. This use is mechanistically and clinically distinct from compounded low-dose naltrexone at 0.5, 4.5 mg, which is the focus of the remainder of this brief.

Branded product: ReVia (naltrexone HCl 50 mg tablet) and Vivitrol (naltrexone XR 380 mg IM suspension)

Alcohol use disorder (full-dose naltrexone, FDA-approved) fda approved

FDA-approved at 50 mg orally and 380 mg intramuscularly.

Naltrexone HCl 50 mg orally and Vivitrol 380 mg IM are FDA-approved for the treatment of alcohol use disorder. As with opioid use disorder, this indication is at full dose and is mechanistically distinct from compounded LDN 2526.

Branded product: ReVia and Vivitrol

Fibromyalgia (off-label, low-dose) well studied

Studied in multiple small randomized trials across Stanford and Denmark; well-studied for this compound at LDN doses, with a 2024 multi-center randomized trial available.

Two single-site Stanford trials 12 established the modern LDN fibromyalgia evidence base. The open-label pilot (n=10) reported a ~30% within-subject reduction in fibromyalgia symptom score on 4.5 mg LDN. The 2013 randomized double-blind placebo-controlled crossover trial (n=31) reported a 28.8% reduction in fibromyalgia pain on LDN versus 18.0% on placebo, with greater responder rates at the LDN-stable period. Parkitny and Younger (2017) 4 extended these data mechanistically with a demonstration of reduced serum IL-1β, IL-6, and TNF-α over 8 weeks 3. The Bruun-Plesner et al. (2020) 31 dose-response investigation in 25 women identified 3.88 mg as the modal effective dose across 1.0, 6.0 mg, and the Due Bruun et al. (2024, Lancet Rheumatol) 32 99-women randomized placebo-controlled trial of naltrexone 6 mg over 12 weeks did not meet its primary pain-outcome endpoint, although the LDN arm showed a numerically larger improvement and a significant memory-domain benefit on the FIQR. The Driver and D'Souza (2023) 33 14-year enterprise-wide Mayo Clinic retrospective in 115 patients reported a 65% symptomatic improvement rate. The Vatvani et al. (2024) 34 meta-analysis and Partridge et al. (2023) 35 systematic review both characterize the evidence direction as consistent with benefit but underpowered; trial-sequential analysis indicates further RCTs are required for definitive conclusion. The Patten 2018 18 and Toljan-Vrooman 2018 17 and Leiber-Parker 2025 45 reviews consolidate fibromyalgia as the strongest single-indication signal for LDN in the chronic-pain literature.

Crohn's disease (off-label, low-dose) well studied

Studied in small randomized trials at Penn State Children's Hospital with subsequent Dutch observational replication; well-studied for this compound at LDN doses, with updated Cochrane synthesis.

The Smith laboratory at Penn State Children's Hospital developed the Crohn's disease evidence base across three trials 567. The 2007 open-label adult pilot in 17 patients reported a reduction in CDAI on 4.5 mg LDN. The 2011 randomized double-blind placebo-controlled trial (n=40) reported 78% clinical response and 33% endoscopic mucosal healing on LDN versus 28% and 8% on placebo. The 2013 pediatric pilot (n=12 adolescents) established tolerability and within-subject CDAI signal in younger patients. Lie et al. (2018, J Transl Med) 36 published an observational cohort of adult IBD patients (Crohn's disease and ulcerative colitis) treated with 4.5 mg LDN at the Erasmus MC IBD center in the Netherlands, reporting tolerability and clinical benefit. The 2014 Cochrane review by Segal et al. 8 and the 2018 update by Parker et al. 37 both characterize the body of evidence as low-certainty but consistent across the small-RCT corpus, supporting a Tier 2 (well-studied for the compound) posture.

Multiple sclerosis (off-label, low-dose) emerging

Studied in three small randomized trials; emerging-to-well-studied for this compound at LDN doses.

Three randomized or prospective trials provide the contemporary MS evidence. Gironi et al. (2008, Mult Scler) 38 conducted a 40-patient pilot trial in primary progressive MS, the first prospective LDN-MS trial, reporting tolerability and modest signal on quality-of-life and spasticity outcomes over 6 months. Sharafaddinzadeh et al. (2010) 9 randomized 96 Iranian adults with relapsing-remitting or secondary-progressive MS to 4.5 mg LDN or placebo for 17 weeks and reported significant improvement in the MSQOL-54 mental health domain. Cree et al. (2010) 10 randomized 80 U.S. adults with MS in an 8-week crossover and reported improvement in self-reported quality of life on LDN. None of these trials demonstrated effect on disability progression or relapse rate, and all are small and single-center. Pharmacoepidemiology in Norway after a 2013 LDN prescribing surge 2324 suggests reduced co-medication use in new LDN-prescribed MS patients but is observational and unrandomized 18.

Complex regional pain syndrome (off-label, low-dose) emerging

Case-series evidence with a systematic literature review available.

Chopra and Cooper (2013) 12 reported sustained symptom and functional improvement in two patients with longstanding CRPS treated with 4.5 mg LDN. Soin et al. (2021, Pain Physician) 39 systematically reviewed the LDN-CRPS literature and identified additional small-case reports supporting the Chopra and Cooper findings; randomized trial evidence is absent. Mechanistic rationale rests on the TLR4/glial-modulation account of LDN action 113.

Inflammatory dermatologic conditions (psoriasis, Hailey-Hailey, lichen planopilaris) emerging

Case-level and small-series evidence; systematic review available.

Albers et al. (2017, JAMA Dermatol) 40 reported sustained clearance of recalcitrant Hailey-Hailey disease lesions in three patients on 3.0, 4.5 mg LDN, the first peer-reviewed evidence in this rare autosomal-dominant acantholytic disease. Bridgman and Bruce-Brand (2018) 14 reported psoriasis vulgaris response in a single patient. The Ekelem et al. (2019) systematic review 15 in JAMA Dermatology consolidates LDN evidence across Hailey-Hailey disease, lichen planopilaris, psoriasis, and other chronic inflammatory dermatologic conditions, with most evidence at case-series level. Frech et al. (2011) 16 reported LDN benefit for pruritus in systemic sclerosis.

Myalgic encephalomyelitis / chronic fatigue syndrome (off-label, low-dose) emerging

Mechanistic and case-level evidence.

Cabanas et al. (2019) 21 demonstrated that naltrexone restores impaired TRPM3 ion channel function in natural killer cells from ME/CFS patients, providing a mechanistic basis for the off-label use that had accumulated in clinical practice. Cabanas et al. (2021) 43 and Eaton-Fitch et al. (2022) 22 extended the TRPM3/NK-cell pharmacodynamic findings in a larger ME/CFS cohort and consolidated the mechanistic rationale. Bolton et al. (2020, BMJ Case Rep) 44 independently reported case-level chronic fatigue syndrome response to 4.5 mg LDN. Randomized symptom-outcome trials are not yet published.

Chronic non-malignant pain (general off-label use) emerging

Reviewed across palliative-care and chronic-pain pharmacology updates.

Trofimovitch and Baumrucker (2019) 19 reviewed LDN as a possible nonopioid modality for chronic non-malignant pain syndromes across the published evidence. Younger (2014) 3 characterized LDN as a novel anti-inflammatory treatment for chronic pain. Patten et al. (2018) 18 consolidated efficacy and safety across the major indications. Single-arm and case-series evidence in chronic pain has accumulated across small studies but no well-powered multi-indication chronic-pain RCT has been completed.

Autism spectrum conditions preclinical

Systematic review concludes the evidence does not support efficacy at the core-symptom level.

Roy et al. (2015) 13 systematically reviewed opioid antagonists including low-dose naltrexone for core symptoms of autism spectrum conditions in children and concluded that the evidence does not support efficacy. This indication is included here for completeness of the off-label literature but is not a Tier 2 posture and should not be prescribed against the published systematic review.

Hailey-Hailey disease (off-label, low-dose) emerging

Single-center case series; emerging evidence for this rare autosomal-dominant acantholytic disorder.

Albers et al. (2017, JAMA Dermatol) 40 reported sustained clearance of recalcitrant Hailey-Hailey disease lesions in three patients on 3.0, 4.5 mg LDN at the Emory University Department of Dermatology, the first peer-reviewed evidence in this rare autosomal-dominant acantholytic disease, where conventional therapies (topical corticosteroids, topical calcineurin inhibitors, surgical intervention) are commonly inadequate. The Ekelem et al. (2019) systematic review 15 consolidated this evidence with subsequent case-level reports. No randomized trial in Hailey-Hailey disease has been conducted.

Post-acute sequelae of COVID-19 / long COVID (off-label, low-dose) emerging

Two small open-label / observational cohorts; emerging evidence.

O'Kelly et al. (2022, Brain Behav Immun Health) 41 published a 38-patient interventional pre-post study of 1.0, 4.5 mg LDN over 2 months in long COVID at the Mater Misericordiae University Hospital long-COVID clinic in Dublin, reporting improvement in WHO long-COVID symptom-score domains including recovery from acute illness, mobility, daily activities, energy, pain, sleep, and concentration. Bonilla et al. (2023, Int Immunopharmacol) 42 reported a 59-patient Stanford retrospective cohort with improvement in fatigue, post-exertional malaise, and pain-domain scores over 2 months of LDN. Both studies are uncontrolled and short-duration. The mechanistic rationale rests on overlap between post-COVID symptomatology and the proposed TLR4/glial-modulation and TRPM3-restoration accounts of LDN in fibromyalgia and ME/CFS 112143. Randomized placebo-controlled trials are pending.

Off-label use

Off-Label Uses of Low-Dose Naltrexone (LDN)

Fibromyalgia well studied

Off-label; supported by small Stanford and Danish RCTs, dose-response and meta-analytic synthesis, and a mechanistic cytokine demonstration.

Younger et al. (2013) randomized crossover trial in 31 women reported 28.8% pain reduction on LDN vs 18.0% on placebo 2. Parkitny and Younger (2017) demonstrated reductions in serum IL-1β, IL-6, and TNF-α over 8 weeks 4. Bruun-Plesner 2020 dose-response found 3.88 mg as the modal effective dose across 1.0, 6.0 mg 31. Due Bruun 2024 99-women RCT of naltrexone 6 mg did not meet its primary pain endpoint but showed numerically larger LDN improvement and a significant FIQR memory-domain benefit 32 13. Driver 2023 Mayo Clinic retrospective in 115 patients reported 65% symptomatic improvement 33. Vatvani 2024 meta-analysis and Partridge 2023 systematic review characterize the evidence direction as consistent with benefit but underpowered 3435.

Crohn's disease well studied

Off-label; supported by Penn State RCTs (adult and pediatric) and a Cochrane systematic review.

Smith et al 5. randomized adult trial reported 78% clinical response and 33% mucosal healing on LDN 6. Pediatric pilot established tolerability 7. Cochrane review characterized evidence as low-certainty but consistent 8.

Multiple sclerosis emerging

Off-label; supported by two small randomized trials and observational pharmacoepidemiology.

Sharafaddinzadeh 2010 and Cree 2010 both reported improvement in self-reported quality of life on LDN; neither demonstrated effect on disability progression 910. Norwegian pharmacoepidemiology supports broader real-world signal but is observational 2324.

Complex regional pain syndrome (CRPS) emerging

Off-label; case-series-level evidence.

Chopra and Cooper (2013) report sustained CRPS symptom and functional improvement with 4.5 mg LDN 12.

Inflammatory dermatologic disease (psoriasis, Hailey-Hailey, lichen planopilaris, systemic sclerosis pruritus) emerging

Off-label; small-series and systematic-review evidence.

JAMA Dermatology systematic review consolidates LDN evidence across multiple chronic inflammatory dermatologic indications 15. Individual case-report evidence in psoriasis 14 and systemic sclerosis pruritus 16.

Myalgic encephalomyelitis / chronic fatigue syndrome emerging

Off-label; mechanistic and case-level evidence.

Naltrexone restores impaired TRPM3 ion channel function in NK cells from ME/CFS patients 214322. Bolton et al. (2020) report case-level response to 4.5 mg LDN 44. Randomized symptom-outcome trials are not yet published.

Hailey-Hailey disease emerging

Off-label; case-series evidence in a rare autosomal-dominant acantholytic disorder.

Albers et al. (2017, JAMA Dermatol) reported sustained clearance of recalcitrant Hailey-Hailey lesions in three patients on 3.0, 4.5 mg LDN 40; the Ekelem 2019 systematic review consolidates this with subsequent case-level reports 15. No randomized trial in Hailey-Hailey disease has been conducted.

Post-acute sequelae of COVID-19 / long COVID emerging

Off-label; two small open-label / observational cohorts.

O'Kelly et al. (2022, n=38) 41 and Bonilla et al. (2023, n=59) 42 reported improvement in long-COVID symptom-score domains (fatigue, post-exertional malaise, pain, sleep, concentration) over 2 months of LDN. Both studies are uncontrolled; randomized placebo-controlled trials are pending.

FDA-approved use

FDA-Approved Uses of Low-Dose Naltrexone (LDN)

BrandIndicationYearRoute
ReVia (and authorized generic naltrexone HCl tablet) Treatment of alcohol use disorder; blockade of the effects of exogenously administered opioids in detoxified opioid-use-disorder patients 1984 Oral, 50 mg once daily
Vivitrol Treatment of alcohol use disorder; prevention of relapse to opioid dependence following opioid detoxification 2006 Intramuscular extended-release suspension, 380 mg once every 4 weeks

Naltrexone hydrochloride is FDA-approved as a 50 mg oral tablet (ReVia and authorized generics) and as a 380 mg intramuscular extended-release suspension (Vivitrol). The 50 mg oral product was approved in 1984 for opioid use disorder and extended to alcohol use disorder in 1995. Vivitrol was approved in 2006 for alcohol use disorder and in 2010 for prevention of relapse to opioid dependence. Both labels carry warnings regarding precipitated opioid withdrawal in opioid-dependent patients and hepatotoxicity at supratherapeutic doses, and require documented opioid-free interval before initiation in opioid-use-disorder patients 2526.

Low-dose naltrexone (typically 0.5, 4.5 mg orally) is not FDA-approved for any indication. No commercial low-dose product exists on the U.S. market. The 50 mg manufactured tablet cannot be split or dispensed at the low-dose-range strengths without compounding; LDN is therefore inherently a 503A patient-specific compounded preparation.

Compounded use

Compounded Low-Dose Naltrexone (LDN) (503A)

Low-dose naltrexone is inherently a compounded preparation 247. The FDA-approved manufactured naltrexone products, ReVia 50 mg tablet and Vivitrol 380 mg intramuscular suspension, are not available at the 0.5, 4.5 mg strength range used clinically as LDN, and the 50 mg tablet is not formulated for accurate split-dosing to those strengths. Pharmacies that prepare LDN do so under 503A on patient-specific prescriptions, using naltrexone HCl active pharmaceutical ingredient and a compatible diluent in oral capsules, occasionally as troches or transdermal cream where the prescriber documents an oral-route limitation 1720 6.

Because no commercial low-dose product exists, LDN is not 'essentially a copy' of an FDA-approved drug in the sense intended by section 503A and FDA's 2018 essentially-a-copy guidance 27. The compounded preparation is mechanistically distinct from the FDA-approved 50 mg or 380 mg use cases: at 0.5, 4.5 mg, the mu-opioid receptor occupancy is partial and transient (~4, 6 hours), the therapeutic rationale is the proposed endogenous opioid rebound and TLR4 glial modulation rather than complete and sustained opioid receptor blockade, and the labeled indication (substance-use disorder) does not apply. The dose ratio between approved and compounded products is approximately 10, 100× 8.

The compounded LDN evidence base was generated using compounded preparations or pharmacy-prepared liquid dilutions from the start, there is no manufactured comparator at this dose range. Compounded LDN preparations are therefore the standard of evidence as well as the standard of clinical practice in this dose range. Quality considerations particular to compounded LDN include: accuracy of low-strength formulation (sub-milligram dosing demands careful API weighing and capsule blending), excipient profile (avoidance of fillers to which the patient is sensitive), and consistency across refills 910.

RonanRx prepares LDN under 503A only on patient-specific prescriptions. The pharmacist confirms the prescribed indication is consistent with the published off-label literature, confirms the dose is within the studied 0.5, 4.5 mg range, and confirms the patient is not concurrently on opioid analgesia for pain (which would be blunted by LDN) or in opioid-use-disorder maintenance (where LDN would precipitate withdrawal) 2517.

Formulations and routes

Low-Dose Naltrexone (LDN) Formulations and Routes

FormConcentrationDescription
Compounded oral capsule 0.5, 1, 1.5, 3, or 4.5 mg per capsule Naltrexone HCl active pharmaceutical ingredient compounded with a compatible filler (e.g., microcrystalline cellulose, avoiding lactose or calcium carbonate where these are part of the rationale for the compound) into size-3 or size-4 gelatin or hypromellose capsules. 4.5 mg is the most-studied single strength across the fibromyalgia, Crohn's disease, and multiple sclerosis trials [younger2013, smith2011, sharafaddinzadeh2010]. Lower strengths (0.5, 3 mg) are used for dose titration during initiation or for patients sensitive to higher doses.26929
Compounded oral troche / sublingual 0.5, 4.5 mg per troche Alternative dosage form for patients with swallowing limitations. Pharmacokinetics differ from capsule presentation due to partial sublingual absorption and bypass of first-pass metabolism [toljan2018]. Not the formulation used in the published randomized trials.17
Compounded transdermal cream Custom Less common formulation; offered where the prescriber documents an oral-route contraindication. Bioavailability and PK have not been characterized in the LDN-trial literature.17
Manufactured naltrexone HCl 50 mg tablet (reference product, not LDN) 50 mg ReVia and authorized generics; FDA-approved for opioid- and alcohol-use disorder. Cannot be split or used at LDN doses without compounding [fda_label_revia].25
Manufactured naltrexone XR 380 mg IM suspension (reference product, not LDN) 380 mg/vial Vivitrol; FDA-approved for alcohol- and opioid-use disorder. Not used at LDN doses [fda_label_vivitrol].26

Routes used in published literature: oral, sublingual, transdermal, troche.

Dosing

Low-Dose Naltrexone (LDN) Dosing

RoutePopulationRangeDurationStudy type
Oral Adults, fibromyalgia 1.5 mg once nightly for 1, 2 weeks, increase to 3 mg once nightly for 1, 2 weeks, then 4.5 mg once nightly as maintenance Initial trial of 8, 12 weeks before judging response; continued indefinitely if response is sustained Randomized double-blind placebo-controlled crossover trial; open-label pilot214
Oral Adults, Crohn's disease 4.5 mg once nightly (the dose used in the Smith trials) 12 weeks to clinical response, with continuation in responders Randomized double-blind placebo-controlled trial; open-label pilot658
Oral Pediatric, Crohn's disease 0.1 mg/kg once nightly (capped at 4.5 mg) in the Smith 2013 pediatric pilot 8 weeks in the published trial Open-label pediatric pilot7
Oral Adults, multiple sclerosis 4.5 mg once nightly (Sharafaddinzadeh 2010 used 4.5 mg for 17 weeks; Cree 2010 used 4.5 mg in an 8-week crossover) 8, 17 weeks in the published trials; continued indefinitely in clinical practice where benefit is documented Two small randomized trials910
Oral Adults, other off-label indications (CRPS, inflammatory dermatologic disease, ME/CFS, chronic pain) 1.5, 4.5 mg once nightly, typically titrated as for fibromyalgia Typically 8, 12 week trial before judging response Case series and small open-label studies12151416211917

The standard LDN dose across the published randomized trials is 4.5 mg once nightly orally. Most prescribers titrate from 1.5 mg for 1, 2 weeks, to 3 mg for 1, 2 weeks, to a 4.5 mg maintenance dose to minimize the initial sleep-disturbance and vivid-dream adverse events that occur on initiation 21718. Once-nightly dosing is preferred because the proposed transient opioid receptor blockade is hypothesized to be most clinically useful during the overnight period; daytime dosing is described in the literature but is the exception.

Doses above 4.5 mg are sometimes prescribed in clinical practice but are outside the studied range. Doses below 1.5 mg are sometimes used for highly sensitive patients (e.g., starting at 0.5 mg) but have not been independently characterized in the randomized trials. The pediatric Crohn's disease pilot 7 used a weight-based 0.1 mg/kg dose capped at 4.5 mg.

Critical prescriber-level considerations: (1) LDN will precipitate opioid withdrawal in opioid-dependent patients, and (2) LDN will partially blunt the analgesic effect of opioid agonists. Patients on chronic opioid analgesia (including buprenorphine-containing products) or in opioid-use-disorder maintenance should not receive LDN. The pharmacist's review confirms absence of these contraindications at every dispense 2517.

Doses listed are literature context, not patient instructions. Dosing decisions are made by the prescribing doctor and tailored to the individual patient.

Safety

Low-Dose Naltrexone (LDN) Safety

Safety overview

Low-dose naltrexone has a favorable safety profile across the published evidence. The most-frequent adverse events in the randomized fibromyalgia and Crohn's trials are vivid or unusual dreams, transient sleep disturbance during initiation, and mild gastrointestinal upset 264. These effects are typically self-limited or resolved by dose reduction. In the Younger 2013 fibromyalgia trial 2, adverse events did not differ meaningfully between LDN and placebo periods. The Toljan-Vrooman 2018 review 17 and Patten 2018 review 18 consolidate safety across the broader off-label evidence and characterize LDN as well-tolerated at the 1, 4.5 mg dose range.

The pharmacology-driven safety considerations relate to concomitant opioid exposure rather than to LDN itself. LDN will precipitate withdrawal in opioid-dependent patients, this is a class effect of opioid receptor antagonists 2526 and applies at the low-dose range as well as the FDA-approved 50 mg or 380 mg doses, though with smaller magnitude. LDN will partially blunt the analgesic effect of opioid agonists, including buprenorphine-containing products and tramadol. Patients on chronic opioid analgesia or in opioid-use-disorder maintenance should not be initiated on LDN.

Hepatotoxicity warnings carried on the FDA-approved 50 mg and 380 mg products were derived from studies at supratherapeutic (300 mg/day) doses 25. At LDN doses, hepatic adverse events have not been reported in the randomized trial corpus, and baseline-and-follow-up liver function monitoring is not routinely required, though prescribers commonly check liver enzymes at baseline. The Younger 2014 review 3 and Toljan-Vrooman 2018 review 17 both characterize hepatic safety at LDN doses as a non-issue in the published evidence.

Special situations: emergency analgesia in a patient on LDN may require higher-than-usual opioid doses to overcome the partial receptor blockade, patients should carry a wallet card or medical alert documenting LDN use. Surgical anesthesia planning should account for LDN; the typical recommendation is to discontinue LDN 24, 48 hours before scheduled surgery requiring opioid analgesia.

Contraindications

LDN is contraindicated in: current opioid dependence (precipitated withdrawal); patients receiving chronic opioid analgesia where opioid effect cannot be safely blunted; patients on buprenorphine-containing products (precipitated withdrawal); known hypersensitivity to naltrexone or any compounded excipient 252617.

LDN should be used with caution in: acute hepatitis or liver failure (despite the absence of LDN-dose hepatotoxicity in the randomized literature, the FDA-approved labels carry hepatotoxicity warnings at supratherapeutic doses and prescribers reasonably avoid LDN in active liver injury); pregnancy and lactation (no controlled human safety data at LDN doses; full-dose naltrexone is FDA Pregnancy Category C); and patients with anticipated need for opioid analgesia (planned surgery, oncology pain management).

Drug interactions

The dominant interaction is with opioid receptor agonists. LDN partially blocks mu-opioid receptors during its dosing interval (~4, 6 hours after a 4.5 mg dose) and will: (1) precipitate withdrawal in opioid-dependent patients, (2) blunt the analgesic effect of full mu-agonists (morphine, oxycodone, hydrocodone, fentanyl) given concurrently, and (3) precipitate withdrawal in patients on buprenorphine-containing products 2526. Tramadol's mu-agonist component is similarly affected.

Naltrexone is metabolized primarily by dihydrodiol dehydrogenase (a non-CYP enzyme) to 6-β-naltrexol, the active metabolite. CYP450-mediated drug interactions are not a clinically significant concern at LDN doses 2517. No specific drug-drug interactions outside the opioid class have been highlighted in the LDN trial literature.

Adverse events

Across the published randomized trials and review literature, the most commonly reported adverse events with LDN are: vivid or unusual dreams (10, 37% across trials, typically diminishing after the first 1, 2 weeks), insomnia or transient sleep disturbance during initiation (5, 20%), mild gastrointestinal upset (5, 15%), and headache (5, 10%). Adverse-event-driven discontinuation in the randomized trials has been low (<10%) and not different from placebo arms 9.

The Cree 2010 MS trial 10 reported a similar adverse-event rate between LDN and placebo periods in the crossover design. The Smith 2011 Crohn's trial 6 reported a comparable adverse-event rate between LDN and placebo arms with no serious adverse events attributed to study drug. The Younger 2013 fibromyalgia trial 2 reported no significant difference in adverse events between the LDN and placebo treatment periods 4. The Patten 2018 review 18 and Toljan-Vrooman 2018 review 17 consolidate the overall AE profile as mild and self-limited at the studied doses.

Rare events reported in case-level literature include mood changes (rarely worsened depression, more often improved mood as a co-effect of pain reduction), and very rare reports of transaminase elevation; the 2017 Norwegian pharmacoepidemiology analysis 23 did not identify a population-level adverse-event signal in approximately 11,000 LDN prescription episodes 19.

Monitoring

Monitoring Low-Dose Naltrexone (LDN) Therapy

Baseline assessment: review of current and anticipated opioid use (including buprenorphine-containing products, tramadol, and opioid-containing cough preparations), confirmation of indication consistent with published off-label literature, and review of baseline pain or disease-activity scores against which response can be judged 2. Many prescribers obtain baseline liver enzymes despite the absence of LDN-dose hepatotoxicity in the trial literature; this is reasonable but not strictly required by the published evidence 2517.

On therapy: re-assessment of symptoms at 8, 12 weeks against the baseline (the duration over which the randomized fibromyalgia and Crohn's trials demonstrated treatment effect) 26. Patients who do not respond at 12 weeks at the 4.5 mg dose are unlikely to respond with continued dosing and may be candidates for discontinuation or alternative therapy. Patients who respond should be reassessed periodically and continued indefinitely while clinically beneficial. Dose adjustment for adverse events is typically downward to 3 mg or 1.5 mg with re-titration as tolerated.

Special populations

Low-Dose Naltrexone (LDN) in Special Populations

Pregnancy

There are no controlled human safety data for low-dose naltrexone during pregnancy. The FDA-approved full-dose naltrexone products carry FDA Pregnancy Category C labeling on the basis of animal studies showing developmental effects at exposures higher than those used clinically. The standard clinical practice is to discontinue LDN before a planned pregnancy or as soon as pregnancy is confirmed, unless the clinical indication is severe enough that benefit clearly outweighs the unknown risk 2517.

Lactation

Limited human lactation data are available. Naltrexone and its active metabolite are excreted in breast milk in small quantities at full doses; the magnitude at LDN doses is presumed to be substantially lower but has not been independently characterized. The standard recommendation is to weigh the developmental and health benefits of breastfeeding against the clinical need for LDN and any potential effect on the breastfed infant 25.

Pediatric

The only published pediatric LDN trial is the Smith 2013 open-label Crohn's disease pilot in adolescents 7, which used 0.1 mg/kg once nightly (capped at 4.5 mg) for 8 weeks and reported tolerability and within-subject CDAI signal in 12 patients. There are no randomized trials of LDN in children for fibromyalgia, multiple sclerosis, or any other indication. The Roy 2015 systematic review 13 of opioid antagonists for autism spectrum conditions in children concluded the evidence did not support efficacy for core symptoms.

Geriatric

Older adults have been included in the LDN randomized trials but have not been separately analyzed. No age-specific dose adjustment is supported by the published evidence; the standard initiation and titration schedule applies 17.

Renal impairment

Naltrexone is metabolized hepatically; renal clearance is a minor pathway 17. No dose adjustment is supported by the published LDN evidence on the basis of renal function. The FDA-approved full-dose labeling notes caution in significant renal impairment without specific dose recommendations 25.

Hepatic impairment

Naltrexone is metabolized hepatically. The FDA-approved 50 mg label carries hepatotoxicity warnings derived from supratherapeutic-dose (300 mg/day) studies; at the 1, 4.5 mg LDN range, hepatic adverse events have not been reported in the randomized trial corpus 25173. LDN should still be avoided in active liver injury or acute hepatitis.

Evidence quality

Low-Dose Naltrexone (LDN) Evidence Quality

The LDN evidence base is heterogeneous and small-trial-dominated. The strongest signals are in fibromyalgia (Stanford 12, Danish 3132, and Mayo Clinic real-world 33 data, plus a mechanistic cytokine demonstration 4 and meta-analytic synthesis 3435) and Crohn's disease (three Penn State trials 567, a Dutch observational cohort 36, plus two Cochrane reviews 837). Multiple sclerosis evidence comprises three small randomized or prospective trials 38910 plus observational pharmacoepidemiology 2324. Other indications (CRPS 1239, Hailey-Hailey disease 40, other inflammatory skin disease 141516, ME/CFS, long COVID 4142, chronic non-malignant pain) rest on case series, systematic reviews of case-level evidence, or small open-label work. No multi-center phase III trial has been completed in any LDN indication; the Due Bruun 2024 trial 32 is the largest LDN RCT to date and did not reach its primary endpoint, although it showed favorable secondary signals.

Effect sizes in the randomized trials are clinically meaningful where reported, a 28.8% vs 18.0% pain reduction in fibromyalgia 2, 78% vs 28% clinical response in Crohn's disease 6, improvement in MSQOL-54 mental health domain in MS 9, but the trials are small (n=31, 40, 96 respectively) and single-center. The Due Bruun 2024 trial (n=99) 32, although the largest LDN-fibromyalgia RCT to date, did not reach its primary pain endpoint at 6 mg over 12 weeks, complicating the simple narrative that LDN is unambiguously efficacious in fibromyalgia 19. The Vatvani 2024 meta-analysis with trial-sequential analysis 34 characterizes the pooled evidence as consistent in direction but underpowered for definitive conclusion. The Cochrane reviews 837 explicitly characterize the Crohn's evidence as low-certainty, and the Patten 2018 18, Toljan-Vrooman 2018 17, and Leiber-Parker 2025 45 reviews all note that the consistent direction of effect across small trials must be confirmed in larger, multi-center studies before LDN can be recommended as first-line therapy in any indication.

Mechanistic plausibility is on stronger footing. The transient-opioid-blockade rationale articulated by Bihari and consolidated by Younger and Toljan 317 is biologically coherent and consistent with the modest, short-duration receptor occupancy expected at 4.5 mg doses. The TLR4 glial mechanism 11 provides an opioid-receptor-independent pathway that is supported by the Parkitny 2017 cytokine demonstration 4 in humans and the rodent neuropathic pain work in the Hutchinson laboratory. The TRPM3-restoration mechanism in NK cells 214322 provides a third candidate mechanism specifically relevant to ME/CFS and possibly to overlapping post-acute COVID symptomatology. The combination of mechanistic plausibility with consistent (if small) randomized signals supports the Tier 2 (well-studied for the compound) posture in fibromyalgia and Crohn's disease and an emerging-evidence posture for MS, CRPS, dermatologic disease, ME/CFS, and long COVID. The 2024 Due Bruun null primary endpoint 32 is the most important counter-signal in the literature and is appropriately reflected in this brief's posture: LDN is reasonable as a Tier 2 option for selected fibromyalgia patients but cannot be characterized as definitively proven 44.

Major studies

Major Low-Dose Naltrexone (LDN) Clinical Studies

StudyDesignParticipantsDurationFinding
Younger and Mackey (2009, Pain Med), fibromyalgia pilot Open-label, single-blind, single-site within-subject crossover pilot trial of 4.5 mg LDN at Stanford 10 14 weeks (4 weeks baseline, 8 weeks treatment, 2 weeks washout) Approximately 30% within-subject reduction in fibromyalgia symptom score on 4.5 mg LDN compared with baseline; established feasibility and tolerability for the subsequent randomized trial 1
Younger et al. (2013, Arthritis Rheum), fibromyalgia RCT Randomized, double-blind, placebo-controlled, single-site crossover trial of 4.5 mg LDN vs placebo 31 12 weeks active treatment per period 28.8% reduction in fibromyalgia pain on 4.5 mg LDN vs 18.0% on placebo; greater responder rate (≥30% pain reduction) on LDN; no significant difference in adverse events between periods 2
Parkitny and Younger (2017, Biomedicines), fibromyalgia cytokine PD Open-label, within-subject assessment of serum pro-inflammatory cytokines before and after 8 weeks of 4.5 mg LDN 8 8 weeks Significant reductions in serum IL-1β, IL-6, and TNF-α after 8 weeks of LDN; provides human pharmacodynamic substrate for the TLR4/glial mechanism 4
Younger et al. (2014, Clin Rheumatol), LDN anti-inflammatory review Narrative review of LDN mechanism and clinical evidence in chronic pain and autoimmune conditions — — Consolidates the opioid-rebound and TLR4-glial mechanisms with the contemporary clinical evidence; characterizes LDN as a novel anti-inflammatory modality with the strongest signals in fibromyalgia and Crohn's disease 3
Smith et al. (2007, Am J Gastroenterol), Crohn's open-label pilot Open-label, single-site pilot trial of 4.5 mg LDN in adults with active Crohn's disease 17 12 weeks Significant within-subject reduction in CDAI on 4.5 mg LDN; 67% remission at week 4 and 89% at week 12; established the dose and duration for the subsequent randomized trial 5
Smith et al. (2011, Dig Dis Sci), Crohn's adult RCT Randomized, double-blind, placebo-controlled, single-site trial of 4.5 mg LDN vs placebo with endoscopic confirmation of mucosal healing 40 12 weeks 78% clinical response (≥70-point CDAI reduction) and 33% endoscopic mucosal healing on LDN vs 28% and 8% on placebo; key randomized evidence supporting Tier 2 posture for Crohn's disease 6
Smith et al. (2013, J Clin Gastroenterol), Pediatric Crohn's pilot Open-label pediatric pilot trial of 0.1 mg/kg LDN (capped at 4.5 mg) in adolescents with moderate-to-severe Crohn's disease 12 8 weeks Reduction in pediatric CDAI on LDN with acceptable tolerability; established a pediatric dosing scaffold extending the adult evidence 7
Segal et al. (2014, Cochrane Database Syst Rev), Crohn's Cochrane review Cochrane systematic review and meta-analysis of LDN for induction of remission in Crohn's disease — — Two RCTs (n=46 children plus the adult Smith 2011 RCT) showed a higher rate of clinical response and endoscopic improvement with LDN compared with placebo; the body of evidence was characterized as low-certainty owing to small trial size and single-center conduct, but consistent in direction of effect 8
Sharafaddinzadeh et al. (2010, Mult Scler), Multiple sclerosis RCT Randomized, double-blind, placebo-controlled, single-center trial of 4.5 mg LDN vs placebo in Iranian adults with relapsing-remitting or secondary-progressive multiple sclerosis 96 17 weeks Significant improvement in the mental health domain of MSQOL-54 on LDN; no demonstrated effect on disability progression or relapse rate 9
Cree et al. (2010, Ann Neurol), Multiple sclerosis crossover RCT Randomized, double-blind, placebo-controlled, single-center crossover trial of 4.5 mg LDN vs placebo in U.S. adults with multiple sclerosis 80 8 weeks per period Improvement in self-reported quality of life on LDN; no demonstrated effect on disability progression; favorable tolerability with no severe adverse events 10
Hutchinson et al. (2008, Eur J Neurosci), TLR4 mechanism Preclinical mechanistic study in rodent neuropathic pain models with stereoselective and non-stereoselective opioid antagonists, including TLR4-knockout animals — — Both naloxone and naltrexone, and their R-enantiomers, which do not bind opioid receptors, reverse neuropathic pain hypersensitivity through TLR4 antagonism on microglia; established the opioid-receptor-independent mechanism that underpins much of the LDN clinical rationale 11
Chopra and Cooper (2013, J Neuroimmune Pharmacol), CRPS case series Case series of LDN in complex regional pain syndrome 2 — Sustained symptom and functional improvement on 4.5 mg LDN in two patients with longstanding CRPS; first published evidence supporting LDN in CRPS 12
Roy et al. (2015, J Intellect Disabil Res), Autism systematic review Systematic review of opioid antagonists (including low-dose naltrexone) for core symptoms of autism spectrum conditions in children — — Available evidence does not support efficacy of opioid antagonists for core autism symptoms; concluded that LDN should not be recommended on the basis of the published trial corpus for this indication 13
Bridgman and Bruce-Brand (2018, JAAD Case Rep), Psoriasis case Single-patient case report of LDN in psoriasis vulgaris 1 — Sustained clearance of psoriasis vulgaris on 4.5 mg LDN; first published case-level evidence in psoriasis 14
Ekelem et al. (2019, JAMA Dermatol), Dermatologic systematic review Systematic review of LDN in chronic inflammatory dermatologic conditions — — Reviewed available evidence across Hailey-Hailey disease, lichen planopilaris, psoriasis, and other chronic inflammatory dermatologic conditions; most evidence at case-series level, with consistent direction of effect supporting further controlled study 15
Frech et al. (2011, Int J Rheumatol), Systemic sclerosis pruritus Open-label case series of LDN for pruritus in systemic sclerosis 3 — Improvement in pruritus with 4.5 mg LDN in three patients with systemic sclerosis 16
Toljan and Vrooman (2018, Med Sci), Comprehensive therapeutic-utilization review Narrative review of LDN therapeutic utilization across autoimmune, inflammatory, and chronic pain conditions — — Consolidates mechanism (transient opioid antagonism plus TLR4/glial modulation) and clinical evidence; characterizes LDN as a low-risk modality with the strongest evidence in fibromyalgia and Crohn's disease and emerging evidence across multiple sclerosis, CRPS, inflammatory dermatologic disease, and chronic non-malignant pain 17
Patten et al. (2018, Pharmacotherapy), Safety and efficacy review Narrative review of LDN safety and efficacy in multiple sclerosis, fibromyalgia, and Crohn's disease — — Characterizes LDN as well-tolerated at 1, 4.5 mg with mild and self-limited adverse events; reviews efficacy signals across the three major indications with consistent direction of effect across small randomized and open-label studies 18
Trofimovitch and Baumrucker (2019, Am J Hosp Palliat Care), Palliative care update Pharmacology update reviewing LDN as a nonopioid modality for chronic non-malignant pain — — Synthesizes the LDN chronic-pain evidence base for palliative care and chronic-pain practitioners; recommends LDN as a reasonable option in selected chronic non-malignant pain patients given the favorable safety profile 19
Brown and Panksepp (2009, Med Hypotheses), Clinical-rationale review Narrative review consolidating the LDN clinical-rationale literature for disease prevention and quality-of-life applications — — Establishes the contemporary framing of LDN as an immune-modulating, low-side-effect option across a heterogeneous indication catalog; supports continued randomized evaluation 20
Raknes and Småbrekke (2017, Pharmacoepidemiol Drug Saf), Norway prescribing surge Drug utilization analysis of LDN prescribing in Norway following a 2013 national-media-driven surge in prescriptions 11247 2013, 2014 dispensing window Documented an unprecedented surge in LDN prescribing with patient and prescriber characteristics consistent with autoimmune and chronic pain indications; provides observational real-world signal at population scale 23
Raknes and Småbrekke (2017, PLoS One), MS medication-use change Quasi-experimental analysis of co-medication use among new LDN users with multiple sclerosis in Norwegian prescription registry — — Reduced use of co-medications (including immunomodulators and analgesics) among new LDN-prescribed MS patients; observational and not causal but consistent with the small-RCT signals 24
Cabanas et al. (2019, Front Immunol), ME/CFS TRPM3 mechanism Translational electrophysiology study of TRPM3 ion channel function in natural killer cells from ME/CFS patients vs healthy controls — — Demonstrates that naltrexone restores impaired TRPM3 channel function in NK cells from ME/CFS patients; provides mechanistic basis for the off-label use that had accumulated in clinical practice 21
Eaton-Fitch et al. (2022, J Transl Med), ME/CFS TRPM3 confirmation Translational electrophysiology study extending the TRPM3/NK-cell pharmacodynamic finding in a larger ME/CFS cohort — — Confirms impaired TRPM3-dependent calcium influx in ME/CFS NK cells and restoration by naltrexone; supports continued investigation of LDN in this indication 22
Bruun-Plesner et al. (2020, Pain Med), Fibromyalgia dose-response Open-label dose-response investigation of LDN across 1.0, 2.0, 3.0, 4.0, 4.5, and 6.0 mg in women with fibromyalgia 25 Up to 22 weeks per participant across escalating-dose periods Identified 3.88 mg as the modal effective dose with substantial inter-individual variability; informs the rationale for individualized titration rather than a fixed 4.5 mg target 31
Due Bruun et al. (2024, Lancet Rheumatol), Fibromyalgia RCT (FINAL trial) Randomized, double-blind, placebo-controlled, single-center parallel-group trial of naltrexone 6 mg once daily vs placebo in women with fibromyalgia 99 12 weeks Primary endpoint (between-group difference in 0, 10 NRS pain at week 12) did not reach statistical significance, although the LDN arm showed a numerically larger improvement and a significant FIQR memory-domain benefit; largest LDN-fibromyalgia RCT to date and the first to use the Danish Sygehus Sønderjylland 6 mg formulation 32
Driver and D'Souza (2023, Biomedicines), Mayo Clinic 14-year retrospective Enterprise-wide retrospective analysis of LDN-treated patients across fibromyalgia and other chronic pain conditions at Mayo Clinic 115 14 years (2008, 2022) 65% symptomatic improvement rate on LDN; identified body-pain extent and prior opioid exposure as predictors of treatment discontinuation; largest real-world LDN dataset in chronic pain to date 33
Vatvani et al. (2024, Korean J Pain), Fibromyalgia meta-analysis Systematic review and meta-analysis of randomized controlled trials of LDN in fibromyalgia, with trial-sequential analysis — — Direction of effect consistent with benefit across pooled trials; trial-sequential analysis indicates further RCTs are required for definitive conclusion on efficacy; characterizes safety profile as favorable across the pooled corpus 34
Lie et al. (2018, J Transl Med), Erasmus MC IBD cohort Observational cohort of LDN 4.5 mg in adult patients with active Crohn's disease and ulcerative colitis at the Erasmus MC IBD center, Netherlands — — Reported tolerability and clinical benefit in IBD patients, extending the Smith laboratory Crohn's evidence into a European observational cohort 36
Parker et al. (2018, Cochrane Database Syst Rev), Updated Crohn's Cochrane review Updated Cochrane systematic review and meta-analysis of LDN for induction of remission in Crohn's disease, replacing the 2014 Segal review — — Two RCTs in adults and one pediatric trial showed a higher rate of clinical response and endoscopic improvement with LDN compared with placebo; body of evidence remained low-certainty owing to small trial size 37
Gironi et al. (2008, Mult Scler), Primary progressive MS pilot Prospective single-arm pilot trial of 4.5 mg LDN in primary progressive multiple sclerosis 40 6 months Tolerability and modest signal on quality-of-life and spasticity outcomes; first prospective LDN-MS trial and precursor to the Sharafaddinzadeh and Cree randomized work 38
Soin et al. (2021, Pain Physician), CRPS systematic review Systematic literature review of LDN for chronic regional pain syndrome — — Identified case-series and small-case-report evidence supporting the Chopra and Cooper findings; no randomized trial evidence; recommended controlled investigation given consistent direction of small-case response 39
Albers et al. (2017, JAMA Dermatol), Hailey-Hailey case series Case series of LDN in recalcitrant Hailey-Hailey disease at the Emory University Department of Dermatology 3 — Sustained clearance of recalcitrant Hailey-Hailey lesions in three patients on 3.0, 4.5 mg LDN; first peer-reviewed evidence in this rare autosomal-dominant acantholytic disease 40
O'Kelly et al. (2022, Brain Behav Immun Health), Long COVID open-label Single-arm interventional pre-post study of 1.0, 4.5 mg LDN over 2 months in long COVID at the Mater Misericordiae long-COVID clinic, Dublin 38 8 weeks Significant improvement in WHO long-COVID symptom-score domains including recovery from acute illness, mobility, daily activities, energy, pain, sleep, and concentration; first prospective LDN-long-COVID dataset 41
Bonilla et al. (2023, Int Immunopharmacol), Stanford long COVID retrospective Retrospective cohort of LDN-treated long-COVID patients at Stanford 59 2 months mean follow-up Improvement in fatigue, post-exertional malaise, and pain-domain scores over 2 months of LDN; uncontrolled but consistent with the O'Kelly findings 42

Mechanism detail

Detailed Mechanism of Low-Dose Naltrexone (LDN)

Naltrexone is a competitive antagonist at mu-, kappa-, and delta-opioid receptors with highest affinity at mu. Oral bioavailability of the parent compound is approximately 5, 40% due to extensive first-pass metabolism to 6-β-naltrexol, an active metabolite with longer half-life that contributes to clinical effect. Plasma half-life of the parent is approximately 4 hours; the metabolite extends pharmacodynamic effect to approximately 10, 12 hours 25. At the 50 mg dose used for substance-use disorder, central mu-opioid receptor occupancy is essentially complete throughout the dosing interval. At 4.5 mg, occupancy is partial and short-lived, supporting the 'transient blockade' rationale for LDN.

The endogenous opioid rebound hypothesis was articulated by Bihari and colleagues in the 1980s and reviewed in the modern era by Younger and Mackey (2014) and Toljan and Vrooman (2018) 317. Mechanistically, brief mu-opioid antagonism is proposed to relieve negative feedback inhibition on enkephalinergic and beta-endorphin neurons in the periaqueductal gray, hypothalamus, and dorsal horn, leading to a compensatory increase in endogenous opioid peptide synthesis and receptor sensitivity. Once the antagonist clears, the upregulated system is hypothesized to produce a net analgesic, anti-inflammatory state. Direct human pharmacodynamic measurements of this rebound effect remain limited.

The TLR4 mechanism is independent of opioid receptor binding. Hutchinson and colleagues (2008) demonstrated that the R-enantiomers of naloxone and naltrexone, which do not bind opioid receptors, reverse neuropathic pain hypersensitivity in rodent models, and that this effect is abolished in TLR4-knockout animals 11. TLR4 is expressed on microglia, astrocytes, and peripheral macrophages; its activation drives a pro-inflammatory transcriptional program including IL-1β, IL-6, and TNF-α. Antagonism of TLR4 by low-dose naltrexone is proposed to dampen the central neuroinflammatory state underlying fibromyalgia central sensitization, multiple sclerosis disease activity, and inflammatory bowel disease symptomatology. The Parkitny and Younger (2017) demonstration that 8 weeks of LDN reduced serum IL-1β, IL-6, and TNF-α in women with fibromyalgia 4 provides indirect human pharmacodynamic support for the TLR4 mechanism.

A third hypothesis, relevant specifically to Crohn's disease, is direct enteric mucosal healing through opioid growth factor (OGF, -enkephalin) and the OGF-receptor (OGFr) axis 67. Brief mu-antagonism with low-dose naltrexone is proposed to alter OGF tone in intestinal epithelium, supporting mucosal repair. This rationale, developed in the Smith laboratory at Penn State, motivated the placebo-controlled trial design 6 that demonstrated endoscopic mucosal healing as a secondary endpoint.

Pharmacology

Low-Dose Naltrexone (LDN) Pharmacokinetics & Pharmacodynamics

Pharmacokinetics

Naltrexone is well absorbed after oral administration with extensive first-pass metabolism. The foundational human pharmacokinetic characterization is Verebey et al. (1976, Clin Pharmacol Ther) 30 in opioid-dependent volunteers receiving 50, 200 mg oral doses, which established the disposition profile that is carried into modern LDN dosing. Oral bioavailability of the parent compound is approximately 5, 40%; the principal active metabolite is 6-β-naltrexol, formed by dihydrodiol dehydrogenase. Plasma half-life of the parent is approximately 4 hours and of 6-β-naltrexol approximately 12 hours 2530. Time to maximum plasma concentration after an oral dose is approximately 1 hour. Naltrexone and its metabolite are eliminated primarily via the kidneys. LDN-specific human pharmacokinetic data at the 0.5, 4.5 mg dose range are sparse, most published PK characterization is at the 50, 200 mg FDA-approved dose range, and LDN-dose disposition is inferred by linear extrapolation.

At the 4.5 mg LDN dose, plasma concentrations are correspondingly lower than at the 50 mg FDA-approved dose, and central mu-opioid receptor occupancy is partial and short-lived (~4, 6 hours). This brief, partial occupancy is the pharmacokinetic substrate for the proposed transient-blockade-and-rebound mechanism articulated by Younger (2014) and Toljan-Vrooman (2018) 317. Compounded preparations may show modest formulation-specific differences in absorption rate and bioavailability that have not been independently characterized in PK studies.

Pharmacodynamics

Pharmacodynamic effects of LDN that have been characterized in human studies include reduction in serum pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) over 8 weeks of treatment 4, improvement in patient-reported pain and symptom-day scores in fibromyalgia 12, reduction in CDAI and endoscopic mucosal-healing rate in Crohn's disease 67, and restoration of TRPM3 ion channel function in NK cells in ME/CFS 2122. The TLR4 antagonist activity demonstrated preclinically by Hutchinson et al. (2008) 11 is the proposed mechanistic substrate for the cytokine and pain-modulation effects.

Direct human in vivo PD characterization of the proposed endogenous-opioid rebound (β-endorphin, met-enkephalin, OGF dynamics) remains limited. Most of the human PD evidence for LDN is captured at the clinical-endpoint level rather than at the biochemical-target level.

Comparative formulations

Comparing Low-Dose Naltrexone (LDN) Formulations

There is no manufactured low-dose naltrexone product on the U.S 2910. market. The FDA-approved naltrexone products are ReVia (50 mg oral tablet) and Vivitrol (380 mg IM extended-release suspension), both used at full mu-opioid-blockade doses for substance-use disorder, mechanistically and clinically distinct from LDN 2526 6.

Compounded LDN preparations vary in capsule shell, filler, and overage tolerance per the compounding pharmacy. The randomized trials used pharmacy-prepared 4.5 mg oral preparations; cross-pharmacy bioequivalence has not been independently characterized 2. Patients who respond to LDN at one pharmacy and lose response on switching pharmacies should consider whether the formulation has changed.

Storage

Low-Dose Naltrexone (LDN) Storage and Handling

Compounded LDN oral capsules are stored at controlled room temperature (20, 25°C) in tight, light-resistant containers, with beyond-use date assigned per USP General Chapter <795> for nonsterile compounded preparations 29. The manufactured naltrexone 50 mg tablet is also stored at room temperature.

Cold-chain handling is not required for LDN oral capsules.

RonanRx operations

Low-Dose Naltrexone (LDN) Compounding & Operations

503A compounding

Low-dose naltrexone is prepared under 503A on patient-specific prescriptions in state-licensed compounding pharmacies. RonanRx prepares LDN oral capsules per USP General Chapter <795> for nonsterile pharmaceutical compounding, with documented active ingredient sourcing, weight-verification at sub-milligram strengths, content-uniformity verification per the pharmacy's quality-management system, and full lot traceability 29 28. Because the most-studied LDN doses (0.5, 4.5 mg) are an order of magnitude below the smallest commercially manufactured naltrexone strength, sub-milligram weighing accuracy is the principal quality-control consideration; pharmacies typically use trituration with a compatible filler (microcrystalline cellulose or similar) followed by capsule blending to achieve consistent dose-per-capsule.

Beyond-use dating, ingredient identity verification, and content-uniformity assessment follow USP <795> requirements 28. Each compounded batch is documented per state board of pharmacy retention rules with full traceability from API lot through dispensing.

Because no FDA-approved low-dose naltrexone product exists, LDN is not 'essentially a copy' of an approved drug in the sense intended by section 503A's essentially-a-copy restriction 27 28. The compounded preparation is the only way to access naltrexone at the studied LDN dose range.

Pharmacist review

Each prescription for compounded LDN undergoes pharmacist review prior to dispensing. The review confirms: a prescribed indication consistent with the published off-label literature (fibromyalgia, Crohn's disease, multiple sclerosis, complex regional pain syndrome, inflammatory dermatologic disease, ME/CFS, chronic non-malignant pain); a prescribed dose within the studied 0.5, 4.5 mg range; and the absence of concomitant opioid analgesia (full mu-agonists, buprenorphine-containing products, tramadol with mu-agonist component) or opioid-use-disorder maintenance therapy that would be incompatible with LDN 2517 26.

RonanRx does not fill prescriptions for LDN at doses substantially above 4.5 mg (which approach the manufactured 50 mg use case and lose the LDN-specific therapeutic rationale), and confirms with prescribers when the indication or dose falls outside the studied evidence base. The pharmacist also confirms patient understanding of: the off-label nature of LDN use; the absence of an FDA-approved low-dose product; the once-nightly dosing schedule and titration; the requirement to disclose LDN use before any surgical procedure or initiation of opioid analgesia; and the absence of demonstrated benefit for autism spectrum core symptoms 13 2.

Quality and traceability

Active pharmaceutical ingredient (naltrexone HCl) is sourced from FDA-registered facilities with documented certificates of analysis. Each compounded LDN batch is recorded with lot numbers traceable to API source, compounding date, beyond-use date, content-uniformity verification, and dispensing pharmacist of record. Finished product lot records are retained per state board of pharmacy retention requirements.

Cold chain

LDN oral capsules are not a cold-chain product. Standard controlled room-temperature storage applies. Shipping is performed at ambient temperature with no special temperature handling required.

FAQ

Frequently Asked Questions About Low-Dose Naltrexone (LDN)

What is low-dose naltrexone (LDN)?

LDN is a compounded preparation of naltrexone hydrochloride at 0.5, 4.5 mg once daily, about one-tenth the FDA-approved 50 mg oral dose used for opioid- and alcohol-use disorder 25. There is no commercial low-dose product on the U.S 17. market, so LDN is always prepared by a compounding pharmacy on a patient-specific prescription.

Is LDN FDA-approved?

No. The FDA-approved naltrexone products are ReVia (50 mg oral tablet) and Vivitrol (380 mg intramuscular extended-release suspension), both for substance-use disorder 2526. LDN at 0.5, 4.5 mg is not FDA-approved for any indication. It is prescribed off-label on the basis of the published clinical literature.

What is LDN used for?

Off-label prescribing is most common for fibromyalgia, Crohn's disease, and multiple sclerosis, where small randomized trials support a Tier 2 (well-studied) posture 269. LDN is also used in complex regional pain syndrome, inflammatory dermatologic conditions, myalgic encephalomyelitis/chronic fatigue syndrome, and chronic non-malignant pain, where the evidence is at the case-series or systematic-review level 17 18.

How does LDN work?

Two mechanisms are proposed and both are likely operative. First, brief partial blockade of mu-opioid receptors during the ~4, 6-hour dosing interval is hypothesized to trigger a compensatory increase in endogenous opioid (β-endorphin, met-enkephalin) tone after the drug clears 4. Second, naltrexone antagonizes Toll-like receptor 4 on microglia, dampening glial pro-inflammatory cytokine release, a mechanism independent of opioid receptors that is supported by the Parkitny 2017 demonstration of reduced serum IL-1β, IL-6, and TNF-α after 8 weeks of LDN 31711.

What is the standard LDN dose?

4.5 mg once nightly is the dose used in the randomized fibromyalgia and Crohn's disease trials 26. Most prescribers titrate from 1.5 mg for 1, 2 weeks, to 3 mg for 1, 2 weeks, to a 4.5 mg maintenance dose to minimize initiation-related sleep disturbance and vivid dreams 17.

What are the side effects?

Most common are vivid or unusual dreams, transient sleep disturbance during initiation, mild gastrointestinal upset, and headache. These typically diminish over the first 1, 2 weeks 18. Adverse-event discontinuation rates in the randomized trials have been low and not different from placebo arms 2617.

Can I take LDN with pain medication?

Not with opioid pain medications. LDN blocks mu-opioid receptors during its dosing interval and will blunt the effect of opioid analgesics (morphine, oxycodone, hydrocodone, fentanyl, tramadol) and precipitate withdrawal in patients on buprenorphine-containing products or in opioid-use-disorder maintenance. Non-opioid analgesics (acetaminophen, NSAIDs, gabapentinoids, antidepressant-class analgesics) are compatible with LDN 2517.

Is LDN safe in pregnancy or breastfeeding?

There are no controlled human safety data for LDN in pregnancy. The full-dose product is FDA Pregnancy Category C. Standard clinical practice is to discontinue LDN before a planned pregnancy or as soon as pregnancy is confirmed unless the clinical indication is severe. Lactation data are limited; the manufactured-product label notes excretion in breast milk at full doses 2517.

Why isn't LDN available as a commercial product?

Naltrexone went off patent decades ago, and no manufacturer has pursued FDA approval for the low-dose indication 173. The randomized evidence base, while consistent in direction across small trials, has not been brought through a multi-center phase III program that would support a new manufactured product. Compounded LDN is therefore the standard of clinical practice in this dose range, as well as the standard of evidence 8.

Does RonanRx sell LDN directly to patients?

No. Compounded LDN requires a patient-specific prescription written by a licensed prescriber for an identified patient with a documented clinical indication, plus pharmacist review before dispensing. RonanRx is not a direct-to-consumer storefront 28.

Clinician resource

Download the Low-Dose Naltrexone (LDN) Clinical Monograph (PDF)

The full white paper covers every section on this page plus chemical identity, evidence grading, indication-by-indication summaries, research gaps, and reference appendix. Suitable for sharing with prescribing doctors and pharmacist reviewers.

Download information packet ↓

References

References

  1. [younger2009] Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Medicine. 2009. PMID 19453963. (accessed 2026-05-11)
  2. [younger2013] Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis and Rheumatism. 2013. PMID 23359310. (accessed 2026-05-11)
  3. [younger2014] Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology. 2014. PMID 24526250. (accessed 2026-05-11)
  4. [parkitny2017] Parkitny L, Younger J. Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia. Biomedicines. 2017. PMID 28536359. (accessed 2026-05-11)
  5. [smith2007] Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Low-dose naltrexone therapy improves active Crohn's disease. American Journal of Gastroenterology. 2007. PMID 17222320. (accessed 2026-05-11)
  6. [smith2011] Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, Zagon IS. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn's disease: a randomized placebo-controlled trial. Digestive Diseases and Sciences. 2011. PMID 21380937. (accessed 2026-05-11)
  7. [smith2013] Smith JP, Field D, Bingaman SI, Evans R, Mauger DT. Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn's disease: a pilot study. Journal of Clinical Gastroenterology. 2013. PMID 23188075. (accessed 2026-05-11)
  8. [segal2014] Segal D, MacDonald JK, Chande N. Low dose naltrexone for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews. 2014. PMID 24558033. (accessed 2026-05-11)
  9. [sharafaddinzadeh2010] Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, Majdinasab N, Shalbafan B. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Multiple Sclerosis. 2010. PMID 20534644. (accessed 2026-05-11)
  10. [cree2010] Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Annals of Neurology. 2010. PMID 20695007. (accessed 2026-05-11)
  11. [hutchinson2008] Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). European Journal of Neuroscience. 2008. PMID 18662331. (accessed 2026-05-11)
  12. [chopra2013] Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). Journal of Neuroimmune Pharmacology. 2013. PMID 23546884. (accessed 2026-05-11)
  13. [roy2015] Roy A, Roy M, Deb S, Unwin G, Roy A. Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. Journal of Intellectual Disability Research. 2015. PMID 24589346. (accessed 2026-05-11)
  14. [bridgman2018] Bridgman AC, Kirchhof MG. Treatment of psoriasis vulgaris using low-dose naltrexone. JAAD Case Reports. 2018. PMID 30238048. (accessed 2026-05-11)
  15. [ekelem2019] Ekelem C, Juhasz M, Khera P, Mesinkovska NA. Utility of Naltrexone Treatment for Chronic Inflammatory Dermatologic Conditions: A Systematic Review. JAMA Dermatology. 2019. PMID 30484835. (accessed 2026-05-11)
  16. [frech2011] Frech T, Novak K, Revelo MP, Murtaugh M, Markewitz B, Hatton N, Scholand MB, Frech E, Markewitz D, Sawitzke AD. Low-dose naltrexone for pruritus in systemic sclerosis. International Journal of Rheumatology. 2011. PMID 21918649. (accessed 2026-05-11)
  17. [toljan2018] Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. Medical Sciences. 2018. PMID 30248938. (accessed 2026-05-11)
  18. [patten2018] Patten DK, Schultz BG, Berlau DJ. The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders. Pharmacotherapy. 2018. PMID 29377216. (accessed 2026-05-11)
  19. [trofimovitch2019] Trofimovitch D, Baumrucker SJ. Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic, Nonmalignant Pain Syndromes. American Journal of Hospice and Palliative Care. 2019. PMID 30917675. (accessed 2026-05-11)
  20. [brown2009] Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Medical Hypotheses. 2009. PMID 19041189. (accessed 2026-05-11)
  21. [cabanas2019] Cabanas H, Muraki K, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S. Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Frontiers in Immunology. 2019. PMID 31736966. (accessed 2026-05-11)
  22. [eatonfitch2022] Eaton-Fitch N, Du Preez S, Cabanas H, Muraki K, Staines D, Marshall-Gradisnik S. Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients. Journal of Translational Medicine. 2022. PMID 35172836. (accessed 2026-05-11)
  23. [raknes2017] Raknes G, Småbrekke L. A sudden and unprecedented increase in low dose naltrexone (LDN) prescribing in Norway. Patient and prescriber characteristics, and dispense patterns. A drug utilization cohort study. Pharmacoepidemiology and Drug Safety. 2017. PMID 27670755. (accessed 2026-05-11)
  24. [raknesIBD2018] Raknes G, Småbrekke L. Low dose naltrexone in multiple sclerosis: Effects on medication use. A quasi-experimental study. PLoS One. 2017. PMID 29099849. (accessed 2026-05-11)
  25. [fda_label_revia] U.S. National Library of Medicine — DailyMed. Naltrexone Hydrochloride Tablet, Film Coated — Prescribing Information (DailyMed). DailyMed Structured Product Labeling. 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21b43dab-015c-c82f-ba6e-27da0ec12fc5 (accessed 2026-05-11)
  26. [fda_label_vivitrol] Alkermes, Inc. (via DailyMed). Vivitrol (Naltrexone) Kit — Prescribing Information (DailyMed). DailyMed Structured Product Labeling. 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd11c435-b0f0-4bb9-ae78-60f101f3703f (accessed 2026-05-11)
  27. [fda_essentially_a_copy] U.S. Food and Drug Administration. Compounded Drug Products That Are Essentially Copies of Approved Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act — Guidance for Industry. FDA Guidance for Industry. 2018. https://www.fda.gov/media/98973/download (accessed 2026-05-11)
  28. [fda503a] U.S. Food and Drug Administration. Compounding Laws and Policies — Section 503A of the Federal Food, Drug, and Cosmetic Act. FDA Drug Compounding. 2024. https://www.fda.gov/drugs/human-drug-compounding/compounding-laws-and-policies (accessed 2026-05-11)
  29. [usp_795] United States Pharmacopeia. USP General Chapter <795> Pharmaceutical Compounding — Nonsterile Preparations. USP Compounding Compendium. 2023. https://www.usp.org/compounding/general-chapter-795 (accessed 2026-05-11)
  30. [verebey1976] Verebey K, Volavka J, Mulé SJ, Resnick RB. Naltrexone: disposition, metabolism, and effects after acute and chronic dosing.. Clinical Pharmacology and Therapeutics. 1976. PMID 954353. (accessed 2026-05-11)
  31. [bruunPlesner2020] Bruun-Plesner K, Blichfeldt-Eckhardt MR, Vaegter HB, Lauridsen JT, Amris K, Toft P. Low-Dose Naltrexone for the Treatment of Fibromyalgia: Investigation of Dose-Response Relationships.. Pain Medicine. 2020. PMID 32068870. (accessed 2026-05-11)
  32. [dueBruun2024] Due Bruun K, Christensen R, Amris K, Vaegter HB, Blichfeldt-Eckhardt MR, Bye-Møller L, Astrup BS, Wæhrens EE, Toft P. Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial.. The Lancet Rheumatology. 2024. PMID 38258677. (accessed 2026-05-11)
  33. [driver2023] Driver CN, D'Souza RS. Efficacy of Low-Dose Naltrexone and Predictors of Treatment Success or Discontinuation in Fibromyalgia and Other Chronic Pain Conditions: A Fourteen-Year, Enterprise-Wide Retrospective Analysis.. Biomedicines. 2023. PMID 37189705. (accessed 2026-05-11)
  34. [vatvani2024] Vatvani AD, Patel P, Hariyanto TI, Yanto TA. Efficacy and safety of low-dose naltrexone for the management of fibromyalgia: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.. The Korean Journal of Pain. 2024. PMID 39344363. (accessed 2026-05-11)
  35. [partridge2023] Partridge S, Quadt L, Bolton M, Eccles J, Thompson C, Colasanti A, Bremner S, Burrage J, Campbell C, Cipinova V, Critchley H, Davies G, Garfinkel S. A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia.. Heliyon. 2023. PMID 37206027. (accessed 2026-05-11)
  36. [lie2018] Lie MRKL, van der Giessen J, Fuhler GM, de Lima A, Peppelenbosch MP, van der Ent C, van der Woude CJ. Low dose Naltrexone for induction of remission in inflammatory bowel disease patients.. Journal of Translational Medicine. 2018. PMID 29523156. (accessed 2026-05-11)
  37. [parker2018] Parker CE, Nguyen TM, Segal D, MacDonald JK, Chande N. Low dose naltrexone for induction of remission in Crohn's disease.. Cochrane Database of Systematic Reviews. 2018. PMID 29607497. (accessed 2026-05-11)
  38. [gironi2008] Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.. Multiple Sclerosis. 2008. PMID 18728058. (accessed 2026-05-11)
  39. [soin2021] Soin A, Soin Y, Dann T, Buenaventura R, Ferguson K, Atluri S. Low-Dose Naltrexone Use for Patients with Chronic Regional Pain Syndrome: A Systematic Literature Review.. Pain Physician. 2021. PMID 34213865. (accessed 2026-05-11)
  40. [albers2017] Albers LN, Arbiser JL, Feldman RJ. Treatment of Hailey-Hailey Disease With Low-Dose Naltrexone.. JAMA Dermatology. 2017. PMID 28768313. (accessed 2026-05-11)
  41. [okelly2022] O'Kelly B, Vidal L, McHugh T, Woo J, Avramovic G, Lambert JS. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study.. Brain, Behavior, & Immunity - Health. 2022. PMID 35814187. (accessed 2026-05-11)
  42. [bonilla2023] Bonilla H, Tian L, Marconi VC, Shafer R, McComsey GA, Miglis M, Yang P, Bonilla A, Eggert L, Geng LN. Low-dose naltrexone use for the management of post-acute sequelae of COVID-19.. International Immunopharmacology. 2023. PMID 37804660. (accessed 2026-05-11)
  43. [cabanas2021] Cabanas H, Muraki K, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S. Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment.. Frontiers in Immunology. 2021. PMID 34326841. (accessed 2026-05-11)
  44. [bolton2020] Bolton MJ, Chapman BP, Van Marwijk H. Low-dose naltrexone as a treatment for chronic fatigue syndrome.. BMJ Case Reports. 2020. PMID 31911410. (accessed 2026-05-11)
  45. [leiber2025] Leiber KK, Parker RW. Therapeutic Uses and Efficacy of Low-Dose Naltrexone: A Scoping Review.. Cureus. 2025. PMID 40271304. (accessed 2026-05-11)

How to access

How to Access Low-Dose Naltrexone (LDN)

Compounded Low-Dose Naltrexone (LDN) is dispensed under 503A on a patient-specific prescription. Pick the path that matches where you're starting from.

For doctors

Offer this medication.

A pharmacist will follow up within two business days. We'll cover state availability, supported formulations, and what integration looks like for your clinic.

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Patient with a doctor

Receive your prescription.

If your doctor has already prescribed Low-Dose Naltrexone (LDN), sign up so we can prepare and ship your medication. The signup wizard collects intake and connects you to the prescribing workflow.

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Patient without a doctor

Find a partner clinic.

RonanRx prescribes through partner clinics — we don't initiate prescriptions on this site. See how the referral works and how to find a clinic in your state that has evaluated patients for Low-Dose Naltrexone (LDN).

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