Iron for long COVID
IRON
What is iron?
All living organisms need iron. Iron is a mineral required for growth and development by our bodies [[1]]. Iron is used to shuttle oxygen from the lungs all over the body, including to muscles and our brains. Beyond its involvement in oxygen transport, iron also plays a role in the immune response. We also use iron to make hormones [[1]].
What does iron do in the body?
Iron is essential in biological processes such as oxygen transport, energy production, and the synthesis of nucleic acids like DNA. Iron is also involved in the body’s antiviral response; in a viral infection, the quickly-replicating viruses compete for iron with the person’s cells. Iron balance also influences the immune response. Low iron levels are associated with altered growth of immune cells, higher levels of pro-inflammatory molecules, and increased oxidative stress. In COVID-19, markers of low iron status can be both risk factors and prognostic indicators. These iron measures include ferritin, a protein used to store iron that stimulates pro-inflammatory compounds; high ferritin levels are linked to COVID-19 severity and mortality [[2]].
How can iron help alleviate certain Long COVID symptoms and pathophysiology?
Iron deficiency can be expected after COVID-19 and can contribute to long-term outcomes in terms of symptoms [[3]]. Changes in iron balance can linger for at least two months after acute COVID-19 infection. Therefore, monitoring iron levels in patients with Long COVID is essential. Fatigue and difficulty breathing (dyspnea) are symptoms of iron deficiency, so supplementation with iron may help improve these symptoms in Long COVID patients with deficient iron. Iron deficiency is linked to impaired performance as well as non-resolving lung disorders in people who are post-COVID-19. Iron supplementation may also reduce inflammation and improve immune response to COVID-19 vaccination [[2]]. In one study of Long COVID, iron deficiency was not associated with structural lung impairment but was linked to impaired stress resilience [[3]].
Lumbrokinase for long COVID
LUMBROKINASE
What is lumbrokinase?
Lumbrokinase is a substance that is naturally found in earthworms. Lumbrokinase comes from the scientific name for earthworms, which is Lumbricus. Lumbrokinase has been used as a traditional medicine in China, Japan, and other Asian countries for centuries to support the body’s healthy circulation. To harvest lumbrokinase and other healthy compounds present in earthworms, the earthworms can be dried and powdered, then taken as an oral supplement to support healthy circulation [[1]].
What does lumbrokinase do in the body?
Lumbrokinase refers to a collection of enzymes isolated from the earthworm. There are two ways lumbrokinase supports healthy blood circulation. It can break down a protein called fibrin, which is an insoluble protein that forms during blood clotting. It can also create plasmin, a substance that breaks down blood clots. As a result, lumbrokinase shows promise in reducing the aggregation of blood clots, dissolving the blood clots, and making blood less viscous and more able to flow. Lumbrokinase does not adversely affect organ systems or body tissues [[1]].
How can lumbrokinase help alleviate certain Long COVID symptoms and/or pathophysiology?
Lumbrokinase is already being used to treat stroke, heart disease, deep vein thrombosis, and diabetes. It is also used to help the cardiovascular system stay healthy. Given the heightened risk for blood clotting disorders in Long COVID, lumbrokinase can be used to maintain healthy cardiovascular function [[1]]. Most of interest to Long COVID, lumbrokinase’s anticoagulant and fibrin degrading properties make it an ideal choice to help patients with improved circulation [[2]].
Hydroxy-Beta-Methylbutyrate for long COVID
HYDROXY-BETA-METHYLBUTYRATE
What is hydroxy-beta-methylbutyrate?
Hydroxy-beta-methylbutyrate, or HMB, is a substance made during the body’s breakdown of the amino acid leucine [[1]].
What does hydroxy-beta-methylbutyrate do in the body?
HMB has many roles in the body. It is involved in forming proteins from amino acids, insulin activity, increase and growth of muscle cells, and stem cell growth and specialization into mature cells, among other functions [[2]].
HMB reduces muscle damage from exercise, strengthens muscle, improves aerobic performance, and heightens fatigue resistance. In older people, HMB can reduce sarcopenia, or the loss of muscle and strength that occurs when people get older and exercise less. Optimal effects of HMB in older people occur with oral supplementation in conjunction with exercise [[1]].
In frail older people, HMB supplementation helps reduce the decline of muscle mass and preserve muscle function, especially for older patients who are in hospital stays [[2]].
HMB may regulate the immune and inflammatory responses, especially under stress. It was found to exhibit anti-inflammatory effects, protect against muscle breakdown, and improve pulmonary function in patients in the intensive care unit for chronic obstructive pulmonary disease [[2]].
How can hydroxy-beta-methylbutyrate help alleviate certain Long COVID symptoms and pathophysiology?
HMB’s role in supporting muscle mass, its immune and anti-inflammatory properties, and its effects on physiology affected by COVID-19 make it useful for people dealing with Long COVID. HMB may also potentially affect the brain and cognition [[2]].
Butyrates such as HMB may be linked to chronic fatigue disease through “good” intestinal bacteria in the gut-brain axis [[3]]. Since symptoms in chronic fatigue and Long COVID overlap, HMB may play a similar role for long-haulers, though more evidence is needed.
Nattokinase for long COVID
NATTOKINASE
What is nattokinase?
Nattokinase is a substance found in the Japanese dish natto, a staple in the Asian nation for centuries. Natto is a “vegetable cheese” made of fermented soybeans [[1]]. Eating natto is linked to reduced death from heart disease, owing to natto’s activity reducing coagulation and clotting. Researchers found that a natto extract contains an enzyme that prevents viral infection, such as that from SARS-CoV-2, the virus that causes COVID-19. Lastly, nattokinase, part of natto, degrades the spike proteins of the novel coronavirus without being toxic to cells. Therefore, scientists believe that nattokinase can be used to protect cells [[2]].
What does nattokinase do in the body?
In the body, nattokinase has several functions. It acts as a fibrinolytic, which means that it breaks up blood clots. It is also an anticoagulant, which means that it plays a role in helping prevent blood clots. Lastly, it degrades the spike proteins found in the virus that causes COVID-19, SARS-CoV-2. However, the degradation is not specific to the novel coronavirus, which means that nattokinase may break down other proteins, too [[1]].
How can nattokinase help alleviate certain Long COVID symptoms and/or pathophysiology?
The outstanding aspect of nattokinase is its vascular effects, which are relevant to Long COVID patients. Nattokinase’s role in clotting and preventing clotting can combat post-COVID clotting disorders. Strokes and cardiac incidents are more common post-COVID, and coagulation abnormalities can be part of Long COVID [[3]].
Nattokinase also degrades the spike protein of SARS-CoV-2, the virus that causes COVID-19 [[4]]. This can be useful because the virus can be found in Long COVID patients for some time after the acute disease phase.
What else should I know about nattokinase?
Some people are allergic to nattokinase, which can lead to skin irritation. Also, those patients taking anticoagulants should consult a doctor who can closely supervise their clotting before starting a nattokinase regimen [[5]].
Lactoferrin for long COVID
LACTOFERRIN
What is lactoferrin?
Lactoferrin is a mammalian protein found in milk, whether from an animal or human. It is also found in saliva. As an iron-binding protein, lactoferrin is used to balance iron levels in the body. While too little iron can lead to anemia, too much iron can be toxic, so lactoferrin helps keep the balance [[1]]. When lactoferrin binds to iron, this reduces the iron’s bioavailability so that the body’s iron concentration remains balanced [[2]].
What does lactoferrin do in the body?
Scientists have called lactoferrin a “miracle molecule” because it has many different properties. It is antimicrobial, antiviral, antioxidant, and immunostimulatory and can regulate DNA activity [[3]]. Lactoferrin can act defensively against microbes, and it also has antiviral activity, which it can perform in multiple ways, including binding to viruses or virus receptors. Lactoferrin’s antiviral activity extends to SARS-CoV-2, the virus that causes COVID-19; lactoferrin can bind to the spike protein and cell surface components. Lactoferrin may also dampen the inflammatory cascade by directly acting upon inflammatory cascades and its actions related to iron levels [[2]].
How can lactoferrin help alleviate certain Long COVID symptoms and pathophysiology?
Lactoferrin can be helpful for patients with acute COVID-19 and patients with Long COVID [[2]]. It can interact directly with the virus that causes COVID-19 to neutralize it. It can also inhibit inflammatory activity, characteristic of Long COVID [[4]]. Lactoferrin can also degrade blood clots, activate growth factors to support the healthy function of the body’s tissues, and remove excess proteins that collect in the body. Human lactoferrin, from human tissues, is known to reduce the problem of coagulation that can be characteristic of patients who have experienced COVID-19 [[4]].
Sulbutiamine for long COVID
SULBUTIAMINE
What is sulbutiamine?
Sulbutiamine is a manmade version of vitamin B1. It was developed in Japan in the 1960s to treat beriberi, which is vitamin B1 deficiency [[1]]. It is known mainly for its effects on cognition and fatigue.
What does sulbutiamine do in the body?
Sulbutiamine is widely used in endurance sports for its anti-fatigue, cognitive enhancement, and antioxidant effects. It can also have neuroprotective effects [[1]]. Sulbutiamine is used in medicine to treat fatigue, thiamine deficiency, and concentration difficulties. The supplement improves brain function regarding memory, concentration, and mood. In rodent studies, sulbutiamine modulates acetylcholine activity in the hippocampus. Sulbutiamine exerts anti-oxidant and anti-apoptotic properties, which can prevent cells from dying due to oxidative damage. Medical applications of sulbutiamine outside of cognitive enhancement and fatigue include depression, diabetes polyneuropathy, and erectile dysfunction. Sulbutiamine may also be an anti-cancer supplement, as its analog, thiamine, is [[2]].
How can sulbutiamine help alleviate certain Long COVID symptoms and/or pathophysiology?
Sulbutiamine is known for its anti-fatigue effects in healthy populations and those suffering from various diseases [[3]]. Sulbutiamine could be used to reduce fatigue in Long COVID alongside other treatments. In patients with multiple sclerosis, sulbutiamine, supplemented alongside disease-modifying treatment, reduced fatigue symptoms [[4]]. Therefore, sulbutiamine may have particularly restorative and/or regenerative activities relevant to the central nervous system. COVID long-haulers suffer from cognitive issues and debilitating “brain fog” as well as both physical and mental exhaustion, so sulbutiamine could be a way to improve those symptoms via supplementation.
Lastly, as sulbutiamine was developed as a replacement for vitamin B1 or thiamine, the same effects seen for Long COVID with thiamine may generally apply for sulbutiamine, though this hypothesis needs further testing. Thiamine can help reduce inflammation in Long COVID and, in one study, reduced the neurological burden of Long COVID patients [[5]].
Melatonin for long COVID
MELATONIN
What is melatonin?
Melatonin is a hormone produced by the brain’s pineal gland in darkness. Melatonin synthesis relies on the amino acid tryptophan [[1]].
What does melatonin do in the body?
Melatonin helps regulate the sleep-wake cycle and helps us sleep. Light exposure at nighttime can block the production of melatonin [[2]]. While it is known as a sleep-promoting molecule, it also activates a molecule called NRF2, which plays an antioxidant role and prevents macrophages from acting in pro-inflammatory ways [[3]].
At high doses, melatonin can be a robust scavenger of free radicals, a feat accomplished by interacting with enzymes that boost the body’s antioxidant defenses [[1]].
Relevant to SARS-CoV-2, the virus that causes COVID-19, researchers believe melatonin has a variety of helpful functions: impairing COVID-19 infection; anti-oxidant, anti-inflammatory, and immunoregulatory properties; restoring and maintaining a sleep-wake cycle (also known as the circadian rhythm); treating comorbidities of COVID-19 including metabolic syndrome, diabetes, and cardiovascular issues; neuroprotection; boosting function of COVID-19 vaccines [[4]].
How can melatonin help alleviate certain Long COVID symptoms and pathophysiology?
Because of its antioxidant, anti-inflammatory, and immune-modulatory properties, melatonin can reduce symptoms associated with COVID-19. It also activates molecular activities inside the body’s cells that increase the expression of enzymes that make the potent antioxidant glutathione, which is another powerful supplement for Long COVID [[4]].
Brain inflammation is thought to lead to lesions in the brain, which can contribute to Long COVID symptoms such as “brain fog.” Melatonin can treat delirium and can also help improve sleep-wake cycles for COVID patients in the ICU and Long COVID patients who have circadian rhythm problems [[4]].
Lastly, in its role in protecting cells, melatonin can help prevent conditions that make COVID-19 outcomes worse, such as diabetes, metabolic syndrome, and cardiovascular diseases [[4]].
Melatonin can potentially serve as a neuroprotective supplement to help Long COVID patients with “brain fog” – the cognitive dysfunction experienced by many Long COVID patients. It may also be useful to control pain in Long COVID patients [[4]].
Sulforaphane for long COVID
SULFORAPHANE
What is sulforaphane?
Sulforaphane is a plant-derived substance known to possess anti-cancer properties; more recently, its effects in fighting COVID-19 have become known [[1]]. It is found in cruciferous vegetables with exceptionally high concentrations in broccoli. Because it is found in plants we already eat, sulforaphane is generally well-tolerated [[2]].
What does sulforaphane do in the body?
Sulforaphane is an antioxidant and anti-inflammatory compound known to inhibit the effects of pro-inflammatory molecules [[3]]. It is also neuroprotective, meaning it has protective effects on the nervous system, including the brain and spinal cord. As a known anti-cancer agent, sulforaphane reduces the impact of oxidative stress on the body’s cells, inhibiting inflammatory activity. Sulforaphane inhibits the cytokines involved in the cytokine storm of COVID-19 [[2]], which is linked to Long COVID [4]].
How can sulforaphane help alleviate certain Long COVID symptoms and/or pathophysiology?
Animal studies suggest that it can improve endothelial function by blocking oxidative stress [[5]]. A study of broccoli capsules containing sulforaphane to treat COVID-19 concluded that sulforaphane could potentially protect against severe illness [[6]]. A study of sulforaphane in COVID found that it was potentially an anti-inflammatory mediator in COVID-19, reducing the gene expression of inflammatory compounds [7]]. However, laboratory research also suggests that sulforaphane may be less effective in older people than in younger populations [[5]].
Olive Polyphenol for long COVID
HYDROXYTYROSOL (OLIVE POLYPHENOL)
What is hydroxytyrosol?
Hydroxytyrosol is a substance found in olive oil. It is a polyphenol, which means it is a plant-based compound known to protect against cell damage due to inflammation and oxidative stress [[1]].
What does hydroxytyrosol do in the body?
Hydroxytyrosol has anti-oxidant and anti-inflammatory properties. It reduces the activity of cytokines, which are part of the immune response, especially in severe COVID, and can lead to Long COVID. It also prevents oxidative stress and inflammation in cells infected with SARS-CoV-2, the virus that causes COVID-19 [[2]].
How can hydroxytyrosol help alleviate certain Long COVID symptoms and pathophysiology?
Given that Long COVID is characterized by oxidative stress and inflammation, hydroxytyrosol can help via its actions preventing oxidative stress and inflammation in cells infected with COVID-19.
Research suggests, furthermore, that lingering SARS-CoV-2 virus can contribute to the pathophysiology of Long COVID and that these effects can be counteracted by antioxidants, including hydroxytyrosol, which reduce oxidative stress in cells [[3]].
Olive leaf extract improved the clinical status of hospitalized acute COVID-19 patients, improving respiratory rate and oxygen saturation [[4]]. Because olive polyphenols can improve acute COVID outcomes, they may show clinical promise for Long COVID, although more research is needed.
Combined with the amino acid arginine, hydroxytyrosol could deter the formation of harmful pro-inflammatory substances such as peroxynitrite, which is implicated in COVID-19-related organ dysfunction. Lessening inflammation, supporting immune function, protecting against damage from free radicals, and preventing blood vessel injury are just some things that arginine and hydroxytyrosol can do together [[2]].
Cistanche Tubulosa Extract for long COVID
CISTANCHE TUBULOSA EXTRACT (CTE)
What is cistanche tubulosa extract or CTE?
Cistanche tubulosa extract, or CTE, is a traditional Chinese herbal medicine that protects the gut [[1]]. CTE comes from the cistanche tubulosa plant, a perennial parasitic herb found in the Chinese desert. Cistanche tubulosa is a bright yellow and beige desert plant that is parasitic in that it obtains all or part of its nutrition from other plants [[2]].
What does cistanche tubulosa extract or CTE do in the body?
Over 120 bioactive ingredients have been found in cistanche tubulosa [[3]]. CTE can have neuroprotective, immune function, antioxidant, anticancer, and liver protective effects. One study of CTE in mice found that, via restoring gut microbiota balance, CTE produced antidepressant-like effects and elevated the level of brain-derived neurotrophic factor, a significant growth factor in healthy brain function [[4]].
How can cistanche tubulosa extract or CTE help alleviate certain Long COVID symptoms and/or pathophysiology?
A compound isolated from cistanche tubulosa called echinacoside was found to stimulate the production of immune cells called T cells, which attack foreign particles in the body [[3]]. It was also found to boost levels of growth hormone. Hormonal insufficiencies are an aspect of Long COVID. Growth hormone deficiency, in particular, is linked to fatigue in Long COVID patients [[3], [5]]. Cistanche tubulosa’s many immune-supporting, neuroprotective, anticancer, and liver-protective effects can also potentially help improve cognitive symptoms and reduce inflammation in long COVID patients dealing with those issues.
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