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Medications

Off-label medications used in ME/CFS (low-dose naltrexone, rapamycin, pyridostigmine, aripiprazole and more) and what the evidence really shows.

6 min read Last reviewed 8 November 2026

Low-dose naltrexone (LDN)

What it is

Naltrexone at full dose (50 mg) blocks opioids and is used for alcohol and opioid dependence. At low doses (0.5–4.5 mg) it’s used off-label in ME/CFS, fibromyalgia, Long COVID, MS and Crohn’s disease.

How it might work

  1. Briefly blocking opioid receptors overnight triggers a rebound rise in the body’s own endorphins the next day. People with ME/CFS have lower levels of beta-endorphin.1
  2. It calms the brain’s immune cells (microglia), which may reduce neuroinflammation.2
  3. It restores the TRPM3 calcium channel in immune cells, according to Griffith University’s lab work. See The science.

The evidence, honestly

Study Type Result
Finnish series, 2019 (218 patients)3 Open-label 74% reported a positive response. Symptoms returned when people paused and improved when they restarted.
Griffith preliminary data4 Open-label 83% reported improvement (unpublished, cited in a trial registration). It justified running a placebo-controlled trial, but isn’t evidence the drug works.
Irish pilot, 2022 (38 Long COVID patients started LDN)5 Open-label Adjacent field Improvements in fatigue, function and sleep
Griffith lab studies, 2021–20256,7,8 Lab study TRPM3 function restored. Patients reported improved thinking and immune symptoms, but not pain, sleep or dizziness.
Small fibromyalgia trials9 RCT Adjacent field Positive for pain and fatigue (31 people)
FINAL trial, Denmark (99 women with fibromyalgia)10 RCT Adjacent field Missed on pain; some signal for memory
Canadian post-COVID trial (UBC), 202611,12 RCT Adjacent field No better than placebo on fatigue or any other outcome. See below.

The Canadian trial

  • Led by Dr Luis Nacul at the University of British Columbia and funded by the Canadian Institutes of Health Research and the UK ME Association.
  • A Phase 2 trial in post-COVID fatigue syndrome (Long COVID with ME/CFS-type fatigue). People who had ME/CFS before COVID were excluded. 160 people enrolled; LDN was built up to 4.5 mg/day over 16 weeks. Registry: NCT05430152.
  • LDN did not reduce fatigue more than placebo. The first results were presented at a conference in May 2026.13 The full results, posted in October 2026 (81 people on LDN, 79 on placebo), found no benefit on fatigue, pain, overall symptoms, daily step counts or quality of life. LDN was well tolerated. The paper hasn’t been peer-reviewed yet.12
  • More than 40% of the placebo group felt better. This is why open-label figures like “74%” or “83%” can’t be taken at face value.

Why LDN is still worth discussing

  • The Canadian trial only included post-COVID illness. People with classic ME/CFS, e.g. after glandular fever, may respond differently. It counts against LDN in Long COVID more than in ME/CFS.
  • It was too small to detect a benefit in a subgroup. Its other measures (pain, symptoms, steps, quality of life) didn’t improve either, so this is a hope rather than a reason to expect benefit.
  • LDN is cheap, generally safe and reversible.

Practicalities (Australia)

  • Prescription only. Made by a compounding pharmacy, roughly $40–60 a month.
  • Commonly started low (0.5–1 mg) and increased slowly, e.g. by 0.5 mg every 1–2 weeks, to 3–4.5 mg. That takes about 6 weeks.
  • Usually taken at night. If it causes vivid dreams or insomnia (the most common side effects, usually temporary), switching to the morning often helps.
  • Judge after 2–3 months at the target dose. A two-week pause afterwards shows whether it was doing anything.
  • It blocks opioid painkillers (codeine, tramadol, oxycodone). Tell every doctor and dentist, and stop it before planned surgery as advised.
  • Many GPs haven’t prescribed it. See our Find a doctor list of LDN prescribers, or ask Emerge Australia.
  • Griffith University’s placebo-controlled LDN trial (TreatMELC), which includes people with ME/CFS, opened in October 2026. See trials. Note that you’re usually not eligible if you’re already taking LDN.

Low-dose rapamycin (sirolimus) Open-label

  • Rapamycin is an immune-modulating drug. At low weekly doses it’s being studied in ME/CFS.
  • Simmaron Research (US): of 70 patients who reached the first checkpoint, 52 (74%) improved in fatigue, PEM and dizziness on standing, at 6 mg a week. It was generally well tolerated.14
  • People whose illness started after an infection appeared to respond better, which suggests it may suit infection-triggered or EBV-associated ME/CFS. This comes from the researchers’ preliminary analysis rather than the published paper.15
  • No placebo group, so it needs a controlled trial. A placebo-controlled follow-up is planned for mid-2027.
  • Rapamycin affects the immune system and needs monitoring. Some Australian specialists prescribe it.

Pyridostigmine (Mestinon) RCT

  • In a placebo-controlled study of 45 people, a single dose of pyridostigmine improved how the heart and circulation respond to exertion in ME/CFS: peak oxygen use rose on the drug and fell on placebo.16
  • Most relevant for people with dizziness on standing or POTS.
  • The LIFT trial (Brigham and Women’s Hospital, Boston, with the Open Medicine Foundation) is testing it alone and together with LDN.17

Low-dose aripiprazole (Abilify) Open-label

  • At a tiny fraction of its psychiatric dose (0.2–2 mg a day), a Stanford clinic review found 74% of 101 patients improved in fatigue, brain fog, sleep and PEM.18
  • But in a large patient survey (3,925 people), more than half reported a positive effect while more than a fifth reported a negative one, and loss of effect over time is commonly reported.19
  • The first placebo-controlled trial (PAIS-AriSE, Charité Berlin) is due to start in late 2026.20

Guanfacine + NAC Adjacent field

Used for brain fog. A small Yale case series in Long COVID (12 people, 8 improved) found benefit.21 It’s cheap and available, but some people with ME/CFS report crashing on it.

Other treatments being studied

Treatment Evidence Notes
Hyperbaric oxygen (HBOT) Observational Charité22 Improvement in a published cohort of 30 who had 40 sessions; the comparison with 20 sessions was presented at the Berlin conference. Expensive.
Vagus nerve stimulation (at-home ear device) Trial under way, recruitment closed STIMPACT, Luxembourg23
Stellate ganglion block Adjacent field Trials starting Long COVID only. NIH’s Block-LC is expected to open later in 2026.
rTMS (magnetic brain stimulation) Adjacent field Small pilot Long COVID, 10 people, no results published24
EECP (external counterpulsation) Adjacent field Small data Long COVID, no control group25
Wearable magnetic device (Fareon) Adjacent field Small sham-controlled pilot (30 people), published Sept 2026 Small improvements on some memory and attention tests in Long COVID; a larger trial is needed26,27
Intermittent hypoxia-hyperoxia (IHHT) Placebo-controlled trial starting REenergizeME, Aarhus, Denmark (women with ME/CFS)28

See all current trials and 2026 results.

References

  1. Beta-endorphin levels in peripheral blood mononuclear cells of patients with chronic fatigue syndrome Observational
    Conti F et al., Clinical and Experimental Rheumatology, 1998. 16 CFS patients vs 10 controls; beta-endorphin markedly lower
  2. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain Hypothesis
    Younger J, Parkitny L, McLain D, Clinical Rheumatology, 2014. Review of proposed mechanisms: TLR4 antagonism on microglia and endorphin upregulation
  3. Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Open-label
    Polo O, Pesonen P, Tuominen E, Fatigue: Biomedicine, Health & Behavior, 2019. Retrospective series of 218 patients; 73.9% reported a positive response
  4. Low Dose Naltrexone for the treatment of long COVID-19 (ACTRN12623001042639) Registry
    Griffith University NCNED, ANZCTR, 2023. Background cites unpublished NCNED retrospective data reporting improvement in 83% of ME/CFS patients on LDN
  5. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study Open-label
    O'Kelly B et al., Brain, Behavior, & Immunity – Health, 2022. 52 enrolled, 38 started LDN, 36 completed
  6. Potential therapeutic benefit of low dose naltrexone in ME/CFS: role of transient receptor potential melastatin 3 ion channels in pathophysiology and treatment Lab study
    Cabanas H, Muraki K, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S, Frontiers in Immunology, 2021. 9 patients taking LDN vs 9 controls; TRPM3 currents in the same range as controls
  7. Impaired TRPM3-dependent calcium influx and restoration using naltrexone in natural killer cells of ME/CFS patients Lab study
    Eaton-Fitch N et al., Journal of Translational Medicine, 2022. 10 patients vs 10 controls
  8. Low-dose naltrexone restored TRPM3 ion channel function in natural killer cells from long COVID patients Lab study
    Sasso EM et al., Frontiers in Molecular Biosciences, 2025. 9 Long COVID patients on LDN, 9 untreated, 9 controls
  9. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial RCT
    Younger J, Noor N, McCue R, Mackey S, Arthritis & Rheumatism, 2013. n=31; pain reduced 28.8% vs 18.0% on placebo
  10. Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial RCT
    Due Bruun K et al., Lancet Rheumatology, 2024. 99 women, 12 weeks; primary pain endpoint not met; memory improved (secondary outcome)
  11. A Double Blind Randomized Trial of Low-dose Naltrexone for Post-COVID Fatigue Syndrome (NCT05430152) Registry
    Nacul L, University of British Columbia, ClinicalTrials.gov, 2026. 160 enrolled; pre-existing ME/CFS excluded; primary outcome fatigue at 16 weeks
  12. Low Dose Naltrexone for Post-COVID Fatigue Syndrome: A Randomized Controlled Trial RCT
    Naik H, Nacul L et al., medRxiv (preprint), 2026. Full results of NCT05430152, posted 26 Oct 2026, not yet peer-reviewed: 160 people (81 LDN, 79 placebo), up to 4.5 mg/day for 16 weeks; no difference in fatigue (-0.76, 95% CI -4.18 to 2.67), pain, symptoms, daily steps or quality of life
  13. International ME/CFS conference roundup: setbacks and new hopes for therapeutic research News
    Rücker M, The Sick Times, 2026. Coverage of the International ME/CFS Conference, Berlin, 7–8 May 2026
  14. Low-dose rapamycin alleviates clinical symptoms of fatigue and PEM in ME/CFS patients via improvement of autophagy: a pilot study Open-label
    Ruan BT et al. (Simmaron Research), Journal of Translational Medicine, 2025. 109 enrolled; 52 of 70 (74%) who reached day 30 were responders; 6 mg weekly; no placebo group
  15. Low-dose rapamycin trial News
    Simmaron Research, 2026
  16. Neurovascular dysregulation and acute exercise intolerance in ME/CFS: a randomized, placebo-controlled trial of pyridostigmine RCT
    Joseph P et al. (Systrom DM), Chest, 2022. n=45; single 60 mg dose; peak VO2 rose on pyridostigmine and fell on placebo
  17. LIFT: Life Improvement Trial (NCT06366724) Registry
    Brigham and Women's Hospital, ClinicalTrials.gov, 2025
  18. Off label use of aripiprazole shows promise as a treatment for ME/CFS: a retrospective study of 101 patients Open-label
    Crosby LD et al., Journal of Translational Medicine, 2021. 75 of 101 (74%) improved at 0.2–2.0 mg/day
  19. Patient-reported treatment outcomes in ME/CFS and long COVID Observational
    Eckey M et al., PNAS, 2025. TREATME survey, n=3,925
  20. PAIS-AriSE: Post-acute Infectious Syndrome – Aripiprazole Symptom Evaluation (NCT07714213) Registry
    Charité – Universitätsmedizin Berlin, ClinicalTrials.gov, 2026
  21. Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in 'Long-COVID19' Open-label
    Fesharaki-Zadeh A, Lowe N, Arnsten AFT, Neuroimmunology Reports, 2022. 12 patients; 8 improved
  22. Hyperbaric oxygen therapy improves clinical symptoms and functional capacity and modulates thalamic connectivity in ME/CFS: a prospective cohort study Observational
    Kim L et al. (Scheibenbogen C), Journal of Translational Medicine, 2026. 30 patients completed 40 sessions; the 20-session comparison was presented at the Berlin conference (May 2026)
  23. STIMPACT: transcutaneous auricular vagus nerve stimulation in post-COVID and ME/CFS (NCT06968104) Registry
    University of Luxembourg, ClinicalTrials.gov, 2025
  24. rTMS for Long COVID cognitive symptoms (NCT06586398) Registry
    UCLA, ClinicalTrials.gov, 2026. Completed March 2026, n=10; no results published
  25. Enhanced external counterpulsation for management of symptoms associated with long COVID Open-label
    Sathyamoorthy M et al., American Heart Journal Plus, 2022
  26. Microtesla magnetic therapy for cognitive impairment in long COVID: a randomized pilot study RCT
    Canori A et al. (Putrino D), Brain Communications, 2026. 30 people, 2:1 active vs sham: active beat sham on some memory and attention tests (p=0.026–0.049); feasibility pilot
  27. Fareon announces oral presentation of first-in-class biophysics treatment News
    Fareon, 2026. Sham-controlled pilot NCT06739668, n=30, Long COVID
  28. REenergizeME: intermittent hypoxia-hyperoxia treatment in ME/CFS (NCT07317401) Registry
    Aarhus University, ClinicalTrials.gov, 2026