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.

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.

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.

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.

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.

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 proprietary multi-component nutraceutical targeting mitochondrial dysfunction, oxidative stress, and serotonin synthesis in fibromyalgia. Conversino et al. (2020, PMID 32204554) randomized 60 FM patients to Migratens® vs. acupuncture for 3 months; Migratens® significantly reduced pain at 1 and 3 months but not at 6-month follow-up, and did not improve FIQ-R or FSS scores. No placebo-controlled RCT exists — acupuncture served as the active comparator. Independent replication is lacking.

A human IgG1 antibody fragment that selectively blocks the neonatal Fc receptor (FcRn), accelerating the degradation of pathogenic IgG autoantibodies. Investigated for dysautonomia and post-exertional malaise in PC-POTS (post-COVID POTS). The Phase 2 RCT (NCT05633407) showed no clinically meaningful improvement in the primary endpoint for efgartigimod-treated PC-POTS patients; the open-label extension study (NCT05918978) was subsequently terminated. However, a subset of trial participants reported significant improvement in tachycardia and PEM, as reported by The Sick Times.

A synthetic mineralocorticoid used off-label for POTS to increase blood volume through sodium and water retention, reducing orthostatic symptoms like dizziness and tachycardia.

Combination therapy pairing guanfacine (α2A-adrenoceptor agonist, FDA-approved for ADHD) with NAC (antioxidant and glutathione precursor). Case series data showed some improvements in brain fog and cognitive symptoms in Long COVID patients.

Breathing 100% oxygen at pressures greater than atmospheric (typically 1.5–3.0 ATA) in a pressurized chamber. Multiple RCTs have shown improvements in cognitive function, fatigue, and quality of life in Long COVID patients through enhanced mitochondrial function and reduced neuroinflammation.

Two non-selective phosphodiesterase inhibitors investigated for Long COVID through anti-inflammatory and vasodilatory properties. Both inhibit neutrophil degranulation and modulate cytokine sensitivity; ibudilast additionally acts as a TLR4 inhibitor. No controlled trials completed yet.

A systemic enzyme complex (ImmunoSEB: serrapeptase, bromelain, papain, etc.) plus a Bacillus spore-forming probiotic blend (ProbioSEB). An industry-sponsored double-blind placebo-controlled RCT (n=200, 14 days) found 91% fatigue resolution in treated vs 15% in controls on the Chalder Fatigue Scale. Note: study sponsored by manufacturer Advanced Enzyme Technologies; short 14-day follow-up; replication needed.

Pooled polyclonal IgG from thousands of donors, with broad immunomodulatory actions including autoantibody neutralization, complement inhibition, and B/T-cell regulation. A Long COVID case series (Thompson et al., Front Immunol 2023, n=9) reported significant improvement in pulmonary, neurological, and cardiac symptoms in patients with documented immune perturbations; a retrospective case-control study (Hogeweg et al., J Intern Med 2023, n=10 IVIG vs matched controls) found substantially greater improvement in IVIG-treated patients. The Yale NeuroCOVID Clinic retrospective case-control study of IVIG for post-COVID small fiber neuropathy (McAlpine et al. 2024, n=8 treated) reported 63% full resolution of neuropathic symptoms. No RCT completed. RECOVER-AUTO is studying IVIG for autonomic dysfunction.

A selective HCN4 channel blocker that reduces heart rate by blocking the funny current of the sinus node. A randomized double-blind placebo-controlled crossover trial (Taub et al. 2021, n=22 hyperadrenergic POTS) demonstrated significant reductions in heart rate and improvements in quality of life. A prospective cohort study of 55 COVID-associated POTS patients (Abdelnabi et al. 2023) found 78% reported symptom improvement within 7 days, with significant heart rate reductions and improved HRV.

A humanized monoclonal antibody that blocks CCR5, originally developed for HIV. An exploratory placebo-controlled trial (n=54, NCT04678830, Gaylis et al. Clin Infect Dis 2022) in Long COVID missed its primary endpoint: adjusted composite symptom score difference was –1.0 (not significant). Mechanistic signal observed — leronlimab-treated responders showed significant increases in cell surface CCR5 levels.

A prodrug stimulant converted to dexamphetamine. No published RCT exists specifically for lisdexamfetamine in ME/CFS or Long COVID. Prescribing is largely extrapolated from the pilot dexamphetamine RCT (PMID 12515836) and clinical experience.

A non-selective opioid antagonist that at low doses (1.5–4.5 mg) acts as a TLR4 inhibitor, glial cell modulator, and causes endorphin rebound. Pre-post study data shows improvements in pain, brain fog, sleep, and other Long COVID and ME/CFS symptoms.

An open-label trial of transdermal LDN combined with NAD+ supplementation for persistent post-COVID fatigue showed improvements in fatigue, physical functioning, social functioning, and emotional well-being.

A fibrinolytic enzyme complex derived from earthworms, studied for anticoagulant and thrombolytic properties. Targets microclot formation and platelet hyperactivation hypothesized to cause persistent symptoms. Clinical evidence is limited to ongoing trials and anecdotal reports.

Combination of a CCR5 antagonist and a statin targeting persistent S1 protein in CD16+ monocytes. A case series testing maraviroc + pravastatin (n=18, Patterson et al., Front Med 2023) reported improvement on 5 clinical scales at 6–12 weeks. Key limitations: patients were pre-selected from those already reporting improvement; lead author holds the CCR5 patent for Long COVID. A Phase III RCT (n=252) is underway testing maraviroc + atorvastatin.

A biguanide antidiabetic agent investigated for Long COVID prevention and ME/CFS treatment. The COVID-OUT RCT demonstrated early metformin use reduced Long COVID incidence by ~41% at 10 months. Efficacy for treating established Long COVID remains unproven.

A CNS stimulant that blocks dopamine and norepinephrine reuptake. A double-blind crossover RCT (n=60, Blockmans et al. Am J Med 2006) showed statistically significant improvements in fatigue and concentration vs placebo, but only 17% of patients were clinical responders on fatigue and 22% on concentration. A follow-up observational study found ~1 in 3 patients benefit long-term.

A second-generation tetracycline antibiotic with anti-inflammatory and neuroprotective properties. Acts primarily through suppression of MMP-9 and iNOS, reducing neuroinflammation. Clinical evidence suggests particular benefit for early-stage patients, with improvements in tachycardia and neuropathic pain.

A non-amphetamine eugeroic approved for narcolepsy and shift-work sleep disorder, used off-label in ME/CFS and Long COVID for fatigue and neurocognitive deficits. A 2022 literature review (Pliszka, Am J Psychiatry Residents' Journal) summarized modafinil's antioxidant and anti-inflammatory preclinical effects and its clinical efficacy for fatigue in TBI (FSS mean difference –0.82, p=0.02) and excessive daytime sleepiness in Parkinson's disease, proposing it as a candidate for Long COVID fatigue and brain fog. A BMJ Case Reports case series (Garg et al. 2021, PMID 33753384, n=3) of treatment-resistant ME/CFS patients (mean illness duration 17.7 years) found that modafinil added to CBT led to clinically meaningful improvement in energy, pain, and concentration in 2/3 patients, with all 3 achieving social recovery (return to work or full-time training) at 10–24 months. No Long COVID-specific RCT exists.

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.

A selective CysLT1 receptor antagonist FDA-approved for asthma. In Long COVID and MCAS, targets inflammatory pathways involving mast cell degranulation and leukotriene-mediated inflammation. Evidence limited to observational studies and ongoing trials.

A fibrinolytic enzyme derived from fermented soybeans that degrades fibrin. Hypothesized to address fibrin amyloid microclots in Long COVID that impair microcirculation. Evidence limited to anecdotal reports and patient surveys; no controlled trials completed.

Nicotinamide riboside (NR) is a vitamin B3 precursor that raises intracellular NAD+ levels. COVID-19 infection is hypothesized to deplete NAD+ via CD38 upregulation and PARP activation, contributing to fatigue, immune dysregulation, and mitochondrial dysfunction in Long COVID. The first dedicated RCT (Wu et al., eClinicalMedicine 2025, PMID 41357333, n=58, 24 weeks, 2000 mg/day NR vs. placebo) found no statistically significant between-group differences in primary cognitive outcomes. The trial was underpowered and 51% of the NR group dropped out by 20 weeks. Industry-sponsored (Niagen Bioscience)

Low-dose transdermal nicotine (7.5 mg/day) activates nicotinic acetylcholine receptors (nAChRs), hypothesized to be dysregulated in Long COVID via spike protein binding. Primary evidence is an n=4 case series (Leitzke, Bioelectron Med 2023) in which 3/4 patients achieved full symptom resolution in 15–26 days; no control group. A 2025 review with PET imaging case report found ~73.5% self-reported improvement in a patient survey. The spike-displacement mechanism is disputed; the science is evolving. Ongoing RCTs underway.

An oral antiviral combination originally developed for acute COVID-19. The STOP-PASC and PAX LC RCTs both showed negative results for Long COVID treatment, though isolated case reports describe symptom improvement. Current evidence for Long COVID use is inconclusive.

A stable salt of L-ornithine and L-aspartic acid playing a role in ammonia detoxification via the urea cycle. A published metabolic modeling study (Xiao et al., 2025, PMID 40649860) used genome-wide constraint-based modeling of muscle transcriptomics (ME/CFS) and metabolomics (Long COVID PEM) to identify downregulation of alanine/aspartate and arginine/proline pathways, proposing LOLA as a candidate to replenish these deficits. No clinical trial has been completed; this is computational/mechanistic rationale only.

A Krebs cycle intermediate available as a dietary supplement, hypothesized to enhance mitochondrial function in ME/CFS through NAD+ elevation and mitochondrial biogenesis. An ongoing clinical trial is investigating its efficacy for fatigue reduction. Sponsored by Terra Biological LLC

An extracorporeal procedure removing and replacing plasma to eliminate autoantibodies, inflammatory mediators, and microclots. The España-Cueto et al. Phase II RCT (Nat Commun 2025, n=50, six sessions TPE vs sham) found no improvement in any efficacy endpoint vs placebo, though TPE was safe; the authors noted treatment was applied ~2 years post-onset, possibly too late. Primary case series anchor: Kiprov et al. F1000Research 2022 (n=1 Long COVID, full symptom resolution after 3 TPE cycles). A Cochrane-style systematic review (Fox et al. 2023) concluded evidence is insufficient to recommend plasmapheresis for Long COVID outside of trials.

A serotonin 5-HT2A agonist psychedelic. A published case report (Chopra et al., Clin Case Rep 2024, PMID 38813452) describes a Long COVID patient with significant symptomatic relief after self-medicating with psilocybin and MDMA. A fibromyalgia open-label pilot study protocol (Bornemann et al., Front Psychiatry 2024, PMID 38983371) with brain imaging biomarkers is underway. Rationale: neuroinflammation, default mode network dysregulation, and central sensitization overlap between Long COVID, fibromyalgia, and depression, where psilocybin has shown efficacy. Controlled trials specifically for Long COVID or ME/CFS do not yet exist.

An acetylcholinesterase inhibitor that enhances cholinergic neurotransmission. In POTS, improves orthostatic tachycardia and cardiac output by enhancing vagal tone. Positive crossover RCTs in POTS show improved heart rate control and exercise tolerance.

An mTOR kinase inhibitor developed as an immunosuppressant and anti-rejection drug. A decentralized uncontrolled pilot trial (Ruan et al., J Transl Med 2025, n=86 ME/CFS patients at 6 specialist centers) administered low-dose rapamycin 6 mg/week for 90 days; significant reductions were observed in fatigue (BAS, SSS, MFI, SF-36) and PEM, with improvements correlating with increased autophagy markers. No placebo control; study is unblinded. A PolyBio/Mount Sinai Long COVID RCT and a Simmaron/Putrino trial are underway. The anecdotal evidence base that preceded these trials drew considerable patient attention after a widely-circulated social media account described recovery from severe PEM.

A five-carbon monosaccharide that is a structural component of ATP. An open-label uncontrolled pilot study (n=41, Teitelbaum et al. 2006) reported 66% of ME/CFS and fibromyalgia patients experienced significant improvement in energy, sleep, cognition, and pain at 5g TID. No placebo control; two co-authors were employed by or consultants for Valen Labs (manufacturer). A 2012 follow-up open-label multicenter study (n=257) showed similar results but was also unblinded and uncontrolled. No independent RCT has been completed.

A synthetic double-stranded RNA TLR3 agonist. The Phase III RCT (n=234, Strayer et al. PLoS One 2012) showed a statistically significant 21.3% improvement in exercise treadmill tolerance on ITT analysis (p=0.047). A post-hoc subgroup analysis found patients with 2–8 years disease duration responded at over twice the ITT rate; the non-target subset (n=133) showed no significant benefit. FDA has refused to approve twice.

A monoclonal antibody targeting CD20+ B cells, investigated in ME/CFS based on hypothesized autoimmune pathophysiology. The definitive RituxME Phase III trial (n=151, Fluge et al. Ann Intern Med 2019) showed no benefit: response rate was 26.0% with rituximab vs 35.1% with placebo (not significant). Rituximab is not an effective treatment for unselected ME/CFS patients.

A PDE5 inhibitor that increases cyclic GMP, causing vasodilation. A Johns Hopkins pilot RCT (NCT00598585, Rowe et al., n=14 ME/CFS with NMH) completed in 2010 but results were never published in a peer-reviewed journal — a significant limitation. Mechanistic rationale remains strong: cerebral hypoperfusion and endothelial dysfunction are documented in ME/CFS and Long COVID, and PDE5 inhibition improves microvascular blood flow. Two Long COVID case reports have described symptomatic improvement. An independent published RCT is needed.

Ultrasound-guided local anesthetic injection near the stellate ganglion to block the cervical sympathetic chain, allowing autonomic "reboot." Long COVID evidence: Liu & Duricka (J Neuroimmunol 2022) case series (n=2) reported resolution of fatigue, brain fog, orthostatic intolerance, anosmia; Pearson et al. (Cureus 2023) retrospective cohort (n=41 self-referred patients, no control) found 86% reported relief at follow-up. A prospective olfactory dysfunction pilot (Peterson et al., Otolaryngol 2024, PMID 37750244, n=15) showed feasibility. All studies are uncontrolled; no RCT yet.

Polyclonal human IgG administered subcutaneously, explored as a home-based alternative to IVIG for Long COVID with small fiber neuropathy or immune deficiency presentations. No dedicated Long COVID RCT exists.

A monoclonal antibody targeting HERV-W Envelope protein (HERV-W-Env), expressed on lymphocytes post-SARS-CoV-2, hypothesized to drive persistent neurological damage. A Phase 2 RCT (GNC-501, GeNeuro/Theranexus, n=203, HERV-W-Env-positive Long COVID patients, Switzerland/Spain/Italy) failed to meet its primary endpoint of fatigue reduction or most secondary endpoints; results have been disclosed via press release only, with no peer-reviewed publication.

An alpha-2-delta calcium channel ligand and the first drug FDA-approved for fibromyalgia (2007). Reduces neuronal excitability and central sensitization by inhibiting voltage-gated calcium channels at presynaptic terminals, decreasing the release of excitatory neurotransmitters including glutamate, norepinephrine, and substance P. RCTs demonstrated significant reductions in pain scores and improvements in sleep quality and global function.

A serotonin-norepinephrine reuptake inhibitor (SNRI) FDA-approved for fibromyalgia (2008), as well as major depressive disorder and generalized anxiety disorder. Modulates descending pain inhibitory pathways via enhanced serotonergic and noradrenergic signaling in the dorsal horn. Multiple RCTs demonstrated significant reductions in pain, fatigue, and depressive symptoms in fibromyalgia patients.

A serotonin-norepinephrine reuptake inhibitor (SNRI) FDA-approved specifically for fibromyalgia (2009), notable for preferentially inhibiting norepinephrine reuptake at a higher ratio than serotonin — the reverse of duloxetine. Phase 3 RCTs demonstrated significant improvements in pain, global function, and fatigue. Unlike duloxetine, milnacipran is not approved for depression in the US, reflecting its distinct pharmacological profile.

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.

An anti-PD-1 monoclonal antibody approved for multiple cancers, now being investigated for neurological Long COVID (neuro-PASC) based on evidence of T cell exhaustion and persistent immune dysregulation following SARS-CoV-2 infection. A NINDS-sponsored Phase 1 open-label safety trial (PD1-PASC I, n=15) is administering a single intravenous dose and tracking safety, functional outcomes, and markers of immune exhaustion over 6 months. Evidence is currently limited to mechanistic rationale; safety data from this trial will determine whether larger efficacy trials are warranted.

A purified glycosaminoglycan mixture (80% fast-moving heparin fraction + 20% dermatan sulfate) that restores the endothelial glycocalyx, reduces fibrinogen, vWF, D-dimer, CRP, and IL-6. Two Long COVID studies support its use: TUN-EndCOV (Charfeddine et al., Front Cardiovasc Med 2022, n=290 quasi-experimental) showed significant improvement in endothelial function (EQI) and reduction in chest pain, palpitations, and fatigue at 21 days; a double-blind placebo-controlled RCT (Gonzalez-Ochoa et al. 2024, n=~100 convalescent COVID patients) showed significant reductions in TM, vWF, D-dimer, CRP, and IL-6 at 8 weeks. OTC in Europe; prescription required in US.

An essential B vitamin critical for mitochondrial energy metabolism (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, transketolase). An open-label RCT (Tehrani et al., Arch Clin Infect Dis 2024, n=66) of thiamine in post-acute COVID-19 syndrome showed significant improvement in fatigue, sleep disturbance, and other symptoms vs. supportive care alone. A Costantini case series (BMJ Case Rep 2013) showed high-dose thiamine (600–1800 mg/day) significantly reduced fatigue in fibromyalgia. An informal survey of 55 ME/CFS/fibromyalgia patients found ~65% reported large benefits from high-dose thiamine. Mechanism in these conditions may be pharmacological (not purely nutritional), as benefits occur even without frank deficiency.

An SSRI and potent sigma-1 receptor (S1R) agonist. Its primary RCT evidence is for acute COVID-19: the TOGETHER trial (Lancet Glob Health 2021, n=1497) found early fluvoxamine reduced hospitalization by ~31%; a JAMA 2020 trial (n=152) found reduced clinical deterioration. For established Long COVID, no RCT exists; evidence is limited to mechanistic rationale and case reports of improvement in neuropsychiatric symptoms, fatigue, and autonomic dysfunction. The ACTIV-6 trial (JAMA 2023, n=1288) found no benefit for acute COVID-19. Current Long COVID relevance: plausible mechanism via sigma-1R-mediated ER stress reduction, anti-inflammatory effects, and serotonin modulation; appropriate for patients with concurrent anxiety or OCD.

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.

A humanized monoclonal antibody that blocks the IL-6 receptor (IL-6R), reducing downstream JAK-STAT3 inflammatory signaling. IL-6 is persistently elevated in a subset of Long COVID patients. Tocilizumab is approved for RA, giant cell arteritis, and cytokine release syndrome. For Long COVID, evidence is preclinical and mechanistic; no completed RCT exists for this indication, though the persistent IL-6 elevation rationale parallels its established use in cytokine storm syndromes. A sub-group of Long COVID patients with elevated IL-6 and inflammatory markers may represent the most plausible candidates for a trial.

A gut microbiome-derived metabolite of ellagitannins (found in pomegranates, walnuts, raspberries) that activates mitophagy via PINK1/Parkin pathway, clearing dysfunctional mitochondria. A double-blind RCT (Liu et al., JAMA Netw Open 2022, PMID 35050355) in older adults (n=66) found 1,000 mg/day urolithin A for 4 months significantly improved muscle endurance and mitochondrial biogenesis markers (PGC-1α) vs. placebo. A second RCT (Singh et al., Cell Rep Med 2022, n=88 middle-aged adults) missed its primary endpoint (peak power output) but found significant improvements in muscle strength and mitochondrial biomarkers at both 500 mg and 1000 mg/day doses. No disease-specific RCT in ME/CFS or Long COVID has been published.

A half-life-extended anti-SARS-CoV-2 monoclonal antibody (IgG1λ) targeting the spike protein receptor-binding domain. FDA EUA-authorized (March 2024) for COVID-19 pre-exposure prophylaxis in moderately-to-severely immunocompromised individuals; not authorized for Long COVID treatment. Repurposing rationale: neutralization of persistent viral antigens hypothesized to drive ongoing immune dysregulation, neuroinflammation, and microvascular dysfunction in Long COVID. Primary Long COVID evidence: Baratta et al. reported rapid symptomatic improvement in fatigue, PEM, dysautonomia, and brain fog; effects waned at ~2 months, consistent with the drug's ~45-day half-life. A 36-patient UCSF RCT of a related mAb (AER002, Peluso et al., Spring 2025 symposium, unpublished) found no significant difference in PROMIS-29 or inflammatory markers vs placebo. Invivyd formed the SPEAR Study Group (July 2025, with Peluso, Proal, Putrino) to design rigorous controlled Long COVID trials. Safety profile from CANOPY Phase 3 trial.

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.

An anti-spike monoclonal antibody (AstraZeneca) that neutralises SARS-CoV-2, investigated for COVID-19 prevention in immunocompromised individuals and as a potential Long COVID treatment via antigen burden reduction. The Phase 3 SUPERNOVA RCT (Haidar et al., Lancet Infect Dis 2025, n=3,349 immunocompromised participants across 18 countries, NCT05648110) demonstrated a 34.9% relative risk reduction in symptomatic COVID-19 due to any variant (p=0.0006) and 42.9% RRR against non-Phe456Leu-containing variants (p=0.0012) vs comparator. No efficacy was shown against Phe456Leu-containing variants (KP.2*, KP.3*) that dominated as of late 2024. Serious adverse events related to trial intervention occurred in 0.1% of the sipavibart group vs 0.4% comparator; no serious cardiovascular or thrombotic events were considered related to sipavibart. Evidence for Long COVID treatment specifically remains limited to the antigen-clearance mechanistic rationale and the broader mAb case series literature; a dedicated Long COVID RCT is ongoing.

Beta-adrenergic receptor antagonists used off-label for POTS, inappropriate sinus tachycardia (IST), autonomic symptoms, anxiety, and migraines in Long COVID. Low-dose propranolol (20 mg daily) has the most evidence for POTS, particularly hyperadrenergic POTS. In the Harvard/Stanford TREATME Study, 51% of Long COVID patients (n=195) reported moderate to much better improvement with cardioselective beta blockers; 40% (n=169) with non-cardioselective agents. Recommended across multiple clinical care guidelines including the 2015 Heart Rhythm Society, Bateman Horne Center, and 2021 ME/CFS Clinician Coalition.

An alpha-1 adrenergic agonist that increases peripheral vascular resistance, used for orthostatic hypotension (OH) and neuropathic POTS. A double-blind placebo-controlled crossover study in 20 patients found midodrine improved postural tachycardia in neuropathic POTS but not hyperadrenergic POTS. In the Harvard/Stanford TREATME Study, 26.5% of Long COVID patients (n=49) reported moderate to much better symptom improvement. Recommended in the 2015 Heart Rhythm Society Expert Consensus, Bateman Horne Center, AAPM&R, and 2021 ME/CFS Clinician Coalition guidelines.

A dual-action mast cell stabilizer and H1 receptor antagonist. Superior to second-generation antihistamines alone due to its combined mechanism. In the Harvard/Stanford TREATME Study, 24% (n=50) reported moderate to much better improvement. Must be compounded in the US. Recognized in the Bateman Horne Center Clinical Care Guide for ME/CFS, Long COVID, and IACCs.

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.

Antivirals targeting herpesvirus reactivations (EBV, VZV, CMV, HHV-6) documented post-COVID. EBV DNA was detected in 27% of people post-COVID vs 13% of controls. In the TREATME Study: valacyclovir 22.5% improvement (Long COVID, n=49), 26.5% (ME/CFS, n=147); acyclovir 19% (Long COVID, n=21); valganciclovir 21% (ME/CFS, n=52); Truvada/tenofovir 25% (Long COVID, n=12).

A serotonin antagonist and reuptake inhibitor (SARI) used for sleep dysfunction in Long COVID and ME/CFS. Meta-analyses of 40+ RCTs confirm trazodone extends sleep time and may improve sleep quality vs placebo. Typical dosing: 25–50 mg 1 hour before bed, titrated to 100–150 mg.

GLP-1 receptor agonists initially approved for diabetes and weight management, now emerging as investigational therapy for Long COVID and MCAS. A 2025 case series in MCAS patients found 89% (42/47) had symptom improvement. Preclinical studies show GLP-1 suppresses microglial inflammation, relevant to POTS pathophysiology. A tirzepatide trial for Long COVID completed enrollment of 1,000 US participants in December 2025 and remains ongoing.

An H2 receptor antagonist that may prevent SARS-CoV-2 spike protein entry into endothelial cells and attenuates cytokine storm. In combination with H1 antihistamines, up to 72% of Long COVID patients showed symptom reduction (Glynne et al.). In the Harvard/Stanford TREATME Study, 20% of Long COVID patients (n=300) reported moderate to much better improvement on famotidine; a combination of H1 + H2 blocker showed 35% improvement (n=194). A large cluster RCT investigating famotidine + loratadine in Long COVID is ongoing.

An activity management strategy that prevents and mitigates post-exertional malaise (PEM) by keeping activity levels within individual energy limits. In the Harvard/Stanford TREATME Study, 37% of Long COVID patients (n=119) reported moderate to much better improvement. Recommended in clinical guidelines from the Mayo Clinic Proceedings of ME/CFS, Bateman Horne Center, and 2021 ME/CFS Clinician Coalition. #MEAction and Long COVID Physio provide free implementation guides.

A foundational lifestyle intervention for POTS and orthostatic hypotension, with clinical guidelines recommending 2–3 L water and 10–12 g sodium chloride daily. In the Harvard/Stanford TREATME Study, 33% of Long COVID patients (n=1,169) reported moderate to much better improvement with oral fluids and electrolytes. Recommended in the 2021 ME/CFS Clinician Coalition, Bateman Horne Center, 2015 Heart Rhythm Society, and Mayo Clinic Proceedings guidelines.

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 gentle massage technique targeting lymphatic and glymphatic flow, used in ME/CFS and Long COVID for fatigue and neurological symptoms. A study of 20 Long COVID patients (weekly Perrin Technique sessions + daily home self-massage) reported 41.8% reduction in fatigue-related state scores in men and 60.5% in women. In the Harvard/Stanford TREATME Study, 25% of ME/CFS patients (n=83) and 14% of Long COVID patients (n=14) reported moderate to much better improvement. Note: muscle tissue manipulation may trigger PEM.