Long COVID Part 3: Evidence-Based Vitamins, Herbs, Nutrient, and Other Supplements

Long COVID affects an estimated 10 to 33% of people who recover from SARS-CoV-2 infection [1] Symptoms like crushing fatigue, brain fog, muscle pain, and shortness of breath can persist for months or even years after the initial illness.

In Long COVID Part 1, we addressed the underlying mechanisms driving these symptoms. Together, the mechanisms create a vicious cycle that standard medical care often struggles to break.

In Long COVID Part 2, we covered non-supplemental therapies including ozone, hyperbaric oxygen therapy, and photobiomodulation.

In this article, Part 3, we cover vitamins, minerals, botanical adaptogens, and targeted nutraceuticals show real promise for interrupting these cycles and supporting recovery.

Importantly, most of these supplements only have plausible supportive mechanisms or only one clinical trial supporting their effectiveness for Long COVID. Therefore, their use may remain empirical and should be in consultation with your healthcare provider. While Mediskill is only reporting on studies and does not sell any products, it’s important to keep in mind that supplement brands may fund clinical trials with the goal of marketing their products. Conversely, the lack of proof is not proof against a remedy’s safety and effectiveness.

Bottom line: No single supplement is a magic bullet for Long COVID. But a targeted combination addressing inflammation, mitochondrial energy, and immune regulation may meaningfully improve quality of life. [2,3,4,5]

Why Supplements Matter in Long COVID Recovery

Long COVID or post-acute sequelae of COVID is not just "lingering symptoms." It involves measurable biological disruptions that create self-reinforcing loops of illness. Understanding these mechanisms explains why targeted nutritional support can help.

Key pathological mechanisms in Long COVID that supplements may help with include:

• Chronic neuroinflammation driven by elevated pro-inflammatory cytokines like IL-6, IL-1, and TNF-alpha [3,6]
• Oxidative stress from excessive reactive oxygen species (ROS) overwhelming the body's antioxidant defenses [7,8,3]
• Mitochondrial dysfunction, which impairs cellular energy production and drives persistent fatigue [8,9]
• Endothelial glycocalyx damage, where the protective lining of blood vessels degrades, impairing circulation and oxygen delivery [10,11,12]
• Gut microbiome disruption, which alters immune signaling and can perpetuate systemic inflammation [13]

Nutritional deficiencies are both a risk factor for developing Long COVID and a consequence of the disease itself. Chronic inflammation burns through antioxidants and key micronutrients at an accelerated rate. [14,15,16,2]

Key takeaway: Supplements and other effective complementary interventions for Long COVID work best when they target these specific biological disruptions rather than just masking symptoms.

Vitamin D: The Immune Regulator

Vitamin D deficiency is one of the most consistent findings in Long COVID patients. A large retrospective cohort study (N=68,379 SARS-CoV-2 survivors) found that vitamin D deficiency significantly increased the risk of developing post-acute sequelae, including fatigue, cognitive impairment, and respiratory symptoms. [17] [STRONG]

Vitamin D plays roles both at preventing the infections, keeping the symptoms mild, and supporting Long COVID recovery through several mechanisms [18,15,16]:

• Modulating immune function by regulating both innate and adaptive immune responses
• Reducing pro-inflammatory cytokine production, which helps calm the chronic inflammation driving Long COVID symptoms
• Supporting respiratory function and reducing the severity of ongoing pulmonary complaints
• Neuroprotective effects that may help address brain fog and cognitive difficulties

Vitamin D deficiencies are associated with more severe acute COVID-19 outcomes and a higher likelihood of persistent neuropsychiatric symptoms like headache, fatigue, anosmia (loss of smell), and hyposmia (reduced sense of smell) lasting beyond 12 weeks. [16]
Importantly, chronic inflammation may lower serum vitamin D levels, which may partly explain why low vitamin D seems to predispose people to Long COVID. [19]

Vitamins C and D work synergistically to support immune function. Both vitamins are commonly deficient in people with respiratory infections, and combined supplementation may offer multi-level immune support during recovery. [15] [MODERATE]

Bottom line: Getting your serum 25-OH vitamin D levels tested is one of the simplest and most impactful first steps. Deficiency is correctable, and the evidence linking low vitamin D to worse Long COVID outcomes is robust. [17,18,15,16]

Vitamin C: Antioxidant and Immune Support

Vitamin C is a potent water-soluble antioxidant that directly neutralizes reactive oxygen species. In the context of Long COVID, where oxidative stress is a central driver of tissue damage and symptom persistence, maintaining adequate vitamin C status is critical. [15,3]

How vitamin C supports Long COVID recovery:

• Scavenges free radicals and regenerates other antioxidants like vitamin E.
• Supports white blood cell function, including neutrophil activity and lymphocyte proliferation.
• Enhances epithelial barrier function, which helps protect against secondary infections.
• Works synergistically with vitamin D to provide multi-level immune defense. [15]

Deficiency in vitamin C predisposes individuals to increased risk and severity of respiratory infections, and the metabolic demands of chronic illness can rapidly deplete stores. [15]

Long COVID patients dealing with ongoing inflammation may have higher-than-normal requirements. [MODERATE]

Magnesium: The Overlooked Mineral

Magnesium is involved in over 600 enzymatic reactions in the body, and its relevance to COVID-19 and Long COVID is significant. A comprehensive review found that magnesium homeostasis plays a critical role in immune function, inflammation regulation, and cardiovascular health, all of which are disrupted in Long COVID. [14] [MODERATE]

Magnesium's relevance to Long COVID includes:

• Anti-inflammatory effects that help modulate the cytokine response
• Muscle and nerve function support, relevant to the myalgia (muscle pain) and neurological symptoms common in Long COVID
• Cardiovascular protection, since magnesium deficiency is linked to endothelial dysfunction and increased clotting risk
• Sleep quality improvement, which is frequently disrupted in Long COVID patients
• Energy metabolism support, as magnesium is essential for ATP (cellular energy) production [14]
• Vitamin D activation, function, and metabolism, including in immunomodulation and respiratory functions

Hypomagnesemia (low magnesium) has been observed in COVID-19 patients and may contribute to the severity and persistence of symptoms. [14] Since magnesium is commonly under-consumed in Western diets even before illness, supplementation is a practical intervention.

Bottom line: Magnesium is inexpensive, widely available, and addresses multiple Long COVID mechanisms simultaneously. Forms like magnesium glycinate or magnesium threonate tend to be better absorbed and gentler on the stomach. [14]

Zinc: Immune Defense and Neurological Support

Zinc deficiency compounds the immune dysregulation already present in Long COVID. A retrospective study (n=55) examining the effects of both vitamin D and zinc deficiency found that low levels of either nutrient worsened acute inflammatory and neuropsychiatric symptoms, including headache, fatigue, and loss of smell, that persisted beyond 30 days or longer than 12 weeks after infection. [16] [MODERATE]

Zinc supports Long COVID recovery by:

• Enhancing antiviral immune responses, including T-cell function and natural killer cell activity
• Reducing inflammation through modulation of NF-kB signaling
• Supporting neurological function, which is relevant to brain fog and cognitive complaints
• Maintaining epithelial barrier integrity in the gut and respiratory tract [16,2]

Zinc and vitamin D deficiencies frequently co-occur, and addressing both simultaneously may produce better outcomes than correcting either alone. [16]

Coenzyme Q10 (CoQ10): Mitochondrial Energy Rescue

Persistent fatigue is the hallmark symptom of Long COVID, reported in the majority of patients across studies. [20] At the cellular level, this fatigue traces back to mitochondrial dysfunction, where the energy-producing organelles in your cells fail to generate adequate ATP. [8]

Coenzyme Q10 (CoQ10) is a critical component of the mitochondrial electron transport chain. It functions as both an energy carrier and a powerful lipid-soluble antioxidant that protects mitochondrial membranes from oxidative damage. [8] [MODERATE]

A comprehensive overview of CoQ10 supplementation in post-viral fatigue syndrome (which includes Long COVID) found that:

• CoQ10 levels are often depleted in patients with post-viral fatigue.
• Supplementation supports mitochondrial bioenergetics and may help restore normal energy production.
• CoQ10 also reduces oxidative stress within mitochondria, breaking the cycle of damage and dysfunction.
• The antioxidant properties of CoQ10 complement its role in energy metabolism, addressing two key Long COVID mechanisms simultaneously. [8]

Bottom line: If fatigue is your dominant Long COVID symptom, CoQ10 is one of the most mechanistically justified supplements to discuss with your provider. [8,3]

Probiotics and Synbiotics: Restoring the Gut-Immune Axis

The gut flora is a central regulator of immune function, neurotransmitter production, and systemic inflammation. In Long COVID, gut microbiome disruption is both a consequence of infection and a driver of ongoing symptoms. [13]  

A 2025 review in Gut found that SARS-CoV-2 infection causes persistent alterations in gut microbial composition, including [13]:

• Reduced microbial diversity and loss of beneficial species
• Increased intestinal permeability (leaky gut), allowing bacterial components to enter the bloodstream and trigger immune activation
• Altered production of short-chain fatty acids and other metabolites that regulate inflammation

These gut changes correlate with the severity and duration of Long COVID symptoms, particularly fatigue, brain fog, and mood disturbances. [13]

A randomized, placebo-controlled trial tested a 3-month synbiotic supplementation (a combination of probiotics and prebiotics) in adult patients with post-COVID chronic fatigue syndrome. The study measured patient-reported outcomes, exercise tolerance, and brain and muscle metabolism. [21]  

Bottom line: Gut health is a foundational piece of Long COVID recovery. Synbiotic supplementation targeting the gut-immune axis represents a promising and low-risk intervention. [13,21]

Glycocalyx Support: Protecting Your Blood Vessels

One of the lesser-known but clinically important consequences of COVID-19 is damage to the endothelial glycocalyx, a delicate, gel-like layer that lines the inside of all blood vessels. This protective coating regulates vascular permeability, prevents clotting, and facilitates nutrient exchange. [10,11,12]

COVID-19 progressively degrades this glycocalyx layer, contributing to endothelial dysfunction, impaired circulation, and increased cardiovascular risk even after the acute infection resolves. [11] [MODERATE]

A randomized, placebo-controlled trial (N=57 convalescent patients, 14 days after mild-to-moderate COVID-19) tested a glycocalyx dietary supplement containing glucosamine sulfate and fucoidan for 4 months. Key findings:

• The supplement group showed improved endothelial glycocalyx thickness
• Vascular function improved compared to placebo.
• The intervention was given to 29 patients in the supplement group versus 28 in the placebo group. [10]

Therapeutic strategies targeting the glycocalyx have been reviewed as a promising approach for conditions involving endothelial damage, including COVID-19, sepsis, diabetes, and kidney disease. [12]

Bottom line: Glycocalyx damage may explain why some Long COVID patients experience circulation problems, exercise intolerance, and cardiovascular symptoms. Targeted supplementation with glucosamine sulfate and fucoidan shows early but encouraging results. [10,12]

Ashwagandha: The Adaptogenic Powerhouse

Ashwagandha (Withania somnifera) is one of the most studied adaptogenic herbs, and its pharmacological profile aligns remarkably well with the pathological mechanisms of Long COVID. Its active compounds, called withanolides, have demonstrated immunomodulatory, anti-inflammatory, antioxidant, and antiviral properties across multiple studies. [22,23,24,25,26]

Why ashwagandha is relevant to Long COVID:

• Immunomodulation: Ashwagandha modulates both innate and adaptive immune responses, helping to rebalance an immune system stuck in overdrive. Animal studies show it influences T-cell differentiation and neutrophil function in COVID-19 models. [25]
• Anti-inflammatory activity: Withanolides reduce pro-inflammatory cytokines, which are elevated in Long COVID and drive many of its symptoms. [22,26]
• Antioxidant protection: The herb scavenges free radicals and supports endogenous antioxidant systems, countering the oxidative stress central to Long COVID pathology. [22,27]
• Adaptogenic stress response: Ashwagandha helps regulate the hypothalamic-pituitary-adrenal (HPA) axis, which governs the stress response and is frequently dysregulated in Long COVID. [27,28]

The interest in ashwagandha for Long COVID is strong enough that a randomized, placebo-controlled clinical trial (the APRIL Trial) is currently underway specifically to evaluate ashwagandha for promoting recovery in Long COVID patients. The trial protocol highlights ashwagandha's immune-strengthening and anti-inflammatory properties as the rationale for investigation. [29] [PRELIMINARY]

In silico (computer modeling) studies have also identified withanolides as potential multi-target agents against SARS-CoV-2, with binding affinity to key viral proteins. [24]

Bottom line: Ashwagandha addresses fatigue, brain fog, sleep disruption, and immune dysregulation through multiple mechanisms. While dedicated Long COVID trials are still in progress, the existing evidence for its effects on the individual symptoms that define Long COVID is substantial. [29,22,30,31,27]

Rhodiola Rosea and Ginkgo Biloba: Targeting Brain Fog and Mental Fatigue

Cognitive impairment and mental fatigue are among the most distressing and persistent neuropsychiatric symptoms of Long COVID. A 2024 review in the Journal of Neural Transmission examined the potential of Rhodiola rosea and Ginkgo biloba as multi-target treatments for these specific symptoms. [9] [PRELIMINARY]

The review identified neuroinflammation, oxidative stress, and mitochondrial dysfunction as the common pathophysiological mechanisms underlying post-COVID cognitive impairment and fatigue. Importantly, it noted that single-target pharmaceutical drugs have not yet been successful in treating these symptoms, which is why multi-target botanical agents may offer an advantage. [9]

Rhodiola rosea:

• Functions as a phytoadaptogen that helps the body resist physical, chemical, and biological stressors.
• Has been specifically explored for its potential in post-COVID fatigue. [32,28]
• Adaptogenic herbs like Rhodiola may help correct the dysregulated stress response seen in Long COVID patients. [28]

Ginkgo biloba:

• Provides neuroprotective and anti-inflammatory effects in the central nervous system.
• Supports cerebral blood flow, which may be impaired in Long COVID due to endothelial dysfunction.
• Combined with Rhodiola, it offers a complementary multi-target approach to cognitive recovery. [9]

Bottom line: For Long COVID patients whose primary complaints are brain fog, difficulty concentrating, and mental exhaustion, the combination of Rhodiola rosea and Ginkgo biloba targets the specific neurological mechanisms involved. [9,28]

Specialized Pro-Resolving Mediators (SPMs) and Omega-3 Fatty Acids

Chronic inflammation in Long COVID is not just about having too many pro-inflammatory signals. It is also about a failure of inflammation resolution, the active biological process that turns off inflammation once it has served its purpose. [6]

Specialized Pro-Resolving Mediators (SPMs), including compounds like 17-HDHA and 14-HDHA, are lipid mediators derived from omega-3 fatty acids that actively resolve inflammation. A randomized controlled trial protocol (ARACOV-02) is investigating whether specialized nutritional intervention with SPMs, combined with telerehabilitation, can improve outcomes in Long COVID patients experiencing dyspnea, fatigue, anxiety, depression, and reduced quality of life. [6] [Ongoing]

The trial rationale highlights that SARS-CoV-2 triggers an excessive immune response characterized by the release of IL-6, IL-1, TNF-alpha, and reactive oxygen species, and that SPMs may help resolve this inflammatory cascade. [6]

Omega-3 fatty acids (EPA and DHA) serve as the precursors for SPM production and have independent anti-inflammatory effects relevant to Long COVID recovery. [3,4]

Oxaloacetate: A Novel Approach to Fatigue

A non-randomized controlled clinical trial tested anhydrous enol-oxaloacetate (AEO) in patients with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and Long COVID fatigue. [33] [PRELIMINARY]

Key details of the trial:

• Participants: ME/CFS and Long COVID fatigue patients
• Intervention: Oxaloacetate supplementation (specific dose per protocol)
• Rationale: Oxaloacetate supports mitochondrial energy metabolism and may help address the bioenergetic deficit underlying persistent fatigue
• Design: Non-randomized controlled clinical trial
• The study found that oxaloacetate treatment addressed both mental and physical fatigue in these patient populations. [33]

This is a novel intervention that targets the same mitochondrial dysfunction pathway as CoQ10 but through a different mechanism, supporting the citric acid cycle (the core energy-producing pathway in mitochondria). [33]

Hydroxytyrosol and L-Arginine: Antioxidant and Vascular Support

Hydroxytyrosol, a polyphenol found in olive oil, and L-arginine, an amino acid, have been reviewed for their combined antioxidant, anti-inflammatory, and immunostimulant properties in the context of COVID-19 and Long COVID. [7]  [PRELIMINARY]

• Hydroxytyrosol is one of the most potent natural antioxidants, with strong free radical scavenging capacity.
• L-arginine is the precursor to nitric oxide (NO), which relaxes blood vessel walls and improves circulation. This is particularly relevant given the endothelial dysfunction seen in Long COVID.
• Together, they address oxidative stress and vascular impairment simultaneously. [7]

Multi-Ingredient Nutraceutical Formulations

Some researchers have taken a combination approach, designing multi-ingredient supplements that target several Long COVID mechanisms at once.

A study tested a unique dietary supplement formulation combining beta-caryophyllene, pregnenolone, and seven other compounds in Long COVID patients (N=not specified in available data). The researchers first demonstrated that beta-caryophyllene and pregnenolone had a significant synergistic effect in resolving inflammation in animal models of sepsis. They then combined these with additional ingredients to create a formulation specifically designed to alleviate Long COVID symptoms. [1] [PRELIMINARY]

Hydrogen-Rich Water: Targeting Fatigue Through Antioxidant Mechanisms

A pilot, single-blind, randomized, placebo-controlled trial tested hydrogen-rich water (HRW) consumption for 14 consecutive days in Long COVID patients. [34] [PRELIMINARY]

Key details:

• Fatigue was significantly alleviated in the HRW group compared to placebo.
• Dyspnea (shortness of breath) did not improve with HRW.
• The proposed mechanism is hydrogen's antioxidant and anti-inflammatory properties.
• The study was a pilot trial, meaning it was designed to test feasibility and generate preliminary data. [34]

Bottom line: Hydrogen-rich water showed a specific benefit for fatigue but not breathlessness, suggesting it may address oxidative stress-related fatigue pathways without affecting the respiratory mechanisms driving dyspnea. [34]

NAC (N-Acetylcysteine) for Oxidative Stress and Endothelial Protection

N-acetylcysteine (NAC) is one of the most studied supplements for Long COVID, with clinical evidence spanning glutathione restoration, respiratory recovery, and vascular protection. Aside from being an established treatment for respiratory conditions, it directly addresses several core drivers of Long COVID, including oxidative stress, endothelial dysfunction, and immune dysregulation.

Restoring Glutathione Levels

Long COVID is characterized by a persistent deficit in glutathione (GSH), disrupting redox signaling, and weakening immune defenses and detoxification. [35]

NAC serves as a potent oral precursor to GSH. Once absorbed, NAC provides the rate-limiting amino acid cysteine, which cells use to synthesize new glutathione. This makes NAC one of the most practical and accessible strategies for replenishing GSH in Long COVID patients.

Long-term Recovery RCT

The strongest clinical evidence for NAC in COVID-19 recovery comes from a randomized, double-blind, placebo-controlled trial by Li et al. (2025). [36]

This trial enrolled 64 (32 in each group) COVID-19 patients and evaluated post-discharge NAC treatment on patient-reported outcomes (PROs). Key study details:

• Dose: 600 mg NAC, twice daily
• Duration: Treatment from hospital admission through long-term follow-up, with patients monitored up to 6 months post-discharge
• Design: Randomized, double-blind, placebo-controlled

The NAC group experienced significantly accelerated improvements in patient-reported outcomes compared to placebo. This is notable because the study captured the full trajectory of recovery, from acute illness through the post-acute phase where Long COVID symptoms typically emerge and persist. 

Vascular and Respiratory Support

Endothelial dysfunction and persistent vascular damage are hallmarks of Long COVID. von Willebrand factor (vWF) is a glycoprotein released by damaged endothelial cells, a reliable marker of this ongoing vascular injury. Elevated vWF drives the hypercoagulable state seen in many Long COVID patients, contributing to microclotting, fatigue, and exercise intolerance. Normalizing vWF suggests NAC addresses not just symptoms but a root vascular mechanism of PASC. [37]

A retroactive study evaluated NAC supplementation in 9 gynecologic patients diagnosed with PASC/Long COVID, 3 of which supplemented with NAC regularly. At 4-year follow-up, the 3 patients had normalized vWF factor, and reduction in shortness of breath, fatigue and brain fog. [37]

Endothelial Defense

An in vitro study exposed endothelial cells to serum collected from patients who had recovered from SARS-CoV-2 infection. Post-COVID serum triggered pro-inflammatory and pro-coagulant responses in the endothelial cells, mimicking the vascular damage seen clinically. When NAC was applied, it protected endothelial cells from these harmful effects. [38]

This finding is important for several reasons:

• It confirms that post-COVID blood itself carries factors that damage blood vessels, even after the acute infection resolves.
• It demonstrates that NAC directly shields endothelial cells from inflammation and clotting activation triggered by these circulating factors.
• It provides a laboratory-level mechanism supporting the clinical improvements seen in the Bellone et al. trial. [37]

Additionally, neuropsychiatric manifestations of Long COVID, including brain fog, anxiety, and depression, involve overlapping oxidative stress pathways. Barlattani et al. (2025) reviewed the role of NAC (alongside acetyl-L-carnitine) in addressing these neuropsychiatric symptoms. They suggest plausible mechanisms that NAC mitigate glutamate neurotoxicity and other mechanisms of PASC-related neuropsychiatric symptoms. [39]

Summary of NAC Evidence for Long COVID

Bottom line: While there are plausible mechanisms that NAC may help with long covid, high-quality evidence is limited. Also, keep in mind that NAC is a precursor to glutathione, an antioxidant. If you combine bio-oxidative therapies with NAC, they should be taken away from each other. 

Nattokinase for Spike Protein Clearance and Microclot Dissolution

Nattokinase, a serine protease enzyme derived from the fermented soybean food natto, targets two central drivers of Long COVID pathology: persistent spike protein and amyloid fibrin microclots. [41] Its dual fibrinolytic and proteolytic actions make it one of the most discussed complementary interventions for PASC.

Spike Protein Degradation

In vitro research demonstrates that nattokinase directly degrades the SARS-CoV-2 spike protein in a dose-dependent and time-dependent manner. Tanikawa et al. (2022) exposed cell lysates expressing spike protein to nattokinase and observed progressive degradation of the S protein. Similarly, nattokinase also degrades the spike protein on the cell surface in a dose-dependent fashion, confirming that the enzyme can act on spike protein both within and on the surface of cells. [41]

This finding is significant because the spike protein itself exhibits pathogenic characteristics independent of viral replication. It can:

• Trigger NLRP3 inflammasome activation and cytokine release in lung epithelial cells. [42]
• Promote amyloidogenic processes in blood, contributing to abnormal clotting. [43]
• Drive endothelial dysfunction, a hallmark finding in Long COVID patients. [44]
• Cause ferroptosis and oxidative stress in human endothelial cells. [45]

The spike protein's role in Long COVID pathology extends beyond inflammation. It has uncanny similarities with amyloid-disease-associated blood coagulation disturbances and neurological complications. [43] Multiple reviews identify persistent spike protein as a unifying mechanism behind the diverse symptom clusters of PASC, including fatigue, cognitive dysfunction, and cardiovascular complications. [46,47,48]

Fibrinolytic Activity

Beyond spike protein degradation, nattokinase is a potent fibrinolytic enzyme with well-documented effects on blood clot dissolution and anticoagulation.

In a double-blind, placebo-controlled crossover study (N=12), Kurosawa et al. (2015) administered a single oral dose of 2,000 FU (fibrinolysis units) of nattokinase to healthy young males. Blood was drawn at baseline and at multiple time points after ingestion. Compared to placebo, the nattokinase group showed:

• Significantly enhanced fibrinolysis (clot-dissolving activity)
• Improved anticoagulation profiles across multiple coagulation parameters
• Effects detectable from a single dose [49]

Addressing Amyloid Microclots

One of the most distinctive pathological findings in Long COVID is the presence of amyloid fibrin microclots in the blood. These are not ordinary blood clots. They are dense, misfolded fibrin deposits with amyloid-like properties that resist the body's normal clot-dissolving mechanisms. [43]

The SARS-CoV-2 spike protein directly promotes amyloidogenesis of fibrin. Nyström and Hammarström (2022) demonstrated that the spike protein drives the formation of these abnormal amyloid fibrin structures, which correlate with the coagulation disturbances and neurological symptoms seen in Long COVID. [43]

These microclots are particularly problematic because they are resistant to standard enzymatic fibrinolysis. Rasouli et al. (2025) confirmed that amyloid microclots implicated in thrombotic complications across pathological conditions, including Long COVID, resist conventional enzymatic breakdown, creating a significant therapeutic challenge. [50]

Nattokinase addresses this challenge through its unique proteolytic properties. Multiple reviews identify nattokinase as a promising intervention for targeting these resistant microclots in the context of Long COVID management. [51]

Bottom line: The combination of spike protein degradation, fibrinolytic activity, and the ability to target amyloid microclots makes nattokinase a uniquely multi-targeted intervention for the vascular and inflammatory pathology of Long COVID.

Some clinical protocols for Long COVID now include nattokinase as part of a broader spike protein clearance strategy, often combined with other complementary agents. [47]

Safety Note

Due to its potent fibrinolytic effects, nattokinase requires careful consideration in certain populations. The same properties that make it effective against microclots also mean it can significantly alter coagulation parameters. [49]

Key safety considerations include:

• Anticoagulant interactions with medications or herbs. [52]
• Pre-surgical use: Nattokinase should be discontinued before any planned surgical procedures due to its blood-thinning effects.
• Monitoring: Individuals using nattokinase for Long COVID should work with a qualified healthcare provider to monitor coagulation parameters, especially if they have a history of bleeding disorders.

Conclusion

Long COVID is a complex and heterogenous condition, where the presentation and symptoms can differ significantly from person to person. Understandably, there is no one effective treatment or magic bullet, whether conventional or alternative. Many dietary supplements have plausible mechanisms that may support the recovery of Long COVID, although the clinical evidence remains limited. Most clinical studies have been small, single-centered, or may have conflicts of interest. 

Given the high prevalence and lack of real solutions for Long COVID, supplements and other complementary treatments should remain in the toolbox for Long COVID recovery. You should not be self-treating by introducing all of these supplements. Instead, work with a qualified healthcare provider to identify specific dysfunctions and introduce targeted therapies.

References:

‍

1 Gaylis, N. B., Kreychman, I., Sagliani, J., Mograbi, J. and Gabet, Y. (2022) The results of a unique dietary supplement (nutraceutical formulation) used to treat the symptoms of long-haul COVID. Front. Nutr., Frontiers Media SA 9, 1034169

2 Tosato, M., Ciciarello, F., Zazzara, M. B., Pais, C., Savera, G., Picca, A., et al. (2022) Nutraceuticals and dietary supplements for older adults with long COVID-19. Clin. Geriatr. Med., Elsevier BV 38, 565–591

3 Marchesi, N., Allegri, M., Bruno, G. M., Pascale, A. and Govoni, S. (2025) Exploring the potential of dietary supplements to alleviate pain due to long COVID. Nutrients, MDPI AG 17, 1287

4 Bigman, G., Rusu, M. E., Shelawala, N., Sorkin, J. D., Beamer, B. A. and Ryan, A. S. (2025) A comprehensive scoping review on diet and nutrition in relation to long COVID-19 symptoms and recovery. Nutrients, MDPI AG 17, 1802

5 Bradbury, J., Wilkinson, S. and Schloss, J. (2023) Nutritional support during long COVID: A systematic scoping review. J. Integr. Complement. Med., SAGE Publications 29, 695–704

6 Carpallo-Porcar, B., Jiménez-Sánchez, C., Calvo, S., Irún, P., Kolesnyk-Sumskaya, E., Aller-Blanco, A. I., et al. (2025) ARACOV-02. Specialized nutritional intervention and telerehabilitation in patients with long COVID: Protocol of a randomized controlled trial. PLoS One, Public Library of Science 20, e0321811

7 Pérez de la Lastra, J. M., Curieses Andrés, C. M., Andrés Juan, C., Plou, F. J. and Pérez-Lebeña, E. (2023) Hydroxytyrosol and arginine as antioxidant, anti-inflammatory and immunostimulant dietary supplements for COVID-19 and long COVID. Foods, MDPI AG 12, 1937

8 Mantle, D., Hargreaves, I. P., Domingo, J. C. and Castro-Marrero, J. (2024) Mitochondrial dysfunction and coenzyme Q10 supplementation in post-viral fatigue syndrome: An overview. Int. J. Mol. Sci., MDPI AG 25, 574

9 Mueller, J. K. and Müller, W. E. (2024) Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea. J. Neural Transm. (Vienna), Springer Science and Business Media LLC 131, 203–212

10 Pavlidis, G., Kountouri, A., Katogiannis, K., Thymis, J., Nikolaou, P. E., Chania, C., et al. (2025) Effects of 4-month treatment with glycocalyx dietary supplement on endothelial glycocalyx and vascular function after COVID-19 infection. Eur. J. Clin. Invest., Wiley 55, e70058

11 Fels, B., Acharya, S., Vahldieck, C., Graf, T., Käding, N., Rupp, J., et al. (2022) Mineralocorticoid receptor-antagonism prevents COVID-19-dependent glycocalyx damage. Pflugers Arch., Springer Science and Business Media LLC 474, 1069–1076

12 Machin, D. R., Sabouri, M., Zheng, X. and Donato, A. J. (2023) Therapeutic strategies targeting the endothelial glycocalyx. Curr. Opin. Clin. Nutr. Metab. Care, Ovid Technologies (Wolters Kluwer Health) 26, 543–550

13 Lau, R. I., Su, Q. and Ng, S. C. (2025) Long COVID and gut microbiome: insights into pathogenesis and therapeutics. Gut Microbes, Informa UK Limited 17, 2457495

14 Trapani, V., Rosanoff, A., Baniasadi, S., Barbagallo, M., Castiglioni, S., Guerrero-Romero, F., et al. (2022) The relevance of magnesium homeostasis in COVID-19. Eur. J. Nutr., Springer Science and Business Media LLC 61, 625–636

15 Carr, A. C. and Gombart, A. F. (2022) Multi-level immune support by vitamins C and D during the SARS-CoV-2 pandemic. Nutrients, MDPI AG 14, 689

16 Chen, K.-Y., Lin, C.-K. and Chen, N.-H. (2023) Effects of vitamin D and zinc deficiency in acute and long COVID syndrome. J. Trace Elem. Med. Biol., Elsevier BV 80, 127278

17 Wu, J.-Y., Liu, M.-Y., Hsu, W.-H., Tsai, Y.-W., Liu, T.-H., Huang, P.-Y., et al. (2024) Association between vitamin D deficiency and post-acute outcomes of SARS-CoV-2 infection. Eur. J. Nutr., Springer Science and Business Media LLC 63, 613–622

18 Barrea, L., Verde, L., Grant, W. B., Frias-Toral, E., Sarno, G., Vetrani, C., et al. (2022) Vitamin D: A role also in long COVID-19? Nutrients, MDPI AG 14, 1625

19 Yin, K. and Agrawal, D. K. (2014) Vitamin D and inflammatory diseases. J. Inflamm. Res., Dove Medical Press Ltd. 7, 69–87

20 Joli, J., Buck, P., Zipfel, S. and Stengel, A. (2022) Post-COVID-19 fatigue: A systematic review. Front. Psychiatry, Frontiers Media SA 13, 947973

21 Ranisavljev, M., Stajer, V., Todorovic, N., Ostojic, J., Cvejic, J. H., Steinert, R. E., et al. (2024) 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., Springer 64, 28

22 Saggam, A., Limgaokar, K., Borse, S., Chavan-Gautam, P., Dixit, S., Tillu, G., et al. (2021) Withania somnifera (L.) Dunal: Opportunity for clinical repurposing in COVID-19 management. Front. Pharmacol., Frontiers Media SA 12, 623795

23 Dhawan, M., Parmar, M., Sharun, K., Tiwari, R., Bilal, M. and Dhama, K. (2021) Medicinal and therapeutic potential of withanolides from Withania somnifera against COVID-19. J. Appl. Pharm. Sci., Journal of Applied Pharmaceutical Science 11, 006–013

24 Borse, S., Joshi, M., Saggam, A., Bhat, V., Walia, S., Marathe, A., et al. (2021) Ayurveda botanicals in COVID-19 management: An in silico multi-target approach. PLoS One, Public Library of Science (PLoS) 16, e0248479

25 Rizvi, Z. A., Babele, P., Madan, U., Sadhu, S., Tripathy, M. R., Goswami, S., et al. (2023) Pharmacological potential of Withania somnifera (L.) Dunal and Tinospora cordifolia (Willd.) Miers on the experimental models of COVID-19, T cell differentiation, and neutrophil functions. Front. Immunol., Frontiers Media SA 14, 1138215

26 Singha, P. S., Ghosh, R. and Ghosh, D. (2024) Immunomodulatory Phytocompounds from Withania somnifera (L.) Dunal (Ashwagandha) Against COVID-19. Trends Immunother., UK Scientific Publishing Limited 8, 2703

27 Wiciński, M., Fajkiel-Madajczyk, A., Sławatycki, J., Szambelan, M., Szyperski, P., Wojciechowski, P., et al. (2025) Ashwagandha (Withania somnifera) and Its Effects on Well-Being-A Review. Nutrients, MDPI AG 17, 2143

28 Sankova, M. V., Mesitskaya, D. F., Andreev, D. A. and Sankov, A. V. (2023) Possible perspectives for using phytoadaptogens in post-COVID period. Med. Counc., Remedium, Ltd. 0, 190–198

29 Mallinson, P. A. C., Joshi, M., Mathpathi, M., Perkins, A., Clayton, T., Shah, A. S., et al. (2025) Ashwagandha (Withania somnifera (L.) Dunal) for promoting recovery in long covid: protocol for a randomised placebo-controlled clinical trial (APRIL Trial). BMJ Open, BMJ 15, e094526

30 Leonard, M., Dickerson, B., Estes, L., Gonzalez, D. E., Jenkins, V., Johnson, S., et al. (2024) Acute and repeated ashwagandha supplementation improves markers of cognitive function and mood. Nutrients, MDPI AG 16, 1813

31 Cheah, K. L., Norhayati, M. N., Husniati Yaacob, L. and Abdul Rahman, R. (2021) Effect of Ashwagandha (Withania somnifera) extract on sleep: A systematic review and meta-analysis. PLoS One 16, e0257843

32 Wegener, T., Edwards, D. and Kasper, S. (2023) The potential role of Rhodiola rosea L. extract WS® 1375 for patients with post-COVID-19 fatigue. hbT, The Heathbook company AG 8 https://doi.org/10.36000/hbt.2023.09.001

33 Cash, A. and Kaufman, D. L. (2022) Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial. J. Transl. Med., Springer Science and Business Media LLC 20, 295

34 Tan, Y., Xie, Y., Dong, G., Yin, M., Shang, Z., Zhou, K., et al. (2024) The effect of 14-day consumption of hydrogen-rich water alleviates fatigue but does not ameliorate dyspnea in Long-COVID patients: A pilot, single-blind, and randomized, controlled trial. Nutrients, MDPI AG 16, 1529

35 Labarrere, C. A. and Kassab, G. S. (2022) Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease. Front. Microbiol., Frontiers Media SA 13, 979719

36 Li, L., Ye, L., He, H., Chai, C., Tong, Y., Zhang, Y., et al. (2025, December 12) Long-term N-acetylcysteine treatment accelerates improvement in patient-reported outcomes for COVID-19 patients: A randomized, double-blind, placebo-controlled trial. medRxiv, medRxiv https://doi.org/10.64898/2025.12.10.25342003

37 Bellone, S., Siegel, E. R. and Santin, A. D. (2025) 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., Elsevier BV 57, 101682

38 Rajewska-Tabor, J., Sosińska-Zawierucha, P., Pyda, M., Lesiak, M. and Bręborowicz, A. (2023) Protective role of N-acetylcysteine and Sulodexide on endothelial cells exposed on patients’ serum after SARS-CoV-2 infection. Front. Cell. Infect. Microbiol., Front Cell Infect Microbiol 13, 1268016

39 Barlattani, T., Celenza, G., Cavatassi, A., Minutillo, F., Socci, V., Pinci, C., et al. (2025) Neuropsychiatric manifestations of COVID-19 disease and post COVID Syndrome: The role of N-acetylcysteine and acetyl-L-carnitine. Curr. Neuropharmacol., Curr Neuropharmacol 23, 686–704

40 Deshpande, A., Irani, N., Balkrishnan, R. and Benny, I. R. (2020) A randomized, double blind, placebo controlled study to evaluate the effects of ashwagandha (Withania somnifera) extract on sleep quality in healthy adults. Sleep Med., Elsevier BV 72, 28–36

41 Tanikawa, T., Kiba, Y., Yu, J., Hsu, K., Chen, S., Ishii, A., et al. (2022) Degradative effect of nattokinase on spike protein of SARS-CoV-2. Molecules, MDPI AG 27, 5405

42 Chittasupho, C., Srisawad, K., Arjsri, P., Phongpradist, R., Tingya, W., Ampasavate, C., et al. (2023) Targeting spike glycoprotein S1 mediated by NLRP3 inflammasome machinery and the cytokine releases in A549 lung epithelial cells by nanocurcumin. Pharmaceuticals (Basel), MDPI AG 16, 862

43 Nyström, S. and Hammarström, P. (2022) Amyloidogenesis of SARS-CoV-2 spike protein. J. Am. Chem. Soc., American Chemical Society (ACS) 144, 8945–8950

44 Trimarco, V., Izzo, R., Zanforlin, A., Tursi, F., Scarpelli, F., Santus, P., et al. (2022) Endothelial dysfunction in long-COVID: New insights from the nationwide multicenter LINCOLN Study. Pharmacol. Res., Elsevier BV 185, 106486

45 Jankauskas, S. S., Kansakar, U., Sardu, C., Varzideh, F., Avvisato, R., Wang, X., et al. (2023) COVID-19 causes ferroptosis and oxidative stress in human endothelial cells. Antioxidants (Basel), MDPI AG 12, 326

46 Theoharides, T. C. and Conti, P. (2021) Be aware of SARS-CoV-2 spike protein: There is more than meets the eye. J. Biol. Regul. Homeost. Agents, China Scientific Research Publishing Pte. Ltd. 35, 833–838

47 Hulscher, N., Procter, B. C., Wynn, C. and McCullough, P. A. (2023) Clinical approach to post-acute sequelae after COVID-19 infection and vaccination. Cureus, Springer Science and Business Media LLC 15, e49204

48 Elumalai, N., Hussain, H., Sampath, N., Shamaladevi, N., Hajjar, R., Druyan, B. Z., et al. (2024) SPIKENET: An evidence-based therapy for long COVID. Viruses, MDPI AG 16, 838

49 Kurosawa, Y., Nirengi, S., Homma, T., Esaki, K., Ohta, M., Clark, J. F., et al. (2015) A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles. Sci. Rep., Springer Science and Business Media LLC 5, 11601

50 Rasouli, R., Hartl, B. and D Konecky, S. (2025) Investigation of the synergistic effect of enzymatic and Ultrasound-Induced amyloid microclot degradation. J. Thromb. Thrombolysis, Springer Science and Business Media LLC https://doi.org/10.1007/s11239-025-03220-0

51 Chatterjee, D. and Maparu, K. (2025) Long COVID syndrome: exploring therapies for managing and overcoming persistent symptoms. Inflammopharmacology, Springer Science and Business Media LLC 33, 4097–4113

52 Di Minno, A., Frigerio, B., Spadarella, G., Ravani, A., Sansaro, D., Amato, M., et al. (2017) Old and new oral anticoagulants: Food, herbal medicines and drug interactions. Blood Rev., Elsevier BV 31, 193–203

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