"Caffeine Salicylate" - A Novel Compound?

[Sativa]

I have been experimenting with creating Sodium & Magnesium salts of Salicylic acid (see this thread).
I then had the idea to combine two Peat favourites - Caffeine & Salicylic acid!

The procedure for making Caffeine Salicylate is quite straight-forward.
You'll need pure Caffeine powder & Salicylic acid powder - both OTC & easily available.

Caffeine is a base which can react with acids to form salts. A well characterized salt of caffeine is caffeine salicylate formed by using salicylic acid.

...since caffeine is a base and can accept a proton, it can react with an acid to form a salt. If salicylic acid is used, the result is caffeine salicylate...

Preparation of Caffeine Salicylate
Using a balance weigh 50 mg of caffeine and 37 mg of salicylic acid .. and dissolve them in 4ml of toluene in a small 25ml flask by warming on a steam bath.
[Source]

Note: You can adjust the weights to something more practical, just ensure you keep the same ratio.
(eg; increase above mg weights by factor 100 = 5g Caffeine, 3.7g SA)

I've attached a PDF detailing a lab method for creating this compound, as another example of the process (CaffeineSalicylateLab.pdf). It uses some non-OTC chemicals for the re-crystallization step; which I intend to bypass, opting for basic evaporation instead. I will probably use IPA/ethanol/water.

Here is the Pubchem entry for Caffeine Salicylate: Caffeine salicylate

Here is the abstract of a paper which uses this compound (PDF attached - Theraputic effects of Caffeine Salicylate.pdf).
—
Enhancement in Cortical Arousal by Caffeine Salicylate in Experimental Animal Models

Objective: It is aimed to evaluate contribution of two molecules of Caffeine salicylate, a combinatorial product, in the CNS stimulant, anti-inflammatory and an analgesic property in experimental animal models.
Material and Methods: Caffeine salicylate is synthesized by one step reaction from caffeine and salicylic acid. Actophotometer and open field test were used for the CNS stimulant activity whereas formalin induced rat paw edema and tail immersion test were used to evaluate anti-inflammatory and analgesic properties in experimental animals.
Results: The locomotor activity was increased from 37.1% for caffeine to 49.24% for caffeine salicylate. In open field test; number of crossing and rearing were increased from 42.34 % to 54.89% and 17.26% to 27.87% respectively. The % inhibition on rat paw edema 16.40% and 18.75% with caffeine salicylate as against diclofinac 51.0% and 62.5% at 60 and 120 min. respectively. The tail withdrawal time was prolonged by 25% with caffeine salicylate as against 78.88 % with pentazocine in wistar rats. The results of all experimental animal models were statistically significant.
Conclusion: The enhancement in the cortical arousal by caffeine salicylate over caffeine may be due to contribution of antioxidant property of salicylate besides adenosine antagonism and mobilization of intracellular calcium induced dopamine release by caffeine portion of caffeine salicylate. The mild analgesic and anti-inflammatory activities of caffeine salicylate may be due to inhibition of prostaglandin synthesis and an antioxidant properties of salicylate portion of caffeine salicylate.
[source]
—

Q: What's this acid + base chemical reaction all about then?
As an example of the acid + base procedure; to make the Sodium salt of Salicylic Acid (aka sodium salicylate):
I mix SA & Sodium bicarbonate in water, stirred every few hours (whenever I remember) to speed up the reaction.
After the bubbles disappear & fizzing stops, I pour the solution into a Pyrex dish & evaporate in an oven at medium/low temperature (keeping a close eye on things to ensure no burning etc)
I then scrape up the dried somewhat fluffy NaSali crystals & store in an airtight jar.
Mine were 80-90% dry when I stored them. I use them in a simple water tincture + pipette.
Quite straight-forward!

Spoiler: Detailed procedure for making the Sodium salt of Salicylic acid

...I used 138 grams of salicylic acid from the drugstore and 84 grams of baking soda.
This yielded 160 (theoretical) grams of sodium salicylate, 18 grams of CO2, and 48 grams of water.
...I dissolved the baking soda in warm water, and added the salicylic acid bit by bit.
Several additions were made, allowing the production of gas to stop in between to prevent overflowing.

 

[lampofred]

Ha I love these science experiment threads.

If you can find a specific purpose for this, something it does different/better than just caffeine and aspirin taken separately, you could probably patent it like Peat did with Progest-E and sell it...

 

[Sativa]

If you can find a specific purpose for this, something it does different/better than just caffeine and aspirin taken separately, you could probably patent it like Peat did with Progest-E

Note - Aspirin is acetylsalicylic acid (ASA), I prefer to use salicylic acid (SA) - this avoids having an acetyl- group floating around, as well as speeding up the metabolism of SA since there's no need to remove the acetyl- group from SA.

I am mainly fueled by experimentation...i'm not really bothered about patenting anything...
btw, I don't even drink coffee!

I have been enjoying taking my diy Sodium Salicylate - especially for its anti-cortisol properties. I've also been using pure & natural Vit E oil + Squalene, olive oil derived (its a cool cholesterol precursor)
I've got 10g pure Methylene Blue arriving soon... i'm contemplating what chemistry I can do with that...

 

[lampofred]

Note - Aspirin is acetylsalicylic acid (ASA), I prefer to use salicylic acid (SA) - this avoids having an acetyl- group floating around, as well as speeding up the metabolism of SA since there's no need to remove the acetyl- group from SA.

I am mainly fueled by experimentation...i'm not really bothered about patenting anything...
btw, I don't even drink coffee!

Well if you find some unique health promoting use for it, then making it popular and selling it at a reasonable price would be a service to people, not a money grab. Like Haidut's supplements.

But only if it does something that caffeine and salicylic acid can't do individually.

 

[Sativa]

Sounds good.

But only if it does something that caffeine and salicylic acid can't do individually.

Well, if anyone knows... let me know!
Aside from some papers, I haven't found any information on the human use of Caffeine salicylate...

The paper I linked might offer some insight into the therapeutic potential of Caffeine salicylate actually:

Conclusion: The enhancement in the cortical arousal by caffeine salicylate over caffeine may be due to contribution of antioxidant property of salicylate besides adenosine antagonism and mobilization of intracellular calcium induced dopamine release by caffeine portion of caffeine salicylate. The mild analgesic and anti-inflammatory activities of caffeine salicylate may be due to inhibition of prostaglandin synthesis and an antioxidant properties of salicylate portion of caffeine salicylate.

Essentially a combination of the properties of both molecules.
Perhaps having them in a combined form alters the metabolism of each...

Perhaps @haidut might have some insight...

 

[lampofred]

I love your posts, they remind me of visionofstrength's posts...

I don't have any pure powders but I'm going to go mix various combos of aspirin, Vitamin D, methylene blue, sodium chlorite, salt, hydrochloric acid, etc. and see if I get any cool bubbles...

 

[haidut]

Sounds good.


Well, if anyone knows... let me know!
Aside from some papers, I haven't found any information on the human use of Caffeine salicylate...

The paper I linked might offer some insight into the therapeutic potential of Caffeine salicylate actually:


Essentially a combination of the properties of both molecules.
Perhaps having them in a combined form alters the metabolism of each...

Perhaps @haidut might have some insight...

I think it is a great experiment, but like any salts, upon ingestion the mixture is likely quickly hydrolyzed back into caffeine and salicylic acid. So, orally it will probably be quite similar to taking caffeine and aspirin together as separate ingredients. Since skin has less of a tendency to metabolize salts, it would be interesting to try it topically.
As far as the cortisol-blocking effects - any type of salicylic acid derivative that metabolizes back into salicylic acid would have this effect. So, aspirin, pure salicylic acid, magnesium/sodium/potassium salts, etc would all have this effect. Salicylic acid is the molecule that inhibits the synthesis of cortisol.
Salicylate Downregulates 11β-HSD1 Expression in Adipose Tissue in Obese Mice and in Humans, Mediating Insulin Sensitization

 

[Sativa]

I think it is a great experiment, but like any salts, upon ingestion the mixture is likely quickly hydrolyzed back into caffeine and salicylic acid. So, orally it will probably be quite similar to taking caffeine and aspirin together as separate ingredients.

Ah - makes sense.
Perhaps, upon hydrolyzation, the close proximity of both components might elicit an influence upon their pharmacodynamics etc? just a thought.

I'm also contemplating other Caffeine salts, eg ascorbate, gluconate, bicarbonate, acetate etc... and also other amines!

eg, Agmatine. It has some extensive pharmacology going on, interacting with multiple areas, including NO, sigma receptors & mitochondria enhancement, if i remember correctly. Available as the sulfate salt; perhaps it has potential.

...I asked Ray Peat directly, and he responded:
"Her symptoms and history are very suggestive of hypothyroidism.
Progesterone and vitamins D & K protect against excessive nitric oxide.
Agmatine (a natural parallel to aminoguanidine) is another substance
that lowers NO and eye pressure."

Ray Peat - Autism Newsletter notes - May 2018
...
Things in the environment, or substances produced in reactions to environmental stress, that might cause autism, include prenatal and neonatal exposure to radiation, including isotopes from the power industry, bomb testing, Chernobyl, and Fukashima; exposure to air pollution, including nitrogen oxides, ozone, carbon monoxide, sulfur dioxide, and particles; aluminium, lead, mercury, manganese, arsenic, cadmium, chromium, manganese, and nickel; acetaminophen, infections, endotoxin, exogenous and endogenous estrogens, hypothyroidism, progesterone deficiency, agmatine deficiency, serotonin excess, endogenous nitric oxide, and Vitamin D deficiency. All of these have established associations with the risk of autism.

When energy is deficient, cells are susceptible to damage from normal levels of stimulation. Restraining excitatory reactions is at lease protective, and of often improves functioning. Anti-excitotoxic substances include progesterone, memantine, minocycline, and agmatine.

Aspirin
(lowers ALL - eNOS, iNOS, nNOS
conflicting - possibly raises eNOS)
Agmatine
(raises eNOS
lowers nNOS, iNOS)
Caffeine
(lowers eNOS
iNOS?
nNOS?)
Methylene Blue
(lowers eNOS, iNOS, nNOS)
Progesterone
(raises eNOS,
lowers iNOS, nNOS)

Agmatine has roles as an NMDA antagonist, a neuronal nitric oxide inhibitor (not related to "the pump" in any way), interacts with serotonin receptors (including 5-HT3 antagonist), and is an activator of both alpha-2-adrenergic receptors and imidazoline receptors. Agmatine may directly block calcium channels, and can indirectly inhibit potassium channels.
...
Neurological effects appear to follow a bell-curve pattern, maxing out at an estimated 500 mg human equivalent for somebody around 150 lbs (based on the limited evidence using oral agmatine in rats). The neuropathic pain reduction is dose dependent.

https://www.tandfonline.com/doi/full/10.1080/24750573.2018.1426696
Found this interesting. Peat has made comparisons between autism and schizophrenia in the past.

Schizophrenia is one of the most severe psychiatric disorders with about 1% prevalence. It has been proved that glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonists such as MK-801 and phencyclidine cause schizophrenia-like behaviours in rodents. Agmatine is an endogenous amine synthesized from decarboxylation of arginine and has been thought to be a neurotransmitter/neuromodulator. It binds to imidazoline and alfa adrenergic receptors and blocks cation channelled receptors, such as nicotinic acetylcholine, 5-HT3 serotonergic, and NMDA receptors. It is an endogenous inhibitor of nitric oxide synthase.
...Herein, the aim of our study is to investigate the effect of subchronic agmatine treatment on sensorimotor gating, visual recognition memory, and social functions in subchronic MK-801 model of schizophrenia in rats.

Conclusion: Subchronic MK-801 administration revealed sensorimotor gating, social and cognitive deficits in rats. Subchronic agmatine treatment improved cognitive deficits and increased socialization in rats although it was ineffective for sensorimotor gating deficits..

Nitric oxide and polyamines have one thing in common: arginine. This amino acid can make both: Arginine can release nitric oxide to become ornithine and also, to add insult to injury, then become a polyamine through the enzyme ornithine decarboxylase. While the simple four‐carbon diamine that results isn't particularly harmful, it can find the others and polymerize into a larger one called spermidine. This long‐chained carbon and nitrogen molecule puts the word poly in polyamines (and also puts cancer in your prostate.) This molecule binds with DNA directly and lowers its replication velocity during routine PCR.

Polyamines and methylglyoxal work in opposite directions, in the same way, like the yin–yang pair of cellular proliferation

So, a potential strategic solution to mitigate polyamine formation from oral agmatine metabolism would be to increase methylglyoxal, either via glyoxylase I inhibitors or:

Curcumin is both a glyoxylase I inhibitor and a cyclooxygenase-2 inhibitor, making it a double-acting carcinostatic agent.
...you can take hints from curcumin's mechanism of action and use more water-soluble glyoxylase I and cyclooxygenase-2 inhibitors for other cancers.

Pau d'Arco has the most powerful natural glyoxylase I inhibitors known: lapachol and β-lapachone.
...
The amino acid L-threonine will become methylglyoxal within the body (through aminoacetone intermediate), so pau d'arco with L-threonine would appear to be a safe and all-natural Szent-Györgyi-approved approach—with a Koch Seal of Approval™—to raise intracellular methylglyoxal levels. Add to this a Gerson-type diet (sans the linoleic acid-containing flaxseed oil) and you'd probably be reversing tumors in a manner similar to the lab-rats given such things.

Glyoxylase I & II together turn methylglyoxal into lactic acid (lactic acid = not desirable!).

And finally, some papers on Agmatine:
—
Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience?
Jul 26, 2017
DOI: 10.1042/BCJ20170007

Agmatine, the decarboxylation product of arginine, was largely neglected as an important player in mammalian metabolism until the mid-1990s, when it was re-discovered as an endogenous ligand of imidazoline and α2-adrenergic receptors. Since then, a wide variety of agmatine-mediated effects have been observed, and consequently agmatine has moved from a wallflower existence into the limelight of clinical neuroscience research. Despite this quantum jump in scientific interest, the understanding of the anabolism and catabolism of this amine is still vague.

Agmatine metabolism:

—
Synthesis and Thermophysical Characterization of New Biologically Friendly Agmatine-Based Ionic Liquids and Salts by Experimental and Computational Approach
May 17, 2019
https://doi.org/10.1021/acssuschemeng.9b01515
For the first time, the dicationic biological molecule agmatine in the synthesis of three novel ionic liquids, agmatine ibuprofenate, agmatine salicylate, and agmatine nicotinate, as well as of six salts, agmatine citrate, agmatine ascorbate, agmatine glutamate, agmatine m-hydroxybenzoate, agmatine nitrate, and agmatine chloride, was used.
—

 

[Sativa]

I'm going to go mix various combos of aspirin, Vitamin D, methylene blue, sodium chlorite, salt, hydrochloric acid, etc. and see if I get any cool bubbles...

Please be careful with your combinations... i'm contemplating MB mixes, but due to unknown chemical interactions, i'm being very cautious in my combinations... I've got some organic chemistry experience/insight so this... helps!

Be careful with MB, sodium chlorite etc...

Sodium chlorite is an inorganic sodium salt in which chlorite is the counterion. It has a role as an oxidising agent. It is an inorganic sodium salt and a chlorite salt.

Methylene blue indicates the presence of oxidizing agents because it is oxidized itself by these compounds. When electrons are stripped from methylene blue, the resulting molecule imparts a blue color to the solution--giving a clear sign of a chemical change.

ascorbic acid. Because the vitamin is an acid, it is reasonably stable in acidic solutions, but in neutral or basic solutions it is easily and rapidly oxidized by dissolved oxygen. Because vitamin C is so readily oxidized, it is easier to analyze vitamin C using an oxidation-reduction titration rather than an acid-base titration.

 

[Sativa]

I'm also contemplating making salts (of caffeine; agmatine etc) using Nicotinic acid (aka niacin; vitamin B3)...

Here is some RP relevant research on Agmatine's metabolic interactions.
It apparently stimulates the endogenous synthesis of allopregnanolone via activation of the PPAR-α receptor & PGC1α! (paper attached)
Agmatine seems to have a protective effect on mitochondria and modulates fatty acid metabolism, oxygen consumption & ATP synthesis; also seems to prevent dysfunction of Complex I in renal cortex mitochondria, and indirectly regulates cytochrome c oxidase activity.
Agmatine diminished incomplete fatty acid oxidation, decreased fat but increased protein mass, increased hepatic ureagenesis and gluconeogesis but decreased glycolysis.

—
Agmatine is transported into liver mitochondria by a specific electrophoretic mechanism

Agmatine transport in liver mitochondria may be of physiological importance as an indirect regulatory system of cytochrome c oxidase activity and as an inducer mechanism of mitochondrial-mediated apoptosis.
[Agmatine is transported into liver mitochondria by a specific electrophoretic mechanism]

—
The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

Agmatine, an endogenous metabolite of arginine, selectively suppresses growth in cells with high proliferative kinetics, such as transformed cells, through depletion of intracellular polyamine levels. In the present study, we depleted intracellular polyamine content with agmatine to determine if attrition by cell death contributes to the growth-suppressive effects. We did not observe an increase in necrosis, DNA fragmentation, or chromatin condensation in Ha-Ras-transformed NIH-3T3 cells administered agmatine. In response to Ca2+-induced oxidative stress in kidney mitochondrial preparations, agmatine demonstrated attributes of a free radical scavenger by protecting against the oxidation of sulfhydryl groups and decreasing hydrogen peroxide content. The functional outcome was a protective effect against Ca2+
[The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis]

—
Agmatine effects on mitochondrial membrane potential and NF-κB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY5Y cells.

Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in the CNS in several models of cellular damage. However, the mechanisms involved in these protective effects in neurodegenerative diseases are poorly understood. The present study was undertaken to investigate the effects of agmatine on cell injury induced by rotenone, commonly used in establishing in vivo and in vitro models of Parkinson's disease, in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). We report that agmatine dose-dependently suppressed rotenone-induced cellular injury through a reduction of oxidative stress. Similar effects were obtained by spermine, suggesting a scavenging effect for these compounds. However, unlike spermine, agmatine also prevented rotenone-induced nuclear factor-κB nuclear translocation and mitochondrial membrane potential dissipation. Furthermore, rotenone-induced increase in apoptotic markers, such as caspase 3 activity, Bax expression and cytochrome c release, was significantly attenuated with agmatine treatment. These findings demonstrate mitochondrial preservation with agmatine in a rotenone model of apoptotic cell death, and that the neuroprotective action of agmatine appears because of suppressing apoptotic signalling mechanisms. Thus, agmatine may have therapeutic potential in the treatment of Parkinson's disease by protecting dopaminergic neuron
[Agmatine effects on mitochondrial membrane potential and NF-κB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY... - PubMed - NCBI]

—
Different behavior of agmatine in liver mitochondria: Inducer of oxidative stress or scavenger of reactive oxygen species?

Agmatine acts as a competitive inhibitor of nitric oxide synthase (NOS) [4] and induces ornithine decarboxylase antizyme [5] and spermidine/spermine acetyl transferase [6]. In fact, in all species agmatine is metabolized by agmatinase to urea and putrescine [7], suggesting that it is a polyamine precursor. In mammals, agmatine is not only synthesized “in situ” by ADC but is also taken up by exogenous sources and transported to several organs, in particular the liver, by an energy-dependent mechanism [8]. It has been reported that, in rat hepatocytes, increased agmatine concentration, by provoking polyamine depletion, promotes apoptosis by increasing caspase-3 activity. This occurs through mitochondrial swelling and release of cytochrome c[9]. Agmatine has also been found in neuronal mitochondria[10], and its metabolic enzymes, ADC and agmatinase, have also been recognized in mitochondria [11], [12], [13], as well as the imidazoline receptor, I2, which binds agmatine although its function is still unknown [14]. Very recently it has also been found that agmatine is transported into liver mitochondria by an energy-dependent mechanism, exhibiting strict electrophoretic behavior and requiring high membrane potential (ΔΨ) in order to operate [15].

The transport of agmatine in RLM accounts for its up-regulation in ureagenesis, demonstrated in perfused liver [16], coupled with stimulation of β-oxidation [17]. Indeed, agmatine is also able to prevent dysfunction of Complex I in renal cortex mitochondria [18], most probably by phosphorylating the AQDQ subunit of the complex [19]. It has been proposed that these findings may have important implications for the prevention of mitochondrial diseases related to faulty Complex I [18].

All these observations, revealing close relationships between this amine and mitochondria, taken together with previous reports on interactions among biogenic amines and mitochondria, particularly at the level of oxygen consumption and ATP synthesis...
[Different behavior of agmatine in liver mitochondria: Inducer of oxidative stress or scavenger of reactive oxygen species? - ScienceDirect]

—
Anti-Atherosclerotic Action of Agmatine in ApoE-Knockout Mice

...Atherosclerosis is an inflammatory disease in which dysfunction of mitochondria play an important role, and disorders of lipid management intensify this process. Agmatine, an endogenous polyamine formed by decarboxylation of arginine, exerts a protective effect on mitochondria and modulates fatty acid metabolism.
[Anti-Atherosclerotic Action of Agmatine in ApoE-Knockout Mice]

—
The molecular and metabolic influence of long-term Agmatine consumption

Subsequently, AGM induced a widespread impact on gene expression and metabolic profiling, including: (a) activation of peroxisomal proliferator-activated receptor-α (PPARα), and its coactivator PGC1α; (b) increased expression of PPARγ and genes regulating thermogenesis, gluconeogenesis, and carnitine (Car) biosynthesis and transport. The changes in gene expression were coupled with improved tissue and systemic levels of Car and short chain AcylCar, increased βoxidation and diminished incomplete fatty acid oxidation, decreased fat but increased protein mass, increased hepatic ureagenesis and gluconeogesis but decreased glycolysis. These metabolic changes were coupled with reduced weight gain and a curtailment of the hormonal and metabolic derangements associated with HFD-induced obesity. The findings suggest that AGM elevated the synthesis and level of cAMP, thereby mimicking the effects of caloric restriction with respect to metabolic reprogramming.

[Attachment: https://raypeatforum.com/community/attachments/metabolic-influence-of-agmatine-pdf.14186/]

 

[Sativa]

Further insight into methylglyoxal, thanks to Travis.

A potential strategic solution to mitigate polyamine formation from oral agmatine metabolism would be to increase methylglyoxal

Ideas put forward by Travis:
...
Consume l-threonine (dkk-1 inhibitor, increases methylglyoxal an arginine/polyamine inhibitor)
Consume lapchone (glyoxalase l inhibitor which stops methylglyoxal created by l-threonine being destroyed and turned into lactic acid)

Lapodin/Threonine prevents the glutathione antioxidant system so more ROS to kill the cancer cell with Methylglyoxal (@Travis)
Sodium acetate helps to further knock out Lactic acid and maintain cellular potential

You would certainly expect a fair amount of interplay between arginine, urea, and methylglyoxal. It's easy to see how methylglyoxal can turn-off cancer by transforming the some molecular growth factors, such as nitric oxide and polyamines, into more inert molecules such as substituted allantoins and pyrimidines. Or is it the other way around? . . . where these nitrogen compounds lower methylglyoxal and it's this that causes growth? I suspect the former. The glyoxylase system could be an endogenous recycling mechanism for amines, an another way in which the cell regulates growth.

Dehydroascorbate, the oxidized form of vitamin C, is the main form of the molecule in the healthy cell. Szent-Gyorgyi believed that it, and other oxidative molecules, possibly including substances related to methylglyoxal, served to maintain cellular respiration, and to prevent cancer.

 

[Sativa]

The benzoate & succinate forms of Caffeine/Agmatine/etc might be interesting, especially since both benzoic & succinic acids have useful & relevant 'peaty' pro-metabolic properties. Other bases such as Magnesium & Calcium could be used...eg Mg Benzoate, Ca Succinate etc

Of course, it could always be simpler to take these things separately ... but I have a sense of adventure, and experimentation.

Been taking about 250 mg 1-2 times a day for a few months. Usually [succinic acid] reacted with an equal amount of magnesium carbonate to form magnesium succinate.
...
I combine succinic acid & magnesium carbonate into a small pan with some water.
Then I bring it to a boil. It seems to need quite a bit of heat to speed up the reaction, producing magnesium succinate.

If you want to react all of the magnesium carbonate use 1.4 parts succinic acid to 1 part magnesium carbonate (by weight).

Succinic acid had been studied for even longer than inosine and it has a myriad of health effects, many of them overlapping with inosine. As a Krebs cycle intermediate, its main metabolic effect is the stimulation of the Krebs cycle activity as well as the flow of electrons along the electron transport chain (ETC).
The final effects of these stimulations is of course the increase in ATP synthesis. So, the presence of succinic acid in Cardenosine is due to its role as a stimulator (and an indirect source) of ATP synthesis.

Succinic acid stimulates succinic dehydrogenase and the electrons succinic acid provide subsequently flow along the ETC, assuming the ETC is working properly. However, if somebody takes succinic acid and their ETC is not functioning well for some reason then there won't be as much boost in ATP synthesis, compared to if the ETC was operating well... One way to circumvent a malfunctioning ETC is using MB (e.g. Oxidal: Caffeine, MB, Benzoic acid). It provides an alternative electron acceptor for that electron flow originating from succinic acid, and it has been shown to restore electron flow along the ETC in various pathologies. And in case of well-working ETC it can speed up ATP synthesis even more than succinic acid would on its own.

 

[Sativa]

Malic acid, forming the malate salt, could be an interesting ingredient. It's a key player in the mitochondrial synthesis of ATP.

"In certain bacteria which have similar microanatomical and biochemical properties as mitochondria, malate acts as an electron donor and generates a large proton motive force believed to be the driving force for the mitochondrial synthesis of ATP."

"Relatively small amounts of exogenous malate are required to increase mitochondrial oxidative phosphorylation and ATP production. Once an elevated mitochondrial malate concentration is attained, it may support an increased rate of substrate transport into the mitochondria without depleting its own matrix concentration, for malate is regenerated...

"Following endurance training of athletes, muscles were characterized by a 50% increase in the malate-aspartate shuttle enzymes, where malate plays a key role. In humans as well as in other animals tested, when there is increased demand for ATP, there is also an increased demand and utilization of malate."

 

[Sativa]

More on succinic acids pro-metabolic properties + insight on proper dose quantities & frequency, thanks haidut!

Also sweet insight into Sodium Acetate, which apparently.boosts internal CO² production... + iirc, Na Acetate
binds to phosphate; so a good way of reducing P absorption!

Some Krebs cycle intermediates stimulate its activity & some of them suppress excessive glycolysis.
...
Succinic acid is a VERY beneficial one because it stimulated the activity of the Krebs cycle, inhibits excessive glycolysis, and in higher doses acts just like the drug Mildronate - i.e. suppresses the enzyme BBOX, which synthesizes carnitine. So, succinic acid is a fatty acid oxidation inhibitor in higher doses. The effective concentration (IC50) is about 70uM/L, which can be achieved with 250mg - 300mg dose. This matches Ray's recommendations of 250mg twice a day

Succinic and malic acids are strong chelators and can deplete iron sometimes. I would not take more than 200mg - 300mg doses 1-2 times daily.

—

Insight on acetic acid (acetate), in the context of 'acetate salts' eg Calcium acetate, Sodium acetate, magnesium acetate, caffeine acetate etc...

Actually, any of the Krebs cycle intermediates can be fed and will work just as well as if somebody was eating food. The safest one is probably succinic acid. The others, especially malic acid and oxaloacetate tend to inhibit SADH and thus lower ETC activity. Acetic acid is OK but in high amounts does shift the functioning towards Fatty Acid Synthesis. (note:Aspirin inhibits FAS) Ingesting a lot of exogenous acetic acid is not the same as synthesizing it as a result of PDH and bound to coenzyme A. There is probably a sweet point beyond which exogenous acetic acid is risky, while getting it from food conversion through PDH is rate-limited.
...adding a catalyst like MB can avoid that buildup of acetic acid and this has been confirmed in animal studies.

I am curious about the effects of the salt sodium acetate and it's ability to to increase CO2 in the body by undergoing its metabolism.
It seems from these studies that CO2 can increase significantly after ingestion. I thought I just throw it out there if anybody could comment on it.
Seems relatively easy to make from vinegar and baking soda.
...
https://pureapps2.hw.ac.uk/ws/portalfiles/portal/4771546
http://www.jbc.org/content/199/1/127.full.pdf

These observations indicate that sodium acetate infusion results in substantial extrapulmonary CO2 loss, which leads to a relative decrease of total and alveolar ventilation. Metabolic and respiratory effects of infused sodium acetate in healthy human subjects. - PubMed - NCBI

Pharmacology of Sodium Acetate
Acetate is the conjugate base of acetic acid and is used as a buffer in many biochemical applications.
...
After injection and cellular uptake, the two-carbon acetate anion forms acetyl CoA and enters the citric acid cycle; the final by-products, carbon dioxide and water, are in a rapid equilibrium with bicarbonate through the catalyst activity of carbonic anhydrase...
https/www.ncbi.nlm.nih.gov/pmc/articles/PMC3771004/

 

[Sativa]

Insight on alkaline mineral [Potassium bicarbonate salt] intake; contrasted with Sodium intake(Na:K ratio), KHCO³ reduces calcium loss/excretion, K promotes insulin secretion (thanks @Amazoniac)

RP has mentioned that body can handle a big excess of alkaline mineral intake.
...asked about potassium bicarbonate vs sodium bicarbonate, he mentioned that sodium bicarbonate is safer as people are good at excreting sodium more than potassium.

The body will not absorb potassium if magnesium deficient

- Potassium Causes Calcium Retention in Healthy Adults | The Journal of Nutrition | Oxford Academic
"The administration of 60 mmol/d of KHCO3 to healthy adults reduced urinary calcium excretion by 0.9 mmol/d and caused calcium balance to become equivalently more positive. Other studies showed that 90 mmol/d of KHCO3 reduced both daily and fasting urinary calcium excretion rates, whereas deprivation of either KCl or KHCO3, using synthetic diets, was accompanied by increased daily and fasting urinary calcium excretion rates. A significant inverse relationship between the changes in urinary calcium and the changes in urinary potassium was observed.
Co evaluation of additional data suggested that the fall in urinary calcium during potassium administration may be related to .../... suppression of calcitriol synthesis..."

- https://www.kidneyinternational-online.org/article/S0085-2538(15)47155-8/
"KHCO3 was superior to KCl as an adjunct to HCTZ [hydrochlorothiazide], inducing a twofold greater reduction in urine calcium excretion

- Potassium administration decreases and potassium deprivation increases urinary calcium excretion in healthy adult
"Both daily urinary Ca excretion and fasting UCaV/GFR [calcium pee/glomerular filtration of the rates] returned toward or to control at the end of recovery. These observations indicate that: 1) KHCO3 decreases fasting and 24-hour urinary Ca excretion...

"In conclusion, the dietary inclusion of KHCO₃ instead of KCl as K source could be beneficial for the prevention of CaOx urolith formation in cats, since there is an association between a lower renal Ca excretion and a generally higher urine pH. The utilisation of K is distinctly influenced by the K salt, which may be especially practically relevant when using diets with low K levels."

- Fortnightly review: Beneficial effects of potassium

https://chrismasterjohnphd.com/2018/08/14/best-way-supplement-potassium/
"[Potassium] stimulates insulin, and so you could get hypoglycemia if you took potassium on an empty stomach. That doesn’t happen when you eat potassium in food because the potassium is mixed in with the—even vegetables have at least a little bit of glucose, where the potassium drips into your system, and the glucose drips into your system at the same time, and you get the proper balance."

 

[Sativa]

More in-depth insight to Potassium:Sodium ratio:

People many years ago -- for example -- would consume a 16:1 potassium to sodium ratio.

Na:K ratio only matters in the context of are you getting enough sodium. The human body has an incredible affinity for potassium and is able to hold on to it very well when potassium intake is low.

 

[Sativa]

+ iirc, Na Acetate
binds to phosphate; so a good way of reducing P absorption!

I've just realised I've mixed up Sodium acetate with Calcium acetate!
CaAcetate is used for binding & removing excess phosphate!

Calcium can also bind to other minerals such as phosphate, and aid in their removal from the body. Calcium acetate is used to control phosphate levels to keep them from getting too high in people with kidney failure.

One DIY method involves putting egg shells in vinegar, and waiting till the fizzing stops.
I intend to powder my egg shells using a coffee grinder, then make various Calcium salts by mixing the powder with an acid... eg Salicylic, acetic, succinic etc.

—
As a general overall summary so far, theres easy DIY salts for:

• Increasing internal CO² levels
• Binding & removing Phosphate
• Reducing Calcium excretion
• Enhancing ATP production/cycle
• Improving aspirin/salicylic acid absorption/reducing GI irritation

 

[Sativa]

Here's the entry for different salts based on salicylate/succinate as found in -
"Merck's 1896 index : an encyclopedia for the physician and the pharmacist stating the and synonyms ... of the chemicals and drugs used in medicine, in chemistry, and in the arts"

Sodium Salicylate Merck
NaCrH^Oj.— Lustr., wh. scales ; sweetish, saline taste.— Sol.
0.9 W., 6 A., G. — Antirhenm., Antisep., Antipyr.— U es :
Rheum., neural., pleurisy, scarlat., chorea, pericarditis,
migraine, &c.—Dose 2-30 grains (0.13-3 Gm.).—Max. B. 60
grains (4 Gm.), single
Potassium Salicylate Merck c. v.— oz. .29
KCtHjOj.— Wh., sl'y deliq. pwd.Sol. W., A. — Antirheum.,
Antipyr., Analg. — Uses: Rheum., pleurisy, pericarditis,
lumbago, muscular pains, &c. — Bose 6-15 grains (0.4-1 Gm.).

Caffeine Salicylate Merck — vials. — oz. 1.25
C8H10N4O2.C7H8O3.— Wh., cryst. masses.- -Sol. W., A., with
decomp
Caffeine Succinate Merck — vials.— oz. 2.50
(C8H,uN40.2).j.C4H„04. - Wh., cryst. masses. — Sol. A., W.
decomp.

Calcium Succinate Merck c v.— oz. .54
(Normal Calcium Succinate^. — CaC^H^Oj -f H,,0. — Pine,
colorl., transp., cryst. need.—
Magnesium Succinate Merck c. v.— oz. .34
MgCjHiOi.— Wh. pwd.—
Sodium Succinate Merck. — Pure, cryst.
Na2C4H404-|-Gn,0.— Wh., monoclinic prisms.—

 

[Sativa]

More from Merck's 1896 index - acetate & benzoate salts...

Caffeine Acetate
C8HioN402(C2H40,,).i.— True salt, but unstable. — Fine, wh.,
need. -like cryst. ; exhale acetic acid on expos.- /Sol. W., with
decomp.— r/6<'« S Doses: As caffeine.— Caw/. Keep well closed.
Caffeine Benzoate .— True salt
C8HioN40.,.C;Ha0.i. — Wh., cryst. pwd. — Decomp. W. —
Uses & Dose : As caffeine.

Calcium Benzoate
Ca(C,H50.j).^+3H.>0. — Wh. pwd., or efflor. cryst.— Sol.
W. — Alter., Antisep. — Uses: Scrof. affect., & rachitis.— iJo^e
10-30 grains (0.65-1.95 Qva.^.— Caut. Keep well stoppered.
Magnesium Benzoate
Mg(C,H,02)o.— Wh. nwd. — Sol. W. — Antilithic, Antisep.,
Alter.- Uses : Lithaemia, rh^ira., ccrof., cirrhosis of liver,
&c.—Bose 3-23 grains (0.2-1.3 Gm.).
Potassium Benzoate
KC;H^Oo-(-3H..O.— Wh., cryst., efflores. masses.— 50^. W., A.
— Dose 5-20 grains (0.32-1.3 Gm.). — Caut. Keep fr. air.

 

[Sativa]

An additional strategy to reducing phosphate (and PTH) levels, is to supplement with vitamin B3 aka naicin/niacinamide.

High phosphate levels, alongside low Calcium, results in increased release of PTH, which directly increases cortisol.

Haidut has mentioned that 1g niacinamide (also niacin) daily lowered both phosphate & PTH (parathyroid hormone).
PTH & excess phosphate act as powerful suppressors of metabolism.

"...recent clinical studies have confirmed niacinamide’s effectiveness in reducing blood phosphate levels"
—
"With low vit B3, there is a gross excess of phosphate & deficiency of calcium."

I've already mentioned 2 OTC salts with relevant properties re Ca:P balance:
• Calcium acetate - binds & removes Phosphate
• Potassium bicarbonate reduces Calcium excretion aka loss

Calcium acetate is used to control phosphate levels to keep them from getting too high in people with kidney failure.

KHCO3 induced a twofold greater reduction in urine calcium excretion

...administration of 60 mmol/d of KHCO3 to healthy adults reduced urinary calcium excretion by 0.9 mmol/d and caused calcium balance to become equivalently more positive.