Medications

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.
2. It calms the brain’s immune cells (microglia), which may reduce neuroinflammation.
3. It restores the TRPM3 calcium channel in immune cells, according to Griffith University’s lab work. See The science.

The evidence, honestly

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.
• 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.
• Detailed results (e.g. on pain, sleep, dizziness and subgroups) aren’t published yet. Figures reported so far come from conference coverage.

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 measured fatigue. If LDN helps a subgroup with brain fog or sleep, a fatigue-focused trial could miss that.
• It was too small to detect a benefit in a subgroup.
• 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 is starting a placebo-controlled LDN trial (TreatMELC) in Australia. 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.
• People whose illness started after an infection responded better, which suggests it may suit infection-triggered or EBV-associated ME/CFS.
• 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, pyridostigmine improved how the heart and circulation respond to exertion in ME/CFS.
• 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.

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.
• But in a patient survey, only 32% reported feeling moderately or much better, and the effect often wore off.
• The first placebo-controlled trial (PAIS-AriSE) is getting under way.

Guanfacine + NAC Adjacent field

Used for brain fog. A small Yale study in Long COVID found benefit. It’s cheap and available, but some people with ME/CFS report crashing on it.

Other treatments being studied

See all current trials and 2026 results.