# Low-Dose Naltrexone (LDN): A Patient Guide for ME/CFS **Prepared by:** Pedro Cheung MD **Last Updated:** September 2026 **Prepared for Patient Education | Evidence reviewed September 2026** --- > **Who this handout is for:** People with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) who want enough information to discuss the **risks and benefits** of low-dose naltrexone (LDN) with their clinician. > > **Important:** LDN is prescribed **off-label**. The U.S. Food and Drug Administration (FDA) has approved naltrexone for opioid and alcohol use disorders, **not** for ME/CFS, fibromyalgia, or Long COVID.[^1] There is **no FDA-approved medication that cures ME/CFS**.[^2][^3] Whether LDN is reasonable for you is a shared decision with your clinician — not something to start on your own. --- ## What Is Naltrexone? Naltrexone is an **opioid-receptor antagonist**. At the standard tablet strength of **50 mg**, it blocks opioid receptors so that opioid drugs (and, in alcohol use disorder, some of the rewarding effects of alcohol) have little effect. It has been FDA-approved since 1984.[^1] **Low-dose naltrexone (LDN)** means much smaller amounts — typically **0.5 to 4.5 mg per day**, occasionally up to 6 mg in research. At these doses, naltrexone is being used off-label for chronic pain, neuroinflammation, and post-viral illness. It is **not** the same treatment as 50 mg naltrexone for addiction, and it is **not** a painkiller in the opioid sense.[^4][^5] Because commercial tablets are 50 mg, LDN usually has to be **compounded** (custom-made) by a specialty pharmacy. --- ## Why Consider LDN for ME/CFS? ME/CFS is a serious, multisystem disease. Core features include:[^2][^6] - Profound fatigue that is not relieved by rest - **Post-exertional malaise (PEM)** — a delayed crash after physical, cognitive, or sensory effort - Unrefreshing sleep - Cognitive problems (“brain fog”) - Often orthostatic intolerance (symptoms worse upright) Pacing, PEM-avoidance, sleep, orthostatic, and pain care remain the foundation. NICE guidance is that symptoms can be managed but there is currently **no cure**, and that people with ME/CFS may be **more sensitive to medicines** than others — so doses should start lower and increase more slowly than usual.[^3] Specialist groups (including the U.S. ME/CFS Clinician Coalition and the Bateman Horne Center) list LDN as an **off-label option** that may help neuroinflammation-related pain, sleep, and cognitive fatigue in some patients.[^2][^7] That is clinical practice, not an FDA indication. --- ## How Might LDN Work? Researchers have proposed several mechanisms. These are **working hypotheses**. A laboratory finding does not mean you will feel better. **1. Brief opioid-receptor blockade, then a “rebound.”** Standard-dose naltrexone occupies opioid receptors for many hours. At low dose, blockade is shorter (on the order of hours, given naltrexone’s ~4-hour half-life). The idea is that the body then increases its own endorphins and opioid receptors for the rest of the day, which might ease pain and improve well-being.[^1][^4][^5] **2. Calming overactive immune cells in the nervous system (microglia).** Naltrexone can block **Toll-like receptor 4 (TLR4)** on microglia, the brain’s immune cells. Chronically activated microglia release inflammatory chemicals linked to pain, fatigue, cognitive fog, and unrefreshing sleep. This anti-inflammatory action appears to be separate from classic opioid blockade and may be more relevant at low doses.[^5] **3. TRPM3 ion channels in immune cells (ME/CFS-specific lab work).** A calcium channel called **TRPM3** is impaired in natural killer (NK) cells from people with ME/CFS (and in some people with post-COVID illness). In a small patch-clamp study, NK cells from **nine ME/CFS patients already taking LDN** showed restored TRPM3 currents compared with the known ME/CFS pattern.[^8] A 2024 review argued that TRPM3 dysfunction might also affect small nerves and the brain, and that naltrexone’s effect on this channel is a plausible reason some patients report benefit.[^9] > Laboratory restoration of an ion channel is **not** the same as a proven clinical treatment. It is one reason LDN is biologically interesting in ME/CFS. --- ## What Does the Research Show? Read this section as a **risk-benefit briefing**, not as a promise of benefit. The evidence for LDN in ME/CFS is still limited. Uncontrolled clinic series often look more positive than blinded trials. ### ME/CFS — what we have | Study | Design | What it found | Limits | |---|---|---|---| | Polo, Pesonen, Tuominen 2019[^10] | Retrospective clinic records, **218** people with ME/CFS on 3.0–4.5 mg/day, average follow-up 1.7 years | **73.9%** reported *some* improvement (often alertness, physical or cognitive function); **18.3%** reported none; **4.6%** stopped early because of side effects; **13.8%** stopped for lack of effect. No severe or long-term adverse effects recorded | No placebo group; improvement was whatever patients mentioned — not a rating scale. Open-label clinic care | | Bolton, Chapman, Van Marwijk 2020[^11] | BMJ Case Reports, **3** people | Responses ranged from substantial daily-function gains to partial symptom relief; doses 4–12 mg | Tiny; uncontrolled | | Cabanas et al. 2021[^8] | Lab study, 9 patients already on LDN vs 9 controls | TRPM3-like currents in NK cells looked restored in the LDN group | Not a treatment trial; no clinical outcomes | There is still **no published, peer-reviewed randomized trial** whose primary result confirms that LDN reduces ME/CFS symptoms better than placebo. **Important 2026 update — first RCT in post-COVID illness that meets ME/CFS-style criteria:** A Health Canada–authorized Phase II trial (NCT05430152) at the University of British Columbia randomized adults with **post-COVID fatigue syndrome** (IOM/NAM ME/CFS criteria after SARS-CoV-2) to LDN titrated from 1 mg to 4.5 mg/day or placebo for 16 weeks (target 160 people; actual enrollment reported as 160).[^12] The trial is **completed** (primary completion February 2026).[^13] At the International ME/CFS Conference in Berlin (May 2026), Luis Nacul presented **preliminary, unpublished** results: **66** people received LDN and **71** received placebo. LDN **did not reduce fatigue** (the primary outcome) more than placebo. More than **40%** of the placebo group reported subjective improvement — a reminder that uncontrolled “I got better on LDN” stories can overstate the drug’s effect. Analyses of **pain** and **subgroups** were still pending. Nacul asked whether LDN might still help some people; that question is not answered by the primary fatigue result.[^14] Until a peer-reviewed paper appears, treat the Berlin presentation as **early conference data**, not a final published result. As of mid-August 2026, the ME Association reported that the manuscript is **being submitted for publication**.[^26] ### Long COVID / post-COVID fatigue (overlaps ME/CFS) - A **2026 systematic review and meta-analysis** in *BMJ Open* (search through 5 May 2026) found **no published RCTs** of LDN for Long COVID. Four small before-after studies (155 people) were pooled. Effects looked moderate for fatigue (Hedges’ g = −0.74), brain fog (g = −0.53), and sleep (g = −0.60), and large for pain and daily function (both g = −0.93). Certainty was **low** because there was no placebo comparison. No serious adverse events were reported in the two studies that tracked safety.[^15] That review closed **before** the UBC trial’s conference presentation, so it does not include the first RCT. - A **2024 retrospective clinic cohort** (108 veterans) reported that LDN was associated with a higher chance of chart-documented improvement than physical therapy alone (**adjusted hazard ratio 5.04**, 95% CI 1.22–20.77). Fatigue and pain both improved in the LDN group. This is observational, with a wide confidence interval, and cannot prove cause and effect.[^16] - Patient surveys (for example OMF TREATME, ~951 LDN reports) often show that about **60%** notice some benefit and about **29%** rate it “moderate to much better.” Those numbers match clinic series — and they are **higher than what blinded trials find**, which is why surveys cannot replace RCTs.[^27] ### Fibromyalgia (related, not the same disease) Many people with ME/CFS also have fibromyalgia-type pain. LDN’s **best-known trials** are in fibromyalgia. Early small studies were encouraging; **larger, longer, blinded trials in 2024–2026 have been negative**. - **Younger 2009 and 2013** (small Stanford/UAB trials, 4.5 mg): pain fell more on LDN than placebo (in 2013, about **29% vs 18%** reduction); mood and life satisfaction improved; fatigue and sleep did not; no serious side effects.[^17][^18] - **Bested et al. 2023** (Denmark, crossover, 4.5 mg, 52 people completing): **no** clinically relevant analgesic effect or FIQR improvement vs placebo. Treatment periods were only three weeks.[^19] - **Bruun et al. 2024, *Lancet Rheumatology* (FINAL trial)** (Denmark, parallel RCT, **6 mg** for 12 weeks, 99 women): LDN was **not superior to placebo for pain** (difference −0.34 on a 0–10 scale, p = 0.27). Side-effect rates were similar to placebo. A secondary signal suggested possible improvement in **memory problems**; that finding did not survive correction for multiple tests.[^20] - **FINAL follow-up analyses (2025–2026):** A CNS Drugs paper found a difference in one lab pain-modulation test (conditioned pain modulation), but it was **not linked to actual pain improvement** and may be a chance finding.[^28] An August 2026 *Pain Management Nursing* analysis found **no** 30% response-rate advantage for LDN over placebo on fatigue, sleep, tenderness, stiffness, depression, or memory.[^29] - **Vatvani et al. 2024 meta-analysis** of 4 RCTs (222 people) still found a **small average pain reduction** (mean difference −0.86) and higher pressure-pain thresholds, **without** improvement in overall fibromyalgia impact (FIQR). Vivid dreams and nausea were more common on LDN; serious adverse events were not. Meta-analyses that pool older positive pilots with newer negative trials can look more favorable than the best single studies.[^21] - **INNOVA 2026, *European Journal of Pain*** — first **12-month** fibromyalgia RCT (96 women, **4.5 mg** daily vs placebo). LDN was **not better than placebo** for pain or key secondary outcomes at 3, 6, or 12 months. At 3 months, pain fell 0.33 points on LDN vs 0.64 on placebo. Responder rates were low in both arms (≥30% pain improvement: **10.6% LDN vs 18.4% placebo**). People who *believed* they were on LDN reported more improvement — a reminder of expectation effects. Presented at EULAR 2026; the investigators said LDN is **not recommendable as routine fibromyalgia care** on this evidence.[^30] **Take-home for ME/CFS care:** fibromyalgia is the closest RCT evidence we have. Early small trials looked positive; the two largest modern parallel-group trials (**FINAL 6 mg, 12 weeks**; **INNOVA 4.5 mg, 12 months**) did **not** beat placebo for pain, and INNOVA did not beat placebo for fatigue or function either. A small average pain effect in older pooled data does not override those results. ### Independent 2026 evidence reviews Two 2026 reviews, plus a Consensus academic search of the peer-reviewed literature, reach a similar conclusion: - **Gouda, Aitcheson & Steadman, *Advances in Therapy* (April 2026):** 105 studies, including 15 RCTs across pain, autoimmunity, gut, skin, post-infectious illness, mental health, and oncology. **Early positives from uncontrolled studies were rarely replicated in placebo-controlled trials.** Most evidence is case reports and small feasibility studies. LDN is generally safe, inexpensive, and well tolerated (typical dose 4.5 mg). **Current evidence does not support routine clinical use.** It may still have a **pragmatic role in treatment-resistant cases** if its experimental status is explained clearly. N-of-1 trials may help identify individual responders.[^31] - **Byambasuren et al., *BMJ Open* (2026):** no published Long COVID RCTs at the time of search; low-certainty pre–post improvements only.[^15] - As of September 2026 there is still **no published peer-reviewed RCT** showing LDN superior to placebo for ME/CFS fatigue. The highest-quality nearby RCTs (fibromyalgia FINAL and INNOVA; UBC post-COVID fatigue, conference only) are **negative or unpublished-negative on their primary endpoints**. The pattern is consistent: **open-label series look better than blinded trials.** That does not mean LDN never helps anyone. It does mean a 2–3 month trial should be framed as an N-of-1 experiment, not as a proven disease-modifying therapy. --- ## Realistic Expectations - LDN is **not a cure** and is **not a substitute for pacing**. It will not make PEM safe to ignore.[^3][^7] - If it helps, people more often describe **less pain, a bit more mental clarity, or slightly better sleep** — not a return to pre-illness function.[^7][^10] - Response is individual. A substantial minority feel no benefit.[^10] - Clinic series and specialist experience suggest giving a trial **8–12 weeks** at a tolerated dose (sometimes up to 3 months) before deciding it has failed.[^7][^10] - Because placebo responses in this field can exceed **40%**, feeling better in the first weeks does not by itself prove the drug is working. The reverse is also true: early vivid dreams or insomnia do not mean the trial has failed.[^14][^30] - People with ME/CFS often need **lower starting doses** and **slower increases** than standard medical practice.[^3] - 2026 blinded trials in fibromyalgia and the first post-COVID ME/CFS-criteria RCT **did not confirm** a group-level benefit. If you and your clinician still try LDN, treat it as a personal experiment with a planned stop date, not as standard of care.[^14][^26][^30][^31] --- ## Dosing: How Is LDN Taken? There is no FDA-approved ME/CFS dose. What follows is **common specialist and trial practice**, to discuss with your prescriber — not a recipe to copy. | Step | Typical approach | |---|---| | **Start** | 0.5–1.5 mg daily. Very sensitive or severe ME/CFS: **0.1–0.5 mg** liquid | | **Increase** | Every 1–4 weeks as tolerated (NICE: slower than usual practice) | | **Usual target** | **3.0–4.5 mg** once daily (Bateman Horne: 1.5–4.5 mg)[^7] | | **Research range** | UBC trial: 1 → 2 → 3 → 4.5 mg; LIFT trial: 1.5 → 3.0 → 4.5 mg; one fibromyalgia RCT used 6 mg[^12][^20][^22] | | **When to take it** | Often at **bedtime**. If vivid dreams or insomnia dominate, switch to **morning**[^7] | | **Form** | Compounded capsule or liquid. Liquid allows finer titration | | **If no benefit** | Polo’s clinic stopped LDN after about **6 months** without effect[^10] | > **“Start low, go slow.”** Your clinician will match the schedule to how sensitive you are. Do not split 50 mg tablets at home to approximate a low dose — the dose will not be accurate. **Surgery or emergency pain care:** LDN can blunt opioid pain medicines. For planned procedures that may need opioids, LDN is usually **held 24–72 hours** beforehand (confirm with surgery and anesthesia). In an emergency, pain medicine should **not** be withheld solely because you take LDN; the Bateman Horne Center notes that at these doses the blockade is weak and largely gone within about 24 hours of the last capsule.[^23] --- ## Possible Benefits Based on available studies and specialist use, LDN **may**: - Reduce some chronic or nociplastic **pain** in a subset of people — small early trials and some meta-analyses suggest a modest effect; the two largest modern fibromyalgia RCTs did **not** confirm it[^7][^17][^20][^21][^30] - Slightly improve **alertness, physical function, or cognition** in some people with ME/CFS (uncontrolled clinic series and patient surveys)[^10][^27] - Help **sleep quality** in some (not shown in the 2013 fibromyalgia RCT or in INNOVA/FINAL secondary analyses)[^7][^18][^29][^30] - Be worth a time-limited trial when **neuroinflammation or central pain** is a major part of your picture **and** first-line measures (pacing, sleep, orthostatic care, standard pain options) are not enough — matching the 2026 review’s “treatment-resistant, experimental” framing[^7][^31] It has **not** been shown, in a published blinded trial, to treat PEM, orthostatic intolerance, or ME/CFS as a whole. The first RCT in post-COVID illness meeting ME/CFS-style criteria, presented in 2026, did **not** beat placebo on fatigue.[^14] --- ## Side Effects and Risks LDN is generally **well tolerated**. In a systematic review of 89 oral-naltrexone RCTs (11,194 people, many doses), naltrexone did **not** increase serious adverse events versus placebo (RR 0.84, 95% CI 0.66–1.06).[^24] Fibromyalgia and ME/CFS series at 1–6 mg likewise have not shown a signal for serious harm.[^10][^20][^21] ### Common (usually early, often fade) - **Vivid or unusual dreams** (the most characteristic LDN effect) - Insomnia or broken sleep (try morning dosing) - Nausea - Headache - A temporary increase in fatigue, dizziness, or pain - Decreased appetite ### Less common - Anxiety, irritability, or mood change - Muscle or joint aches - Stomach upset or diarrhea Polo: **4.6%** stopped during introduction because of adverse effects (insomnia and nausea were typical).[^10] Bruun (6 mg): discontinuation due to adverse events was **8%** on LDN vs **6%** on placebo.[^20] ### Serious (rare; described mainly at standard 50 mg doses) - Allergic reaction (rash, swelling, trouble breathing) - Liver injury — historically associated with **much higher** doses (hundreds of milligrams). Still: stop and call your clinician for jaundice, dark urine, or severe right-upper-abdominal pain.[^1] - Worsening depression or suicidal thinking (labeled warning in addiction-treatment populations; tell your clinician about mood history)[^1] - **Precipitated opioid withdrawal** if any opioid (including tramadol, codeine cough syrup, or kratom) is in your system[^1] > **Call your clinician promptly** for yellowing of skin or eyes, severe abdominal pain, marked mood change, allergic symptoms, or withdrawal (sweating, vomiting, agitation, gooseflesh) after a first dose. --- ## Warnings and Contraindications ### Do not take LDN if you: - Take **any opioid** — morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, codeine, **tramadol**, buprenorphine, methadone, or similar. Naltrexone can trigger **acute opioid withdrawal**, which can be severe.[^1] **Kratom** is not on the FDA label but acts on opioid receptors; treat it the same way and tell your clinician if you use it. - Are in **acute opioid withdrawal**, or would fail a naloxone challenge / opioid urine screen.[^1] - Have a known **allergy** to naltrexone.[^1] - Have **acute hepatitis or liver failure** (listed as a contraindication on some generic naltrexone labels).[^1] ### Discuss carefully with your clinician if you: - Have chronic **liver or kidney** disease - Are **pregnant, trying to conceive, or breastfeeding** (human data at low dose are sparse) - Have a history of **opioid use disorder** (special planning; overdose risk rises after naltrexone is stopped because tolerance is lower)[^1] - Have significant **depression** - Might need **opioid anesthesia or emergency opioids** ### Key drug interactions[^1] | Drug / class | Concern | |---|---| | **All opioid pain, cough, and antidiarrheal medicines** (including tramadol) | Blocked analgesia; precipitated withdrawal if dependent | | **Kratom** | Opioid-receptor activity — treat as an opioid | | **Thioridazine** | Older labeled interaction (rarely used now) | | Other medicines | Give your full list to the prescriber and compounding pharmacist | LDN does **not** cause a disulfiram-like reaction with alcohol.[^1] Alcohol often worsens ME/CFS independently of LDN. --- ## How to Obtain LDN 1. A licensed clinician writes a prescription for a **specific low dose** (for example, 1 mg capsules, or a 0.5 mg/mL liquid). 2. A **compounding pharmacy** prepares it. Ask for a pharmacy with compounding accreditation (for example PCAB) if one is available. 3. **Insurance** often does **not** cover compounded LDN. Out-of-pocket cost is commonly on the order of **$30–$80 per month**, but confirm locally. 4. Capsules are convenient at a stable dose; **liquid** is better while you are finding the lowest tolerated dose. Do not buy “LDN” from unverified online sellers. Dose and purity are not assured. --- ## What Is Coming Next | Trial | What it is | Status (as of September 2026) | |---|---|---| | **NCT05430152** — UBC / Nacul, post-COVID fatigue meeting ME/CFS criteria, LDN vs placebo, 16 weeks[^12][^13] | First sizable RCT in an ME/CFS-like post-COVID cohort | **Completed** Feb 2026. Berlin conference: primary **fatigue** endpoint **not met**; >40% placebo improvement; pain and subgroups pending. Manuscript **being submitted**; **not yet peer-reviewed**[^14][^26] | | **NCT06366724 (LIFT)** — Systrom / Open Medicine Foundation: LDN, pyridostigmine (Mestinon), both, or neither; 160 people with ME/CFS and orthostatic intolerance[^22] | Factorial RCT; function and exercise-physiology outcomes | Protocol published August 2026; still recruiting; estimated primary completion ~September 2026 | | **NCT07285473** — Younger / UAB / NINDS: remote **Alabama** dose-finding (1.5, 3.0, 4.5, 6.0 mg, blinded order, 2 months each) in ME/CFS (ICC criteria), n ≈ 75; primary outcome PROMIS Fatigue[^25] | UG3 dose-finding step of a 5-year NIH program. A later UH3 RCT (~150 people, LDN vs placebo, intended to be nationwide and remote, including bedbound participants) is **not yet registered** | **Not yet recruiting** as of 21 August 2026; estimated start **1 October 2026**; primary completion ~April 2028. Younger has said the registered protocol is dose-finding only[^32] | | U.S. **RECOVER** pediatric LDN concept | Mentioned in conference coverage as in planning[^14] | Not a completed trial | --- ## Questions to Ask Your Doctor Before a trial of LDN, consider: - [ ] Given my other medicines (especially anything opioid-like) and liver history, am I a candidate? - [ ] What starting dose do you recommend, and how slowly should I increase? - [ ] Capsules or liquid? Which compounding pharmacy? - [ ] Bedtime or morning, given my sleep? - [ ] Do I need baseline liver tests? - [ ] How long should I stay on a stable dose before we decide it is not helping? - [ ] What would make us stop (side effects, no change, upcoming surgery)? - [ ] How does LDN fit with pacing, orthostatic treatment, and pain care — not instead of them? --- ## Bottom Line LDN is an inexpensive, usually well-tolerated, **off-label** option that ME/CFS specialists sometimes use for pain, neuroinflammation, and cognitive fatigue. The **biology is plausible** (microglia / TLR4; TRPM3 in NK cells). **Uncontrolled clinic series and patient surveys** still report that a majority notice some improvement. **Blinded evidence in 2026 is less encouraging.** The first RCT in post-COVID illness that looks like ME/CFS (UBC/Nacul), presented in 2026 but not yet published, **did not beat placebo on fatigue**. Two large modern fibromyalgia RCTs — FINAL (6 mg, 12 weeks) and INNOVA (4.5 mg, 12 months) — **did not beat placebo for pain**, and INNOVA did not beat placebo for other key symptoms either. A 2026 narrative review of 105 studies concluded that **current evidence does not support routine clinical use**, though a time-limited trial can still be reasonable when standard care has not helped and the uncertainty is explained.[^14][^26][^30][^31] Serious harm at 1–4.5 mg appears uncommon, but LDN is **dangerous if you take opioids** (including tramadol or kratom). A carefully titrated **2–3 month trial** can still be a shared decision if you understand that group-level benefit is unproven, pacing remains essential, and “feeling better” in an open-label trial is not the same as proof. **Decide with a clinician who knows ME/CFS — not from a bottle bought online.** --- ## Footnotes and References [^1]: DailyMed. Naltrexone hydrochloride tablets — FDA prescribing information (indications: alcohol dependence and blockade of exogenous opioids; contraindications including opioid analgesics, opioid dependence, acute withdrawal, hypersensitivity; hepatotoxicity warning; opioid-containing cough/antidiarrheal/analgesic interactions; tramadol called out in opioid-free interval). Example label: [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f30f885-d0cd-4fa6-a8e0-142f08a56792](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f30f885-d0cd-4fa6-a8e0-142f08a56792). Naltrexone initial U.S. approval: 1984. [^2]: Bateman L, Bested AC, Bonilla HF, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management. *Mayo Clinic Proceedings.* 2021;96(10):2629–2645. doi:[10.1016/j.mayocp.2021.07.004](https://doi.org/10.1016/j.mayocp.2021.07.004). Up to 91% of U.S. patients remain undiagnosed; NAM 2015 criteria; LDN listed among pharmacologic options for pain; start low and titrate slowly. [^3]: National Institute for Health and Care Excellence. *Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management* (NG206). 2021 (surveillance review 24 January 2025: no change to recommendations). Do not offer medicines or supplements to *cure* ME/CFS; people with ME/CFS may be more intolerant of drugs — consider starting lower and increasing gradually. [https://www.nice.org.uk/guidance/ng206](https://www.nice.org.uk/guidance/ng206). Evidence review F found **no RCT evidence** for LDN in ME/CFS at guideline development. [https://www.ncbi.nlm.nih.gov/books/NBK579665/](https://www.ncbi.nlm.nih.gov/books/NBK579665/) [^4]: Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. *Pain Medicine.* 2009;10(4):663–672. PMID: 19453963. [^5]: 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;33(4):451–459. doi:[10.1007/s10067-014-2517-2](https://doi.org/10.1007/s10067-014-2517-2). PMC3962576. Microglia / TLR4 hypothesis. [^6]: Institute of Medicine (National Academy of Medicine). *Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness.* Washington, DC: National Academies Press; 2015. [^7]: Bateman Horne Center. *Clinical Care Guide.* First edition, 2025. LDN 1.5–4.5 mg nightly for neuroinflammation, central pain, cognitive fatigue; morning dosing if vivid dreams; gradual titration because of medication sensitivity. [https://batemanhornecenter.org/wp-content/uploads/2025/05/Clinical-Care-Guide-First-Edition-2025-1.pdf](https://batemanhornecenter.org/wp-content/uploads/2025/05/Clinical-Care-Guide-First-Edition-2025-1.pdf). See also Hoppers M. Exploring the Potential of Low Dose Naltrexone (LDN) for ME/CFS and Beyond. Bateman Horne Center, September 2024. [https://batemanhornecenter.org/exploring-the-potential-of-low-dose-naltrexone-for-me-cfs/](https://batemanhornecenter.org/exploring-the-potential-of-low-dose-naltrexone-for-me-cfs/) [^8]: 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;12:687806. doi:[10.3389/fimmu.2021.687806](https://doi.org/10.3389/fimmu.2021.687806). PMID: 34326841. [^9]: Löhn M, Wirth KJ. Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone. *Journal of Translational Medicine.* 2024;22:630. doi:[10.1186/s12967-024-05412-3](https://doi.org/10.1186/s12967-024-05412-3). PMID: 38970055. [^10]: Polo O, Pesonen P, Tuominen E. Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). *Fatigue: Biomedicine, Health & Behavior.* 2019;7(4):207–217. doi:[10.1080/21641846.2019.1692770](https://doi.org/10.1080/21641846.2019.1692770). [^11]: Bolton MJ, Chapman BP, Van Marwijk H. Low-dose naltrexone as a treatment for chronic fatigue syndrome. *BMJ Case Reports.* 2020;13(1):e232502. doi:[10.1136/bcr-2019-232502](https://doi.org/10.1136/bcr-2019-232502). PMID: 31911410. [^12]: Naik H, Cooke E, Boulter T, et al. Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia. *BMJ Open.* 2024;14(5):e085272. doi:[10.1136/bmjopen-2024-085272](https://doi.org/10.1136/bmjopen-2024-085272). PMID: 38740499. NCT05430152. [^13]: ClinicalTrials.gov. NCT05430152: Low-dose Naltrexone for Post-COVID Fatigue Syndrome. Status: completed; primary completion 15 February 2026; study completion 28 February 2026; actual enrollment 160. [https://clinicaltrials.gov/study/NCT05430152](https://clinicaltrials.gov/study/NCT05430152) [^14]: Rücker M. International ME/CFS Conference roundup: Setbacks and new hopes for therapeutic research. *The Sick Times.* 26 May 2026. Nacul preliminary RCT: 66 LDN vs 71 placebo, 16 weeks, 1–4.5 mg; primary fatigue endpoint not met; >40% placebo subjective improvement; pain and subgroups pending. [https://thesicktimes.org/2026/05/26/international-me-cfs-conference-roundup-setbacks-and-new-hopes-for-therapeutic-research/](https://thesicktimes.org/2026/05/26/international-me-cfs-conference-roundup-setbacks-and-new-hopes-for-therapeutic-research/) [^15]: Byambasuren O, et al. Effect of low-dose naltrexone for long COVID: a systematic review and meta-analysis. *BMJ Open.* doi:[10.1136/bmjopen-2025-111253](https://doi.org/10.1136/bmjopen-2025-111253). Literature search through 5 May 2026; no published RCTs; 4 pre-post studies, n = 155; low-certainty symptom improvements; no serious adverse events in the studies that reported safety. [^16]: Tamariz L, Bast E, Klimas N, Palacio A. Low-dose naltrexone improves post-COVID-19 condition symptoms. *Clinical Therapeutics.* 2024;46(3):e101–e106. doi:[10.1016/j.clinthera.2023.12.009](https://doi.org/10.1016/j.clinthera.2023.12.009). PMID: 38267326. [^17]: Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. *Pain Medicine.* 2009;10(4):663–672. [^18]: 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 & Rheumatism.* 2013;65(2):529–538. doi:[10.1002/art.37734](https://doi.org/10.1002/art.37734). PMID: 23359310. [^19]: Bested K, Jensen LM, Andresen T, et al. Low-dose naltrexone for treatment of pain in patients with fibromyalgia: a randomized, double-blind, placebo-controlled, crossover study. *PAIN Reports.* 2023;8(4):e1080. doi:[10.1097/PR9.0000000000001080](https://doi.org/10.1097/PR9.0000000000001080). [^20]: Bruun KD, Christensen R, Amris K, et al. Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial. *The Lancet Rheumatology.* 2024;6(1):e31–e39. doi:[10.1016/S2665-9913(23)00278-3](https://doi.org/10.1016/S2665-9913(23)00278-3). PMID: 38258677. NCT04270877. [^21]: 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. *Korean Journal of Pain.* 2024;37(4):367–378. doi:[10.3344/kjp.24202](https://doi.org/10.3344/kjp.24202). PMID: 39344363. (The May 2026 general naltrexone handout cited this paper as “Almutairi”; the first author is Vatvani.) [^22]: Meadows D, Squires J, Dibble J, et al. Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial. *Trials.* 2026. doi:[10.1186/s13063-026-09943-6](https://doi.org/10.1186/s13063-026-09943-6). NCT06366724. Published 12 August 2026. [^23]: Bateman Horne Center. *Low-Dose Naltrexone (LDN): A Note to Providers.* 2023. LDN is a very low dose; may be less active within 24 hours of last dose; do not withhold emergency opioids solely because of LDN. [https://batemanhornecenter.org/wp-content/uploads/2023/09/Low-Dose-Naltrexone-LDN-A-Note-to-Providers-.pdf](https://batemanhornecenter.org/wp-content/uploads/2023/09/Low-Dose-Naltrexone-LDN-A-Note-to-Providers-.pdf). See also Chiang T-H, Schmitt K, Nelson A. Management of patients on low-dose naltrexone: a clinical review for urgent care providers. *Journal of Urgent Care Medicine.* 2023;17(10):11–16. [^24]: Bolton M, Hodkinson A, Smith SC, et al. Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis. *BMC Medicine.* 2019;17:10. doi:[10.1186/s12916-018-1242-0](https://doi.org/10.1186/s12916-018-1242-0). PMID: 30651111. [^25]: ClinicalTrials.gov. NCT07285473: Low-Dose Naltrexone For ME/CFS: Dose-Finding (Younger, University of Alabama at Birmingham; NINDS grant 1UG3NS141843-01A1). Status as of 21 August 2026: not yet recruiting; estimated start 1 October 2026; estimated primary completion 1 April 2028; n ≈ 75; Alabama residents; ICC criteria; PROMIS Fatigue primary. [https://clinicaltrials.gov/study/NCT07285473](https://clinicaltrials.gov/study/NCT07285473) [^26]: The ME Association. Treatment: Clinical trials into the use of LDN in ME/CFS, Long Covid and Fibromyalgia. 17 August 2026. Notes Nielsen et al. FINAL secondary analysis (negative 30% response rates) and that the MEA-funded UBC/Nacul trial’s preliminary negative results are being submitted for publication. [https://meassociation.org.uk/2026/08/treatment-clinical-trials-into-the-use-of-ldn-in-me-cfs-long-covid-and-fibromyalgia/](https://meassociation.org.uk/2026/08/treatment-clinical-trials-into-the-use-of-ldn-in-me-cfs-long-covid-and-fibromyalgia/) [^27]: Eckey M, et al. Patient-reported treatment outcomes in ME/CFS and long COVID (TREATME). *Proceedings of the National Academy of Sciences.* 2025. Among ~951 LDN reports, about 60% noted some benefit and about 29% “moderate to much better” for selected symptoms (fatigue/PEM/brain fog were among those scored). Uncontrolled survey; selection and recall bias apply. [^28]: Bruun KD, et al. Effect of Naltrexone on Spinal and Supraspinal Pain Mechanisms and Functional Capacity in Women with Fibromyalgia: Exploratory Outcomes from the Randomized Placebo-Controlled FINAL Trial. *CNS Drugs.* 2025. doi:[10.1007/s40263-025-01183-7](https://doi.org/10.1007/s40263-025-01183-7). CPM difference not associated with clinical pain improvement. [^29]: Nielsen A, et al. Symptom Response to Low-Dose Naltrexone in Fibromyalgia: An Exploratory Analysis of the Randomized Placebo-Controlled FINAL Trial. *Pain Management Nursing.* Available online 12 August 2026. doi:[10.1016/j.pmn.2026.07.020](https://doi.org/10.1016/j.pmn.2026.07.020). No significant 30% response-rate differences vs placebo for tenderness, fatigue, sleep, depression, memory, or stiffness. [^30]: Rodríguez-Freire L, et al. Efficacy of Low-Dose Naltrexone in Women With Fibromyalgia Syndrome: A 12-Month Randomised, Double-Blind, Placebo-Controlled Single-Centre Clinical Trial (INNOVA Study). *European Journal of Pain.* 2026. doi:[10.1002/ejp.70321](https://doi.org/10.1002/ejp.70321). LDN 4.5 mg not superior to placebo over 12 months. EULAR 2026 presentation summarized in Callari M. Low-Dose Naltrexone Fails to Outperform Placebo for Pain in Fibromyalgia. *Medscape.* 6 June 2026. [^31]: Gouda AHK, Aitcheson NEC, Steadman KJ. Low-Dose Naltrexone: What is the Evidence? A Narrative Review. *Advances in Therapy.* 2026;43:2852–2870. doi:[10.1007/s12325-026-03612-5](https://doi.org/10.1007/s12325-026-03612-5). PMID: 42060160. Search February 2026; 105 studies, 15 RCTs; does not support routine clinical use; possible pragmatic role in treatment-resistant cases. [^32]: Younger J. NIH-funded LDN program (UG3 dose-finding then UH3 RCT). ClinicalTrials.gov NCT07285473 and NINDS 1UG3NS141843-01A1. Health Rising interview, 3 September 2026; Younger YouTube updates June–August 2026 noting the registered protocol is dose-finding, not the full RCT. --- _This handout is intended for educational purposes and does not constitute medical advice. Please consult your healthcare provider before starting, stopping, or changing any medication._ _Evidence summary current as of September 2026. Literature reviewed via PubMed/ClinicalTrials.gov and a Consensus academic search of peer-reviewed papers._