Candidate Therapeutics for Long COVID & PACVS

Mechanism

100% oxygen at 1.5–2.0 atmospheres absolute (ATA) induces multiple systemic effects: hyperoxia drives angiogenesis via VEGF; neuroplasticity via BDNF and stem cell mobilisation; improves mitochondrial electron transport efficiency; reverses hypoxia-inducible factor (HIF-1α) changes in chronically hypoxic tissue; reduces microglial activation and NLRP3 inflammasome neuroinflammation.

Evidence in Long COVID

Double-blind, sham-controlled RCT (n=73). 40 daily 90-minute HBOT sessions at 2.0 ATA with 100% O₂. Primary endpoint (cognitive performance) significantly improved vs. sham. Also significantly improved: energy levels, sleep quality, and pain. Brain MRI showed increased regional cerebral blood flow.

Limitation: Expensive; requires 40 daily sessions at specialist centres. Not studied in PACVS specifically.

Mechanism

15-nucleotide single-stranded DNA aptamer that sterically neutralises a broad spectrum of functional autoantibodies against G-protein–coupled receptors (GPCR-AAbs). Functional GPCR-AAbs (β₁AR, β₂AR, α₁AR, M₂/M₃ AChR, AT₁R, ETaR) are found in ~60% of Long COVID patients and are proposed to drive dysautonomia, POTS, tachycardia, and fatigue by constitutively activating these receptors.

Evidence

Open-label pilot (n=13 Long COVID): 12/13 showed symptom improvement after BC007 infusion, including reduced fatigue, cognitive improvement, and improved dysautonomia symptoms. Phase 2 RCT ongoing (NCT04957810). Testing methodology for GPCR-AAbs validated by Wallukat et al. and Nolen et al. groups.

Testing for GPCR-AAbs: Cell Trend GmbH (Germany) offers commercial autoantibody testing used in research contexts.

Mechanism

Synthetic vasoactive intestinal peptide (VIP) agonist. VIP receptors VPAC1 and VPAC2 are highly expressed on ACE2+ cells (alveolar type II, mast cells, enteric neurons, immune cells). VIP is a potent immunosuppressive neuropeptide: reduces IL-6, TNF-α, IL-1β; protects alveolar epithelium from apoptosis; modulates autonomic tone via parasympathetic co-transmission; down-regulates mast cell degranulation.

Evidence

Phase 2b/3 data in acute COVID-19 respiratory failure showing reduced mortality signal (NCT04505722). Post-acute respiratory Long COVID signals in open-label extension. Mechanism directly relevant to MCAS, autonomic dysregulation, and pulmonary manifestations of both Long COVID and PACVS. No PACVS-specific RCT yet.

Mechanism

Recombinant human IL-1 receptor antagonist (IL-1Ra). Competes at IL-1R1 to block both IL-1α and IL-1β signalling. Reduces downstream NLRP3 inflammasome effects including pyroptosis, IL-18 release, and gasdermin D pore formation. IL-1β is persistently elevated in Long COVID neuroinflammation and brain fog. Autoinflammatory hypothesis: unresolved NLRP3 activation drives chronic post-viral symptoms.

Evidence

SAVE-MORE trial (Kyriazopoulou et al. Nat Med 2021, n=594): anakinra significantly reduced mortality and ICU admission in severe COVID-19 with suPAR elevation. Multiple COVID-19 RCTs confirm IL-1 pathway relevance. No Long COVID-specific RCT yet; T2 based on IL-1β elevation in Long COVID + acute COVID RCT data.

Mechanism

Glycosaminoglycan heparinoid mixture (80% fast-moving heparin fraction + 20% dermatan sulfate). Primary action: restores and protects the endothelial glycocalyx — the polysaccharide layer lining all blood vessels — which is degraded by COVID-19-associated endothelial inflammation. Also inhibits thrombin and Factor Xa, reduces PAI-1, and suppresses NF-κB-mediated endothelial inflammation. LDL endothelial penetration is reduced.

Evidence

Prospective RCT (n=243) in post-COVID patients with evidence of endothelial dysfunction. Sulodexide group showed significantly reduced late-onset thrombotic events and hospitalisation compared to placebo. Endothelial dysfunction is a central feature of Long COVID; no PACVS-specific RCT exists but mechanism directly applies.

Mechanism

SSRI with the highest sigma-1 receptor (S1R) agonist activity in its class. S1R agonism: (1) stabilises IRE1α ER stress sensor, suppressing IRE1α-driven cytokine production (IL-6, IL-8, TNF-α); (2) reduces acid sphingomyelinase (ASM) activity, impairing ceramide-mediated SARS-CoV-2 cell entry; (3) inhibits platelet serotonin uptake, relevant to the Long COVID serotonin depletion hypothesis (Woolf/Bhatt 2023). Reduces mast cell activation signals.

Evidence

TOGETHER platform RCT (Reis et al. Lancet Glob Health 2022, n=741): 32% reduction in hospitalisation/emergency care in early COVID-19. Mechanism extrapolated to Long COVID via serotonin pathway. Observational (Hellmuth et al. UCSF): SSRI use associated with reduced Long COVID incidence. No Long COVID RCT for fluvoxamine specifically; "mixed" reflects strong acute-phase evidence with uncertain LC translation.

Mechanism

Serine protease (subtilisin-like) produced by Bacillus subtilis var. natto during soybean fermentation. Directly cleaves fibrin; inactivates PAI-1 (plasminogen activator inhibitor-1), thereby prolonging tPA activity and overall fibrinolytic capacity. In vitro (Liu et al. 2022): nattokinase degrades the SARS-CoV-2 spike protein N-terminal domain, raising interest in dissolving spike-driven amyloid fibrin microclots documented by the Pretorius group.

Evidence

T3 based on: (1) in vitro spike protein degradation (Liu 2022); (2) observational Long COVID use in microclot treatment protocols (Pretorius/Kell group, observational cohort); (3) cardiovascular fibrinolytic RCTs in other conditions. No Long COVID-specific RCT completed. Caution: may interact with anticoagulants; no formal safety data in LC populations.

Mechanism

Methylxanthine phosphodiesterase inhibitor. Elevates cAMP in red blood cells → improved RBC membrane flexibility and deformability, allowing passage through narrowed capillaries. Also reduces fibrinogen levels; inhibits TNF-α transcription via cAMP/NF-κB; reduces leukocyte adhesion; weak anti-platelet aggregation. RBC deformability deficits have been documented in Long COVID blood by the Pretorius group, contributing to microvascular dysfunction.

Evidence

Observational case data and clinical rationale based on Long COVID hyperviscosity documentation. Small pilot data in post-COVID fatigue with hemorheological abnormalities. No Long COVID RCT. Well-established safety profile in peripheral arterial disease. "Mixed" because specific LC RCT data is lacking despite strong mechanistic rationale.

Mechanism

Ultrasound-guided injection of long-acting local anaesthetic (bupivacaine 0.5%, 5–10 mL) at or near the stellate ganglion — the confluence of inferior cervical and first thoracic sympathetic ganglia. Transiently disrupts sympathetic efferents to the head, neck, arm, and heart. Proposed mechanism in Long COVID: resets hyperactivated sympathetic tone, normalises elevated plasma norepinephrine/epinephrine. Lipov et al. proposed nerve growth factor (NGF) re-signalling via anaesthetic diffusion as a longer-lasting reset mechanism.

Evidence

Case series (Rae et al. 2022, n=3) in Long COVID with POTS/dysautonomia: all three showed improvement in HR, orthostatic tolerance, and fatigue after SGB. Lipov et al. observational data in post-COVID autonomic symptoms. Must be performed by trained anaesthesiologist under ultrasound guidance. Established use in PTSD and hot flashes supports safety profile. No RCT in Long COVID yet.

Mechanism

Removes large circulating macromolecules from blood plasma: GPCR autoantibodies; anti-phospholipid antibodies; fibrinogen; spike protein antigens; immune complexes; complement fragments; and amyloid microclot fragments. Plasma exchange (TPE) replaces removed plasma with albumin or fresh frozen plasma. Immunoadsorption (IA) specifically targets IgG via Protein-A columns, allowing plasma return. Both methods directly reduce the autoantibody and microclot burden implicated in Long COVID and PACVS.

Evidence

Jaeger B et al. (Berlin/Hamburg Long COVID clinic, 2021–2023): case series of ~100 patients showing 70–80% symptomatic improvement after 3–5 cycles of apheresis. Pretorius group observational data on microclot reduction post-apheresis. No RCT in Long COVID. Expensive, invasive, and specialist-only. Ongoing controlled studies in Germany.

Mechanism

Non-absorbable synthetic rifamycin derivative (<0.4% systemic absorption). Selectively targets gut microbiota without altering host commensal ecology as broadly as systemic antibiotics. Reduces small intestinal bacterial overgrowth (SIBO); decreases endotoxin (LPS) production and translocation across the intestinal barrier; reduces TLR4 signalling cascade; improves tight junction protein expression (ZO-1, occludin); increases Faecalibacterium prausnitzii — a key butyrate producer reduced in Long COVID.

Evidence

Liu Q, et al. Gut 2022: prospective cohort documenting gut microbiota disruption in Long COVID persisting for 6+ months, including reduced F. prausnitzii and Eubacterium rectale with increased opportunistic pathogens. Rifaximin RCTs in IBS (Pimentel et al.) and hepatic encephalopathy demonstrate mechanism. Pilot Long COVID gut restoration data emerging. No formal Long COVID RCT published as of mid-2026.

Mechanism

Angiotensin receptor blocker (AT₁R blocker). Among ARBs, telmisartan uniquely acts as a partial PPAR-γ agonist — providing anti-inflammatory, anti-fibrotic, and mast cell-stabilising effects beyond blood pressure reduction. AT₁R blockade shifts renin-angiotensin-aldosterone signalling toward ACE2 → angiotensin 1-7 → Mas receptor (vasoprotective, anti-inflammatory axis). SARS-CoV-2 dysregulates RAS in both acute and post-acute phases; normalisation may reduce endothelial and mast cell hyperreactivity.

Evidence

Pilot observational data and case reports in Long COVID with vascular/dysautonomia features. Lobo-Ferreira et al. and others have suggested ARB benefit; NCT studies ongoing. No completed Long COVID-specific RCT as of mid-2026. Antihypertensive with excellent long-term safety profile. "Mixed" due to absence of controlled LC trial data despite strong mechanistic case.

Mechanism

Endogenous saturated fatty acid amide (N-palmitoylethanolamine), produced on demand from membrane phosphatidylethanolamine. PPAR-α nuclear receptor agonist: suppresses NF-κB, reduces mast cell degranulation, and decreases production of TNF-α, IL-1β, and histamine. GPR55 and GPR119 partial agonism. In dorsal root ganglia and microglia, PEA reduces neuroinflammatory gene expression. Endogenous PEA levels are found to be altered in Long COVID plasma (Petrosino et al. 2022).

Evidence

Petrosino et al. 2022: altered N-acylethanolamine (including PEA) levels in Long COVID plasma vs. controls. Schweiger V et al. 2019: RCT in fibromyalgia (overlapping symptomology with Long COVID) showing significant pain reduction with ultra-micronised PEA. MCAS is a recognised sub-phenotype of Long COVID and PACVS where PEA is increasingly used clinically. No Long COVID-specific RCT yet.

Mechanism

Complex of six distinct fibrinolytic serine proteases extracted from Lumbricus rubellus earthworm. Acts on a broader substrate range than nattokinase: degrades fibrin, fibrinogen, and fibrin degradation products; activates both plasminogen and tissue plasminogen activator (tPA); degrades fibrin more specifically than streptokinase, potentially with less risk of systemic haemorrhagic complications. Higher molecular weight substrates mean potentially more targeted fibrinolysis.

Evidence

Case series in post-COVID hypercoagulability and fatigue showing symptom improvement. Cardiovascular observational and controlled data in China. More fibrin-specific than streptokinase in mechanistic comparisons. No Long COVID RCT. Used empirically in some Long COVID microclot treatment protocols (alongside nattokinase) due to complementary substrate specificity.

Mechanism

First-generation antihistamine with potent 5-HT2A, 5-HT2B, and 5-HT2C serotonin receptor antagonist activity (stronger serotonin antagonism than most antihistamines). Blocks excess serotonin signalling in the enteric nervous system — relevant to the Long COVID serotonin hypothesis (Woolf et al. Nature 2023: intestinal serotonin depletion drives vagal dysfunction and widespread Long COVID symptoms). Also an H1 antihistamine (MCAS benefit). Appetite stimulant; reduces nausea and abdominal dysmotility in POTS.

Evidence

Used in POTS and dysautonomia specialty clinics for GI symptom management (case series). Relevant to Long COVID serotonin hypothesis (Rosen DA/Bhatt DL, Nature 2023). No Long COVID RCT. Established H1 antihistamine with decades of use; well-characterised safety profile. Causes sedation and appetite increase — relevant considerations for LC patients.

Mechanism

Carbonic anhydrase II and IV inhibitor. Reduces CSF production at choroid plexus → decreases intracranial pressure (ICP) — relevant if Long COVID brain fog involves occult intracranial hypertension (proposed by Iadecola and others). Separately: sensitises CO₂ chemoreceptors, correcting the hypocapnia-mediated "air hunger" that many Long COVID patients report (despite normal O₂ saturation). Weakly diuretic. First-line treatment for idiopathic intracranial hypertension (IIH).

Evidence

Case series and clinical practice reports in Long COVID brain fog and air hunger subgroups, particularly where neurological involvement is suspected. Formal Long COVID RCT lacking. Well-established in IIH and altitude sickness. "Mixed" because benefit appears subgroup-specific (patients with ICP or hypocapnia features); systemic use untested in LC.

Mechanism

Cysteine protease complex from Ananas comosus (pineapple) stem. In vitro: Bhaskara Rao et al. (2021) demonstrated complete digestion of the SARS-CoV-2 spike S1 subunit and the ACE2 receptor by bromelain, and by bromelain combined with acetylcysteine (NAC). NF-κB inhibition reduces downstream cytokine production (IL-1β, IL-6, TNF-α). Also reduces prostaglandin E2 via COX pathway modulation. Oral bioavailability is limited but some absorption confirmed by human studies.

Evidence

T5 based on in vitro spike degradation data and anti-inflammatory case reports. NCT04429789 evaluated bromelain + acetylcysteine in COVID-19 as a nasal spray. No Long COVID RCT. Often co-administered with nattokinase and NAC in clinical practice for putative spike protein dissolution. Anti-inflammatory RCTs exist in other conditions (sinusitis, osteoarthritis).

Mechanism

Stimulates de novo mitochondrial biogenesis via PGC-1α upregulation and CREB phosphorylation — the same pathway activated by exercise and caloric restriction. Functions as a redox cofactor in bacterial respiration and influences mammalian cells through signalling rather than direct enzymatic activity. Activates DJ-1 (PARK7), a mitochondrial neuroprotective protein mutated in early-onset Parkinson's. May upregulate nerve growth factor (NGF) synthesis. Acts as a potent antioxidant, quenching ROS in both mitochondrial and cytosolic compartments.

Evidence & Long COVID Rationale

Harris et al. 2013 (n=76 human crossover): 20 mg/day PQQ significantly altered mitochondrial-related urinary metabolites and reduced CRP and IL-6 vs. placebo. Stites et al. 2016: PQQ-deficient diet caused immune impairment in weanling mice. Mitochondrial biogenesis is demonstrably impaired in Long COVID PBMCs (Guntur et al. Cell Rep Med 2022) and in PACVS patients with fatigue and post-exertional malaise. No Long COVID RCT.

Mechanism

Ubiquinone (CoQ10) covalently linked to triphenylphosphonium (TPP⁺) cation. The permanently cationic TPP⁺ group drives ~1000-fold accumulation in the mitochondrial matrix, driven by the large negative mitochondrial membrane potential. Positioned exactly at the inner membrane surface where ETC Complexes I and III generate superoxide (O₂•⁻). Far more potent than conventional CoQ10 supplementation, which cannot efficiently reach the intramitochondrial site of ROS generation. Protects Complex I integrity and reduces mitochondrial membrane potential decay.

Evidence

Extensive preclinical data in oxidative stress, ischaemia-reperfusion, and metabolic disease models (Murphy/Smith group, MRC Cambridge). Lees et al. 2022 Aging: pilot human cardiovascular trial showing reduced markers of oxidative stress and improved vascular function. Mitochondrial superoxide overproduction documented in Long COVID PBMCs and endothelial cells. No Long COVID RCT. Oral formulation available as dietary supplement (10–20 mg/day).

Mechanism

Natural polyamine synthesised from putrescine (also found in wheat germ, aged cheese, mushrooms). Induces macroautophagy by inhibiting EP300 (a histone acetyltransferase) — derepressing ATG5, ATG12, and other autophagy genes. Promotes mitophagy: selective clearance of damaged, ROS-generating mitochondria. Supports hypusination of eukaryotic initiation factor 5A (eIF5A), essential for translating mitochondrial proteins. Plasma spermidine levels decline with age and post-viral illness.

Evidence

Madeo F, et al. Science 2018: comprehensive review establishing spermidine's autophagy-inducing role and longevity associations. Schroeder S, et al. 2021: human trial in older adults showing improved immune response. Impaired autophagy has been documented in Long COVID with accumulation of protein aggregates and dysfunctional organelles. No Long COVID RCT. Dietary sources include wheat germ (~24 nmol/g), aged cheese, and fermented soy products.

Mechanism

Isoquinoline alkaloid from Berberis species. AMPK activation: mild Complex I inhibition raises intracellular AMP:ATP ratio → AMPK activation → metabolic reprogramming toward catabolism, fatty acid oxidation, and mitochondrial biogenesis. NLRP3 inflammasome inhibition: reduces IL-1β, IL-18, and pyroptosis — directly relevant to post-viral autoinflammation. mTORC1 inhibition enhances autophagy. SIRT1 upregulation. In vitro antiviral activity against SARS-CoV-2 (Ji et al. 2020, Front Pharmacol). Modulates gut microbiome: increases Akkermansia muciniphila.

Evidence

Over 100 human RCTs in metabolic syndrome, type 2 diabetes, and PCOS — demonstrating AMPK pathway effects in humans. Ji S, et al. Front Pharmacol 2020: SARS-CoV-2 antiviral activity in vitro at μM concentrations. NLRP3 inhibition confirmed in multiple inflammatory disease models. No Long COVID or PACVS RCT. T6 because LC-specific human data is absent despite robust mechanistic and metabolic RCT basis.

Mechanism

Taurine-conjugated ursodeoxycholic acid. Primary action: inhibits the unfolded protein response (UPR) / ER stress — specifically suppresses IRE1α/XBP1 splicing and PERK/ATF4 phosphorylation branches. This is significant because SARS-CoV-2 spike protein (S1 and full-length) activates ER stress in alveolar, endothelial, and immune cells, driving apoptosis and inflammation. TUDCA reduces ER stress-triggered apoptosis via mitochondrial membrane stabilisation (reduces cytochrome c release). Neuroprotective via PKCε and PKCα activation. Well-established in cholestatic liver disease.

Evidence

Paganoni et al. 2020 (NEJM): TUDCA Phase 2 RCT in ALS showed significant slowing of disease progression — the first positive ALS drug trial in decades, directly attributable to ER stress/UPR pathway. SARS-CoV-2 spike protein activation of ER stress documented in multiple cell types (Bhatta 2021). No Long COVID or PACVS RCT. TUDCA is commercially available as a supplement (250–750 mg/day). T6 because LC-specific data absent; mechanism is directly relevant to spike protein pathology.

Mechanism

NR is a bioavailable NAD⁺ precursor that bypasses the rate-limiting de novo synthesis pathway: NR → NMN → NAD⁺. Raising intracellular NAD⁺ restores activity of NAD⁺-dependent enzymes — sirtuins (SIRT1–7, mitochondrial deacetylases governing gene expression and metabolic reprogramming), PARPs (DNA damage repair), and CD38 (immune regulation). Systemic NAD⁺ depletion in Long COVID and PACVS is plausibly driven by PARP hyperactivation (DNA damage from spike/immune response), CD38 upregulation (chronic inflammation), and impaired mitochondrial ETC generating less NADH recycled to NAD⁺.

Evidence

Guzmán-Vélez et al. 2025 (Lancet eClinicalMedicine): first randomised, placebo-controlled trial of NR (Niagen, 1000 mg/day × 5–10 weeks) in Long COVID. Primary and secondary endpoints did not reach statistical significance vs. placebo — study was underpowered due to high dropout (reinfection, relocation, medication changes). Within-group vs. baseline: significant improvements in fatigue, sleep quality, and depressive symptoms at 10 weeks; NAD⁺ increased 3.1-fold; trend toward improved executive function. T2 classification reflects the RCT design despite null primary result. A larger Norwegian RCT (n=310) was completed approximately 2024; results pending publication.

Direction "Mixed": Within-group improvements are encouraging but between-group significance was not achieved. Underpowering (not drug failure) is the most plausible explanation. Larger confirmatory trial results awaited.

Mechanism

Photobiomodulation therapy (PBMT) uses near-infrared (NIR, 800–1100 nm) and red (630–700 nm) light to stimulate mitochondrial cytochrome c oxidase (Complex IV), the terminal electron acceptor of the ETC. Photon absorption by the copper and heme centres of Complex IV increases its catalytic activity, boosts the proton gradient, and directly raises mitochondrial ATP production. Secondary effects include reduced NO-mediated Complex IV inhibition (restoring oxygen utilisation), reduced oxidative stress, and modulation of inflammatory cytokines (IL-1β, TNF-α) via downstream NF-κB suppression.

Evidence

No completed Long COVID RCT. Mechanistic rationale is established (Hamblin group, Cambridge): cytochrome c oxidase is the primary photoacceptor and the same complex impaired in Long COVID PBMCs (Guntur et al. Cell Rep Med 2022). Small pilot series in ME/CFS and post-viral fatigue report cognitive and energy improvements. T5 rating reflects the absence of controlled LC-specific data; the mechanism is directly relevant to documented mitochondrial ETC impairment in Long COVID.