Long COVID has emerged as a complex, multisystem disorder characterized by persistent or newly evolving symptoms beyond the acute phase of COVID-19. Affecting an estimated 10% to 30% of recovered individuals, long COVID represents a major clinical and public health challenge. Patients commonly present with fatigue, dyspnea, cognitive impairment (brain fog), autonomic instability, thrombo-inflammatory manifestations and neuropsychiatric disturbances.
The heterogeneity of clinical phenotypes necessitates a multidimensional pharmacotherapeutic strategy. At present, most pharmacological interventions remain empirical, guided by evolving insights into pathophysiology rather than definitive randomized trial evidence.
Multiple mechanistic pathways have been proposed to explain long COVID, including viral persistence in tissue reservoirs, chronic immune activation, autoimmunity, endothelial dysfunction, mitochondrial injury, microvascular thrombosis and autonomic nervous system dysregulation. (1) These overlapping mechanisms suggest that combination pharmacotherapy, tailored to dominant clinical phenotypes, may ultimately prove more effective than single-agent approaches.
Antiviral, anti-inflammatory and immunomodulatory therapies
One of the most widely discussed therapeutic hypotheses involves persistent viral reservoirs driving chronic inflammation. This has led to interest in antiviral agents such as nirmatrelvir/ritonavir and remdesivir beyond the acute infection phase. Observational data indicate that early antiviral therapy during the acute COVID-19 phase may reduce the incidence of long COVID, possibly by limiting viral replication and downstream immune activation. (2) However, evidence supporting antiviral use in established long COVID remains preliminary, and such therapy is currently recommended primarily within clinical trial settings rather than routine practice. (3)
Anti-inflammatory and immunomodulatory therapies constitute another major pharmacotherapeutic pillar. Low-dose corticosteroids have been used in selected patients, particularly those with persistent pulmonary inflammation or imaging features characteristic of pneumonia. (4) Although symptomatic and radiologic improvement has been documented (5), long-term steroid use carries risks including metabolic complications and secondary infections. (3-6)
Targeted cytokine inhibition has also been explored. (7) Elevated IL-6 and TNF-a levels in some long COVID cohorts provide a rationale for biologic therapies such as tocilizumab and infliximab, though controlled data remain sparse. Similarly, JAK inhibitors, such as baricitinib, may attenuate chronic cytokine signaling, representing a mechanistically plausible but still investigational option.
Anticoagulant and antiplatelet therapies, endothelial health
Microvascular pathology has gained increasing attention in long COVID research. Studies demonstrating fibrin amyloid microclots and endothelial injury have prompted investigation into anticoagulant and antiplatelet therapies. Direct oral anticoagulants, low-dose aspirin and combination antiplatelet regimens have been used in exploratory protocols. Some reports describe improvement in fatigue and cognitive dysfunction following anticoagulation, possibly through enhanced microvascular perfusion. Nonetheless, bleeding risk necessitates cautious patient selection, and large randomized trials are required before widespread therapeutic endorsement.
Endothelial dysfunction further contributes to impaired oxygen delivery, exercise intolerance, and vascular dysregulation. Pharmacotherapies targeting endothelial health include statins, which exert anti-inflammatory and plaque-stabilizing effects, as well as ACE inhibitors and angiotensin receptor blockers that modulate renin-angiotensin signaling disrupted by SARS-CoV-2. Adjunctive therapies, such as L-arginine and nitric oxide donors, are also being explored for their role in improving vascular reactivity and tissue oxygenation.
Autonomic dysfunction and neuropsychiatric manifestations
Autonomic dysfunction, particularly postural orthostatic tachycardia syndrome, is frequently observed in long COVID. Pharmacological management is largely extrapolated from established dysautonomia treatment protocols. Beta-blockers such as propranolol or metoprolol are used to control tachycardia, while ivabradine offers selective sinus node inhibition without reducing blood pressure. Volume-expanding agents such as fludrocortisone and vasoconstrictors like midodrine may be beneficial in patients with orthostatic intolerance. (8)
These drugs are typically combined with nonpharmacological measures including salt supplementation and compression garments.
Neuropsychiatric manifestations, such as depression, anxiety, sleep disturbances and cognitive impairment, are prominent contributors to long COVID morbidity. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are commonly prescribed for mood disorders and may also exert anti-inflammatory and microglial-modulating effects. (9) Bupropion has been used to address fatigue and attentional deficits, while modafinil may improve wakefulness and cognitive performance in selected cases.
Additional therapies, precision medicine
Emerging evidence suggests a role for mast cell activation in long COVID symptomatology. Consequently, antihistamines such as cetirizine and loratadine (H1 blockers), along with famotidine (H2 blocker), have been used empirically. Mast cell stabilizers such as cromolyn sodium have also been trialled. Case series report improvement in fatigue, tachycardia and neurocognitive symptoms, though robust randomized evidence remains limited. (10)
Mitochondrial dysfunction and impaired cellular bioenergetics may underlie exertional intolerance and chronic fatigue. Metabolic adjuncts including coenzyme Q10, L-carnitine, nicotinamide riboside and alpha-lipoic acid are widely used as supportive therapies. While mechanistically appealing, these interventions lack large-scale clinical validation.
Low-dose naltrexone has attracted attention for its immunomodulatory and microglial inhibitory effects. Small observational studies suggest benefit in fatigue, pain and neuroinflammatory symptoms, paralleling its use in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. (11)
Pulmonary sequelae, including interstitial lung abnormalities and evolving fibrosis, represent another therapeutic domain. Antifibrotic agents such as pirfenidone and nintedanib are being evaluated for their potential to prevent long-term structural lung damage in post-COVID patients with fibrotic progression.
Given the marked heterogeneity of long COVID, precision medicine frameworks are gaining prominence. Patients may be stratified into dominant phenotypes, such as inflammatory/autoimmune, thrombotic/endothelial, autonomic, viral persistence or neurocognitive, which allow mechanism-targeted pharmacotherapy. Biomarker discovery, immunologic profiling and advanced imaging are expected to refine such stratification models.
Remaining gaps and limitations
Despite rapid progress, major research gaps persist. There is an urgent need for large randomized controlled trials, validated biomarkers, drug-repurposing platforms and longitudinal safety data. International collaborative consortia continue to accelerate therapeutic discovery and evidence synthesis.
In conclusion, pharmacotherapy for long COVID remains an evolving frontier shaped by mechanistic complexity and clinical heterogeneity. Current treatment strategies rely heavily on repurposed antivirals, anti-inflammatory agents, anticoagulants, autonomic modulators and symptom-directed therapies. While early evidence supports selected interventions in phenotype-specific contexts, universally accepted, guideline-endorsed pharmacological treatments remain limited. The future of long COVID management lies in precision, mechanism-based therapeutics integrated within multidisciplinary care frameworks.
References
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- Xie Y, Choi T, Al-Aly Z. Association of treatment with nirmatrelvir and the risk of post-COVID-19 condition. JAMA Intern Med. 2023;183(6):554-564. DOI: 1001/jamainternmed.2023.0743.
- Cao B, Soriano JB, Wang Q, et al. Clinical practice guideline for long COVID prevention and treatment. Eur Respir J. 2026;68(1):2502611. DOI: 1183/13993003.02611-2025.
- Ntiamoah P, Biehl M, Ruesch V, et al. Corticosteroid treatment for persistent pulmonary infiltrates following COVID-19 infection: clearing the fog. Ann Thorac Med. 2024;19(1):74-80. DOI: 4103/atm.atm_121_23.
- Myall KJ, Mukherjee B, Castanheira AM, et al. Persistent post-COVID-19 interstitial lung disease. An observational study of corticosteroid treatment. Ann Am Thorac Soc. 2021;18(5):799-806. DOI: 1513/AnnalsATS.202008-1002OC.
- Kulkarni S, Durham H, Glover L, et al. Metabolic adverse events associated with systematic corticosteroid therapy - a systematic review and meta-analysis. BMJ Open. 2022;12(12):e061476. DOI: 10.1136/bmjopen-2022-061476.
- Jamilloux Y, Henry T, Belot A, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020;19(7):102567. DOI: 1016/j.autrev.2020.102567.
- Dani M, Dirksen A, Taraborrelli P, et al. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clin Med (Lond). 2021;21(1):e63-e67. DOI: 7861/clinmed.2020-0896.
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- Weinstock LB, Brook JB, Walters AS, et al. Mast cell activation symptoms are prevalent in Long-COVID. Int J Infect Dis. 2021;112:217-226. DOI: 10.1016/j.ijid.2021.09.043.
- Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014;33(4):451-459. DOI: 10.1007/s10067-014-2517-2.
