What drugs are currently in clinical trials for the treatment of Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)?

Current Clinical Trial Drugs for ME/CFS

While no FDA-approved drugs exist specifically for ME/CFS, several pharmacological agents are currently being investigated or used off-label based on ME/CFS literature and overlapping conditions, with the most promising evidence supporting low-dose naltrexone, low-dose aripiprazole, antivirals for herpesvirus reactivation, and immunomodulatory agents like intravenous immunoglobulin and cyclophosphamide. 1, 2

Pharmacological Agents Under Investigation

Neuroinflammation and Pain Management

• Low-dose naltrexone shows promise for treating pain, fatigue, and neurological symptoms in ME/CFS, with substantial anecdotal reports of success within the patient community 1
• Low-dose aripiprazole is being explored for fatigue, unrefreshing sleep, and brain fog based on ME/CFS literature 1

Antiviral Therapies

• Valaciclovir, famciclovir, and valganciclovir are being investigated for viral persistence and reactivations of Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), and varicella zoster virus (VZV) 1
• Paxlovid has shown promise in long COVID case reports and warrants further investigation for ME/CFS given the viral persistence hypothesis 1

Immunomodulatory Approaches

• Intravenous immunoglobulin (IVIG) is recommended for immune dysfunction in ME/CFS, though consultation with an immunologist is advised for implementation 1
• Cyclophosphamide demonstrated a 55% overall response rate in an open-label phase II trial of 40 ME/CFS patients, with 68% of responders maintaining remission at 4-year follow-up 3
• BC007 neutralizes G protein-coupled receptor autoantibodies and has shown promise in long COVID case reports, suggesting potential application in ME/CFS 1

Anticoagulant Therapies

• Triple anticoagulant therapy showed resolution of symptoms in all 24 patients in one study addressing abnormal clotting, with additional trials in progress 1
• Apheresis has shown promise in alleviating symptoms, theoretically by removing microclots and reducing autoantibodies, though it is expensive and benefits remain uncertain 1

Metabolic and Mitochondrial Support

Supplements with Evidence Base

• Coenzyme Q10 and D-ribose have shown promise in treating fatigue in ME/CFS literature and may deserve further study 1
• Pycnogenol statistically significantly improved physiological measurements including reduction in oxidative stress and quality of life scores in pilot studies 1

Symptom-Specific Pharmacotherapy

Autonomic Dysfunction (POTS)

• β-blockers, pyridostigmine, fludrocortisone, and midodrine are pharmacological options prioritized based on specific constellation of symptoms 1

Mast Cell Activation

• H1 and H2 antihistamines, particularly famotidine, are used to alleviate a wide range of symptoms following mast cell activation syndrome protocols, though they treat symptoms rather than underlying mechanisms 1

Gastrointestinal Symptoms

• Probiotics showed potential in pilot studies for alleviating both gastrointestinal and non-gastrointestinal symptoms 1
• Sulodexide demonstrated reduction in symptom severity in a small trial of patients with endothelial dysfunction 1

Important Contraindications

Agents NOT Recommended

• Stimulants (including methylphenidate) are specifically recommended against by the VA/DoD Clinical Practice Guideline, as harms outweigh benefits including potential for abuse, aggression, exacerbation of bipolar illness and hypertension 1
• Mifepristone is recommended against due to potential risks outweighing benefits 1
• Long-term opioid medications are not recommended for ME/CFS management 1
• Exercise and graded exercise therapy are contraindicated, as physical activity worsened the condition in 75% of patients with less than 1% showing improvement 1

Critical Considerations

Study Limitations

The current evidence base is limited by small-scale pilot studies, heterogeneous study designs, lack of placebo controls, and the highly heterogeneous nature of ME/CFS itself 4, 5, 6. Most treatments require urgent clinical trialing with rigorous experimental designs 1, 2.

Mechanistic Targets

Future drug development focuses on multiple mechanisms including improving natural killer cell function, removing autoantibodies, immunosuppression, antioxidants, and mitochondrial support 1, 2. Common features across ME/CFS patients include immune dysregulation and mitochondrial dysfunction, providing rational targets for intervention 2.

Funding Barriers

A significant limitation to robust trials is lack of funding, leaving many newer treatment options underexplored including anticoagulants and antivirals 1.