Ivabradine for long COVID
IVABRADINE
What is Ivabradine?
Ivabradine is a medication used to treat heart conditions.
What does Amantading do in the body?
Ivabradine slows the electrical conduction in the heart which subsequently slows the heart rate.
How can Ivabradine help alleviate certain long COVID symptoms and pathophysiology?
The use of ivabradine in long COVID (post-acute sequelae of SARS-CoV-2 infection, PASC) is based on limited but emerging scientific evidence. According to the 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 by the American College of Cardiology, ivabradine has been used in patients with severe fatigue exacerbated by beta-blockers and calcium-channel blockers.
This recommendation is based on a small trial involving 22 patients with postural orthostatic tachycardia syndrome (POTS). The trial found that ivabradine improved heart rate and quality of life over one month[1]. Additionally, a perspective article suggests that ivabradine may be helpful in managing COVID-19-related cardiovascular complications due to its heart rate-lowering effects and various additional benefits, such as anti-inflammatory and anti-oxidant actions[2]. However, these findings are preliminary and derived from small-scale studies or theoretical benefits rather than large, randomized controlled trials specifically targeting long COVID. While there is some evidence supporting the use of ivabradine for managing cardiovascular symptoms in long COVID, it is primarily based on small studies and expert opinion. More extensive clinical trials are needed.
1.Gluckman TJ, Bhave NM, Allen LA, et al. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and other Myocardial involvement, Post-Acute Sequelae of SARS-COV-2 Infection, And return to play. Journal of the American College of Cardiology. 2022;79(17):1717-1756. doi:10.1016/j.jacc.2022.02.003
2.Baka T, Repova K, Luptak I, Simko F. Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A perspective. Current Pharmaceutical Design. 2022;28(19):1581-1588. doi:10.2174/1381612828666220328114236
Amantadine for long COVID
AMANTADINE
What is Amantadine?
Amantadine is a medication used to treat abnormal movements in conditions such as Parkinson’s disease.
What does Amantadine do in the body?
Amantadine has mild effects on dopamine neurons, but we’re not sure exactly how it works for Parkinson’s. It also seems to stop a virus from infecting cells, but we don’t fully understand how it works. While Amantadine has some antiviral properties, it is no longer recommended as an antiviral in clinical practice. [1]
How can Amantadine help alleviate certain long COVID symptoms and pathophysiology?
When it comes to long COVID, especially post-COVID-19 fatigue, there’s limited but hopeful evidence for using amantadine. One study found that patients who took amantadine for two weeks had less fatigue compared to those who didn’t, as measured by the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS). [2] However, other studies looked at different aspects of COVID-19 and how amantadine is used to treat it.
For example, one study found no significant improvements in fatigue among unvaccinated patients with early, mild to moderate COVID-19. [3] Another study emphasized the need for more standardized and robust studies on long COVID.[4]. The treatment has also been considered for fatigue in other conditions, such as Multiple Sclerosis. A Cochrane Database of Systematic Reviews found that amantadine is generally well-tolerated. However, the evidence supporting its effectiveness in reducing MS-related fatigue is still limited and inconsistent [5]. While Amantadine has the potential to reduce post-COVID-19 fatigue, but we need more large-scale, well-controlled studies to confirm its effectiveness and safety in this context.
1.Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa. Clinical Infectious Diseases. 2018;68(6):e1-e47. doi:10.1093/cid/ciy866
2.Harandi AA, Pakdaman H, Medghalchi A, et al. A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue. Scientific Reports. 2024;14(1). doi:10.1038/s41598-024-51904-z
3Rejdak K, Fiedor P, Bonek R, et al. Amantadine in unvaccinated patients with early, mild to moderate COVID‐19: A randomized, placebo‐controlled, double‐blind trial. European Journal of Neurology. 2023;31(1). doi:10.1111/ene.16045
4.Chee YJ, Fan BE, Young BE, Dalan R, Lye DC. Clinical trials on the pharmacological treatment of long COVID: A systematic review. Journal of Medical Virology. 2022;95(1). doi:10.1002/jmv.28289
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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]].
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