Post-acute COVID-19 syndrome, or long COVID, now affects millions of people all over the world. Symptoms may be far-reaching and impact almost any system of the body. While some people experience mild symptoms, others may have a more debilitating clinical picture. While our understanding of the mechanisms involved in long COVID has grown over the past few years since the onset of the pandemic, a greater variety of treatment options is still needed. This article discusses underlying mechanisms involved in long COVID pathogenesis and natural therapies that may address these mechanisms.
AlwanNA, JohnsonL. Defining long COVID: Going back to the start. Medicine (Baltimore), 2021; 2:501–504.
2.
HouY, GuT, NiZ, et al.Global prevalence of long COVID, its subtypes and risk factors: An updated systematic review and meta-analysis. medRxiv, 2025.
3.
JiaH, NeptuneE, CuiH. Targeting ACE2 for COVID-19 therapy: Opportunities and challenges. Am J Respir Cell Mol Biol, 2021; 64:416–425.
4.
SilvaMJA, RibeiroLR, GouveiaMIM, et al.Hyperinflammatory response in COVID-19: A systematic review. Viruses, 2023; 15:553.
5.
AmbrosinoP, CalcaterraIL, MosellaM, et al.Endothelial dysfunction in COVID-19: A unifying mechanism and a potential therapeutic target. Biomedicines, 2022; 10:812.
6.
MonsalveDM, Acosta-AmpudiaY, AcostaNG, et al.NETosis: A key player in autoimmunity, COVID-19, and long COVID. J Transl Autoimmun, 2025; 10:100280.
7.
Serrano-GonzaloI, Menéndez-JandulaB, Franco-GarcíaE, et al.Neutrophil extracellular traps and macrophage activation contibute to thrombosis and post-covid syndrome in SARS-CoV-2 infection. Front Immunol, 2025; 16:1507167.
8.
VollbrachtC, KraftK. Oxidative stress and hyper-inflammation as major drivers of severe COVID-19 and long COVID: Implications for the benefit of high-dose intravenous vitamin C. Front Pharmacol, 2022; 13:899198.
9.
WuML, LiuFL, SunJ, et al.SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury. Signal Transduct Target Ther, 2021; 6:428.
10.
HermansLE, WassermanS, XuL, et al.Long COVID prevalence and risk factors in adults residing in middle- and high-income countries: Secondary analysis of the multinational Anti-Coronavirus Therapies (ACT) trials. BMJ Glob Health, 2025; 10:e017126.
11.
StoneJK, BermanSE, ZhengW, et al.From brain fog to COVID toe: A head-to-toe review of long COVID. Ajpps, 2023; 2:12.
12.
PelusoMJ, DeeksSG. Mechanisms of long COVID and the path toward therapeutics. Cell, 2024; 187:5500–5529.
13.
KuriA, JacobsBM, JacobsBM, et al.Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom. BMC Public Health, 2020; 20:912.
14.
IndariO, GhoshS, BalAS, et al.Awakening the sleeping giant: Epstein–Barr virus reactivation by biological agents. Pathog Dis, 2024; 82:ftae002.
15.
KempkesB, RobertsonES. Epstein-Barr virus latency: Current and future perspectives. Curr Opin Virol, 2015; 14:138–144.
16.
TarascoMC, IacominoN, MantegazzaR, et al.COVID-19, Epstein-Barr virus reactivation and autoimmunity: Casual or causal liaisons? J Microbiol Immunol Infect, 2025; 58:508–516.
17.
GoldJE, OkyayRA, LichtWE, et al.Investigation of long covid prevalence and its relationship to epstein-barr virus reactivation. Pathogens, 2021; 10:763.
18.
ZubchenkoS, KrilI, NadizhkoO, et al.Herpesvirus infections and post-COVID-19 manifestations: A pilot observational study. Rheumatol Int, 2022; 42:1523–1530.
19.
KayaMO, PamukcuE, YakarB. The role of vitamin D deficiency on COVID-19: A systematic review and meta-Analysis of observational studies. Epidemiol Health, 2021; 43:e2021074.
20.
SchlossJV. Nutritional deficiencies that may predispose to long COVID. Inflammopharmacology, 2023; 31:573–583.
21.
ChenKY, LinCK, ChenNH. Effects of vitamin D and zinc deficiency in acute and long COVID syndrome. J Trace Elem Med Biol, 2023; 80:127278.
22.
MatsudaY, TokumasuK, OtsukaY, et al.Symptomatic characteristics of hypozincemia detected in long COVID patients. J Clin Med, 2023; 12:2062.
23.
AminT, PatelNJ, ChaudhariB. Association between vitamin D deficiency and long COVID symptoms in post-hospitalized patients: A prospective cohort study. Eur J Cardiovasc Med, 2025; 15:357–360.
24.
CharoenpornV, TungsukruthaiP, TeacharushatakitP, et al.Effects of an 8-week high-dose vitamin D supplementation on fatigue and neuropsychiatric manifestations in post-COVID syndrome: A randomized controlled trial. Psychiatry Clin Neurosci, 2024; 78:595–604.
25.
AtiehO, DaherJ, DurieuxJC, et al.Vitamins K2 and D3 improve long COVID, fungal translocation, and inflammation: Randomized controlled trial. Nutrients, 2025; 17:304.
26.
SeelyD, LegacyM, ConteE, et al.Dietary supplements to reduce symptom severity and duration in people with SARS-CoV-2: A double-blind randomised controlled trial. BMJ Open, 2023; 13:e073761.
27.
RanisavljevM, StajerV, TodorovicN, et al.The effects of 3-month supplementation with synbiotic on patient-reported outcomes, exercise tolerance, and brain and muscle metabolism in adult patients with post-COVID-19 chronic fatigue syndrome (STOP-FATIGUE): A randomized Placebo-controlled clinical trial. Eur J Nutr, 2025; 64:80.
28.
TabatabaeizadehSA. Zinc supplementation and COVID-19 mortality: A meta-analysis. Eur J Med Res, 2022; 27:70.
29.
Olczak-PrucM, SzarpakL, NavolokinaA, et al.The effect of zinc supplementation on the course of COVID-19—A systematic review and meta-analysis. Ann Agric Environ Med, 2022; 29:568–574.
30.
PennisiR, TrischittaP, CostaM, et al.Update of natural products and their derivatives targeting epstein–barr infection. Viruses, 2024; 16:124.
31.
PorterRS, BodeRF. A review of the antiviral properties of black elder (Sambucus nigra L.) Products. Phytother Res, 2017; 31:533–554.
32.
DeshpandeS, MundheN, DeshpandeV, et al.Potential use of Immunodaat® (Botanical extract of Elderberry -Sambucus Nigra L.) in the management of Post Covid-19 symptoms- a comparative, multi-centric, randomized, clinical study. medRxiv, 2022.
33.
AnconaG, AlagnaL, AlteriC, et al.Gut and airway microbiota dysbiosis and their role in COVID-19 and long-COVID. Front Immunol, 2023; 14:1080043.
34.
GiannosP, ProkopidisK. Gut dysbiosis and long COVID‐19: Feeling gutted. J Med Virol, 2022; 94:2917–2918.
35.
HorvathA, HabischH, PrietlB, et al.Alteration of the gut–lung axis after severe COVID-19 infection and modulation through probiotics: A randomized, controlled pilot study. Nutrients, 2024; 16:3840.
36.
RanisavljevM, StajerV, TodorovicN, et al.The effects of 3-month supplementation with synbiotic on patient-reported outcomes, exercise tolerance, and brain and muscle metabolism in adult patients with post-COVID-19 chronic fatigue syndrome (STOP-FATIGUE): A randomized Placebo-controlled clinical trial. Eur J Nutr, 2025; 64:1–11.
37.
GodlewskaBR, SylvesterAL, EmirUE, et al.Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: A 7T magnetic resonance spectroscopy study. Mol Psychiatry, 2025; 1–12.
38.
OstojicSM. Diagnostic and pharmacological potency of creatine in post-viral fatigue syndrome. Nutrients, 2021; 13:503.
39.
LauRI, SuQ, LauISF, et al.A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): A randomised, double-blind, placebo-controlled trial. Lancet Infect Dis, 2024; 24:256–265.
40.
LauRI, SuQ, ChingJYL, et al.Fecal microbiota transplantation for sleep disturbance in post-acute COVID-19 syndrome. Clin Gastroenterol Hepatol, 2024; 22:2487–2496.e6.
41.
MolnarT, LehoczkiA, FeketeM, et al.Mitochondrial dysfunction in long COVID: Mechanisms, consequences, and potential therapeutic approaches. Geroscience, 2024; 46:5267–5286.
42.
NoonongK, ChatatikunM, SurinkaewS, et al.Mitochondrial oxidative stress, mitochondrial ROS storms in long COVID pathogenesis. Front Immunol, 2023; 14:1275001.
43.
GunturVP, NemkovT, de BoerE, et al.Signatures of mitochondrial dysfunction and impaired fatty acid metabolism in plasma of patients with post-acute sequelae of COVID-19 (PASC). Metabolites, 2022; 12:1026.
44.
BarlettaMA, MarinoG, SpagnoloB, et al.Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome. Clin Exp Med, 2023; 23:667–678.
45.
NaureenZ, DautajA, NodariS, et al.Proposal of a food supplement for the management of post-COVID syndrome. Eur Rev Med Pharmacol Sci, 2021; 25:67–73.
46.
ChenLZ, CaiQ, ZhengPF. Mitochondrial metabolic rescue in post-COVID-19 syndrome: MR spectroscopy insights and precision nutritional therapeutics. Front Immunol, 2025; 16:1597370.
47.
BelloneS, SiegelER, SantinAD. N-acetylcysteine (NAC) supplementation improves dyspnea and may normalize von Willebrand plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID. Gynecol Oncol Rep, 2025; 57:101682; doi: 10.1016/j.gore.2025.101682
48.
CalvaniR, GiampaoliO, MariniF, et al.; Beetroot juice intake positively influenced gut microbiota and inflammation but failed to improve functional outcomes in adults with long COVID: A pilot randomized controlled trial. Clin Nutr, 2024; 43:344–358.
49.
CalvaniR, GervasoniJ, PiccaA, et al.; Effects of l-arginine plus vitamin c supplementation on l-arginine metabolism in adults with long COVID: Secondary analysis of a randomized clinical trial. Int J Mol Sci, 2023; 24:5078.
50.
TosatoM, CalvaniR, PiccaA, et al.; Effects of l-Arginine plus vitamin C supplementation on physical performance, endothelial function, and persistent fatigue in adults with long COVID: A Single-Blind Randomized Controlled Trial. Nutrients, 2022; 14:4984.
51.
AlmannaiM, El-HattabAW. Nitric oxide deficiency in mitochondrial disorders: The utility of arginine and citrulline. Front Mol Neurosci, 2021; 14:682780.
52.
IzzoR, TrimarcoV, MoneP, et al.Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey. Pharmacol Res, 2022; 183:106360.
53.
SzarvasZ, ReyffZA, PeterfiA, et al.Effects of NAD+ supplementation with oral nicotinamide riboside on vascular health and cognitive function in older adults with peripheral artery disease: Results from a pilot 4-week open-label clinical trial. J Pharmacol Exp Ther, 2025; 392.
54.
NorheimKL, Ben EzraM, HeckenbachI, et al.Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial. Nat Aging, 2024; 4:1772–1781.
55.
ConzeD, BrennerC, KrugerCL. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Sci Rep, 2019; 9:9772.
56.
OrrME, KotkowskiE, RamirezP, et al.A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. Geroscience, 2024; 46:665–682.
57.
MartensCR, DenmanBA, MazzoMR, et al.Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun, 2018; 9:1286.
58.
AlaediniA, LightmanS, WormserGP. Is low cortisol a marker of long COVID? Am J Med, 2024; 137:564–565.
59.
SunadaN, HondaH, NakanoY, et al.Hormonal trends in patients suffering from long COVID symptoms. Endocr J, 2022; 69:1173–1181.
60.
KatoA, TokumasuK, YamamotoK, et al.Clinical and endocrine features of orthostatic intolerance detected in patients with long COVID. Sci Rep, 2024; 14:17025.
61.
LeeJS, ChoiY, JoungJY, et al.Clinical and laboratory characteristics of fatigue-dominant long-COVID subjects: A Cross-Sectional Study. Am J Med, 2025; 138:346–353.e1.
62.
KleinJ, WoodJ, JaycoxJR, et al.Distinguishing features of long COVID identified through immune profiling. Nature, 2023; 623:139–148.
63.
YavropoulouMP, TsokosGC, ChrousosGP, et al.Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID. Clin Immunol, 2022; 245:109133.
64.
SeoIH, ParkB, KimH, et al.The effects of G1899 Korean red ginseng extract powder on long COVID for acute COVID19 infection: A randomized, double-blind, placebo-controlled trial. J Ginseng Res, 2025; 49:470–477.
65.
KarosanidzeI, KiladzeU, KirtadzeN, et al.Efficacy of adaptogens in patients with long COVID-19: A randomized, quadruple-blind, placebo-controlled trial. Pharmaceuticals (Basel), 2022; 15:345.
66.
LarsenNW, StilesLE, ShaikR, et al.Characterization of autonomic symptom burden in long COVID: A global survey of 2,314 adults. medRxiv, 2022.
67.
WooMS, ShafiqM, FitzekA, et al.Vagus nerve inflammation contributes to dysautonomia in COVID-19. Acta Neuropathol, 2023; 146:387–394.
68.
TaveeJ. Current concepts in long COVID-19 brain fog and postural orthostatic tachycardia syndrome. Ann Allergy Asthma Immunol, 2024; 133:522–530.
69.
LabordeS, AllenMS, BorgesU, et al.Effects of voluntary slow breathing on heart rate and heart rate variability: A systematic review and a meta-analysis. Neurosci Biobehav Rev, 2022; 138.
70.
DonnellyD, GeorgiadisE, StavrouN. A meta-analysis investigating the outcomes and correlation between heart rate variability biofeedback training on depressive symptoms and heart rate variability outcomes versus standard treatment in comorbid adult populations. Acta Biomed, 2023; 94.
71.
FarrowMR, WashburnK. A review of field experiments on the effect of forest bathing on anxiety and heart rate variability. Glob Adv Health Med, 2019; 8:2164956119848654.
72.
HamvasS, HegyiP, KissS, et al.Acupuncture increases parasympathetic tone, modulating HRV—Systematic review and meta-analysis. Complement Ther Med, 2023; 72:102905.
73.
Pfoser-PoschacherV, KeilaniM, SteinerM, et al.Feasibility and acceptance of transdermal auricular vagus nerve stimulation using a TENS device in females suffering from long COVID fatigue. Wien Klin Wochenschr, 2025; 137:635–641.
74.
GuideriF, AcampaM, HayekY, et al.Effects of acetyl-L-carnitine on cardiac dysautonomia in Rett syndrome: Prevention of sudden death? Pediatr Cardiol, 2005; 26:574–577.
75.
NaganoM, ShimizuK, KondoR, et al.Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res, 2010; 31:231–237.
Krystel-WhittemoreM, DileepanKN, WoodJG. Mast cell: A multi-functional master cell. Front Immunol, 2015; 6:620.
78.
ArunS, StoranA, MyersB. Mast cell activation syndrome and the link with long COVID. Br J Hosp Med (Lond), 2022; 83:1–10.
79.
SchiefferE, SchiefferB. The rationale for the treatment of long-Covid symptoms—A cardiologist’s view. Front Cardiovasc Med, 2022; 9:992686.
80.
Anonymous. Australasian Society of Clinical Immunology and Allergy. Diagnosis and Investigation of Mast Cell Activation Disorders and Syndrome Position Paper. 2025. Available from: www.allergy.org.au/patients/patient-support-organisations [Last accessed: November14, 2025].
81.
SumantriS, RengganisI. Immunological dysfunction and mast cell activation syndrome in long COVID. Asia Pac Allergy, 2023; 13:50–53.
ZhouE, WuZ, ZhuX, et al.Histamine triggers the formation of neutrophil extracellular traps via NADPH oxidase, ERK and p38 pathways. Vet Immunol Immunopathol, 2021; 235:110234.
84.
QuC, FuhlerGM, PanY. Could histamine H1 receptor antagonists be used for treating COVID-19? Int J Mol Sci, 2021; 22:5672.
85.
WuML, XieC, LiX, et al.Mast cell activation triggered by SARS-CoV-2 causes inflammation in brain microvascular endothelial cells and microglia. Front Cell Infect Microbiol, 2024; 14:1358873.
86.
EnnisM, TiligadaK. Histamine receptors and COVID-19. Inflamm Res, 2021; 70:67–75.
87.
SalvucciF, CodellaR, CoppolaA, et al.Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation. Front Cardiovasc Med, 2023; 10:1202696.
88.
AkanchiseT, AngelovaA. Potential of nano-antioxidants and nanomedicine for recovery from neurological disorders linked to long COVID syndrome. Antioxidants (Basel), 2023; 12:393.
89.
BardelčíkováA, MiroššayA, ŠoltýsJ, et al.Therapeutic and prophylactic effect of flavonoids in post‐COVID‐19 therapy. Phytother Res, 2022; 36:2042–2060.
90.
WengZ, ZhangB, AsadiS, et al.Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One, 2012; 7:e33805.
91.
CatalanoA, IacopettaD, CeramellaJ, et al.Are nutraceuticals effective in COVID-19 and post-COVID prevention and treatment? Foods, 2022; 11:2884.
92.
LiuS, WangY, YingL, et al.Quercetin Mitigates Lysophosphatidylcholine (LPC)-Induced Neutrophil Extracellular Traps (NETs) formation through inhibiting the P2X7R/P38MAPK/NOX2 pathway. Int J Mol Sci, 2024; 25:9411.
93.
BasyrevaLY, ShmelevaEV, IvanovVA, et al.The effect of vitamin D3 on neutrophil extracellular trap formation in high-glucose conditions. Bull Exp Biol Med, 2023; 176:137–142.
94.
GiuntaS, GiordaniC, De LucaM, et al.Long-COVID-19 autonomic dysfunction: An integrated view in the framework of inflammaging. Mech Ageing Dev, 2024; 218:111915.
95.
CamiciM, Del DucaG, BritaAC, et al.Connecting dots of long COVID-19 pathogenesis: a vagus nerve-hypothalamic-pituitary- adrenal-mitochondrial axis dysfunction. Front Cell Infect Microbiol, 2024; 14:1501949.
96.
ShafqatA, OmerMH, AlbalkhiI, et al.Neutrophil extracellular traps and long COVID. Front Immunol, 2023; 14:1254310.
97.
Hromić-JahjefendićA, MahmutovićL, SezerA, et al.The intersection of microbiome and autoimmunity in long COVID-19: Current insights and future directions. Cytokine Growth Factor Rev, 2025; 82:43–54.
98.
BrockMV, BosmansF. A multi-hit model of long covid pathophysiology: The interaction between immune triggers and nervous system signaling. Trans Am Clin Climatol Assoc, 2024; 134:149–164.
99.
HansenKS, JørgensenSE, CömertC, et al.Genetic landscape and mitochondrial metabolic dysregulation in patients suffering from severe long COVID. J Med Virol, 2025; 97:e70275.
100.
BonillaH, PelusoMJ, RodgersK, et al.Therapeutic trials for long COVID-19: A call to action from the interventions taskforce of the RECOVER initiative. Front Immunol, 2023; 14:1129459.
101.
AmirkiaV, HeinrichM. Natural products and drug discovery: a survey of stakeholders in industry and academia. Front Pharmacol, 2015; 6:237.