Treatment Database

A carbonic anhydrase inhibitor used for idiopathic intracranial hypertension (IIH), prescribed off-label in ME/CFS and Long COVID for patients with suspected elevated intracranial pressure. The key reference (PMID 24756514) is the NORDIC multicenter RCT (n=165) demonstrating acetazolamide improves visual field function and reduces papilledema in IIH. ME/CFS use is based on clinical extrapolation — practitioners such as Drs. Kaufman and Ruhoy report subjective improvement in headache, fatigue, and neurological symptoms in a subset of patients with suspected intracranial hypertension, but no controlled trials have been conducted in ME/CFS.

A tricyclic antidepressant (TCA) widely used at low doses (10–50 mg at night) for fibromyalgia pain, non-restorative sleep, and comorbid ME/CFS symptoms. A Cochrane review found amitriptyline provides clinically useful pain relief in a minority of fibromyalgia patients (NNT ~4–5) despite modest overall trial quality; a 2024 fibromyalgia management update noted amitriptyline had among the strongest associations with reduced sleep disturbance and fatigue and improved quality of life. It is not a first-line agent by rigorous RCT standards but remains a mainstay of clinical practice for pain-sleep overlap. Also used off-label for IBS, migraine prophylaxis, and neuropathic pain.

HELP (Heparin-induced Extracorporeal LDL Precipitation) apheresis and related filtration-based apheresis (INUSpheresis) remove fibrinogen, autoantibodies, lipids, inflammatory cytokines, and oxidative markers from plasma. A prospective observational study (n=27 Long COVID patients, Mol Psychiatry 2023) found significant pre/post reductions in GPCR autoantibodies (28–48%), CRP, IL-6, fibrinogen (70%), and H₂O₂ (>90%) in those reporting clinical improvement. A cohort of 1,111 patients with ME/CFS (including 13% with Long COVID) reported ~74% symptom improvement 6 months after treatment. No RCT yet; no sham control.

An atypical antipsychotic that at low doses (0.5–2 mg) acts as a dopamine system stabilizer, theorized to modulate neuroinflammation and dopaminergic signaling. A retrospective Stanford study of 101 ME/CFS patients found 74% of participants reported improvement in fatigue, brain fog, unrefreshing sleep, and post-exertional malaise.

An HMG-CoA reductase inhibitor being investigated for Long COVID based on pleiotropic anti-inflammatory, endothelial-protective, and immunomodulatory effects. Observational data suggests statins may reduce microclot formation, endothelial dysfunction, and systemic inflammation.

Structured, recumbent-to-upright graded reconditioning programs (e.g., the modified Dallas/Levine and CHOP autonomic protocols) are recommended for POTS to improve orthostatic tolerance and cardiovascular deconditioning — but only when carefully adapted for patients with post-exertional malaise, since standard graded exercise therapy can be harmful in ME/CFS and PEM-predominant Long COVID. When PEM is present, symptom-titrated, recumbent, and heart-rate-capped approaches are used to avoid triggering crashes. Distinct from pacing: this targets autonomic reconditioning rather than pure energy conservation.

A selective JAK1/JAK2 inhibitor approved for rheumatoid arthritis, being studied for Long COVID based on its ability to modulate cytokine signaling and reduce inflammation. Targets the JAK-STAT pathway involved in immune dysregulation.

A DNA aptamer designed to neutralize agonistic autoantibodies against G-protein coupled receptors (GPCR-fAAbs), particularly β1-adrenergic and muscarinic receptors. The completed reCOVer phase IIa RCT (n=30) in GPCR-fAAb-positive Post-COVID patients demonstrated significant improvements in fatigue (FACIT, FSS, Bell scores) and quality of life, with a good safety profile. A separate larger Phase II trial (BLOC, NCT05911009, n=119, Berlin Cures) failed to show superiority over placebo in November 2024, leading to the company's insolvency.

An orally bioavailable, blood-brain-barrier-permeable small molecule with dual anti-inflammatory and insulin-sensitizing properties. Bezisterim selectively inhibits inflammation-driven ERK signaling and modulates NF-κB activation, reducing downstream expression of inflammatory cytokines. The Long COVID mechanistic rationale: persistent SARS-CoV-2 spike protein and RNA are hypothesized to drive chronic TLR4-mediated NF-κB activation, producing the neuroinflammation, metabolic dysfunction, and blood-brain barrier disruption underlying cognitive impairment and fatigue. The compound was tested in Phase 2 trials for Alzheimer's disease (NCT05227820) and Parkinson's disease (NCT05083260), providing indirect mechanistic validation. No published Long COVID efficacy data exists yet. The ADDRESS-LC trial (NCT06847191, funded by a $13.1M DoD CDMRP award) is currently enrolling across multiple sites. Primary outcome: change in Cogstate Cognition battery.

Monoclonal antibodies (mAbs) targeting residual SARS-CoV-2 viral antigens in Long COVID. Scheppke et al. (2023, PMID 37944296) reported complete, rapid remission of severe Long COVID in three index cases following casirivimab/imdevimab infusion, proposing a viral persistence mechanism. Evidence is currently limited to uncontrolled observational reports; no published RCT yet.

Second-generation H1 receptor antagonists targeting mast cell activation (MCAS) as a driver of Long COVID symptoms. A prospective observational study by Glynne et al. (J Investig Med 2022) of 65 Long COVID patients found significant reduction in mean symptom burden with H1 receptor antagonists, accompanied by characteristic T-cell alterations. An Italian prospective study (n=14 treated vs 13 controls, 20 days) found 29% of treated patients achieved full resolution vs 0% controls. Clinical experience from Glynne et al.'s practice (>200 patients) suggests 65–70% respond, with skin and GI symptoms improving first, followed by brain fog and fatigue. STIMULATE-ICP trial (UCL, loratadine + famotidine) is ongoing. Mechanism includes blocking H1-mediated cytokine signaling and potentially blocking HRH1 as an alternative SARS-CoV-2 entry receptor.

Triple antiplatelet/anticoagulant therapy targeting microclot formation and impaired fibrinolysis in Long COVID. Acts synergistically to reduce platelet activation and thrombin generation. Preprint data suggests potential symptom resolution for fatigue, cognitive dysfunction, and pain.

A lipid-soluble antioxidant and mitochondrial electron transport chain cofactor. Evidence is condition-specific: multiple small positive RCTs exist for fibromyalgia; a 207-patient RCT of CoQ10+NADH in ME/CFS showed within-group improvement but no statistically significant intergroup difference; and a double-blind crossover RCT in Long COVID (n=121, 500mg/day) found no significant benefit over placebo. A meta-analysis across 13 RCTs (n=1,126, mixed conditions) found a modest pooled effect on fatigue. Evidence is stronger for fibromyalgia than ME/CFS or Long COVID.

Ankle-to-waist compression garments (≥20 mmHg at ankle) reduce venous pooling and improve cardiac preload in POTS. Medical-grade waist-high compression reduced heart and improved symptoms in patients with POTS. In the Harvard/Stanford TREATME Study, 26% of Long COVID patients (n=430) reported moderate to much better improvement. Note: donning full-leg compression garments may itself trigger PEM.

A combination of CoQ10 and alpha-lipoic acid targeting mitochondrial dysfunction and oxidative stress. A prospective observational study (n=174, Barletta et al., Clin Exp Med 2022) found 53.5% complete fatigue response in treated vs 3.5% in controls. Not randomized or blinded; a subsequent RCT of CoQ10 monotherapy in Long COVID showed no benefit, suggesting the combination or population may matter.

A combination targeting mitochondrial dysfunction, oxidative stress, and microcirculation impairment in fibromyalgia. An open label uncontrolled study demonstrated significant improvements in pain, fatigue, and quality of life measures.

A combined formulation of coenzyme Q10 and NADH (nicotinamide adenine dinucleotide + hydrogen), targeting mitochondrial dysfunction through complementary mechanisms. A 207-patient RCT in ME/CFS showed within-group improvement on fatigue and quality-of-life measures but no statistically significant intergroup difference versus placebo, limiting conclusions about efficacy.

Combination targeting mitochondrial dysfunction and oxidative stress in ME/CFS. Open-label trials show reductions in lipid peroxidation markers and improvements in fatigue and quality of life. CoQ10 is an electron carrier; selenium is a cofactor for glutathione peroxidase.

A mast cell stabilizer that reduces inflammatory substance release from activated mast cells. Oral cromolyn: 36% of Long COVID patients (n=33) reported moderate to much better improvement in the Harvard/Stanford TREATME Study; intranasal cromolyn was less effective (10.5%, n=38). Multiple delivery forms available (oral liquid, inhaler, eye drops, topical). Recognized in the Bateman Horne Center Clinical Care Guide for treating MCAS in ME/CFS and Long COVID.

A sublingual low-dose cyclobenzaprine formulation FDA-approved for fibromyalgia in August 2025, the first new drug approved for the condition in over 15 years. Unlike oral cyclobenzaprine (a muscle relaxant), the sublingual route bypasses hepatic first-pass metabolism, reducing production of the long-acting metabolite norcyclobenzaprine and allowing a lower effective dose (5.6 mg vs 10–30 mg oral). Its proposed mechanism targets nonrestorative sleep, a core feature of fibromyalgia. Two of three phase 3 RCTs (RELIEF and RESILIENT; ~1,000 patients combined) met the primary endpoint of reduced daily pain at 14 weeks, with secondary endpoints including sleep quality and fatigue also significantly improved.