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Might TCM Help in the COVID-19 Pandemic?

Published on December 27, 2021

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In the fight against Covid-19, we need all hands on-deck. Whilst vaccination, physical distancing and strong hygiene practices remain priority interventions, one strategy that has received less attention in Western countries is the use of herbal and, in particular, Traditional Chinese Medicine (TCM) as a preventative and potentially therapeutic agent.

Before we dive in, it is important to state upfront that this article in no way seeks to promote TCM as a replacement for vaccination and other critical Covid measures, but rather to understand its potential as a complement to mainstream therapies. Further the application of TCM should always be done under the supervision of a qualified practitioner.

Background on Traditional Chinese Medicine

Traditional Chinese Medicine has been in use for over 2000 years in over 320 epidemics faced by China. Chinese herbal medicine therapy is essentially a mixture of herbs prescribed by Chinese herbalists depending on the patient’s illness and based on core diagnostic patterns (inspection, listening, smelling, inquiry, and palpation). Whilst focus on pathogens is important, treating patients as an organic whole is the focus of TCM hence the central role of herbal compounds which help the immune system and other body systems to prevent and/or respond to pathogens.

The core clinical theories on viral flu-like illnesses were established by Chinese medical practitioners as far back as the Han Dynasty (206 BCE–220 CE) in a foundational text called “The Discussion of Cold-Induced Disorders” (Shang Han Lun) written by Zhang Zhong-Jing. Since then TCM practitioners have continued to learn and evolve their treatments, and today there are over 100 TCMs available for use in treating epidemics.

In modern day China, TCM is routinely used alone and in tandem with Western allopathic medicine to treat a wide range of different health conditions. Similar branches of medicine are used in South Korea, Japan and other parts of Asia.

Traditional Chinese Medicine and Covid-19

Since the beginning of the Covid-19 outbreak in Wuhan in late 2019, TCM was widely deployed across China to slow down the surge in infections. This was in part influenced by the Chinese experience with using TCM during the SARS epidemic. Studies found that when compared with Western Medical Treatment alone, TCM could help to reduce SARS fatality rates, improve oxygen saturation in critically ill patients, and alleviate symptoms such as dyspnea. Other studies by Luo et al. in 2020 and Lau et al in 2005 found that TCM was an effective preventative measure for SARS.

Soon after Covid-19 appeared in China, the National Administration of Traditional Chinese Medicine (NATCM) commissioned a team of experts to develop a traditional Chinese herbal medicine treatment program for the virus. On 24 January 2020, the first case of an early stage Covid patient who was cured by TCM was reported in Beijing.^[1] The following day, another cured patient was reported.^[2]

On 27 January 2020, an updated traditional Chinese herbal medicine treatment program was issued by China’s National Health Commission and NATCM which required health authorities to use traditional Chinese herbal medicine alongside Western medicine in the treatment of Covid-19.^[3] TCM practitioners break Covid down into seven different stages (prevention, observation, initial, middle, severe, critical and recovery), with different herbal treatments prescribed for each.

In March 2020, another clinical case went public showing that a herbal formulation recommended by China’s National Health Commission was effective in attenuating acute respiratory distress syndrome in a mild Covid-19 patient.

Since then several further case-studies and reviews of TCM used during the Covid-19 pandemic have been published demonstrating TCM’s therapeutic effects. One such review, published last November concluded:

The combination of western medicine and TCM in treatment [is] of great significance for the prevention and treatment of COVID-19.

Effects Are Strongest With Early Interventions

Researchers find that TCM is most effective in addressing symptoms when applied early in the progression of Covid-19. In a May 2020 study of 102 early-stage Covid-19 patients treated with TCM, researchers found that “clinical symptom disappearance time was shortened by 2 days, the recovery time of body temperature was shortened by 1.7 days, [and] the average length of stay in hospital was shortened by 2.2 days”. They concluded that the “early intervention [with] TCM is an important way to improve cure rate, shorten the course of disease, delay disease progression and reduce mortality rate.” and that “the reason why TCM works is not only to inhibit the virus, but [it] might block the infection, regulate the immune response, cut off the inflammatory storm, and promote the repair of the body.’”

Further, Li et al.’s, 202 0 meta-analysis showed that herbal medicines are effective in halting the progression of Covid-19 from mild to critical, decreasing hospitalization rates, shortening the duration of hospital stays, as well as alleviating COVID-19 associated symptoms like fever, cough, fatigue, and inflammation.

What Might Be the Mechanisms at Work?

Based on recent in silico results, numerous natural compounds from TCM botanicals have been found highly potent in blocking the enzyme function and membrane receptors of coronavirus.

In a meta analysis of the most used botanicals in TCM for Covid-19 published in October 2020, Huang et al. found the nine most common herbal ingredients were: Glycyrrhizae Radix Et Rhizoma (Glycyrrhiza inflata Batalin), Forsythiae Fructus [Forsythia suspensa (Thunb.) Vahl], Lonicerae Japonicae Flos (Lonicera Japonica Thunb.), Scutellariae Radix (Scutellaria baicalensis Georgi), Platycodonis Radix [Platycodon grandiflorum (Jacq.) A. DC.], Menthae Haplocalycis Herba (Mentha canadensis L.), Gardeniae Fructus (Gardenia jasminoides J.Ellis), Gypsum Fibrosum, and Moschus (Moschus anhuiensis).

Huang et al’s integrated network analysis on these nine herbs identified eighteen botanical compounds with drug-like potential. Ten of those compounds are flavonoid derivatives. Flavonoids are known to protect cell membranes, and have antioxidant and anti-inflammatory properties.

Huang et al. concluded that the therapeutic effect of these eighteen compounds for Covid-19 was in influencing the COX-2 and MAPK mediated inflammatory pathways. The COX-2 enzyme is induced during inflammation and tissue repair. Data shows that COX-2 plays a role in driving the lung inflammation and injury caused by Covid-19. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. It is thought that the overwhelming inflammatory response in Covid-19 is caused in part by upregulated p38 activity.

Since the compounds studied by Huang et al have been used in dietary supplements for a long time, their toxicity is negligible, which makes them safe to be employed as prophylactic agents, under the supervision of an experienced health practitioner.

In March 2020, Zhang et al screened databases of anti-viral botanical compounds and found 13 compounds that exist in TCM also had potential anti-Covid-19 activity. 125 Chinese herbs were found to contain 2 or more of these 13 compounds, leading the authors to conclude that “Chinese herbal treatments classically used for treating viral respiratory infection might contain direct anti-2019-nCoV [Covid-19] compounds.”

A July 2020 study by Yang et al. went further, examining the active components of two TCMs – Qing-Fei-Pai-Du (QFPD) and Ma-Xin-Shi-Gan (MXSG), both used by the Chinese Government to treat Covid. Their research identified 129 active compounds which fell into four categories: flavonoids, glycosides, carboxylic acids, and saponins. Together these compounds were found to regulate multiple complement, coagulation cascades and thrombin systems to interfere with infection pathways. One major compound in MXSG, glycyrrhizic acid (found in licorice), played an anti-inflammatory role in blocking toll-like-receptors (immune receptors that play an important role in Covid-19) and in suppressing IL-6 production (a predictor of respiratory failure in severe Covid cases).

In June 2020, Li et al. published the results of an in-vitro study of the antiviral activity of Lian hua qing wen (LH), a TCM patent medicine comprising 13 herbs, which is a recommended TCM COVID treatment according to Chinese Government Guidelines. They found that the treatment of Vero E6 cells (African Green Monkey kidney cells which have been used for Coronavirus research in cell-culture based infection models since 2003) with LH resulted in an inhibition of SARS-CoV-2 replication and a corresponding reduction in several pro-inflammatory markers at the mRNA level.

A study of Liu Shen, a TCM used widely for treating infectious diseases, which was conducted by Ma et al. in August 2020, found that it exerted inhibitory effects against SARS-CoV-2 replication and virus-induced inflammation in vitro probably via suppressing the NF-κB pathway. This pathway drives the expression of numerous pro-inflammatory genes, including those encoding for cytokines and chemokines. It also plays a role in regulating the inflammasome, which are innate immune system receptors and sensors that activate inflammatory responses in the presence of pathogens.

In a February 2021 paper, Capodice and Chubak highlight several molecules from a wide variety of TCM herbs that have potent antiviral and immune modulating properties in treating Covid-19. Further research is needed to confirm whether these molecules behave similarly when combined together.

What Could All of This Mean?

Whilst further research is needed to dig into the exact mechanisms and full potential of TCM in treating and preventing Covid-19, the initial findings are promising.

Herbal and Chinese Medicine have long been used to treat respiratory illness and viral infections. They have minimal toxicity, can be administered orally and are widely accessible, making them strong candidates for long-term prophylactic use.

Given that those with weaker immune systems are at greater risk of Covid-19 infection, herbal medicines like TCM which can help to modulate the immune system and dampen down the uncontrolled inflammation that occurs in Covid-19, could, as Lei and Liu conclude, offer potential as a preventive or even therapeutic agent alongside other Covid treatments.

As the Covid virus continues to mutate and countries grapple with the tragedy of this Pandemic, all modes of treatment that have minimal risks and proven benefits should be given serious consideration. Herbal and Traditional Chinese Medicine may be one such contender.

Additional Notes

^[1] Article reads: “A patient diagnosed with 2019-nCoV pneumonia was discharged from Beijing”

^[2] Article reads: “One patient with 2019-nCoV pneumonia was discharged today in Beijing, with a total of two discharged”

^[3] Pneumonitis Diagnosis and Treatment Program for New Coronavirus Infection (Trial Version 4). In. Edited by The General Office of the National Health and Health Commission of China, Office of the State Administration of Traditional Chinese Medicine. Beijing; 2020.

^[4] For example: Ren et al, Traditional Chinese Medicine for Covid Treatment, Pharmacological Research, May 2020; Zhang et al, The clinical benefits of Chinese patent medicines against COVID-19 based on current evidence, Pharmacological Research, July 2020; Zhao et al, Prevention and treatment of COVID-19 using Traditional Chinese Medicine: A review, Phytomedicine, August 2020; Wu et al, Traditional Chinese Medicine as a complementary therapy in combat with COVID-19—A review of evidence-based research and clinical practice, Journal of Advanced Nursing, November 2020; Zheng et al, Efficacy of Traditional Chinese Medicine on COVID-19: Two Case Reports, Feb 2021.

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This article was published originally on June 3, 2021

Covid Notes: Thiamine Reduces Thrombosis and Mortality

by Chandler Marrs, PhD

Published on August 30, 2021

6619 views

covid notes: thiamine reduces mortality and thrombosis

A recently published retrospective study showed ICU patients receiving thiamine therapy had a significantly reduced thrombosis and mortality rate compared to patients not treated with thiamine. The study, conducted in two hospitals in Saudi Arabia reviewed the cases of 738 critically ill Covid patients admitted to the ICU. As this was a retrospective study looking solely at electronic medical records, there was no determination of thiamine deficiency or clinical criteria to determine who received thiamine or at what dose. This was simply a review of all cases during a defined period of time that were admitted to the ICU and who, based upon clinical judgement of the treating physician, may have been prescribed thiamine.

Study Details

Among 738 patients, 83 had received IV or oral thiamine in doses ranging 50-200mg per day for an average of 7 days. This was in addition to whatever medical or pharmaceutical interventions provided. Using a statistical tool called a propensity score, the researchers then selected pair matches to those 83 patients for further analysis of several endpoints. The endpoints evaluated included:

Association between thiamine use as an adjunctive therapy with in-hospital and 30 day mortality
Duration of mechanical ventilation, length of stay and complications such as
- Acute kidney injury
- Thrombosis
- Respiratory failure
- Acute liver injury

Results

Across all variables, patients who received thiamine faired significantly better than those who did not. The most striking findings included mortality and thrombosis reduction. Thiamine reduced in-hospital and 30-day mortality by 61% and 63%, respectively compared to propensity matched controls. Additionally, critically ill ICU patients who received thiamine were 81% less likely to develop thrombosis, and non-significantly less likely to develop kidney damage or liver damage. Inasmuch as thrombosis is major contributor to mortality with COVID, this finding is huge.

Things to Consider

As this was a retrospective study and there were no determinations regarding deficiency or guidelines regarding dosing or other treatment protocols given concurrently, it is difficult to fully appreciate the role of thiamine in COVID recovery by traditional research parameters. Nevertheless, if we look at the role of thiamine in energy metabolism, in immune function, in controlling hypoxia, it makes sense that no matter what other confounding variables may detract from or enhance recovery prospects, thiamine, by its very mechanisms of action, would improve outcomes; something that we have been proposing since well before the pandemic began. Maybe now, more will listen.

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The Cytokine Theory of Disease, COVID, and Nutrition

by Derrick Lonsdale MD, FACN, CNS

Published on April 22, 2021

7800 views

The cytokine theory of disease states that an over production of cytokines causes the clinical manifestations of illness. Much effort has been expended to determine how cytokines are regulated in normal health. Cytokines play a broad role to help the immune system respond to diseases and drugs. Cytokines may be considered “good” when stimulating the immune system to fight a foreign pathogen or attack tumors. They may be considered “bad” when their expression causes inflammatory disease as in rheumatoid arthritis, asthma, or Crohn’s disease. What is often missed in these considerations is that the inflammatory response itself is dependent upon the proper functioning of the autonomic system, which is dependent upon mitochondrial capacity and mitochondrial capacity is dependent upon proper nutrition.

The Inflammatory Reflex

The inflammatory reflex is a physiological pathway in which the autonomic nervous system detects the presence of inflammatory stimuli and modulates cytokine production. Afferent signals to the brain are transmitted via the vagus nerve, activating reflex efferent signaling, that releases acetylcholine in the vicinity of macrophages within the reticuloendothelial system. The production of acetylcholine is crucial to the activity of this reflex which is known also as the cholinergic anti-inflammatory reflex.

The peripheral nervous and immune systems were traditionally thought of as serving separate functions, but new insights into neurogenic inflammation suggest that this is not the case. Nociceptor neurons possess many of the same recognition pathways for danger as immune cells. Understanding the interaction of peripheral neurons with immune cells may lead to the suppression of immunopathology. We now know that the nervous system, through the vagus nerve, can modulate the cytokine response induced by microbial invasion or tissue injury. This cholinergic anti-inflammatory pathway is mediated by nicotinic acetylcholine receptors on tissue macrophages, leading to decreased production of pro-inflammatory cytokines. Activation of the sympathetic nervous system also has anti-inflammatory effects.

The cholinergic anti-inflammatory pathway is part of the parasympathetic nervous system and it can be also entitled as an anti-inflammatory reflex. Stopping production of pro-inflammatory cytokines is its major task. Acetylcholinesterase terminates the neurotransmission, so cholinesterase inhibitors can be beneficial by the prolongation of the reflex. It depends on termination of the vagus nerve into blood, and the release of acetylcholine. Acetyl CoA, used for the synthesis of acetylcholine, is derived from mitochondrial pyruvate dehydrogenase and there is a small pool of choline with cholinergic nerve endings available for acetylcholine synthesis.

Cytokines and Covid-19

The clinical effects of Covid-19 are reported to be from a cytokine storm and clinical and laboratory features confirm. Like sepsis, severe Covid-19, is marked by an overwhelming inflammatory response, central to the development of lethal organ failure. Immunologic complications such as macrophage activation syndrome result in cytokine storm syndrome and acute respiratory distress syndrome, which may also occur in some patients. Although the physiological and pathological aspects of Covid-19 infection are poorly understood, current research progress indicates the effectiveness of anti-cytokine therapy. Given the role of autonomic dysfunction with human inflammatory diseases, including rheumatoid arthritis, diabetes and sepsis, it is possible that dysautonomia is an etiology in common to those diseases. Recent work indicates that vagal nerve signaling mechanisms are strongly influenced by the nutrient status. Nutrient delivery to the gut activates neuroendocrine mechanisms that control digestion, energy intake and utilization. Could nutrient status impact cytokine response?

Nutrition, Immunity, and Autonomic Function

The immune system protects the host from pathogenic organisms. It is always active, carrying out surveillance and its activity is enhanced if an individual becomes infected. Increased activity is accompanied by an increased rate of metabolism, requiring energy, substrates for biosynthesis and regulatory molecules, all of which are ultimately derived from diet. A number of vitamins and trace elements have key roles in supporting antibacterial and antiviral defense. Dietary approaches to achieve a healthy microbiota can also benefit the immune system. Thiamine is an essential cofactor for 4 enzymes involved in production of energy and the total body stores are relatively small. Thiamine deficiency (TD) can develop in patients undergoing acute metabolic stress, such as any form of severe infection, surgical procedures or severe trauma. TD can cause heart failure, peripheral neuropathy, Wernicke encephalopathy, gastrointestinal beriberi and/or the appearance of unexplained lactic acidosis. Consequently, clinicians need to consider TD in patients admitted to intensive care units.

Acetylcholine synthesis, the neurotransmitter used by the vagus nerve, depends on the presence of its precursors, acetyl coenzyme A (AcCoA) and choline. AcCoA is derived from mitochondrial pyruvate dehydrogenase, the cofactors for which are thiamine and magnesium. There is a small pool of choline within cholinergic nerve endings available for acetylcholine synthesis. The prevalence of TD in critically ill patients due to coronavirus disease 2019 is higher in patients with diabetes, a disease in which TD is common. When in excess, pyruvate and lactate that accumulate from TD, can increase the stabilization of the hypoxia-inducible 1-alpha transcription factor, independent of low oxygen. For this reason, TD causes what has been called pseudo-hypoxia. HIF stabilization activates pro-inflammatory cytokines.

An HIV positive woman, four days after recurrent episodes of vomiting, the herald of gastrointestinal beriberi, developed severe dysautonomia, frequently its earliest sign. TD, often overlooked, is frequent in HIV infected patients. Treatment with parenteral thiamine in this patient induced dramatic improvement within a few days.

A significant number of SARS-CoV-2 (COVID-19) pandemic patients have developed chronic symptoms lasting weeks or months, symptoms that are very similar to those described for myalgic encephalomyelitis/chronic fatigue syndrome. The current literature reveals an understanding of the role that mitochondria, oxidative stress and antioxidants may play in this syndrome.

Covid-19, Cytokinemia, and Thiamine

Although the inflammatory characteristics of the Covid-19 infection are incompletely understood, there is strong evidence of cytokinemia, typically found in macrophage activation syndrome and marking the degree of severity. Since we know that inflammation is controlled by the cholinergic anti-inflammatory reflex, it presents a potential for treatment by stimulation of the vagus nerve or by prolonging the action of its neurotransmitter, acetylcholine. Its synthesis is dependent on acetyl CoA from the citric acid cycle and choline from endogenous synthesis or diet. Thiamine is essential in processing glucose as the primary fuel of the brain and its deficiency causes beriberi, the prime example of an energy deficient disease. Although vitamin deficiency is considered to be rare in America because of vitamin enrichment by the food industry, it has been shown that a high ingestion of empty calories, particularly from carbohydrates, overwhelms the oxidative power of the micronutrients, particularly thiamine. We have called this high calorie malnutrition, a classical oxymoron since malnutrition is generally associated with absence of food, leading to starvation. Beriberi has a vast number of symptoms, none of which are pathognomonic. If TD is suspected, a common laboratory test is to measure the blood concentration of thiamine or the activity of the thiamine dependent enzyme transketolase, both of which are generally in the normal range even in moderate TD. This is because the thiamine content would be satisfactory for a diet containing a healthy concentration of calories. The calorie/micronutrient ratio is the important measure required.

The symptoms are produced by energy deficiency in the controls of the autonomic/endocrine axis in the hind brain that is particularly sensitive to TD. They are not crippling and the many sufferers are able to visit a physician where a series of laboratory studies are either nonspecific or normal. Beriberi has a long morbidity and a low mortality and is the prototype for dysautonomia in its early stages. The patient may appear to be relatively well and may even be obese. The usual and customary laboratory studies are usually normal or misleadingly nonspecific. The patient is often told that it is psychosomatic. The evidence suggests that high calorie malnutrition is common in America and may lead to energy deficiency, particularly in the brain, ensuring an essentially unfit individual. If and when such an individual is infected by the Covid -19 virus, there is insufficient energy to drive the complex activities of the cholinergic anti-inflammatory reflex. A deficiency of micronutrients, with a particular emphasis on thiamine, would ensure that the defenses of the body, organized and guided by the brain, would fail to perform an adequate protection from the invading pathogen.

Consider Thiamine for Covid-19

It has been shown in an animal study that thiamine tetrahydrofurfuryl disulfide (TTFD), an over the counter drug for attenuation of fatigue, improves energy metabolism, using the forced swimming test. The swimming duration using TTFD, was significantly longer than that of control rats and was not achieved using thiamine. The clinical use of TTFD has been reviewed. It is hypothesized that TD is precipitated in Covid-19 patients as in sepsis, both being examples of a severe form of energy requiring stress, as defined by Selye. Even if TD cannot be proved in the ER, a simple clinical trial with TTFD might expose the truth of the many symptoms attributed to the virus and particularly those experienced by the so-called “Longhaulers”. The polysymptomatic incidence is mindful of the clinical expression of beriberi. It is worth remembering that as long ago as 1936, Sir Rudolph Peters found that there was no difference in the respiration between TD and thiamine sufficient pigeon brain cells until glucose was added to the preparation. The cells with adequate thiamine immediately began to respire while there was no effect in the TD cells. He called this the catatorulin effect.

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Image credit: www.scientificanimations.com, CC BY-SA 4.0, via Wikimedia Commons.

COVID Notes: “I Don’t See A Role For Mitochondria.” Say What?

by Chandler Marrs, PhD

Published on April 12, 2021

5733 views

covid notes mitochondria immune function

A persistent notion in medicine is that the only time mitochondria precipitate, or in any way influence illness, is when mDNA mutations are involved and/or with frank starvation. Absent those two events, the magical mitochondria will keep chugging along and there is no need to consider their impact on health or disease. This belief emanates partly from another all-too-persistent notion that holds tightly to a compartmentalized model of organismal function, suggesting that each bodily system and thus each disease process is unique and distinctly separate from everything else, and partly from the way most folks are taught about mitochondria – by rote memorization of the Krebs cycle. As a result and except in specific circumstances, most physicians and many researchers see no role for mitochondria in health or disease.

This is true with COVID as well. Even though COVID presents disparately across patient populations, is clearly not limited by body compartment or system, and not only does not fit within any diagnostic model to date but shatters everything we think we know about illness, folks are reticent, nay adamant, that mitochondria are not involved. COVID is not a mitochondrial illness, they proclaim. To that end, on a somewhat regular basis, I see posts, threads, and comments about just how unimportant mitochondria are to COVID and really, to health in general.

Stressed Mitochondria, Inflammation, and COVID

Some months ago, a gentleman argued that the chronic inflammation caused by COVID was related solely to altered immune function similar to that seen in conditions like rheumatoid arthritis or lupus. He went on to say that he did not see any role for mitochondria in this. Similarly, another gentleman was equally adamant that there was no known relationship between “mitochondrial health impacting which immune response or pathway will be activated.” He argued further that my suggestion of stressed mitochondria triggering the inflammatory responses seen in COVID-related blood pressure drops and cytokine storms was not possible per the tenets of modern immunology. It was foolhardy for me to consider otherwise.

Beyond the obvious faceplant response – ‘as if the immune system could function without the help of the mitochondria; as if anything could function without the mitochondria’ – there is an ample amount of research linking mitochondrial function to immune function predating COVID and a burgeoning body of research linking mitochondrial response to COVID severity. Indeed, some of the more recent research suggests that not only does SARS- COV2, the viral protein associated with COVID directly influence mitochondrial function like many other viruses do, but also that it is only the host variables e.g. mitochondrial fitness that determine how far the virus is allowed to progress. Mitochondria, it appears, are the determining factor of illness severity, something I have been saying since the beginning of this pandemic.

When this particular series of ‘COVID does not involve the mitochondria’ comments came up, I was speaking about the hijacking of the mTOR pathway by other viruses and speculating as to whether COVID might do the same. The mTOR pathway includes a set of enzymes that regulate cell and mitochondrial metabolism via multiple mechanisms. Though mTOR are not mitochondrial proteins, as they are located in the cytosol adjacent to another set of organelles called lysosomes, they provide critical signaling to mitochondria involving energy metabolism and stress response. In fact, mTOR coordinate mitochondrial energy consumption and production. They initiate these nutrient signals by binding or unbinding themselves to the lysosomes. Among those signals that mTOR respond to is protein or amino acid status. Low protein effectively inhibits mTOR enzymes. Absent outright starvation, which is entirely possible in critical illness, protein metabolism is dependent upon mitochondrial function. Specifically, protein catabolism and synthesis both require energy or ATP, which in turn requires an array of micronutrient co-factors to power mitochondrial enzymes, the machinery involved in these processes.

Returning to the claim that the COVID cytokine response was akin to the autoimmune diseases like arthritis or lupus, that claim is absolutely correct. The response is akin to one of an autoimmune disease process, but what most fail to recognize is that autoimmune disease process is itself tied to the mitochondria, through multiple channels, including mTOR. Since these conversations arose from a post on viral hijacking of mTOR and the inflammatory patterns observed with autoimmunity, let us dig into those relationships.

Th-17 Cells, mTOR and the Mitochondria

Common to both the severe and long COVID and autoimmune illness, are hyperactive pro-inflammatory Th17 cells with underactive anti-inflammatory Treg cells. Th17 modulation is tied to mitochondrial fitness. The Th17 response is thiamine dependent. Thiamine is the rate limiting co-factor to key enzymes involved in mitochondrial energy production, including those at the entry points for the glucose, fatty acid, and amino acid pathways and other enzymes within the TCA/Krebs cycle. Thiamine deficiency derails mitochondrial energy production, shifting it from oxidative phosphorylation and towards aerobic and eventually, anaerobic glycolysis. Even aerobic glycolysis, however, is thiamine dependent. These shifts in energy production are mitochondrial danger signals to the immune cells, including Th17 proinflammatory response. The mTOR proteins, are also involved. When oxidative phosphorylation, glutamine metabolism, and fatty acid synthesis, all which are thiamine dependent, are lagging and energy wanes (e.g. with insufficient thiamine or other mitochondrial nutrients), mTORs energy metabolism becomes anaerobic and pro-inflammatory – e.g. Th17s upregulate and the anti-inflammatory Treg cells downregulate.

Renowned mitochondrial researcher Robert Naviaux would tell us that in both autoimmunity, and in COVID, particularly Long COVID, the mitochondria are stuck in battleship mode; that they lack the energy not only to complete the tasks at hand, but to create more energy. Dr. Lonsdale would tell us that this is because the mitochondria lack the sufficient nutrients to convert food into energy, especially thiamine. From our book, notice how many times thiamine, vitamin B1, is required. Notice also, how many other micronutrients are required to convert food substrates, glucose, proteins, and fatty acids into ATP.

Now consider the high calorie, low nutrient composition of the modern American diet, the metabolic dysfunction associated with the severity and chronicity of COVID, and the range of inflammatory disorders afflicting many of the patients who develop severe and/or long COVID. These are connections that must be recognized.

We know that absent sufficient mitochondrial nutrients, energy wanes. When energy wanes, inflammatory cascades remain unchecked; among them, hyperactive pro-inflammatory Th17 and underactive anti-inflammatory Treg cells. We have to consider also that although pharmaceutical interventions may abrogate that inflammation superficially and temporarily, they do nothing resolve the underlying issue, which is micronutrient deficiency. Since most, if not all, medications damage mitochondria by one mechanism or another, their use, while necessary in some instances, ultimately imperil mitochondrial capacity and exacerbate any underlying energy deficiency as well. So, when we look at folks most at risk for the more severe cases of COVID and/or those who develop symptoms consistent with Long COVID, it is important address the inflammatory response caused by the lack of sufficient energy.

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An Open Letter Regarding Thiamine and COVID

by Robert Olney

Published on March 31, 2021

6773 views

Prior to the US election, in October of 2020, I found that the Biden campaign was interested in emailing me. I decided to try and get this letter setting out my concerns about COVID to Mr. Biden. I have no idea if he saw it or not. It is being published here as an open letter to whomever might consider implementing thiamine therapy in the prevention and treatment of COVID and other disease processes. It has been edited to fit the format of the website.

Dear Mr. Biden,

Greetings from Canberra Australia. I am writing to you because I believe I have something important to say about the pandemic, but find myself in somewhat of a dilemma. It may sound hard to believe but I think you may be the only person who can help.

I want to begin by telling you about Dr. Derrick Lonsdale. He is 96 years old, born in 1924. He began his medical career in England in 1948 and after emigrating to the U.S. spent 20 years practicing as a pediatrician at the Cleveland Clinic, which you visited recently. After leaving there he practiced privately, retiring at the age of 88 in 2013. He has written over 100 published papers. To this day he writes articles and helps people with their health problems through a website called Hormones Matter run by his colleague Dr. Chandler Marrs.

As a result of his experiences at Cleveland Clinic, Dr. Lonsdale became particularly interested in the subject of thiamine deficiency. As you may know, in the same way that vitamin C deficiency is linked to the disease scurvy and vitamin D deficiency is associated with rickets, thiamine, or vitamin B1, deficiency is responsible for the wasting disease beriberi. The common understanding is that this is a disease of the past and of a third world beset by malnutrition, which has been eliminated in the West by fortifying processed food such as flour with thiamine. As such it has seemingly passed out of the collective memory of modern medicine. Dr. Lonsdale on the other hand made the biochemical study of thiamine deficiency his life’s work.

Understanding Thiamine in the Context of Mitochondria

Each of the trillions of cells that make up the body contain mitochondria – self-contained electrochemical machines which take in fuel and oxygen supplied by the blood and use them to generate an electric charge – effectively a battery. This charge is used to supply energy in a chemical form usable by the cell to allow it to function. The other end-products are water and carbon dioxide – this is respiration at the cellular level. The process involves a series of chemical reactions, each reaction requiring the presence of an enzyme specific to that reaction, provided by the mitochondrion. Each enzyme also requires one or more cofactors to be present for the associated reaction to proceed efficiently. These enzyme cofactors are supplied via the blood and are none other than the vitamins and minerals we are all familiar with, particularly the B vitamins – thiamine, riboflavin, niacin, folic acid, B12 and others, and minerals like magnesium, zinc, copper, manganese and iron. If anything interferes with this chemical “symphony”, such as a deficiency of one or more of these cofactors, energy production will be impaired and the cell will not be able to function as it should.

Thiamine has been found to have a particularly important role to play. It acts as a cofactor in five of these enzyme moderated reactions, one of which occurs right at the beginning of the whole process, converting the supplied fuel (glucose) into a form usable in subsequent steps. In one of Dr. Lonsdale’s analogies, thiamine is like the spark plugs in an internal combustion engine (the mitochondrion), igniting the fuel/air mixture, turning the released energy into, in this case, mechanical rather than chemical energy, which is used to propel the car (the cell) forward. If the spark plugs are not working properly (if thiamine is deficient), the car will run poorly, if at all.

It is not hard to see the implications of this. At the level of a human being, thiamine deficiency results in beriberi (meaning “weakness”, or “I can’t”). The cells of the body are unable to provide the energy the body needs to function. If the deficiency is not corrected death may follow. At the cellular level, if a virus or bacterium attacks, or if certain cells start to misbehave, the body has cellular defenses to deal with the situation. But if the cells lack energy, these defenses are likely to fail and the body will be overwhelmed. Drs. Lonsdale and Marrs concern themselves with ensuring the mitochondria are in the best shape possible, identifying anything which affects their performance, such as drugs and other chemicals which might cause deficiencies, or genetic defects, and trying to correct such problems generally by means of nutrition, thus maximizing the body’s natural defenses.

This is where the trouble begins. According to Dr. Lonsdale, ever since Louis Pasteur’s discoveries about microorganisms, the paradigm under which medicine has operated is “kill the enemy”, in other words find ways to kill the bacteria and viruses and wayward cells which threaten us with disease, generally using drugs. The idea of helping to strengthen the natural defenses of the body is dismissed out of hand, on the assumption that the issue of nutrient deficiency belongs to the distant past. As the future commander-in-chief of the armed forces of the United States, if one of your military heads came to you and said that you only need offensive weapons and there is no need to worry about the state of your defensive capability, I’m sure that you would send them on their way. Yet that accurately depicts current medical practice. Dr. Lonsdale has for many years tried to persuade his colleagues that thiamine deficiency in particular is a very real problem of the present and the future, particularly in Western societies, for reasons I will go into, and that much of the disease we see is in fact due to it. For his trouble, he has been resolutely ignored, deemed irrelevant and consigned to history by all but a few. All, that is, except perhaps for the many people he has helped. As he tells it, every time he cured someone orthodox medicine had declared incurable, it was put down to “spontaneous remission”.

How I Found Thiamine

I became interested in this subject because of what happened to my elderly mother, now 90. Early in 2019 she came down with a nasty virus. Prior to that she’d had some health problems but was in pretty good shape overall. She recovered but never really got over it. Her longstanding breathing problems became worse. She started to have digestion problems and was back in hospital a few months later with pancreatitis. Back home, every morning after breakfast she had to sit for a few hours because she felt too weak to do anything. On one occasion she had an attack of vertigo, fell and couldn’t get up again. She was seeing several doctors and they were examining her and doing blood tests and trying different drugs on her but I felt they weren’t really helping her much. I resolved to try and work out what was going on. It wasn’t long before I came across Dr. Lonsdale and the subject of thiamine deficiency. What I learnt was that an event that was stressful to the body such as an infection could trigger a state of thiamine deficiency, and that the elderly were particularly vulnerable. I began to think that this was what happened to my mother.

I also had one or two health issues. In 2010, I was diagnosed with thyroid cancer and had it removed. I had occasional heart palpitation episodes, and remembered hearing that the answer for this was vitamin B1. I also have restless legs syndrome. As a result of this new interest in health, I learned about low-carb diets. Around March 2020 I started on a “healthy keto and intermittent fasting” diet and started taking thiamine regularly, along with magnesium, another essential cofactor which is needed for thiamine to work, and encouraged my mother, and my family, to take it. Purely coincidentally, this was also when the COVID crisis was ramping up.

As I learned more, I began to suspect that there was a connection between thiamine deficiency and COVID and that taking thiamine and magnesium might be protective against it. By this time the world was in lockdown, and I thought this would defeat the virus, so there was no need to say anything. By mid-August it was clear that things were spiraling out of control. Around this time, I realized that Drs. Lonsdale and Marrs were very well aware of what was happening and had done what they could to make it known to the world, but it had fallen on deaf ears. I decided I had to try and do something. Having had very little to do with social media, I started using Twitter to try and tell as many people and organizations as I could about the connection between COVID and thiamine deficiency, and have continued doing so to the present, learning more in the process. Everything I have learnt has only strengthened my conviction. Like them, I have had absolutely no response from anyone in a position to be able to do anything and as far as I can tell I have had absolutely no impact and am not going to. I don’t feel like I can just leave it, so that is why I have now turned to you.

Thiamine and Dysautonomia

In 2017, Drs. Lonsdale and Marrs published a book entitled “Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition”, which more or less represents Dr. Lonsdale’s life’s work. The premise of the book is that thiamine deficiency, beriberi, affects the autonomic nervous system, leading to dysautonomia. The autonomic nervous system controls all of the functions that the body carries out automatically without conscious thought, such as breathing, cardiac function, digestion, sleeping, reacting to stimuli and so on. Basically, this system goes out of whack, resulting in all sorts of strange and seemingly unrelated symptoms particularly affecting the brain, heart, nervous system and digestion. “High calorie malnutrition”, the end result of the typical western diet, is largely responsible.

Beriberi is normally associated with just straight malnutrition or lack of food, and conjures up images of emaciated people. Using the above term Drs. Lonsdale and Marrs are making the point that a diet high in “empty” calories, especially from sugar, but low in micronutrients, predisposes one to the disease, because the available thiamine required to process the fuel is overwhelmed by the amount of fuel being supplied. In terms of the car analogy, the engine is flooded. So the obese could have beriberi. Anyone else nutritionally challenged, such as diabetics, could have it. Basically anyone, young or not, whether they look ill or not, could have it if their nutritional status is compromised. Dr. Lonsdale has for many years been trying to warn us that the Western world is primed for an epidemic of beriberi, waiting for something to come along that would trigger it.

Thiamine, COVID, and an Epidemic of Beriberi

About two weeks after I began tweeting about thiamine, I learned about COVID long-haulers for the first time. These are the people who get over the initial infection, only to find that they continue to have problems for many months afterwards. By now there are perhaps hundreds of thousands in this category. Having learned about the many and varied symptoms of dysautonomia associated with thiamine deficiency, I was stunned to realize that the symptoms of long-haulers, described in an endless succession of media reports as the bizarre and mysterious symptoms of COVID, are exactly the same as those of mild thiamine deficiency. Despite my numerous efforts to point this out, such reports continue to appear to this day. Of course when I checked back with what Dr. Marrs had been saying on Twitter, I found she was already pointing all this out months earlier.

To me the implications of this are enormous. It suggests that the world has completely misunderstood the nature of the pandemic and as a result of this wrong understanding the wrong decisions are being made. While undoubtedly highly contagious, I believe COVID is not the highly novel, pathogenic and virulent virus we are led to believe. Rather it is similar to, but somewhat more severe than, what we have experienced previously, the effect of which has been to unleash an epidemic of, not the version we know from history, but a modern-day equivalent form of beriberi, attributable to our generally poor nutritional status and any other environmental contributors to poor mitochondrial function.

As one example of the decisions being made, one could consider what has been happening in intensive care units around the world. Perhaps the most characteristic aspect of COVID is loss of pulmonary function, known as Acute Respiratory Distress Syndrome (ARDS). While I am no expert, it seems an assumption being made is that to overcome this just requires an increased supply of oxygen by means of a ventilator. Earlier I described respiration as it takes place at the cellular level. In terms of normal combustion everyone knows one needs three things: fuel, oxygen, and a source of ignition. It’s the same at the cellular level – it’s not enough to have glucose and oxygen, you need thiamine to act as the spark plug, followed by the chain of reactions that take place inside the mitochondrion. Perhaps thiamine deficiency, and therefore failure to initiate this reaction chain, rather than lack of oxygen, is what’s really going on. While I could find numerous general references to the use of thiamine in clinical care, when I looked at ICU protocols specifically for COVID promulgated by organizations such as WHO and CDC and in Australia, I did not find any reference to using thiamine.

There are other observations one can make. One of the seemingly mysterious features of the pandemic is that many people who get infected are completely asymptomatic. I interpret this as meaning these people have good nutritional status, and mitochondria that are working efficiently, and their cellular defenses are consequently able to deal with the virus. Also, people with a lower socioeconomic background seem to be more severely affected. This is understandable as they might only have access to cheaper, less nutritious food and are therefore more likely to be in a state of incipient thiamine deficiency when they encounter the virus. And of course, as Boris Johnson learned and as many doctors are starting to understand, a poor diet, despite access to plenty of food, leading to obesity, makes one vulnerable, the answer being to improve the diet, which doctor Lonsdale tells us should be a low carbohydrate, “real food” diet, which even now is not what nutrition guidelines recommend.

Consider Thiamine

This brings me to the main purpose of this letter. In the absence of, or in addition to, a vaccine, I believe that an emergency program of mass daily supplementation with thiamine and magnesium, and a longer term aim of improved diet, could help to protect the U.S. and indeed the world population, from the virus. One might put it as a policy goal of ensuring thiamine sufficiency in the general population. This could provide an alternative to the devastating human and economic consequences of the actions currently being taken or contemplated, whether lockdowns, border closures, or so-called “herd immunity” options. I imagine this would be a very large undertaking, more than just education as this would probably result in all existing supplies vanishing, but presumably much less than the expected vaccination program, given that both micronutrients are well-known, cheap and non-toxic. Of course, all this would need to be verified before taking action. If one can measure the level of intracellular thiamine sufficiency or deficiency in the body it should be straightforward to test hypotheses, e.g. that long-haulers are in a state of deficiency, that those who were asymptomatic have a good level of sufficiency, and so on. One difficulty with this is apparently that because of the lack of interest in this subject there is currently almost no laboratory where such measurements can be made.

The Stress of Illness

It was only a couple of weeks ago that I realized Dr. Lonsdale actually made this suggestion himself. In an article published on March 20, 2020 on the Hormones Matter website, entitled “What Can Selye Tell Us About COVID-19? Survival Requires Energy”, he said:

We believe that we have shown evidence that thiamine and magnesium supplementation are inherently necessary in a population in which nutrition is imperfect. … Moreover, if we consider the requisite ‘energy’ required to stave off any illness, might we also consider bolstering the nutrient stores e.g. host defense in at-risk populations, as a way to reduce the risk and severity of the illness? Doing so may help ensure the adequacy of energy in meeting the unseen enemy.

You will recall that this was right at the beginning of the period when deaths started to ramp up in the U.S. One wonders how different things might have been if he had been listened to.

The biggest challenge, however, could lie elsewhere. This pandemic has brought us to an extraordinary place. Suppose that Dr. Lonsdale is right. This gives rise to an incredible dichotomy. On one side there is 96 year old Dr. Lonsdale, who has few resources and at his age may not be in a position to advocate for himself, but who with a vast amount of experience behind him has a simple idea that explains an awful lot, including many diseases which medical orthodoxy cannot explain or treat, which therefore get labelled psychosomatic. He has a proposal which is easily testable, could easily be trialled, is simple and relatively cheap to implement, and could have enormous health and economic benefits. Without going into details, it could potentially lead to generally improved mental health, reduced levels of crime and reduced vulnerability to virtually all forms of disease, including viral threats that we have yet to encounter, with consequently greatly reduced health costs and productivity benefits for all economies. This would usher in a science based health renaissance, the likes of which has never been seen before.

On the other side is the entire medical establishment with its vast resources, having an entrenched position, which is unable to, indeed cannot afford to, so much as entertain the possibility that Dr. Lonsdale could be correct. You also have the pharmaceutical industry pouring billions into drug development and searching for a vaccine. A vaccine may well be found, which might head off this crisis of credibility. Or it may not. Or the virus may mutate regularly, rendering a vaccine next to impossible as with cold viruses. One thing to note is that, if the pandemic at its core is the result of a nutrient deficiency, then no drug or combination of drugs that does not correct the deficiency can possibly overcome it. On top of that, you have the food industry with its vested interests in keeping the world hooked on its cheaply made, highly addictive products based on sugar and processed carbohydrates, which Dr. Lonsdale tells us lies at the core of the problem. The pandemic is forcing us to face the inconvenient truth that this entire edifice may be unsustainable.

I’m sure you can appreciate why I think you may be the only person who might have a chance of getting us from where we are to where we could be. I’m sure you would have people to advise you on health matters. If Dr. Lonsdale is right, and you ask them for advice on this, it seems likely they will just dismiss the entire notion out of hand. If we are to avoid unthinkable levels of human and economic loss, you may have to shake the foundations of the medical establishment to its very core, to get it to accept that we need defense as well as offense in order to successfully do battle with the invisible enemy.

In the end, it may simply be a matter of going back to where it all began – back to Hippocrates, who, as Dr. Lonsdale likes to remind us, said “Let food be thy medicine and medicine be thy food.”

A Few Final Observations

I hope you get to meet Dr. Lonsdale. I strongly suspect the fact that he is still active at such an advanced age is not an accident. I imagine he has been taking his own advice. I would not be at all surprised to learn that he has lived most of his life without any significant disease. I would very much like to see him get the recognition he deserves before he dies.

If I’m right about thiamine deficiency leading to weakness in the response of cellular defenses, this could have an impact on the effectiveness of any vaccine that may be developed, since it has to piggyback on the existing cellular mechanisms. It may turn out that the underlying problem of thiamine deficiency has to be recognized and addressed even if a vaccine is produced.

I am very much a layman, so am not someone from whom to seek advice. If I hear that you are interested in pursuing this I will let Dr. Marrs know. She would be the best person to contact in the first instance.

Lastly, it seems to me that, if dealt with wisely, this has the potential to demolish the foundations of the incredible tower of disinformation that besets the American people and bring it crashing to the ground, perhaps ushering in a new, sorely lacking respect for science. Exactly how and when that might be brought about I have no idea. I’ll leave that up to you.

Good luck in your new adventure.

Robert Olney

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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COVID Notes: Considering Drug Induced Mitochondrial Damage

by Chandler Marrs, PhD

Published on March 15, 2021

4977 views

COVID notes drug induced mitochondrial damage

Much has been written about the associations between COVID severity, chronicity, and pre-existing conditions. Top among those conditions include cardiovascular disease and diabetes, likely type 2, but both are lumped together. What has not been discussed is why this would be the case. On a basic level, fighting two illnesses takes more energy than fighting one. This is obvious. What is not obvious is that many modern illnesses, especially cardiovascular disease and type 2 diabetes, begin in the mitochondria as a consequence of diet and lifestyle. Statistically, 80% of cardiovascular disease and 78-83% of type 2 diabetes can be traced back to longstanding dietary, lifestyle and environmental issues* that effectively diminish mitochondrial energetic capabilities and disrupt metabolic flexibility; and the remainder that did not originate from diet and lifestyle are certainly affected by these variables.

To function effectively and to convert the foods we eat into energy or ATP, the mitochondria require sufficient vitamins and minerals, 22 of them, in fact. Western diets, while high in calories, are woefully low in these micronutrients, even when fortified, creating what we refer to as high calorie malnutrition. Against this dietary backdrop, reduced ATP then leads to a constant, low level molecular hypoxia. This is not a hypoxia of obstruction or exertion, but more fundamental. For without proper nutrients, mitochondria can neither utilize oxygen effectively to create ATP, nor do they have sufficient ATP to traffic the O2 into the hemoglobin where it can be pumped into circulation to feed tissues and organs. It is a subtle desaturation, at least initially, but one that initiates all sorts of compensatory reactions to mitigate risk; reactions that are necessary and lifesaving in the short term but become increasingly harmful as time passes.

With insufficient ATP, inflammatory and immune reactions become disrupted and even seemingly chaotic; hormone and electrolyte regulation becomes imbalanced and organ and brain function diminishes. We get disrupted autonomic function (dysautonomia), which cycles back and further disrupts everything else. Depression, anxiety and other mental health issues are also common. This underlying mitochondrial distress is part of the reason why patients with comorbid conditions are at increased risk of not only developing but succumbing to COVID, or really, any virulent pathogen. Their mitochondria are already taxed. They are already carrying low-level hypoxia and, in a very real way, they simply do not have the energy to mount or manage a successful defense.

Now, to add insult to already injured mitochondria, we prescribe medications to manage these conditions rather than correct the root cause, which remember is mitochondrial distress. These medications, while they effectively provide the semblance of health, likely cause more damage to an already damaged system. That is, we get more normal labs, or in the case of antidepressants or anxiolytics, we may feel better, but they do nothing to correct the problem. They only exacerbate it further.

An Unappreciated Factor in COVID Severity and Chronicity

A little appreciated fact in medicine, all pharmaceuticals damage mitochondrial function by some mechanism or another. I have published extensively on this topic here on HM and in our book. Sometimes they deplete critical micronutrients and other times they directly distress, damage and/or deform the mitochondrial membrane by forcibly overriding the regulation of key enzymes involved in ATP production. This, of course, is often compounded by poor nutrition and nearly continuous exposures to chemical toxicants in the environment. It is a perfect cycle of destruction. Poor nutrition causes poorly functioning mitochondria, which decreases ATP while increasing cell level hypoxia, which then initiates inflammation and alters immune reactivity, and rather than correct this, we prescribe medications to override what are necessary reactions to poor nutrition and environmental exposures. These medications then elicit additional damage, further decreasing mitochondrial efficiency and ATP, which necessitates extra nutrients to maintain ATP and stave off more damage.

When we consider the association between COVID severity and comorbid health issues, it must be against the backdrop of nutrition and pharmaceutically and environmentally induced mitochondrial damage. The only variables we can control directly are nutrition and pharmaceutical exposures. We can add more nutrition and we can apply medications more cautiously, but more often than not, we choose to do neither. We ignore nutrient status and stack medications on top of each other endlessly, all the while wondering why the patient’s health continues to decline.

Common Drugs Block Vitamins B1, B9, B12, and CoQ10

To illustrate the state of drug-induced mitochondrial hypoxia that plague so many of the patients threatened by COVID, let us look one common medication that as of 2017, 78 million Americans were taking: metformin. Metformin damages the mitochondria by multiple mechanisms that ultimately lead to reduced ATP, entrenched molecular hypoxia, inflammatory cascades and altered immune reactivity. This, of course, is in addition to the neurological sequelae.

Perhaps the most critical nutrient for in mitochondrial health is thiamine. Thiamine, is blocked by metformin. Metformin blocks vitamin B1 – thiamine – uptake by multiple mechanisms. When metformin is present, a set of transporters that normally bring thiamine into the cell to perform its task as a cofactor in the machinery that converts carbs to ATP, brings metformin into the cell instead, replacing thiamine altogether. The transporters involved are the SLC22A1, also called the organic cation transporter 1, [OAT1] and the SLC19A3. Metformin also blocks the lactate pathway and acetyl coenzyme A carboxylase (an enzyme necessary to process fatty acids into fuels). Thiamine is critical for mitochondrial function and its position as gateway substrate into the each the of the pathways leading to the electron transport chain, means that insufficient or deficient thiamine limits ATP production, induces cell level hypoxia and all of the inflammatory cascades that go with this process.

Metformin also depletes vitamins B12 and B9, which are responsible for hundreds of enzymatic reactions and particularly important in central nervous system function including myelination (how many cases of diabetic neuropathy or multiple sclerosis are really vitamin b12 deficiency?) One study found almost 30% of Metformin users were vitamin B12 deficient. For the US alone, that’s 26 million people who could be vitamin B12 deficient and likely do not know that they are deficient. What happens when one is B12 deficient? Inflammation increases, along with homocysteine concentrations, which is a very strong and independent risk factor for heart disease (the very same disease metformin is promoted to prevent). What else happens when B12 is deficient? Poor iron management, better known as pernicious anemia.

Metformin tanks CoEnzyme Q10 which effectively cripples mitochondrial ATP production even further, by as much as 48% in muscles. Imagine having to function in such a reduced capacity. Now imagine having to fight a deadly virus or recover from one. Finally, if the reductions in nutrients and ATP weren’t sufficiently troubling, metformin also interferes with the body’s innate toxicant metabolism pathways, the P450 enzymes, rendering those who use this drug less capable of effectively metabolizing a whole host of other medications and environmental toxicants.

This is one medication. Very few adults who go down this pathway are prescribed just one medication. With metformin, one is likely also to have a statin, perhaps a blood pressure medicine, and if the patient is a women, some form of birth control or hormone replacement. Many are also on antidepressants or anxiolytics. Statins, for example, severely deplete CoQ10, further crippling the electron transport chain. Synthetic hormones deplete a whole host of nutrients (thiamine, riboflavin, pyridoxine, folate, vitamin B12, ascorbic acid, and zinc) while damaging mitochondria via multiple mechanisms.

Long COVID and Medication

Just as the use of medications leading up to and during the illness impact the functioning of one’s mitochondria, the use of medications across time, as one recovers from the infection, will negatively impact mitochondrial capacity as well. This, of course, is in addition to the demand COVID itself places on mitochondrial energy capacity. Data suggests that at least 10% and upwards of 80% of COVID survivors have lingering symptoms. Among the most common are fatigue, brain fog, muscle pain and weakness, and breathing difficulties along with an array of dysautonomias. These are classical indicators of ailing mitochondria and yet common treatment protocols involve more of the same medications and none of the nutrients needed to support them. As we go forward and recover from the COVID pandemic, I think it is incumbent upon us to look at mitochondrial health more closely.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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*Environmental issues should be considered as the totality of chemical exposures from environmental, agricultural, industrial, and pharmaceutical sources. Environmental exposures damage mitochondria and should not be excluded as contributing factors to illness.

COVID Notes: Ca2+ and Heart Function

by Chandler Marrs, PhD

Published on January 14, 2021

3998 views

I have been looking into calcium (Ca2+) management and heart function after reading a report where a Ca2+ storm was identified in COVID infected cardiomyocytes. I am not convinced that the calcium storm or the heart damage found by the researchers was unique to COVID infected cardiomyocytes or any other cells, but may simply represent a final common pathway of impending mitochondrial collapse. I am working on a more comprehensive paper regarding the intricacies of the Ca2+ management by the mitochondria in the heart, but that will take a few more weeks to finish. In the meantime, I have found some interesting connections regarding calcium, magnesium (Mg+), caffeine, thiamine, and the mitochondria that I would like to share. Here are some notes from a paper entitled: Independent modulation of the activity of alpha-ketoglutarate dehydrogenase complex by Ca2+ and Mg2+.

Calcium, Magnesium, and ATP Production

Ca2+ activates oxidative phosphorylation (OXPHOS) at physiological concentrations but inhibits it at supraphysiologic concentrations. OXPHOS refers to the enzymatic conversion of food into energy (ATP) by the mitochondria. Adequate ATP is an absolute necessity for life. That means that the Ca2+ storm, proposed by SARS-CoV-2 direct cardiac damage through spike-mediated cardiomyocyte fusion, would effectively shut down mitochondrial function completely, which in turn, could be considered the cause of death.

The relationship between Ca2+ and Mg+ is particularly interesting when one considers this tidbit of information.

…we show that the effect of Mg2+ on KGDHC [alpha-ketoglutarate dehydrogenase complex – a key mitochondrial enzyme involved in ATP production] activity depends upon the presence of thiamine pyrophosphate [TPP]. In the absence of TPP, Mg2+ inactivates whereas Ca2+ stimulates the enzyme’s activity.

Among the reasons I find this interesting is that many health protocols favor high-dose magnesium supplementation often chronically and almost always absent thiamine. In the absence of thiamine, high-dose magnesium therapy presumptively would derail OXPHOS, which, as part of the major energy pathway of the mitochondria, would create problems with Ca2+ management in the cardiomyocyte, potentially exacerbating heart function. Indeed, the absence of the thiamine alone will cause these problems, but when combined with high dose Mg+ therapy, we would potentially exacerbate this cascade. I cannot help but wonder if these high-dose magnesium protocols aren’t doing more harm than good as far as mitochondrial and heart function are concerned.

Additionally, magnesium competes with Ca2+ at the ryanodine receptor (receptor on the sarcoplasmic reticulum [heart version of endoplasmic reticulum] that sequesters intracellular Ca2+) to inhibit the release of intracellular Ca2+. Magnesium counteracts Ca2+ activation/release suggesting that the use of Mg+ to temper these reactions to Ca2+ might be warranted in some cases, particularly where deficiency is present. However, it also suggests that in the absence of sufficient thiamine, magnesium will inactivate the KGDHC, which will imperil ATP production and ultimately lead to poor Ca2+ management; a key factor in heart failure.

Caffeine and Sodium

Caffeine increases the sensitivity of the ryanodine receptor – meaning less Ca2+ is required to open the receptor and release Ca2+ stores. Given how many of us are addicted to caffeine, this is problematic. Doubly concerning when one considers how many folks are not only addicted to caffeine but also deficient in key micronutrients like thiamine, the other B vitamins as well as in magnesium and even calcium. Insufficient micronutrients coupled with regular and usually excessive caffeine intake would negatively impact heart function and may be at the root of much of the cardiovascular disease and dysfunction experienced by vast swaths of the population.

As one might expect, an overload of Ca2+ stimulates mitochondrial permeability transition pore (mPTP) opening and mitochondrial swelling, resulting in mitochondrial injury, apoptosis, cardiac remodeling, and ultimately the development of heart failure. The cascade includes excessive ROS which then creates a demand for more energy/ATP to resolve. Since, in the absence of thiamine, magnesium inactivates KGDHC, and KGDHC is both a rate-limiting step in ATP production, but also performs anti-oxidant duties, this pattern can easily become a death spiral. Caffeine expedites this process.

Finally, the main outward pump of Ca2+ from the mitochondria is not only ATP dependent but also requires sufficient sodium (Na) because for every 1 molecule of Ca2+ kicked out of the mitochondria, 3-4 Na’s are pumped in. Here too, I cannot help but think this process is disturbed by the low sodium intake promoted by heart health advocates.

How Does This Affect the COVID Heart?

If the report that initiated this search SARS-CoV-2 direct cardiac damage through spike-mediated cardiomyocyte fusion is correct and COVID, like other viral infections, infects the heart causing dysregulation of Ca2+ management, which impairs mitochondrial OXPHOS, which further impairs Ca2+ management, then we ought to be considering giving COVID patients thiamine. Indeed, I have argued throughout this pandemic, we ought to be utilizing thiamine and supporting mitochondrial function more aggressively. This is just one more reason.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, and like it, please help support it. Contribute now.

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COVID Notes: A Calcium Tsunami in COVID Infected Cardiomyocytes

by Chandler Marrs, PhD

Published on November 30, 2020

8100 views

In July 2020, I became ill with what may have been something related to COVID, or not, as there was no testing that was easily available to confirm. The illness affected my heart function. Since then I have been following the research on COVID-related heart damage. Over recent months, several studies have been published showing the mechanisms of viral-related heart damage. It appears that viral heart infection is not exclusive to COVID. So it is entirely possible that what I experienced was not COVID, but just some random and bizarre viral infection. Nevertheless, my experience was odd enough that it may be of use to someone and so I am publishing it here along with some thoughts on potential mechanisms.

Some Background

I am a 53-year-old, generally healthy, though overweight by traditional standards, powerlifter with several world records in my federation, age, and weight class. I train 4-5 days per week and have for the last several years. Before that, I did Crossfit and before that, I played water polo for decades. Physical fitness has always been a part of my lifestyle. I eat healthy, and largely organic, and I don’t drink or smoke. I have not taken any medications in over a decade, not even ibuprofen. Although as a young woman, I, like so many young women, inhaled ibuprofen on a monthly basis along with a laundry list of other medications prescribed by physicians. My one remaining chemical vice pre-infection was a cup of iced coffee every morning after workout. Now, post-infection, I cannot tolerate even a minimal amount of caffeine.

As the pandemic was approaching, we purchased some home gym equipment and put a gym in our living room to keep training. We have continued to train at home throughout. For the first few months, we rarely left the house. Prior to the closures, I would access a variety of bodywork modalities to help my body maintain its ability to lift heavy and to manage longstanding neck and shoulder injuries. This included regular massage and several different forms of chiropractic care. With the closures, I did not access these services for months and it was taking a toll. In May, I began accessing some chiropractic care again. At the end of June at one particular appointment, I think I was exposed. A few days later, I became ill, but not in the traditional manner described by the media or the studies.

Asymptomatic COVID or Something Else?

It began with odd bouts of breathlessness when climbing stairs or doing normal everyday activities. Since I had no fever or cough and felt fine, I went on with life. A few days passed and just before we were to drive to our cabin for some rest and relaxation, I developed lower GI symptoms such that I remained home. That also passed within a few days and I thought whatever it was had resolved. I was wrong. Soon after, absolute exhaustion hit, and my blood pressure and heart rate climbed. Over the next few weeks, I battled increasingly high blood pressure (150-160s/110-120s), heart rate (90s – my normal is in the 50s), edema, and pounding pressure in my head. I had no fever but experienced intense hot flashes or flushing. My pulse ox remained in the mid-90s throughout. It felt like everything was out of sync, including my autonomic system.

Among the oddest experiences were the episodes of pressure, swelling, and blood pressure spikes. I would get these seemingly random bouts of pressure in my head and heart. I would be sitting or standing, it didn’t matter, and all of a sudden everything would go haywire. I could watch my hands and feet swell up multiple times their normal size over a matter of minutes. The pressure in my head would increase, and along with it, my blood pressure would spike. On several occasions, I worried that I would stroke out or have a heart attack. Additionally, my pulse was irregular and thready. My heart fluttered and skipped beats. I could feel the missed beats and arrhythmic patterns through the blood pressure cuff. Needless to say, I could not function for several weeks and mostly slept, well more than normal.

I could not work out the first week at all. I could barely stay awake. The second week, I could lift a little, but had to rest for several minutes after each very light lift. I would become out of breath, my heart would pound out of my chest and pulse through the back of my skull and neck. Again though, my O2 levels per the pulse oximeter were fine. My heart rate was high for me, but otherwise fine. My blood pressure was not, so I was very careful. During this time, I could not put a barbell on my back to squat. When I did, it felt as if there was just too much pressure in my head. It was horribly disconcerting and harkened thoughts of stroke. It took about 5-6 weeks before I could put the barbell on my back without the excessive pressure and return to some semblance of a normal but light workout. It took another few weeks before I could do any volume.

While all of this was happening, I still took no medications, except aspirin periodically to thin my blood in the event I was potentially clotting. I continued my normal regimen of 200mg of Allithiamine. I may have upped it to 300mg a few times. I upped my magnesium from 100-200mg per day to ~400mg depending upon the blood pressure. When my pressure spiked, I would pop a magnesium or two to bring it down a bit. I began taking fish oil again, about 2 grams per day. I continued my normal multi-vitamin along with extra vitamins A, D, and K2 and added 1-2 g of vitamin C. I had been taking a zinc, and copper combination since March as well.

At about 3 weeks in, I sought more specialized chiropractic care where the practitioner adjusts the atlas. I had used it previously before everything shut down and hoped it would help relieve some of the pressure in my head and neck. Soon after, I also began acupuncture to help clear some of the edema and manage my blood pressure better. Over the next several weeks, everything gradually improved. It was probably 8+ weeks or so before I felt more normal, before the edema subsided completely, and everything stabilized.

The experience was so strange though that I am not sure what exactly happened. Was this what might be deemed an asymptomatic or mild expression of COVID or some other viral infection? Because I was not able to be tested I’ll never know but in recent weeks research has come out detailing more of the mechanisms involved in COVID-related heart infections. One particular study struck me as a possible mechanistic explanation of what I imagine might have been happening. This study, together with some insight into mitochondrial function, suggests a picture of heart stress, provoked by the virus that was functionally similar to wet beriberi despite the fact that I was taking thiamine. I suspect the mechanism identified in this study against the backdrop of the individual’s underlying mitochondrial fitness may determine COVID morbidity and mortality in cases where the heart is preferentially affected.

The Ca2+ Tsunami in COVID Infected Cardiomyocytes

The study, SARS-CoV-2 direct cardiac damage through spike-mediated cardiomyocyte fusion, involved a series of experiments investigating the physiological and electrochemical properties of COVID-infected cardiomyocytes. The cells were derived from an autopsy of a 35-year-old woman who died suddenly in her sleep. She was three months postpartum and in the week prior had experienced mild fever, and cough, and had been light-headed but no other symptoms. At autopsy, she tested positive for COVID but per the report had no evidence of lung infiltration. To clarify the cause of death, myocardial cells were examined. What they found was that while the virus had not affected her lungs, viral proteins were identified in her the cells of her heart.

Through a series of tests and experiments, the researchers discovered that the viral proteins infected the electromechanically coupled cardiomyocytes building a bridge between cells, such that the virus was able to disturb the electrical potential/rhythm of the heart muscle. These cell-to-cell conduits then provided the

…pathoanatomical substrate for aberrant electrophysiological activity, electro-mechanical dysfunction, and fatal arrhythmia.

Additionally, they found that the altered electro-physiology in the infected cells was marked by prolonged action potentials, delayed after polarizations, and erratic beating frequency e.g. notable dysrhythmia. Importantly, they observed a pathological calcium (Ca2+) flux, which they describe as ‘tsunami-like waves’.

We suggest that SARS-CoV-2 spike glycoprotein-induced membrane changes directly injure CMs [cardiomyocytes], heightening cardiac arrhythmia risk even at low viral load and in the absence of widespread lymphocytic myocarditis-mediated tissue destruction.

The low viral load and the Ca2+ tsunami are what struck me most. Could it be that in some individuals, who are predisposed either genetically or epigenetically, the virus preferentially affects heart cells largely bypassing the lungs? In this case, a low viral load would be sufficient to cause problems, particularly, if the mechanism identified in this case holds. While it is clear that viral-infused cardiomyocytes would wreak havoc on the electrical potential of the heart, a sudden influx of calcium, well, that could be deadly, particularly if, as the report suggests, the cardiomyocytes are fused. The electrical potential would quickly overwhelm the cells’ ability to re-establish rhythm.

COVID, Calcium, and Cardiac Function

Backing up just a bit, the activity of cells like the cardiomyocytes, neurons, and muscles, is dependent upon a tightly choreographed series of changes in ion flux. See figure 1. With stimulus, sodium (Na+) channels open and Na+ floods the cell. This is the action potential mentioned above. Immediately following Na+, potassium (K+) channels open and K+ flows out, slowly at first and then more quickly as more channels open, and with it, Ca2+ comes rushing into the cell. The outflow of potassium prevents additional repolarization for a brief period while the buildup of Ca2+ feedbacks and eventually closes the Ca2+ channels. All of this happens within milliseconds and is highly regulated. If the timing is off or any of these ions are out of balance, arrhythmias develop.

COVID Notes - calcium heart function — Figure 1. Action potential of the cardiomyocyte.

Of these ions, it is the Ca2+ influx that is responsible for signal transduction, for setting into motion pathways that tell the cell how to respond to external and internal stimuli. As such, calcium homeostasis is of critical importance for cell function. A rapid influx of supraphysiological levels of Ca2+, as was evidenced in the study above, would induce a hyper-contractible state, disturb the timing of the electrical signals, and eventually, completely overwhelm the capacity to clear the excess, invoking apoptotic and necrotic death pathways depending upon mitochondrial ATP availability. Each of these markers has been found in the COVID-infected heart. These same disturbances may be also found in a condition called wet beriberi – thiamine deficiency that affects the heart. Similarly, cardiomyopathy, dyspnea (breathlessness), and elevated troponin, other common findings attributed to the COVID heart, are also associated with cardiac beriberi. Given my research on thiamine deficiency/beriberi, I cannot help but wonder if what we are seeing in COVID heart patients is some manifestation of the same process.

Although electrochemical research on both COVID and thiamine deficient myocardial function is lacking, as much of the research appears to focus on gross morphological changes mediated by inflammatory infiltrates, and we do not know if the Ca2+ tsunami identified in the aforementioned study is common across both disease processes, it is logically possible. Inasmuch as mitochondria provide the energy substrate that permits contraction and relaxation of the cardiomyocyte as well as Ca2+ management and sequestration, mitochondrial function may sit at the nexus of virally mediated cardiac events. To the extent that thiamine is critical for each of the key pathways involved in ATP production, insufficiency would impair these actions. And finally, since mitochondrial fitness is unique to the individual, this might explain why, even when there is clearly visible cardiac damage, symptom expression is mild or absent altogether in some individuals but deadly in others. This may be what is happening with athletes who are COVID positive and display limited symptomology but develop myocarditis. This may have been the case with me as well. Again though, without proper testing, this is speculation on my part. Nevertheless, the Ca2+ tsunami aptly describes a potential underlying mechanism for what I experienced.

If this turns out to be correct, the questions then become 1) why does COVID preferentially affect the heart and not the lungs in some individuals, 2) are the mitochondria the determining factor of severity and survival, and if so, 3) are there things we can do to support the mitochondria and maximize survival? While I do not know the answer to question 1, I have argued from the beginning of this pandemic that the determining factor in COVID morbidity and mortality comes down to mitochondrial fitness. To the extent mitochondrial fitness is determined by nutrient availability, thiamine especially, the answer to question 3, is yes, we can do something to improve outcomes. In a subsequent post, I will explore these questions more closely.

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COVID - Page 2

Background on Traditional Chinese Medicine

Traditional Chinese Medicine and Covid-19

Effects Are Strongest With Early Interventions

What Might Be the Mechanisms at Work?

What Could All of This Mean?

Additional Notes

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Study Details

Results

Things to Consider

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The Inflammatory Reflex

Cytokines and Covid-19

Nutrition, Immunity, and Autonomic Function

Covid-19, Cytokinemia, and Thiamine

Consider Thiamine for Covid-19

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Thiamine, COVID, and an Epidemic of Beriberi

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The Stress of Illness

A Few Final Observations

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An Unappreciated Factor in COVID Severity and Chronicity

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Some Background

Asymptomatic COVID or Something Else?

The Ca2+ Tsunami in COVID Infected Cardiomyocytes

COVID, Calcium, and Cardiac Function

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