Long COVID—defined as symptoms persisting ≥ 2 months beyond acute SARS-CoV-2 infection without alternative explanation—now affects an estimated 65 million people worldwide and lacks any approved, evidence-based therapy; the present overview therefore synthesizes current mechanistic insights and catalogs experimental interventions ranging from supervised rehabilitation to antivirals, anticoagulants, anti-inflammatories, nutraceuticals and emerging biologics. Key pathogenic drivers include persistent viral reservoirs, chronic low-grade inflammation with IL-1β/IL-6/TNF-α elevation, micro-clot formation via spike-protein–fibrinogen interactions, auto-immunity, gut dysbiosis and mitochondrial dysfunction. These pathways translate into multi-organ sequelae: endothelial dysfunction, myocarditis, neuro-inflammation, small-fiber neuropathy, ME/CFS-like fatigue, menstrual irregularities, glucose intolerance and renal or hepatic injury.
Non-pharmacological management remains first-line for mild, early-stage cases. Randomized trials show that online, group-based physical and mental rehabilitation improves quality of life, while breathing exercises and inspiratory-muscle training restore cardiorespiratory fitness. Pacing strategies, cognitive–speech therapy, olfactory retraining and dietary counselling are adjuncts, but unmoderated exercise can exacerbate inflammation, so graduated, symptom-titrated programmes are mandatory.
Antiviral agents initiated during acute COVID-19 modestly lower post-acute sequelae. Ensitrelvir reduced long-COVID incidence by 25% in Japanese out-patients, and nirmatrelvir/ritonavir or molnupiravir cut risk ~ 25% in high-risk groups, yet favipiravir showed minimal benefit. Monoclonal antibodies against the spike protein are being explored for neuro-toxicity, but phase-3 data are pending.
Symptom-specific drugs target thrombosis, autonomic dysfunction and immune dysregulation. Low-dose naltrexone improves fatigue and reduces platelet aggregation; apheresis removes micro-clots and auto-antibodies but is costly and short-lived. β-blockers mitigate postural-tachycardia syndrome, while famotidine, intravenous immunoglobulin, SGLT-2 inhibitors and GLP-1 agonists are piloted for neuro-psychiatric, immune and cardio-renal symptoms.
Upstream anti-inflammation represents the most active therapeutic frontier. Metformin initiated within seven days of infection lowered long-COVID risk 41% by dampening mTOR signalling. Combined plant extracts enriched in quercetin, curcumin and piperine improved fatigue scores versus placebo. Sulphur-thermal-water inhalation and enzymatically liberated salmon oil decreased CRP and restored lung barrier integrity. Baricitinib and rapamycin, both repositioned JAK/mTOR inhibitors, are entering multi-centre trials aiming to interrupt broad STAT3-mediated inflammation.
Gut-microbiome modulation with synbiotic SIM01 relieved systemic symptoms at six months, while high-dose vitamins C/D, coenzyme Q10, magnesium and creatine–glucose blends improved energy metabolism and endothelial function in small RCTs. N-acetyl-cysteine and the amino-acid blend AXA1125 enhanced mitochondrial respiration and reduced fatigue in early-phase studies.
Novel biologics explore fibrin-driven neuro-inflammation: a humanized antibody that neutralises the inflammatory domain of fibrinogen is in phase-1 trials after murine models showed protection from neuronal loss. DNA aptamer BC007, which scavenges G-protein-coupled-receptor auto-antibodies, reversed fatigue and capillary hypoperfusion in a single case; larger studies are awaited. Hyperbaric oxygen improved cognitive, sleep and pain domains in a 6-month RCT, while acupuncture case series reported reductions in brain-fog and arthralgia.
Vaccination offers modest secondary prevention: a 15–41% lower long-COVID incidence after breakthrough infection, but among those already symptomatic only 17% improved post-booster, 21% worsened and 62% remained unchanged.
Overall, therapeutic signals are emerging, yet most evidence derives from small, open-label or surrogate-endpoint trials; large, platform adaptive RCTs with unified case definitions and biomarker stratification are urgently needed. Pending such data, a pragmatic, multidisciplinary pathway combines early antiviral therapy, cautious graded exercise, targeted anti-thrombotic and anti-inflammatory agents, gut-microbiome support and personalised rehabilitation—an approach that acknowledges long COVID’s heterogeneous, multi-system nature while awaiting definitive, mechanism-based cures.

DOI
10.1007/s11684-025-1149-z