Thiamine, CO2, and restoring energy balance

I read something a while ago that I still think about surprisingly often...

I came across a random post where someone commented that they had been taking vitamin B1, thiamine, and had noticed that their "luck" seemed to have increased while taking it. I've since tried to find the post again and it seems to have been deleted, but it got me thinking.

This line of thinking raises some interesting questions for me, particularly because I'm inclined to agree! Thiamine does seem to increase luck in some sense, but the question is why?

I'll come back to this idea later. First, I want to discuss something else, the question of how megadoses of thiamine work to provide such unique benefit. The RDI for thiamine is set at only 1.2mg daily, so why wouldn't 100mg have the same benefit as 1,000mg given that they're both exponentially more than this?

In my previous article on thiamine I touched on one common explanation seen in the research, that in many conditions such as alcoholism or diabetes thiamine transport might be impaired causing poor absorption. With oral intake it is possible gut absorption could alter this as well, similar to the higher risk of B12 and other B-vitamin deficiencies in IBS.

In these cases, it's likely that IV thiamine injections or very high dose supplements are necessary to reach the same level of effect. A high enough dose could bypass the deficient transporters and allow thiamine to pass into cells via diffusion, particularly with the fat-soluble forms like benfotiamine or TTFD.

In this article I want to expand on these concepts, and introduce a few new mechanisms which I have come to believe may be just as crucial in the benefits seen from megadoses of thiamine.

Thiamine metabolism

 

Once this thiamine enters the cell it would allow the cell to upregulate activity of key enzymes and pathways. Notably thiamine is a cofactor for both transketolase and pyruvate dehydrogenase. These are two of the most crucial steps in feeding the byproducts of glycolysis (glucose metabolism) into the TCA cycle and electron transport chain. To put it simply, without thiamine our mitochondria cannot properly use glucose as a source of protons and electrons to fuel ATP production.

Impaired glucose oxidation is a significant issue in underlying disease pathology. When cells are unable to maintain proper flexibility between glucose and fatty acid oxidation metabolism as a whole is impaired. The diseases particularly associated with impaired glucose oxidation are those that thiamine has shown clinical usefulness in treating, such as type 2 diabetes and alcoholism.

Thiamine is also a central cofactor in the creation of acetyl-coa from both beta oxidation and amino acid/ketoacid metabolism. Acetyl-coa is the cornerstone of the acetylation processes I laid out in a previous article.

While clinical thiamine deficiency is very common in these disorders, mild deficiencies likely occur at a much higher rate in the general population (similar to magnesium deficiency).

 

This chart is an excellent overview of some of the crucial elements of thiamine metabolism. The main thiamine transporters in the gut, bloodstream, and cells, are THTR1 and THTR2. These are believed to be impaired in certain diseases, and this is why fat-soluble thiamine analogs are so potent compared to regular thiamine. For example, benfotiamine is absorbed about 5x better than thiamine hydrochloride.

Once thiamine enters cells lining the gut or elsewhere in the body it enters a state surprisingly similar to that of ATP. In its activated form it can also collect a chain of up to three phosphate bonds, where the phosphate groups are donated to it from ATP. There are also dephosphorylating enzymes (ACPP and THTPA) that convert thiamine back to either its "free" or diphosphate group state.

In essence, phosphate groups are constantly being cycled between ATP and thiamine within the cell. The strangest aspect of this cycling is that the triple-phosphate form (TTP) does not have a clear known function as far as I can find.

The diphosphate form (TPP) is used as a cofactor for the various enzymes I have mentioned such as transketolase and pyruvate dehydrogenase. (In the graphic above the thiamine-dependent enzymes are highlighted in purple.)

However, TTP levels are tightly regulated within the cell suggesting an important role. One paper I found briefly mentions TTP having an effect on chloride channels, but I was unable to find much info on its other possible roles.

This brings us to an interesting question. Does activated thiamine possess a "high energy phosphate bond" similar to ATP? I think so, however this deserves some clarification.

Thiamine and the high-energy phosphate bond

First off, I think the term "high-energy phosphate bond" is misleading in some sense. In the 1950's and 1960's two researchers, Manuel Morales and Richard Podolsky, published several papers laying out thermodynamic calculations for the free energy released by the breaking of the phosphate bond chain of ATP.

This paper is a good summary of their work. It points out several things, but most notably that ATP contains no more potential stored energy than any other molecule with a chain of multiple phosphate groups! They point out that the idea of ATP as a uniquely "energy rich" molecule is a fallacy, and that while the phosphate groups are still a source of stored energy, ATP is nowhere near potent enough to act as the sole source of energy for the cell.

Their work is also a key component of Gilbert Ling's Association-Induction hypothesis. I've touched on this before, but I plan to write an in depth overview of his work soon as well. Ling believed that the idea of ATP-dependent "pumps" as the sole regulators of mineral balance within the cell made little sense. He even went so far as to suggest that the real role of ATP was to unwind proteins through donating phosphate groups to them

 

Ling suggested that by unwinding these proteins, the amine and carboxyl groups in the proteins structure would then organize water between the proteins making it more coherent. Ling also suggested that rather than ion pumps pulling sodium, potassium, etc., in and out of the cell that these opened proteins would have affinity for certain ions causing the cell to reach an equilibrium, with more potassium/sodium for example.

When we look at the triphosphate form of thiamine in this context it is difficult to believe there isn't something deeper going on here. Especially given the fact that its only researched function as far as I can find is it's ability to influence ion channels.

Whether or not you believe that ATP's primary role is the storage of energy, it certainly does have the ability to do this as well. This works because of the electrostatic repulsion of the phosphate groups, meaning that the creation of ATP is one of the ways cells work against entropy.

There are other widely recognized phosphate-bond energy storage molecules in biology. These include the less common guanosine triphosphate (GTP) and cytosine triphosphate (CTP), both of which possess the same nucleotide and ribose base as ATP. There is also the well-known creatine phosphate, which stores energy by setting aside one of the phosphate groups from ATP. This phosphate group can then be donated back to create ATP when the cell's reserves run low. In invertebrate organisms, arginine phosphate serves a similar function to creatine phosphate in mammals.

Given the array of phosphate energy stores in biology, I think it makes sense to add thiamine triphosphate to this list. It may act directly on proteins or ion channels similar to ATP, or it may act as a "reserve" for phosphate groups that can then be donated back to make more ATP as needed similar to creatine phosphate.

This just adds further to the significant benefit to energy levels and metabolism seen with high dose thiamine supplementation. I really hope this particular form of activated thiamine gets the attention it deserves in the research field.

The nature of CO2

This brings us to our second unique mechanism of thiamine in the body, its ability to increase both CO2 creation and retention.

CO2 is highly beneficial for life in general. It acts as a stabilizing agent, scavenging free radicals into various non-toxic acids (source). It is also protective of proteins containing the reactive ferrous form of iron, preventing Fenton reactions. One paper even calls it a "universal inhibitor of the generation of active oxygen forms."

Perhaps the best example of this property in history is the first major extinction event on Earth, known as the Great Oxidation Event.

At this time early forms of photosynthesis were thought to be used, but they were primarily using the vitamin A analog retinal which absorbs green spectrum light. This photosynthesis did not produce oxygen as a byproduct, though retinal would go on to play a key role in vision instead. When other bacteria developed the ability to use porphyrins to capture more broad spectrum light energy, they quickly flourished producing oxygen as a byproduct.

This shift in the biosphere quickly increased the oxygen level, first in the ocean then in the atmosphere as a whole. The issue with this was that early anaerobic organisms had no preparation for the high reactivity of oxygen vs. other gases like CO2 and nitrogen. They were also relying heavily on using transition metals like iron and copper as cofactors for redox reactions. These metals oxidize and create free radicals very easily in the presence of oxygen.

The bacteria lost the stabilizing environment of a high CO2 atmosphere in favor of a reactive oxygen rich environment. The result was that around 80% of life on earth died off by the end of this atmospheric shift. The bacteria that survived and learned to utilize oxygen through aerobic respiration, and to buffer themselves with appropriate antioxidants, went on to become our cells and mitochondria.

Beyond its stabilizing effects on various organisms, there are a few other effects of carbon dioxide that are important to understand. Two that are particularly key are the Bohr effect and the Haldane effect.

 

The Bohr effect was originally discovered by Christian Bohr, who observed that as blood became more acidic or as CO2 concentration increased, oxygen's binding affinity to hemoglobin was reduced. For example, during exercise when more CO2 is released by tissues it will cause more O2 to dissociate from hemoglobin allowing more oxygenation of tissues.

You'll also see the shifts back and forth between carbonic acid (H2CO3), the stored form of carbon dioxide produced by its combination with water, and bicarbonate (HCO3-) which is produced as carbonic acid is broken down. It is this breakdown of carbonic acid that increases acidity (free protons/H+ are a marker of acidity) with bicarbonate as a byproduct. CO2 itself is also a Lewis acid.

This brings us to the Haldane effect. This effect demonstrates that when higher concentrations of O2 are present in red blood cells both CO2 and free protons are displaced. This is because deoxygenated hemoglobin has a stronger ability to act as a proton acceptor. These protons are then released to recombined with bicarbonate ions, which neutralizes the acidity by producing carbonic acid, which stored CO2 can then be released from.

There are technically three ways that CO2 can travel in red blood cells. Most of it is in the form of bicarbonate ions, as I've already covered, and a small amount is freely dissolved. There is another form worth mentioning, known as carbamino groups.

CO2 has the ability to complex with the amino acids lysine and arginine in various proteins, including hemoglobin. This forms carbaminohemoglobin. This process is also dependent on oxygen saturation, and acts as an extension of the Haldane effect.

The ability of proteins and tissues to be saturated with CO2 is also relevant in the storage of CO2 in various organs, most notably bone. Bone seems to act as a reservoir of CO2, largely in the form of bicarbonate, carbonate, and some carbamino groups. These carbonate and bicarbonate ions may act as an essential ph buffer.

I've talked before about the balance between two enzymes, acid phosphatases and alkaline phosphatases, that determine bone stability. Alkaline phosphatases are magnesium dependent, and increase the stability of calcium in bone. Acid phosphatases are iron dependent, and cause more calcium to be released from bone. Elevated acid phosphatase are one of the primary marker used to assess osteoporosis.

I found some evidence to suggest that while CO2 itself is acidic, higher levels in the form of bicarbonate in bone may directly counteract bone resorption. This may serve a physiological role in the regulation of bone stability.

These are just a few of the roles of carbon dioxide in the human body.

Living at high-altitude

 

 

Something that is often related to the various beneficial effects of CO2 is the health effects of being at a high altitude. Living at high altitude is highly beneficial, for a number of reasons.

I have discussed high altitude before in the context of deuterium, the heavier isotope of hydrogen that is found in water and food in the highest concentration near sea level and near the equator. This is because when precipitation occurs heavier isotopes tend to be released from the atmosphere first, while lighter isotopes make it up to higher elevation.

Deuterium is problematic because the protons that are produced from its ionization have a neutron attached, so they are twice the mass of protons produced from regular hydrogen. This slows down single-proton dependent reactions such as the ATPase enzyme due to the kinetic isotope effect, which shows deuterium reacts exponentially more slowly than isolated protons despite having only twice the mass.

Deuterium's ability to impact mitochondrial function has sparked interest in deuterium depleted water as a therapy for cancer, and other studies. I found this paper particularly interesting. It found an antidepressant effect of deuterium depletion in mice, and points out a correlation between geographically higher levels of deuterium in tap water with higher rates of depression in different parts of the US (see Fig. 1 in the research paper).

This study looked at the impact of deuterium depletion on metabolic health, and found that when subjects were given deuterium-depleted water they showed improvements in fasting blood glucose and insulin, higher HDL, and lower blood sodium content. The authors theorized the improvement in blood sodium could be due to the improvement in function of the proton-dependent sodium antiporter.

Food and water at high altitude are naturally deuterium depleted, and this seems to improve various aspects of energy production. Another factor that comes into play when living at high altitude is the shift in balance between O2 and CO2.

Once humans reach an altitude of around 6,900ft there is a distinct drop in oxygenation of hemoglobin. This occurs as a result of lower atmospheric oxygen levels, and causes a reduced excretion of CO2 since the Haldane effect is lessened.

There are both short- and long-term adaptations to these altitude effects. In the short term, the body senses this reduction in oxygen and increases respiratory depth and rate. Since the body is retaining more bicarbonate rather than excreting it as CO2, the blood becomes more alkaline which prevents the respiratory rate from being fully increased, and the kidneys take several days to increase bicarbonate excretion to compensate for this. This is the main reason that the acute phase of altitude sickness lasts several days.

The primary class of drugs prescribed to manage altitude sickness are known as carbonic anhydrase inhibitors. These drugs have various effects via increasing the levels of CO2 by inhibiting the enzyme that converts it back and forth into carbonic acid. The most common of these is acetazolamide. Through this process it increases respiratory rate by increasing CO2 itself which stimulates respiration, and promoting a diuretic effect that enhances the excretion of bicarbonate. Rather than completely inhibiting altitude sickness, these effects speed up acclimatization to high altitude.

Carbonic anhydrase inhibitors are also useful in the treatment of a number of other diseases. Their diuretic properties are useful in the management of edema, and they are commonly used to reduce intracranial or intraocular pressure in different disorders. Like many diuretics however, they have several serious side effects.

Adaptation to high altitude is highly beneficial. It is common for athletes to live and train at high altitude for months or years before competing in major sporting events like the Olympics at sea level. These adaptations mainly compensate for the lower oxygen levels. These include lowered lactate production, increased hematocrit and RBC synthesis, increased myoglobin, increased capillary blood flow, increased mitochondrial biogenesis, and increase in respiratory enzyme function (such as the ETC and TCA cycle).

These changes are highly protective of health. They promote better use of oxidative resources like oxygen and more efficient flow of energy through the organism. It may be logical to think that these changes are simply compensating, bringing the system back up to baseline rather than improving it. However, we see a reduction in disease rates at high altitude that seems to suggest an overall improvement in some aspects.

Notably, the rates of heart disease mortality are significantly lower at high altitude. We also see a lower prevalence of obesity. Living at altitude also seems to reduce risk of dying from stroke. Various studies have also shown an increase in the thyroid hormones T3 and T4 at high altitude, while TSH is not increased. Other hormones including testosterone and cortisol are increased as well, though this may not carry over into long term acclimatization.

The maps at the start of this section illustrate this well. You can see the influence of other factors with lower mortality along coastlines and in the far south (more sun exposure, particularly UV-B year round), but there is a significant correlation between living further north and at higher altitude and better overall health. This is primarily due to CO2, sunlight, and deuterium depletion.

Thiamine and CO2

Now let's expand on the relationship between thiamine and CO2. I've come to believe that thiamine may be one of the single most potent substances in increasing CO2 levels in the human body since it does so in at least two distinct ways.

Many people assume that CO2 is the main byproduct of ATP being creating. Actually, this isn't true, since most of our ATP is created via the electron transport chain. Each O2 molecule is split in half to form two water molecules, since it acts as the terminal electron acceptor in the ETC by combining with protons and electrons. This makes water the primary byproduct of metabolism.

CO2 is the byproduct of the secondary processes of energy production, glycolysis and the TCA cycle. The more I dug into the interplay between thiamine and CO2 the more surprised I was. It turns out that all five of the primary enzymes thiamine acts as a cofactor for produce CO2 as a byproduct!

Pyruvate dehydrogenase (PDH), a-ketoglutarate dehydrogenase (aKGDH), and branched-chain ketoacid dehydrogenase (BCKDH), all operate through a similar mechanism. Each uses thiamine to convert the cofactor Coa-SH into CO2, and NAD+ into NADH. By supplying the mitochondria with NADH these enzymes are also providing electrons and protons to complex I of the electron transport chain.

The other two primary thiamine-dependent enzymes are less clear cut, but produce CO2 as well. Transketolase normally works by connecting the pentose phosphate pathway to glycolysis, and its presence is necessary for the production of the cofactor NADPH which plays a role in numerous processes in the body. Transketolase normally reacts with xylulose-5-phosphate and ribose-5-phosphate, however it can use several alternate substrates. When transketolase reacts with b-hydroxypyruvate instead, it also produces CO2 as a byproduct.

Lastly, HACL1 also produces CO2. In this case it does so indirectly. Its main byproduct formyl-coa is rapidly degraded into formic acid, and from there formic acid is converted into CO2 to dispose of it.

Even more interesting is the fact that every single one of these enzymes involves magnesium in some way. This is unsurprising since magnesium is a cofactor for hundreds of enzymes in the body, and some researchers have even estimated that more than 40% of the total enzymes in the body utilize magnesium. The combination of magnesium and thiamine, which I suggest to everyone using thiamine as a supplement, will strongly promote each of these pathways. Other cofactors such as calcium play a role here as well.

I've even found some evidence that thiamine diphosphate itself can form a complex with magnesium. This may work similarly to ATP. For those that don't know, most free ATP in the cell exists in the form of Mg-ATP, and this is thought to stabilize its structure and play a role in its function. Magnesium and thiamine diphosphate may work together in a similar way.

The other way that thiamine increases CO2 is by acting as a carbonic anhydrase inhibitor itself. This landmark study from 2011 pointed out this unique mechanism. They tested thiamine on three subsets of the carbonic anhydrase enzyme, and compared it to two thiamine analogs and three pharmaceutical carbonic anhydrase inhibitors.

Overall, thiamine performed the best, though it was not more potent than the pharmaceutical drugs. It seems these analogs were the researcher's attempt to create a cross between thiamine and the structures of more classical carbonic anhydrase inhibitors, but plain thiamine itself had the highest affinity toward all three forms of the enzyme tested.

Thiamine was relatively similar to acetazolamide in its affinity, though it ranged from roughly a 1.5-6 fold lower affinity. Given that acetazolamide is administered in doses ranging from 250-1,000mg daily, it's logical that in high doses of 1-3 grams daily thiamine may act as a significant inhibitor of carbonic anhydrase.

On top of this, edema is one of the common symptoms of thiamine deficiency. This is a condition known as "wet beriberi" in the medical literature, and it is treated with thiamine administration. This further illustrates that thiamine plays a crucial role in regulating carbonic anhydrase levels in the body.

Thiamine is perhaps the only substance that has the ability to increase CO2 levels through this dual mechanism. Both by directly stimulating metabolism, and in higher doses by increasing the retention of CO2 within the body via inhibiting carbonic anhydrase. It improves proton and electron flow, and powerfully stabilizes the organism as a whole.

This is one of the primary mechanisms by which it improves such a wide variety of health conditions. This also partially explains why very high doses seem to provide additional benefit, since they have a stronger inhibiting effect on carbonic anhydrase.

Metabolism and luck

Now, let's return to the idea I began this article with, how might thiamine increase luck?

There is a concept in psychology that I've long been fond of, called the balance between "fluid intelligence" and "crystallized intelligence." The state of fluid intelligence is defined by openness, and the ability to adapt to new circumstances, and incorporate new experiences. Crystallized intelligence is a state of enhanced accessibility of existing memories, but less centrality of new memories and experiences.

As we age, it is considered normal for intelligence to shift from "fluid" to "crystallized." This is responsible for the trope that your grandparents have seemingly endless stories, but take a long time to figure out new technology, while a child grasps it more quickly.

I came across this interesting study recently correlating fluid intelligence with the rate of metabolism in the brain. There is a large body of research like this linking metabolism within the brain itself with intelligence and general mood. There is even evidence suggesting that the cognitive limits of an individual are defined by how long their brain can maintain proper oxidative metabolism in a given mental task. Markers of non-oxidative metabolism are associated with cognitive fatigue.

Since the brain is unique in that it depends primarily on glucose as its energy substrate (with ketones as a fallback), brain metabolism is dependent on proper glycolysis. In some research higher intelligence is also associated with better ability to use glucose under mentally challenging conditions. Thiamine is instrumental in supporting this.

This study even points out the similarity between the state of neurodegeneration, and the state of thiamine deficiency, where both are marked by hypometabolism in the brain. This study suggests the use of thiamine to prevent markers of cognitive decline, including increased levels of lactate and cerebral acidosis, markers of the same non-oxidative metabolism I mentioned in mental fatigue.

I view luck as a state very similar to synchronicity. Both depend not just on external actions we have no control over, but also the way we perceive and interact with the world. You might consider yourself particularly lucky if you find a dollar or spare change on the ground, but you're more likely to notice things like this if you're in a state of heightened awareness.

By increasing the flow of energy through the body, particularly via glucose in the brain, thiamine increases our awareness and makes us more conscious. The world around us then responds in kind. We're more likely to notice small details, and approach the world with a sense of openness and optimism. We become less prone to fatigue, stress, and rumination, when we have the proper cofactors to use energy. This translates to a very real increase in luck.

In my experience, inhibitory substances like magnesium, inositol, and taurine also promote a more optimistic mindset. Factors like cortisol and glutamate seem to promote negative thoughts and anxiety, and make situations feel more out of control than they really are. Substances that reduce this "noise" by promoting GABA signaling allow to see things more clearly. This is another reason why I find thiamine and magnesium such a powerful combination.

Health can often appear complicated and overwhelming, but even starting with simple things like supplementing thiamine and magnesium can lead to tangible changes. This allows us to recognize how much power we have to change our circumstances for the better. Good health doesn't happen overnight, but if you start making steps forward you will reach your destination.