ME/CFS Research :: Treatments

Treatments

The following are trialed, proposed, hypothetical, speculative, or imaginary treatments for ME/CFS. This is not a recommendation list for patients but rather a list of treatments that require further research.

Proposed or Speculative Repurposed Drugs

For Orthostatic Hypotension, POTS, and/or Exercise Intolerance
- droxidopa (Northera)
- fludrocortisone
- indomethacin (ref. Kochar 1979)
- midodrine (Proamatine)
- propranolol
  - Brevetti 1979 - In a patient with orthostatic hypotension and supine hypertension, low-dose propranolol appears to normalise the response to the posture change, by restoring normal vasoconstriction in the upright position.
  - Li 2012 - Reverses IgG β2-adrenergic and M3-muscarinic agonistic autoantibody-mediated vasodilation in orthostatic hypotension when combined with NG-nitro-l-arginine methyl ester. Note ME/CFS is also associated with these autoantibodies (Loebel 2016).
- pyridostigmine (Mestinon)
  - Joseph 2022 - Improved ventricle filling pressure and oxygen uptake during exercise in ME/CFS in double-blind, placebo-controlled trial.
For Blood Flow
- sildenafil (Viagra)
- pentoxifylline (Trental) - for microcirculation, immune modulation
  - For Long COVID: Reviewed by Monji 2020, Livieratos 2024, Ramzi 2024
  - Reduced TNF-α and CRP (Brie 2016)
  - Clinical Trial for Long COVID in Ottawa/Toronto
- ginkgo biloba - natural alternative to pentoxifylline?
spironolactone
- improve left ventricle function
- antiviral for EBV
- not recommended for male patients
- Proposed for MS treatment: Li 2025
metformin
- Note: also see metformin entry in Antivirals section
- may redress T-cell hyperproliferation in ME/CFS, at least in female patients (Shankar 2025)
- may reduce risk of rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis (Liao 2025)
- improves mouse model of gulf war illness when combined with MitoQ; treatment activated AMPK signaling, reduced oxidative stress, attenuated inflammation, rescued autophagy and improved mitochondrial respiration (Cai 2025)
- modulate the gut microbiome and enhance intestinal barrier function (Chen 2024)
- reduced hyperactivation of B-cells in vitro in Primary Sjogren's Disease patient samples (Luo 2023)
- ex vivo studies showed metformin increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS patients, where patients had impaired AMPK activation and glucose uptake in primary skeletal muscle cell cultures (Brown 2018)
- improved Fibromyalgia, which may be in part due to insulin resistance (Pappolla 2019)
  (retracted due to inadequate ethics approval procedures and concerns regarding patient data confidentiality)
- suppresses systemic autoimmunity in mice through inhibiting B cell differentiation into plasma cells (Lee 2017)
- energy metabolism may be at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer (Foretz 2014)
- has unique, intrinsic actions specifically at the level of terminal arterioles, which are completely independent of its antidiabetic effect (Wiernsperger 2012)
- has potential for reducing microvascular dysfunction and a capacity to stimulate slow wave arteriolar vasomotion and improve functional capillary density, whereby nutritive flow can be re-established; metformin's properties have also been demonstrated in non-diabetic animals or humans, suggesting they are intrinsic to the drug and not secondary to diabetic metabolic improvement (Wiernsperger 2003)
- Caveats:
  - increases lactic acid -- already elevated in ME/CFS
  - decreases mitochondria respiration (Andrzejewski 2014) -- conflicting evidence wrt mitochondria
  - negatively affects monocytes (Montani 2019)
low dose naltrexone (LDN)
- Restores TRPM3 ion channel & NK cell function
- Long Covid trial: Sasso 2025
- For ME/CFS: Löhn & Wirth 2024
- For ME/CFS & Long Covid: Sasso 2022
- For Sjögren's: Zashin 2020
low dose aripiprazole (Abilify)
- "Dopamine D2 receptor agonists have been shown to mediate neuroinflammation, microglial activation, and cell death in animal models and humans. This suggests that dopamine-modulating drugs like aripiprazole may lead to clinical improvement in fatigue and cognitive symptoms in ME/CFS." An open label trial was completed. (Crosby 2021)
hydroxychloroquine (Plaquenil)
Immunomodulators/Monoclonal Antibodies
- rituximab (successful Phase II trial, failed Phase III trial)
- cyclophosphamide (Fluge & Mella)
- daratumumab (Fluge & Mella)
- next-generation B cell-depleting anti-CD20 antibodies
  (proposed in Robinson 2024 for systemic autoimmune diseases, these deplete both blood and tissue B cells more efficiently than rituximab)
  - obinutuzumab, ocrelizumab or ofatumumab
- subcutaneous ofatumumab (Kesimpta) (for better tissue penetration)
- rapamycin (siroliums/Rapamune) (D Peterson) (clinical trial ongoing)
- JAK inhibitors, e.g. tofacitinib (Xeljanz) and baricitinib (Olumiant)
- abatacept or belatacept (inhibit T cell activation)
- checkpoint inhibitors (to clear peristent pathogens; might cause autoimmunity or rheumatic disease)
- leflunomide or teriflunomide (anti-rheumatic/immune suppressant/anti-EBV)
  - Bilger 2017 - inhibits EBV replication
- efgartigimod (Vyvgart)
- IVIG
- IgM-enriched IVIG (Pentaglobin)
- glatiramer acetate (Copaxone)
  - Jensen 2024 - prevent demyelination in ME/CFS
aprotinin (Trasylol)
Antivirals (new trials should be a minimum 9 months, but preferably a minimum 12 months)
- General and comparative research
  - Friedrichs 2004 - Comparison of antivirals against EBV in vitro with PCR
  - Drosu 2020 - Test of tenofovir and other drugs against EBV in vitro
- valacyclovir (Valtrex)
  - Lerner 2007 - clinical trial in CFS
  - Hoshino 2009 - reduced latent EBV infected B cells in healthy subjects
- famciclovir (Famvir) - similar efficacy as valacyclovir, less neurotoxicity
- valganciclovir (Valcyte)
  - Montoya 2013 - clinical trial in CFS
  - Yager 2017 - reduced saliva EBV shedding in healthy subjects
- cidofovir (Vistide) - intravenous antiviral
- brincidofovir (Tembexa / CMX001) - oral cidofovir prodrug
- artesunate - injection or oral?
- tenofovir disoproxil fumarate
- tenofovir alafenamide better tissue & PBMC penetration and lower toxicity than TDF
- metformin - has antiviral effect; for SARS-CoV-2 in Long COVID (Bramante 2024) (other effects, see above)
- valproic acid/sodium valproate (Depakote)
  - can inhibit EBV
  - induces lysis of EBV+ cancer cells when combined with ganciclovir (Jones 2010)
- hydroxyurea - eliminates EBV episomes from latently infected cells in vitro (Chodosh 1998). Does it work in vivo?
Vitamins and Supplements
- B1/Thiamine (IBD-associated fatigue trial)
- Creatine (open-label ME/CFS trial)
- Coenzyme Q10 (review by Mantle 2024)
- Thymoquinone/Nigella Sativa (ref Zihlif 2012)
  - inhibits growth of EBV-infected B cells, also weakly inhibits non-infected B cells
  - reduces survival and induces apoptosis of EBV-infected B cells
  - prevents latent replication by inhibiting latent genes EBNA-2 and to a lesser extent EBNA-1
  - a concentration of 12 microM/L might be ideal? requiring 410 mg of thymoquinone orally?
Other
- Stem cell infusion
  - improvement in two young adult and pediatric dysautonomia patients (Numan 2017)
  - improvement in Long COVID, particularly immune parameters (Tang 2024)

Proposed or Speculative Combination Protocols

LDN + pyridostigmine (proposed by D Systrom, clinical trial ongoing)
rituximab + anti-EBV drug (proposed by T Craddock, N Klimas - no known plans for trial)
rituximab + IVIG (proposed by A Ahmed - for generalized autoimmune disease)
EBV reactivation agent + anti-EBV drug
(highly speculative, potential to worsen autoimmunity?)
(review of this strategy in lymphoma - Kong 2024)
- EBV reactivation agents
  - sodium butyrate
    - requires frequent or continuous IV dosing
    - encourage butyrate production with prebiotics and probiotics?
  - arginine butyrate (Perrine 2006)
  - 5-azacytadine, romidepsin, trichostatin A, or nanatinostat (Kong 2024)
  - chidamide (Xu 2023)
  - valproic acid?
  - nanatinostat (under development) (Haverkos 2023)
bone marrow transplant (highly speculative, high risk of death)

Under Development

Ampligen (rintintolimod / poly i:poly c12u)
Astellas Pharma ASP0367 (for mitochondrial myopathy)
~~Berlin Cures BC007 (for Long COVID)~~
- Failed trial
Immunoadsorption (trial in Germany)
Inspiritol (nebulized inhaled glutathione and other ingredients)
Mitodicure MDC002
Salubrinal (inhibits cellular stress response) (Warrayat 2024)
VK-2019 (Latent EBV inhibitor)
WinSanTor WST057 (topical pirenzepine) (for peripheral neuropathy)

Imaginary

Anti-CD21 antibody (to eliminate EBV infected cells and vulnerable cells)
- CD21, aka Complement Receptor 2 or EBV-receptor, is used by EBV to enter cells
- Anti-CD21 antibodies are currently available for lab experiments only (e.g. BD Biosciences
- Possible paradox: CD21 expression improves survivability of DLBC lymphoma in mice (Otsuka 2024)
Thymoquinone prodrug (to decrease EBV infected cell survival, needs better bioavailability)
A drug to selectively dilate capillaries and constrict large veins (to improve orthosatic tolerance and tissue perfusion)

Editor's Comment

On rituximab: A promising pilot study in three patients led to a small double-blind placebo-controlled trial of rituximab in ME/CFS, which was successful. However, a larger follow-up study was negative. It is interesting to note that the three pilot patients all had ME/CFS triggered by EBV, and some had lymphoma. The question remains whether rituximab might work better in a carefully selected subgroup of patients – perhaps those whose illness was triggered by EBV, or who have comorbid autoimmune conditions, lymphoma, or maybe prolonged lymphadenopathy, which might be considered pre-lymphoma. However, even in EBV-associated ME/CFS, a problem with anti-CD20 treatment is the resuling immune suppression; if ME/CFS is caused in part by poor immune function then this treatment may worsen the condition.

On antivirals: Clinical trials of antivirals in ME/CFS have generally led to small, but underwhelming results (trials of antivirals in multiple sclerosis, believed to be caused by Epstein-Barr virus, have also lead to marginal benefit). Longer-duration trials (at least 12 months) and/or combination with immunomodulatory drugs are possible avenues to explore in the future. Measurement of EBV latent viral load, such as in Hoshino 2012, or saliva shedding, such as in Yager 2017, could improve understanding and interpretation of results. T Craddock/N Klimas argue that EBV from epithelial cells may serve as a kind of (editor's words) "co-reservoir," with B cells and other immune cells, making it necessary to target the virus from multiple angles in order to successfully reduce the viral load. Other research has pointed to increased latent replication of EBV in ME/CFS patients, which cannot be targeted by current antiviral drugs (VK-2019 might be able to do this).